MXPA06006024A - Prevention and/or reduction of photoreceptor degeneration with retinoids - Google Patents

Abstract

The present invention provides a method for reducing and/or preventing degeneration of photoreceptors in the eye of a human caused by radiation in the visible range which comprises administering to said mammal a retinoid compound having RAR beta and/or RAR-delta-selective agonist activity, and more specifically Tazarotene.

Description

PREVENTION AND / OR REDUCTION, WITH RETINOIDS OF THE DEGENERATION OF PHOTORECEPTORS Field of the Invention This invention relates to the administration of selective retinoid agonists for RARβ and / or RARs to a human to prevent and / or reduce photoreceptor damage caused by visible light, eg, blue light.

Background of the Invention It has been observed that isotretinoin (13-cis retinoic acid or ACCUTANE®) can protect the photoreceptors of rats and mice from light damage. (See Sparrow, PNAS, April 15, 2003, Vol. 100 No. 8, 4353-4354 See also Seiving et al., PNAS, February 13, 2001, Vol 98, No. 4, 1835-1840) . However, it is well known that isotretinoin causes birth defects and is a non-selective retinoid, that is, it is not selective for the retinoid receptor subtype. Tazarotene is a selective retinoid agonist for RARß and RARs that has been used for the treatment of psoriasis and / or acne. (See U.S. Patent 5,089,509). Tazarotene and other related retinoids are described for treatment against various diseases and conditions Ref .: 172808 sensitive to treatment with retinoid compounds. (See US Patents 5,750,693, 6,090,826 and 6,344,463). Also, it has recently been reported that tazarotene in certain retinoid agonists are useful for preventing proliferation of retinal pigment epithelium following surgery or trauma as a result of eye diseases associated with choroidal neovascularization, such as age-related macular degeneration and Histoplasmosis syndrome. (See, U.S. Patents Nos. 5,824,685, 6,075,032, 6,071,924, 6,372,753, 5, 437, 291 and 5, 674, 205).

