WO2023107796A1 - Ophthalmic formulations for macular degeneration - Google Patents

Abstract

Age-related macular degeneration (AMD) or similar ocular diseases or disorders is treated with an ophthalmic or ocular administration of an inwardly rectifying potassium channel Kir7.1 activating synthetic progestins in a therapeutically effective concentration. Such ophthalmic or ocular administration includes topical and/or intraocular administration.

Description

Ophthalmic formulations for macular degeneration

[001] This invention was made with government support under AG070755 awarded by the National Institutes of Health. The government has certain rights in the invention.

[002] This application claims priority to US Ser. 63/288,587, filed: Dec 11, 2021, the disclosure of which is herein incorporated by reference.

[003] Introduction

[004] Age-related macular degeneration (AMD) is a leading cause of blindness, and its prevalence increases with age. Dry form of AMD, for which no treatment exists, accounts for 90% of all cases. Additionally, women are bearing a disproportionate amount of the AMD burden: about 2/3 of AMD patients are women. The earliest manifestations of AMD are an accumulation of a yellow substance called drusen that is a cause of dysfunction of retinal pigment epithelium (RPE). RPE is a caretaker tissue responsible for the maintenance of the retina and dysfunction in RPE results in retina degeneration and blindness. Out of many other factors that decline with age, are the levels of steroids progesterone and dehydroepiandrosterone (DHEA). Interestingly, they have been shown to exert potent neuroprotective actions. However, the mechanism behind this is not known. The RPE controls transepithelial transport of ions to establish a constant ion composition in the subretinal space to maintain constant excitability of the retina. In order to fulfill these functions, the RPE relies on a specific set of ion channels, and one of them is indispensable for healthy RPE function. This channel is inwardly rectifying potassium channel Kir7.1 (gene name kcnjld), and is vital for normal RPE physiology (Shimura, M. et al. J Physiol 2001 ). In humans, the loss-of-function mutations in kcnjl3 caused profound pathophysiology of RPE and blindness (Shahi et al. Scientific reports (2017); Hejtmancik, J. F. et al. American journal of human genetics (2008); Pattnaik, B. R. et al. PLoS One 2013). The RPE-specific deletion of this channel leads to photoreceptor degradation (Roman et al. , Experimental eye research 2018). The Kir7.1 dysfunction leads to altered transepithelial ion transport, cellular debris accumulation in the subretinal space, drusen formation, inflammation, all of which triggers retinopathy. Thus, to sustain healthy RPE, the function of its essential potassium channel Kir7.1 must be maintained at a high level. Recently, our group has discovered that female sex steroid progesterone (Bjbrkgren I, et al. J of Gen Physiology. 2021), and dehydroepiandrosterone (DHEA) specifically and potently activates the inwardly rectifying potassium channel Kir7.1, an essential protein expressed in the RPE, and the one that is also required for normal RPE function. We have also confirmed that recombinantly expressed human or mouse Kir7.1, as well as Kir7.1 expressed in murine RPE are activated by progesterone in the identical manner. This finding revealed that female sex steroid progesterone is an endogenous direct activator of potassium channel Kir7.1, a principal potassium channel in RPE. What is needed is the identification of therapeutic agents that can modulate Kir7.1 function and sustain normal RPE physiology.

[005] The invention described in the current application identifies potential modulators of Kir7.1. Kir7.1 is potently activated by two synthetic steroids, the compounds used to prevent premature labor, such as FDA-approved progestagens 17-alpha-hydroxyprogesterone caproate (aka Makena™) and dydrogesterone. The current application describe novel therapeutic applications of these steroids given their unique ability to activate Kir7.1 and methods and tools to administer these compounds in therapeutical concentrations to AMD patients, as well as patients with other forms of ophthalmic diseases and disorders.

[006] Summary of the Invention

[007] The invention provides methods and compositions an ocular disease or pathology, particularly age-related macular degeneration (AMD), and similar ophthalmic pathologies, including without limitation, wet age-related macular degeneration, dry age-related macular degeneration, diabetic retinopathy, diabetic macular edema, retinopathy, hypertensive retinopathy, retinitis pigmentosa and idiopathic retinopathy.

