Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K33/00—Medicinal preparations containing inorganic active ingredients
• • 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
• • 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
  • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
• • 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
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/50—Pyridazines; Hydrogenated pyridazines
  • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
• • 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
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
• • 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

Definitions

• the present invention relates generally to the field of ocular medicine. More particularly, it concerns methods for treating ocular disorders and for maintaining ocular health.
• the present invention relates more specifically to a method for improving visual function and optimizing the health of the optic nerve and retina by increasing blood flow therein through the application of an effective amount of a composition including an agent that increases cyclic-guanosine monophosphate (cyclic-GMP) levels, either directly, or by stimulating cyclic-GMP synthesis, or by inhibiting cyclic-GMP selective phosphodiesterase(s) .
• cyclic-GMP cyclic-guanosine monophosphate
• the vision process in general involves a complex pathway into the brain. To see, light must enter through the cornea and the lens; penetrate the back of the eye through the retina; pass the ganglion cells and bipolar cells; then pass down to the outer plexiform layers through the synaptic vesicle, the inner fiber, the nucleus, the outer fibers, the terminal bars, the cilium; and finally reach the photoreceptors, which can be considered to carry out the instant film processing of the visual light beam.
• the light beam After the light beam has been processed in the photoreceptor disks, it passes back through the cilium, the ellipsoid, myoid, Mueller cells, outer fiber, nucleus, inner fiber, synaptic vesicle, the outer plexiform layer, inner nuclear layer, the bipolar cells, the inner plexiform layer, finally reaching the ganglion cells where it is processed into an axon signal. After it reaches the ganglion cells, the signal is transported through the optic nerve fibers to the brain where it is assessed and compounded by the visual brain lobes to form the visual picture. It is believed that the uninterrupted signal carried by the retina, the optic nerve head, and the optic nerve fibers is the most crucial part of the process for creating the visual picture. Adequate blood flow nurtures the tissues along this path and, therefore, assures axonal flow.
• the human eye and indeed the eye structure of most mammals
• Retinal circulation accounts for only about 2% of total eye circulation, but this 2% is critical to the health of the eye's neural connection to the brain, i.e., the 1.2 million axons which make up the nerve trunk known as the optic nerve.
• the cell bodies containing the genetic material and metabolic machinery for this connection are all located in the inner layer of the retina, and derive virtually all of their blood supply (i. e. , including energy, oxygen/carbon dioxide, and metabolic by-product exchange) from the locally auto- regulated retinal circulation. Any significant compromise to the retinal circulation is typically accompanied by visual loss.
• the vast majority of the eye's inner circulation passes through the uveal system, a sponge-like, erectile tangle of vessels that lies behind the retina and its pigment epithelium.
• This vascular bed provides a rich supply of nutrients to the metabolically active photoreceptors of the outer retina, and the pigment epithelium which supports them.
• this seemingly excessive blood supply acts as a heat sink to absorb thermal energy from focused light which could otherwise damage neural tissues.
• the choroidal circulation the part of the uveal vascular bed lying directly behind the retina, has some local regulation characteristics, but is also supplied with autonomic nerves capable of producing major changes in circulatory volume in response to stimuli, not necessarily generated in the eye itself.
• Autoregulation in the retina is analogous to that found in the brain, so if intraocular pressure is reduced, circulation in the retina is not necessarily increased. This point is clearly illustrated as a coincidental feature of the examples of hyperventilation (to blow off carbon dioxide and thereby reduce circulation to all the intrinsic vessels of the eye) and treatment with latanoprost (increasing the flow of clear fluid out of the eye), which both produce significant reduction of intraocular pressure, but with which visual function may actually be simultaneously diminished.
• Circulation in the retina also is highly pH-dependent. Studies in which various gases are introduced via the respiratory system into the blood stream clearly demonstrate that as the CO level increases and pH decreases, circulation to the retina typically increases by upward of 40% from the baseline level observed during breathing of atmospheric air. Conversely, breathing pure oxygen produces a profound decrease in circulation in the retina. This latter response may be in part responsible for the disease process known as retrolental fibroplasia, or retinopathy of prematurity, which causes total or partial blindness in many premature infants.
• cAMP cyclic 3', 5'-adenosine monophosphate
• beta-adrenergic impulses in several tissues are mediated intracellularly by a second messenger, cAMP.
• cAMP is produced from ATP by a membrane bound enzyme, adenylate cyclase.
• cAMP is believed further to activate steps in a chain of processes leading to protein phosphorylation and final biologic activity.
• the cAMP step is a process of short duration because cAMP is rapidly and efficiently degraded intracellularly by cAMP phosphodiesterases, which are present in abundance.
