RHO KINASE INHIBITOR-RELEASING IMPLANTS AND RELATED METHODS OF USE - Patent application

Abstract

The present disclosure relates to an intracameral implant for treating and / or preventing corneal disorders, diseases, and / or conditions, such as corneal endothelial dystrophy. The intracameral implant can be configured to provide sustained release of a therapeutic agent, such as a Rho kinase inhibitor, over an extended period of time. The intracameral implant can include a non-bioabsorbable anchor or a bioabsorbable matrix.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 034,273, entitled "RHO KINASE INHIBITOR RELEASING IMPLANTS AND RELATED METHODS OF USE," filed June 3, 2020, which is incorporated by reference in its entirety.

[0002] The present disclosure relates to intracameral implants for treating and / or preventing corneal disorders, diseases, and / or conditions, such as corneal endothelial dystrophies. Methods of making and / or using the implants are also disclosed. [Background technology]

[0003] Rho kinase (ROCK), also known as Rho-associated protein kinase, is a serine-threonine protein kinase. ROCK is a downstream effector of the GPTase RhoA. ROCK typically occurs in mammals in two isoforms: ROCK1 and ROCK2. A variety of substrates are phosphorylated by ROCK. For example, ROCK phosphorylates myosin light chain phosphatase, causing the accumulation of phosphorylated myosin. ROCK can also act to directly phosphorylate myosin light chain. This phosphorylation, in addition to the action of ROCK on RhoACPI-17 and LIM-1 and LIM-2 kinases, can result in the assembly and / or stabilization of actin fibers and / or filaments. This assembly and stabilization of actin fibers and / or filaments can regulate cellular adhesion points, contraction, migration and proliferation. ROCK can also act through ICAM-1 (intercellular adhesion molecule-1) to suppress nitric oxide (NO) levels via inhibition of nitric oxide synthase. Summary of the Invention

[0004] ROCK has been shown to be expressed in the human cornea, and cell culture, in vivo animal studies, and small-scale human case studies have demonstrated that topical administration of Rho kinase inhibitors (ROCK inhibitors) may be beneficial in the treatment and prevention of corneal disorders, diseases, and / or conditions, including corneal endothelial dystrophies.

[0005] For example, the effect of ROCK inhibitors on corneal endothelial cells in animal models has been studied in vitro and in vivo. Okumura (Okumura N, Okazaki Y. Inoue R.; Effect of the Rho-Associated Kinase Inhibitor Eye Drop (Ripasudil) on Corneal Endothelial Wound Healing. Invest Ophthalmol Vis Sci 2016) evaluated the effect of ROCK inhibitors on human corneal endothelial cells (HCECs) in vitro as well as in a rabbit corneal endothelial injury model. In vitro, HCECs were seeded in culture plates for 24 h and then treated with ROCK inhibitors (0.3-100 μM ripasudil, 10 μM Y-27632, or 10 μM fasudil) for 48 h. The ROCK inhibitor ripasudil at 0.3-30 μM significantly enhanced DNA and endothelial cell proliferation.

[0006] The effect of the ROCK inhibitor ripasudil on an in vivo rabbit corneal endothelial injury model was also evaluated by slit lamp, BrdU, Ki67, Na / K ATPase. A freeze model and a scrape model were utilized. Topical 0.4% or 0.8% ripasudil eye drops were then administered BID or QID, respectively. In the freeze model, wounds were smaller in ROCK inhibitor-treated eyes, and less cloudy corneas were observed compared to the control group. Proliferation was better in a dose-dependent manner in ROCK inhibitor-treated eyes. In the scrape model on day 14, ripasudil-treated eyes were clear (5 / 6), compared with 0 / 6 in the control group. Corneal thickening was abolished by 1 / 3 with ripasudil, with no difference from the control.

[0007] Meekins (Meekins L. Rosado-Adames N. Maddala R., Corneal Endothelial Cell (CECs) Migration and Proliferation Enhanced by Rho Kinase (ROCK) Inhibitors in In Vitro and In Vivo Models. Invest Ophthalmol Vis Sci 2016) evaluated the ROCK inhibitors Y-27632 and H-1152 on porcine cell proliferation in vitro. Porcine corneal endothelial cells (CECs) were grown to confluence and scratched. 10 μM Y-27632 or 2.5 μM H-1152 were incubated for 2, 24 and 48 hours. Cells initially grew into a monolayer, and cells treated with ROCK inhibitors showed a monolayer with polygonal structures and tight junctions. Migration of cells from the scratch was enhanced by the ROCK inhibitor. In a rabbit model of corneal endothelial dysfunction, 2 drops of 1 mM H-1152 ophthalmic solution were instilled QID (4 times a day) for 3 days, followed by TID (3 times a day) for 7 days to evaluate the effect. Corneal thickness in rabbits was less in H-1152-treated animals than in controls.

