Pharmaceutical compositions and intravitreal drug delivery systems for the treatment of ocular diseases - Patents.com

Abstract

The present disclosure relates to a biodegradable ocular implant comprising a biodegradable polymer containing a compound (e.g., edonentan) or a pharma-ceutically acceptable salt thereof. Also disclosed is a method of treating ocular diseases using the biodegradable ocular implant and a method of preparing the biodegradable ocular implant. Examples of debilitating ocular diseases include glaucoma, diabetic retinopathy (DR), retinal vein occlusion (RVO), and retinopathy of prematurity (ROP). These ocular diseases can cause various long-term damage to the eye, and ultimately cause blindness.

Description

[Technical field]

[0001] Related Applications This application claims priority to U.S. Provisional Patent Application No. 63 / 182,559, filed April 30, 2021, and U.S. Provisional Patent Application No. 63 / 287,737, filed December 9, 2021, the entire contents of each of which are incorporated by reference herein for all purposes. [Background technology]

[0002] background Examples of debilitating eye diseases include glaucoma, diabetic retinopathy (DR), retinal vein occlusion (RVO), and retinopathy of prematurity (ROP). These eye diseases can cause various long-term damage to the eye and can ultimately cause blindness. Newborns, juveniles, adults of all ages, and the elderly are affected, but only a handful of treatments exist. These treatments address only a subset of eye diseases and slow but do not prevent blindness. The annual economic burden in the United States alone is over $100 billion.

[0003] The options for treating eye diseases are still very limited, mainly due to lack of therapeutic efficacy.Efforts have been devoted to enhancing drug therapeutic efficacy while minimizing side effects in treating or improving eye diseases.One such effort includes the development of novel biodegradable eye implants that provide better permeability, treatability, and controlled release at target site.

[0004] Edentan is a highly selective and highly potent endothelin A receptor antagonist. Edentan was developed as a second generation analogue after the discontinuation of the first clinical candidate, BMS-193884, which was being developed for the treatment of congestive heart failure (CHF). Edentan was in Phase I clinical trials until April 2002, when its development was discontinued.

[0005] There remains a need to more effectively reduce the incidence of, treat or otherwise ameliorate glaucoma, DR, RVO, and ROP. [Brief description of the drawings]

[0006] [Figure 1] FIG. 1 shows the drug release profile of edonentan in disk punches of exemplary formulations (each containing a polymer matrix incorporating edonentan). Up to 70% of edonentan was released from most formulations within 100 days as determined by high performance liquid chromatography (HPLC). In vitro release results show that the amount of edonentan released decreases with increasing ratio of polylactic acid (PLA) to polyglycolic acid (PGA) and increasing molecular weight of the polymer. Formulation 1 (50 / 50 RG503 / RG503H) has a more rapid release due to the lower ratio of PLG to PGA compared to formulation 2 (65 / 35 PLA / PGA). Formulation 4 (50 / 50 502 / 502H) has a more rapid release due to the lower molecular weight of the polymer compared to formulation 1 (50 / 50 503 / 503H). The results also showed that RG753S had the slowest release profile among the formulations tested, and that mixtures of RG753S with other faster releasing formulations provided extended, sustained drug release while maintaining sufficient drug release at earlier time points.

[0007] [Diagram 2] Figure 2 shows the elution rate profiles of edonentan in disc punches of exemplary formulations (each containing a polymer matrix incorporating edonentan). The in vitro release results show that for each polymer matrix, there is a peak edonentan release at 10-35 days, followed by a sustained steady state release for some matrices, as determined by HPLC, with a decrease in elution rate.

[0008] [Diagram 3]Figure 3 shows the drug release profile of edonentan in implants of exemplary formulations (each containing a polymer matrix incorporating edonentan). The in vitro release results show that the combination of the polymer matrix and edonentan provides sustained release of the active substance as determined by HPLC.

[0009] [Figure 4] FIG. 4 shows the elution rate profile of edonentan in implants of exemplary formulations, each containing a polymer matrix incorporating edonentan. In vitro release results show that the polymer matrix controls the initial release of edonentan, with peak release ranging from day 17 to day 92, as determined by HPLC. In vitro release results show that the amount of edonentan released decreases with increasing ratios of polylactic acid (PLA) to polyglycolic acid (PGA) and increasing molecular weight of the polymer. Mixtures of RG753S with other more rapid releasing formulations provide extended, sustained drug release while maintaining sufficient drug release at earlier time points.

