Field of the invention

The technical field of the present invention relates to topical ophthalmic solution of quinolone antibacterial agent. More particularly, the present invention relates to a container for delivering the topical ophthalmic solution of fluoroquinolone antibacterial agent.

Background of the invention

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

Treating infections in ocular tissues can be 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.

Fluoroquinolones are a class of synthetic antibacterial agents that were approved for ocular therapy in 1991 and have become popular therapy for the treatment and prevention of various ocular infections. These agents are synthetic, broad-spectrum, rapidly bactericidal, and have good penetration into ocular tissues. Their main mechanism of action is the inhibition of bacterial enzymes needed for bacterial DNA synthesis.
Various fluoroquinolones that are approved for ocular therapy include ciprofloxacin marketed by Alcon Laboratories, Inc. under the name CILOXAN (Ciprofloxacin 0.3%) ophthalmic solution, norfloxacin by Merck under the name CHIBROXIN® (Norfloxacin 0.3%) ophthalmic solution, ofloxacin by Allergan under the trade name OCUFLOX® (ofloxacin 0.3%) ophthalmic solution, levofloxacin by Santen under the trade name QUIXIN ® and IQUIX ® (Levofloxacin 0.5% and 1.5%) ophthalmic solution, gatifloxacin by Allergan under the trade name ZYMAR® and ZYMAXID® (Gatifloxacin 0.3% & 0.5%) ophthalmic solution and moxifloxacin is marketed by Alcon Laboratories, Inc. under the name VIGAMOX® (Moxifloxacin 0.5%) ophthalmic solution.

VIGAMOX® contain 0.5% of moxifloxacin as active substance and boric acid, sodium chloride and water as inactive ingredients. The pH of the solution is adjusted to 6.8 using hydrochloric acid/sodium hydroxide. VIGAMOX® has to be administered one drop three times a day for 7 days and is supplied in 3ml fill of 6ml Drop-Tainer® dispensing system. As per the Summary basis of approval of VIGAMOX®, the volume of each drop is ~38ul.

The concentrations of the antibiotics in the compositions will vary depending on the intended use of the compositions (i.e. treatment of existing infections or prevention of post-surgical infections), and the relative antimicrobial activity of the specific antibiotic selected. The antimicrobial activity of antibiotics is generally expressed as the minimum concentration required to inhibit the growth of a specified pathogen which is referred as the "minimum inhibitory concentration" or "MIC".

Following are the patents /patent publications that disclose topical ophthalmic formulations of quinolone antibiotics:

US 4,551,456 discloses a method of treating ocular bacterial infections which comprises topical ocular administration to an infected eye, of 0.015-1.5 mg of an antibiotic selected from norfloxacin, ofloxacin, pefloxacin. This patent further discloses ophthalmic formulation comprising norfloxacin, sodium acetate, benzalkonium chloride, disodium edetate, sodium chloride, hydrochloric acid and purified water.

6,333,045 discloses an aqueous liquid composition which comprises Gatifloxacin or its salt and disodium edetate, wherein the composition is in the form of eye drops, ear drops or nasal drops.

US 6,716,830 and US 7,671,070 discloses a topical ophthalmic composition comprising moxifloxacin or a pharmaceutically useful hydrate or salt thereof in a concentration of 0.1 to 1.0 wt % and pharmaceutically acceptable vehicle.

US 2009/0137539 discloses an aqueous, preserved, multi-dose, topically administrable ophthalmic or otic solution composition consisting essentially of 0.5-0.6% (w/v) moxifloxacin; 0.10-0.12% (w/v) dexamethasone phosphate; 0.005-0.02% (w/v) edetate disodium; 0.5-0.75% (w/v) sodium chloride; 0.2-0.4% (w/v) boric acid; either 0.1-0.3% (w/v) sorbitol or 0.005-0.015% benzalkonium chloride; a non-ionic surfactant in an amount of 0.04-0.06% (w/v); a pH-adjusting agent in an amount sufficient to cause the composition to have a pH from 7.5-8.1; and water.

US 2009/0306128 discloses an aqueous composition comprising fluoroquinolone antibiotic and a vehicle including sodium chloride, surfactant, a borate/polyol complex antimicrobial system; and polysaccharide viscosity enhancing agent.

