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WO2011072141A1 - Compositions et procédés pour le traitement de la dégénérescence maculaire - Google Patents

Compositions et procédés pour le traitement de la dégénérescence maculaire Download PDF

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Publication number
WO2011072141A1
WO2011072141A1 PCT/US2010/059719 US2010059719W WO2011072141A1 WO 2011072141 A1 WO2011072141 A1 WO 2011072141A1 US 2010059719 W US2010059719 W US 2010059719W WO 2011072141 A1 WO2011072141 A1 WO 2011072141A1
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WIPO (PCT)
Prior art keywords
compound
cyclodextrin
macular degeneration
compounds
composition
Prior art date
Application number
PCT/US2010/059719
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English (en)
Inventor
Thomas A. Jordan
John Clifford Chabala
Gerald D. Cagle
Original Assignee
Neuron Systems, Inc.
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Filing date
Publication date
Application filed by Neuron Systems, Inc. filed Critical Neuron Systems, Inc.
Priority to JP2012543284A priority Critical patent/JP5885670B2/ja
Priority to CA2782015A priority patent/CA2782015C/fr
Priority to US13/514,769 priority patent/US9814701B2/en
Publication of WO2011072141A1 publication Critical patent/WO2011072141A1/fr
Priority to US15/782,470 priority patent/US20180092882A1/en
Priority to US18/241,598 priority patent/US12097188B2/en

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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/423—Oxazoles condensed with carbocyclic rings
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • 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