[008] In an aspect the invention provides an ophthalmic, topical formulation or intraocular delivery of an inwardly rectifying potassium channel Kir7.1 activating synthetic progestins. In another aspect, the invention provides for a pharmaceutical composition suitable for ocular administration of an inwardly rectifying potassium channel Kir7.1 activating synthetic progestin. In another aspect, the pharmaceutical composition is formulated at a therapeutically effective dose that is suitable for ocular administration.

[009] In embodiments:

[010] the progestin is selected from 17-alpha-hydroxyprogesterone caproate and/or dydrogesterone;

[Oil] the progestin is at a therapeutically effective concentration of 0.01-10% or 0.05-2% or 0.1-1%;

[012] the progestin is at a concentration of 0.0004-0.02% or 0.005-0.02% or 0.001-0.01%; [013] the formulation is in the form of an ophthalmic gel, ointment, suspension or solution, (lubricant), cyclodextrin containing mixture of via intraocular injection.;

[014] the formulation is in the form of a polymeric solid or semi-solid formulation that is a membrane, lens, wafer or microspheres, or via a complex with cyclodextrin containing suspension or solution; [015] the formulation is in the form a polymeric solid or semi-solid formulation that is a hydrogel contact lens;

[016] the formulation is in unit dosage form, such as a loaded contact lens, eye drop, depot or bollus;

[017] the formulation is packaged in an eye drop dispenser; and/or injected via an intraocular route of administration;

[018] the formulation further comprising excipients and features suitable for direct, topical delivery to the eye, selected from the group consisting of ophthalmically suitable clarity, pH buffer, tonicity, viscosity, stability and sterility.

[019] In an aspect the invention provides a method of using a disclosed formulation, comprising administering the formulation to an eye in need thereof. In another aspect, the composition is formulated for topical administration as a liquid or a semi-solid. In another aspect, the composition is formulated for intraocular administration including but not limited to intravitreal injection, periocular injection, sub-Tenon injection, suprachoroidal injection and intracameral injection. In another aspect, the composition is formulated for extended release, including but not limited to an intraocular implant for extended release.

[020] In an aspect the invention provides a method of treating an eye in need thereof, the method comprising delivering to the eye an inwardly rectifying potassium channel Kir7.1 activating synthetic progestin as mentioned above and/or their modification.

[021] In embodiments:

[022] the eye is determined to be afflicted with an ocular disease or pathology; and/or

[023] further comprising detecting a resultant improvement of the eye or diminution of the ocular disease or pathology.

[024] In an aspect the invention provides use of an inwardly rectifying potassium channel Kir7.1 activating progestin as treatment against dry age-related macular degeneration and disorders of the retinal pigment epithelium via modulation of Kir7.1 activity.

[025] In embodiments the progestin is selected from 17-alpha-hydroxyprogesterone caproate and dydrogesterone.

[026] The invention encompasses all combinations of the particular embodiments recited herein, as if each combination had been laboriously recited.

[027] Brief Description of the Drawings

[028] Figs. 1A-1D. Native Kj_r7.1 expressed in RPE and recombinant K.,,7. 1 are activated by steroid hormone progesterone (P4) in similar manner. A) An inwardly rectifying current, characteristic for Kir7.1 (blue), is detected in whole cell recordings from murine RPE cells and is activated by P4 (red) and inhibited by Kj_r7.1 specific antagonist VU590 (black). B) immunostaining from an isolated RPE cells showing membrane K^.l staining (red). Nuclei are stained by DAPI (blue). C) Dose-response of P4 potentiation of Kir7.1 expressed in HEK293.

