Netarsudil ophthalmological formulations with less toxicity

Abstract

A formulation of netarsudil has been developed which is efficacious with reduced redness and pain. The formulation appears to deliver at least as much drug to the eye in animal studies based on the demonstration that it reduced IOP at least as well as did RHOPRESSA®. The data shows improved IOP lowering efficacy with higher concentrations of netarsudil, while still reducing key side effects like ocular redness, as compared to RHOPRESSA®.

Description

[0001]NETARSUDIL OPHTHALMOLOGICAL FORMULATIONS WITH LESS TOXICITY CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Application No. 63 / 578,811 filed August 25, 2023, which is incorporated herein by reference in its entirety. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with government support under Grant No. EY031041 awarded by the National Institutes of Health. The government has certain rights in the invention. FIELD OF THE INVENTION This invention is generally in the field of ophthalmological formulations of netarsudil. BACKGROUND OF THE INVENTION Glaucoma is a group of eye diseases which in most cases produce increased pressure within the eye. This elevated pressure is caused by a backup of fluid in the eye. Over time, it causes damage to the optic nerve. The aqueous humor is constantly circulating through the anterior chamber. It is produced by the ciliary body, situated behind the iris. It flows between the iris and the lens and, after nourishing the cornea and lens, flows out through a very tiny spongy tissue, only one-fiftieth of an inch wide, called the trabecular meshwork, which serves as the drain of the eye. The trabecular meshwork is situated in the angle where the iris and cornea meet. When this drain becomes clogged, aqueous can not leave the eye as fast as it is produced, causing the fluid to back up. The backed up fluid causes increased pressure to build up within the eye. This is called open (wide) angle glaucoma. The pressure causes the eye to give at the weakest point, which is the site in the sclera at which the optic nerve leaves the eye. The optic nerve is part of the central nervous system and carries visual information from the eye to the brain. This cranial nerve is made up of over one million nerve axons, which are nerve fiber extensions of the retinal ganglion cells. When the eye pressure is increased and / or other inciting factors exist, the optic nerve becomes damaged and the retinal ganglion cells undergo a slow process of cell death termed “apoptosis.” The death of the retinal cells and degeneration of the nerve fibers results in permanent vision loss. Early diagnosis and treatment of glaucoma can help prevent blindness. 1 45677417.1 Treating ocular disorders presents many problems for drug delivery. The preferred means for ocular drug delivery is via the topical route, due to ease of access and patient compliance. Ocular mucosa plays an important role in drug . Glaucoma treatment often starts with prescription eye drops. Some may decrease eye pressure by improving how fluid drains from the eye. Others decrease the amount of fluid the eye makes. Prescription eye drop medicines include: Prostaglandins. These increase the outflow of the fluid in the eye, helping to reduce eye pressure. This category include latanoprost (Xalatan), travoprost (Travatan Z), tafluprost (Zioptan), bimatoprost (Lumigan) and latanoprostene bunod (Vyzulta). Possible side effects include mild reddening and stinging of the eyes, darkening of the iris, darkening of the pigment of the eyelashes or eyelid skin, and blurred vision. This class of drug is prescribed for once-a- day use. Beta blockers. These reduce the production of fluid in the eye, helping to lower eye pressure. Examples include timolol (Betimol, Istalol, Timoptic) and betaxolol (Betoptic S). Possible side effects include difficulty breathing, slowed heart rate, lower blood pressure, impotence and fatigue. This class of drug can be prescribed for once- or twice-daily use depending on the condition. Alpha-adrenergic agonists. These reduce the production of the fluid that flows throughout the inside of the eye. They also increase the outflow of fluid in the eye. Examples include apraclonidine (Iopidine) and brimonidine (Alphagan P, Qoliana). Possible side effects include irregular heart rate, high blood pressure, fatigue, red, itchy or swollen eyes, and dry mouth. This class of drug is usually prescribed for twice-daily use but sometimes can be prescribed for use three times a day. Carbonic anhydrase inhibitors. These reduce the production of fluid