Brief Description of the Invention This invention provides a use for reducing and / or preventing photoreceptor degeneration in the eye of a mammal caused by radiation in the visible range, eg, blue light, which comprises administering to the mammal a retinoid compound that have selective agonist activity for RARß and / or RARg. In particular, the invention provides a use for the treatment against diseases and conditions as a result of or caused by exposure to visible radiation, especially radiation in the spectrum of the blue band of the visible spectrum, for example, radiation of about 480 nm. These diseases or conditions include, among others, age-related non-exudative macular degeneration (ARMD), macular degeneration age-related exudative (ARMD), choroidal neovascularization, diabetic retinopathy, central serous chorioretinopathy, cystoid macular edema, diabetic macular edema, retinal degeneration due to myopia, placoid pigment multifocal epitheliopathy, Behcet's disease, pelleted retinochoroidopathy, of infectious origin ( syphilis, lyme disease, tuberculosis, toxoplasmosis), intermediate uveitis (pars planitis), multifocal choroiditis, multiple evanescent white dot syndrome (DS), ocular sarcoidosis, posterior scleritis, serpiginea choroiditis, subretinal fibrosis and uveitis syndrome. Vogt-Koyanagi-Harada syndrome, punctate internal choroidopathy, multifocal placoid pigment posterior epitheliopathy, acute retinal pigment epitheliitis, acute macular neuroretinopathy, diabetic retinopathy, arterial retinal occlusive disease, central retinal vein occlusion, disseminated intravascular coagulopathy , occlusion of branched retinal vein, hypertensive changes in fundus, ocular ischemic syndrome, retinal arterial microaneurysms, coat disease, parafoveal telangiectasis, hemiretinal vein occlusion, papilloflebitis, central retinal artery occlusion, retinal branched-line artery occlusion, carotid artery disease (CAD), frozen branched angiitis, sickle cell retinopathy and other hemoglobinopathies, angioid streaks, vitreoretinopathy Familial exudative disease of Eales, sympathetic ophthalmia, uveitic retinal disease, retinal detachment, trauma, laser, photodynamic therapy, photocoagulation, hypoperfusion during surgery, radiation retinopathy, retinopathy by bone marrow transplantation, proliferative vitreous retinopathy and epirrethinal membranes, ocular histoplasmosis, ocular toxocariasis, presumed syndrome of ocular histoplasmosis (POHS), endophthalmitis, toxoplasmosis, retinal diseases associated with HIV infection, choroidal disease associated with HIV infection, uveitis associated with HIV infection, viral retinitis, acute retinal necrosis, progressive acute retinal necrosis, retinal diseases fungi, ocular syphilis, ocular tuberculosis, diffuse unilateral subacute neuroretinitis, myiasitis, retinitis pigmentosa, systemic disorders associated with retinal dystrophies, congenital stationary nocturnal blindness, cone dystrophy, Stargardt's disease and flavimaculatus fudus, in Best's disease, paternal dystrophy of retinal pigmented epithelium, x-linked retinoscitis, Sorsby's fundus dystrophy, benign concentric maculopathy, Bietti's crystal dystrophy, pseudoxanthone elasticum, retinal detachment, macular hole, giant retinal tear, associated retinal disease with tumors, congenital hypertrophy of the retinal pigment epithelium (RPE), posterior uveo melanoma, choroidal hemangioma, choroidal osteoma, choroidal metastasis, combined hematoma of the retina and retinal pigmented epithelium, retinoblastoma, vasoproliferative tumors of the ocular fundus, retinal astrocytoma and intraocular lymphoid tumors. Preferably, the retinoid compound is selected from the group comprising tazarotene, ie ethyl-6- [2- (4,4-dimethyl-thiochroman-6-yl) ethyl] nicotinate, tazarotenic acid and other lower alkyl esters of the tazarotenic acid, for example C2-C3 alkyl esters of tazarotenic acid such as methyl 6- [2- (4, -dimethyl-thiochroman-6-yl) ethyl] nicotinate, 6- [2- (4, 4-dimethyl- thiochroman-6-yl) ethyl] nicotinate of i-propyl, 6- [2- (4, 4-dimethyl-thiochroman-6-yl) ethyl] n-butyl icotinate, etc.

Brief Description of the Figures Figure 1 shows the effect of exposure to test rats in blue light, at a wavelength of 480 nm. In particular, this Figure shows the photoreceptor layer of test subjects that is severely damaged. Figure 2, in comparison to Figure 1, shows the protective effect to the photoreceptor layer of the test rats dosed with retinoids or brimonidine. Figure 3 shows the protective effect to the photoreceptor layer of test rats dosed with an agonist RAR or an RXR agonist as quantified by ERG. Figure 4 shows the response relative to the quantified ERG of the photoreceptor layer of the test rats dosed with retinoids or brimonidine. Figure 5 shows a loss of the protective effect of a RAR agonist when dosed together with a RAR antagonist.

