Drug – bio-affecting and body treating compositions – Topical body preparation containing solid synthetic organic... – Ophthalmic preparation
Reexamination Certificate
1994-05-24
2001-10-30
Kulkosky, Peter F. (Department: 1615)
Drug, bio-affecting and body treating compositions
Topical body preparation containing solid synthetic organic...
Ophthalmic preparation
Reexamination Certificate
active
06309630
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to ophthalmic formulations and more particularly, ophthalmic formulations of nonsteroidal anti-inflammatory agents, particularly diclofenac sodium.
2. Description of the Related Art
Cyclooxygenase is essential in the biosynthesis of prostaglandins which have been shown in many animal models to be mediators of intraocular inflammation. Although sterioidal compounds have been used to treat such inflammation, non-steroidal anti-inflammatory agents, from the group of drugs known as cyclooxygenase inhibitors; have been substituted for steroids because they have not shown the same propensity to produce side-effects in ocular tissues as ophthalmic steroids. Non-steroidal agents are also widely prescribed to reduce pain and inflammation in a wide number of tissues. When used as topical agents in the eye, they suppress inflammatory responses and to prevent particular side-effects of surgical trauma (on the pupil preventing surgical meiosis), fluid accumulating in the back of the eye after cataract surgery (post-surgical macular edema) and the appearance of inflammatory cells and vessel leakage in the anterior chamber. Topical application of non-steroidal anti-inflammatory agents in the eye also appears to relieve some of the itching due to allergic conjunctivitis. Diclofenac sodium, suprofen, and flurbiprofin are non-steroidal anti-inflammatory agents that have been used for the treatment of postoperative inflammation in patients who have undergone cataract extraction.
Anti-inflammatory agents have in the past 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 usually used to avoid potential irritation caused by the particles of a 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. 4,829,083 to Doulakas relates to stabilization of mercury-containing preservatives in liquid or gel ophthalmic medicaments with addition of 2-amino-2-hydroxymethyl-1,3-propanediol or a homologue thereof.
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.
Most non-steroidal anti-inflammatory agents, when used in a topical solution, however, sting upon placement in the eye. The transient burning and stinging causes tearing, which in turn, washes the drug away from the eye, resulting in reduced bioavailability of the drug. The conventional solutions of non-steroidal anti-inflammatory agents generally have a pH of 7.0 to about 8.0. This pH level provides complete solubility of the drug, thereby allowing for a high concentration of the drug to be immediately available to the cornea. The high concentration of the drug on the eye aggravates the burning and stinging effects of the drug.
The present invention provides topical ophthalmic formulations containing non-steroidal anti-inflammatory agents which reduce or eliminate the stinging and burning experienced with solutions of anti-inflammatory agents. Formulations of the present invention may be useful for treatment of any condition that may be treated by a non-steroidal anti-inflammatory agent.
Accordingly, it is an object of the invention to provide novel topical ophthalmic formulations containing non-steroidal anti-inflammatory agents.
It is a further object of the invention to provide a novel method of treating the eye.
SUMMARY OF THE INVENTION
One embodiment of the present invention is a topical ophthalmic composition for treatment of the eye comprising an aqueous suspension of a non-steroidal anti-inflammatory agent, the composition having a pH and concentration of agent chosen to ensure that at least some of the agent is in suspension.
The present invention also provides a method for treating diseases of the eye, including inflammation, by topically applying such suspensions to eyes in need of treatment.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a composition for treating the eye topically comprising an aqueous mixture of a non-steroidal anti-inflammatory agent, wherein the composition has a pH of about 4.0 to about 8.0, preferably about 5.0 to about 6.8, and at least some of the agent is maintained as a reservoir established in suspension at the pH of the formulation. The amount established in suspension may vary depending on therapeutic needs but it will be at least an amount sufficient to have a therapeutic effect on the eye upon delayed release from the suspension over a period of time. A sufficient amount of agent will also be present in solution to have an immediate therapeutic effect upon topical ophthalmic application. Typically, about 80% to about 90% of the total agent contained in the mixture will be in suspension, but this may vary depending on how much of the agent is desired for delivery and the duration of delivery desired. The amount of therapeutic agent in suspension may, for instance, range from about 70% to about 99% or about 10% to about 99% by weight of the total amount of agent contained in the mixture. The compositions will not, however, have 100% of the agent in suspension. Some amount will be in solution to provide the immediate therapeutic effect.
Compositions of the present invention may have a pH of about 4 to about 8 depending on the solubility characteristics of the agent. In a preferred embodiment where diclofenac is the therapeutic agent, a preferred pH range is about 5.0 to about 6.8. The concentration of the agent and the pH of the composition will be selected to ensure that a sufficient amount of the therapeutic agent is in suspension to provide a therapeutic effect upon delayed deliver. In this way, the portion of the agent in solution is immediately available for therapeutic effect while the portion in suspension serves as a reservoir and is released slowly over time.
The solubility of non-steroidal anti-inflammatory agents is pH dependent, i.e., normally the higher the pH, the higher the solubility of the drug in the formulation. For instance, below a pH of about 6.8, as in the present invention, a formulation containing 1% diclofenac sodium, has virtually all of the diclofenac in suspension. Formulating the composition as a suspension rather than as a solution inhibits immediate contact between the drug and tissues of the eye and in that way reduces the stinging and burning sensation experienced when a solution of such drugs places all of the drug in immediate contact with the ocular tissues.
As demonstrated by Tables 1, 2 and 3, the percentage of diclofenac sodium, suprofen, and flurbiprofen in suspension is dependent on concentration and pH. Thus, by providing at least some of the diclofenac in suspension, via pH control, lower transient burning and stinging would be observed when administered to patients.
TABLE 1
Percent Diclofenac Sodium in Suspension
Concentration of
Diclofenac Sodium
in the Formulation
pH
.001
.01
.1
1.0
3.7
100
100
100
100
4.0
99
99
99
99
4.6
90
99
99
99
5.2
20
92
99
99
5.9
0
50
95
99
6.3
0
0
76
98
6.5
0
0
35
93
7.3
0
0
0
64
TABLE 2
Percent Suprofen in Suspension
Concentration of
Suprofen in
the Formulation
pH
.001
.01
.1
1.0
5.0
4.0
0
0
77
98
99
5.0
0
0
45
95
99
6.0
0
0
0
54
95
7.0
0
0
0
0
68
TABLE 3
Percent Flu
Bowman Lyle M.
Patel Rajesh
Shen Peng
Arnold & Porter
InSite Vision Incorporated
Kulkosky Peter F.
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