WO2008134616A2 - Use of intravitreal viscosurgical injection agents for repair of rhegmatogenous (bullous) retinal detachment - Google Patents

Description

USE OF INTRAVITREAL VISCOSURGICAL INJECTION AGENTS FOR REPAIR OF RHEGMATOGENOUS (BULLOUS) RETINAL DETACHMENT

REFERENCE TO RELATED APPLICATION [0001] This application claims priority from U.S. Provisional Patent Application Serial No. 60/914,413, filed April 27, 2007, the entire content of which application is hereby incorporated herein by reference.

FIELD OF THE INVENTION [0002] The present invention pertains to the field of surgical methods for repair of rhegmatogenous retinal detachment through the use of a tamponade agent that eliminates the need for subsequent aspiration of the tamponading agent and post-surgical positioning of patients, thus, improving the operative success rate and long term maintenance of retinal reattachment

BACKGROUND OF THE INVENTION

[0003] The separation of the neuroretina from underlying pigment epithelium (retinal detachment) leads to severe and irreversible loss of vision. Traditional vitreoretinal surgical methods to correct the detachment are hampered by the high complication rate and incomplete rescue of acceptable vision. Recent advances in surgical techniques and the use of intravitreal agents have begun to improve the surgical outcome. Lewis H, Am J Ophthalmol, 1994; 118:559-68; Ibanez HE, et al., Arch Ophthalmol, 1995; 113:62-69; Lim JI, et al., Ophthalmology, 1995; 102:1393-99; Kamei M, et al., Am J Ophthalmol, 1996; 121:267-75; Haupert CL, et al., Am J Ophthalmol, 2001; 131:208-15. [0004] The use of viscoelastics has been common for temporary reformation of the anterior chamber ocular chambers for many years. Non-aqueous tamponade agents are traditionally employed in the posterior segment (intravitreal space) of the eye to allow sufficient time for a tear or hole to reattach. Viscoelastics are solutions that have viscous, elastic, and pseudoplastic properties generally acting as both viscous liquids and as elastic solids or gels. (US Pat. No. 5,792,103.) Common agents are illustratively sodium hyaluronate sold under the trade names Healon®, Provisc®, Viscoat®, and DisCoVisc®. Use of these viscoelastics has been restricted to temporary manipulation of retinotomies and similar procedures. [0005] While the use of perfluorocarbons is presently the first choice surgical technique, requirements of highly involved and difficult patient post surgical positioning remain due to buoyancy factors. Fluorohydrocarbon gases commonly employed as a pneumatic displacement agent are illustratively perfluoropropane gas (C₃Fs), sulfur hexafluoride (SF₆), or perfluoro-n- octane (CsF₁₈). The use of silicon oil as a tamponade agent does not possess similar buoyancy issues, however, this tamponade agent presents its own complications in that it requires a total vitrectomy and is immiscible with vitreous and has the possibility of migrating into the brain. Eller AW, et al., Am J. Ophthal, 2000; 129:685-88. Thus, there exists a need for an improved surgical regime for the repair of rhegmatogenous retinal detachment through the use of viscoelastics.

SUMMARY OF THE INVENTION

[0006] The invention provides methods for the repair of retinal detachment. An inventive method according to the present invention comprises preparing the eye for surgery, injecting a single viscoelastic into the vitreous of the eye, making one or more incisions in the sclera, removing material from the subretinal area, and reattaching the retina.

[0007] In one embodiment of the present invention, the vascoelastic is selected from the group comprising: sodium hyaluronate; hyaluronic acid, its salts and mixtures thereof, chondroitin sulfate, methylcellulose, silicon oil and perfluorocarbon [0008] In a particular embodiment of the present invention, the viscoelastic comprises at least one of: a) sodium hyaluronate; b) hyaluronic acid; c) a salt of hyaluronic acid; d) a polymer variant of hyaluronic acid; e) a salt of d); f) a mixture of at least two polymer variants of hyaluronic acid; g) a mixture of at least two salts of polymer variants of hyaluronic acid; h) a mixture of at least two of a), b), c), d), e), f), and g); i) chondroitin sulfate; j) methylcellulose; k) silicon oil; or 1) perfluorocarbon.