Definitions

  • Macular degeneration is a leading cause of progressive blindness.
  • the macula is the central region of the retina and contains the fovea where high acuity central vision is processed.
  • Macular degeneration is a neurodegenerative disease in the macula that progressively causes disabling deficits in visual function.
  • Age-related macular degeneration is the most common form and first appears at middle age or later.
  • AMD age-related macular degeneration
  • FAF fundus auto-fluorescence
  • RPE retinal pigment epithelial
  • A2E is a reaction product of all- trans retinaldehyde (RAL) and phosphatidylethanolamine (PE), a membrane phospholipid found in the disc membranes of photoreceptor outer segments.
  • the RAL that reacts with PE escapes from the visual cycle (step 3b in Figure 1), a metabolic pathway in the back of the eye that (i) converts vitamin A from an alcohol (retinol) to a photo-reactive aldehyde (1 ⁇ -cis- retinaldehyde) for use in photo-transduction by opsin proteins in photoreceptor cell outer segments, and (ii) converts RAL to retinol after photo-transduction.
  • retinol an alcohol
  • a photo-reactive aldehyde (1 ⁇ -cis- retinaldehyde
  • RAL converts RAL to retinol after photo-transduction.
  • A2E precursors form reversibly in photoreceptor outer segments, which are ingested by neighboring RPE cells after diurnal shedding.
  • A2E The final and irreversible step in the biosynthesis of A2E takes place in the acidic environment of RPE cell lysosomes.
  • A2E accumulates in RPE cells, it gradually poisons them by multiple cytotoxic mechanisms including lysosomal failure. This leads to the accumulation of undigested cellular debris called lipofuscin, which contains A2E and can be detected clinically by FAF.
  • lipofuscin As RPE cells deteriorate, they lose their ability to participate in the visual cycle and are unable to provide photoreceptors with other metabolic support required for normal retinal function (see Figure 1 ; Lamb TD, Pugh EN, Dark adaptation and the retinoid cycle of vision. Prog. Retinal and Eye Res. 2004;23 :307). As their metabolic support is withdrawn, photoreceptors fail to renew their shed outer segments and visual function is progressively lost. Reducing A2E formation will allow RPE cells to recover from A2E poisoning and resume their normal metabolic support of photoreceptor cells.
  • WO 2006/127945 discloses compounds and compositions that have been shown to reduce the formation of A2E, which as described above is the underlying etiology of macular degeneration including dry AMD and Stargardt's disease. These compounds are designed to inhibit A2E biosynthesis by reducing the amount of free RAL available for reaction with PE in photoreceptor outer segments, which is the first step in the A2E biosynthetic pathway. These compounds are lipophilic by design (i.e.
  • logP or clogP which are called logD or clogD respectively at pH 7.4 as used herein
  • logP or clogP which are called logD or clogD respectively at pH 7.4 as used herein
  • a different way to reduce A2E biosynthesis is to inhibit one or more proteins of the visual cycle, because when the visual cycle is inhibited, less RAL escapes the visual cycle and becomes available to react with PE and form A2E precursors.
  • Chronic treatment with a visual cycle inhibitor has been shown to reduce A2E synthesis in mouse (Radu et al, Treatment with isotretinoin inhibits lipofuscin accumulation in a mouse model of recessive Stargardt's macular degeneration. Proc Natl Acad Sci U S A. 2003; 100:4742).
  • neuroprotection mechanisms of action including but not limited to neurotrophic receptor agonists, anti-inflammatory compounds including complement cascade inhibitors, anti- apoptosis compounds, steroids and anti-oxidant compounds, and limiting the progression to wet AMD with VEGF receptor blockers which mitigate the effects of VEGF signaling by RPE cells that are in severe oxidative stress as a consequence of A2E toxicities.
  • topical ocular administration minimizes systemic exposure compared to oral dosing.
  • the present invention provides formulations and methods for topical ocular dosing of lipophilic compounds which treat macular degeneration (including dry AMD, GA secondary to dry AMD, wet AMD and Stargardt's disease) by reducing the formation of A2E and other naturally occurring bis-retinoids, by reacting covalently with free RAL that escapes the visual cycle and would otherwise form precursors of these compounds.
  • Figure 1 depicts the visual cycle.
  • Figure 2 depicts a time profile of the concentration of 14 C-Compound A in ng/g of ocular tissue.