D) HEK293 express Kir7.1 on the plasma membrane. Lower panel: individual HE293 cells show clear membrane expression of Kir7.1

[029] Figs 2A-2E. Human K.,,7. 1 is specifically regulated by progesterone (P4) and two synthetic steroids. A) The average current fold increase of human Kj_r7.1 when cells were incubated with 10 pM of P4, estogen (E2), estrone (E2), DHEA-sulfate (DHEA-S), cortisol (CORT), and DHEA. The steroids were applied in different orders for each cell, with P4 always added in the last order. B) The average current fold increase of human K.,,7- 1 when cells were incubated with 10 pM of P4, and different concentrations of 17-hydroxyprogesterone caproate (17OHPC). C) 17OHPC is more potent than P4 and requires longer time to washout. D). The average current fold increase of human K„7. 1 when cells were incubated with 10 pM of dydrogesterone (DYG). E) representative recording of Kir7.1 potentiation by DYG. 17-OHPC and DYG chemical structures are shown.

[030] Description of Particular Embodiments of the Invention

[031] Unless contraindicated or noted otherwise, in these descriptions and throughout this specification, the terms “a” and “an” mean one or more, the term “or” means and/or. It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein, including citations therein, are hereby incorporated by reference in their entirety for all purposes. [032] The invention provides topical or injectable ophthalmic methods and compositions for treating an ocular disease or pathology, particularly age-related macular degeneration (AMD), with an inwardly rectifying potassium channel Kir7.1 activating synthetic progestin, particularly in the form of form of an ophthalmic gel, ointment, suspension or solution, such as a polymeric solid or semi-solid formulation, like a membrane or lens, wafer or microspheres, and particularly in the form a polymeric solid or semi-solid formulation like a hydrogel contact lens or via intraocular injectables.

[033] Materials and methods for making such formulations are exemplified herein, and/or known in the art; for example, hydrogels in ophthalmic applications are reviewed in Kirchhof, Eur J Pharm Biopharm. 2015 Sep;95(Pt B):227-38, and recent developments in ocular drug delivery are reviewed in Chen, J Drug Target. 2015;23(7-8):597-604. [034] Applicable protocols for manufacturing, loading and delivering drugs in gel materials like contacts lenses and wafers are well-known in the art, e.g. Hsu et al., 2014, J Drug Deliv Sci Tech 24(2), 123-35, Review of ophthalmic drug delivery by contact lenses; 6. Alambiaga- Caravaca, et al., Int. J. Pharm. 2021 ;606: 120921.

[035] Applicable polymeric controlled release microspheres (eg. Yandrapu et al., J Ocul Pharmacol Ther. 2013 Mar; 29(2): 236-248), based on biodegradable polymers such as poly (lactic acid) (PLA), poly(glycolic acid) (PGA), and their copolymers, poly(lactic-co-glycolic) acid (PLGA) are known, as are applicable nanoparticles and nanostructured materials, e.g. Kim et al., Ther Deliv. 2015 Dec; 6(12): 1365-1376; Ciolino et a., Opthalmology 2016, 123 (10), 2085-92; Nanoparticles J Biomater Sci Polym Ed. 2014;25(l): 18-31; Bian et al.Invest Ophthalmol Vis Sci. 2016 Jun; 57(7): 3222-3230).

[036] A topical solution containing the progestin can contain a physiologically compatible vehicle, as those skilled in the ophthalmic art can select using conventional criteria. The ophthalmic vehicles include, but are not limited to, saline solution, water polyethers such as polyethylene glycol, polyvinyls such as polyvinyl alcohol and povidone, cellulose derivatives such as methylcellulose and hydroxypropyl methylcellulose, petroleum derivatives such as mineral oil and white petrolatum, animal fats such as lanolin, polymers of acrylic acid such as carboxypolymethylene gel, vegetable fats such as peanut oil and polysaccharides such as dextrans and dextrins like cyclodextrins (e.g. alpha-, beta-, gamma-cyclodextrins), and glycosaminoglycans such as sodium hyaluronate and salts such as sodium chloride and potassium chloride.

