Drug – bio-affecting and body treating compositions – Ophthalmic – Glaucoma
Reexamination Certificate
1998-12-23
2002-04-09
Webman, Edward J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Ophthalmic
Glaucoma
C424S486000, C424S488000
Reexamination Certificate
active
06369116
ABSTRACT:
TECHNICAL FIELD
The present invention relates to controlled-release biodegradable implants for use in glaucoma filtration surgery.
BACKGROUND OF THE INVENTION
Glaucoma filtration surgery (GFS) is the mainstay of surgical intervention for patients whose glaucoma remains progressive after medical therapy. In this procedure, a sclerectomy is performed to create a permanent fistula between the anterior chamber and the subconjunctival space. The procedure is designed to create a filtering bleb which provides an alternative passageway for the drainage of aqueous humor from the eye, thereby easing intraocular pressure and helping to improve the patient's vision.
Unfortunately, the failure rate of GFS can be as high as 25%, depending on preoperative risk factors, and even higher for more complicated cases. Shields, A Study Guide for Glaucoma, 2nd Edition, pp. 463-77 (Baltimore: Williams & Wilkins 1987). The most significant cause of these failures is the formation of excessive scar tissue by fibroblasts at the episcleral-conjunctival interface, which obstructs the release of fluid from the anterior chamber of the eye via the filtering bleb. Without the benefit of the alternative passageway created by the surgery, the intraocular pressure eventually returns to its pre-surgical elevated level.
Post-operative administration of a variety of therapeutically active agents has been investigated in the prior art to inhibit the inflammatory response, and in particular to help prevent fibroblast proliferation at the surgical site and the consequent formation of collagenous scar tissue. These include anti-inflammatory agents such as corticosteroids and non-steroidal anti-inflammatory drugs (NSAIDs), thrombolytic agents, antimetabolites and/or anti-proliferative agents. Chang,
J. Ocular Pharm. Ther.
14:75-95 (1998). Typically, the desired active agent is administered via subconjunctival injection several times after the conclusion of GFS. The disadvantage of patient discomfort with these repeated subconjunctival injections, however, is obvious. Moreover, frequent subconjunctival injections of certain useful active agents such as 5-flourouracil (5-FU) can cause additional complications. Lee et al.,
Ophthalmic Surg
18:187 (1987).
Alternatively, a single subconjunctival injection of the desired active agent can be followed by topical eyedrops for up to three months post-operatively. This alternative procedure is equally unsatisfactory, however, since both the amount of active agent contacting the surgical site and the duration of exposure to the agent are very limited, typically resulting in bursts of drug delivery at each administration with nothing in between. Further, strict adherence to the eyedrop regime is crucial to the success of the procedure, and often neglected by many patients once beyond the constant oversight of medical professionals. Thus, a sustained- and controlled-release form of these active agents would be highly desirable.
Prior art attempts to formulate drug delivery systems suitable for the GFS procedure have failed to meet this need. Repeated investigations using bioerodible polyanhydride discs impregnated with 5-flourouracil (5-FU) achieved only limited success, had greatly varying release rates, and resulted in unacceptable ocular toxicity. Jampel, Arch.
Ophthalmol.
108:430-435 (1990). Accordingly, a need still exists for an effective, pharmaceutically-acceptable implant which can provide both sustained and controlled release of the active agent directly to the surgical site.
Relevant Literature
U.S. Pat. No. 4,997,652 and 4,853,224 disclose biocompatible implants for introducing into an anterior chamber or posterior segment of an eye for the treatment of an ocular condition. U.S. Pat. Nos. 5,164,188, 5,443,505, 5,766,242 and 5,824,072 describe methods of treating ocular conditions by introduction of biocompatible implants comprising drugs of interest into the suprachoroidal space or pars plana of the eye. U.S. Pat. No. 5,501,856 describes biodegradable intra-ocular implants to be applied to the interior of the eye for treatment of disorders in retina/vitreous body or for glaucoma.