WO 2011/143093 discloses an ophthalmic dispensing device that controls the delivery of drops of the fluid comprising a nozzle adapted to be attached to a neck of a bottle, the nozzle including a) a main body having an internal chamber, b) a dispensing tip at one end of the main body and having an egress orifice, with the internal chamber fluidly connecting the egress orifice with fluid in the bottle, and c) a baffle permanently fixed in the internal chamber

The above prior art discloses the ophthalmic formulations of various quinolone antibiotics with different concentrations supplied in different dispensers. With the aim of developing an alternate and cost effective formulation of fluoroquinolone antibacterial agent, the inventors of the present invention developed topical ophthalmic formulation comprising more than 1% by weight of fluoroquinolone antibacterial agent that is supplied in a container that increases the number of doses.

Objective of the invention

Accordingly, the objective of present invention is to provide a stable ophthalmic composition comprising fluoroquinolone antibacterial agent, and one or more pharmaceutically acceptable excipients, wherein the said composition is nonirritating to the eye.
Yet another objective of the present invention is to provide a stable ophthalmic composition comprising fluoroquinolone antibacterial agent that is therapeutically equivalent to reference product.

Summary of the invention

Accordingly, the present invention provides a multidose container for delivering the topical ophthalmic solution at a concentration more than 1% by weight of fluoroquinolone antibacterial agent.

Detailed description of the invention

Formulations usually contain one or more active ingredients, together with pharmaceutical excipients that possess the required stability and purity in order to be suitable for safe and efficacious administration. During storage, potency of a drug may decline due to degradation of the drug or interaction of the drug with excipients used in the formulations. Further, purity of the formulations may change due to leaching of chemicals into the medicament from the container system components that are in contact with the medicament. Thus, selection of the composition of the container is an important part of product development.

In another embodiment, the multi dose container includes three components i.e. (i) container holding the ophthalmic solution; (ii) a dispensing nozzle to deliver the solution and (iii) a cap to seal the container after application.

These containers are packaged using blow-fill seal system or vacuum fill seal system.
In another embodiment, the container is made of suitable materials, such that it does not react with the contents of the container, ensuring availability of a desired amount of drug throughout the shelf life of the product, and is selected from high density or low density polyethylene resins or polypropylene and is cylindrical shaped with 13 mm neck finish and 13mm nozzle and 13mm cap.

In long term treatments with ophthalmic solutions, cost effectiveness of an ophthalmic solution might influence the patient adherence. The ophthalmic dosage form is easy to administer, but has inherent drawback that most of the instilled volume is eliminated from the pre-corneal area resulting in poor bioavailability and also results in poor patient compliance. This can be overcome by supplying the ophthalmic solution in a container that is capable of delivering the solution with reduced drop volume that can be achieved by decreasing the diameter of the aperture i.e. the greater the diameter of aperture, the greater the drop created. In like manner, the small diameter results in small drop size.

Due to decreased drop volume the number of doses that can be instilled into the eye will be more. With the reduction in drop volume, the instilled solution retains in the cornea with out being eliminated, there by increases the corneal absorption.

In another embodiment, the container used in the present invention delivers the solution with the drop volume ~ 15-25, preferably 15-20 ul.

In another embodiment, the fluoroquinolone antibacterial agent is selected from ciprofloxacin, gatifloxacin, norfloxacin, levofloxacin, moxifloxacin, trovafloxacin, besifloxacin and its salts.

In another embodiment, the present invention also provides a multidose container for delivering the topical ophthalmic solution in an amount equivalent to Vigamox at a concentration more than 1% by weight of moxifloxacin.

In yet another embodiment, a method of administering the topical ophthalmic solution which is supplied in a multidose container that is capable of delivering said solution with reduced drop volume in an amount equivalent to Vigamox® at a concentration more than 1% by weight of moxifloxacin.

In another embodiment, the present invention also provides a topical ophthalmic formulation comprising more than 1% by weight of moxifloxacin or its salt thereof and one or more pharmaceutically acceptable excipients.

In another embodiment, the present invention also provides a topical ophthalmic formulation comprising more than 1% by weight of fluoroquinolone antibacterial agent and one or more pharmaceutically acceptable excipients.

In another embodiment, the pharmaceutically acceptable excipients are selected from tonicity adjusting agent, buffer, preservative, chelating agent, viscosity enhancing agent, pH adjusting agent.

Solutions that are isotonic with the lachrymal secretions cause minimal discomfort to the corneal tissue. Hence, the tonicity of the solution has to be adjusted to maintain the formulation at an osmolality of at least about 200 mOsmol/kg. Suitable tonicity adjusting agent is selected from sodium chloride, potassium chloride, boric acid, glycerin, propylene glycol, mannitol, sorbitol, glucose and the like.

To stabilize or to maintain the ophthalmic formulation at the desired pH, an effective minor amount of at least one buffer component has to be incorporated into the ophthalmic formulation. Suitable buffer is selected from phosphate buffer, acetate buffer, borate buffer and citrate buffer.