• cAMP is produced when adenylate cyclase is activated through the activation of many receptors. This stimulation is mediated by G s and by inhibition of at least one other protein belonging to the G, class of G proteins. It is known that there are at least ten tissue-specific adenylate cyclase isozymes, each having a unique pattern of regulatory responses. Some of these isozymes are inhibited by G protein ⁇ subunits, others are stimulated by these subunits if concurrently stimulated by the ⁇ subunit of G s , others are stimulated by Ca 2+ or Ca 2+ - calmodulin complexes. Adrenergic drugs mediate the production of c AMP.
• diseases which may be amenable to treatment with agents capable of modulating ocular blood flow include, but are not limited to, optic nerve disease, retinal disease or choroidal disease. More specific disorders include, but are not limited to, macular edema or macular degeneration.
• Macular edema for example, is defined as swelling within the retina in the critically important central visual zone at the posterior pole of the eye. An accumulation of fluid tends to distract the retinal neural elements from one another and from their local blood supply, creating a dormancy of visual function in the area. Usually, the process is self-limiting, but occasional permanent visual disability results from macular edema. Often times, the swelling may take many months to clear.
• cystoid macular edema Two types of cystoid macular edema are: (a) those without vascular leakage: retinitis pigmentosa and other pigmentary retinal degenerative disorders, early stage macular hole, and choroidal neovascularization; and (b) those with vascular leakage: diabetic retinopathy: branch retinal vein occlusion; intermediate uveitis; and ideopathic retinal telangiectasis.
• Another even more common chronic condition is macular degeneration.
• hard accumulations of lipofuscin a metabolic waste product, tend to accumulate between the photoreceptors and the villi of the retinal pigment epithelium. These accumulations gradually enlarge, and in their early pathologic phase create discrete accumulations known as drusen.
• the lipofuscin is believed to accumulate as a result of the breaking off of the photoreceptor elements. Shedding of the cellular components of the photoreceptors is constantly occurring in a healthy retina. Good retinal pigment epithelial metabolism generally ensures a rapid clearance of such catabolic by-products of vision.
• the present invention provides a method for treating an optic nerve disease by increasing ocular blood flow, perfusion and/or circulation.
• Ocular blood flow is generally improved by applying a pharmacologically effective amount of an agent that enhances ocular vascular blood flow either directly to the eye or systemically.
• agent that enhances ocular vascular blood flow refers to cyclic-GMP analogs, agents that inhibit cyclic-GMP phosphodiesterase(s) (PDE), agents that increase the activity of guanylate cyclase, agents that increase levels of cyclic-GMP, or agents that increase levels of nitric oxide (NO) in the tissues of the eye.
• PDE cyclic-GMP phosphodiesterase(s)
• NO nitric oxide
• agents that either enhance the production or increase the availability or longevity of NO, thereby activating guanylate cyclase would increase levels of cyclic-GMP and cause an increase in ocular blood flow.
• the optic nerve disease to be treated includes but are not limited to normotensive excavatory optic neuropathy, ischemic optic neuropathy, toxic optic neuropathy, traumatic optic neuropathy, or idiopathic optic neuropathy.
• normotensive excavatory optic neuropathy include primary optic atrophy, ocular ischemic syndrome, shock-associated optic atrophy or chronic systemic hypotension.
• ischemic optic neuropathy include anterior ischemic optic neuropathy, posterior ischemic optic neuropathy, giant cell arteritis, or Foster-Kennedy syndrome.
• Examples of toxic optic neuropathy include drug induced optic neuropathy or nutritional optic neuropathy.
• Examples of traumatic optic neuropathy include inflammatory optic neuropathy or neuroretinitis.
• idiopathic optic neuropathy include optic nerve drusen or benign intracranial hypertension.
• multiple optical nerve diseases occurring in the same patient are treated using the compositions and methods of the invention.
• the invention provides methods for treating retinal disease by administering a composition comprising an agent that enhances ocular vascular blood flow to a patient suffering from a retinal disease or applying the composition directly to the affected eye.
• the retinal disease to be treated may be retinal neovascularization, ischemic hematologic/rheologic disorders or toxic maculopathy.
• Examples of retinal neovascularization include a diabetes related form of retinal neovascularization, hemoglobinopathy or inflammatory vascular narrowing.
• the diabetes related form of retinal neovascularization is may be, for example, diabetic macular edema, ischemia and neovascularization or non-proliferative diabetic retinopathy.
• hemoglobinopahy is sickle cell trait.
• inflammatory vascular narrowing include lupus, collagen vascular diseases, HIV retinopathy, CMV retinopathy or sarcoidosis.
• ischemic hemotologic/ rheologic disorder include central retinal vein occlusion or branch retinal vein occlusion.
• toxic maculopathy include drug related maculopathy or chloroquine retinopathy.
• multiple retinal diseases occurring in the same patient are treated using the compositions and methods of the invention.