in the eye. Examples include dorzolamide and brinzolamide (Azopt). Possible side effects include a metallic taste, frequent urination, and tingling in the fingers and toes. This class of drug is usually prescribed for twice-daily use but sometimes can be prescribed for use three times a day. Miotic or cholinergic agents increase the outflow of fluid from the eye. An example is pilocarpine (Isopto Carpine). Side effects include headache, eye ache, smaller pupils, possible blurred or dim vision, and nearsightedness. This class of medicine is usually prescribed to be used up to four times a day. Because of potential side effects and the need for frequent daily use, these medicines are not prescribed very often anymore. 2 45677417.1 Rho kinase inhibitor. This lowers eye pressure by suppressing the rho kinase enzymes responsible for fluid increase. It is available as netarsudil (RHOPRESSA®) and is prescribed for once-a-day use. Side effects include eye redness and eye discomfort. RHOPRESSA®is an FDA-approved eyedrop, with the active agent netarsudil at a concentration of 0.02% w / w, that is used for treating patients with glaucoma. It is considered among the best agents in terms of lowering intraocular pressure in humans with glaucoma, which is key to preserving vision in these patients. However, RHOPRESSA®has not performed well as a product (disappointing sales) primarily because it causes major ocular redness and ocular pain / ache. Therefore, it is an object of the invention to provide improved formulations for delivery of glaucoma agents such as netarsudile with greater efficacy and safety and / or fewer side effects. SUMMARY OF THE INVENTION A formulation of netarsudil has been developed which is efficacious with reduced redness and pain. The formulation appears to deliver at least as much drug to the eye in animal studies based on the demonstration that it reduced IOP at least as well as did RHOPRESSA®. RHOPRESSA®is an FDA-approved eyedrop, with the active agent netarsudil at a concentration of 0.02% w / w, that is used for treating patients with glaucoma. However, RHOPRESSA® causes major ocular redness and also causes ocular pain / ache in some patients. The data shows improved IOP lowering efficacy with higher concentrations of netarsudil, while still reducing key side effects like ocular redness, as compared to RHOPRESSA®. The formulations contain between 0.2 and 0.5 mg netarsudil dimesylate or other salt of netarsudil, preferably 0.28 or 0.42 mg netarsudil dimesylate / ml, formulated in a PLURONIC®triblock polymer, preferably POLOXAMER 407, in a range of 11-13%, most preferably 12%, and polyethylene glycol 400, in range of 0.2-0.6 % w / v, most preferably 0.4% w / v, typically also containing agents such as benzalkonium chloride or polyquaternium-1 for sterility, boric acid, mannitol, and sodium chloride to adjust pH to 5.0 and osmolarity of about 150 mOsm / kg. The polymer formulation is referred to herein as “OcuGel”. In the most preferred embodiments, the formulation contains: Active 0.28 mg / mL of netarsudil dimesylate (for 0.02% w / v netarsudil) or 0.42 mg / mL of netarsudil dimesylate (for 0.03% w / v netarsudil) 3 45677417.1 Polymer 120 mg / mL Poloxamer 407 (12% w / w) 4 mg / mL polyethylene glycol 400 (0.4% w / v) Agents to adjust tonicity, pH, osmolarity 0.6 mg / mL boric acid (10 mM) 1.83 mg / mL mannitol (10 mM) pH adjusted to about 5 with HCl Osmolality adjusted to about 150 mOsm / kg with NaCl Optional agents to preserve sterility 0.15 mg / mL benzalkonium chloride (0.015% w / v) Examples demonstrate efficacy and reduced side effects in animals as well as human subjects. BRIEF DESCRIPTION OF THE DRAWINGS FIGs.1A and 1B are graphs of the change in intraocular pressure (ΔIOP) after topical dosing with OcuGel NM 0.02% or OcuGel NM 0.03% compared to RHOPRESSA®0.02% in normotensive rabbits (n = 5 per group). Dotted line denotes the starting average IOP (ΔIOP = 0). The data is presented as mean ± SEM, *p < 0.05. FIG.1B is a graph of the cumulative ΔIOP (area under the curve, AUC) after topical dosing with of RHOPRESSA®or OcuGel NM 0.03%. The cumulative ΔIOP was calculated as the area under the curve over the 24 hours measurement period (AUClast, n = 5). The data is presented as mean ± SEM, *p < 0.05. DETAILED DESCRIPTION OF THE INVENTION I. DEFINITIONS As generally used herein “pharmaceutically acceptable” refers to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit / risk ratio. “Biocompatible” and “biologically compatible”, as used herein, generally refer to materials that are, along with any metabolites or degradation