Classifications

• • 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
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
  • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
• • 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

• IOL intraocular lens
• the standard of care for cataract removal is phacoemulsification with intraocular lens implantation, which uses energy from ultrasound to break up the eye’s innate lens into smaller pieces, which are then aspirated from the eye.
• the energy introduced into the eye during phacoemulsification can result in undesirable endothelial injury resulting in corneal edema and endothelial cell loss.
• Endothelial cell loss has been widely studied in the literature with mean percentages varying from 0.4 to 27.7% depending on the surgical technique (Tsorbatzoglou, 2007).
• the corneal endothelium is a single layer of hexagonal cells that sit on a modified basement membrane (Descemet membrane) which lines the inner surface of the cornea. This monolayer forms a barrier between the aqueous humor of the anterior chamber of the eye and the cornea.
• the endothelial cells contain Na+/K+ pumps that return water to the aqueous humor, causing the corneal stroma to remain in a state of relative dehydration, thereby maintaining corneal transparency.
• ECD endothelial cell density
• the pump function starts to decrease, the cornea thickens, and the resultant corneal edema leads to a visual haze due to impairment of corneal transparency (Van den Bogerd, 2018).
• endothelial damage due to intraocular surgery or implants can cause endothelial failure, ultimately necessitating corneal transplantation.
• Ripasudil is a selective inhibitor of Rho-kinase (ROCK), a serine-threonine protein kinase which binds with low-molecular weight G protein Rho to form the Rho/Rho-kinase signalling system (Ishizaki, 1996).
• ROCK Rho-kinase
• Rho/Rho-kinase signalling system Ishizaki, 1996.
• Okumura and colleagues tested the hypothesis that ripasudil could be used as a treatment for corneal injuries (Okumura, 2011).
• Fujimoto and colleagues conducted a retrospective observational study of 13 subjects (16 eyes) with glaucoma who had undergone cataract surgery with ripasudil prescribed from the day after surgery for 6 months. (Fujimoto, 2021).
• WO 2022/159533 discloses methods for treating Fuchs endothelial corneal dystrophy (“FECD”) with ripasudil, and the use of ripasudil to promote healing in FECD patients following descemetorhexis.
• FECD Fuchs endothelial corneal dystrophy
• US 9,844,556 B2 discloses the use of ripasudil for the prevention of secondary cataract and anterior capsule contraction.
• Ripasudil ophthalmic solution 0.4% has been marketed in Japan for the treatment of glaucoma and ocular hypertension since December 2014.
• the present disclosure relates to ripasudil-based ophthalmic treatments following intraocular surgery.
• the method both improves post-surgical outcomes, particularly visual acuity following such surgeries, and reduces side effects including, but not limited to, ocular irritation and gastrointestinal upset or irritation.
• the disclosure provides a method of improving visual acuity following intra-ocular surgery in a patient having confluent central guttae in the Descemet membrane and a cataractous lens in an eye, wherein the intraocular surgery comprises removing a central portion of the Descemet membrane from the eye and replacing the lens in the eye, comprising: (a) topically administering to the eye a therapeutically effective amount of ripasudil or a pharmaceutically acceptable salt thereof four times per day for twelve or more weeks following the surgery; and (b) improving the patient’s visual acuity.
• the disclosure provides a method of returning corneal thickness to pre-surgery values, and maintaining said pre-surgery values following cessation of treatment, following intra-ocular surgery in a patient having confluent central guttae in the Descemet membrane and a cataractous lens in an eye, wherein the intraocular surgery comprises removing a central portion of the Descemet membrane from the eye and replacing the lens in the eye, comprising: (a) topically administering to the eye a therapeutically effective amount of ripasudil or a pharmaceutically acceptable salt thereof four times per day for twelve or more weeks following the surgery; (b) returning corneal thickness in the eye to pre-surgery values; and (c) maintaining corneal thickness at said pre-surgery levels following cessation of said administering.
• the disclosure provides a method of returning corneal thickness to pre-surgery values, and maintaining said pre-surgery values following cessation of treatment, following intra-ocular surgery in a patient having a cataractous lens in an eye, wherein the intraocular surgery comprises replacing the lens in the eye, comprising: (a) topically administering to the eye a therapeutically effective amount of ripasudil or a pharmaceutically acceptable salt thereof four times per day for twelve or more weeks following the surgery; (b) returning corneal thickness in the eye to pre-surgery values; and (c) maintaining corneal thickness at said pre-surgery levels following cessation of said administering.
• the disclosure provides a method of improving surgical outcomes from intra-ocular surgery in a patient having confluent central guttae in the Descemet membrane and a cataractous lens in an eye, wherein the intraocular surgery comprises removing a central portion of the Descemet membrane from the eye and replacing the lens in the eye, comprising: (a) topically administering to the eye a therapeutically effective amount of ripasudil or a pharmaceutically acceptable salt thereof four times per day for twelve or more weeks following the surgery; and (b) improving a surgical outcome selected from central corneal endothelial cell density, peripheral corneal endothelial cell density, endothelial cell coefficient of variation and hexagonality, return of central corneal thickness to pre-surgery baseline, clearance of corneal edema, best corrected distance visual acuity (BCVA), Visual Function Questionnaire-25 (VFQ- 25) domains and total score, and combinations thereof.
• BCVA best corrected distance visual acuity
• VFQ- 25 Visual Function Questionnaire-25 domains and total score
• the disclosure provides a method of preventing or reducing adverse events resulting from intra-ocular surgery in a patient in need thereof having an endothelial cellular density (ECD) greater than 1,500 cells/mm 2 , comprising topically administering to the patient a therapeutically effective amount of ripasudil or a pharmaceutically acceptable salt thereof following the intra-ocular surgery.
