Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
  • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
  • A61P27/06—Antiglaucoma agents or miotics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

• This invention relates to the use of angiostatic steroids administered via subconjunctival or subtenon's injections as an adjunct to glaucoma filtration surgery.
• Glaucomas arc a group of debilitating eye diseases that arc the leading cause of irreversible blindness in the United States in blacks and Hispanics, the second leading cause of blindness in whites in the United States, and a leading cause of blindness in all countries, including both developed and less developed nations.
• the disease is estimated to affect between 0.4% and 3.3% of all adults over 40 years old (Leske, M. C. et al. (1983); Bengtsson, B. (1989); Strong, N. P. (1992)).
• the prevalence of the disease rises with age to over 6% of those 75 years or older (Strong, N. P., (1992)).
• IOP intraocular pressure
• the etiology of glaucoma is still the subject of much research in the U.S. and other countries.
• the causes of the disease are still not entirely clear, it is known that the trabecular meshwork of the eye plays a key role in this disease, particularly with respect to the maintenance of fluid dynamics within the eye. Specifically, if the trabecular meshwork does not function as well as it should, this malfunction leads to a relative obstruction of the normal ability of aqueous humor to leave the eye and an elevation of IOP, resulting in progressive visual loss, visual disability and blindness, if not treated appropriately and in a timely fashion.
• Elevations of intraocular pressure may also occur as a result of the use of corticosteroids to treat inflammatory diseases.
• Corticosteroids particularly glucocorticoids, are currently used to treat a variety of inflammatory diseases.
• glucocorticoids have been used by the medical community to treat certain disorders of the back of the eye, in particular: Kenalog® (triamcinolone acctonidc), Cclcstonc Soluspan® (betamethasone sodium phosphate), Dcpo-Mcdrol® (methylprednisolone acetate), Decadron® (dexamethasone sodium phosphate), Decadron L.
• A.® (dexamethasone acetate), and Aristocort® (triamcinolone diacetate).
• Disorders that have been treated in this way include macular edema following vein occlusion and diabetic retinopathy.
• Triamcinolone has also been administered following cataract surgery, and administered to eyes with macular edema associated with other vitreo- retinopathies.
• glucocorticoids for the treatment of, for example, retinal edema and age-related macular degeneration (AMD).
• AMD age-related macular degeneration
• Bausch & Lomb and Control Delivery Systems have recently obtained FDA approval for fluocinolone acetonide delivered via an intravitreal implant for the treatment of macular edema.
• Oculex Pharmaceuticals is studying a dexamethasone implant for persistent macular edema.
• ophthalmologists are experimenting with intravitreal injection of triamcinolone acetonide for the treatment of recalcitrant cystic diabetic macular edema and for exudative AMD.
• Glucocorticoids can increase the expression of myocilin (MYOC) in the trabecular meshwork, thus increasing myocilin protein secretions.
• MYOC myocilin
• GLClA glaucoma linkage site with mutations found in glaucoma patients. It is expressed in a variety of tissu.es, including the trabecular meshwork. It is believed that the increase in the expression of MYOC resulting from administration of glucocorticoids causes congestion of the trabecular meshwork, which in turn causes an elevation of JOP.
• IOP elevation can occur as quickly as 4 days and reach IOPs approaching or exceeding 60 mm Hg (Singh et al. 2004). Usually, the IOP elevation begins 2 to 3 weeks after injection of the steroid (Epstein et al. 1997) and can last 6 to 8 months (Jonas 2003; Jonas 2004).
• Topical application of IOP- lowering medications has provided some relief from the resulting increase in IOP, but in many cases, docs not sufficiently lower the IOP to avoid damage to ocular tissues.
• many patients are prescribed multiple IOP-lowering medications, all of which must be self-administered via topical application, to address their elevated IOP.
• Treatment regimens currently available for patients exhibiting elevated TOP typically include the topical application, from once daily to multiple times per day, of one or multiple eyedrops or pills containing an IOP-lowering compound. Also, pills that decrease the amount of aqueous humor created can be given between two and four times daily. It is estimated that approximately 40% (Ocular Hypertensive Treatment Study; "OHTS”) of those with early glaucoma and approximately 75% (Collaborative Initial Glaucoma Treatment Study; "CIGTS”) of those with more advanced glaucoma require more than one glaucoma medication to adequately lower the IOP. Both compliance and adjunctive therapy are important problems in glaucoma therapy.
