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Patent Issued for Pharmaceutical Compositions and Methods for Treating Age-Related Macular Degeneration with Melatonin Analogues

August 6, 2014



By a News Reporter-Staff News Editor at Biotech Week -- A patent by the inventors Baron, David (Skokie, IL); Hirai, Keisuke (Osaka, JP); Shintani, Yasushi (Osaka, JP); Uchikawa, Osamu (Osaka, JP), filed on June 17, 2009, was published online on July 22, 2014, according to news reporting originating from Alexandria, Virginia, by NewsRx correspondents (see also Takeda Pharmaceuticals U.S.A., Inc.).

Patent number 8785491 is assigned to Takeda Pharmaceuticals U.S.A., Inc. (Deerfield, IL).

The following quote was obtained by the news editors from the background information supplied by the inventors: "Age-related macular degeneration ('AMD') is defined by the gradual destruction of sharp, central vision in older individuals. The macular area of the retina processes central vision, and is adjacent to the optic nerve and near the center of the optic axis. AMD occurs in two forms, dry and wet.

"Dry AMD is defined by the gradual loss of retinal pigment epithelial (RPE) and photoreceptor cells in the macula. Drusen, or yellow deposits under the retina, are often found in people over 60 and represent an early indication of developing AMD, but do not in and of themselves cause vision loss. Early AMD is defined by several small drusen or less frequent medium-sized drusen. Intermediate AMD is defined by more medium-sized drusen or a few large drusen. At this stage, visual disturbances may be reported. Advanced dry AMD is defined by loss of photoreceptors and supporting cell types in the macula with accompanying progressive vision loss.

"Wet AMD is less common and is characterized by growth of abnormal blood vessels beneath the macular epithelium. These vessels are fragile and leak blood and exudates that separate the macular retina from underlying structures. Wet AMD advances more quickly than dry AMD. Rather than blurry vision characteristic of dry AMD, wet AMD is associated with the perception of straight-line grids as wavy especially at their center. The wet form develops in people who initially present with the dry form and is always considered an advanced form of AMD.

"Current treatment for dry AMD consists of a regimen of specific high-dose anti-oxidants (vitamins C, E, beta carotene), and copper and zinc (National Eye Institute's Age-Related Eye Disease Study [AREDS] formulation) that reduce the risk of progression of intermediate AMD to advanced AMD. However, this treatment is not indicated for early AMD due to lack of efficacy. Wet AMD is treated with laser surgery to destroy abnormal vasculature but may not be indicated for most cases. New abnormal vessels may develop after initial treatment.

"Photodynamic therapy is also used to destroy abnormal vessels.

"Yet another treatment option is direct injection of the anti-VEGF (vascular endothelial growth factor) antibody fragment ranibizumab (LUCENTIS, Genentech) which is now approved for the treatment of wet AMD. This treatment may slow vision loss and in some cases actually improves vision. However, it requires intravitreal injection and subsequent monitoring for increases in ocular pressure. Retinal detachment or infection may occur along with red eye, vitreous floaters and pain. In addition, bevacizumab is currently being used off-label as an intravitreal injection to treat AMD (Costa et al., Investigative Ophthamology and Visual Science, 47: 4569-4578, 2006).

"Melatonin has been shown to control eye pigmentation (i.e., melanin) and thereby regulate the amount of light that can reach the photoreceptors. Melatonin levels produced by the pineal gland are known to decrease with age in humans, as do levels of melanin in retinal pigment epithelial cells (RPE) (Sarna, T. et al., Exp. Eye Res., 76: 89-98, 2003). Melatonin is also synthesized by photoreceptor cells with a circadian rhythm similar to that of the pineal gland (Weichmann, A. F., Exp. Eye Res., 42: 507-527, 1986). The diminution may decrease the protection from oxidative damage afforded to the RPE by melanin. RPE dysfunction, which is thought to follow oxidative damage, is a well-known initiator of age-related macular degeneration (AMD).

