Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
2000-10-20
2004-04-27
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C424S400000, C424S423000, C424S426000, C424S427000, C424S428000, C424S429000
Reexamination Certificate
active
06726918
ABSTRACT:
TECHNICAL FIELD
This invention relates to methods for treating inflammation-mediated conditions of the eye by implanting into the vitreous of the eye a bioerodible implant comprising a steroidal anti-inflammatory agent and a bioerodible polymer. Specifically, these methods may be used in the protection and treatment of tissues damaged by or susceptible to damage by inflammation-mediated conditions such as uveitis, by providing therapeutic levels of an anti-inflammatory agent to the vitreous of the eye.
BACKGROUND ART
Glucocorticoids are an important part of treatment in severe anterior, intermediate, posterior, and panuveitis. A major problem with present drug therapy is the inability to achieve adequate intraocular drug concentration. In particular, uveitis is well known for its long duration due in part to the difficulties associated with poor intraocular penetration of topical medications into the posterior segment (Bloch-Michel E. (1992). “Opening address: intermediate uveitis,” In
Intermediate Uveitis, Dev Ophthalmol.
W. R. F. Böke et al. eds., Basel: Karger, 23:1-2; Pinar, V.
Intermediate uveitis.
Massachusetts Eye & Ear Infirmary Immunology Service at <http://www.immunology.meei.harvard.edu/imed.htm> (visited in 1998); Rao, N. A. et al. (1997). “Intraocular inflammation and uveitis” In
Basic and Clinical Science Course.
Section 9 (1997-1998) San Francisco: American Academy of Ophthalmology, pp. 57-80, 102-103, 152-156; Böke, W. (1992). “Clinical picture of intermediate uveitis,” In
Intermediate Uveitis, Dev Ophthalmol.
W. R. F. Böke et al. eds., Basel: Karger, 23:20-7; Cheng C-K et al. (1995). “Intravitreal sustained-release dexamethasone device in the treatment of experimental uveitis,”
Invest Ophthalmol Vis Sci.
36:442-53). Systemic glucocorticoid administration may require prolonged exposure of high plasma concentrations (administration of 1 mg/kg/day for 2-3 weeks) so that therapeutic levels can be achieved in the eye (Pinar, V. “Intermediate uveitis,” Massachusetts Eye & Ear Infirmary Immunology Service at <http://www.immunology.meei.harvard.edu/imed.htm> (visited in 1998)). These high drug plasma levels often lead to systemic side effects such as hypertension, hyperglycemia, increased susceptibility to infection, peptic ulcers, psychosis, and other complications (Cheng C-K et al. (1995). “Intravitreal sustained-release dexamethasone device in the treatment of experimental uveitis,”
Invest Ophthalmol Vis Sci.
36:442-53; Schwartz, B. (1966). “The response of ocular pressure to corticosteroids,”
Ophthalmol Clin North Am
6:929-89; Skalka, H. W. et al. (1980). “Effect of corticosteroids on cataract formation,” Arch Ophthalmol 98:1773-7; Renfro, L. et al. (1992). “Ocular effects of topical and systemic steroids,”
Dermatologic Clinics
10:505-12). In addition, overall drug delivery to the eye may be poor due to the short drug plasma half-life limiting exposure into intraocular tissues. The most efficient way of delivering drug to the posterior segment is to place it directly in the vitreous (Maurice, D. M. (1983). “Micropharmaceutics of the eye,”
Ocular Inflammation Ther
1:97-102; Lee, V. H. L. et al. (1989). “Drug delivery to the posterior segment” Chapter 25 In
Retina.
T. E. Ogden and A. P. Schachat eds., St. Louis: C V Mosby, Vol. 1, pp.483-98; Olsen, T. W. et al. (1995). “Human scleral permeability: effects of age, cryotherapy, transscleral diode laser, and surgical thinning,”
Invest Ophthalmol Vis Sci
36:1893-1903). Intravitreal injections have shown promising results, however, due to the short intraocular half-life of glucocorticoids (approximately 3 hours), intravitreal injections must be repeated to maintain drug levels which increases the potential for side effects such as retinal detachment, endophthalmitis, and cataract (Maurice, D. M. (1983). “Micropharmaceutics of the eye,”
Ocular Inflammation Ther
1:97-102; Olsen, T. W. et al. (1995). “Human scleral permeability: effects of age, cryotherapy, transscleral diode laser, and surgical thinning,”
Invest Ophthalmol Vis Sci
36:1893-1903; Kwak, H. W. and D'Amico, D. J. (1992). “Evaluation of the retinal toxicity and pharmacokinetics of dexamethasone after intravitreal injection,”
Arch Ophthalmol
110:259-66). Topical, systemic, and periocular glucocorticoid treatment must be monitored closely due to toxicity and the long-term side effects associated with chronic systemic drug exposure sequelae (Rao, N. A. et al. (1997). “Intraocular inflammation and uveitis” In
Basic and Clinical Science Course.
