Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
2000-09-07
2002-11-05
Azpuru, Carlos A. (Department: 2165)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C424S078040
Reexamination Certificate
active
06475508
ABSTRACT:
INTRODUCTION
1. Technical Field
The present invention relates to methods and pharmaceutical compositions involving the use of polymers for the closure of retinal breaks.
2. Background
Successful management of rheginatogenous retinal detachment is predicated upon closure of all retinal breaks. A rheginatogenous retinal detachment occurs when vitreous fluid passes through a hole in the retina and the retina separates from the retinal pigment epithelium. When retinal detachment is treated with vitrectomy, closure of retinal breaks generally requires creation of a chorioretinal adhesion around each break (Michels et al.,
Retinal Detachment
, Klein E A, Ed. C V Mosby Co., St. Louis, Mo., 1990, pp 440, 847, 890-892). These adhesive lesions are generated with either laser photocoagulation or cryotherapy. Maximal chorioretinal adhesion is ordinarily achieved within 2 weeks following treatment (Bloch et al.,
Am J Opthalmol
71:666-673 (1971); Yoon et al.,
Ophthalmol
95:1385-1388 (1988)). To keep the retina in apposition with the retinal pigment epithelium during this time, prolonged intraocular tamponade with gas or silicone oil is utilized (Norton et al.,
Am J Ophthalmol
68:1011-1021 (1969); Norton et al.,
Trans Am Acad Ophthalmol Otolaryngol
77:85-98 (1973); Lean et al.,
Trans Ophthalmol Soc
(UK) 102:203-205 (1982); Gonvers M,
Ophthalmologica
184:210-218 (1982); Petersen J.,
Graefe's Arch Clin Exp Ophthalmol
225:452-456 (1987)).
When long acting gases such as SF
6
or C
3
F
8
are used, patients often must keep their head in a face down position for 2 weeks after surgery (Michels et al.,
Retinal Detachment
, Klein E A, Ed. C V Mosby Co., St. Louis, Mo., 1990, pp 890-892). This causes considerable discomfort in most patients, and not uncommonly, is the most difficult hurdle in post-operative management. Additionally, intraocular gas may be associated with a number of ocular complications including, cataract, glaucoma, corneal edema, and creation of retinal folds (Fineberg et al.,
Am J Ophthalmol
79:67-76 (1975); Abrams et al.,
Am J Ophthalmol
94:165-171 (1982); Foulks et al.,
Arch Ophthalmol
105:256-259 (1987); Lewen et al.,
Arch Ophthalmol
105:1212-1214 (1987)). Another potential disadvantage of gas as an intraocular tamponade is that by sequestering inflammatory factors between the bubble interface and the retina, it may promote scar tissue formation on the retinal surface (Charles, S.,
Vitreous Microsurgery
, Williams & Wilkins, Baltimore, Md., 1987, p 135). As this scar tissue contracts, it can distort the retinal surface, and may cause re-detachment of the retina (proliferative vitreoretinopathy) (Machemer R.,
Brit J Ophthalmol
62:737-747 (1978); Laqua et al.,
Am J Ophthalmol
80:913-929 (1975)).
Using silicone oil as a post-operative intraocular tamponade has the advantage that the patient is not required to position face down for more than one day post-operatively. However, unlike gas, which is slowly reabsorbed into the blood stream, silicone must be surgically removed from the eye as a secondary procedure to prevent silicone induced ocular complications such as cataract, glaucoma, band keratopathy, corneal decompensation and promotion of proliferative vitreoretinopathy (PVR) (Federman et al.,
Ophthalmol
95:870-876 (1988); Sternberg et al.,
Arch Ophthalmol
102:90-94 (1985)).