• ECD endothelial cellular density
• the disclosure provides a method of preventing or reducing adverse events resulting from intra-ocular surgery in a patient at increased risk of such adverse events, comprising topically administering to the patient a therapeutically effective amount of ripasudil or a pharmaceutically acceptable salt thereof following the intra-ocular surgery, wherein: (a) the surgery comprises phacoemulsification with intraocular lens implantation; and (b) the patient is at increased risk of adverse events due to one or a combination of anterior chamber depth, phacoemulsification power and duration, hard and large nucleus, endothelial contact from nuclear fragments, IOL, air bubbles, irrigation fluid, implantation technique, type of IOL, short axial length, free radical release, small pupil, and toxicity of medications given during surgery.
• the disclosure provides a method of improving post-surgical outcomes from intra-ocular surgery in a patient in need thereof having an endothelial cellular density (ECD) greater than 1,500 cells/mm 2 , comprising topically administering to the patient a therapeutically effective amount of ripasudil or a pharmaceutically acceptable salt thereof following the intra-ocular surgery; wherein the post-surgical outcome is selected from: (a) central corneal endothelial cell density; (b) peripheral corneal endothelial cell density; (c) endothelial cell coefficient of variation and hexagonality; (d) return of central corneal thickness to pre-surgery baseline; (e) clearance of corneal edema; (f) best corrected distance visual acuity (BCVA); (g) Visual Function Questionnaire-25 (VFQ-25) domains and total score; and (h) combinations thereof.
• ECD endothelial cellular density
• the disclosure provides a method of improving post-surgical outcomes from intra-ocular surgery in a non-glaucomatous patient, comprising topically administering to the patient a therapeutically effective amount of ripasudil or a pharmaceutically acceptable salt thereof following the intra-ocular surgery; wherein the post-surgical outcome is selected from: (a) central corneal endothelial cell density; (b) peripheral corneal endothelial cell density; (c) endothelial cell coefficient of variation and hexagonality; (d) return of central corneal thickness to pre-surgery baseline; (e) clearance of corneal edema; (f) best corrected distance visual acuity (BCVA); (g) Visual Function Questionnaire-25 (VFQ-25) domains and total score; and (h) combinations thereof.
• the post-surgical outcome is selected from: (a) central corneal endothelial cell density; (b) peripheral corneal endothelial cell density; (c) endothelial cell coefficient of variation and hexagonality; (d) return of central
• the disclosure provides a method of preventing adverse events from intra-ocular surgery comprising phacoemulsification with intraocular lens implantation in a non- glaucomatous patient in need thereof, comprising topically administering to the patient a therapeutically effective amount of ripasudil or a pharmaceutically acceptable salt thereof following the intra-ocular surgery.
• the disclosure provides a method of preventing adverse events from intra-ocular surgery comprising phacoemulsification with intraocular lens implantation in a patient in need thereof, comprising topically administering to the patient four times daily a therapeutically effective amount of ripasudil or a pharmaceutically acceptable salt thereof following the intraocular surgery.
• the disclosure provides a method of preventing or reducing adverse events resulting from intra-ocular surgery comprising phacoemulsification with intraocular lens implantation in a patient in need thereof having an endothelial cellular density (ECD) greater than 1,500 cells/mm 2 , comprising topically administering to the patient a therapeutically effective amount of ripasudil or a pharmaceutically acceptable salt thereof following the intra-ocular surgery.
• ECD endothelial cellular density
• the disclosure provides a method of improving post-surgical outcomes from intra-ocular surgery comprising phacoemulsification with intraocular lens implantation in a patient in need thereof having an endothelial cellular density (ECD) greater than 1,500 cells/mm 2 , comprising topically administering to the patient a therapeutically effective amount of ripasudil or a pharmaceutically acceptable salt thereof following the intra-ocular surgery; wherein the post-surgical outcome is selected from: (a) central corneal endothelial cell density; (b) peripheral corneal endothelial cell density; (c) endothelial cell coefficient of variation and hexagonality; (d) return of central corneal thickness to pre-surgery baseline; (e) clearance of corneal edema; (f) best corrected distance visual acuity (BCVA); (g) Visual Function Questionnaire-25 (VFQ-25) domains and total score; and (h) combinations thereof.
• ECD endothelial cellular density
• the disclosure provides a method of improving surgical outcomes from intra-ocular surgery in a patient having confluent central guttae in the Descemet membrane of any eye, comprising: (a) removing a central portion of the Descemet membrane from the eye; and (b) topically administering to the eye a therapeutically effective amount of ripasudil or a pharmaceutically acceptable salt thereof four times per day for twelve or more weeks following the surgery.
• Yet another embodiment provides a preservative-free liquid solution of ripasudil hydrochloride comprising from 0.3% (w/v) to 0.5% (w/v) ripasudil hydrochloride, based on the weight of the free base of ripasudil excluding any waters of hydration.
• the disclosure provides a preservative-free liquid solution of ripasudil hydrochloride comprising: (a) from 0.3% (w/v) to 0.5% (w/v) ripasudil hydrochloride, based on the weight of the free base of ripasudil excluding any waters of hydration; (b) an optional pH buffer; (c) from 1.5% (w/v) to 2.0% (w/v) glycerol; (d) sodium hydroxide q.s. to a pH of from 4 to 7.5; and (e) purified water q.s. to 100%.
• the word “comprise” and variations of the word, such as “comprising” and “comprises,” means “including but not limited to,” and is not intended to exclude, for example, other additives, components, integers or steps.