[0010] [Diagram 5] FIG. 5 shows the time course of edonentan plasma levels during an 8-week single-dose intravitreal ocular toxicity study in Dutch-belted rabbits in the 2-implant and 3-implant groups.

[0011] [Figure 6] FIG. 6 shows the time course of edonentan retinal levels during a 12-week single-dose intravitreal ocular pharmacokinetic study in Dutch-belted rabbits administered two implants of the injection molded and ram extruded products.

[0012] [Figure 7] FIG. 7 shows the time course of edonentan RPE / choroid levels during a 12-week single-dose intravitreal ocular pharmacokinetic study in Dutch-belted rabbits administered two implants of the injection molded product and the ram extruded product.

[0013] [Figure 8] FIG. 8 shows an exemplary overlay of the XRPD patterns of Forms 1-4.

[0014] [Figure 9] FIG. 9 shows an exemplary XRPD pattern of Form 1.

[0015] [Figure 10] FIG. 10 shows an exemplary XRPD pattern of Form 2.

[0016] [Figure 11] FIG. 11 shows an exemplary XRPD pattern of Form 3.

[0017] [Figure 12] FIG. 12 shows an exemplary XRPD pattern of Form 4.

[0018] [Figure 13] FIG. 13 shows an exemplary DSC curve for Form 1.

[0019] [Figure 14] FIG. 14 shows an exemplary DSC curve for Form 2.

[0020] [Figure 15] FIG. 15 shows an exemplary DSC curve for Form 3.

[0021] [Figure 16] FIG. 16 shows an exemplary DSC curve for Form 4.

[0022] [Figure 17] FIG. 17 shows the XRPD characteristic peaks of crystalline Form 4 shown in FIG.

[0023] [Figure 18]FIG. 18 shows the time course of edonentan retinal levels during a 12-week single-dose intravitreal ocular pharmacokinetic study in pigmented rabbits administered two implants of the injection molded product.

[0024] [Figure 19] FIG. 19 shows the time course of edonentan RPE / choroid levels during a 12-week single-dose intravitreal ocular pharmacokinetic study in pigmented rabbits administered two implants of the injection molded product. Summary of the Invention [Means for solving the problem]

[0025] Abstract The present disclosure provides a biodegradable ocular implant and its use for treating an ocular disease selected from glaucoma, diabetic retinopathy (DR), retinal vein occlusion (RVO), and retinopathy of prematurity (ROP). In some embodiments, the biodegradable ocular implant comprises a biodegradable polymer comprising a compound selected from the group consisting of edonentan, tezosentan, A-182086, clazosentan, S1255, ACT-132577, enrasentan, and sparsentan, or a pharma- ceutically acceptable salt thereof. Preferably, in an embodiment, the biodegradable ocular implant comprises a compound of Formula I: [ka] or a pharma- ceutically acceptable salt thereof.

[0026] The disclosure also provides a method of treating an ocular disease, the method comprising contacting an ocular tissue of a subject with a biodegradable ocular implant described herein, wherein the ocular disease is selected from the group consisting of glaucoma, diabetic retinopathy (DR), retinal vein occlusion (RVO), and retinopathy of prematurity (ROP), and the compound is present in an amount therapeutically effective to treat the ocular disease.

[0027] Also provided herein is a method of making an ocular delivery device, comprising subjecting a biodegradable polymer having a compound incorporated therein to injection molding, wherein the compound is a compound of Formula I: [ka] or a pharma- ceutically acceptable salt thereof.

[0028] The details of one or more embodiments of the disclosure are set forth in the description below. Other features, objects, and advantages of the disclosure will be apparent from the drawings, description, and claims that follow. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0029] Detailed Description The present disclosure arises from the discovery that certain biodegradable ocular implants comprising a biodegradable polymer having a compound incorporated therein, wherein the compound is preferably edonentan, are suitable for preventing, treating, or otherwise ameliorating ocular diseases, including, but not limited to, glaucoma, diabetic retinopathy (DR), retinal vein occlusion (RVO), and retinopathy of prematurity (ROP). The present disclosure is further described below.

[0030] compound The biodegradable ocular implants and methods of use thereof described herein include biodegradable polymers that contain the compounds described herein (e.g., edonentan, tezosentan, A-182086, clazosentan, S1255, ACT-132577, enrasentan, and sparsentan, or pharma- ceutically acceptable salts thereof).It can be appreciated that the compounds contemplated herein are endothelin receptor antagonists.