  • Figure 3 depicts effects of RA treatment on dark adaptation rate in the mouse after acute TO or IP administration of 13-czs-retinoic acid.
  • One embodiment of the present invention provides pharmaceutical compositions for treating macular degeneration (including dry AMD, GA secondary to dry AMD, wet AMD and Stargardt's disease).
  • macular degeneration including dry AMD, GA secondary to dry AMD, wet AMD and Stargardt's disease.
  • the root cause of macular degeneration is the cytotoxic accumulation in RPE cells of naturally occurring bis-retinoids including A2E. This accumulation can be lowered pharmacologically by limiting the amount of free RAL that escapes the visual cycle and otherwise reacts with PE to form their precursors. As the accumulation of these compounds is reduced pharmacologically, RPE cells can recover from cytotoxic damage and resume their metabolic support of photoreceptors which is essential for normal visual function.
  • publications WO 2006/127945 compounds are described which reduce A2E accumulation in this manner and are therefore useful in treating macular degeneration.
  • the instant application incorporates by reference the subject matter of WO 2006/127945.
  • Lipophilic compounds which reduce A2E and thereby treat macular degeneration including dry AMD and Stargardt's disease by other means (e.g. by inhibiting the visual cycle) are also included within the scope of this invention.
  • Such compounds include ACU-4429. All such compounds have a logP or clogP greater than 0.
  • topical ocular administration minimizes systemic exposure compared to oral dosing.
  • most topical formulations have failed to deliver efficacious levels of drug to the retina which is the site of the mechanism of action.
  • a lipophilic active agent and a cyclodextrin, or chemically modified cyclodextrin including trimethyl- ⁇ - cyclodextrin, 2-hydroxyethyl-P-cyclodextrin, 2-hydroxypropyl-P-cyclodextrin, 3- hydroxypropyl-P-cyclodextrin, and ⁇ -cyclodextrin sulfobutylether sodium salt (or potassium salt)
  • efficacious levels of the lipophilic active agent are delivered to the back of the eye and specifically to the RPE and retina.
  • compositions of a lipophilic active agent and an oligomeric or a polymeric carrier such as a cyclodextrin or chemically modified cyclodextrin including trimethyl-P-cyclodextrin, 2-hydroxyethyl-p-cyclodextrin, 2- hydroxypropyl-P-cyclodextrin, 3-hydroxypropyl-P-cyclodextrin, and ⁇ -cyclodextrin sulfobutylether sodium salt (or potassium salt) are useful for the treatment of macular degeneration (including dry age-related macular degeneration, GA secondary to dry AMD, wet AMD and Stargardt's disease).
  • macular degeneration including dry age-related macular degeneration, GA secondary to dry AMD, wet AMD and Stargardt's disease.
  • One exemplification of the present invention is represented by a topical ophthalmic composition containing an active lipophilic compound and an oligomeric or a polymeric carrier such as a cyclodextrin, or a chemically modified cyclodextrin including trimethyl-p-cyclodextrin, 2-hydroxyethyl- -cyclodextrin, 2-hydroxypropyl-P-cyclodextrin, 3- hydroxypropyl-P-cyclodextrin, and ⁇ -cyclodextrin sulfobutylether sodium salt (or potassium salt) in an aqueous solution or a gel dispersion.
  • an active lipophilic compound and an oligomeric or a polymeric carrier
  • an oligomeric or a polymeric carrier such as a cyclodextrin, or a chemically modified cyclodextrin including trimethyl-p-cyclodextrin, 2-hydroxyethyl- -cyclodextrin, 2-
  • Such active lipophilic compounds include those that reduce A2E by reacting covalently with RAL, e.g. the compounds of WO 2006/127945.
  • Illustrative of such compounds are those described in WO 2006/127945 the contents of which application are herein incorporated by reference.
  • Exemplifying the compounds which may be employed in the instant invention are the compounds of formula
  • X, Y, and Z are each, independently, N, CH, C with the NH 2 attached, or absent, such that one of X, Y, and Z is N; p is 0, 1, 2, or 3,
  • B is a halogen atom, hydroxyl, carbamoyl, amino, or aryl, A is s D is unbranched lower alkyl.
  • compound A of paragraph (00027) of WO 2006/ 127945 and pharmaceutically acceptable salts thereof may be employed in the instant invention.
  • L is a single bond or CH 2 ;
  • X, Y, and Z are each, independently, N, NH, O, S, CB, CH, or absent, such that one of X, Y, and Z is N or
  • the amount of active agent in the composition will vary dependent on the intrinsic activity of the compound. However, for compounds of formula la and formula Ilia the amount will generally be from 0.01-1.0% weight/volume and more particularly 0.1% to 0.5% weight/volume.
