Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
1998-05-08
2001-07-24
Fay, Zohreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
C514S912000
Reexamination Certificate
active
06265444
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to ophthalmic compositions and more particularly, to ophthalmic compositions containing a divalent cation and a non-steroidal anti-inflammatory agent and/or to ophthalmic compositions containing a preservative system.
2. Description of the Related Art
Non-steroidal anti-inflammatory agents can be used in a variety of ophthalmic treatments such as for treating ocular tissue inflammation and its associated pain. Additional uses include (i) preventing particular side-effects from surgical trauma (e.g., on the pupil preventing surgical meiosis), (ii) preventing fluid accumulation in the back of the eye after cataract surgery (post-surgical macular edema) and (iii) preventing the appearance of inflammatory cells and vessel leakage in the anterior chamber. Diclofenac, suprofen, and flurbiprofin are specific examples of non-steroidal anti-inflammatory agents that have been used for the treatment of postoperative inflammation in patients who have undergone cataract extraction. Topical application of non-steroidal anti-inflammatory agents in the eye also appears to relieve some of the itching due to allergic conjunctivitis.
In the past, anti-inflammatory agents, in general, have been administered in solutions at neutral pH. Injection of anti-inflammatory agents in the form of a suspension has also been proposed. Suspensions have been used for topical ophthalmic applications when the drug is not very soluble. However, when the drug is soluble, at an acceptable pH, solutions are normally used to avoid potential irritation caused by the particles of the suspension. The following patents illustrate ophthalmic solutions containing non-steroidal anti-inflammatory agents, including diclofenac.
U.S. Pat. No. 4,960,799 to Nagy concerns a storage stable aqueous solution of sodium ortho-(2,6-dichlorophenyl)aminophenylacetate acid, which is the chemical name for diclofenac sodium, for topical treatment of ocular inflammation. The solution taught by Nagy has a pH of about 7.0 to 7.8.
U.S. Pat. No. 4,829,088 to Doulakas also relates to an ophthalmic medicament containing diclofenac sodium in aqueous solution. The solution contains 2-amino-2-hydroxymethyl-1,3-propanediol as a preservative.
U.S. Pat. No. 5,110,493 to Cherng-Chyi et al. relates to ophthalmic non-steroidal anti-inflammatory drug formulations containing a quaternary ammonium preservative and a non-ionic surfactant.
Patent Abstracts of Japan, Vol. 8, No. 7, Abs. Gp. C-204, concerning Japanese published application 58-174309 (pub. Oct. 13, 1983) relates to an antiphlogistic eye drop composition containing (1) a non-steroidal antiphlogistic agent having a carboxyl group in its structure and (2) a physiologically permissible calcium or magnesium salt. The salt is described as an irritation mitigating agent and is normally added in an amount of 1-1.5 mol per 1 mol of the non-steroidal agent. Sodium diclofenac is specifically mentioned as the non-steroidal antiphlogistic agent and the pH of the composition is preferably maintained in the 7-8 range.
However, a problem with the use of non-steroidal anti-inflammatory agents, as recognized in the above-mentioned Japanese published application, is that stinging or burning sensations are commonly experienced during the first few minutes after topical administration on the eye. Not only are patients who experience such stinging likely to avoid regularly taking their medication, they also receive less benefit from each application. Specifically, the stinging causes tearing which washes away the drug. Having physically removed a portion of the drug from the eye by tearing, the bioavailability of the drug is reduced.
In addressing the stinging problem, it has been proposed to supply a portion of the non-steroidal anti-inflammatory agent in suspension form, as is described in commonly assigned co-pending application Ser. No. 08/248,500, filed May 24, 1994 (the entire contents of which are hereby incorporated by reference). The particle must dissolve before it can treat the eye. By providing some of the active agent as a particle, the flow of the drug onto the eye is delayed; i.e., providing some of the active agent as a particle reduces the initial concentration of the drug contacting the eye. This delay in drug delivery contrasted with the prior compositions wherein all of the agent was in solution, owing to a pH of 7-8, thereby immediately providing to the cornea a high concentration of the drug. The high concentration of the drug on the eye was believed to aggravate the burning and stinging effects of the drug.
While some improvements have been made with respect to the stinging problem by such a technique, there is still a segment of the population that will experience stinging when topically administering non-steroidal anti-inflammatory ophthalmic compositions. Accordingly, further improvements are desirable.
Additionally, preserving an ophthalmic composition that contains a non-steroidal anti-inflammatory agent can be problematic. Conventional broad spectrum antimicrobial agents like benzalkonium chloride (BAK) tend to interact with the non-steroidal anti-inflammatory agents over time and thereby reduce the efficacy of the medication. Indeed, as a general matter, preservatives in ophthalmic compositions are not entirely satisfactory. Effective, broad spectrum antimicrobials tend to reduce the storage stability of the composition and/or have adverse interactions with other components.
A useful preservative system that seeks to overcome some of these deficiencies is disclosed in U.S. Pat. Nos. 5,576,028 and 5,607,698. These systems use a low amount of hydrogen peroxide, or a hydrogen peroxide source, as a preservative in combination with a peroxy stabilizer. The stabilizer is preferably a phosphonic acid such as diethylene triamine penta(methylene-phosphonic acid) and the like which are commercially available from Monsanto under the DEQUEST brand name. Although this system is quite useful, certain improvements in storage stability would be desirable.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide an ophthalmic composition that contains a topically effective amount of a non-steroidal anti-inflammatory agent and that is no more irritating than conventional eye drops.
It is another object of the present invention to provide a non-steroidal anti-inflammatory agent-containing ophthalmic composition that can be taken by a large segment of the population without experiencing stinging or irritation.
A further object of the present invention is to provide a preserved ophthalmic composition that exhibits good stability during storage.
Another object of the present invention is to provide a method for treating diseases of the eye, including inflammation, by topically applying to eyes in need of such treatment a non-steroidal anti-inflammatory agent-containing ophthalmic composition.
Preferred forms of the invention contemplated accomplish at least some of the above objects. One embodiment of the invention is an ophthalmic composition comprising an aqueous medium containing an effective amount of a non-steroidal anti-inflammatory agent, wherein at least about 80 mol. % of said agent is in the form of a precipitate, and at least about 0.5 equivalents of a pharmacologically acceptable divalent cation per mole of said non-steroidal anti-inflammatory agent; said aqueous medium having a pH of from about 4.0 to 6.7. Another embodiment of the invention relates to a method for treating an eye, which comprises administering to an eye in need thereof an effective amount of such an ophthalmic composition. A further aspect of the present invention relates to a method for making such an ophthalmic composition. Another preferred embodiment of the present invention relates to an ophthalmic composition that is formed by combining at least (1) sodium diclofenac, (2) a divalent metal salt, (3) a water insoluble, water-swellable polymer, and (4) water.
A further embodiment of the invention is an ophthalmic composition
Bowman Lyle M.
Memarzadeh Eric B.
Pfeiffer James F.
Roy Samir
Arnold & Porter
Fay Zohreh
InSite Vision Incorporated
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