[0031] In certain embodiments, the compound is a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof. The compound of formula I is also known as edonentan. Edonentan has the chemical name N-[[2'-[[(4,5-dimethyl-3-isoxazolyl)amino]sulfonyl]-4-(2-oxazolyl)[1,1'-biphenyl]-2-yl]methyl]-N,3,3-trimethylbutanamide (molecular weight 536.6 g / mol). Methods for preparing edonentan are well known to those skilled in the art. Suitable methods are disclosed, for example, in U.S. Pat. No. 6,043,265.

[0032] In some embodiments, the compound is A-182086, which has the structure: [ka] or a pharma- ceutically acceptable salt thereof.

[0033] A-182086 has the chemical name (2R,3R,4S)-4-(2H-1,3-benzodioxol-5-yl)-2-(3-fluoro-4-methoxyphenyl)-1-[2-(N-propylpentane-1-sulfonamido)ethyl]pyrrolidine-3-carboxylic acid (molecular weight 578.7 g / mol). Methods for preparing A-182086 are well known to those skilled in the art. Suitable methods are disclosed, for example, in U.S. Pat. No. 6,162,927.

[0034] In various embodiments, the concentration of a compound (e.g., a compound of Formula I, A-182086) present in the biodegradable polymer in the biodegradable ocular implant is from about 5% w / w to about 95% w / w (e.g., from about 10% w / w to about 95% w / w, from about 15% w / w to about 95% w / w, from about 20% w / w to about 95% w / w, from about 25% w / w to about 95% w / w, from about 30% w / w to about 95% w / w, from about 35% w / w to about 95% w / w, from about 40% w / w to about 95% w / w, from about 45% w / w to about 95% w / w, about 50% w / w to about 95% w / w, about 55% w / w to about 95% w / w, about 60% w / w to about 95% w / w, about 65% w / w to about 95% w / w, about 70% w / w to about 95% w / w, about 75% w / w to about 95% w / w, about 80% w / w to about 95% w / w, about 85% w / w, about 95% w / w, about 9 0% w / w to about 95% w / w, about 5% w / w to about 10% w / w, about 5% w / w to about 15% w / w, about 5% w / w to about 20% w / w, about 5% w / w to about 25% w / w, about 5% w / w to about 30% w / w, about 5% w / w to about 35% w / w, about 5% w / w to about 40% w / w, about 5% w / w to about 45% w / w, about 5% In certain embodiments, the concentration of the compound present in the biodegradable polymer in the biodegradable ocular implant is from about 20% w / w to about 60% w / w, from about 5% w / w to about 55% w / w, from about 5% w / w to about 60% w / w, from about 5% w / w to about 65% w / w, from about 5% w / w to about 70% w / w, from about 5% w / w to about 75% w / w, from about 5% w / w to about 80% w / w, from about 5% w / w to about 85% w / w, and from about 5% w / w to about 90% w / w. w / w (e.g., about 20% w / w to about 55% w / w, about 20% w / w to about 50% w / w, about 20% w / w to about 45% w / w, about 20% w / w to about 40% w / w, about 20% w / w to about 35% w / w, about 20% w / w to about 30% w / w, about 20% w / w to about 25% w / w, about 25% w / w to about 60% w / w, about 30% w / w to about 60% w / w, about 35% w / w to about 60% w / w, about 40% w / w to about 60% w / w, about 45% w / w to about 60% w / w, about 50% w / w to about 60% w / w, about 55% w / w to about 60% w / w).In certain embodiments, the concentration of the compound present in the biodegradable polymer in the biodegradable ocular implant is about 25% w / w to about 45% w / w. In certain embodiments, the concentration of the compound present in the biodegradable polymer in the biodegradable ocular implant is about 40% w / w to about 50% w / w (e.g., about 40% w / w to about 45% w / w, about 45% w / w to about 50% w / w). In various embodiments, the concentration of the compound is about 5% w / w, about 10% w / w, about 15% w / w, about 20% w / w, about 25% w / w, about 30% w / w, about 35% w / w, about 40% w / w, about 45% w / w, or about 50% w / w. In various embodiments, the concentration of the compound is about 30% w / w. In various embodiments, the concentration of the compound is about 40% w / w. In various embodiments, the concentration of the compound is about 45% w / w. In various embodiments, the concentration of the compound is about 50% w / w.