• choroidal disease is treated by applying a therapeutically effective amount of a composition comprising at least a first agent that increases ocular blood flow to an affected eye.
• choroidal disease include, but are not limited to, an ischemic disorder of the posterior choroid, degenerative subretinal neovascularization, diabetic choroidal ischemia, inflammatory subretinal neovascularization, or non-age related choroidal ischemia.
• ischemic disorder of the posterior choroid include degenerative drusen of the macula (i.e. dry age related macular degeneration), macular retinal pigment epithelial atrophy, and retinal pigment epithelial detachment.
• degenerative subretinal neovascularization is wet age related macular degeneration.
• diabetic choroidal ischemia include diabetic choroidopathy.
• inflammatory subretinal neovascularization include presumed ocular histoplasmosis syndrome.
• nonage related choroidal ischemia include myopic degeneration or high myopia.
• multiple choroidal diseases occurring in the same patient are treated using the compositions and methods of the invention.
• compositions and methods described herein are useful for treating a patient suffering from an optical nerve disease and a retinal disease.
• the methods of the invention are further effective for the treatment of macular disorders such as macular edema, macular degeneration, drusen, macular disorders related to hypertension, angioma, papillitis, neuroretinitis or pigmentary retinal degenerative disorders, toxic maculopathy and maculopathy secondary to rheologic abnormalities.
• the methods of the invention are useful for treatment of macular edema with or without vascular leakage.
• macular edema without vascular leakage examples include retinitis pigmentosa, pigmentary retinal degenerative disorder, early stage macular hole, or choroidal neovascularization.
• macular edema with vascular leakage examples include diabetic retinopathy, branch retinal vein occlusion, intermediate uveitis or ideopathic retinal telangiectasis.
• the methods of the invention may also be used to inhibit or prevent the accumulation of lipofuscin in an eye.
• the agent to be included in the composition is a cyclic-GMP analog, a compound that inhibits cyclic-GMP PDE(s), a compound that activates guanylate cyclase, or a compound that increases levels of cyclic- GMP.
• Preferred cyclic-GMP analogs include 8-bromoguanosine-3,5-cyclic monophosphate.
• Preferred agents that inhibit cyclic-GMP PDE(s) include sildenafil citrate, dipyridamole, zaprinast, filaminast, denbufyllene, piclamilast, or zardaverine, carboline derivatives, pyridocarbazole derivatives, or quinozolinone compounds.
• the PDE inhibitor is selective for PDE type 5 (PDE5) or PDE type 6 (PDE6).
• Preferred agents that activate guanylate cyclase include sodium azide, sodium nitrite, hydroxylamine, hydrazines, nitroglycerine, nitroprusside, nitrosureas or nitrosamines.
• NO levels may also be increased by NO donors or NO synthase stimulators and such compounds are useful in the compositions for use in the methods of the invention.
• NO donors include sodium nitroprusside, nitroglycerine, SIN-1 , isosorbide mononitrate, isosorbide dinitrate, diethylenetriamine NO, glycerol trinitrite, pentaerytrityl tetranitrite, mannitol hexanitrite, inositol hexanitrite or propatyl nitrate.
• Preferred NO synthase stimulators include 2-aryl- ⁇ -thiophens.
• compositions include nitrosated and/or nitroxylated PDE inhibitors or polymeric material that releases NO. Combinations of two or more of the agents listed above are also contemplated in certain aspects of the present invention.
• Preferred methods of application include oral and parenteral (including ophthalmic, transdermal, pulmonary, nasal, buccal or sublingual). More specifically, the compositions may be administered by way of a solution, gel, semisolid, suspension, metered dose device, transdermal patch or film.
• kits for treatment of ocular disorders including a sealed container housing a composition comprising an agent that increases ocular vascular blood flow and instructions for administering the composition to a patient suffering from an ocular disorder such that the patient's ocular blood flow is increased.
• the compositions included in the kit of the invention include agents as described above.
• the present invention also provides an effective treatment for maintaining the health of the eye and effectively treating various other ocular conditions by improving ocular blood flow in the retina and choroid of the eye and in and about the optical nerve.
• the present invention contemplates administration of the compositions described herein to subjects with normal vision for the purpose of increasing visual function including but not limited to visual acuity, contrast sensitivity and perimetric light sensitivity.
• FIG. 1A is a graph of retinal blood flow as measured by Heidelberg Retinal
• FIG. IB is a graph of retinal blood velocity as measured by Heidelberg
• FIG. 2A is a graph of 4.26 SF cpd contrast sensitivity (visual function) for two test subjects over time.
• FIG. 2B is a graph of 8.53 SF cpd contrast sensitivity (central macular visual function) for two test subjects over time.
• FIG. 3A provides Humphrey Frequency Doubling Technology (FDT) visual field reports for a first test subject baseline (left) and post-application (right) conditions.