• the word “comprise” and variations of the word, such as “comprising” and “comprises,” means “including but not limited to,” and is not intended to exclude, for example, other additives, components, integers or steps.
• “Therapeutically effective amount” means that amount which, when administered to a human for supporting or affecting a metabolic process, or for treating or preventing a disease, is sufficient to cause such treatment or prevention of the disease, or supporting or affecting the metabolic process.
• ranges are given by specifying the lower end of a range separately from the upper end of the range, or specifying particular numerical values, it will be understood that a range can be defined by selectively combining any of the lower end variables, upper end variables, and particular numerical values that is mathematically possible.
• a range when a range is defined as spanning from one endpoint to another, the range will be understood also to encompass a span between and excluding the two endpoints.
• drug therapy method of treatment, and terms of similar import is recited, it will be understood that the therapy can be accomplished through any suitable route of administration using any acceptable dosage form, and that the drug can be administered as the free base, a salt, or an ester or other prodrug moiety.
• treatment means to reduce the occurrence of a symptom or condition, or to relieve or alleviate at least one symptom associated with such condition, or to slow or reverse the progression of such condition, or to manage or affect the metabolic processes underlying such condition.
• the terms also denote to arrest, delay the onset (i.e., the period prior to clinical manifestation of a disease) and/or reduce the risk of developing or worsening a disease or adverse event.
• preventing” or “reducing” an adverse event will include reducing the risk of an adverse event, or reducing the severity of an adverse event, or delaying the onset of an adverse event, in a single patient or a patient population.
• compositions of the disclosure refers to molecular entities and other ingredients of such compositions that are physiologically tolerable and do not typically produce untoward reactions when administered to a subject (e g., a mammal such as a human).
• Ripasudil a derivative of fasudil, is a rho kinase inhibitor drug marketed in Japan as Glanatec® for the treatment of glaucoma and ocular hypertension.
• the compound has the following chemical structure: and is present in the preferred solutions of the present disclosure as a hydrochloride salt, more preferably the dihydrate hydrochloride salt.
• ripasudil When the term “ripasudil” is used herein, without any further qualifier, it will be understood to refer to ripasudil free base or any pharmaceutically acceptable salt or hydrate thereof, in any pharmaceutically acceptable crystalline or amorphous form.
• ripasudil ripasudil hydrochloride, or ripasudil hydrochloride dihydrate
• concentration is based on the weight of the anhydrous ripasudil free base, without considering the contributing weight of the hydrochloride ion or any waters of hydration, unless stated expressly to the contrary.
• the disclosure provides in one embodiment a method of improving visual acuity following intra-ocular surgery in a patient having confluent central guttae in the Descemet membrane and a cataractous lens in an eye, wherein the intraocular surgery comprises removing a central portion of the Descemet membrane from the eye and replacing the lens in the eye, comprising: (a) topically administering to the eye a therapeutically effective amount of ripasudil or a pharmaceutically acceptable salt thereof four times per day for twelve or more weeks following the surgery; and (b) improving the patient’s visual acuity.
• the disclosure provides a method of returning corneal thickness to presurgery values, and maintaining said pre-surgery values following cessation of treatment, following intra-ocular surgery in a patient having confluent central guttae in the Descemet membrane and a cataractous lens in an eye, wherein the intraocular surgery comprises removing a central portion of the Descemet membrane from the eye and replacing the lens in the eye, comprising: (a) topically administering to the eye a therapeutically effective amount of ripasudil or a pharmaceutically acceptable salt thereof four times per day for twelve or more weeks following the surgery; (b) returning corneal thickness in the eye to pre-surgery values; and (c) maintaining corneal thickness at said pre-surgery levels following cessation of said administering.
• the disclosure provides a method of returning corneal thickness to pre-surgery values, and maintaining said pre-surgery values following cessation of treatment, following intra-ocular surgery in a patient having a cataractous lens in an eye, wherein the intraocular surgery comprises replacing the lens in the eye, comprising: (a) topically administering to the eye a therapeutically effective amount of ripasudil or a pharmaceutically acceptable salt thereof four times per day for twelve or more weeks following the surgery; (b) returning corneal thickness in the eye to pre-surgery values; and (c) maintaining corneal thickness at said pre-surgery levels following cessation of said administering.
• the disclosure provides a method of improving surgical outcomes from intra-ocular surgery in a patient having confluent central guttae in the Descemet membrane and a cataractous lens in an eye, wherein the intraocular surgery comprises removing a central portion of the Descemet membrane from the eye and replacing the lens in the eye, comprising: (a) topically administering to the eye a therapeutically effective amount of ripasudil or a pharmaceutically acceptable salt thereof four times per day for twelve or more weeks following the surgery; and (b) improving a surgical outcome selected from central corneal endothelial cell density, peripheral corneal endothelial cell density, endothelial cell coefficient of variation and hexagonality, return of central corneal thickness to pre-surgery baseline, clearance of corneal edema, best corrected distance visual acuity (BCVA), Visual Function Questionnaire-25 (VFQ- 25) domains and total score, and combinations thereof.
• BCVA best corrected distance visual acuity
• VFQ- 25 Visual Function Questionnaire-25 domains and total score
• the disclosure provides a method of preventing or reducing adverse events resulting from intra-ocular surgery in a patient in need thereof having an endothelial cellular density (ECD) greater than 1,500 cells/mm 2 , comprising topically administering to the patient a therapeutically effective amount of ripasudil or a pharmaceutically acceptable salt thereof following the intra-ocular surgery.