Detailed Description of the Invention Tazarotene has been used for the treatment of acne and psoriasis and other diseases known to be sensitive to retinoid treatment. Also, it has recently been reported that tazarotene and other retinoid agonists are useful in the prevention of retinal pigment epithelial proliferation after surgery or trauma or as a result of ocular diseases associated with choroidal neovascularization, such as macular degeneration associated with age and histoplasmosis syndrome. It has surprisingly been found that tazarotene can be used for the treatment of diseases and / or eye conditions caused by exposure to visible radiation, radiation in the blue band of the spectrum. Although one does not wish to be limited by theory, it is postulated that tazarotene is effective as a result of its ability to act as a selective retinoid agonist for RARß and / or RAR ?. (The selective retinoid for RARβ and / or RAR ?, used in the use of the present invention, is preferably incapable of agonist activity on any of the RXR receptors, and has a potency of RARa / RARβ greater than 15 and / or RARa / RAR? Greater than 30 as determined in accord with the simultaneous transfection evaluation of Example 1 of US Patent 6,075,032.More preferably, the retinoid used in the use of the present invention has a higher RARa / RARβ potency than 15 and RARa / RAR? Greater than 30. See Table 1 of US Patent 6,075,032). A preferred embodiment of the present invention is the use of tazarotene for the treatment against age-related macular degeneration, diabetic retinopathy and / or retinitis pigmentosa resulting from radiation, by contacting the eye of the person suffering from these conditions with a therapeutically effective amount of tazarotene. The therapeutically effective amount of tazarotene is an effective amount of the active agent, to achieve the desired effect. The desired therapeutic effect depends on the amount in the administration program, the condition of the person treated, etc., as is known per se. To achieve the therapeutic effect of selective retinoids for RARß and / or RAR? in the use of the present invention, the retinoid can be administered systemically, for example orally or topically, for example by ophthalmic drops or selective injection of the eye site, depending on the condition being treated, the need for site-selective treatment, the amount of retinoid administered and other considerations. The invention also relates to the use of tazarotene and other selective retinoids for RARβ and / or RAR? for the preparation of ophthalmological compositions for the treatment of ARMD, diabetic retinopathy and / or retinitis pigmentosa. That is, tazarotene is mixed with a conventional and ophthalmologically compatible vehicle, for example, aqueous solutions such as physiological saline solutions, oily solutions or ointments. The vehicle can contain the ophthalmologically compatible preservatives such as benzalkonium chloride, surfactants such as polysorbate 80, liposomes or polymers such as methylcellulose, polyvinyl alcohol and hyaluronic acid which can be used to increase the viscosity. As used herein, the term "therapeutically effective amount" of tazarotene and other selective retinoid agonists for RARβ or a RAR? is an amount calculated to maintain the therapeutic level in the eye, if it is introduced directly into the vitreous cavity, in the periocular space or in the blood flow, if it is administered peripherally for the desired period of time in a human or animal to make effective treatment against the adverse condition. The therapeutic amount may vary according to the potency of each selective retinoid agonist for RARß and / or RAR ?, the amount required for the desired therapeutic effect or other effects, the rate of elimination or unfolding of the substance in the body once has entered the vitreous cavity or blood flow and the amount of RAR agonist in the formulation. According to conventional practices in prudent formulation, a dose near the lower end of the useful range of a particular agent is usually used at the beginning and the dose increases or decreases as indicated from the response observed as in the routine procedure of the physician. For direct administration into the vitreous cavity of the eye, an amount in the range between 50 and 150 μg may be administered one or more times to achieve the desired therapeutic effect. Alternatively, a combination of intravitreal and subconjunctival injection of the retinoid may be used, either simultaneously or at separate intervals to administer the retinoid. For intravitreal injection, it is preferred that the RAR agonist be injected into the anterior vitreous cavity using topical or retrovulvar anesthesia. In an alternative embodiment, the RAR agonist is introduced intravitreally using a vehicle of administration of the drug. For example, the RAR agonist can be dissolved in a biologically inert liquid and also be useful as a mechanical plug to help hold the retina in place, preferably an oil such as silicone oil in which the retinoid is soluble. However, for RAR agonists that have partial miscibility, a liquid other than oil may be used. It has been found that the therapeutic effects of the retinoids of this invention can be delayed during the manifestation and are reversible. Therefore, it may be advantageous to administer retinoids using a use to decrease the release, for example by intravitreous injection of the dose of retinoid encapsulated in microvesicles such as liposomes, from which the dose is released and over the course of several days, preferably between about 3 to 20 days. Alternatively, the drug can be formulated for prolonged release as during incorporation into a sustained release polymer from which the drug dose is released slowly over several days, for example 2 to 30 days. The prolonged release formulation can be placed in the eye by intravitreal, subconjunctival, periocular, intrascleral or subrretinal injection. The retinoid can be incorporated into a bioerodible polymer such as the acid copolymer polylactic-glycolic acid, for example Oculex®. The ophthalmological compositions of the invention can be administered in a variety of ways. For an administration use, the ophthalmological composition is applied topically in the eye. For topical application, the ophthalmological composition can be formulated with a vehicle that is compatible with the eye and preferably facilitates the penetration of tazarotene into the eye. For this mode of application, the active agent can be formulated in the form of ophthalmic drops (where the tazarotene or another retinoid selective for RARß and / or RAR? Is dissolved in a physiological solution), in the form of ointments, in the form of a liposomal solution , etc. It is contemplated that the tazarotene dosage levels as used in the ophthalmic drops of the present invention are adjusted as necessary by the lack of response, rapidity of response required, potency of the tazarotene solution, etc. The use of the present invention can be practiced alone or in conjunction with other therapies. The invention is further illustrated by the following examples which are specific modes illustrative of the practice of the invention and are not intended to limit the scope of the appended claims. Adult rats were used in the following examples Male albino Sprague-Dawley (weighing 400 + 30 g). After 18 hours of adaptation to darkness, the animals were housed in specially designed acrylic cages and exposed to a high intensity of fluorescent blue light (12000 LUX) (480 nm) for 8 hours. The light intensity was quantified by a digital light meter. Each animal was housed separately. The room was maintained at a temperature of 22.8 ° C during the experiment. The animals were dosed orally with the appropriate retinoid or a positive control, ie brimonidine, for 5 days with the last dose administered 2 hours before exposure to blue light. After exposure to light, the animals were kept in a dark room and recovered for an additional 5 days. The retinal function was evaluated with a rapid ERG analysis. The retinal structure was evaluated by histology.