• FDT Humphrey Frequency Doubling Technology
• FIG. 3B provides Humphrey Frequency Doubling Technology (FDT) visual field reports for a second test subject baseline (left) and post-application (right) conditions.
• FDT Humphrey Frequency Doubling Technology
• FIG. 4A is a graph of pulsatile ocular blood flow (OBF) for two test subjects over time.
• FIG. 4B is a graph of intraocular pressure measured concomitantly with
• FIG. 5A is a graph of blue field density (perimacular retinal capillary circulatory volume) for two test subjects over time.
• FIG. 5B is a graph of blue field mean velocity (perimacular retinal capillary circulatory speed) for two test subjects over time.
• FIG. 6A Humphrey visual field tests, showing extent of the perpetual progression of field loss despite maintaining intraocular pressures (IOP) from 6-10 mmHg without medication.
• Pericentral thresholds clockwise from superionasal were 26, 26, 14, and 25 dB.
• FIG. 6B Clockwise progression of pericentral threshold values was 28, 29,
• FIG. 7A Humphrey 10-2 visual field test, prior to and one hour after ingestion of 50 mg oral sildenafil.
• FIG. 7B Humphrey visual field test showing visual thresholds of 26, 28, and 27 decibels across the central six degrees above the horizontal meridian, and 16 of the 17 superotemporal loci now had positive thresholds, 15 of which were in double- digits.
• choroidal blood flow may be accompanied by minimal visual function change.
• retinal circulation is very tightly regulated within the brain. The majority of the eye's inner circulation passes through the uveal system, lying behind the retina and its pigment epithelium. Choroidal circulation is part of the vascular bed lying directly behind the retina and contains autonomic nerves capable of producing major changes in circulatory volume in response to stimuli, which may be generated within the eye or outside of the eye.
• the vision process is quite complex, it is believed that the signal carried by the retina, the optic nerve head, and the optic nerve fibers is the most crucial part of the process. Adequate blood flow nurtures the tissue along this path and assures transport of the signal. Many ocular disorders are known to involve some kind of blockage of or hindrance to optic blood flow.
• the human choroid which supports the metabolic function of the outer retina, is an erectile tissue, analogous in certain respects to the corpus cavernosum.
• the fenestrated choroidal vasculature is highly responsive to both local and neurogenic stimuli, and the uveal system of which it is part may hold up to 98% of the intraocular blood volume.
• Choroidal blood flow has recently been reported to be decreased in macular degeneration, the leading cause of acquired blindness in North America.
• the inventor reasoned that agents capable of modulating ocular blood flow would be of therapeutic value in the treatment of a range of choroidal, retinal, and axonal disorders, provided circulatory augmentation can be achieved without debilitating metabolic compromise or vascular leakage.
• the methods of the invention include administering agents that increase ocular blood flow to a patient suffering from such an ocular disease state.
• Table 1 sets forth a number of the disease states that would benefit from treatment using the methods of the present invention.
• optic disease states for which increased ocular blood flow is beneficial. Those are optic nerve disease, retina disease and choroidal disease. Within those general categories are a number of additional categories with more specific examples provided for illustration. Of course, those skilled in the art would understand that other disease states in which ocular blood flow is a factor would benefit from treatment using the methods of the invention. The benefits of the present invention are described in more detail below using a specific type of choroidal disease, age related macular degeneration, for illustration purposes only. It will be understood that the present methods and compositions are useful for the treatment of any optic disease state.
• Age-related macular degeneration is the leading cause of visual loss among Americans over 60 years of age. As the macula degenerates, central reading vision deteriorates while peripheral vision is rarely affected. There are two forms of
• ARMD dry or atrophic ARMD
• wet or exudative ARMD is associated with abnormal blood vessel growth (subretinal neovascularization) and accounts for a high proportion of the most severe visual destruction encountered among ARMD patients.
• Wet ARMD only accounts for 10% of ARMD cases. Because of its dramatic pathologic course, wet ARMD has received much attention, and numerous treatment modalities have been devised to abate this form of the disease, most of which are directed toward destroying the invading, leaky blood vessels by laser or other means. Dry ARMD is far more prevalent, progresses more slowly, and accounts for 90% of ARMD cases.
• ARMD accumulation of lipofuscin, an aggregate of breakdown products from the outer retina, occurs in the interspace between the retinal photoreceptors and the villiform pigment epithelial cells with which they interdigitate.
• the retinal pigment epithelium (RPE) is a vital metabolic factory, which reprocesses photopigment and carries out many critical support and transport processes, maintaining retinal function.
• the outermost layer of the anatomic sandwich supporting retinal function is the choroid, a highly vascular tissue which supplies nutrients to and which clears catabolites from this highly active tissue complex. Lipofuscin builds up in the interface between the RPE and choroid in diseased eyes.