• ECD endothelial cellular density
• the disclosure provides a method of preventing or reducing adverse events resulting from intra-ocular surgery in a patient at increased risk of such adverse events, comprising topically administering to the patient a therapeutically effective amount of ripasudil or a pharmaceutically acceptable salt thereof following the intra-ocular surgery, wherein: (a) the surgery comprises phacoemulsification with intraocular lens implantation; and (b) the patient is at increased risk of adverse events due to one or a combination of anterior chamber depth, phacoemulsification power and duration, hard and large nucleus, endothelial contact from nuclear fragments, IOL, air bubbles, irrigation fluid, implantation technique, type of IOL, short axial length, free radical release, small pupil, and toxicity of medications given during surgery.
• the disclosure provides a method of improving post-surgical outcomes from intra-ocular surgery in a patient in need thereof having an endothelial cellular density (ECD) greater than 1,500 cells/mm 2 , comprising topically administering to the patient a therapeutically effective amount of ripasudil or a pharmaceutically acceptable salt thereof following the intra-ocular surgery; wherein the post-surgical outcome is selected from: (a) central corneal endothelial cell density; (b) peripheral corneal endothelial cell density; (c) endothelial cell coefficient of variation and hexagonality; (d) return of central corneal thickness to pre-surgery baseline; (e) clearance of corneal edema; (f) best corrected distance visual acuity (BCVA);(g) Visual Function Questionnaire-25 (VFQ-25) domains and total score; and (h) combinations thereof.
• ECD endothelial cellular density
• the disclosure provides a method of improving post-surgical outcomes from intra-ocular surgery in a non-glaucomatous patient, comprising topically administering to the patient a therapeutically effective amount of ripasudil or a pharmaceutically acceptable salt thereof following the intra-ocular surgery; wherein the post-surgical outcome is selected from: (a) central corneal endothelial cell density; (b) peripheral corneal endothelial cell density; (c) endothelial cell coefficient of variation and hexagonality; (d) return of central corneal thickness to pre-surgery baseline; (e) clearance of corneal edema; (f) best corrected distance visual acuity (BCVA); (g) Visual Function Questionnaire-25 (VFQ-25) domains and total score; and (h) combinations thereof.
• the post-surgical outcome is selected from: (a) central corneal endothelial cell density; (b) peripheral corneal endothelial cell density; (c) endothelial cell coefficient of variation and hexagonality; (d) return of central
• the disclosure provides a method of preventing adverse events from intra-ocular surgery comprising phacoemulsification with intraocular lens implantation in a non- glaucomatous patient in need thereof, comprising topically administering to the patient a therapeutically effective amount of ripasudil or a pharmaceutically acceptable salt thereof following the intra-ocular surgery.
• the disclosure provides a method of preventing adverse events from intra-ocular surgery comprising phacoemulsification with intraocular lens implantation in a patient in need thereof, comprising topically administering to the patient four times daily a therapeutically effective amount of ripasudil or a pharmaceutically acceptable salt thereof following the intraocular surgery.
• the disclosure provides a method of preventing or reducing adverse events resulting from intra-ocular surgery comprising phacoemulsification with intraocular lens implantation in a patient in need thereof having an endothelial cellular density (ECD) greater than 1,500 cells/mm 2 , comprising topically administering to the patient a therapeutically effective amount of ripasudil or a pharmaceutically acceptable salt thereof following the intra-ocular surgery.
• ECD endothelial cellular density
• the disclosure provides a method of improving post-surgical outcomes from intra-ocular surgery comprising phacoemulsification with intraocular lens implantation in a patient in need thereof having an endothelial cellular density (ECD) greater than 1,500 cells/mm 2 , comprising topically administering to the patient a therapeutically effective amount of ripasudil or a pharmaceutically acceptable salt thereof following the intra-ocular surgery; wherein the post-surgical outcome is selected from: (a) central corneal endothelial cell density; (b) peripheral corneal endothelial cell density; (c) endothelial cell coefficient of variation and hexagonality; (d) return of central corneal thickness to pre-surgery baseline; (e) clearance of corneal edema; (f) best corrected distance visual acuity (BCVA);(g) Visual Function Questionnaire-25 (VFQ-25) domains and total score; and (h) combinations thereof.
• ECD endothelial cellular density
• the disclosure provides a preservative-free liquid solution of ripasudil hydrochloride comprising: (a) from 0.3% (w/v) to 0.5% (w/v) ripasudil hydrochloride, based on the weight of the free base of ripasudil excluding any waters of hydration; (b) an optional pH buffer; (c) from 1.5% (w/v) to 2.0% (w/v) glycerol; (d) sodium hydroxide q.s. to a pH of from 4 to 7.5; and (e) purified water q.s. to 100%.
• the patient has peripheral ECD ungradable in all areas (nasal, temporal, superior, and inferior) due to a medical reason such as guttae, corneal edema, or striae and baseline BCVA>0.
• the ripasudil can also be supplemented by an antibiotic and/or a steroid.
• the methods of the current invention may additionally further comprise after step (a) topically administering to the treated eye a broad-spectrum antibiotic, preferably 0.5% moxifloxacin hydrochloride and a glucocorticoid, preferably 1% prednisolone acetate.
• the methods also can prevent or reduce or reduce the risk of adverse events.
• the methods also can be practiced to prevent or reduce or reduce the risk of one or more adverse events selected from corneal edema, endothelial cell loss, corneal scarring, reduced visual acuity, cystoid macular edema, increased intraocular pressure, posterior capsular opacification (secondary cataract), chronic uveitis, fibrin formation, protein leakage from the breakdown of the blood- aqueous barrier, retinal detachment, posterior vitreous detachment, photophobia, ocular irritation, gastrointestinal toxicities, and relapse edema.
• the methods can be practiced to reduce or prevent corneal adverse events.