  • a compound as described above may be used or a pharmaceutically acceptable salt of said compound.
  • the term lipophilic compound is meant to include the compound and its pharmaceutically acceptable salts.
  • a pharmaceutically acceptable salt herein means a salt that is capable of being topically delivered to the eye of a patient.
  • the carrier in the composition is an oligomeric or a polymeric carrier such as a cyclodextrin including trimethyl-p-cyclodextrin, 2-hydroxyethyl ⁇ -cyclodextrin, 2- hydroxypropyl- -cyclodextrin, 3-hydroxypropyl-P-cyclodextrin, and ⁇ -cyclodextrin sulfobutylether sodium salt (or potassium salt).
  • a cyclodextrin including trimethyl-p-cyclodextrin, 2-hydroxyethyl ⁇ -cyclodextrin, 2- hydroxypropyl- -cyclodextrin, 3-hydroxypropyl-P-cyclodextrin, and ⁇ -cyclodextrin sulfobutylether sodium salt (or potassium salt).
  • ⁇ -cyclodextrin sulfobutylether sodium salt Exemplifying an oligomeric or a polymeric carrier is ⁇ -cyclod
  • the amount of ⁇ -cyclodextrin sulfobutylether sodium salt in the aqueous preparation may range from about 0.01% to 30% weight/volume. In one illustration the concentration of ⁇ -cyclodextrin sulfobutylether sodium salt is 5-25% weight/volume. Further illustrating the concentration of ⁇ -cyclodextrin sulfobutylether sodium salt is 9.5-20%) weight/volume. In one exemplification the concentration of ⁇ -cyclodextrin sulfobutylether is 9.5% weight/volume.
  • each lipophilic agent may be formulated with each of the excipients.
  • the composition may contain saline and be buffered with for example a phosphate buffer so that the pH of the composition is brought to a pH range of 5.5-8.5 or more particularly a pH of 6.5-7.5.
  • a preservative may optionally be included in the composition. Such preservatives can include both chemical stabilizers and antiseptics.
  • Compounds such as Compounds A are stable under the conditions of use, however other compounds may require the use of other excipients such as anti-oxidants.
  • a second embodiment of the invention is directed to a method of treating macular degeneration (including dry age-related macular degeneration, GA secondary to dry AMD, wet AMD and Stargardt's disease), by administering a topical formulation of an active lipophilic compound and a carrier to the eye(s) of a patient.
  • macular degeneration including dry age-related macular degeneration, GA secondary to dry AMD, wet AMD and Stargardt's disease
  • the present invention provides a topical ophthalmic composition for use in treating macular degeneration wherein said composition comprises an active lipophilic compound and a carrier or a pharmaceutically acceptable salt thereof in an aqueous solution.
  • Exemplifying the carrier is ⁇ -cyclodextrin sulfobutylether or a pharmaceutically acceptable sat thereof.
  • the active lipophilic compound in each of these embodiments includes those that reduce A2E by reacting with RAL, e.g. the compounds of WO 2006/127945. Examples of such compounds are those described in WO 2006/127945. Exemplifying such compounds are Compounds A, B and C. Lipophilic Compounds which function by other mechanisms such as ACU-4429 are also included.
  • the term lipophilic compound is meant to include both the compound and its pharmaceutically acceptable salts.
  • the excipient in the formulation is oligomeric or polymeric such as a cyclodextrin or a chemically modified cyclodextrin, more particularly including ⁇ -cyclodextrin sulfobutylether sodium salt (or potassium salt).
  • each lipophilic compound formulated with each excipient.
  • the formulation may be buffered to a pH range of 5.5-8.5 or more particularly a pH of 6.5-7.5.
  • the buffer may be a phosphate buffer.
  • the formulation may be applied as an aqueous solution or a gel dispersion and the solution may be a saline solution. The accumulation of lipofuscin occurs in RPE cells in the back of the eye.
  • topical compositions as described herein deliver pharmacologically active levels of lipophilic active drug safely to the back of the eye after topical ocular administration and are therefore useful in the treatment of macular degeneration (including dry age-related macular degeneration, GA secondary to dry AMD, wet AMD and Stargardt's disease). Efficacious levels are defined as those that reduce A2E accumulation significantly in animal studies.