• the present invention is grounded on the discovery that increasing ocular blood flow, particularly in the retina of the eye is a safe and effective way to maintain the health of the eye and to treat various ocular disorders that have in their etiology inadequate vascular blood flow, such as macular edema and macular degeneration. While the precise theory is not completely understood, improved (i.e., increased) blood flow in and to the retina and choroid of the eye can greatly improve retinal and optic nerve health which, in turn, effectively combats macular edema, macular degeneration, and other ocular disorders.
• guanylate cyclase catalyzes the conversion of guanidine triphosphate (GTP) to cyclic-GMP.
• GTP guanidine triphosphate
• guanylate cyclase When activated, cyclic-GMP levels increase.
• Murad et al. used nitrogen containing compounds, such as sodium azide, sodium nitrite and hydroxylamine, to activate guanylate cyclase and discovered that these compounds are converted to an active intermediate, nitric oxide (NO), that is directly involved in the activation of guanylate cyclase and the subsequent conversion of GTP to cyclic-GMP.
• NO nitric oxide
• agents that activate guanylate cyclase through the formation of the intermediate NO are particularly useful in the methods of the present invention.
• the compositions of the invention may include more than one agent that activates guanylate cyclase.
• cyclic-AMP is also known to increase vascular blood flow, however, it operates through a significantly different pathway than that of cyclic-GMP.
• certain adrenergic drugs mediate the production of cyclic-AMP, thereby decreasing intraocular pressure and increasing vascular blood flow. Therefore, this mechanism of action is significantly different from the pathway followed by cyclic-GMP in the stimulation of ocular vascular blood flow as described herein.
• agents that activate guanylate cyclase such as sodium azide, sodium nitrite, or hydroxylamine
• other agents that activate guanylate cyclase increase NO levels and/or increase cyclic-GMP levels also would increase ocular blood flow and improve vision.
• Other guanylate cyclase activators include hydrazines, nitroglycerine, nitroprusside, nitrosureas and nitrosamines.
• Agents that increase NO levels include those agents that are nitric oxide donors, stimulate nitric oxide synthase or increase availability or longevity of nitric oxide.
• Agents that stimulate nitric oxide synthase include 2-aryl- ⁇ -thiophens, described for example, in U.S. Patent No. 5,811,437. incorporated herein by reference or other compounds described, for example, in U.S. Patent No. 5,478,946, incorporated herein by reference.
• Agents that are nitric oxide donors include sodium nitroprusside, nitroglycerine, SIN-1, isosorbide mononitrate, isosorbide dinitrate, diethylenetriamine/NO, glycerol trinitrite, petnaerytrityl tetranitrite, mannitol hexanitrite, inositol hexanitrite, or propatyl nitrate.
• Other compounds useful in the compositions of the invention include nitrosated and/or nitrosylated PDE inhibitors (as described, for example, in U.S. Patent Nos.
• compositions of the invention may include more than one agent that increases NO levels.
• compositions of the invention may include more than one inhibitor of cyclic-GMP PDE(s).
• Zaprinast and dipyridamole are both known to be inhibitors of the type 5 PDE family and would, therefore, be expected to act to increase ocular blood flow in the methods of the present invention.
• Other PDE inhibitors useful in the methods of the invention include filaminast, denbufyllene, piclimalist, pentoxyfilline, carboline derivatives (as described, for example, in U.S. Patent No. 6,043,252, incorporated herein by reference), pyridocarbazole derivatives (as described, for example, in U.S. Patent No. 6,018,046, incorporated herein by reference) or quinozolinone compounds (as described, for example, in U.S. Patent No. 6,087,368, incorporated herein by reference).
• compositions of the invention may include a combination of any of the above described agents.
• sildenafil preferably the citrate salt.
• Sildenafil is known to cause smooth muscle relaxation and an increase in blood flow, and is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific PDE type 5 (PDE5).
• Sildenafil citrate is designated chemically as l-[3-(6.7-dihydro-l-methyl-7-oxo-3-propyl-lH-pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyp henyl] sulfonyl-4-methylpiperazine citrate and has the following structural formula:
• Sildenafil citrate is a white to off-white crystalline powder with a solubility of 3.5 mg/mL in water and a molecular weight of 666.7. Sildenafil citrate has most recently been utilized as the basis for an oral therapy for erectile dysfunction and has been marketed by Pfizer Labs under the trademark Viagra ® . Publications relating to benign visual side-effects (e.g., blue-shift in vision, light-sensitivity, and blurring noted to occur in some patients) of sildenafil prompted the FDA to insist on product insert warnings.