Heller,
Biodegradable Polymers in Controlled Drug Delivery,
in: CRC Critical Reviews in Therapeutic Drug Carrier Systems, Vol. 1, CRC Press, Boca Raton, Fla., 1987, pp. 39-90, describes encapsulation for controlled drug delivery. Heller in: Hydrogels in Medicine and Pharmacy, N.A. Peppes ed., Vol. III, CRC Press, Boca Raton, Fla., 1987, pp 137-149, further describes bioerodible polymers.
Anderson et al.,
Contraception
13:375 (1976) and Miller et al.,
J. Biomed. Materials Res.
11:711 (1977), describe various properties of poly(dL-lactic acid). U.S. Pat. No. 5,075,115 discloses sustained release formulations with lactic acid polymers and co-polymers. Di Colo,
Biomaterials
13:850-856 (1992) describes controlled drug release from hydrophobic polymers.
Charles et al.,
Ophthalmology
98:503-508 (1991); Jampel et al., Arch.
Ophthalmol.
108:430-435 (1990); Lee et al.,
Invest. Ophthalmol Vis. Sci.
29:1692-1697 (1988); and Lee et al.,
Ophthalmology
12:1523-1530 (1987) describe the use of bioerodible polyanhydride delivery systems in glaucoma filtration surgery. Smith and Ashton,
Ophthalmic Surg. Lasers
27:763-767 (1996) describe a non-biodegradable reservoir system for delivery of 5-FU in high-risk glaucoma surgical patients.
SUMMARY OF THE INVENTION
Methods and compositions are provided for improving the success of glaucoma filtration surgery, through the sustained and controlled release of one or more therapeutically active agents directly to the surgical site. Biodegradable implants are provided comprising a biocompatible, biodegradable polymer and one or more active agents configured for placement extrinsic to the vitreous either episclerally or intrasclerally. The implant provides a substantially constant rate of release of the desired active agent or agents to the surgical site for an extended period of time.
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R. Baker, “Controlled Release of Biologically Active Agents,”A Wiley-Interscience Publication,p. 73 (1987).
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T. Jackanicz et al, “Polylactic Acid As A Biodegradable Carrier For Contraceptive Steroids,”Contraception,vol. 8, No. 3:227-235.
R. Miller et al, “Degradation Rates of Oral Resorbable Implants (Polylactates and Polyglycolates): Rate Modification with Changes in PLA/PGA Copolymer Ratios,”J. Biomed. Mater. Res.,vol. 11:711-719 (1977).
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J. Charles, et al, “Use of Bioerodible Polymers Impregnated with Mitomycin in Glaucoma Filtration Surgery in Rabbits,”Ophthalmology,Apr. 1991, vol. 98, No. 4: 503-508.
H. Jampel, et al, “Glaucoma Filtration Surgery in Monkeys Using 5-Fluorouridine in Polyanhydride Disks,”Arch Ophthalmol,Mar. 1990, vol. 108:430-435.
D. Lee, et al, “The Use of Bioerodible Polymers and 5-Fluorouracil in Glaucoma Filtration Surgery,”Investigative Ophthalmology & Visual Science,Nov. 1988, vol. 29, No. 11:1692-1697.
M. Chang, et al, “Basic Science and Clinical Aspects of Wound Healing in Glaucoma Filtering Surgery,”Journal of Ocular Pharmacology and Therapeutics,1998, vol. 14, No. 1:75-95.
D. Lee, et al, “Glaucoma Filtration Surgery in Rabbits Using Bioerodible Polymers and 5-Fluorouracil,”Ophthalomology,Dec. 1987, vol. 94, No. 12:1523-1530.
T. Smith, et al, “Sustained-release subconjunctival 5-Flu
Peng Lin
Wong Vernon
Brezner David J.
Flehr Hohbach Test Albritton & Herbert LLP
Lorenz Todd A.
Oculex Pharmaceuticals, Inc.
Webman Edward J.
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