• the methods can prevent or reduce an adverse event which is a comeal adverse event selected from comeal edema, endothelial cell loss, corneal scarring, and reduced visual acuity.
• the methods are practiced to reduce corneal irritation or eye irritation associated with prior methods, particularly ocular discomfort or gritty sensations.
• the methods also can be practiced to prevent or reduce an adverse event which is a non- corneal adverse event.
• the methods can prevent or reduce an adverse event which is a a non-corneal adverse event selected from cystoid macular edema, increased intraocular pressure, posterior capsular opacification (secondary cataract), chronic uveitis, fibrin formation, protein leakage from the breakdown of the blood-aqueous barrier, retinal detachment, posterior vitreous detachment, photophobia, ocular irritation, gastrointestinal toxicities, and relapse edema.
• the methods are practiced to reduce gastrointestinal toxicities commonly associate with ROCK inhibitors such as gastrointestinal upset.
• the methods are practiced to reduce the incidence of relapse edema.
• any pharmaceutically acceptable solution of ripasudil at a concentration of from 0.1 to 1.0% (w/v) ripasudil, is suitable for practicing the methods of the current disclosure.
• the solution is free of preservatives such as benzalkonium chloride.
• the solution is free of benzalkonium chloride.
• a preferred concentration of ripasudil is from 0.2 to 0.5% (w/v) or approximately 0.4% (w/v) in the solution.
• the solution comprises less than 0.1%, 0.01%, 0.001%, 0.0001%, 0.00001%, or 0.000001% (w/v) preservatives.
• the solution comprises less than 0.1%, 0.01%, 0.001%, 0.0001%, 0.00001%, or 0.000001% (w/v) benzalkonium chloride.
• a preferred formulation will be preservative-free, and will further comprise glycerin, sodium dihydrogen phosphate and sodium hydroxide at a pH of from about 5 to about 7.
• the sodium dihydrogen phosphate can be hydrated or anhydrous, but in a preferred embodiment is the dihydrate.
• the glycerin can be biologically derived or synthetic, and may comprise up to 20% (v/v) water when added to the formulation, but is preferably synthetic and preferably comprises less than 1%, 0.5%, or 0.1% (v/v) water when added to the formulation. If water is present in the glycerin when added to the formulation, it will be understood that the water is not used in any of the calculations of glycerin concentration used in this document.
• Pharmaceutically acceptable carriers include aqueous solutions, non-toxic excipients, including salts, preservatives, buffers and the like, as described, for instance, in Remington's Pharmaceutical Sciences, 15th ed., Easton: Mack Publishing Co., 1405-1412, 1461-1487 (1975), and The National Formulary XIV., 14th ed., Washington: American Pharmaceutical Association (1975), the contents of which are hereby incorporated by reference.
• the pH and exact concentration of the various components of pharmaceutical compositions can be adjusted according to routine skills in the art. See Goodman and Gilman's, The Pharmacological Basis for Therapeutics (7th ed.).
• the formulation used in the methods of the current disclosure is the same formulation that constitutes the seventh principal embodiment of the present disclosure.
• the methods of the present disclosure are practiced with a preservative-free liquid solution of ripasudil hydrochloride comprising: (a) from 0.3% (w/v) to 0.5% (w/v) ripasudil hydrochloride, based on the weight of the free base of ripasudil excluding any waters of hydration; (b) an optional pH buffer; (c) from 1.5% (w/v) to 2.0% (w/v) glycerol;
• the formulation comprises from 0.35% (w/v) to 0.45% (w/v) ripasudil hydrochloride, based on the weight of the free base of ripasudil excluding any waters of hydration.
• the formulation comprises from 0.35% (w/v) to 0.45% (w/v) sodium dihydrogen phosphate, excluding any waters of hydration;
• a particularly preferred formulation comprises (a) approximately 0.4% (w/v) ripasudil hydrochloride, based on the weight of the free base of ripasudil excluding any waters of hydration;
• any of the foregoing embodiments or subembodiments can be further characterized by comprising: (a) approximately 0.49 g/100 mL ripasudil hydrochloride dihydrate; (b) approximately 0.52 g/100 mL sodium dihydrogen phosphate dihydrate; (c) the absence of any preservatives, anti-oxidants, or chelating agents; (d) the absence of benzalkonium chloride; and/or
• Embodiment 1 A method of improving visual acuity following intra-ocular surgery in a patient having confluent central guttae in the Descemet membrane and a cataractous lens in an eye, wherein the intraocular surgery comprises removing a central portion of the Descemet membrane from the eye and replacing the lens in the eye, comprising: (a) topically administering to the eye a therapeutically effective amount of ripasudil or a pharmaceutically acceptable salt thereof four times per day for twelve or more weeks following the surgery; and (b) improving the patient’s visual acuity.
• Embodiment 4 A method of improving surgical outcomes from intra-ocular surgery in a patient having confluent central guttae in the Descemet membrane and a cataractous lens in an eye, wherein the intraocular surgery comprises removing a central portion of the Descemet membrane from the eye and replacing the lens in the eye, comprising: (a) topically administering to the eye a therapeutically effective amount of ripasudil or a pharmaceutically acceptable salt thereof four times per day for twelve or more weeks following the surgery; and (b) improving a surgical outcome selected from central corneal endothelial cell density, peripheral corneal endothelial cell density, endothelial cell coefficient of variation and hexagonality, return of central corneal thickness to pre-surgery baseline, clearance of corneal edema, best corrected distance visual acuity (BCVA), Visual Function Questionnaire-25 (VFQ-25) domains and total score, and combinations thereof.