products thereof, generally non- toxic to the recipient, and do not cause any significant adverse effects to the recipient. Generally 4 45677417.1 speaking, biocompatible materials are materials which do not elicit a significant inflammatory, immune or toxic response when administered to an individual. The terms “gel” and “hydrogel”, as used herein, refers to a swollen, water-containing network of finely-dispersed polymer chains that are water-insoluble, where the polymeric molecules are in the external or dispersion phase and water (or an aqueous solution) forms the internal or dispersed phase. The chains can be chemically crosslinked (chemical gels) or physically crosslinked (physical gels). Chemical gels possess polymer chains that are connected through covalent bonds, whereas physical gels have polymer chains linked by non-covalent bonds or cohesion forces, such as Van der Waals interactions, ionic interaction, hydrogen bonding, or hydrophobic interaction. The polymer chains are typically hydrophilic or contain hydrophilic polymer blocks. “Gel-forming polymers” is used to describe any biocompatible polymer, including homopolymers, copolymers, and combinations thereof, capable of forming a physical hydrogel in an aqueous medium when present at or above the critical gel concentration (CGC). The “critical gel concentration”, or “CGC”, as used herein, refers to the minimum concentration of gel-forming polymer needed for gel formation, e.g. at which a solution-to-gel (sol-gel) transition occurs. The critical gel concentration can be dependent on a number of factors, including the specific polymer composition, molecular weight, temperature, and / or the presence of other polymers or excipients. The term “thermosensitive gel-forming polymer” refers to a gel-forming polymer that exhibits one or more property changes with a change in the temperature. For example, some thermosensitive gel-forming polymers are water soluble below a certain temperature but become water insoluble as temperature is increased. The term “lower critical solution temperature (LCST)” refers to a temperature, below which a gel-forming polymer and solvent are completely miscible and form a single phase. For example, “the LCST of a polymer solution” means that the polymer is uniformly dispersed in a solution at that temperature (i.e., LCST) or lower, but aggregates and forms a second phase when the solution temperature is increased beyond the LCST. “Hydrophilic,” as used herein, refers to molecules which have a greater affinity for, and thus solubility in, water as compared to organic solvents. The hydrophilicity of a compound can be quantified by measuring its partition coefficient between water (or a buffered aqueous solution) and a water-immiscible organic solvent, such as octanol, ethyl acetate, methylene 5 45677417.1 chloride, or methyl tert-butyl ether. If after equilibration a greater concentration of the compound is present in the water than in the organic solvent, then the compound is considered hydrophilic. “Hydrophobic,” as used herein, refers to molecules which have a greater affinity for, and thus solubility in, organic solvents as compared to water. The hydrophobicity of a compound can be quantified by measuring its partition coefficient between water (or a buffered aqueous solution) and a water-immiscible organic solvent, such as octanol, ethyl acetate, methylene chloride, or methyl tert-butyl ether. If after equilibration a greater concentration of the compound is present in the organic solvent than in the water, then the compound is considered hydrophobic. As used herein, the term “treating” includes inhibiting, alleviating, preventing or eliminating one or more symptoms or side effects associated with the disease, condition, or disorder being treated. The term “reduce”, “inhibit”, “alleviate” or “decrease” are used relative to a control, either no other treatment or treatment with a known degree of efficacy. One of skill in the art would readily identify the appropriate control to use for each experiment. For example a decreased response in a subject or cell treated with a compound is compared to a response in subject or cell that is not treated with the compound. As used herein the term “effective amount” or “therapeutically effective amount” means a dosage sufficient to treat, inhibit, or alleviate one or more symptoms of a disease state being treated or to otherwise provide a desired pharmacologic and / or physiologic effect. The precise dosage will vary according to a variety of factors such as subject-dependent variables (e.g., age, immune system