• benign visual side-effects e.g., blue-shift in vision, light-sensitivity, and blurring noted to occur in some patients
• sildenafil might be therapeutically beneficial in an appropriate setting. Elevation of cyclic-GMP levels, a potent vasodilator, is brought about by the effect of sildenafil on PDE activity. Appreciating this mechanism (i.e., the local effects of the PDE inhibitor on intracellular cyclic-GMP), and possible centrally-mediated neurogenic effects, the inventor reasoned that sildenafil could conceivably mediate significant increases in choroidal blood flow. Therefore, changes in vision and ocular blood flow were evaluated among a dozen clinician volunteers before and after taking a single 50 mg oral dose of sildenafil.
• Pulsatile ocular blood flow occurs as a result of cardiac-synchronous filling of the choroidal circulation, in which the majority of the ocular blood volume is found.
• the increase in pulsatile choroidal blood flow after sildenafil administration was probably due to dilatation of the choroidal vessels, because there were no changes in intraocular pressure or systemic pulse amplitude, other major determinants of choroidal blood flow.
• the mechanism associated with sildenafil citrate's use as a therapy for erectile dysfunction may explain its efficacious use in the methods of the present invention.
• the physiologic mechanism of erection of the penis involves release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. NO then activates the enzyme guanylate cyclase, which results in increased levels of cyclic guanosine monophosphate (cGMP), producing smooth muscle relaxation in the corpus cavernosum and allowing inflow of blood.
• NO nitric oxide
• cGMP cyclic guanosine monophosphate
• Sildenafil has no direct relaxant effect on isolated human corpus cavernosum, but enhances the effect of nitric oxide (NO) by inhibiting PDE type 5 (PDE5), which is responsible for degradation of cGMP in the corpus cavernosum.
• PDE5 PDE type 5
• sildenafil causes increased levels of cGMP in the corpus cavernosum, resulting in smooth muscle relaxation and inflow of blood to the corpus cavernosum.
• Agents for use in the methods of the present invention may be delivered orally, parenterally, or may be formulated for direct topical application to the eye.
• applying refers to any of the methods of delivery, including orally, parenterally, topically or otherwise.
• These delivery systems are effective to administer the compositions for use in the methods of the invention to the eye for the purpose of increasing optical nerve and retinal blood flow velocity.
• the compositions can be administered by way of a solution, gel, semisolid, suspension, metered dose device, transdermal patch or film.
• Other means of delivery are also contemplated.
• the routes of administration of sildenafil citrate for example, are typically oral and parenteral (including ophthalmic, transdermal, pulmonary, nasal, buccal, sublingual).
• compositions for use in the methods of the present invention will typically, but not necessarily, comprise a solution, gel, semisolid, suspension, metered dose device, transdermal patch or film including, for example, an agent that enhances ocular blood flow, a buffer system (e.g., hydrochloric acid, sodium hydroxide, boric acid, sodium borate, acetic acid, sodium acetate, sodium biphosphate, monobasic sodium phosphate, dibasic sodium phosphate, sodium carbonate, sodium acid phosphate, disodium phosphate, sodium thiosulfate; 0.1 - 5 % of each, or the like), a preservative system (e.g., benzalkonium chloride 0.01 - 5%, benzethonium chloride 0.01 - 5%, chlorobutanol 0.01 - 5%, methylparaben 0.01 - 5%, propylparaben 0.01 phenylmercuric acetate 0.01 - 5%, phenylmer
• boric acid 0.2 - 0.9%, or the like 0.9%, boric acid 0.2 - 0.9%, or the like
• a vehicle e.g., water, white petrolatum; 5 - 99.9% for each.
• compositions for use in the present invention may include all of the above listed elements, other useful compositions may include less than all of the above listed elements, which generally serve to increase stability, storability, storage life, etc.
• compositions including a compound that enhances ocular blood flow i.e., by increasing NO, increasing cyclic-GMP, and/or inhibiting cGMP PDE, with a buffer system and a vehicle may be useful.
• compositions including a compound that enhances ocular blood flow, with a viscosity- increasing system and an osmolality adjusting system may be useful.
• a preferred composition contains sildenafil citrate in an oral or ophthalmic preparation such as those described above.
• the sildenafil citrate will typically be present in amounts ranging from between about 5 mg to about 500 mg per dose. More preferably, the oral dose will contain from between about 10 mg to about 400 mg of sildenafil citrate, or between about 15 mg and about 300 mg of sildenafil citrate or between about 20 mg and about 250 mg of sildenafil citrate or between about 25 mg and about 200 mg of sildenafil citrate. Most preferably, the oral dose will contain about 50 to 100 mg sildenafil citrate.
• a range for example of between about 5 mg to about 500 mg, includes all integral amounts within the range, i.e., 6 mg, 7 mg, 8 mg, 9 mg etc.. 30 mg, 31 mg, 32 mg, 33 mg, etc., 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, etc., 55 mg, 56 mg, 57 mg, 58 mg, etc., 75 mg, 76 mg, 77 mg, 78 mg, etc. 101 mg, 102 mg, 103 mg, 104 mg, etc., 150 mg, 151 mg, 152 mg, 153 mg, etc.