• IOP intraocular pressure
• eye disorders i.e., glaucoma
• eye disorders i.e., glaucoma
• the low compliance rate for patients with eye disorders may, in part,, be related to variations in treatment regimen, including the number of prescribed daily doses, the number of medications prescribed, the route of administration, methods of compliance assessment and duration of the compliance study period.
• Some literature has estimated compliance to eye drop regimens to range from 40% to 78% (Gurwitz et al. 1998; Spooner et al. 2002; Lee et al. 2000; Patel and Spaeth 1995; Claxton et al. 2001). Whatever the cause, non- compliance leads to inadequate control of intraocular pressure and increased loss of visual field.
• IOP-lowering medications currently available are unable to adequately control elevations of IOP in some patients.
• surgical intervention with either conventional filtration surgery or shunts may be required.
• Such surgery carries with it inherent risks that are substantial, especially in the group of subjects who may have multiple additional risks of failure and complications for filtration surgery.
• Filtration surgery including but not limited to both trabeculectomy and insertion of a seton or valve, is indicated both as a primary therapy and as a last resort for patients with glaucoma who require medical therapy and the prescribed medication regimen is either not tolerated or insufficient to adequately lower the 1OP.
• surgery is the preferred initial intervention.
• Both the Preferred Practice Pattern and the Advanced Glaucoma intervention study suggest that surgery is both safe and effective for glaucoma therapy.
• the Collaborative Initial Glaucoma Intervention Study and the American Academy of Ophthalmology's Preferred Practice Pattern have suggested that for those with initial glaucoma, patients should be given the option between medical, laser and filtration surgery.
• Filtration surgery is based on the creation of a reservoir, called a bleb.
• An opening is created in the wall of the eye that would allow for aqueous humor to pass between the anterior chamber of the eye and the subconjunctival space. This opening, or bleb, must not scar closed, or the fluid made within the drainage system would not function properly. Aqueous humor passes through the bleb into the tear film.
• the invention encompasses methods for treating glaucoma by administering an angiostatic agent, such as an angiostatic cortisene, in the subconjunctival space and the sub tenon's space during or following glaucoma filtration surgery.
• angiostatic agent such as an angiostatic cortisene
• the invention provides a method for preventing scarring to the scleral flap and allowing the ostomy created surgically between the anterior chamber and the subTenon ⁇ subconjunctival space to remain open following fistualization surgery, thereby lowering intraocular pressure (IOP) in a patient having increased 1OP due to glaucoma.
• the method of the invention includes administering to a patient in need thereof who is undergoing bleb filtration surgery, a composition comprising a therapeutically effective amount of an angiostatic agent.
• the angiostatic agent will be administered by subTenon / subconjunctival administration to the anterior segment of the eye.
• Other preferred methods of administering the angiostatic agent include, anterior depot (injection within the site of bleb surgery), irrigating solution, or insertion of an intraocular implant.
• angiostatic agent that is capable of preventing neovascularization and scar tissue at the site of bleb surgery
• the preferred angiostatic agent for use in the methods of the present invention is 4, 9(ll)-prcgnadicn-17oc,21-diol- 3,20-dione-21 -acetate, also known as anecortave acetate, or its corresponding alcohol, 4, 9(ll)-pregnadien-17 ⁇ ,21-diol-3.20-dione, also known as anecortave desacetate.
• the angiostatic agent will be present in the compositions administered according to the methods of the present invention at a concentration between 0.005 and 5.0 weight percent.
• the amount of the angiostatic agent administered by subTenon, subconjunctival, or juxtascleral administration will generally be from about 3 mg to about 30 mg. More preferably, the amount of angiostatic agent administered will be from about 12 mg to about 27 mg. Most preferably, the amount of angiostatic agent administered will be from about 21 mg to about 27 mg.
• FIG. 1 illustrates IOP lowering effects over time of administration of anecortave acetate at the site of filtration bleb surgery in five patients.
• the present invention is based, in part, on a discovery that administration of an angiostatic agent in the subconjunctival space and/or the sub tenon's space during or following glaucoma filtration surgery is more effective at maintaining the IOP-lowering effects of such surgery than methods currently in use.
• Anecortave acetate is an angiostatic agent developed for the inhibition of ocular neovascularization.
