FIELD OF THE INVENTION:

The present invention relates to a fixed dose combination comprising one or more antibiotics and one or more steroidal anti-inflammatory agents for the treatment of ocular infections.

BACKGROUND OF THE INVENTION

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 eyelids, conjunctiva, cornea, and other ocular tissues can occur.

The causes of ocular infections generally come from one of two different sources: the eyelids or the sinuses. The most common reasons why the eyes get infected are through surgery, trauma, low immunity, and improper contact care.

The treatment of choice for treating ocular infections includes antibiotics and steroidal anti-inflammatory agents.

However literature survey revealed that nobody till date has used fixed dose combination containing antibiotic and steroidal anti-inflammatory agent for the treatment of ocular infections.
The present inventors have found that a fixed dose combination comprising one or more antibiotics and one or more steroidal anti-inflammatory agents are effective treatment of ocular infections.

SUMMARY OF THE INVENTION

The present invention is directed to a method of treating ocular infections, comprising administration of a fixed dose combination comprising one or more antibiotics and one or more steroidal anti-inflammatory agents.

In one aspect, the present invention provides a fixed dose combination comprising one or more antibiotics and one or more steroidal anti-inflammatory agents for the treatment of ocular infections.

In yet another aspect, the present invention provides a pharmaceutical composition comprising fixed dose combination comprising one or more antibiotics and one or more steroidal anti-inflammatory agents for the treatment of ocular infections.

In yet another aspect, the present invention provides a process for preparation of a pharmaceutical composition comprising a fixed dose combination comprising one or more antibiotics and one or more steroidal anti-inflammatory agents for the treatment of ocular infections.

In yet another aspect, the present invention provides a method of treating an ocular infections, comprising administering to an affected eye of patient a combination of an effective amount of Azithromycin or its pharmaceutically acceptable hydrates or salts thereof and an effective amount of Loteprednol or its pharmaceutically acceptable esters or salts thereof optionally together with pharmaceutically acceptable excipients.

In yet another aspect, the present invention provides a fixed dose combination comprising an effective amount of Azithromycin or its pharmaceutically acceptable hydrates or salts thereof and an effective amount of Loteprednol or its pharmaceutically acceptable esters or salts thereof for the treatment of ocular infections.

In yet another aspect, the present invention provides a pharmaceutical composition comprising fixed dose combination comprising an effective amount of Azithromycin or its pharmaceutically acceptable hydrates or salts thereof and an effective amount of Loteprednol or its pharmaceutically acceptable esters or salts thereof for the treatment of ocular infections.

In yet another aspect, the present invention provides a process for preparation of a pharmaceutical composition comprising a fixed dose combination comprising an effective amount of Azithromycin or its pharmaceutically acceptable hydrates or salts thereof and an effective amount of Loteprednol or its pharmaceutically acceptable esters or salts thereof for the treatment of ocular infections.

DETAILED DESCRIPTION OF INVENTION

The invention includes the combinational use of one or more and antibiotics one or more anti-inflammatory steroids for the treatment of ocular infections. More specifically, the present invention includes a combinational use of an effective amount of Azithromycin or its pharmaceutically acceptable hydrates or salts thereof and an effective amount of Loteprednol or its pharmaceutically acceptable esters or salts thereof for the treatment of ocular infections.

As used herein, the term "ocular infections" refers to infections which are caused by viruses and bacteria entering the eye. While the eyes are constantly exposed to a variety of germs, bacteria, and viruses, sometimes the body's defenses fail and an eye infection can result. Eye infections are most commonly spread by hand-to-eye contact, infections traveling from the sinuses, or through poor eye hygiene (especially contact-lens hygiene). Other causes include complications from eye surgery, eye trauma, immune deficiency, or other eye problems or illness that result in bacteria or viral growth. Systemic overgrowth of the fungus Candida albicans known as Candidiasis can also cause recurrent eye infections and eye pain. Ocular infections can be conjunctivitis, ophthalmic neonatorum, trachoma, corneal ulcers, keratitis, keratoconjunctivitis, endophthalmitis, infectious uveitis and combinations thereof.

As used herein, the term "antibiotics" refers to drugs which are produced by micro¬organism in nature and isolated from this natural source or synthesized by chemical process which can kill harmful microorganism and cure bacterial infections in human and animals.

As used herein, the term "anti-inflammatory steroids" refers to the drugs that block the synthesis of new histamine release by mast cells, inactivate available histamine, inhibit mast cell degranulation, decrease capillary permeability, and inhibit phospholipase A synthesis, which is used in the production of arachidonic acid and thereby prevent inflammation.