[037] The formulation optionally includes a preservative, such as benzalkonium chloride and other inactive ingredients such as EDTA. However, for chronic (over two weeks) use, preferred formulations are those without any preservatives due to the potential for damage to the comeal epithelium that may result from long term, frequent exposure to preservatives such as benzalkonium chloride. The formulations without preservatives are prepared in a unit dose and stored in a single-use container.

[038] The pH of the formulation is adjusted by adding any physiologically and ophthamologically acceptable pH adjusting acids, bases or buffers to within the range of about 5 to 7.5, preferably 6 to 7. Examples of acids include acetic, boric, citric, lactic, phosphoric, hydrochloric, and the like, and examples of bases include sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate, tromethamine, THAM (trishydroxymethylamino-methane), and the like. Salts and buffers include citrate/dextrose, sodium bicarbonate, ammonium chloride and mixtures of the aforementioned acids and bases. [039] The osmotic pressure of the aqueous ophthalmic composition is generally from about 200 to about 400 milliosmolar (mOsM), more preferably from 260 to 340 mOsM. The osmotic pressure can be adjusted by using appropriate amounts of physiologically and ophthalmologically acceptable ionic or non-ionic agents. Sodium chloride is a preferred ionic agent, and the amount of sodium chloride ranges from about 0.01% to about 1% (w/v), and preferably from about 0.05% to about 0.45% (w/v). Equivalent amounts of one or more salts made up of cations such as potassium, ammonium and the like and anions such as chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate, bisulfate, sodium bisulfate, ammonium sulfate, and the like can be used in addition to or instead of sodium chloride to achieve osmolality within the above-stated range. Further, non-ionic agents such as mannitol, dextrose, sorbitol, glucose and the like can also be used to adjust the osmolality. Other factors for formulation that can be determined by one skilled in the art includes adjusting for suitable tonicity and or viscosity of the formulation. Such formulations may include one or more of the following: an inwardly rectifying potassium channel Kir7.1 activating synthetic progestin in a therapeutically effective amount, a tonicity agent, a viscosity-inducing agent and an aqueous carrier component.

[040] In other embodiments, the present invention can be formulated as a pharmaceutical composition suitable for intraocular injection. Such formulation is well know in the art. There are several routes of intraocular administration including but not limited to intravitreal injection, periocular injection, sub-Tenon injection, suprachoroidal injection, and intracameral injection. One skilled in the art can determine the best route of administration for the present invention and the suitable formulation for such route of administration.

[041] In another embodiment, the present invention can be formulated for extended release. Such formulations are well known in the art and includes intraocular deposit of a depot of a pharmaceutical composition of the present invention that is suitable for extended release.

[042] Example 1. Kir7.1 can be activated by synthetic progestins

[043] We disclose that pharmacological activation of Kir7.1 can compensate for the age- related loss-of-function triggered by the changes in bioactive steroids. We have found that female sex steroid progesterone and DHEA specifically, potently, and directly activate Kir7.1. We have also confirmed that recombinantly expressed Kir7.1 and Kir7.1 expressed in mammalian RPE are activated by progesterone in the identical manner2 (Fig.l). We have found compounds that activate Kir7.1 and mimic endogenous progesterone action. These results demonstrate the molecular mechanism of Kir7.1 -driven control of RPE physiology and reveal Kir7.1 as a novel therapeutic target to sustain normal RPE function. [044] Our initial screen for compounds that potently activate Kir7.1 revealed two drugs, 17- alpha-hydroxyprogesterone (17OHPC) caproate and dydrogesterone (Fig.2). 17OHPC not only specifically and potently activated Kir7.1, but had a much stronger affinity towards Kir7.1 (Fig. 2B-C). 17OHPC is an FDA approved drug known as Makena™, which is used to prevent preterm labor. Dydrogesterone is currently in human trials. Our invention repurposes these drugs for dry age-related macular degeneration and disorders of the retinal pigment epithelium via modulation of Kir7.1 activity, and provides topical, ophthalmic formulations, such as eyedrop based supplementation of Makena to administer to patients diagnosed with early stages of dry AMD.