• BCVA Visual Function Questionnaire-25
• Embodiment 6 A method of preventing or reducing adverse events resulting from intraocular surgery in a patient at increased risk of such adverse events, comprising topically administering to the patient a therapeutically effective amount of ripasudil or a pharmaceutically acceptable salt thereof following the intra-ocular surgery, wherein: (a) the surgery comprises phacoemulsification with intraocular lens implantation; and (b) the patient is at increased risk of adverse events due to one or a combination of anterior chamber depth, phacoemulsification power and duration, hard and large nucleus, endothelial contact from nuclear fragments, IOL, air bubbles, irrigation fluid, implantation technique, type of IOL, short axial length, free radical release, small pupil, and toxicity of medications given during surgery.
• Embodiment 7 A method of improving post-surgical outcomes from intra-ocular surgery in a patient in need thereof having an endothelial cellular density (ECD) greater than 1,500 cells/mm 2 , comprising topically administering to the patient a therapeutically effective amount of ripasudil or a pharmaceutically acceptable salt thereof following the intra-ocular surgery; wherein the post-surgical outcome is selected from: (a) central corneal endothelial cell density; (b) peripheral corneal endothelial cell density; (c) endothelial cell coefficient of variation and hexagonality; (d) return of central corneal thickness to pre-surgery baseline; (e) clearance of corneal edema; (f) best corrected distance visual acuity (BCVA); (g) Visual Function Questionnaire-25 (VFQ-25) domains and total score; and (h) combinations thereof.
• ECD endothelial cellular density
• Embodiment 8 A method of improving post-surgical outcomes from intra-ocular surgery in a non-glaucomatous patient, comprising topically administering to the patient a therapeutically effective amount of ripasudil or a pharmaceutically acceptable salt thereof following the intraocular surgery; wherein the post-surgical outcome is selected from: (a) central corneal endothelial cell density; (b) peripheral corneal endothelial cell density; (c) endothelial cell coefficient of variation and hexagonality; (d) return of central corneal thickness to pre-surgery baseline; (e) clearance of corneal edema; (f) best corrected distance visual acuity (BCVA); (g) Visual Function Questionnaire-25 (VFQ-25) domains and total score; and (h) combinations thereof.
• the post-surgical outcome is selected from: (a) central corneal endothelial cell density; (b) peripheral corneal endothelial cell density; (c) endothelial cell coefficient of variation and hexagonality; (d) return
• Embodiment 9 A method of preventing adverse events from intra-ocular surgery comprising phacoemulsification with intraocular lens implantation in a non-glaucomatous patient in need thereof, comprising topically administering to the patient a therapeutically effective amount of ripasudil or a pharmaceutically acceptable salt thereof following the intra-ocular surgery.
• Embodiment 11 A method of preventing or reducing adverse events resulting from intraocular surgery comprising phacoemulsification with intraocular lens implantation in a patient in need thereof having an endothelial cellular density (ECD) greater than 1,500 cells/mm 2 , comprising topically administering to the patient a therapeutically effective amount of ripasudil or a pharmaceutically acceptable salt thereof following the intra-ocular surgery.
• ECD endothelial cellular density
• Embodiment 12 A method of improving post-surgical outcomes from intra-ocular surgery comprising phacoemulsification with intraocular lens implantation in a patient in need thereof having an endothelial cellular density (ECD) greater than 1,500 cells/mm 2 , comprising topically administering to the patient a therapeutically effective amount of ripasudil or a pharmaceutically acceptable salt thereof following the intra-ocular surgery; wherein the post- surgical outcome is selected from: (a) central corneal endothelial cell density; (b) peripheral corneal endothelial cell density; (c) endothelial cell coefficient of variation and hexagonality; (d) return of central corneal thickness to pre-surgery baseline; (e) clearance of corneal edema; (f) best corrected distance visual acuity (BCVA); (g) Visual Function Questionnaire-25 (VFQ-25) domains and total score; and (h) combinations thereof.
• ECD endothelial cellular density
• a method of improving surgical outcomes from intra-ocular surgery in a patient having confluent central guttae in the Descemet membrane of any eye comprising: (a) removing a central portion of the Descemet membrane from the eye; and (b) topically administering to the eye a therapeutically effective amount of ripasudil or a pharmaceutically acceptable salt thereof four times per day for twelve or more weeks following the surgery.
• Embodiment 22 The method of any of embodiments 1-21, wherein the patient is at increased risk of adverse events due to one or a combination of anterior chamber depth, phacoemulsification power and duration, hard and large nucleus, endothelial contact from nuclear fragments, IOL, air bubbles, irrigation fluid, implantation technique, type of IOL, short axial length, free radical release, small pupil, and toxicity of medications given during surgery.
• a post-surgical outcome selected from: (a) central corneal endothelial cell density; (b) peripheral corneal endothelial cell density; (c) endothelial cell coefficient of variation and hexagonality; (d) return of central corneal thickness to pre-surgery baseline; (e) clearance of corneal edema; (f) best corrected distance visual acuity (BCVA); (g) Visual Function Questionnaire-25 (VFQ-25) domains and total score; and (h) combinations thereof.
• a post-surgical outcome selected from: (a) central corneal endothelial cell density; (b) peripheral corneal endothelial cell density; (c) endothelial cell coefficient of variation and hexagonality; (d) return of central corneal thickness to pre-surgery baseline; (e) clearance of corneal edema; (f) best corrected distance visual acuity (BCVA); (g) Visual Function Questionnaire-25 (VFQ-25) domains and total score; and (h) combinations thereof.