[0008] Okumura (Okumura N. Sakamoto Y. Fujii K., Rho Kinase Inhibitor Enables Cell-Based Therapy for Corneal Endothelial Dysfunction, Nature 2016) demonstrated that corneal endothelial cells could be successfully transplanted into decompensated monkey corneas by supplementing with the ROCK inhibitor Y-27632. A monkey model of corneal endothelial cell damage was created by completely scraping the corneal endothelium from the Descemet's membrane of a cynomolgus monkey using a 20-gauge silicone needle. Monkey CECs (MCECs) administered in combination with the ROCK inhibitor as an intracameral injection of 100 regenerated without adverse events such as glaucoma. 5 × 10 5 CECs were injected into primates with 200 μl of 1 μM ROCK inhibitor. Primates were placed in a face-down position for 3 hours. The ROCK inhibitor enhanced survival and engraftment of injected cultured endothelial cells. Primate CECs administered without ROCK inhibitor did not engraft effectively. At 1 year, MCEC and ROCK inhibitor eyes reached 2000 cells / mm 2 The MCECs without ROCK were less clear (opaque).

[0009] The clinical efficacy of ROCK inhibitors on corneal endothelial cells has also been demonstrated. The cell density of the corneal endothelium is usually about 2500 to 3000 cells / mm. 2 Without being bound to any particular theory, the average cell density is approximately 500-1000 cells / mm depending on the source. 2 Anything less can lead to decompensation (eg, edema and opacity).

[0010] The ROCK inhibitor Y-27632 was shown to be effective in preserving corneal clarity in Fuch corneal dystrophy (Okumura N, Koizumi N, Kay EP, et al. The ROCK Inhibitor Eye Drop Accelerates Corneal Endothelium Wound Healing. IOVS 2013). This was effective in mild cases of corneal endothelial dysfunction (central edema) but not in severe cases (diffuse edema) indicating early treatment or prevention. Some healthy CECs were required. In topically ROCK-treated decompensated corneas, the cornea recovered clarity in 1-2 months. Y-27632 was shown to reduce corneal thickening in Fuch patients.

[0011] Okumura (N. Okumura, R. Inoue, Y. Okazaki et al., Effect of the Rho Kinase Inhibitor Y-27632 on Corneal Endothelial Wound Healing, IOVS 2015) treated three patients with severe corneal edema and corneal opacity. The damage was the result of cataract surgery. A topical dose of 1 mM Y-27632 was administered as eye drops six times a day for four months, followed by eye drops four times a day for another two months. Corneal transparency was restored within one to two months. In another case study, the ROCK inhibitor ripasudil rescued a patient for whom descemetrhexis had failed.

[0012] In September 2019, Kowa submitted an Investigational New Drug application to the U.S. Food and Drug Administration to begin Phase II trials of the ROCK inhibitor ripazudil hydrochloride hydrate. Kowa will examine the efficacy and safety of the drug in patients with corneal endothelial disease.

[0013] Kinoshita et al. (Kinoshita S, Koizumi N.; Ueno M., Injection of Cultured Cells with a ROCK Inhibitor for Bullous Keratopathy, N. Engl J. Med 2018) investigated the injection of the ROCK inhibitor Y-27632 with cultured human CECs in patients with bullous keratopathy. Eleven patients were included, but as of 2018, a total of 33 patients have undergone this procedure. The patients had decompensated corneas and no CECs were detected. Human CECs were then cultured and Y-27632 was added to the medium to obtain 1 × 10 cells per 300 μL. 6 Patients were then placed in a prone, face-down position for 3 hours to facilitate engraftment. The primary endpoint was the number of corneal and CECs >500mm. 2 Secondary endpoints included corneal thickness and BCVA. By week 24, 11 had >500 cells / mm 2 10 have >1000 cells / mm 2 All but one patient had clear corneas, measuring less than 630 μm in diameter. One patient had steroid-induced intraocular pressure (IOP), and no other adverse events.