"Melatonin has been shown to protect human retinal pigment epithelial (RPE) cells in vitro when added diurnally to RPE cell cultures for three consecutive days. This treatment regimen markedly reduced H.sub.2O.sub.2-induced cell death and mitochondrial DNA damage (Liang, F.-Q., et al., Exp. Eye Res., 78: 1069-1075, 2004). Other studies have shown that melanin itself protects the human RPE from light-induced apoptosis (Seagle, B.-L. L., et al., Proc. Natl. Acad. Sci. U.S.A., 102: 8978-8983, 2005) and that melanin free radicals can quench reactive oxygen species (Seagle, B.-L. L., et al. J. Am. Chem. Soc., 127: 11220-11221, 2005). These studies are of interest because melatonin, and presumably its analogs, can raise the level of melanin in the RPE.

"A case-controlled study of dry and wet AMD has recently shown that 3 mg melatonin administered daily at bedtime for at least three months may reduce the extent of retinal pathology over time. Visual acuity remained stable, and the change in the picture of the fundus was remarkable in that few of the examined eyes showed either more retinal bleeding or exudates (Yi, C. et al., Ann. N.Y. Acad. Sci., 1057: 384-392, 2005).

"Melatonin is available over the counter in the US generally as a 3 mg tablet for relief from insomnia or jetlag, but has never been fully tested for efficacy or safety and therefore is sold as an over the counter dietary supplement.

"Ramelteon is a melatonin analog described in U.S. Pat. No. 6,034,239 (hereby incorporated by reference in the entirety), and is currently FDA approved for marketing in the US for treatment of sleep disorders. This non-addictive compound is available in an 8 mg tablet, and numerous GCP compliant clinical trials and drug-drug interaction studies have shown that ramelteon is safe for humans at significant multiples of the therapeutic dose. Ramelteon, a sleep-promoting agent, is chemically designated as (S)--N-[2-(1,6,7,8-tetrahydro-2H-indeno-[5,4-b]furan-8-yl)ethyl]propionam- ide, and is a selective melatonin receptor agonist with high affinity for melatonin MT.sub.1/MT.sub.2 receptors. As a sleep aid, ramelteon appears to act more as a 'switch' rather than exhibiting prominent dose-dependent pharmacology.

"Melatonin, melatonin analogues and anti-VEGF agents have all been proposed as useful pharmacological agents for the treatment of glaucoma. Specifically, it has been suggested that melatonin may be useful for the treatment of glaucoma (Lundmark et al., Exp. Eye Res., 84: 1021-1030, 2007; U.S. Pat. No. 4,654,361 and U.S. Patent Application Publication No. 2007/0207116); U.S. Pat. No. 6,034,239 indicates that ramelteon is useful to treat various disorders accompanies by aging, and also that ramelteon may be useful to treat glaucoma; and off-label use of either bevacizumab or ranibuzumab to treat glaucoma with positive results has been reported (Ichhpujani et al., Can. J. Ophthamol., 42: 812-815, 2007; Cheng et al., Annals Academy of Medicine, 37: 72-74, 2008; Dunavoelgyi et al., Clinical and Experimental Ophthamology, 35:878-880, 2007)."

In addition to the background information obtained for this patent, NewsRx journalists also obtained the inventors' summary information for this patent: "The present invention teaches pharmaceutical compositions and methods for the treatment of age-related macular degeneration in a patient in need thereof. In particular, the present invention teaches the administration of ramelteon or its metabolite, for the treatment and/or prevention of AMD in a patient in need thereof. More specifically, patients identified as having AMD or at high risk for developing AMD can be treated with therapeutic and/or prophylactic amounts of 'ramelteon and/or its metabolite' for preventing or inhibiting the progression of disease.