• BCVA Best corrected
• Embodiment 24 The method of any of embodiments 1-23, comprising reducing one or more adverse events selected from corneal edema, endothelial cell loss, corneal scarring, reduced visual acuity, cystoid macular edema, increased intraocular pressure, posterior capsular opacification (secondary cataract), chronic uveitis, fibrin formation, protein leakage from the breakdown of the blood-aqueous barrier, retinal detachment, posterior vitreous detachment, photophobia, ocular irritation, gastrointestinal toxicities, and relapse edema.
• adverse events selected from corneal edema, endothelial cell loss, corneal scarring, reduced visual acuity, cystoid macular edema, increased intraocular pressure, posterior capsular opacification (secondary cataract), chronic uveitis, fibrin formation, protein leakage from the breakdown of the blood-aqueous barrier, retinal detachment, posterior vitreous detachment, photophobia
• Embodiment 28 The method of any of embodiments 1-27, comprising preventing or reducing an adverse event which is a corneal adverse event selected from corneal edema, endothelial cell loss, corneal scarring, and reduced visual acuity.
• an adverse event which is a corneal adverse event selected from corneal edema, endothelial cell loss, corneal scarring, and reduced visual acuity.
• an adverse event which is a non-corneal adverse event selected from cystoid macular edema, increased intraocular pressure, posterior capsular opacification (secondary cataract), chronic uveitis, fibrin formation, protein leakage from the breakdown of the blood-aqueous barrier, retinal detachment, posterior vitreous detachment, photophobia, ocular irritation, gastrointestinal toxicities, and relapse edema.
• an adverse event which is a non-corneal adverse event selected from cystoid macular edema, increased intraocular pressure, posterior capsular opacification (secondary cataract), chronic uveitis, fibrin formation, protein leakage from the breakdown of the blood-aqueous barrier, retinal detachment, posterior vitreous detachment, photophobia, ocular irritation, gastrointestinal toxicities, and relapse edema.
• Embodiment 38 The method of any of embodiments 1-37, wherein the patient is at increased risk of adverse events due to one or a combination of anterior chamber depth, phacoemulsification power and duration, hard and large nucleus, endothelial contact from nuclear fragments, IOL, air bubbles, irrigation fluid, implantation technique, type of IOL, short axial length, free radical release, small pupil, and toxicity of medications given during surgery.
• a preservative-free liquid solution of ripasudil hydrochloride comprising from 0.3% (w/v) to 0.5% (w/v) ripasudil hydrochloride, based on the weight of the free base of ripasudil excluding any waters of hydration.
• a preservative-free liquid solution of ripasudil hydrochloride comprising: (a) from 0.3% (w/v) to 0.5% (w/v) ripasudil hydrochloride, based on the weight of the free base of ripasudil excluding any waters of hydration; (b) an optional pH buffer; (c) from 1 .5% (w/v) to 2.0% (w/v) glycerol; (d) sodium hydroxide q.s. to a pH of from 4 to 7.5; and (e) purified water q.s. to 100%.
• Embodiment 42 The solution of embodiment 40 or 41, comprising from 0.35% (w/v) to 0.45% (w/v) sodium dihydrogen phosphate, excluding any waters of hydration.
• Embodiment 43 The solution of embodiment 40 or 41, comprising: (a) approximately 0.4% (w/v) ripasudil hydrochloride, based on the weight of the free base of ripasudil excluding any waters of hydration; (b) approximately 0.4% (w/v) sodium dihydrogen phosphate, excluding any waters of hydration; (c) approximately 1.77% (w/v) glycerol; (d) sodium hydroxide q.s. to a pH of from 5 to 7; and (e) purified water q.s. to 100%.
• Example 1 Optimized Ripasudil Eye Drop Formulation K-321 investigational medicinal product will be sterile non-preserved unit dose eye drops containing ripasudil hydrochloride dihydrate equivalent to 0.4% ripasudil.
• each patient underwent descemetorhexis of a study eye selected by the investigator for surgery.
• a digital photo of the study eye was taken immediately before and immediately after the descemetorhexis.
• the investigator performed descemetorhexis to remove central confluent guttae, removing an area of Descemet membrane with a diameter of 4.5 to 5.5 mm. The longest diameter and the shortest diameter was recorded.
• Detailed procedures for performing descemetorhexis are described in several literature references, including, for example, Macsai MS, Shiloach M. Cornea. 2019;38:529-534, and Moloney G, Congote DG, Hirnschall N, et al. Cornea. 2020 Jul 31. doi: 10.1097/ICO.0000000000002437. Online ahead of print.
• Example 3 A Double Masked, Randomized, Placebo Controlled, Parallel Group, 12 Week, Phase 2 Study to Investigate the Safety and Efficacy of Ripasudil Eye Drops After Descemetorhexis in Patients with Fuchs Endothelial Corneal Dystrophy _
• the first period was the treatment period, consisting of a screening visit within a 1-to 4- week screening period, a descemetorhexis and randomisation visit, a 12-week full treatment period containing 7 interim visits (including 1 optional visit at Week 2) and an end-of-treatment (EOT) visit scheduled for Week 12.
• EOT end-of-treatment
• the second period was a follow-up observation period of 40 weeks, including the tapering phase and containing 4 interim visits and an end-of-study (EOS) visit. Patients were not to selfadminister study drug after approximately Week 14. Patients were considered to have completed the study with the completion of their EOS visit (scheduled for Week 52).
• EOS end-of-study
• study drug was dosed by the patient 4 times per day: morning, mid-day, evening, and night.
• Each patient was provided with 2 sets of color-coded ampoule pouches, one set to be applied morning and night (M/N) and the other to be applied mid-day and evening (MD/E).
• M/N morning and night
• MD/E mid-day and evening
• Visit 3 patients did not apply any study drug until after all study measurements had been completed; thereafter on those days, patients started dosing with the dose closest in timing to the dosing regimen and continued with the remaining doses for the day. Additionally, on Visit 3 they applied study drug after the end of the descemetorhexis procedure on Day-1 (Visit2).