[0009] In another embodiment, the viscoelastic comprises at least one of: sodium hyaluronate, hyaluronic acid, chondroitin sulfate, methylcellulose, silicon oil, or perfluoroc arbon . [0010] In another embodiment, the viscoelastic viscoelastic consists of one of: a) sodium hyaluronate; b) hyaluronic acid; c) a salt of hyaluronic acid; d) a polymer variant of hyaluronic acid; e) a salt of d); f) a mixture of at least two polymer variants of hyaluronic acid; g) a mixture of at least two salts of polymer variants of hyaluronic acid; h) a mixture of at least two of a), b), c), d), e), f), and g); i) chondroitin sulfate; j) methylcellulose; k) silicon oil; or 1) perfluoroc arbon .

[0011] In another embodiment, the viscoelastic consists of one of: sodium hyaluronate, hyaluronic acid, chondroitin sulfate, methylcellulose, silicon oil, or perfluorocarbon. [0012] In another embodiment, the viscoelastic is in a pharmaceutically acceptable formulation.

[0013] The invention further provides a method of repair of bullous rhegmatogenous retinal detachment comprising injecting sodium hyaluronate via the pars plana into the vitreous, forming one or more sclerostomies, manipulating the sclera to remove material from the subretinal area, elevating the intraocular pressure in the vitreous to between 25 and 50 mm Hg, and reattaching the retina.

[0014] In one embodiment of the present invention, the method further comprises the step of rinsing the subretinal area with a solution containing tissue plasminogen activator. [0015] In another embodiment, the method further comprises reattaching the retina by the use of laser retinopexy, cryopexy, or diathermy.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] Viscoelastics are widely used in cataract and anterior segment surgery and have been long approved as viscosurgical instruments. Surgical procedures commonly require removal of the product immediately after use. However, complete evacuation is not universally achieved. Failure to remove the viscoelastic may lead to excessive intraocular pressure or other undesirable complications.

[0017] A pressure spike is common with the use of viscoelastics such as sodium hyaluronate in the anterior chamber from which the aqueous humor must drain. However, the instant invention identifies that standard viscoelastics injected into the posterior chamber do not result in similar intraocular pressure problems. Further, in the instant invention the lens is left unmolested while an excellent uniform tamponade is created uniformly repositing the retinal detachment. Thus, the instant invention has utility as a method for successful treatment of bullous rhegmatogenous retinal detachment (RRD). [0018] Hitherto, inherent in most procedures for the resolution of RRD is the use of a liquid or gaseous tamponading agent. These agents, with attendant surgical maneuvers, provide sufficient time for chorioretinal adhesion and prevent seepage of vitreal liquid through the causative break. The majority of conventional tamponading agents in use suffered several drawbacks including poor optical resolution hindering intraoperative or postoperative examination, or requirements for postoperative aspiration. Furthermore, migration of tamponades into the anterior chamber often leads to postoperative morbidity resulting from increased intraocular pressure. Martinez-Castillo V, et al., Ophthalmology, 2007; 114:297-302. [0019] In contrast, many different viscoelastics are optionally suitable for use in the instant invention. These are illustratively air, balanced salt solution, perfluorocarbon gas bubbles, silicon gas bubbles, hydroxy-propyl-methylcellulose (Maltese A, et al., Biomaterials, 2006; 27:5134-42), chitosan glutamate, and sodium hyaluronate. Use of these agents is optionally combined with other modes of resolving the underlying rhegmatogenous retinal detachment including mechanical vitrectomy, laser or cryotreatment, each performed with or without placement of scleral buckling.

[0020] Conventional perfluorocarbon is optionally used in conjunction with the instant invention for the creation of a biphasic bubble in the vitreous fluid that migrates through proper patient positioning to the region of desired action. Perfluorocarbon is illustratively perfluoroethane (C₂F_O), perfluoropropane (C₃Fs), perfluorooctane (CsF₁S), or perfluorodecalin (C_1OF₂₂), but it is appreciated in the art that other agents including for example, other organic agents, air, sulphurhaxaflouride (SF₆), and the like are similarly suitable. Franzco BV, et al., Clin Exp Ophthalmology, 2003; 31:408-414. Perfluorocarbons suitable in the instant invention, and other similarly suitable agents, optionally posses a lower specific gravity than vitreal fluid depending on the retinal region requiring repair. These agents are absorbed by the patient over the course of days to weeks reducing the active tamponade time and allowing for potential rapid reestablishment of normal intraocular pressure. Perfluorocarbons for use in the instant invention are readily available illustratively including CsF_1S sold as Adato-octa from Adatomed in Munich, Germany.