[0014] Thus, it is believed that ROCK inhibitors may be beneficial in the treatment and prevention of corneal disorders, diseases, and / or conditions. Topical administration of ROCK inhibitors has been shown to reduce corneal endothelial dystrophy in cell cultures, animal models, and even in humans. However, concentrations shown to be effective are often in the range of 0.3 μM to 30 μM, which is on the order of 10 ng / mL to 1000 ng / mL. And typical concentrations achieved after topical administration of ROCK inhibitors are often on the order of 5 ng / mL, which is the lower end of the effective range.

[0015] Topical administration in human clinical trials evaluating the effect of ROCK inhibitors on corneal endothelial dystrophies often requires dosing QID~6 times / day for weeks or months. In 2019, a phase 2 clinical trial sponsored by Lions Vision Gift Research and the Eye Bank Association of America was initiated to evaluate the efficacy of the ROCK inhibitor Ripasudil 0.4% eye drops after desmeterohexis in patients with moderate to advanced Hooch endothelial corneal dystrophy. Ripasudil eye drops have been administered 6 times a day for 2 to 4 weeks. Okumura (Okumura, IOVS 2015) treated three patients with severe corneal edema and corneal opacity. The damage was the result of cataract surgery. The patients were given 1 mM of the ROCK inhibitor Y-27632 topically 6 times a day for 4 months, followed by an additional 2 months of topical instillation 4 times a day.

[0016] Thus, topical administration is challenging. For example, topical intraocular administration of drugs often requires high doses due to the poor bioavailability of many topically applied drugs. Typically, only 1% to 5% of a topically administered small molecule eye drop is bioavailable in the aqueous humor. This results in a pulsatile administration of the drug to the ocular surface at very high concentrations, which can cause side effects such as hyperemia and chemosis in the case of ROCK inhibitors. Thus, maintaining therapeutic concentrations of 5ng / mL to 10,000ng / mL is difficult with topical administration.

[0017] The present disclosure is directed to the delivery of ROCK inhibitors via intracameral implants. The implants can achieve sustained delivery of ROCK inhibitors to the eye and can be useful for the treatment and prevention of corneal disorders, diseases, and / or conditions such as corneal endothelial dystrophy. In some embodiments, the implants can be useful for the treatment or prevention of corneal disorders, diseases, and / or conditions (such as corneal endothelial dystrophy) resulting from one or more of ophthalmic surgery, cataract surgery, implant insertion, Fuchs corneal dystrophy, and failed descemetorhexis. Thus, it will be understood that the implants disclosed herein can be used to treat corneal endothelial cell (CEC) damage that is the result of disease (e.g., Fuchs corneal dystrophy) or is the result of iatrogenic conditions such as injury during surgery (e.g., ophthalmic surgery, cataract surgery, implant insertion, and / or failed descemetorhexis).

[0018] In some embodiments, the implant is inserted, embedded, or otherwise placed in the patient's aqueous humor. Once implanted, the implant can deliver the ROCK inhibitor directly to the lumen such that the therapeutic effect of the ROCK inhibitor is maintained for an extended period of time, such as at least 1 week, 2 weeks, 3 weeks, 4 weeks, or more. For example, the implant can deliver the ROCK inhibitor at a rate sufficient to produce a steady-state aqueous humor concentration of the ROCK inhibitor of about 0.001 μM to about 100 μM for an extended period of time (e.g., at least 1 week, 2 weeks, 3 weeks, 4 weeks, or more). In another embodiment, the implant can deliver the ROCK inhibitor at a rate sufficient to produce a steady-state aqueous humor concentration of the ROCK inhibitor of about 0.002 μM to about 0.3 μM for an extended period of time (e.g., at least 1 week, 2 weeks, 3 weeks, 4 weeks, or more).

[0019] In some embodiments, the implant exhibits sustained release of the ROCK inhibitor at a rate sufficient to maintain an aqueous humor concentration of the ROCK inhibitor between about 0.4 ng / mL and about 32,000 ng / mL for an extended period of time (e.g., at least 1 week, 2 weeks, 3 weeks, 4 weeks or more). In another embodiment, the implant exhibits sustained release of the ROCK inhibitor at a rate sufficient to maintain an aqueous humor concentration of the ROCK inhibitor between about 1.0 ng / mL and about 100 ng / mL for an extended period of time (e.g., at least 1 week, 2 weeks, 3 weeks, 4 weeks or more). The required release rate from the implant can be estimated based on the aqueous humor turnover and the desired concentration. Assuming an aqueous humor turnover of 2.5% min and an aqueous humor volume of 250 μL, the first order elimination rate constants are kelim=0.6 hr-1 and t1 / 2=1.15 hours. Using the relationship between the desired steady state concentration and the elimination rate constant, the release is equal to the product of the desired aqueous humor ROCK concentration * kelim * aqueous humor volume. Thus, in some embodiments, the implants disclosed herein can be configured to deliver from about 1.4 ng / day to 115 μg / day for an extended period of time (e.g., at least 1, 2, 3, 4, or more weeks). In another embodiment, the implants disclosed herein can be configured to deliver from about 3.6 ng / day to 1000 ng / day for an extended period of time (e.g., at least 1, 2, 3, 4, or more weeks).