health, etc.), the disease or disorder, and the treatment being administered. The effect of the effective amount can be relative to a control. Such controls are known in the art and discussed herein, and can be, for example the condition of the subject prior to or in the absence of administration of the drug, or drug combination, or in the case of drug combinations, the effect of the combination can be compared to the effect of administration of only one of the drugs. “Excipient” is used herein to include a compound that is not a therapeutically or biologically active compound. As such, an excipient should be pharmaceutically or biologically acceptable or relevant, for example, an excipient should generally be non-toxic to the subject. 6 45677417.1 “Excipient” includes a single such compound and is also intended to include a plurality of compounds. The term “osmolarity”, as generally used herein, refers to the total number of dissolved components per liter. Osmolarity is similar to molarity but includes the total number of moles of dissolved species in solution. An osmolarity of 1 Osm / L means there is 1 mole of dissolved components per L of solution. Some solutes, such as ionic solutes that dissociate in solution, will contribute more than 1 mole of dissolved components per mole of solute in the solution. For example, NaCl dissociates into Na+and Cl- in solution and thus provides 2 moles of dissolved components per 1 mole of dissolved NaCl in solution. Physiological osmolarity is typically in the range of about 280 to about 310 mOsm / L. The term “tonicity”, as generally used herein, refers to the osmotic pressure gradient resulting from the separation of two solutions by a semi-permeable membrane. In particular, tonicity is used to describe the osmotic pressure created across a cell membrane when a cell is exposed to an external solution. Solutes that can cross the cellular membrane do not contribute to the final osmotic pressure gradient. Only those dissolved species that do not cross the cell membrane will contribute to osmotic pressure differences and thus tonicity. The term “hypertonic”, as generally used herein, refers to a solution with a higher concentration of solutes than is present on the inside of the cell. When a cell is immersed into a hypertonic solution, the tendency is for water to flow out of the cell in order to balance the concentration of the solutes. The term “hypotonic”, as generally used herein, refers to a solution with a lower concentration of solutes than is present on the inside of the cell. When a cell is immersed into a hypotonic solution, water flows into the cell in order to balance the concentration of the solutes. The term “isotonic”, as generally used herein, refers to a solution wherein the osmotic pressure gradient across the cell membrane is essentially balanced. An isotonic formulation is one which has essentially the same osmotic pressure as human blood. Isotonic formulations will generally have an osmotic pressure from about 250 to 350 mOsm. PLURONIC®S composed of tribislock PEO–PPO–PEO copolymers of poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO). The PLURONIC®PEO block is hydrophilic and water soluble while the PPO block is hydrophobic and water insoluble. In an aqueous environment, these block copolymers self-assemble into micelles with a hydrophobic PPO center core and a hydrophilic PEO outer shell that interfaces with water. PLURONIC®F-127, also known as Poloxamer 407, s a non-ionic triblock copolymer, poly(ethylene oxide)- 7 45677417.1 poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO), formed by the self-assembly of two monomeric units ethylene oxide and propylene oxide in water and is capable of showing amphiphilic characters in aqueous environment. The LCST of PLURONIC®F-127 can be varied from 25 to 37 °C by the changing concentration of PF127 in the formulation. II. NETARSUDIL COMPOSITIONS A formulation of netarsudil has been developed which is efficacious with reduced redness and pain. The formulation appears to deliver at least as much drug to the eye in animal studies based on the demonstration that it reduced IOP at least as well as did RHOPRESSA®. The data shows improved IOP lowering efficacy with higher concentrations of netarsudil, while still reducing key side effects like ocular redness, as compared to RHOPRESSA®. The formulations contain between 0.2 and 0.5 mg netarsudil dimesylate or other salt of netarsudil, preferably 02-0.3%, 0.28 or 0.42 mg netarsudil / ml, formulated in a PLURONIC®triblock polymer, preferably Poloxamer 407, in a range of 10-15%, most