In one embodiment, the compositions and formulations described herein comprise a first active agent and a second active agent, wherein the first active agent and the second active agent are formulated into the composition or formulation in a manner that allows ophthalmic and/or topical activity of the agents (e.g., by formulating a composition or formulation described herein as a solution, gel, or the like, comprising a first active agent and a second active agent as solutes within the solution, gel, suspension etc.). It is to be understood that such compositions and formulations include compositions and

formulations wherein a substantial portion, a therapeutically effective portion, most or all of the first and second agents are either dissolved or suspended in the liquid medium (e.g., aqueous medium) based on their solubility in liquid medium.

In one advantageous embodiment, the active components of present invention are present in the form of a fixed dose combination, owing to which the administration is simpler for the patients, since both active compounds are contained in one and the same container.

In specific embodiment, the present invention provides a fixed dose combination of Azithromycin or its pharmaceutically acceptable hydrates or salts thereof and Loteprednol or its pharmaceutically acceptable esters or salts thereof.

In yet another embodiment, the antibiotics (e.g. Azithromycin or its pharmaceutically acceptable hydrates or salts thereof) are present in a composition or formulation described herein in an amount of about 0.1 wt % to about 10 wt %, more preferably 1 wt % to2wt%.

In yet another embodiment, the anti-inflammatory steroids (e.g. Loteprednol or its pharmaceutically acceptable esters or salts) are present in a composition or formulation described herein in an amount of about 0.01 wt % to about 5 wt %, more preferably 0.2 wt% to 0.5 wt%.

In yet other embodiment, the ophthalmic composition of present invention has a pH from 4.0 to 8.0, preferably from 4.5 to 7.5, more preferably from 5.0 to 7.0.

In yet another embodiment, the ophthalmic composition of present invention has an osmolarity from 200 to 400 milliosmoles/liter (mOsm/L), preferably from 250 to 375 mOsm/L, and more preferably from 300 to 360 mOsm/L.

In yet another embodiment, the compositions, formulations and active pharmaceutical agent described herein are thermally stable at room temperature, at 25° C with relative humidity 40% or at 40 °C with relative humidity not more than 25% for at least 3 months.

Examples of antibiotics include, but are not limited to, Aminoglycosides such as; Amikacin, Gentamycin, Kanamycin, Neomycin, Netilmicin, Paromomycin, Streptomycin, Tobramycin, Carbapenems such as; Ertapenem, Imipenem, Meropenem, Chloramphenicol, Fluoroquinolones such as; Ciprofloxacin, Gatifloxacin, Gemifloxacin, Grepafloxacin, Levofloxacin, Besifloxacin, Lomefloxacin, Moxifloxacin, Norfloxacin, Ofloxacin, Sparfloxacin, Trovaflqxacin, Glycopeptides such as; Vancomycin, Lincosamides such as; Clindamycin, Macrolides/Ketolides such as; Azithromycin, Clarithromycin, Dirithromycin, Erythromycin, Telithromycin, Cephalosporins such as; 1st Generation - Cefadroxil, Cefazolin, Cephalexin, Cephalothin, Cephapirin, Cephradine, 2nd Generation - Cefaclor, Cefamandole, Cefonicid, Cefotetan, Cefoxitin, Cefprozil, Cefuroxime, Loracarbef, 3rd Generation - Cefdinir, Cefditoren, Cefixime, Cefoperazone, Cefotaxime, Cefpodoxime.Ceftazidime, Ceftibuten, Ceftizoxime, Ceftriaxone, 4th Generation - Cefepime, Monobactams such as; Aztreonam, Nitroimidazoles such as; Metronidazole, Oxazolidinones such as Linezolid, Penicillins such as Amoxicillin, Amoxicillin/Clavulanate, Ampicillin, Ampicillin/Sulbactam, Bacampicillin, Carbenicillin, Cloxacillin, Dicloxacillin, Methicillin, Mezlocillin, Nafcillin, Oxacillin, Penicillin G, Penicillin V, Piperacillin, Piperacillin/Tazobactam, Ticarcillin, Ticarcillin/Clavulanate, Streptogramins such as; Quinupristin/Dalfopristin, Tetracyclines such as; Demeclocycline, Doxycycline, Minocycline, Tetracycline or its physiologically acceptable salts thereof, prodrugs thereof, combinations thereof, mixtures thereof and the like.

