Field of the invention

The technical field of the present invention relates to a stable ophthalmic product, and in particular, to the use of packaging materials to obtain stable ophthalmic product. More particularly, the present invention relates to a topical ophthalmic container provided with a label free of varnish.

Background of the invention

Containers for ophthalmic products are considered as an integral part because they can affect product stability, potency, toxicity and safety, and therefore must be evaluated carefully with variety of tests before selecting for particular active containing composition.

The widely used container components for ophthalmic product are glass and plastic however the use of glass containers has diminished and use of plastic containers have been favored because they weigh less, are more resistant to shock and other mechanical influences, cost less, and offer more design possibilities. Polyethylene preferably LDPE/HDPE i.e. low-density/high-density polyethylene, and polypropylene are the plastics generally used for packing ophthalmic products.

The sum of the packaging components that together contain and protect the ophthalmic dosage form. This includes both primary and secondary packaging components. Packaging materials have been in the focus of such investigations for a long time as the contact time between ophthalmic drug product and packaging material is rather long.

The initial focus of container closure testing centered on the containers compatibility with the drug product, ability to accurately deliver the dose and maintain sterility. With the development of a multitude of formulation and container closure combinations, the risk posed by container closures is no longer considered "basic" evolving to focus on the role of packaging components and their interaction with the drug product. This has resulted in regulators focusing on extractable and Ieachables that may migrate from packaging components and assessing the risk extractable and leachables might pose.

Product containers are identified by applying an adhesive-backed label to an outer surface of the container. Such labels retain their product-identifying purpose by remaining permanently affixed to the container.

The primary concern is the presence of impurities that may be harmful to the patient. Drug-related impurities (process related & degradation products) tend to be well controlled and understood. On the other hand, extractables and leachables that migrate from packaging materials into the drug product during normal storage are less well understood, and may be more difficult to control as they don't have migration or generation pathways that are thoroughly understood.

The most common packaging used in ophthalmics is a semi-permeable polyethylene or polypropylene bottle. Although this packaging system allows for ease of use in dose administration, it does not provide a barrier to migrating chemical moieties and thus poses a challenge in the control of leachables.

Historically, ophthalmic leachables were treated as a quality issue particularly by FDA with specification setting based on batch data and not accounting for ICH guidance. The challenge for the drug manufacturer is that leachables do not have a profile like process or drug related impurities. The leachable profile can vary widely with supplier, ink types and age of plastics used. Having a low and arbitrary limit not accounting for the safety profile of the leachable in the registered drug product specification could lead to batch failures.

The majority of these leachables often are from the label which is in direct contact with the bottle (e.g., adhesive, inks and varnish) and from the carton where leachables can migrate through air. An example of this is the control of benzophenone, a leachable commonly found in UV-based inks/labels which can cause eye irritation. FDA proposed limits for benzophenone of 1 ppm.

Sometimes these leachables are detected as impurity during analysis or it may react with formulation active and/or inactive ingredient and give rise to unknown impurities. Varnish, ink present in the labels migrate through semi-permeable containers into formulated product through time and are detected as impurity during analysis. The inventors of the present invention during their efforts to develop stable ophthalmic products found that the use of unvarnished labels reduces/eliminates the amount of impurities that are leached from the secondary packaging materials.

Objective of the invention

The objective of the present invention is to reduce the amount of impurities that are leached from the primary and/or secondary packaging materials.

Yet another objective of present invention is to provide a stable ophthalmic composition, wherein the said composition is nonirritating to the eye and is packaged in a container provided with unvarnished label

Summary of the invention

Accordingly, the present invention provides a stable ophthalmic product comprising active ingredient and one or more pharmaceutically acceptable excipients packaged in a container provided with a label, wherein said label is substantially free of varnish.

In another embodiment, the present invention also provides the use of label for container of topical ophthalmic solution comprising fluoroquinolone antibacterial agent, wherein said label is substantially free of varnish.