[0035] In an embodiment, the amount of the compound (e.g., compound of formula I, A-182086) present in the biodegradable polymer in the biodegradable ocular implant is from about 1 μg to about 500 μg (e.g., from about 10 μg to about 500 μg, from about 20 μg to about 500 μg, from about 30 μg to about 500 μg, from about 40 μg to about 500 μg, from about 50 μg to about 500 μg, from about 60 μg to about 500 μg, from about 70 μg to about 500 μg, from about 80 μg to about 500 μg, from about 90 μg to about 500 μg, from about 10 ... about 125 μg to about 500 μg, about 150 μg to about 500 μg, about 175 μg to about 500 μg, about 200 μg to about 500 μg, about 225 μg to about 500 μg, about 250 μg to about 500 μg, about 275 μg to about 500 μg, about 300 μg to about 500 μg, about 325 μg to about 500 μg, about 350 μg to about 500 μg, about 375 μg to about 500 μg, about 400 μg to about 500 μg, about 425 μg to about 500 μg, about 450 μg to about 500 μg, and about 475 μg to about 500 μg). In various embodiments, the amount of compound (e.g., compound of Formula I, A-182086) present in the biodegradable polymer in the biodegradable ocular implant is from about 70 μg to about 230 μg (e.g., about 70 μg, about 75 μg, about 80 μg, about 85 μg, about 90 μg, about 95 μg, about 100 μg, about 105 μg, about 110 μg, about 115 μg, about 120 μg, about 125 μg, about 130 μg, about 135 μg, about 140 μg, about 145 μg, about 150 μg, about 155 μg, about 160 μg, about 165 μg, about 170 μg, about 175 μg, about 180 μg, about 185 μg, about 190 μg, about 195 μg, about 200 μg, about 205 μg, about 210 μg, about 215 μg, about 220 μg, about 225 μg, and about 230 μg). In various embodiments, the amount of compound (e.g., compound of Formula I, A-182086) present in the biodegradable polymer in the biodegradable ocular implant is about 165 μg to about 220 μg (e.g., about 165 μg, about 170 μg, about 175 μg, about 180 μg, about 185 μg, about 190 μg, about 195 μg, about 200 μg, about 205 μg, about 210 μg, about 215 μg, and about 220 μg).In various embodiments, the amount of the compound (e.g., a compound of formula I, A-182086) present in the biodegradable polymer in the biodegradable ocular implant is about 150 μg to about 250 μg, about 300 μg to about 550 μg, or about 300 μg to about 600 μg. In various embodiments, the amount of the compound (e.g., a compound of formula I, A-182086) present in the biodegradable polymer in the biodegradable ocular implant is about 330 μg to about 500 μg (e.g., about 330 μg, about 335 μg, about 340 μg, about 345 μg, about 350 μg, about 355 μg, about 360 μg, about 365 μg, about 370 μg, about 375 μg, about 380 μg, about 385 μg, about 390 μg, about 400 μg, about 400 μg, about 45 ... 5 μg, about 390 μg, about 395 μg, about 400 μg, about 405 μg, about 410 μg, about 415 μg, about 420 μg, about 425 μg, about 430 μg, about 435 μg, about 440 μg, about 445 μg, about 450 μg, about 455 μg, about 460 μg, about 465 μg, about 470 μg, about 475 μg, about 480 μg, about 485 μg, about 490 μg, about 495 μg, and about 500 μg).

[0036] Biodegradable Polymers Suitable polymeric materials or compositions for use in the implants described herein include materials that are compatible with the eye, i.e., biocompatible, so as not to cause substantial interference with the function or physiology of the eye. Such polymeric materials may be biodegradable, bioerodible, or both biodegradable and bioerodible.

[0037] The terms "biodegrade" or "biodegradable," as used herein, generally refer to the biologically assisted degradation process that the polymers that make up the implant undergo in a biological environment (e.g., within a subject's body). Biodegradation is understood to include within its scope the processes of absorption, dissolution, breaking down, degradation, assimilation, or otherwise removal of the implant from the body (biological environment).

[0038] The term "polymer", as used herein, includes both homopolymers (polymers with only one type of repeat unit) and copolymers (polymers with more than one type of repeat unit).

[0039] The term "biodegradable polymer" as used herein refers to a polymer that degrades under physiological conditions in vivo. Release of the therapeutic agent occurs simultaneously with or subsequent to the degradation of the biodegradable polymer over time.