[0021] Hyaluronan (sodium hyaluronate or hyaluronic acid [HA]) or physiologically acceptable salt, or polymer variant thereof is optionally used as a tamponade in the instant invention. HA is a member of the glycosaminoglycans and is a natural component of the synovial fluid and extracellular matrix. Physiological HA is a polysaccharide comprised of alternating (1 → 4)-β linked D-glucuronic and (1 → 3)-β linked iV-acetyl-D-grucosamine residues. The high molecular mass and unique viscoelastic properties of HA make it an attractive biomaterial for various medical applications. Kogan G, et al., Biotechnol Lett, 2007; 29:17-25. The HA polymer variants are optionally of varying sizes ranging from a single disaccharide ((I → 4)-β linked D-glucuronic and (1 → 3)-β linked iV-acetyl-D-grucosamine) to a polymeric chain of as much as 3.5 megadaltons. The size of HA polymers is related to underlying biological function. For example, large matrix polymers serve space filling, anti- angiogenic, and immunosuppressive functions whereas polymers of 25-50 disaccharides are inflammatory, immunostimulatory, and angiogenic. Id. Small oligosaccharides are anti- apoptotic and trigger signal transduction pathways. Id. (See Stern R, et al., Eur J Cell Biol, 2006; 85:699-715). Finally, HA may induce tissue repair. Id.

[0022] For the purposes of the invention, an HA polymer variant of any size, or a salt or any mixture thereof, is suitable for use as a viscoelastic in one or more methods of the invention described herein, so long as the method determinably effects the desired retinal repair.

[0023] A viscoelastic suitable for use in the methods of the invention is readily prepared in a pharmaceutically acceptable formulation, including for example, in a physiologically acceptable buffer such as sodium chloride phosphate. [0024] HA is present in nearly all tissues of the vertebrates with the highest concentrations found in the extracellular matrix of soft connective tissues. HA is also a natural component of the vitreous of the eye. Laurent TC, The chemistry, biology, and medical applications of hyaluronan and its derivatives (Portland Press 1998). The viscoelastic properties of HA provide for its use to protect eye tissues and provide space filling during ocularsurgical manipulations. Historically, HA has been used as a substitute or replacement for vitreous fluid lost during cataract surgery or lens implantation. Id. However, fluid replacement with HA in the ocular anterior compartment is associated with increased ocular pressure. In contrast, the use of HA in the instant invention for injection into the posterior chamber does not lead to a pressure spike providing advantages for its use in repair of bullous rhegmatogenous retinal detachment. [0025] The use of HA in the instant invention has several advantages over other tamponades. As HA is a major component of the natural vitreous fluid, its injection does not alter the optical properties of the inner eye allowing more efficient and accurate intraoperative examination and observation of retinal flattening or sealing of a retinal tear. Furthermore, HA provides increased wound healing and lower levels of inflammation promoting a more rapid and complete healing process. HA is available from numerous sources illustratively including that sold under the trade name Provisc® from Alcon Laboratories, Fort Worth, TX.

[0026] The use of HA as the sole tamponade is optionally combined with co-injection of a second agent, illustratively hyaluronidase, as a degrading enzyme to reduce the post-injection concentration of intravitreal HA. Harooni M, et al., Arch Ophthalmol, 1998; 116:1218-21. HA is further optionally combined with chondroitin sulfate or tissue plasminogen activator (tPA). Injection of HA, silicon oil, or perfluorocarbons is optionally combined with sealing or removal of the underlying detachment by the techniques of cryopexy, diathermy, or laser coagulation to prevent leakage of vitreal fluid between the retinal layers. [0027] Three primary surgical methods are illustratively employed for repair of rhegmatogenous retinal detachments. These include a scleral buckling procedure, pneumatic retinopexy, and vitrectomy. Scleral buckling is optionally performed by placing a buckle on the sclera. This buckle is optionally a piece of silicone sponge, rubber, or semi-hard plastic. The presence of the buckle physically reshapes the sclera bringing the retina against the wall of the eye by relieving retinal tension.