[0020] As described in more detail below, various types of implants can be used, including non-absorbable and bioabsorbable implants.Various types of ROCK inhibitors can also be used, including but not limited to isoquinoline, pyridine, pyrimidine, pyrrolopyridine, indazole, and pyrazole-based ROCK inhibitors, their derivatives, prodrugs, salts, and / or cocrystals.In some embodiments, the ROCK inhibitor is selected from at least one of netarsudil, Y-27632, H-1337, ripasudil, or fasudil.Other ROCK inhibitors can also be used.

[0021] In some embodiments, the implant disclosed herein can be configured to release the ROCK inhibitor for an extended period of time.For example, in some embodiments, the implant is configured to release the ROCK inhibitor for at least 1 week, 2 weeks, 3 weeks, 4 weeks or more after implantation into the patient's eye.In other embodiments, the implant releases the ROCK inhibitor for at least 1 month, 2 months, 3 months or 6 months after implantation into the subject's eye.

[0022] In some embodiments, the implant may exhibit a burst release of the ROCK inhibitor that is less than about 40% (w / w) during the first 24 hours from implantation into the patient's eye. In further embodiments, the implant may exhibit a burst release of the ROCK inhibitor that is less than about 10% (w / w) during the first 24 hours from implantation into the patient's eye. In yet another embodiment, the implant may exhibit a burst release of the ROCK inhibitor that is less than about 5% (w / w) during the first 24 hours from implantation into the patient's eye.

[0023] The release rate of the ROCK inhibitor from the implant may also be substantially constant. For example, in some embodiments, the release rate of the ROCK inhibitor from the implant may be substantially constant over the first 1, 2, or 3 month period starting at the end of the burst release or lag phase of the ROCK inhibitor, but not beyond 14 days after the implant or in vitro release study. The lag phase may be defined as the period immediately after implant or immediately after the start of the in vitro release study during which the drug is not released or is released at a rate slower than the constant rate achieved within 30 days.

[0024] The release rate of the ROCK inhibitor from the implant can be near zero order or pseudo-zero order. For example, in some embodiments, the release rate of the ROCK inhibitor from the implant can be near zero order or pseudo-zero order over the first 1, 2, or 3 month period from the implant, starting at the end of the burst release or lag phase of the ROCK inhibitor. Near zero order release and pseudo-zero order release kinetics can be defined as an essentially linear relationship between the cumulative amount of the ROCK inhibitor released from the implant as a function of time in vivo or in vitro release studies.

[0025] The disclosure set forth herein describes non-limiting and non-exhaustive exemplary embodiments, and reference is made to some of such exemplary embodiments that are illustrated in the Figures. [Brief description of the drawings]

[0026] [Figure 1] FIG 1A is a perspective view of an implant according to one embodiment of the present disclosure, FIG 1B is a perspective view of the implant of FIG 1A including a therapeutic composition disposed thereon, and FIG 1C is a cross-sectional view of the implant of FIG 1B along line of sight 1C-1C. [Diagram 2] Figure 2A is a perspective view of an implant according to another embodiment of the present disclosure, and Figure 2B is a cross-sectional view of the implant of Figure 2A, taken along line 2B-2B. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0027] The components of the embodiments, as generally described and illustrated in the figures herein, could be arranged and designed in a wide variety of different configurations. Thus, the following more detailed description of various embodiments, as shown in the figures, is not intended to limit the scope of the disclosure, but is merely representative of various embodiments. While various aspects of the embodiments are illustrated in the drawings, the drawings are not necessarily drawn to scale unless specifically indicated.

[0028] 1A-1C illustrate an intracameral implant 100, according to one embodiment of the present disclosure. More specifically, FIG. 1A illustrates a perspective view of implant 100, FIG. 1B illustrates a perspective view of implant 100 including a therapeutic composition 110 disposed thereon, and FIG. 1C illustrates a cross-sectional view of implant 100 and therapeutic composition 110 of FIG. 1B taken along line of sight 1C-1C.