[0040] In a preferred embodiment, the biodegradable polymer is PLGA (poly(lactic-co-glycolic acid)). PLGA polymers are known to degrade via backbone hydrolysis (bulk erosion), with the end degradation products being lactic acid and glycolic acid, which are non-toxic and considered natural metabolic compounds. Lactic acid and glycolic acid are safely eliminated via the Krebs cycle by conversion to carbon dioxide and water.

[0041] PLGA is synthesized via random ring-opening copolymerization of cyclic dimers of glycolic acid and lactic acid. Successive monomer units of glycolic acid or lactic acid are linked together by ester linkages. The ratio of lactide to glycolide can be varied to change the biodegradation characteristics of the product. By varying the ratio, it is possible to tune the polymer degradation time. Importantly, drug release characteristics are influenced by the rate of biodegradation, molecular weight, and degree of crystallinity of the drug release system. By modifying and customizing the biodegradable polymer matrix, drug delivery profiles can be altered.

[0042] PLGA is primarily cleaved by non-enzymatic hydrolysis of its ester linkages throughout the polymer matrix in the presence of water in the surrounding tissue. PLGA polymers are biocompatible because they undergo hydrolysis in the body to produce the original monomers, lactic acid and / or glycolic acid. Lactic acid and glycolic acid are non-toxic and are safely eliminated by conversion to carbon dioxide and water via the Krebs cycle. The biocompatibility of PLGA polymers has been further tested in both non-ocular and ocular tissues in animals and humans. This finding indicates that the polymer is well tolerated.

[0043] Examples of PLGA polymers that may be utilized in embodiments of the present disclosure include, but are not limited to, Evonik Industries' RESOMER® product line (identified as RG502, RG502H, RG503, RG503H, RG504, RG504H, RG505, RG653H, RG750S, RG752H, RG752S, RG753H, RG753S, RG755S, RG756S, RG757S, and RG858S).

[0044] Such PLGA polymers include both acid and ester terminated polymers with intrinsic viscosities ranging from approximately 0.14 to approximately 1.7 dL / g as measured in an Ubbelhode size 0c glass capillary viscometer at 0.1% w / v in CHCl3 at 25° C. Exemplary polymers for use in various embodiments of the present disclosure may include variations in the molar ratio of D,L-lactide to glycolide from approximately 50:50 to approximately 85:15, including but not limited to 50:50, 65:35, 75:25, and 85:15.

[0045] Other examples of PLGA polymers that may be utilized in embodiments of the present disclosure include those produced by Lakeshore Biomaterials (identified, but not limited to, DLG 1A, DLG 3A, or DLG 4A). Such DLG polymers include both acid (A) and ester (E) terminated polymers with intrinsic viscosities ranging from approximately 0.0.5 to approximately 1.0 dL / g as measured in an Ubbelhode size 0c glass capillary viscometer at 0.1% w / v in CHCl3 at 25° C. Exemplary polymers used in various embodiments of the present disclosure may include variations in the molar ratio of D,L-lactide to glycolide from approximately 1:99 to approximately 99:1, including, but not limited to, 50:50, 65:35, 75:25, and 85:15.

[0046] RESOMERS® identified by “RG” or “DLG” in the product name (e.g., RG752S) have the general structure (V): [ka] The compound is poly(D,L-lactide-co-glycolide) or PLGA having the formula:

[0047] Synthesis of DLG of various molecular weights with various D,L-lactide-glycolide ratios is possible. In one embodiment, DLG with an intrinsic viscosity of about 0.05 to about 0.15 dL / g (e.g., 1A) can be used. In another embodiment, DLG with an intrinsic viscosity of about 0.15 to about 0.25 dL / g (e.g., 2A) can be used.

[0168] Poly(D,L-lactide-co-glycolide) or PLGA copolymers can be synthesized in various ratios of lactide to glycolide (e.g., lactide:glycolide ratio 75:25). These copolymers can be ester-terminated PLGA copolymers, as identified by the suffix "S" in the product name, or acid-terminated PLGA copolymers, as identified by the suffix "H" in the product name.