• a central corneal image analysis reading centre determined central ECD by analysing digital images of the corneal endothelium.
• the study eye descemetorhexis is confirmed to have excised a central area with confluent guttae and a diameter of 4.5 to 5.5 mm.
• Safety assessments included the identification of AEs ocular safety assessments of both eyes (including slit lamp examination without pupil dilation to evaluate the condition of the lids, conjunctiva, anterior chamber, and cornea; intra ocular pressure measurement; and ocular examination with pupil dilation using an indirect ophthalmoscope according to the current standard of practice to evaluate the condition of the vitreous, macula, retina, optic nerve, choroid, and retinal periphery); vital sign measurements; and laboratory examinations.
• Study drug was either K-321 ophthalmic solution containing ripasudil 0.4% (K-321 0.4%) or matching placebo.
• the K-321 treatments comprised either BID or QID dosing of K-321.
• BCVA best corrected distance visual acuity
• EDRS early treatment diabetic retinopathy study
• Example 5 A Double-Masked, Randomized, Placebo-Controlled, Parallel-Group, 12-Week Administration With Two-Week Gradual Dose Taper Phase and 38-Week Follow- Up Phase, Phase 3 Study to Investigate the Safety and Efficacy of Ripasudil (K- 321) Eye Drops After Descemetorhexis in Subjects with Fuchs Endothelial Corneal Dystrophy
• Peripheral ECD ungradable in all areas (nasal, temporal, superior, and inferior) due to a medical reason such as guttae, corneal edema, or striae and baseline BCVA>0
• the ECD values that are available will be taken to calculate an average. If any of the areas are ungradable due to any reason other than a medical reason (eg, guttae, corneal edema, or striae) the subject will be excluded (eg, subjects with any ungradable images due to technical difficulties).
• a medical reason eg, guttae, corneal edema, or striae
• the BCVA baseline will be measured 1 day after descemetorhexis and will be used in stratification for randomization.
• the peripheral ECD measurement to be used for stratification for randomization will be the peripheral ECD measurement at screening (pre-DSO).
• the baseline for central corneal ECD and central corneal endothelial cell parameters (Coefficient of Variation and Hexagonality) will be the post-operative cell density, since this will be zero in all subjects following descemetorhexis and thus will provide a useful baseline measurement.
• the baseline for all other efficacy and safety variables will be the values/measurements obtained at the screening visit (Visit 1).
• the primary efficacy endpoint is time to >40 ETDRS letter improvement in BCVA during the first 12 weeks after descemetorhexis.
• the tertiary efficacy endpoints are:
• V -FUCHS Visual Function and Corneal Health Status
• the study eye descemetorhexis at Visit 2 is confirmed to have excised a central area with confluent guttae and a diameter of 4.5 to 5.5 mm
• Example 6 A Double-Masked, Randomized, Placebo-Controlled, Parallel-Group, 12-Week Administration With Two-Week Gradual Dose Taper Phase and 38-Week Follow- Up Phase, Phase 3 Study to Investigate the Safety and Efficacy of Ripasudil (K- 321) Eye Drops After Simultaneous Cataract Surgery and Descemetorhexis in Subjects with Fuchs Endothelial Corneal Dystrophy
• Peripheral ECD ungradable in all areas (nasal, temporal, superior, and inferior) due to a medical reason such as guttae, corneal edema, or striae and baseline BCVA>0
• ECD Average peripheral ECD >1200 cells/mm 2 and baseline BCVA>0 If any of the values (nasal, temporal, superior, or inferior) are ungradable due to a medical reason (eg, guttae, corneal edema, or striae), the ECD values that are available will be taken to calculate an average. If any of the areas are ungradable due to any reason other than a medical reason (eg, guttae, corneal edema, or striae) the subject will be excluded (eg, subjects with any ungradable images due to technical difficulties).
• a medical reason eg, guttae, corneal edema, or striae
• the BCVA baseline will be measured 1 day after simultaneous cataract surgery and descemetorhexis and will be used in stratification for randomization.
• the peripheral ECD measurement to be used for stratification for randomization will be the peripheral ECD measurement at screening (before simultaneous cataract surgery and descemetorhexis).
• the baseline for central corneal ECD and central corneal endothelial cell parameters (Coefficient of Variation and Hexagonality) will be the post-operative cell density, since this will be zero in all subjects following simultaneous cataract surgery and descemetorhexis and thus will provide a useful baseline measurement.
• the baseline for all other efficacy and safety variables will be the values/measurements obtained at the screening visit (Visit 1). Select endpoints for the study are as follows:
• the primary efficacy endpoint is time to >40 ETDRS letter improvement in BCVA during the first 12 weeks after simultaneous cataract surgery and descemetorhexis.
• the key secondary efficacy endpoints are:
• Time to failure of therapy (defined as events of rescue keratoplasty, rescue treatments other than keratoplasty, study drug discontinuation due to lack of efficacy, and withdrawal from the study due to lack of efficacy) during the 52-week period after simultaneous cataract surgery and descemetorhexis.
• the tertiary efficacy endpoints are:
• Proportion of subjects who experience failure of therapy defined as events of rescue keratoplasty, rescue treatments other than keratoplasty, study drug discontinuation due to lack of efficacy, and withdrawal from the study due to lack of efficacy) at each visit.
• V-FUCHS Corneal Health Status
• the study eye descemetorhexis at Visit 2 is confirmed to have excised a central area with confluent guttae and a diameter of 4.5 to 5.5 mm

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