[0029] As shown in FIGS. 1A-1C, in some embodiments, the implant includes a separate and distinct anchor body 102 and a therapeutic composition 110. The anchor body 102 can include a lower portion 104 and an upper portion 106. The lower portion 104 can be configured to secure and / or attach the anchor body 102 to the patient after insertion and / or implantation. For example, the lower portion 104 can include one or more barbs or protrusions to aid in securing and / or attaching the anchor body 102 to the patient's eye. The upper portion 106 can be configured to receive and / or retain the therapeutic composition 110. For example, the upper portion 106 can include a central region having one or more protrusions to aid in retaining the therapeutic composition 110.

[0030] The anchor body 102 can comprise a variety of materials, including, but not limited to, metallic materials, polymeric materials, composite materials, and combinations thereof. In certain embodiments, the anchor body 102 comprises Nitinol. Other materials can also be used.

[0031] In some embodiments, the anchor body 102 is non-bioabsorbable. In other words, the anchor body 102 can be configured not to biodegrade while placed in a patient's eye for an extended period of time, such as at least six months, at least one year, at least two years, at least five years, or indefinitely. In other embodiments, the anchor body 102 can be configured to biodegrade over a period of time.

[0032] The therapeutic composition 110 may be disposed or otherwise secured onto the anchor body 102. The therapeutic composition 110 may include a carrier matrix and a therapeutic agent. When implanted into a patient's eye, the therapeutic agent is configured to be released. In some embodiments, the therapeutic composition 110 biodegrades to release the therapeutic agent. In further embodiments, an elution membrane 112 may be disposed over the therapeutic composition 110 to control the release of the therapeutic agent. In FIG. 1B and FIG. 1C, for example, an elution membrane 112 is shown disposed over and encapsulating the therapeutic composition 110. The elution membrane 112 may control the release of the therapeutic agent. The elution membrane 112 may also help retain the therapeutic agent on the anchor body 102.

[0033] Various types of elution membrane 112 can be used, including, but not limited to, polymeric materials such as poly(vinyl alcohol), polymethyl methacrylate, polyhydroxyethyl methacrylate polyurethanes such as elastane, polydimethylsiloxane, carbosil (silicone polycarbonate urethane) and ethylene vinyl acetate (EVA). The elution membrane 112 can be configured such that it is semi-permeable and allows for controlled release of the therapeutic agent (e.g., ROCK inhibitor). The delivery system can be designed such that the therapeutic agent (e.g., ROCK inhibitor) is disposed in a reservoir covered by the membrane and diffuses through the membrane, the therapeutic agent can also be dispersed within and diffuse from the membrane, or both. Additionally, the elution membrane 112 can be configured such that the release of the therapeutic agent (e.g., ROCK inhibitor) is substantially constant and / or reproducible. In some embodiments, the elution membrane 112 is configured to release the therapeutic agent at a rate of between about 1.4 ng / day to 115 μg / day over an extended period of time (e.g., at least 1 week, 2 weeks, 3 weeks, 4 weeks or more). In other embodiments, the elution membrane 112 is configured to release the therapeutic agent at a rate of between about 3.6 ng / day and 1000 ng / day for an extended period of time (eg, at least 1 week, 2 weeks, 3 weeks, 4 weeks or more).

[0034] The therapeutic agent can include one or more ROCK inhibitors.Various types of ROCK inhibitors can be used, including but not limited to isoquinoline, pyridine, pyrimidine, pyrrolopyridine, indazole, and pyrazole-based ROCK inhibitors, their derivatives, prodrugs, salts, and / or cocrystals.In some embodiments, the ROCK inhibitor is selected from at least one of netarsudil, Y-27632, H-1337, ripasudil, or fasudil.Other ROCK inhibitors can also be used.