preferably 12%, and polyethylene glycol 400, in range of 0.2-0.6 % w / v, most preferably 0.4% w / v, typically also containing agents such as benzalkonium chloride for sterility, boric acid, mannitol, and sodium chloride to adjust pH to between 4.8 and 5.3, preferably 5.0, and osmolarity to 150 mOsm / kg. The polymer formulation is referred to herein as “OcuGel”. In the most preferred embodiment, the formulation contains: Active 0.28 mg / mL of netarsudil dimesylate (for 0.02% w / v netarsudil) 0.42 mg / mL of netarsudil dimesylate (for 0.03% w / v netarsudil) Polymer 120 mg / mL Poloxamer 407 (12% w / w) 4 mg / mL polyethylene glycol 400 (0.4% w / v) PLURONIC®S are composed of triblock PEO–PPO–PEO copolymers of poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO). The PLURONIC®PEO block is hydrophilic and water soluble while the PPO block is hydrophobic and water insoluble. In an aqueous environment, these block copolymers self-assemble into micelles with a hydrophobic PPO center core and a hydrophilic PEO outer shell that interfaces with water. In the preferred embodiment, PLURONIC®F-127, also known as Poloxamer 407, a non-ionic triblock copolymer, poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO), is used as the carrier for the netarsudil. 8 45677417.1 Polyethylene glycol 400 (PEG 400) is a low-molecular-weight grade of polyethylene glycol with a low-level toxicity. It is very hydrophilic, which renders it a useful ingredient in drug formulations to augment the solubility and bioavailability of weakly water-soluble drugs. It is used in ophthalmic solutions for the relief of burning, irritation and / or discomfort that follows dryness of the eye. PEG "400" indicates that the average molecular weight of the specific PEG is 400. Agents to adjust tonicity, pH, osmolarity 0.6 mg / mL boric acid (10 mM) 1.83 mg / mL mannitol (10 mM) pH adjusted to 5 with HCl Osmolality adjusted to 150 mOsm / kg with NaCl Agents to preserve sterility 0.15 mg / mL benzalkonium chloride (0.015% w / v) III. Methods and Preparations of Netarsudil Formulations Formulations can be prepared as described in the examples below. The formulations can be prepared as liquids for administration. Powder can be made by freeze-drying and reconstituted at the time of use. Dosage formulations will typically be prepared as single or multiple liquid or dry dosage units in an appropriate applicator. A person of ordinary skill in the art will be aware of many options for drug storage and application, such as dual chambered devices that may be used to keep various components separate during storage. IV. Method of Administering Hypotonic Gel-forming Compositions The netarsudil formulation is applied topically to the eye as needed. Typically one to two drops is applied once or twice daily to the eye. The present invention will be further understood by reference to the following non- limiting examples. 9 45677417.1 Examples Example 1: Netarsudil eye drops tested in rabbits for reduced ocular redness Materials and Methods Table 1. OcuGel dimesylate (“OCUGEL NM”) Formulation Preferred Formulation Dosage Embodiment 10 45677417.1 Commercial comparator (RHOPRESSA®) composition RHOPRESSA®(netarsudil 0.02%) is a sterile, buffered aqueous solution of netarsudil dimesylate with a pH of approximately 5 and an osmolality of approximately 295 mOsmol / kg. Each mL of RHOPRESSA®contains 0.2 mg of netarsudil (equivalent to 0.28 mg of netarsudil dimesylate), 0.015% benzalkonium chloride, boric acid, mannitol, sodium hydroxide to adjust pH. OcuGel NM was prepared at netarsudil concentrations of 0.02% and 0.03% with the compositions listed in Table 1. The pH was adjusted to 4.8-5.3 using HCl and the osmolality was adjusted to 150 mOsm / kg using NaCl. IOP was measured in Dutch Belted rabbits (5 per group) using a TONOVET® rebound tonometer while the rabbits were awake and gently restrained. The rabbits were acclimatized to the IOP measurement procedure for 5 days prior to the study to obtain stable IOP readings. Baseline IOP was determined by taking an average of three measurements every other day for 7 days. The right eye of each rabbit was dosed with 50 µL of the OcuGel NM 0.02%, OcuGel NM 0.03%, or RHOPRESSA®0.02% (Aerie Pharmaceuticals) using a P200 pipette. IOP was measured 2, 4, 8, and 24 hours after dosing, and the change in IOP (ΔIOP) from baseline was reported. Data are presented as mean ± SEM and analyzed using one-way ANOVA with multiple comparison with GraphPad Prism 9. The cumulative ΔIOP was characterized by calculating the area under the curve over the 24-hour measurement period from the baseline (AUClast, n = 5), two-tailed t-test was used, *p < 0.05. Results In normotensive Dutch belted rabbits, a single dose of 0.03% (w / v) OcuGel NM provided the largest and most sustained decrease in IOP compared with both 0.02% (w / v) OcuGel NM and RHOPRESSA®at 8 h (Fig.1A). The 0.02% (w / v) OcuGel NM and RHOPRESSA®showed similar IOP lowering profile during the 24 hours study. When summing the area under the curve (AUClast) for the cumulative ΔIOP over the 24 h measurement period after topical dosing, the 0.03% (w / v) OcuGel NM showed a ~1.5-fold greater AUC compared to RHOPRESSA®(p < 0.05) (Fig.1B). 