[0048] In some embodiments, the biodegradable ocular implants of the present disclosure comprise at least one PLGA, where each PLGA is independently selected from the group consisting of RG502, RG502S, RG502H, RG503, RG503H, RG504, RG504H, RG505, RG506, RG653H, RG752H, RG752S, RG753H, RG753S, RG755, RG755S, RG756, RG756S, RG757S, RG750S, RG858, and RG858S. In some embodiments, the biodegradable polymer comprises poly(lactic-co-glycolic acid) (PLGA), where the PLGA is selected from the group consisting of RG502, RG503H, RG503, RG752S, RG753S, RG755S, RG756S, and RG858S. In some embodiments, the biodegradable polymer comprises poly(lactic-co-glycolic acid) (PLGA), wherein the PLGA is selected from the group consisting of RG502, RG503, RG752S, RG753S, RG755S, RG756S, and RG858S. In some embodiments, the biodegradable ocular implant of the present disclosure comprises one PLGA. In some embodiments, the PLGA has a ratio of PLA and PLG of about 65:35.

[0049] In some embodiments, the biodegradable ocular implant of the present disclosure comprises at least two types of PLGA. In some embodiments, the biodegradable polymer comprises at least three types of PLGA (e.g., 3-6 types of PLGA, 3 types of PLGA, 4 types of PLGA, 5 types of PLGA).

[0050] In some embodiments, the biodegradable ocular implants of the present disclosure comprise at least two types of PLGA, where each PLGA is independently selected from the group consisting of RG502, RG502H, RG503, RG503H, RG504, RG504H, RG505, RG653H, RG750S, RG752H, RG752S, RG753H, RG753S, RG755S, RG756S, RG757S, and RG858S. In some embodiments, the biodegradable ocular implants of the present disclosure comprise at least two types of PLGA in a ratio of about 99%:about 1% (e.g., about 98%:about 2%, about 97%:about 3%, about 96%:about 4%, about 95%:about 5%, about 94%:about 6%, about 95%:about 5%, about 94%:about 6%, about 93%:about 7%, about 92%:about 8%, about 91%:about 9%, about 90%:about 10%, about 90%:about 10%, about 89%:about 11%, about 88%:about 12%, about 87%:about 13%, about 87%:about 14%, about 87%:about 15%, about 87%:about 16%, about 87%:about 17%, about 87%:about 18%, about 87%:about 19%, about 97%:about 20%, about 97%:about 21%, about 97%:about 22%, about 97%:about 23%, about 97%:about 24%, about 97%:about 25%, about 97%:about 26%, about 97%:about 27%, about 97%:about 28%, about 97%:about 29%, about 97%:about 30%, about 97%:about 31%, about 97%:about 32%, about 97%:about 33%, about 97%:about 34%, about 97%:about 35%, about 97%:about 36%, about 97%:about 37%, about 97%:about 38%, about 97%:about 39%, about 97%:about 40%, about 97%:about 40%, about %: approx. 13%, approx. 86%: approx. 14%, approx. 85%: approx. 15%, approx. 84%: approx. 16%, approx. 83%: approx. 17%, approx. 82%: approx. 18%, approx. 81%: approx. 19%, approx. 80%: approx. 20%, approx. 79%: approx. 21%, approx. 78%: approx. 22%, approx. 77%: approx. 23%, approx. 76%: approx. 24%, approx. 75%: approx. 25%, approx. 74%: approx. 26%, approx. 73%: approx. 27%, approx. 72%: approx. 28%, approx. 71%: approx. 29%, approx. 70%: approx. 30%, approx. 69%: approx. 31%, approx. 68%: approx. 32%, approx. 67%: 33%, 66%: 34%, 65%: 35%, 64%: 36%, 63%: 37%, 62%: 38%, 61%: 39%, 60%: 40%, 59%: 41%, 58%: 42%, 57%: 43%, 56%: 44%, 55%: 45%, 54%: 46%, 53%: 47%, 52%: 48%, 51%: 49%, 50%: 50%, 49%: 51%, 48%: 52%, 47%: 5 3%, about 46%: about 54%, about 45%: about 55%, about 44%: about 56%, about 43%: about 57%, about 42%: about 58%, about 41%: about 59%, about 40%: about 60%, about 39%: about 61%, about 38%: about 62%, about 37%: about 63%, about 36%: about 64%, about 35%: about 65%, about 34%: about 66%, about 33%: about 67%, about 32%: about 68%, about 31%: about 69%, about 30%: about 70%, about 29%: about 71%, about 28%: about 72%, about 27%: about 73%,26%: 74%, 25%: 75%, 24%: 76%, 23%: 77%, 22%: 78%, 21%: 79%, 20%: 80%, 19%: 81%, 18%: 82%, 17%: 83%, 16%: 84%, 15%: 85%, 14%: 86%, The ratios of PLGA are 13%: about 87%, 12%: about 88%, 11%: about 89%, 10%, 90%, 9%: about 91%, 8%: about 92%, 7%: about 93%, 6%: about 94%, 5%: about 95%, 4%: about 96%, 3%: about 97%, 2%: about 98%, and 1%: about 99%. In some embodiments, the biodegradable ocular implant of the present disclosure comprises at least two types of PLGA in a ratio of about 50% to about 75%: about 25% to about 50% (e.g., about 50% to about 70%: about 30% to about 50%, about 50% to about 65%: about 35% to about 50%, about 50% to about 60%: about 40% to about 50%, and about 55%: about 45%). In certain embodiments, the biodegradable ocular implant of the present disclosure comprises at least two types of PLGA in a ratio of about 50%:about 50%. In an embodiment, the two types of PLGA are RG503 and RG503H. In an embodiment, the two types of PLGA are RG502 and RG502H. In an embodiment, the two types of PLGA are RG504 and RG504H.