[0028] A vitrectomy or pneumatic retinopexy is commonly employed for repair of retinal tears, but similar procedures are optionally used for the repair of bullous retinal detachments. These methods illustratively involve the injection of air, balanced salt solution, or viscoelastic into the vitreous to provide sufficient pressure to force the layers of the retina together thereby squeezing the underlying hemorrhage out though a sclerostomy. Such agents are preferably used to force the layers of a torn retina together to prevent vitreal fluid seepage, and combined with coagulation procedures, allow healing of the retinal separation.

[0029] The optimal method for resolution of subretinal hemorrhage remains controversial. Thompson JT, and Sjaarda RN, Trans Am Ophthalmol Soc, 2005; 103:98-107. Non-limiting examples include: subretinal neovascular membrane and hemorrhage removal with forceps, Scheider A, et al., Graefe's Arch Clin Exp Ophthalmol, 1999; 237:10-15; injection of gas without tPA, Daneshvar H, et al., Can J Ophthalmol, 1999; 34:385-388, Ohji M, et al., Arch Ophthalmol, 1998; 116:1326-1332; injection of intravitreal tPA alone, Chaudhry NA, et al., Ophthalmic Surg Lasers, 1999; 30:176-180; injection of intravitreal tPA with gas, Handwerger BA, et al., Arch Ophthalmol, 2001; 119:28-32; injection of subretinal tPA with displacement by perfluorocarbon liquid, Kamei M, et al., Am J Ophthalmol, 1996; 121:267-275; injection of subretinal tPA followed by hemorrhage evacuation, Lewis H., Am J Ophthalmol, 1994; 118:559-568; vitrectomy with intravitreal injection of tPA with an intraocular gas bubble to help displace the hemorrhage inferiorly, Tsai SC, et al., Kaohsiung J Med Sci, 2003; 19:608-616; and vitrectomy with injection of subretinal tPA combined with a gas bubble. Haupert CL, et al., Am J Ophthalmol, 2001; 131:208-215.

[0030] Modest results have been achieved from subretinal injection of tPA combined with injection of perfluorocarbon liquid during vitrectomy by resolving the clot for more complete removal of the underlying material. Somewhat greater success has been achieved by the use of pneumatic displacement techniques employing gas with or without co-administration of a fibrinolytic. Hassan AS, et al., Ophthalmology, 1999; 106:1900-06; Hesse L, et al., Graefe's Arch Clin Exp Ophthalmol, 1999; 237:273-77; Ohji M, et al., Arch Ophthalmol, 1998; 116:1326-32; Handwerger BA, et al., Arch Ophthalmol, 2001; 119:28-32.