[045] References:

[046] 1. Shimura, M. et al. Expression and permeation properties of the K(+) channel Kir7.1 in the retinal pigment epithelium. J Physiol 531, 329-346, doi:10.1111/j.l469-7793.2001.0329i.x (2001).

[047] 2. Bjbrkgren I, Mendoza S, Chung DH, Haoui M, Petersen N, and Lishko PV. The epithelial potassium channel Kir7.1 is stimulated by progesterone.. J of Gen Physiology. 2021. Oct 4;153(10):e202112924. doi: 10.1085/jgp.202112924. Epub 2021 Aug 13. PMID: 34387656 [048] 3. Roman, D., Zhong, H., Yaklichkin, S., Chen, R. & Mardon, G. Conditional loss of Kenji 3 in the retinal pigment epithelium causes photoreceptor degeneration. Experimental eye research 176, 219-226, doi:10.1016/j.exer.2018.07.014 (2018).

[049] 4. Shahi, P. K. et al. Abnormal Electroretinogram after Kir7.1 Channel Suppression Suggests Role in Retinal Electrophysiology. Scientific reports 7, 10651, doi:10.1038/s41598- 017-11034-1 (2017).

[050] 5. Hejtmancik, J. F. et al. Mutations in KCNJ13 cause autosomal-dominant snowflake vitreoretinal degeneration. American journal of human genetics 82, 174-180, doi:10.1016/j.ajhg.2007.08.002 (2008).

[051] 6. Pattnaik, B. R. et al. Snowflake vitreoretinal degeneration (SVD) mutation R162W provides new insights into Kir7.1 ion channel structure and function. PLoS One 8, e71744, doi:10.1371/journal.pone.0071744 (2013).

Claims

1. A pharmaceutical composition suitable for ocular administration comprising an inwardly rectifying potassium channel Kir7.1 activating synthetic progestin.

2. The pharmaceutical composition of claim 1 wherein the progestin is selected from 17-alpha- hydroxyprogesterone caproate and dydrogesterone.

3. The pharmaceutical composition of claim 1, wherein the ocular administration is topical administration.

4. The pharmaceutical composition of claim 1, wherein the ocular administration is intraocular administration.

5. The pharmaceutical composition of claim 3, wherein the composition is formulated for topical administration as a liquid or a semi- solid.

6. The pharmaceutical composition of claim 5 wherein the composition formulated for topical administration as a semi-solid is selected from the group consisting of a gel, an ointment, suspension and a lubricant.

7. The pharmaceutical composition of claim 4, wherein the intraocular administration is selected from the group consisting of intravitreal injection, periocular injection, sub-Tenon injection, suprachoroidal injection, intracameral injection.

8. The pharmaceutical composition of claim 1 wherein the synthetic progestin is selected from 17-alpha-hydroxyprogesterone caproate and dydrogesterone.

9. A method of treating an eye disease or disorder , the method comprising delivering to the eye a therapeutically effective amountof an inwardly rectifying potassium channel Kir7.1 activating synthetic progestin.

10. The method of claim 9 wherein the eye disease or disorder is selected from the group consisting of wet age-related macular degeneration, dry age-related macular degeneration, diabetic retinopathy, diabetic macular edema, retinopathy, hypertensive retinopathy, retinitis pigmentosa and idiopathic retinopathy.

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11. The method claim 9, wherein the progestin is selected from 17-alpha-hydroxyprogesterone caproate and dydrogesterone.

12. The method of claim 8 further comprising detecting a resultant improvement of the eye or diminution of the ocular disease or pathology.

13. Use of an inwardly rectifying potassium channel Kir7.1 activating synthetic progestin as treatment against dry age-related macular degeneration and other disorders of the retinal pigment epithelium via modulation of Kir7.1 activity.

14. The use of claim 13, wherein the progestin is selected from 17-alpha-hydroxyprogesterone caproate and dydrogesterone.

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