[0051] In some embodiments, the biodegradable polymer comprises at least three different biodegradable polymers. In some embodiments, the biodegradable polymer comprises at least three PLGAs, where each PLGA is independently selected from the group consisting of RG502, RG502H, RG503, RG503H, RG504, RG504H, RG505, RG653H, RG750S, RG752H, RG752S, RG753H, RG753S, RG755S, RG756S, RG757S, and RG858S. In some embodiments, the biodegradable polymer comprises at least three types of PLGA, the at least three types being about 1% to about 95% (e.g., about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, and about 95%): about 1% to about 95% (e.g., about 1%, about 5%, about 10%, about 15%, about 20%, about 25% , about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, and about 95%): about 1% to about 95% (e.g., about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, and about 95%).

[0052] In some embodiments, the biodegradable polymer comprises at least three types of PLGA in a ratio of about 40%:about 40%:about 20%. In some embodiments, the biodegradable polymer comprises at least three types of PLGA in a ratio of about 50%:about 10%:about 40%. In some embodiments, the biodegradable polymer comprises at least three types of PLGA in a ratio of about 10%:about 50%:about 40%. In some embodiments, the biodegradable polymer comprises at least three types of PLGA in a ratio of about 40%:about 40%:about 20%. In some embodiments, the biodegradable polymer comprises at least three types of PLGA in a ratio of about 10%:about 50%:about 40%. In some embodiments, the biodegradable polymer comprises at least three types of PLGA in a ratio of about 20%:about 60%:about 20%. In some embodiments, the biodegradable polymer comprises at least three PLGAs in a ratio of about 20%:about 50%:about 30%. In some embodiments, the biodegradable polymer comprises at least three PLGAs in a ratio of about 15%:about 50%:about 35%. In some embodiments, the biodegradable polymer comprises at least three PLGAs in a ratio of about 15%:about 45%:about 40%. In embodiments, each PLGA is independently selected from the group consisting of RG503, RG503H, and RG753S. In embodiments, each PLGA is independently selected from the group consisting of RG502, RG503, and RG753S. In embodiments, each PLGA is independently selected from the group consisting of RG502, RG503, and RG752S. In certain embodiments, each PLGA is independently selected from the group consisting of RG502, RG503, and RG755S. In certain embodiments, each PLGA is independently selected from the group consisting of RG502, RG503, and RG756S.

[0053] In some embodiments, the biodegradable polymer comprises at least four different biodegradable polymers. In some embodiments, the biodegradable polymer comprises at least four PLGAs, where each PLGA is independently selected from the group consisting of RG502, RG502H, RG503, RG503H, RG504, RG504H, RG505, RG653H, RG750S, RG752H, RG752S, RG753H, RG753S, RG755S, RG756S, RG757S, and RG858S. In certain embodiments, the biodegradable polymer comprises at least four PLGAs, where each PLGA is independently selected from the group consisting of RG502, RG503, RG753S, RG755S, RG756S, and RG858S. In certain embodiments, the biodegradable polymer comprises at least four PLGAs, where each PLGA is independently selected from the group consisting of RG502, RG503, RG753S, and RG858S.