[0035] Various types of matrix materials may also be used in the therapeutic compositions, including, but not limited to, various types of pharma- ceutically acceptable carriers and / or excipients. As used herein, the term "pharma-ceutically acceptable" refers to a substance that does not substantially interfere with the efficacy or biological activity of the active agent (or drug) and is not toxic to the patient in the amounts used. The matrix may be a solution, semi-solid, paste, gel, hydrogel, or solid pellet. Examples of pharma-ceutically acceptable carriers include sterile liquids such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, and sesame oil. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, and ethanol. The composition may also contain wetting or emulsifying agents, surfactants, glidants and lubricants, fillers, disintegrants, tonicity adjusters, and / or pH buffers, if desired. Additional excipients may include polymers such as polylactic acid, poly(lactic-co-glycolic) acid, methylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, ethylcellulose, polycaprolactone, polyorthoesters, polyanhydrides, polyethylene glycol and polyvinylpyrrolidone, polyorthoesters, polyvinyl alcohols, block copolymers of polyesters and polyethylene glycols, or various polyesters and block copolymers, e.g., polyacrylic acids such as poloxamers, and carbomers. The matrix may be composed of ROCK inhibitors dispersed within fatty alcohols, fatty acids, and or triglycerides. Natural polymers such as gellan gum, xanthan gum, hyaluronic acid, gelatin, collagen, chitosan, alginates, pectins, and their salts and cross-linked analogs may also be used as part of the matrix. Cyclodextrins may be included. Surfactants including Pluronics F127 and F68, Polysorbate 20 and Polysorbate 80 can be incorporated.Rheology modifiers such as semi-synthetic cellulose derivatives or Carbopol 940 or Carbopol Ultrez may also be incorporated if desired.

[0036] As previously discussed, the implant 100 can be configured for delivery to a patient, for example, for delivery to the patient's eye. In certain embodiments, the implant 100 can be inserted and / or implanted into the patient's sclera. In some embodiments, the implant 100 can be inserted and / or implanted into the patient's anterior chamber angle. In certain embodiments, the implant 100 can be inserted and / or implanted into Schlemm's Canal. The implant 100 can also be inserted into other areas within the patient's eye. When implanted or otherwise positioned in the patient's eye, the implant 100 can be configured to deliver the ROCK inhibitor directly to the inner space such that the therapeutic effects of the ROCK inhibitor are maintained over an extended period of time.

[0037] 2A and 2B show an intracameral implant 200 according to another embodiment of the present disclosure. More specifically, FIG. 2A shows a perspective view of the implant 200, and FIG. 2B shows a cross-sectional view of the implant 200 along line of sight 2B-2B.

[0038] In the embodiment of Figures 2A-2B, the implant 200 is configured as a bioabsorbable or biodegradable implant. In other words, the implant 200 is configured to biodegrade after implantation into the patient's eye. In some embodiments, the implant 200 includes a therapeutic composition that degrades over the course of hours, days, weeks, or months to maintain release of the therapeutic agent. The residual polymer can further degrade once the implant has released all of the incorporated drug. In some embodiments, the time to degrade the implant 200 is less than 3 times the duration of efficacy, less than 2 times the duration of efficacy, or less than 1.5 times the duration of efficacy.

[0039] 1A-1C, the therapeutic composition 110 can include a carrier matrix and a therapeutic agent. The therapeutic agent can be dispersed in a substantially homogenous manner throughout the carrier matrix and / or implant 200. When implanted in a patient's eye, the therapeutic agent is configured to be released, such as when the therapeutic composition 110 and / or matrix material biodegrades within the patient's eye.

[0040] Any of the matrix materials identified above may be used in the therapeutic composition of 200. In certain embodiments, the matrix material comprises a polymeric material. Exemplary polymeric materials include, but are not limited to, polylactic acid, poly(lactic-co-glycolic) acid, and combinations thereof. Other polymers suitable for forming a biodegradable matrix-type delivery system include, but are not limited to, block copolymers including polyesters, polycaprolactones, polyorthoesters, polyanhydrides. Natural and semi-synthetic polysaccharides including alginic acid and its salts, methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose and their salts, cellulosic polymers such as hyaluronic acid and xanthan gum. Other polymers include polyvinyl alcohol, and polyethylene vinyl acetate.

[0041] In some embodiments, the matrix comprises poly(lactic-co-glycolic acid) having a lactide to glycolide ratio of about 20:80 to about 80:20.Other polymeric materials can also be used.

[0042] As mentioned above, the therapeutic agent can also include one or more ROCK inhibitors.Various types of ROCK inhibitors can also be used, including but not limited to isoquinoline, pyridine, pyrimidine, pyrrolopyridine, indazole, and pyrazole-based ROCK inhibitors, their derivatives, prodrugs, salts, and / or cocrystals.In some embodiments, the ROCK inhibitor is selected from at least one of netarsudil, Y-27632, H-1337, ripasudil, or fasudil.Other ROCK inhibitors can also be used.