Example 1 As shown in Figure 1, the photoreceptor layer is severely damaged by exposure to blue light in this experiment where the animals were not dosed with a retinoid or other neuroprotective agent.

Example 2 The following retinoids were evaluated to avoid damage to the photoreceptor layer of rats subjected to exposure to blue light. Retinoid compound analyzed / receptor selectivity / dose. Tazarotene / (RAR agonist) / 3 mg / kg / day Compound A / (RXR agonist) / 10 mg / kg / day Compound B / (RXR antagonist) / 50 mg / kg / day Compound C / (RXR antagonist) / 3 mg / kg / day Compound A Acid 3,7-dimethyl-6 (S), 7 (S) -methane-7- [1, 1, 4, 4-tetramethyl-1,2,3,4-tetrahydronaphth-7-yl] -2E , 4E-heptadienoic Compound B Acid (2E, 4E, 6E) -7- (3,5-diisopropyl-2-propoxy-phenyl) -6-fluoro-3-methyl-nona-2,4,6-trienoic Compound C 1-2 (6- (2,2-dimethyl- (1H9-4- (4-ethylphenyl) -1-benzothiopyran)) ethynyl] benzoic acid As shown in Figure 2, the thickness of the photoreceptor layer for animals dosed with brimonidine, a well-known neuroprotective agent, is much greater than the thickness of photoreceptor layers of animals dosed alone with the vehicle, or with the antagonist RAR or the RXR antagonist. The thickness of the photoreceptor layer for the RXR agonist is greater than the photoreceptor layer of animals dosed with RAR or RXR agonists but, the photoreceptor layer of the animal dosed with RAR agonist is the best of the retinoids analyzed and almost equivalent in effect to brimonidine. (The RAR agonist, tazarotene, is a selective retinoid for RARβ and RARs The RXR agonist also has some RAR agonist activity). Also, as shown in Figure 3, which is a graph of the ERG wave with respect to time, the RAR agonist and the RXR agonist show a protective effect for the photoreceptor layer when measured by ERG. Figure 4 shows in a bar graph the response relative to the ERG wave for the previous animals after being exposed to blue light.

