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WO2023107796A1 - Formulations ophtalmiques pour la dégénérescence maculaire - Google Patents

Formulations ophtalmiques pour la dégénérescence maculaire Download PDF

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Publication number
WO2023107796A1
WO2023107796A1 PCT/US2022/079781 US2022079781W WO2023107796A1 WO 2023107796 A1 WO2023107796 A1 WO 2023107796A1 US 2022079781 W US2022079781 W US 2022079781W WO 2023107796 A1 WO2023107796 A1 WO 2023107796A1
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WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
progestin
administration
injection
macular degeneration
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2022/079781
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English (en)
Inventor
Polina V. LISHKO
Monika HAOUI
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
University of California Berkeley
University of California San Diego UCSD
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University of California Berkeley
University of California San Diego UCSD
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Application filed by University of California Berkeley, University of California San Diego UCSD filed Critical University of California Berkeley
Publication of WO2023107796A1 publication Critical patent/WO2023107796A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • 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
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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

Definitions

  • Age-related macular degeneration 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.
  • the RPE controls transepithelial transport of ions to establish a constant ion composition in the subretinal space to maintain constant excitability of the retina.
  • 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 ).
  • Kir7.1 gene name kcnjld
  • DHEA dehydroepiandrosterone
  • 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 MakenaTM) 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.
  • 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.
  • AMD age-related macular degeneration
  • 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.
  • the invention provides an ophthalmic, topical formulation or intraocular delivery of an inwardly rectifying potassium channel Kir7.1 activating synthetic progestins.
  • the invention provides for a pharmaceutical composition suitable for ocular administration of an inwardly rectifying potassium channel Kir7.1 activating synthetic progestin.
  • the pharmaceutical composition is formulated at a therapeutically effective dose that is suitable for ocular administration.
  • the progestin is selected from 17-alpha-hydroxyprogesterone caproate and/or dydrogesterone;
  • the progestin is at a therapeutically effective concentration of 0.01-10% or 0.05-2% or 0.1-1%;
  • 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.;
  • 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;
  • the formulation is in unit dosage form, such as a loaded contact lens, eye drop, depot or bollus;
  • the formulation is packaged in an eye drop dispenser; and/or injected via an intraocular route of administration;
  • 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.
  • the invention provides a method of using a disclosed formulation, comprising administering the formulation to an eye in need thereof.
  • the composition is formulated for topical administration as a liquid or a semi-solid.
  • the composition is formulated for intraocular administration including but not limited to intravitreal injection, periocular injection, sub-Tenon injection, suprachoroidal injection and intracameral injection.
  • the composition is formulated for extended release, including but not limited to an intraocular implant for extended release.
  • 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.
  • the eye is determined to be afflicted with an ocular disease or pathology;
  • 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.
  • the progestin is selected from 17-alpha-hydroxyprogesterone caproate and dydrogesterone.
  • FIGs. 1A-1D Native Kj r 7.1 expressed in RPE and recombinant K.,,7. 1 are activated by steroid hormone progesterone (P4) in similar manner.
  • P4 steroid hormone progesterone
  • HEK293 express Kir7.1 on the plasma membrane.
  • Lower panel individual HE293 cells show clear membrane expression of Kir7.1
  • Figs 2A-2E Human K.,,7. 1 is specifically regulated by progesterone (P4) and two synthetic steroids.
  • P4 progesterone
  • the steroids were applied in different orders for each cell, with P4 always added in the last order.
  • 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.
  • AMD age-related macular degeneration
  • Applicable polymeric controlled release microspheres eg. Yandrapu et al., J Ocul Pharmacol Ther. 2013 Mar; 29(2): 236-248
  • biodegradable polymers such as poly (lactic acid) (PLA), poly(glycolic acid) (PGA), and their copolymers
  • PLA poly(lactic-co-glycolic) acid
  • PLGA poly(lactic-co-glycolic) acid
  • 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).
  • 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.
  • water polyethers such as polyethylene glycol
  • polyvinyls such as
  • the formulation optionally includes a preservative, such as benzalkonium chloride and other inactive ingredients such as EDTA.
  • a preservative such as benzalkonium chloride and other inactive ingredients such as EDTA.
  • 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.
  • 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.
  • acids include acetic, boric, citric, lactic, phosphoric, hydrochloric, and the like
  • 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.
  • 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.
  • 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.
  • the present invention can be formulated as a pharmaceutical composition suitable for intraocular injection.
  • a pharmaceutical composition suitable for intraocular injection is well know in the art.
  • 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.
  • 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.
  • Kir7.1 pharmacological activation of Kir7.1 can compensate for the age- related loss-of-function triggered by the changes in bioactive steroids.
  • female sex steroid progesterone and DHEA specifically, potently, and directly activate Kir7.1.
  • recombinantly expressed Kir7.1 and Kir7.1 expressed in mammalian RPE are activated by progesterone in the identical manner2 (Fig.l).
  • Fig.l progesterone

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  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Dermatology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

Selon l'invention, la dégénérescence maculaire liée à l'âge (AMD) ou des maladies ou troubles oculaires similaires est traitée par administration ophtalmique ou oculaire d'un canal potassique rectifiant entrant Kir7.1 activant des progestines synthétiques à une concentration thérapeutiquement efficace. Une telle administration ophtalmique ou oculaire comprend une administration topique et/ou intraoculaire.
PCT/US2022/079781 2021-12-11 2022-11-14 Formulations ophtalmiques pour la dégénérescence maculaire Ceased WO2023107796A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202163288587P 2021-12-11 2021-12-11
US63/288,587 2021-12-11

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WO2023107796A1 true WO2023107796A1 (fr) 2023-06-15

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008070726A2 (fr) * 2006-12-05 2008-06-12 Southern College Of Optometry Traitement de l'œil sec
US8951996B2 (en) * 2011-07-28 2015-02-10 Lipocine Inc. 17-hydroxyprogesterone ester-containing oral compositions and related methods
US20200030304A1 (en) * 2017-03-11 2020-01-30 The Regents Of The University Of California Mitigation of cns disorders by combination therapy using neurosteroids, and ampa blockers
US20210128671A1 (en) * 2015-05-01 2021-05-06 Allysta Pharmaceuticals, Inc. Adiponectin peptidomimetics for treating ocular disorders

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008070726A2 (fr) * 2006-12-05 2008-06-12 Southern College Of Optometry Traitement de l'œil sec
US8951996B2 (en) * 2011-07-28 2015-02-10 Lipocine Inc. 17-hydroxyprogesterone ester-containing oral compositions and related methods
US20210128671A1 (en) * 2015-05-01 2021-05-06 Allysta Pharmaceuticals, Inc. Adiponectin peptidomimetics for treating ocular disorders
US20200030304A1 (en) * 2017-03-11 2020-01-30 The Regents Of The University Of California Mitigation of cns disorders by combination therapy using neurosteroids, and ampa blockers

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