Other less effective methods of retinal fixation to the underlying retinal pigment epithelium include retinal tacks (de Juan et al.,
Am J Ophthalmol
99:272-274 (1985); Burke et al.,
Arch Ophthalmol
105:404-408 (1987)), and cyanoacrylate glue (McCuen et al.,
Am J Ophthalmol
102:199-207 (1986)). Titanium or stainless steel metal retinal tacks have been used to attach the retina to the eye wall to treat giant retinal tears or after large relaxing retinotomies. The tacks do not create a confluent chorioretinal adhesion around the retinal tear and thus require supplemental laser or cryotherapy as well as intraocular tamponade with gas or silicone oil. Tacks are also associated with complications such as choroidal hemorrhage and dislodgment (Lewis et al.,
Am J Ophthalmol
103:672-680 (1987)).
Butyl-2-cyanocrylate glue has been used to close retinal breaks in animal models of experimental retinal detachment (McCuen et al; Hida et al.,
Am J Ophthalmol
103:782-789 (1987); Hida et al., 1988). The glue is applied directly to retinal holes, polymerizing rapidly to form a seal over the retinal hole. While successful at closing the break and creating a chorioretinal adhesion, some intraocular glues can cause local retinal toxicity, possibly from release of formaldehyde and cyanoacetate (Hida et al., 1987).
Patients suffering from retinal detachment are in need of a better method for temporarily closing retinal breaks while chorioretinal adhesions form, thus allowing recovery from surgery with a minimum of discomfort and/or ocular complications.
SUMMARY OF THE INVENTION
The present invention is directed to compositions, methods, and articles of manufacture for the closure of retinal breaks by applying a polymer formulation to the retinal surface in the vicinity of the retinal break. The invention provides methods for closing a retinal break in a mammal, comprising applying to the retinal surface over and around the retinal break a non-toxic polymer formulation comprising at least one polymer precursor, and transforming the polymer formulation into a gel-like coat. In a preferred embodiment, the polymer formulation comprises a photochemically reactive polymer precursor species that can be transformed from a liquid to gel form by exposure to light. Another preferred composition includes a mixture of two mutually reactive polymer precursors.
The invention also provides methods for the management of retinal detachment, comprising replacing the vitreous with gas, creating a chorioretinal adhesion around a retinal break, applying to the retinal surface over and around the retinal break a non-toxic polymer formulation comprising at least one polymer precursor, and transforming the polymer into a gel-like coat.
Also provided are methods for preventing proliferative vitreoretinopathy, comprising applying a non-toxic polymer formulation over and around the retinal break and extending beyond the break by a substantial amount, preferably to cover more than 75% of the retina.
In addition, the invention provides pharmaceutical compositions, methods for preparing such pharmaceutical compositions, and articles for manufacture for use in the methods described above.
DESCRIPTION OF SPECIFIC EMBODIMENTS
This invention pertains to the field of retinal surgery, particularly to the closure of retinal breaks. The invention provides a superior alternative to silicone oil or intraocular gas for post-operative tamponade. The methods of the invention comprise the application of a polymer formulation to the retinal surface over and around the retinal break. More extensive applications of the polymer formulation to the retinal surface can prevent post operative scar tissue formation and recurrent retinal detachment (proliferative vitreoretinopathy). The polymer formulation is applied in liquid form, assuring conformity to irregular tissue surfaces. It is then transformed to a thin, gel-like coat by photopolymerization with a light source. Alternatively, a liquid polymer precursor that auto-polymerizes is applied over the break and adjacent retina. The polymerized gel is bound to the retina and retinal pigment epithelium, and resists displacement with overlying turbulent fluid flow. It is water permeable and allows diffusion of small molecules such as oxygen, glucose and other essential nutrients. While the polymer adheres to the retina, it closes the retinal hole, preventing fluid from passing into the subretinal space.
Before or after application of the polymer formulation to the retinal surface, laser photocoagulation or cryotherapy can be applied around the break to form a chorioretinal adhesion, which reaches adequate strength to prevent retinal detachment by about 10-14 days after surgery (Yoon et a
Hubbell Jeffrey A.
Irvine Alexander R.
Schwartz Daniel M.
Azpuru Carlos A.
Rae-Venter Law Group P.C.
Regents of the University of California
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