EXAMPLE 3 In this Example, the above experiment was repeated with the RAR antagonist, which has antagonistic activity in the ot, ß and d retinoid receptor subtype dosed in combination with the RAR agonist and the RXR agonist. Figure 5 shows that the RAR antagonist severely decreases the effectiveness of both the RAR agonist and the RXR agonists, thus demonstrating that the effectiveness of the RXR antagonist is a result of its RAR agonist activity and not its RXR antagonist activity.

Example 4 The following retinoid compounds were analyzed in the previous use with the results reported below.

Retinoid Compound / selectivity Protective activity of the Tazarotene receptor / (RARß agonist,?) *** Compound A / (agonist RXRa, p,? ** with RAR activity) Compound C / (agonist RARa, ß,?) X Compound B / (antagonist RXRa, ß X r?) Compound D / (antagonist RARa) X Compound E / (agonist RARa) ** Compound F / (agonist RXRa, ß,) X * means a protective effect of a photoreceptor layer for damage from radiation by blue light. Greater effectiveness is shown by increasing the amount of *. x means there is no protective effect.

Compound D 2-fluoro-4 [6 '-2", 2" -dimethyl-4"-tholylchromanyl) -8' -bromo] carbamoylbenzoic acid Compound E 4- [(4-Chloro-3-hydroxy-5, 5, 8, 8-tetramethyl-5, 6,7,8-tetrahydro-naphthalene-2-carbonyl) -amino] -2,6-difluorobenzoic acid Compound F 3-Methyl-7-propyl-6 (S), 7 (S) -methane-7 [1, 1, 4, 4-tetramethyl-l, 2,3,4-tetrahydro-7-yl] -2 acid ( E), 4 (E) -heptadienoic Example 5 In a treatment instance according to a preferred embodiment described above, a male patient aged 64 years and blue eyes is diagnosed with macular degeneration related to age with a duration of approximately 10 years. In both eyes numerous drus cen were documented. The photographs of the fundus are obtained. Treatment with tazarotene according to the preferred use of use described here is initiated in the left or right. After a treatment lasting two years, the treated eye shows no changes in visual activity that was measured at the beginning of treatment. There are also no changes in the fundus, as an increase in the amount or extent of the drusen, compared with the photographs obtained before the start of treatment. Therefore, tazarotene treatment according to the uses of the present invention avoids any of the additional effects of macular degeneration to occur in the treated eye. This is significant because, as described previously, the normal course of ocular regeneration leads to a continuous and constant loss of vision during the passage of time. The above description indicates one embodiment of the present invention. Other configurations or embodiments, which are not set forth with precision, may be practiced under the teachings of the present invention. Although the present invention has been described in the context for the treatment against age-related macular degeneration, tazarotene can also be used for the treatment against retinitis pigmentosa, diabetic retinopathy, ischemic retinopathy, damage caused by surgery, for example laser or mechanical and photodynamic therapy and any of the other diseases and / or conditions described above. Moreover, the present invention is described for treatment against retinitis pigmentosa with tazarotene, the corresponding acid, ie tazarotenic acid, can also be used as well as other esters of lower alkyl Ci to Cs of tazarotenic acid, for example methyl esters or isopropyl of tazarotenic acid. The foregoing description shows certain preferred embodiments of the present invention. Other configurations or modalities, not exhibited with precision, can be taken to the practice under the teachings of the present invention. It is noted that in relation to this date, the best use known by the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (16)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. Use of a retinoid compound having selective agonist activity for RARβ and / or RARs to prepare a medicament to reduce and / or prevent the degeneration of photoreceptors in a human eye caused by radiation in the visible range.
2. 2. The use according to claim 1, wherein the radiation is blue light radiation.
3. 3. The use according to claim 1, wherein the retinoid compound is tazarotenic acid or a lower alkyl ester or a salt thereof.