  • Formulations of a lipophilic active agent and an oligomeric or a polymeric carrier are prepared by stirring an aqueous suspension or solution of a polymeric carrier such as a cyclodextrin, or chemically modified cyclodextrin including trimethyl- -cyclodextrin, 2- hydroxyethyl- -cyclodextrin, 2-hydroxypropyl-P-cyclodextrin, 3-hydroxypropyl-P- cyclodextrin, and ⁇ -cyclodextrin sulfobutylether sodium (or potassium) salt with water, saline or phosphate-buffered saline at a temperature from 20°C to 50°C, but preferably at ambient temperature, for 0.1 -24 hr, depending on the polymeric carrier.
  • a polymeric carrier such as a cyclodextrin, or chemically modified cyclodextrin including trimethyl- -cyclodextrin, 2- hydroxyethyl
  • the lipophilic active agent is added as a solid or neat liquid to the thus formed aqueous suspension or solution of polymeric carrier, and the resulting mixture is stirred at a temperature from 20°C to 50°C, but preferably at ambient temperature, for 0.1-24 hr, but typically from 0.5-2 hr, depending on the lipophilic active agent.
  • the thus formed formulation of a lipophilic active agent and an oligomeric or a polymeric carrier may then be treated with an aqueous solution of an inorganic or organic acid or an inorganic or organic base to adjust the pH of the solution as desired.
  • preservatives including both chemical stabilizers and antiseptics.
  • Example 1 Preparation of a 0.1% w/v aqueous formulation of Compound A with 9.5% w/v ⁇ -cyclodextrin sulfobutylether.
  • the preparation was carried out in a 1000 ml beaker equipped with a stirring bar for mixing. Approximately 60% of the targeted weight of sterile water was added to the beaker. Stirring was adjusted so as not to incorporate air. Anhydrous dibasic sodium phosphate (0.83% of the total batch weight) and sodium phosphate monobasic monohydrate (0.017% of the total batch weight) was added to the vessel and mixed until dissolved, ⁇ - cyclodextrin sulfobutylether (9.5% of the total batch weight) was slowly added to the beaker and the solution mixed until dissolved. Compound A (0.1% of the total batch weight) was slowly added and mixed until dissolved. A sample was extracted and the pH measured. If the pH was not in the range 7.3 ⁇ 0.05 , adjustment was made with IN aqueous NaOH or IN aqueous HC1. The batch weight was measured and the amount of sterile water needed to bring to final batch weight was determined and added.
  • the target tissue for the biological activity of compounds which reversibly react with RAL, e.g. Compounds A, B and C, is the outer segment of retinal photoreceptor cells.
  • TO topical optical
  • Compound A delivers therapeutically useful amounts of, for example, Compound A to the retina
  • C57BL/6 mice, the parent strain of abcr -I- mice (knockout mouse) were treated intraperitoneal ly (IP) with 14 C-Compound A at 10 mg/kg ("efficacious dose"), specifically a dose that when repeated daily for 56 days reduced A2E formation by 71% (p ⁇ 0.01) in the abcr -I- mouse.
  • the eyes of the mice were enucleated and the posterior eyecup was dissected, extracted and analyzed by liquid scintillation chromatography (LSC) for ,4 C-Compound A.
  • LSC liquid scintillation chromatography
  • PK pharmacokinetics
  • Compound A in four intraocular regions of Cynomolgus Macaques was measured after topical dosing of 40 ⁇ per eye of 0.50% weight/volume 1 C-Compound A in ⁇ -cyclodextrin sulfobutylether sodium salt in phosphate- buffered saline.
  • Sampling of intraocular regions (vitreous humor, retina+RPE, anterior eyecup, and posterior eyecup) and blood for PK evaluation was conducted at 0.25, 0.5, 1, 3, 6 and 9 hours post dose.
  • Figure 2 shows the time course of 14 C-Compound A concentration expressed in nanograms (ng ) per gram (g) of ocular tissue.
  • retinoids can be used to demonstrate that a small lipophilic compound in a composition containing ⁇ -cyclodextrin sulfobutylether sodium salt exhibits biological activity in the retina minutes to hours after topical application to the front of the eye.
  • a retinoid useful for this purpose is 13-m-retinoic acid (RA, also known as isotretinoin).
  • RA 13-m-retinoic acid
  • Mice treated IP at 20 mg/kg with RA show visual cycle inhibition ( Figure 3).
  • Independent studies demonstrate that the visual cycle inhibition decreases A2E synthesis (Radu RA, Mata NL, Nusinowitz S, Liu X, Sieving PA, Travis GH.
  • Treatment with isotretinoin inhibits lipofuscin accumulation in a mouse model of recessive Stargardt's macular degeneration. Proc Natl Acad Sci 2003;100:4742).
  • mice treated TO with one or two 30 eyedrops of a composition containing 0.2% weight/volume RA and 20% weight/volume ⁇ -cyclodextrin sulfobutylether sodium salt in phosphate-buffered saline showed a dose-responsive inhibition of DA similar to that observed after IP dosing ( Figure 3) ⁇