Detailed description of the invention

In another embodiment, the product may be in the form of solution, suspension or emulsion.

In another embodiment, the active ingredient is floroquinolone antibacterial agent.

In another embodiment, the pharmaceutical^ 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.

The term "substantially free," as used herein means that the label is associated with less than 10%, preferably less than 5%, in particular less than 2% and most preferably less than 1% of varnish.

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

In another embodiment, the container is made of high density or low density polyethylene resins or polypropylene.

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

In yet another embodiment, the present invention also provides a stable ophthalmic product comprising a fluoroquinolone antibacterial agent and one or more pharmaceutically acceptable excipients packaged in a container made of polyethylene or polypropylene provided with a label, wherein said label is substantially free of varnish.

In yet another embodiment, the present invention also provides a stable ophthalmic product comprising a fluoroquinolone antibacterial agent selected from ciprofloxacin, gatifloxacin, norfloxacin, levofloxacin, moxifloxacin, trovafloxacin, besifloxacin and one or more pharmaceutically acceptable excipients packaged in a container made of polyethylene or polypropylene provided with a label, wherein said label is substantially free of varnish.

The ophthalmic solutions must be clear and free from particulate contamination such as particles, fibres etc. The desired clarity can be obtained by filtration.

In another embodiment, the containers are sterilized by ethylene oxide or gamma radiation.

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 compositions prepared according to example 1 and the placebo formulations are filled in containers as given in tables 1 and 2:

Table 1

Table 2

The formulations as described in Tables 1 and 2 were stored at 60° C for 14 days and then tested by an HPLC method to determine the amount of unknown peak at RRT (Relative Retention Time) 1.25. The data is given in table 3.

Table 3

The compositions prepared according to example 1 and the placebo formulations are filled in glass containers and the varnished labels, over coding ink and diluents dipped inside the solution as given in table 4:

Table 4

The formulations as described in Table 4 were stored at 60° C for 3 days and then tested by an HPLC method to determine the amount of unknown peak at RRT (Relative Retention Time) 1.25. The data is given in table 5.

Table 5

Claims:

1. A stable ophthalmic product comprising active ingredient and one or more pharmaceutically acceptable excipients packaged in a container provided with a label, wherein said label is substantially free of varnish.

2. The product as claimed in claim 1, wherein the active ingredient is fluoroquinolone antibacterial agent.

3. The product as claimed in claim 2, the fluoroquinolone antibacterial agent is selected from ciprofloxacin, gatifloxacin, norfloxacin, levofloxacin, moxifloxacin, trovafloxacin, besifloxacin and its salts.

4. The product as claimed in claim 1, wherein the product is in the form of solution, suspension or emulsion.

5. The product as claimed in claim 1, wherein the pharmaceutically acceptable excipients are selected from tonicity adjusting agent, buffer, preservative, chelating agent, viscosity enhancing agent, pH adjusting agent.

6. The product as claimed in claim 1, wherein the container is made of high density or low density polyethylene resins or polypropylene.

7. The product as claimed in claim 6, the containers are sterilized by ethylene oxide or gamma radiation.

8. A stable ophthalmic product comprising a fluoroquinolone antibacterial agent and one or more pharmaceutically acceptable excipients packaged in a container made of polyethylene or polypropylene provided with a label, wherein said label is substantially free of varnish.

9. A stable ophthalmic product ad claimed in claim 8, comprising a fluoroquinolone antibacterial agent selected from ciprofloxacin, gatifloxacin, norfloxacin, levofloxacin, moxifloxacin, trovafloxacin, besifloxacin and one or more pharmaceutically acceptable excipients packaged in a container made of polyethylene or polypropylene provided with a label, wherein said label is substantially free of varnish.

10. The use of label for container of topical ophthalmic solution comprising fluoroquinolone antibacterial agent, wherein said label is substantially free of varnish.