Examples of steroidal anti-inflammatory agents according to the present invention include, but are not limited to, Loteprednol etabonate, Prednisolone sulfacetamide, Hydrocortisone , Difluprednate, Fluorometholone acetate, Dexamethasone, Prednisolone phosphate , Rimexolone, 21-acetoxypregnenolone, alclometasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clobetasone, clocortolone, cloprednol, corticosterone, cortisone, cortivazol, deflazacort, desonide, desoximetasone, diflorasone, diflucortolone, enoxolone, fluazacort, flucloronide, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone, fluperolone acetate, fluprednidene acetate, fluprednisolone, flurandrenolide, fluticasone propionate, formocortal, halcinonide, halobetasol propionate, halometasone, halopredone acetate, hydrocortarnate, mazipredone, medrysone, meprednisone, methylprednisolone, mometasone furoate, paramethasone, prednicarbate, prednisolone 25-diethylamino-acetate, prednisolone sodium phosphate, prednisone, prednival, prednylidene, tixocortol, triamcinolone, triamcinolone acetonide, triamcinolone benetonide, triamcinolone hexacetonide, prednisone, methylprednisolone, medrysone, triamcinolone or its physiologically acceptable salts thereof, prodrugs thereof, combinations thereof, mixtures thereof and the like.

A pharmaceutical composition according to the present invention may include one or more pharmaceutically acceptable buffering agents, preservatives, tonicity-adjusting agents, pH-adjusting agents, chelating agents, viscosity modifiers and wetting agents.

Examples of buffering agents include, but are not limited to, phosphate buffer, borate buffer, citrate buffer, acetate buffer, carbonate buffer, borate-polyol complexes, boric acid and the like. °
Examples of preservatives include, but are not limited to, benzalkonium chloride, benzethonium chloride, p- oxybenzoates such as methyl p-oxybenzoate or ethyl p-oxybenzoate, benzyl alcohol, phenethyl alcohol, sorbic acid or its salt, thimerosal, chlorobutanol, other quaternary amines and the like, chlorhexidine gluconate and the like.

Examples of tonicity-adjusting agents include, but are not limited to, glycerin, mannitol, sodium chloride, xylitol, and the like.

Examples of the alkaline agents that may be used as pH adjusting agents include, but are not limited to, sodium hydroxide (NaOH), potassium hydroxide (KOH), tromethamine, monoethanolamine, sodium bicarbonate (NaHCO3) and other organic and inorganic bases.
Examples of the acidic agents that may be used as pH adjusting agents include, but are not limited to, hydrochloric acid, citric acid, tartaric acid, lactic acid and other organic and inorganic acids and the like and mixtures thereof.

Examples of chelating agents include, but are not limited to EDTA, disodium edetate, sodium citrate, condensed sodium phosphate and the like.

Examples of viscosity modifiers include, but are not limited to, hydroxypropylmethyl cellulose (hypromellose), carboxypropylmethylcellulose, polyvinylpyrrolidone (Povidone), polyethylene glycol, polyvinyl acetate, and combinations thereof.

Examples of wetting agents include, but are not limited to, cetylpyridinium chloride, tyloxapol, various polysorbates such as Tween®, polyethoxylated substances and poloxamers.

EXAMPLES

The invention will be further illustrated by the following examples, which are intended to be illustrative but not limiting.

Example No. 1

Table No. 1 Ophthalmic Suspension containing Azithromycin Dihydrate Eq. to Azithromycin (1.0 % w/v dissolved) and Loteprednol Etabonate (0.2% w/v suspended) Manufacturing process:

A formulation as shown in table 1 was prepared as follows:

(a) Accurately weighed quantity of Azithromycin Dihydrate and required quantity of Citric acid anhydrous, Disodium Edetate, Tyloxapol and Glycerin were introduced into suitable container and dissolved in sufficient water for injection and stirred until clear colorless solution obtained.

(b) Required quantity of povidone was dissolved in sufficient quantity of water for injection in separate container and stirred till clear solution obtained; this solution was added to solution of step (a) with stirring.

(c) Required quantity of Benzalkonium chloride was dissolved in sufficient quantity of water for injection in separate container and stirred till clear solution obtained; this solution was added to solution of step (a) with stirring to obtain a final solution.

(d) The pH of final solution obtained as per step (c) was adjusted to 6.0 with required quantity of 1N NaOH or 0.1 N HCL stock solution and final volume of desired batch size was made up with sufficient quantity of water for injection.

(e) The solution of step (d) was then filtered through 0.22 u filter.

(f) Accurately weighed quantity of Loteprednol Etabonate (micronized and sterilized) was added to filtered solution of step (e) under laminar air flow unit and homogenized to obtain a final sterile suspension.