[0031] Surgical methods for drainage and removal of underlying hemorrhagic material are preferably initiated by intravitreal injection of HA via the pars plana. Illustratively, a 30-gauge needle is inserted through the pars plana into the intravitreal space into which a desired amount of HA is injected to increase the intraocular pressure and begin to force the retinal surface against the eye wall. It is appreciated that other needle dimensions are similarly operative illustratively including a 27-gauge needle. Further, syringe types operative in the instant invention optionally include manual, automatic, motor driven, and multiple material mixing injection systems. The location of the initial intravitreal injection is optionally at any radial location in the pars plana. [0032] Whether draining blood, intravitreal fluid or combinations thereof, one or more sclerostomies are preferably formed with the radial location of each incision determined by the surgeon based on the location of the underlying retinal detachment and desired removal route of clotted choroidal heme and serous fluid. The combination of increased intraocular pressure and a sclerotic opening forces the underlying hemorrhagic material out from behind the retinal separation. Optionally, the hemorrhagic material is coaxed out by physical manipulation of the area with a muscle hook. Other removal methods are illustratively physical removal with a solid apparatus, rinsing with a liquid medium, or application of a fibrinolytic such as tPA. Numerous other methods in the art are similarly operative for removal of hemorrhagic or coagulated material to allow for complete flattening or reattaching of the retina. [0033] Intraocular pressure is optionally measured by the use of tonometry. Meyer MW, et al., Klin Monatsbl Augenheilkd, 2006; 223:899-903; Abrhams LS, et al., Invest Ophthalmol Vis Sci, 1996; 37:940-44. This allows the surgeon to determine the volume of any additional viscoelastic to be injected so as not to exceed safe pressure levels. [0034] An intraoperative examination is optionally performed to determine if the initial injection of viscoelastic material was sufficient. Optionally, sequential injections of the same viscoelastic or an alternative viscoelastic at any desired volume are performed with an examination between each to identify successful flattening of the retina. Preferably, the number of intravitreal injections are kept to a minimum and controlled in volume and injection rate so as not to increase intraocular pressure beyond safe limits. A preferred endpoint is flattening of 360 degrees of the retinal surface with no folds. A subsequent post-surgical injection of viscoelastic is optionally used to ensure adequate vitreous pressure and retinal attachment. [0035] Standard ocular surgical techniques are performed illustratively including eye stabilization by lidocaine/marcaine retrobulbar and lid blocks. It is appreciated that other anesthetic techniques and agents are similarly operative illustratively including peribulbar blocks or general anesthetic. Optionally, a catheterization system is used to increase patient comfort during and following the surgical procedure. Jonas JB, et al., Can J Anesth, 2002; 49:487-489. [0036] Due to structural and compositional similarities between the eyes of higher vertebrates, it is appreciated in the art that the instant invention is similarly operative in numerous species. Surgical procedures using viscoelastics performed in many species are illustratively management of severe hypotony in humans (Tosi GM, et al., Am J Ophthalmol, 2005; 140:952-54), pars plana vitrectomy in horses (Fruehauf B, et al., Veterinary Ophthalmology, 1998; 1:137-51), vitrectomy in rabbits (Harooni M, et al., Arch Ophthalmol, 1998; 116:1218-21; Knepper PA, et al., Invest Ophthalmol Vis Sci, 1984; 25:286-93), vitrectomy in monkeys (Swann DA, and Constable IJ, Invest Ophthalmol, 1972; 11:164-68; Denlinger JL et al., Exp Eye Res, 1980; 31:101-17), and identification of retinal detachment and other blunt trauma injuries in dogs, cats and horses (Rampazzo A, et al., Veterinary Ophthalmology, 2006: 9:149-55). Further, the role of HA by the injection of hyaluronidase in cattle and rabbit eyes has also been identified. Barany EH, Acta Soc Med Upsal, 1953; 59:260; Barany EH and Scotchbrook S, Acta Phys Scand, 1954; 30:240.

[0037] The present invention is further detailed with respect to the following non-limiting examples. The examples presented below are intended to illustrate particular embodiments of the invention and are not intended to limit the scope of the specification, including the claims.

EXAMPLES Example 1

[0038] A patient presented with profound progressive loss of vision in the left eye with a large bullous rhegmatogenous retinal detachment involving the entire inferior retina, the inferior degrees of the left fundus, and sparing only the 10 to 2 o'clock superior sector. Under informed consent, the left eye was prepped using standard techniques for surgical repair. [0039] The left eye was anesthetized by the use of lidocaine/marcaine retrobular and lid blocks, and the infer rectus was exposed by a 180 degree inferior peritomy. 0.55 ml of sodium hyaluronate was injected into the vitreous via the pars plana at 12 o'clock using a 30-gauge needle. Sclerostomies (3 mm) were formed in the mid-sector of each of the inferior quadrants. Each incision yielded moderate quantities of dark clotted choroidal heme and serous fluid when the posterior globe was agitated with a muscle hook. Intraoperative indirect exam thereafter showed 50% shallowing of the bullous retinal detachment. To further reduce the bullous retinal detachment, a second injection of 0.55 ml sodium hyaluronate was placed intravitreally via the same superior site. Indirect exam confirmed the essential flattening of the inferior retina with shallow radial folds, but now with bullous elevation of the previously attached superior retina. A third 3 mm sclerostomy was formed lateral to the superior rectus insertion, immediately yielding copious subretinal fluid. A final injection of 0.55 ml sodium hyaluronate was placed via pars plana at 6 o'clock elevating intraocular pressure to approximately 45 mmHg, and subsequent indirect exam demonstrated apparent flattening of the retina for 360 degrees with no folds. [0040] The patient was postoperatively treated with oral acetazolamide and presented with 360-degree light projection, flat retina, and intraocular pressure of 12 mmHg. A further intravitreal injection of 0.25 ml sodium hyaluronate was administered two days later. Six days later the retina remained fully attached and visual acuity improved to 12/150 and 360 degree finger confrontation extending beyond 60 degrees in all four quadrants and possessed an intraocular pressure of 14 mmHg. Example 2