• Anecortave acetate is the result of specific chemical modification to the basic Cortisol structure. These modifications have resulted in the creation of an angiostatic "cortisene," which inhibits blood vessel growth, but does not produce glucocorticoid receptor-mediated steroidal side effects.
• Preclinical data show that anecortave acetate exhibits no measurable corticosteroid activity (Clark AF. AL-3789: a novel ophthalmic angiostatic steroid. Exp. Opin. Invest.
• Anecortave acetate is a unique angiostatic agent that upregulates plasminogen activator inhibitor 1 and inhibits both urokinase-like plasminogen activator and matrix metalloproteinase-3, two enzymes necessary for vascular endothelial cell migration during blood vessel growth (DeFaller JM and Clark AF.
• a new pharmacological treatment for angiogenesis In Pterygium, Taylor, HR (ED.) The Hague: Kugler Publications, 2000; 159-181; Perm JS, Rajaratnam VS, Collier RJ and Clark AF. The effect of an angiostatic steroid on neovascularization in a rat model of retinopathy of prematurity. Invest.
• an angiostatic agent such as anecortave acetate
• angiostatic agent is administered to a patient undergoing bleb filtration surgery by subTenon administration to the anterior portion of the eye, near the limbus.
• Agents which inhibit angiogenesis are known by a variety of terms such as angiostatic, anxiolytic or angiotropic agents.
• angiostatic agent means compounds which can be used to inhibit angiogenesis, but that lack the glucocorticoid activity associated with steroids.
• the most preferred compound for use in the methods of the invention is 4,9(1 l)-pregnadien-17oc,21-diol-3,20-dione-21-acetate, also known as anecortave acetate.
• the angiostatic agent may be administered via an irrigating solution at the site of filtering bleb surgery, as an anterior juxtascleral depot, or intravitreally.
• the compositions for use in the methods of the invention are formulated in accordance with methods known in the art, depending on the particular route of administration required.
• the composition will have the formulation set forth in Table 1. Table 1
• anecortave acetate is preferably administered via subTenon, subconjunctival, or juxtascleral injections, near the limbus of the eye, at or within the site of bleb filtration surgery, in order to allow it to more efficiently function to lower the elevated IOP.
• the amount of the anecortave administered via this route of administration is from about 3 mg to about 30 mg.
• the amount of anecortave acetate administered is from about 12 mg to about 27 mg.
• the amount of anecortave acetate administered is from about 21 mg to about 27 mg.
• the most preferred dosage for administration is 24 mg of anecortave acetate.
• the preferred concentration of the angiostatic agent in the composition administered by subTenon or sub conjunctival administration is from 0.005 to 5 weight percent.
• Example 1 is included to demonstrate preferred embodiments of the invention. It should be appreciated by those of skill in the art that the techniques disclosed in the example which follows represent techniques discovered by. the inventor to function well in the practice of the invention, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention.
• Example 1 is included to demonstrate preferred embodiments of the invention. It should be appreciated by those of skill in the art that the techniques disclosed in the example which follows represent techniques discovered by. the inventor to function well in the practice of the invention, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention.
• Example 1 is included to demonstrate preferred embodiments of the invention. It should be appreciated by
• a single administration of approximately 24 mg of anecortave acetate was given via sub Tenon' s administration at the site of bleb filtration surgery, in the inferior or inferior temporal quadrant to eyes of 5 patients with primary open angle glaucoma.
• Five eyes (5 subjects) were either pseudophakic or had failed one prior trabeculectomy.
• 0.8cc of a 3% anecortave acetate suspension was injected into the bleb with a 30 gauge needle. Eyes were followed at one day, one week, one month, and monthly for six months, then quarterly thereafter.
• Mean baseline IOP was 25.4 +/- 3.7 mm Hg. By nine months the mean IOP was 15.8 +/- 10.1 mm Hg with 4 (80%) having an IOP ⁇ 17 mm Hg and > 30% decrease in IOP without any glaucoma medications (see FlG. 1). There was no significant dysasthesia or visual loss. One eye had a hyphema requiring additional surgery and eventually failed (the other eye of that patient had also failed surgery using mitomycin C).
• compositions and/or methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions and/or methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit and scope of the invention. More specifically, it will be apparent that certain agents which arc both chemically and structurally related may be substituted for the agents described herein to achieve similar results. AU such substitutions and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims.

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