11 45677417.1 Example 2. Netarsudil side effects in human volunteers Materials and Methods OcuGel NM 0.02% was prepared as shown in Table 1 and compared to RHOPRESSA®0.02% in a small number of human volunteers to assess symptoms, including ocular pain, stinging, and hyperemia. One adult female (age 41) and three adult males (ages 53-75) self-administered one drop of OcuGel NM 0.02% in one eye and one drop of RHOPRESSA®0.02% in the contralateral eye. In one case of repeated dosing, two drops of OcuGel NM 0.02% were dosed in one eye, compared to a single drop of RHOPRESSA®0.02% in the contralateral eye. Ocular redness and ocular pain / ache were graded over time for up to 24 h. Results In each human volunteer, noticeable and rapid onset of hyperemia was evident in the RHOPRESSA®treated eye, consistent with what has been documented with clinical use. In contrast, one or two drops of OcuGel NM 0.02% caused less ocular hyperemia. Furthermore, in two patients that graded comfort upon installation, the eye dosed with OcuGel NM 0.02% had less severe stinging upon instillation. Finally, in two patients that graded ocular comfort at later timepoints, the eye dosed with OcuGel NM 0.02% had reduced ocular pain / ache as compared to the eye dosed with RHOPRESSA®0.02%. Detailed results are as follows: Subject 1 – White adult male RHOPRESSA®: - Redness severe within 1 h. Lasted >16 h. - “Infectious / Pink Eye” appearance at times >16 h. Clearly noticeable. - Ocular pain / ache (mild at t = 1h, 2h, 3h; moderate at t = 9.5 h). OcuGel NM 0.02%: - Mild hyperemia. Much less than RHOPRESSA®eye. Eye appearance within “normal” range - No stinging on installation - No ocular pain / ache 12 45677417.1 Subject 2 – White adult male. Summary of two experiments with consistent results. RHOPRESSA®: - Moderate stinging for 60 – 75 s upon Installation. - Next Morning: - Eye was red, significant hyperemia in cul de sac and hyperemia in lower to mid- sclera. - Ache originating behind the globe. OcuGel NM 0.02%: - Stinging barely noticeable on installation; less than with RHOPRESSA®and short duration. More comfortable. - Next Morning: - No ocular pain / ache - Hyperemia existed in both palpebral and scleral conjunctiva, but was clearly reduced in both areas compared to that of RHOPRESSA®eye. Subject 3 – White adult male Ocular redness was significantly higher for the RHOPRESSA® eye than the OcuGel NM eye at 30, 60 and 90 minutes after dosing. Hyperemia existed in the scleral conjunctiva for both products at t = 22h, but was markedly reduced compared to the 30-90 min timepoints. Ocular redness was back to baseline for both eyes at the next timepoint measured, t = 48 h. Subject 4 – White adult female Ocular redness was significantly higher for the RHOPRESSA®eye than the OcuGel NM eye at 30 and 120 minutes after dosing. Ocular redness was back to baseline for both eyes at the next timepoint measured, t = 72 h. It was particularly surprising that OcuGel NM 0.02% provides similar IOP reduction in animals compared to RHOPRESSA®(same 0.02% concentration of netarsudil), but the OcuGel NM formulation reduces ocular redness, stinging upon installation, and ocular pain / ache compared to RHOPRESSA®in human volunteers. The results, including that a double dose (two drops) of OcuGel 0.02% caused less ocular redness than a single dose of RHOPRESSA®in a volunteer subject, indicate that a single drop of a higher netarsudil concentration (e.g., 0.03% or 0.04%) is likely to cause less ocular redness while allowing significantly improved IOP lowering efficacy. A reduction in side effects with an improvement in efficacy would be particularly impactful in glaucoma patients. 13 45677417.1 Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of skill in the art to which the disclosed invention belongs. Publications cited herein and the materials for which they are cited are specifically incorporated by reference. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims. 14 45677417.1