• Preferred ophthalmic preparations of the present invention will generally include sildenafil citrate, for example, in concentrations of between about .001 % and about 20 % (weight per volume), including all amounts within the range. More preferably, sildenafil citrate will be present in the ophthalmic preparations in concentrations of between about .01 % and 5 % and most preferably, the ophthalmic preparations of the invention will contain about 1% sildenafil citrate.
• a convenient manner to deliver a metered dose is through the use of a device that is pressurized with a propellant system or is delivered by an aqueous pump spray.
• the propellant system may include 1,1,1,2-tetrafluoroethane (30 -99.9%) and/or 1,1,1,2,3,3,3-heptafluoropropane (30 - 99.9%) or other known propellants.
• ethanol is typically used as a cosolvent (0.5 - 5%), although other solvents may also be useful in conjunction with the methods of the invention.
• the preferred median droplet size distribution for the pulmonary pressurized metered dose inhaler is 2 - 5 microns and the preferred median droplet size distribution for the nasal pressurized metered dose inhaler is 10 - 20 microns.
• Exemplary processes for formulation include the following:
• a quantity of an agent that enhances ocular vascular blood flow such as sildenafil citrate (solubility of 3.5 mg/ml)
• the vehicle contains a cosolvent system to increase the solubility of the drug (agent that enhances ocular vascular blood flow) in the vehicle.
• the pH of the solution is adjusted and the solution is buffered.
• the solution is preserved and the tonicity is adjusted.
• the viscosity of the solution is adjusted by adding a viscosity-increasing agent.
• the final volume of the solution is adjusted using the remainder of the vehicle.
• the solution is packaged in an appropriate container/closure system to optimize stability of the drug substance and the integrity of the finished product.
• the gelling agent is dissolved into an aliquot of water.
• the drug, preservative, stabilizer, buffer and osmolality adjusting agent is dissolved. This blend is combined with the gel and stirred until homogeneous. The temperature may be elevated in order to enhance the mixing process. A high shear homogenizer is preferred to prepare the gel formulation.
• the drug- containing gel is packaged in an appropriate container/closure system to optimize stability of the drug substance and the integrity of the finished product.
• the vehicle is heated using low heat and the preservatives are added to the molten vehicle mixture.
• the drug is then incorporated with continuous mixing into the molten vehicle mixture and homogenized at 2500 - 5000 psi.
• the preparation is removed from the heat source and continuously mixed until congealed at room temperature.
• the finished semisolid is packaged into an appropriate container/closure system to optimize the stability of the drug substance and the integrity of the finished product.
• an amount of micronized agent in excess of the solubility (for example, more than 3.5 mg/ml of sildenafil citrate) is added to an aqueous vehicle containing the surfactant system, preservative system, buffer system, osmolality adjusting agent, and a viscosity increasing system.
• the suspension is homogenized using a high shear mixer (5000 psi pressure) until the drug is uniformly distributed.
• the finished suspension containing the agent that enhance ocular vascular blood flow is packaged into an appropriate container/closure system to optimize the stability of the drug substance and the integrity of the finished product.
• the container/closure system containing the composition will be included in a kit along with instructions for administration effective to increase ocular blood flow.
• the instructions will typically include directions for dosage, application, frequency and other relevant information pertinent to practice of the methods of the invention.
• the film formulation (for delivery to the eye, skin, buccal cavity) is prepared by hot melt extrusion, cast film method, or other methods suitable for the formation of thin films.
• the preferred method is to mix the agent that enhances ocular vascular blood flow, such as sildenafil citrate, with a blend of thermoplastic polymers and hot melt extruding the drug containing mass through a suitable extruder.
• the thickness of the film is manipulated by the components of the formulation and by the operating parameters of the extruder.
• the film containing the drug is cut in a suitable size for ophthalmic, buccal or transdermal application, and packaged in an appropriate container/closure system to optimize the stability of the drug substance and the integrity of the finished product.
• the film packaged in the container/closure system may be included in a kit along with instructions for application of the film effective to increase ocular blood flow, or treat macular disorders, etc., as contemplated by the invention.
• the instructions will typically include such information as location of application of the film, frequency of application, time period of application, etc.
• the instructions may be printed on the outside of the container/closure system housing the film or may be included in the kit separately from the film container/closure system.
• agent that enhances ocular vascular blood flow such as sildenafil citrate
• agent that enhances ocular vascular blood flow such as sildenafil citrate
• ethanol ethanol
• agent that enhances ocular vascular blood flow such as sildenafil citrate
• ethanol ethanol
• an aliquot of the drug concentrate is dispensed into an epoxy-lined aluminum can (or lined Type I glass vial).