Ophthalmic formulations are typically packed in multidose form. In order to inhibit the growth of microbial contaminants and suppress biodegradation preservatives are added. Suitable preservative is selected from benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, chlorobutanol, benzyl alcohol, sodium dehydroacetate, p-hydroxybenzoate and the like. The amount of preservatives may range from about 0.001% to 1.0% by weight.

Suitable viscosity enhancing agent is selected from methylcellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, carboxymethylcellulose, sodium hyaluronate, carboxyvinyl polymer, polyvinyl alcohol, xanthan gum, polyvinyl pyrrolidone and the like..

Suitable chelating agent is selected from edetic acid, edetic acid salts like disodium edetate, sodium edetate, edetate calcium disodium and trisodium edetate and the like.

Suitable pH adjusting agent is selected from hydrochloric acid, sodium hydroxide, acetic acid, phosphoric acid.

The amount of moxifloxacin used in formulation may range from about 1 % to 2% more preferably 1.2% by weight.

In a preferred embodiment, the present invention provides a topical ophthalmic formulation comprising 1.2% by weight of moxifloxacin or its salt thereof and one or more pharmaceutically acceptable additives selected from tonicity adjusting agent, buffer, preservative, chelating agent, viscosity enhancing agent, pH adjusting agent in a suitable vehicle.

The vehicle used according to present invention is water for injection or purified water.
The ophthalmic solutions must be clear and free from particulate contamination such as particles, fibres etc. The desired clarity can be obtained by filtration.

The present invention also provides a method of treating bacterial infections or prevention of post surgical infections of the corneal tissue by administering the topical ophthalmic formulation of the present invention.

The following examples further exemplify the invention and are not intended to limit the scope of the invention. It is obvious to those skilled in the art to find out the composition for other dosage forms and substitute the equivalent excipients as described in this specification or with the one known to the industry.

Example 1

The processing steps involved in manufacturing moxifloxacin ophthalmic
solution as given in example 1 are given below:

i) water for injection was taken in a glass bottle,

ii) sodium chloride was added to water for injection under stirring to get a clear solution,

iii) to the solution of step (ii), boric acid was added under stirring to get a clear solution,

iv) the pH of the solution was checked and adjusted to 6.7 using hydrochloric acid / sodium hydroxide,

v) to the solution of step (iii), moxifloxacin hydrochloride was added under stirring to get a clear solution,

vi) the pH of the solution was checked and adjusted to 6.7 using hydrochloric acid / sodium hydroxide,

vii) making up the volume with water for injection,

viii) the solution of step (vii) was filtered using 0.22um filter and

ix) the solution of step (viii) was filled in LDPE bottle.

The pH and osmolality of the solution prepared according to example-1 and Vigamox® was measured and the results are given in table 1.

The composition described in example 2 and 3 was prepared using the procedure similar to the one described in example 1. Example 2

Example 3

Claims:

1. A multidose container for delivering the topical ophthalmic solution at a concentration more than 1% by weight of fluoroquinolone antibacterial agent.

2. The container of claim 1, is selected from high density or low density polyethylene resins or polypropylene.

3. The container of claim 1, delivers the solution with the drop volume from about 15ul to about 25 ul.

4. The ophthalmic solution of claim 1, wherein the fluoroquinolone antibacterial agent is selected from ciprofloxacin, gatifloxacin, norfloxacin, levofloxacin,
moxifloxacin, trovafloxacin, besifloxacin and its salts.

5. A multidose container for delivering the topical ophthalmic solution in an amount equivalent to Vigamox® at a concentration more than 1% by weight of moxifloxacin.

6. A method of administering the topical ophthalmic solution supplied in a multidose container that is capable of delivering said solution with reduced drop volume in an amount equivalent to Vigamox® at a concentration more than 1% by weight of moxifloxacin.

7. A topical ophthalmic formulation comprising more than 1% by weight of moxifloxacin or its salt thereof and one or more pharmaceutically acceptable excipients.

8. The formulation of claim 6, wherein one or more pharmaceutically acceptable excipients are selected from tonicity adjusting agent, buffer, preservative, chelating agent, viscosity enhancing agent, pH adjusting agent.

9. A topical ophthalmic formulation comprising 1.2% by weight of moxifloxacin or its salt thereof and one or more pharmaceutically acceptable additives selected from tonicity adjusting agent, buffer, preservative, chelating agent, viscosity enhancing agent, pH adjusting agent in a suitable vehicle.

10. A method of treating bacterial infections or prevention of post surgical infections of the corneal tissue by administering the topical ophthalmic formulation as referenced in examples 1 to 3.