Claims

We claim:

1. A netarsudil formulation comprising contain between 0.2 and 0.5 mg netarsudil dimesylate or other salt of netarsudil, formulated in a poloxamer triblock polymer in a range of 10-15%, and polyethylene glycol 400 in range of 0.2-0.6 % w / v, and agents selected from the group consisting of preservatives, tonicity adjusting agents, and pH adjusting agents, the netarsudil formulation having a pH between 4.8 and 5.3, and osmolarity to 150 mOsm / kg.

2. The netarsudil formulation of claim 1 comprising between 0.2 and 0.5 mg netarsudil dimesylate.

3. The netarsudil formulation of claim 1 or 2 comprising 0.28 or 0.42 mg netarsudil / ml.

4. The netarsudil formulation of any of claims 1-3 comprising 12% Poloxamer 407, 0.4% w / v polyethylene glycol 400, benzalkonium chloride, boric acid, mannitol, and sodium chloride to adjust pH to 5.0, and osmolarity to 150 mOsm / kg.

5. The netarsudil formulation of any of claims 1-4 comprising 0.28 mg / mL of netarsudil dimesylate (0.02% w / v netarsudil).

6. The netarsudil formulation of any of claims 1-4 comprising 0.42 mg / mL of netarsudil dimesylate (0.03% w / v netarsudil) 7. The netarsudil formulation of any of claims 1-6 comprising 120 mg / mL Poloxamer 407 (12% w / w), 4 mg / mL polyethylene glycol 400 (0.4% w / v), 0.6 mg / mL boric acid (10 mM), 1.83 mg / mL mannitol (10 mM), wherein the pH is adjusted to 5 with HCl and the osmolality is adjusted to 150 mOsm / kg with NaCl.

8. The netarsudil formulation of any of claims 1-7 comprising 0.15 mg / mL benzalkonium chloride (0.015% w / v).

9. A method of treating an individual with glaucoma, at risk of glaucoma, or having elevated intraocular pressure comprising topically applying to one or both eyes the formulation of any of claims 1-8.

10. The method of claim 9 wherein the individual is a human with glaucoma or having elevated intraocular pressure.

11. The method of claim 10 wherein the individual is an animal with glaucoma or having elevated intraocular pressure. 15 45677417.1

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