[0041] Equine eyes presenting with retinal tear or rhegmatogenous retinal detachments resulting from physical injury, macular degeneration, angiogenic, or other disease will be examined to identify the location and extent of the retinal damage. Eyes will be anesthetized and injected with 0.5 ml of sodium hyaluranate followed by two 3 mm sclerostomies placed at the quadrants on either side of the retinal detachment. After drainage of the underlying hemorrhagic and serous material the region will be probed with a muscle hook to ensure complete removal. An intraocular exam will be performed to identify the condition of the retinal detachment. If additional flattening is required, a second injection of 0.5 ml sodium hyaluronate will be injected with monitoring of intraocular pressure. The procedure will be repeated until the entire 360 degree retinal surface is flat and presents with no folds. The eye will be dressed and monitored for several days.

[0042] Any patents or publications mentioned in this specification are indicative of the levels of those skilled in the art to which the invention pertains. These patents and publications are herein incorporated by reference to the same extent as if each individual publication was specifically and individually indicated to be completely incorporated by reference. [0043] One skilled in the art will readily appreciate that the present invention is well adapted to carry out the objects and obtain the ends and advantages mentioned, as well as those inherent therein. The present examples along with the methods, procedures, treatments, molecules and specific compounds described herein are presently representative of preferred embodiments, are exemplary, and are not intended as limitations on the scope of the invention. It will be apparent that other embodiments exist and are encompassed within the spirit of the invention as defined by the scope of the claims.

Claims

1. A method for the repair of retinal detachment comprising: preparing the eye for surgery, injecting a single viscoelastic into the vitreous of the eye, making one or more incisions in the sclera, removing material from the subretinal area, and reattaching the retina.

2. The method of claim 1 wherein said viscoelastic comprises at least one of: a) sodium hyaluronate; b) hyaluronic acid; c) a salt of hyaluronic acid; d) a polymer variant of hyaluronic acid; e) a salt of d); f) a mixture of at least two polymer variants of hyaluronic acid; g) a mixture of at least two salts of polymer variants of hyaluronic acid; h) a mixture of at least two of a), b), c), d), e), f), and g); i) chondroitin sulfate; j) methylcellulose; k) silicon oil; or

1) perfluorocarbon.

3. The method of claim 2 wherein said viscoelastic comprises at least one of: sodium hyaluronate, hyaluronic acid, chondroitin sulfate, methylcellulose, silicon oil, or perfluorocarbon.

4. The method of claim 1 wherein said viscoelastic consists of one of: a) sodium hyaluronate; b) hyaluronic acid; c) a salt of hyaluronic acid; d) a polymer variant of hyaluronic acid; e) a salt of d); f) a mixture of at least two polymer variants of hyaluronic acid; g) a mixture of at least two salts of polymer variants of hyaluronic acid; h) a mixture of at least two of a), b), c), d), e), f), and g); i) chondroitin sulfate; j) methylcellulose; k) silicon oil; or 1) perfluorocarbon.

5. The method of claim 2 wherein said viscoelastic consists of one of: sodium hyaluronate, hyaluronic acid, chondroitin sulfate, methylcellulose, silicon oil, or perfluorocarbon.

6. The method of any one of claims 2, 3, 4, or 5, wherein said viscoelastic is in a pharmaceutically acceptable formulation.

7. A method of repair of bullous rhegmatogenous retinal detachment comprising dnjecting sodium hyaluronate via the pars plana into the vitreous, forming one or more sclerostomies, manipulating the sclera to remove material from the subretinal area, elevating the intraocular pressure in the vitreous to between 25 and 50 mm Hg, and reattaching the retina.

8. The method of claim 7 further comprising the step of rinsing the subretinal area with a solution containing tissue plasminogen activator.

9. The method of claim 7 further comprising reattaching the retina by the use of laser retinopexy, cryopexy, or diathermy.

10. A method as substantially described or illustrated herein.