• the metering valve (20 - 150 microliter preferably) is crimped onto the neck of the can.
• the propellant system is filled through the valve.
• the canister is mated with an actuator (oral for pulmonary; nasal for delivery to the nose; ophthalmic for delivery, to the eye).
• the agent that enhances ocular vascular blood flow such as sildenafil citrate
• a metered dose aqueous dispersion using a pump.
• the drug is mixed with the surfactant and water. After mixing to dissolve the drug, a viscosity increasing agent is added and the mixture stirred. A preservative system is dispersed and the mixture is stirred.
• the drug formulation is filled into a container (high density polyethylene) and the pump is screwed on.
• compositions comprising the drug yielded similar surprising results:
• sildenafil solution (sildenafil 1% (10 mg/ml in Schein artificial tear solution buffered to pH 8.0)) to his left eye. He reported no discomfort with either drop, and was unaware which eye had received which agent. He repeated visual function testing in both eyes 100 minutes after receiving the eyedrops.
• Contrast sensitivity (CS) ratios to the 1 cycle per degree stimulus were 203 in the right eye and 235 in the left eye prior to treatment.
• the placebo-treated right eye had a CS ratio of 235 after 100 minutes, while the sildenafil-treated eye had a CS ratio of 317 (p ⁇ .0001).
• the increase in CS ratio to the 4 cycle per degree stimulus with sildenafil was similarly spectacular, with values of 194 in the placebo-treated right eye versus 581 in the sildenafil-treated left eye 100 minutes after treatment (p ⁇ .0001).
• Humphrey 10-2 visual fields demonstrated a similar phenomenon.
• the left eye Despite the left eye having a lower light sensitivity than the right prior to treatment, it displayed a significantly higher retinal light sensitivity than the right eye 100 minutes after receiving topical sildenafil.
• the pre-treatment mean threshold value for the 10 degree visual field in the left eye was 31.2 (+/-.19) decibels; 100 minutes after sildenafil eyedrop application this had increased to 32.7 (+/-.17) decibels (p ⁇ 0.0001), a 70% increase.
• Intraocular pressures remained around 10 mmHg in both eyes and did not rise during the study interval. There were no adverse effects or significant visual symptoms elicited, and ocular appearance, pupil diameter, conjunctival and corneal appearance were symmetric and normal in both eyes.
• FIG. 1A and FIG. IB represent patient data from three patients showing an increase in retinal blood flow and blood velocity as measured using scanning laser doppler velocimetry. The data shows the increase over a period of time up to about 85 minutes from administration of 50 mg oral sildenafil citrate (Viagra ® ).
• FIG. 1A is a graph of retinal blood flow as measured by Heidelberg Retinal Flowmetry (HRF) for three test subjects over time.
• FIG. IB is a graph of retinal blood velocity as measured by Heidelberg Retinal Flowmetry (HRF) for three test subjects over time.
• FIG. 2A and FIG. 2B represent patient data from two patients showing an increase in contrast sensitivity over a period of time up to about 75 to 125 minutes from administration of 50 mg oral sildenafil citrate (Viagra ).
• FIG. 2A is a graph of 4.26 SF cpd contrast sensitivity (visual function) for two test subjects over time.
• FIG 2B is a graph of 8.53 SF cpd contrast sensitivity (central macular visual function) for two test subjects over time.
• FIG. 3A and FIG. 3B show an improvement in visual field response for two separate individuals.
• the reports show both baseline (left side of each figure) and post-administration of 50 mg oral sildenafil citrate (Viagra ® ).
• FIG. 3 A provides Humphrey Frequency Doubling Technology (FDT) visual field reports for a first test subject baseline (left) and post-application (right) conditions.
• FIG. 3B provides Humphrey Frequency Doubling Technology (FDT) visual field reports for a second test subject baseline (left) and post-application (right) conditions.
• FDT Humphrey Frequency Doubling Technology
• FIGS. 4A, 4B, 5A and 5B represent patient data from two patients showing other relevant ocular data over a period of time up to about 100 to 200 minutes from administration of 50 mg oral sildenafil citrate (Viagra ® ).
• Fig. 4A is a graph of pulsatile ocular blood flow for two test subjects over time.
• FIG. 4B is a graph of intraocular pressure measured concomitantly with OBF for two test subjects over time.
• Fig. 5A is a graph of blue field density (perimacular retinal capillary circulatory volume) for two test subjects over time.
• Fig. 5B is a graph of blue field mean velocity (perimacular retinal capillary circulatory speed) for two test subjects over time.
• Topical carbonic anhydrase inhibitors and visual function Association with retinal circulation and intraocular pressure in normal eyes.
• Current Concepts on Ocular Blood Flow in Glaucoma (Pillunat IE, Harris A, Anderson DR, Greve EL, eds. Kugler, The Hague, Netherlands) pp. 251-265.

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