[0043] The implant 200 can be formed in a variety of ways. In some embodiments, the implant 200 can be formed by blending a polymeric material with a therapeutic agent. For example, in some embodiments, the therapeutic agent (e.g., a ROCK inhibitor) is milled with one or more polymeric materials. In certain embodiments, the therapeutic agent (e.g., a ROCK inhibitor) is milled with a jet mill or with more polymeric materials. In the above embodiments, the therapeutic agent (e.g., a ROCK inhibitor) can be reduced to a certain particle size. The therapeutic agent (e.g., a ROCK inhibitor) and one or more polymeric materials can then be blended with a mixer to achieve a substantially uniform dispersion. The uniform dispersion can then be formed into an implant. For example, the dispersion or mixture can be extruded into filaments by hot melt extrusion and cut into implants. Other manufacturing methods are also contemplated.

[0044] As previously discussed, the implant 200 can be configured for delivery to a patient, for example, for delivery to the patient's eye. In certain embodiments, the implant 200 can be inserted and / or implanted into the patient's sclera. In some embodiments, the implant 200 can be inserted and / or implanted into the patient's anterior chamber angle. In certain embodiments, the implant 200 can be inserted and / or implanted into Schlemm's canal. The implant 200 can also be inserted into other areas within the patient's eye. When implanted or otherwise positioned in the patient's eye, the implant 200 can be configured to deliver the ROCK inhibitor directly to the inner space such that the therapeutic effects of the ROCK inhibitor are maintained over an extended period of time.

[0045] The present disclosure also provides a method for using the implant disclosed herein. In an aspect, the present disclosure provides a method for introducing a ROCK inhibitor into the eye of a subject. Such a method comprises delivering an implant as described above to the eye of a subject. In another embodiment, the present disclosure provides a method for treating or preventing corneal disorders, diseases, and / or conditions, such as corneal endothelial dystrophy. The corneal disorders, diseases, and / or conditions (such as corneal endothelial dystrophy) may result from one or more of the following: ocular surgery, cataract surgery, insertion of an implant, Huch's corneal dystrophy, and failure of descemetorhexis. Other methods are also contemplated.

[0046] Working Example To further illustrate these embodiments, the following examples are provided, which do not limit the scope of the claimed invention, which is to be determined solely based on the appended claims.

[0047] Example 1 Non-resorbable implants were fabricated by anchoring a therapeutic composition to a nitinol anchor body (e.g., similar to the embodiment described in connection with Figures 1A-1C). The therapeutic composition included the ROCK inhibitor netarsudil. The therapeutic composition was encapsulated and attached to the nitinol anchor body using an elution membrane including either Carbosil or EVA. The elution membrane was semi-permeable to the ROCK inhibitor, allowing for the controlled release of the ROCK inhibitor at a substantially reproducible rate. The Carbosil elution membrane was configured to elute the ROCK inhibitor at a rate of about 0.510 μg / day, and the EVA elution membrane was configured to elute the ROCK inhibitor at a rate of about 0.600 μg / day.

[0048] The in vivo pharmacokinetics of ROCK inhibitors released from implants was studied in Dutch Belted rabbits. Eight female Dutch Belted rabbits were administered the implants through a clear corneal incision in the superior temporal quadrant of the cornea and secured in the anterior chamber angle with a Cabosil or EVA implant. Aqueous humor (AH) samples were tapped and analyzed weekly and at the end of the study.

[0049] Intraocular implantation into the anterior chamber angle of rabbits using implants made from Cabosil or EVA polymer resulted in ROCK inhibitor concentrations in aqueous humor samples over a 30 day period. The aqueous humor concentrations are shown in Table 1. At the end of the 30 day study, the implants were explanted and the amount of ROCK inhibitor remaining was measured. The amount of ROCK inhibitor remaining in the explants for both the Cabosil and EVA configurations was approximately 22.5% w / w. As shown, sustained amounts of ROCK inhibitor were present in each sample over the 30 day period.

[0050] [Table 1]

[0051] Example 2 Bioabsorbable ROCK inhibitor implants can be made using polylactide-co-glycolide (PLGA) and polylactic acid polymers (PLA), where the polymers and blends of polymers can be mixed with a Rho kinase inhibitor, extruded into filaments by hot melt extrusion, and cut into intracameral implants. Examples of polymers that can be used are shown below in Table 2, and compositions are shown in Table 3.

[0052] [Table 2]

[0053] [Table 3]

[0054] The composition can be produced by grinding the ROCK inhibitor and the PLA and PLGA polymers, for example, in a jet mill. This allows for a consistent reduction in particle size of the starting materials. The polymers can then be mixed with the ROCK inhibitor according to the matrix in Table 3. Each mixture can be blended using a turbula mixer to achieve uniform dispersion. The mixed composition can be extruded in a hot melt extruder.