4. 4. The use according to claim 3, wherein the compound is tazarotenic acid or tazarotene.
5. 5. The use according to claim 4, wherein the compound is tazarotene.
6. 6. Use of a retinoid compound having selective agonist activity against RARβ and / or RARg to be made for treatment against diseases or conditions in a mammal as a result of or caused by exposure to visible radiation.
7. 7. The use according to claim 6, wherein the radiation is blue light radiation.
8. 8. The use according to claim 6, wherein the retinoid compound is tazarotenic acid or a lower alkyl ester or a salt thereof.
9. 9. The use according to claim 6, wherein the compound is tazarotenic acid or tazarotene.
10. 10. The use according to claim 4, wherein the compound is tazarotene. The use according to claim 1, wherein the mammal has a condition selected from the group comprising age-related non-exudative macular degeneration (ARMD), age-related exudative macular degeneration (ARMD), choroidal neovascularization , diabetic retinopathy, central serous chorioretinopathy, cystoid macular edema, diabetic macular edema, retinal degeneration due to myopia, multifocal placoid pigment epitheliopathy, Behcet's disease, pelleted retinochoroidopathy, of infectious origin (syphilis, lyme disease, tuberculosis, toxoplasmosis), intermediate uveitis (pars planitis), multifocal choroiditis, evanescent white dots multiple syndrome (ME DS), ocular sarcoidosis, posterior scleritis, serpiginea choroiditis, subretinal fibrosis and uveitis syndrome. Vogt-Koyanagi-Harada syndrome, punctate internal choroidopathy, multifocal placoid pigment posterior epitheliopathy, acute retinal pigment epithelitis, acute macular neuroretinopathy, retinopathy diabetic, arterial occlusive disease of the retina, central retinal vein occlusion, disseminated intravascular coagulopathy, branched retinal vein occlusion, hypertensive changes in fundus, ocular ischemic syndrome, retinal arterial microaneurysms, coat disease, parafoveal telangiectasis, occlusion of hemirretinal vein, papilloflebitis, retinal central artery occlusion, branched retinal artery occlusion, carotid artery disease (CAD), frozen branched angiitis, falsiform cell retinopathy and other hemoglobinopathies, angioid striae, familial exudative vitreoretinopathy, Eales disease , sympathetic ophthalmia, uveitic retinal disease, retinal detachment, trauma, laser, photodynamic therapy, photocoagulation, hypoperfusion during surgery, radiation retinopathy, retinopathy by bone marrow transplantation, proliferative vitreous retinopathy and epirrethral membranes, ocular histoplasmosis, ocular xocariasis, presumed ocular histoplasmosis syndrome (POHS), endophthalmitis, toxoplasmosis, retinal diseases associated with HIV infection, choroidal disease associated with HIV infection, uveitis associated with HIV infection, viral retinitis, acute retinal necrosis, acute retinal necrosis progression, retinal fungal diseases, ocular syphilis, ocular tuberculosis, subacute neuroretinitis diffuse myelitis, retinitis pigmentosa, systemic disorders associated with retinal dystrophies, congenital stationary nocturnal blindness, cone dystrophy, Stargardt's disease, flavimaculatus fundus, Best's disease, paternal dystrophy of retinal pigmented epithelium, retinoscitis linked to the X chromosome, dystrophy of Sorsby's fundus, benign concentric maculopathy, Bietti's crystal dystrophy, pseudoxanthone elasticum, retinal detachment, macular orifice, giant retinal tear, retinal disease associated with tumors, congenital retinal pigment epithelial hypertrophy (RPE), posterior uveal melanoma, hemangioma choroidal, choroidal osteoma, choroidal metastasis, combined hematoma of the retina and retinal pigmented epithelium, retinoblastoma, vasoproliferative tumors of the ocular fundus, retinal astrocytoma and intraocular lymphoid tumors. 12. The use according to claim 11, wherein the condition is macular degeneration related to age. 13. The use according to claim 11, wherein the condition is retinitis pigmentosa. 14. The use according to claim 11, wherein the condition is diabetic retinopathy. 15. The use according to claim 11, wherein the condition is surgical trauma. 16. The use according to claim 11, wherein the condition is laser-induced damage.