"Thus the present invention teaches specific formulations of ramelteon and/or its metabolite pharmaceutical compositions suitable for administration to a patient in need of treatment for AMD, for the prophylactic treatment against AMD, or for the therapeutic and/or prophylactic prevention of advancement of AMD disease in a patient in need thereof.

"The present invention teaches a method for treating and/or preventing age-related macular degeneration in a patient identified as in need thereof, said method comprising identifying a patient in need of treatment for age-related macular degeneration, and administering a therapeutic amount of ramelteon to said patient.

"The present invention teaches a method as above, wherein the patient is identified via visual examination of the patient's eye.

"The present invention teaches a method as above, wherein the patient is identified via screening according to risk-factor criteria.

"The present invention teaches a method as above, wherein said age-related macular degeneration is the dry form.

"The present invention teaches a method as above, wherein said age-related macular degeneration is the wet form.

"The present invention teaches a method as above, wherein said age-related macular degeneration occurs in one eye.

"The present invention teaches a method as above, wherein said age-related macular degeneration occurs in two eyes.

"The present invention teaches a method as above, wherein said administration of ramelteon is via an oral dosage form.

"The present invention teaches a method as above, wherein said administration of ramelteon is via an injectible dosage form.

"The present invention further teaches a method wherein said administration of ramelteon is via a surface absorbent dosage form.

"The present invention teaches wherein said administration of ramelteon is via a skin-patch dosage form.

"The present invention teaches wherein said administration of ramelteon is via a liquid, powder, ointment, paste, gel or cream dosage form.

"The present invention teaches wherein said ramelteon is administered in a dose of from 1 mg to 1000 mg.

"The present invention teaches a method wherein said ramelteon is administered as an isolated metabolite of ramelteon, (S)--N-[2-[4-hydroxy-1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethyl]- propionamide (hereinafter, sometimes referred to as metabolite 1), in a dose of from 1 mg to 1000 mg.

"The present invention teaches wherein administration of a therapeutic amount of ramelteon results in a serum concentration of metabolite 1 of from 1 .mu.g/L to 100 mg/L.

"The present invention teaches wherein said ramelteon is administered in a dose once daily.

"The present invention teaches wherein said ramelteon is administered in the evening.

"The present invention teaches wherein said ramelteon is administered prior to sleep.

"The present invention also teaches wherein said ramelteon is administered in a dose twice daily.

"The present invention teaches wherein said ramelteon is administered in a dose more than twice daily.

"The present invention teaches wherein administration of a therapeutic amount of ramelteon results in a serum concentration of metabolite 1 of from 1 .mu.g/L to 100 mg/L.

"The present invention teaches wherein administration of a therapeutic amount of ramelteon results in a serum concentration of metabolite 1 of from 1 .mu.g/L to 100 mg/L.

"The present invention further teaches a pharmaceutical composition comprising a therapeutic amount of ramelteon, and/or a therapeutic amount of an isolated metabolite of ramelteon, metabolite 1, and a pharmaceutically acceptable carrier, excipient or diluent."

URL and more information on this patent, see: Baron, David; Hirai, Keisuke; Shintani, Yasushi; Uchikawa, Osamu. Pharmaceutical Compositions and Methods for Treating Age-Related Macular Degeneration with Melatonin Analogues. U.S. Patent Number 8785491, filed June 17, 2009, and published online on July 22, 2014. Patent URL: http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=8785491.PN.&OS=PN/8785491RS=PN/8785491

Keywords for this news article include: Takeda Pharmaceuticals U.S.A. Inc., Brain, Glaucoma, Epithalamus, Dosage Forms, Eye Diseases, Legal Issues, Pineal Gland, Therapeutics, Prosencephalon, Retinal Diseases, Retinal Pigments, Biological Pigments, Retinal Degeneration, Central Nervous System, Age-Related Macular Degeneration.

Our reports deliver fact-based news of research and discoveries from around the world. Copyright 2014, NewsRx LLC


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Source: Biotech Week


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