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Abstract

La présente invention porte sur des compositions ophtalmiques topiques d'un composé lipophile et d'un support oligomère ou polymère, les compositions étant utiles dans le traitement et la prévention de la dégénérescence maculaire. L'invention porte également sur des procédés de traitement de la dégénérescence maculaire à l'aide d'une composition ophtalmique topique d'un composé lipophile et d'un support oligomère ou polymère.
PCT/US2010/059719 2009-12-11 2010-12-09 Compositions et procédés pour le traitement de la dégénérescence maculaire WO2011072141A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
JP2012543284A JP5885670B2 (ja) 2009-12-11 2010-12-09 黄斑変性の処置のための組成物および方法
CA2782015A CA2782015C (fr) 2009-12-11 2010-12-09 Compositions ophthalmiques topiques et methodes de traitement de la degenerescence maculaire
US13/514,769 US9814701B2 (en) 2009-12-11 2010-12-09 Compositions and methods for the treatment of macular degeneration
US15/782,470 US20180092882A1 (en) 2009-12-11 2017-10-12 Compositions and methods for the treatment of macular degeneration
US18/241,598 US12097188B2 (en) 2009-12-11 2023-09-01 Compositions and methods for the treatment of macular degeneration

Applications Claiming Priority (2)

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US28574509P 2009-12-11 2009-12-11
US61/285,745 2009-12-11

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US13/514,769 A-371-Of-International US9814701B2 (en) 2009-12-11 2010-12-09 Compositions and methods for the treatment of macular degeneration
US15/782,470 Continuation US20180092882A1 (en) 2009-12-11 2017-10-12 Compositions and methods for the treatment of macular degeneration

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WO2014116836A2 (fr) 2013-01-23 2014-07-31 Aldexa Therapeutics, Inc. Maladies liées à un aldéhyde toxique et traitement
US20150344447A1 (en) * 2013-01-25 2015-12-03 Aldeyra Therapeutics, Inc. Novel traps in the treatment of macular degeneration
US9364471B2 (en) 2005-05-26 2016-06-14 Aldeyra Therapeutics, Inc. Compositions and methods of treating retinal disease
WO2017035077A1 (fr) 2015-08-21 2017-03-02 Aldeyra Therapeutics, Inc. Composés deutérés et leurs utilisations
US10414732B2 (en) 2017-03-16 2019-09-17 Aldeyra Therapeutics, Inc. Polymorphic compounds and uses thereof
US10426790B2 (en) 2016-02-28 2019-10-01 Aldeyra Therapeutics, Inc. Treatment of allergic eye conditions with cyclodextrins
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US11040039B2 (en) 2017-10-10 2021-06-22 Aldeyra Therapeutics, Inc. Treatment of inflammatory disorders
US11197821B2 (en) 2018-09-25 2021-12-14 Aldeyra Therapeutics, Inc. Formulations for treatment of dry eye disease
US11312692B1 (en) 2018-08-06 2022-04-26 Aldeyra Therapeutics, Inc. Polymorphic compounds and uses thereof
WO2022092896A1 (fr) * 2020-10-29 2022-05-05 주식회사 피노바이오 Composition pharmaceutique destinée à être administrée comme collyre à un patient nécessitant une protection de nerf optique
EP3934660A4 (fr) * 2019-03-05 2022-11-23 Cornell University Compositions de matière présentant une activité pour éliminer la lipofuscine de cellules rétiniennes
US11786518B2 (en) 2019-03-26 2023-10-17 Aldeyra Therapeutics, Inc. Ophthalmic formulations and uses thereof
US12029735B2 (en) 2019-05-02 2024-07-09 Aldeyra Therapeutics, Inc. Polymorphic compounds and uses thereof
US12064516B2 (en) 2020-05-13 2024-08-20 Aldeyra Therapeutics, Inc. Pharmaceutical formulations and uses thereof
US12097188B2 (en) 2009-12-11 2024-09-24 Aldeyra Therapeutics, Inc. Compositions and methods for the treatment of macular degeneration
US12098132B2 (en) 2019-05-02 2024-09-24 Aldeyra Therapeutics, Inc. Process for preparation of aldehyde scavenger and intermediates

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CN116057654A (zh) 2020-08-24 2023-05-02 株式会社自动网络技术研究所 电抗器、转换器以及电力变换装置

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US20120302601A1 (en) 2012-11-29
US12097188B2 (en) 2024-09-24
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US20240148700A1 (en) 2024-05-09
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US9814701B2 (en) 2017-11-14
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CA2782015C (fr) 2020-08-25
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