Section 9 (1997-1998) San Francisco: American Academy of Ophthalmology, pp. 57-80, 102-103, 152-156; Schwartz, B. (1966). “The response of ocular pressure to corticosteroids,”
Ophthalmol Clin North Am
6:929-89; Skalka, H. W. and Pichal, J. T. (1980). “Effect of corticosteroids on cataract formation,”
Arch Ophthalmol
98:1773-7; Renfro, L and Snow, J. S. (1992). “Ocular effects of topical and systemic steroids,”
Dermatologic Clinics
10:505-12; Bodor, N. et al. (1992). “A comparison of intraocular pressure elevating activity of loteprednol etabonate and dexamethasone in rabbits,”
Current Eye Research
11:525-30). U.S. Pat. No. 5,501,856 discloses controlled-release pharmaceutical preparations for intraocular implants to be applied to the interior of the eye after a surgical operation for disorders in retina/vitreous body or for glaucoma.
U.S. Pat. No. 5,869,079 discloses combinations of hydrophilic and hydrophobic entities in a biodegradable sustained release implant, and describes a polylactic acid polyglycolic acid (PLGA) copolymer implant comprising dexamethasone. As shown by in vitro testing of the drug release kinetics, the 100-120 &mgr;g 50/50 PLGA/dexamethasone implant disclosed did not show appreciable drug release until the beginning of the fourth week.
U.S. Pat. No. 5,824,072 discloses implants for introduction into a suprachoroidal space or an avascular region of the eye, and describes a methylcellulose implant comprising dexamethasone.
U.S. Pat. Nos. 4,997,652 and 5,164,188 disclose biodegradable ocular implants comprising microencapsulated drugs, and describes implanting microcapsules comprising hydrocortisone succinate into the posterior segment of the eye.
U.S. Pat. No. 5,164,188 discloses encapsulated agents for introduction into the suprachoroid of the eye, and describes placing microcapsules and plaques comprising hydrocortisone into the pars plana.
U.S. Pat. Nos. 5,443,505 and 5,766,242 discloses implants comprising active agents for introduction into a suprachoroidal space or an avascular region of the eye, and describes placing microcapsules and plaques comprising hydrocortisone into the pars plana.
Zhou et al. disclose a multiple-drug implant comprising 5-fluorouridine, triamcinolone, and human recombinant tissue plasminogen activator for intraocular management of proliferative vitreoretinopathy (PVR) (Zhou, T, et al. (1998). “Development of a multiple-drug delivery implant for intraocular management of proliferative vitreoretinopathy,”
Journal of Controlled Release
55: 281-295.)
There is a continued need for efficacious intraocular sustained release drug therapies for patients with inflammatory conditions.
All references cited herein are hereby incorporated by reference in their entirety.
DISCLOSURE OF THE INVENTION
The present invention provides a method for treating an inflammation-mediated condition of the eye, comprising: implanting into the vitreous of the eye a bioerodible implant comprising a steroidal anti-inflammatory agent and a bioerodible polymer, wherein the implant delivers the agent to the vitreous in an amount sufficient to reach a concentration equivalent to at least about 0.05 &mgr;g/ml dexamethasone within about 48 hours and maintains a concentration equivalent to at least about 0.03 &mgr;g/ml dexamethasone for at least about three weeks.
In another embodiment of the invention, a method for treating an inflammation-mediated condition of the eye is provided, comprising: implanting a solid body into the vitreous of the eye, said body
Hu Mae W. L.
Wong Vernon G.
Evans Charesse
Oculex Pharmaceuticals, Inc.
Page Thurman K.
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