[0055] The release of ROCK inhibitors from the implants can be evaluated in vitro. The implants can be placed in 50 mL polypropylene vials containing 45 mL of isotonic saline at pH 7.4 as the release medium. The vials can then be placed on a shaker bath and the medium can be agitated at 37°C. At pre-determined time points, the medium can be sampled and the entire receiver medium replaced with saline. The ROCK inhibitor concentration in the sampled aliquots can be quantified by high performance liquid chromatography (HPLC) using, for example, a Waters Alliance e2695 system equipped with a C-18 Hypersil ODS column. The ROCK inhibitor concentration can be used to define the cumulative in vitro release of the compound from the implants and the daily ROCK inhibitor release rate.

[0056] Any method disclosed herein includes one or more steps or actions for carrying out the described method. Method steps and / or actions may be interchanged with one another. In other words, unless a particular order of steps or actions is required for proper operation of an embodiment, the order and / or use of specific steps and / or actions may be modified. Furthermore, only a portion of a subroutine or method described herein may be a separate method within the scope of the present disclosure. Otherwise, some methods may include only a portion of the steps described in a more detailed method.

[0057] The recitation of a claim using the term "first" with respect to a feature or element does not necessarily imply the presence of a second or additional such feature or element. It will be apparent to those skilled in the art that changes can be made to the details of the above-described embodiments without departing from the underlying principles of the disclosure.

[0058] Throughout this specification, a reference to "one embodiment" or "embodiments" means that a particular feature, structure, or characteristic described in connection with that embodiment is included in at least one embodiment. Thus, references or variations thereof cited throughout this specification are not necessarily all referring to the same embodiment.

[0059] Similarly, in the foregoing description of the embodiments, various features may be grouped together in a single embodiment, drawing, or description thereof for the purpose of streamlining the disclosure. However, this method of disclosure should not be interpreted as reflecting an intention that any claim requires more features than are expressly recited in that claim. Rather, as the following claims reflect, inventive aspects lie in combinations of fewer than all features of any one of the foregoing disclosed embodiments.

[0060] The claims that follow this written disclosure are expressly incorporated herein, with each claim standing on its own as a separate embodiment. The present disclosure includes all permutations of an independent claim and its dependent claims. Furthermore, any additional embodiments that may be derived from the following independent and dependent claims are also expressly incorporated herein.

Claims

1. A non-bioabsorbable anchor; a Rho kinase (ROCK) inhibitor dispersed in a therapeutic composition disposed on the non-bioabsorbable anchor; an elution membrane encapsulating the therapeutic composition, the elution membrane being semi-permeable to the ROCK inhibitor and controlling the release rate of the ROCK inhibitor; 1. An intracameral implant comprising: An intracameral implant configured to be placed in the patient's eye such that the implant is configured to release the ROCK inhibitor into the aqueous humor for sustained delivery of the ROCK inhibitor to the patient for at least two weeks.

2. 10. The intracameral implant of claim 1, wherein the implant is configured to release the ROCK inhibitor such that the aqueous humor concentration of the ROCK inhibitor is between 0.001 μM and 100 μM for at least two weeks.

3. 10. The intracameral implant of claim 1, wherein the implant is configured to release the ROCK inhibitor such that the aqueous humor concentration of the ROCK inhibitor is between 0.4 ng / mL and 32,000 ng / mL for at least two weeks.

4. 4. The intracameral implant of any one of claims 1 to 3, wherein the implant is configured to release the ROCK inhibitor at a rate of between 1 ng / day and 115 μg / day for at least two weeks.

5. The intracameral implant of any one of claims 1 to 4, wherein the ROCK inhibitor is selected from at least one of netarsudil, Y-27632, H-1337, ripasudil, or fasudil.

6. 5. The intracameral implant of any one of claims 1 to 4, wherein the ROCK inhibitor comprises at least one of an isoquinoline, pyridine, pyrimidine, pyrrolopyridine, indazole, or pyrazole-based ROCK inhibitor, derivatives, prodrugs, salts, and / or co-crystals thereof.

7. 10. The intracameral implant of claim 1, wherein the eluting membrane comprises silicone polycarbonate urethane or EVA.

8. The intracameral implant of any one of claims 1 to 6, wherein the implant is biodegradable.

9. The intracameral implant of claim 8 , wherein the ROCK inhibitor is dispersed throughout a polymer matrix.

10. 10. The intracameral implant of claim 9, wherein the polymer matrix comprises at least one of a polylactide-co-glycolide or a polylactic acid polymer.

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