The formulation of example 1 was further subjected to stability studies at 40°C/NMT25%RH, and were analyzed at an intervals of 1M, 2M & 3M and at 25°C/40%RH, were analyzed at an intervals of 1M and 3M, the results obtained are presented in Table No. 3.

Example No. 2

Table No. 1 Ophthalmic Suspension containing Azithromycin Dihydrate Eq. to Azithromycin (1.0 % w/v dissolved) and Loteprednol Etabonate (0.5% w/v suspended) Manufacturing process:

A formulation as shown in table 2 was prepared as follows:

(a) Accurately weighed quantity of Azithromycin Dihydrate and required quantity of Citric acid anhydrous, Disodium Edetate, Tyloxapol and Glycerin were introduced into suitable container and dissolved in sufficient water for injection and stirred until clear colorless solution obtained.

(b) Required quantity of povidone was dissolved in sufficient quantity of water for injection in separate container and stirred till clear solution obtained; this solution was added to solution of step (a) with stirring.

(c) Required quantity of Benzalkonium chloride was dissolved in sufficient quantity of water for injection in separate container and stirred till clear solution obtained; this solution was added to solution of step (a) with stirring to obtain a final solution.

(d) The pH of final solution obtained as per step (c) was adjusted to 6.0 with required quantity of 1N NaOH or 0.1 N HCL stock solution and final volume of desired batch size was made up with sufficient quantity of water for injection.

(e) The solution of step (d) was then filtered through 0.22 u filter.

(f) Accurately weighed quantity of Loteprednol Etabonate (micronized and sterilized) was added to filtered solution of step (e) under laminar air flow unit and homogenized to obtain a final sterile suspension.

The formulation of example 2 was further subjected to stability studies at 40°C/NMT25%RH, and were analyzed at an intervals of 1M, 2M & 3M and at 25°C/40%RH, were analyzed at an intervals of 1M and 3M, the results obtained are presented in Table No. 4.

Table No.3: Azithromycin Dihydrate equivalent to Azithromycin base & Loteprednol Etabonate Ophthalmic Suspension (1.0% w/v & 0.2% w/v) finished product analysis data - initial and on stability M: Month(s) NLT: Not less than NMT: Not more than RH: Relative Humidity Table No. 4: Azithromycin Dihydrate equivalent to Azithromycin base & Loteprednol Etabonate Ophthalmic Suspension (1.0 % w/v & 0.5 % w/v) finished product analysis data - initial and on stability M: Month(s) NLT: Not less than NMT: Not more than RH: Relative Humidity

We claim:

1. A stable pharmaceutical composition comprising an effective amount of Azithromycin or its pharmaceutically acceptable hydrates or salts thereof, an effective amount of Loteprednol or its pharmaceutically acceptable esters or salts thereof and pharmaceutically acceptable excipients.

2. The composition of claim 1, wherein the composition comprises from about 0.1 to about 5 % (w/v) of Azithromycin Dihydrate.

3. The composition of claim 1, wherein the composition comprises from about 0.1 to about 1 % (w/v) of Loteprednol Etabonate.

4. The composition of claim 1, wherein said composition is intended for ocular use.

5. The composition of claim 1, wherein the pharmaceutically acceptable excipients are selected from group consisting of buffering agents, preservatives, tonicity-adjusting agents, pH-adjusting agents, chelating agents, viscosity modifiers, wetting agents and combination thereof.

6. The composition of claim 1, wherein the composition has a pH in the range from 5.0 to 7.0.

7. The composition of claim 1, wherein the composition has an Osmolality in the range from about 300 to 360 mOsml /kg.

8. A process for preparation of a pharmaceutical composition comprising a steps of: (a) dissolving Azithromycin Dihydrate and a pharmaceutically acceptable excipients in water for injection to form a solution; (b) adjusting pH of said solution in the range of 5.0 to 7.0 with pH-adjusting agents; (c) filtering the solution and (d) adding Loteprednol Etabonate to the filtered solution followed by homogenization to obtain a final sterile suspension.

9. A method of treating ocular infections, comprising administering to an affected eye of patient a combination of an effective amount of Azithromycin or its pharmaceutically acceptable hydrates or salts thereof and an effective amount of Loteprednol or its pharmaceutically acceptable esters or salts thereof optionally together with a pharmaceutically acceptable excipients.

10. The method of claim 9, wherein said ocular infections are conjunctivitis, ophthalmic neonatorum, trachoma, corneal ulcers, keratitis, keratoconjunctivitis, endophthalmitis, infectious uveitis and combinations thereof.