[0054] In some embodiments, the biodegradable polymer comprises at least four types of PLGA, the at least four types of PLGA being about 1% to about 95% (e.g., about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, and about 95%): about 1% to about 95% (e.g., about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, and about 95%): about 1% to about 95% (e.g., about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, and about 95%): about 1% to about 95% (e.g., about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, and about 95%). In some embodiments, the biodegradable polymer comprises at least four types of PLGA in a ratio of about 10% to about 30% (e.g., about 10%, about 15%, about 20%, about 25%, and about 30%): about 20% to about 40% (e.g., about 20%, about 25%, about 30%, about 35%, about 40%): about 20% to about 40% (e.g., about 20%, about 25%, about 30%, about 35%, about 40%): about 10% to about 30% (e.g., about 10%, about 15%, about 20%, about 25%, and about 30%). In some embodiments, the biodegradable polymer contains at least four types of PLGA in a ratio of about 1% to about 20% (e.g., about 1%, about 5%, about 10%, about 15%, about 20%): about 40% to about 60% (e.g., about 40%, about 45%, about 50%, about 55%, about 60%): about 20% to about 40% (e.g., about 20%, about 25%, about 30%, about 35%, about 40%): about 1% to about 20% (e.g., about 1%, about 5%, about 10%, about 15%, about 20%).

[0055] In certain embodiments, the biodegradable polymer comprises at least four kinds of PLGA in a ratio of about 20%:about 30%:about 30%:about 20%. In certain embodiments, the biodegradable polymer comprises at least four kinds of PLGA in a ratio of about 10%:about 50%:about 30%:about 10%. Each of the four kinds of PLGA in the biodegradable polymer can be independently selected from the group consisting of RG502, RG503, RG753S, RG755S, RG756S, and RG858S. In some embodiments, each PLGA is independently RG502, RG503, RG753S, or RG858S.

[0056] In some embodiments, the biodegradable polymer comprises RG503, RG502, and RG753S in a ratio of about 40% to about 60%: about 5% to about 20%: about 30% to about 50%. In certain embodiments, the biodegradable polymer comprises RG503, RG502, and RG753S in a ratio of about 50%: about 10%: about 40%.

[0057] In some embodiments, the biodegradable polymer (e.g., PLGA) is substantially biodegraded in about 1 month to about 24 months (e.g., about 2 months to about 24 months, about 5 months to about 24 months, about 7 months to about 10 months, about 10 months to about 24 months, about 12 months to about 24 months, about 15 months to about 24 months, about 17 months to about 24 months, about 20 months to about 24 months, and about 22 months to about 24 months). In some embodiments, the biodegradable polymer (e.g., PLGA) is substantially biodegraded in about 3 months to about 12 months (e.g., about 4 months to about 12 months, about 5 months to about 12 months, about 5 months to about 12 months, about 6 months to about 12 months, about 7 months to about 12 months, about 8 months to about 12 months, about 9 months to about 12 months, about 10 months to about 12 months, and about 11 months to about 12 months). In some embodiments, the biodegradable polymer (e.g., PLGA) is substantially biodegraded in about 12 months to about 18 months (e.g., about 13 months to about 18 months, about 14 months to about 18 months, about 15 months to about 18 months, about 16 months to about 18 months, and about 17 months to about 18 months). In some embodiments, the biodegradable polymer (e.g., PLGA) is substantially biodegraded in about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, or about 12 months.

[0058] Biodegradable eye implants The biodegradable ocular implant described herein comprises a biodegradable polymer that includes a compound incorporated therein. In a preferred embodiment, the compound is a compound of formula I. The biodegradable ocular implant of the present disclosure can treat an ocular disease, comprising contacting the subject's ocular tissue with the biodegradable ocular implant, wherein the ocular disease is selected from the group consisting of glaucoma, diabetic retinopathy (DR), retinal vein occlusion (RVO), and retinopathy of prematurity (ROP), and the compound is present in a therapeutically effective amount to treat the ocular disease.

[0059] In various embodiments, the implant has a diameter of about 300 μm to about 400 μm (e.g., about 300 μm, about 325 μm, about 350 μm, about 375 μm, and about 400 μm) and a length of about 4 mm to about 5 mm (e.g., about 4.1 mm, about 4.2 mm, about 4.3 mm, about 4.4 mm, about 4.5 mm, about 4.6 mm, about 4.7 mm, about 4.8 mm, about 4.9 mm, and about 5 mm). In certain embodiments, the implant has a diameter of about 300 μm and a length of about 4 mm. In certain embodiments, the implant has a diameter of about 340 μm and a length of about 4 mm.

[0060] In various embodiments, the implant has a total weight of about 250 μg to about 450 μg (e.g., about 250 μg, about 270 μg, about 290 μg, about 310 μg, about 330 μg, about 350 μg, about 370 μg, about 390 μg, about 410 μg, about 430 μg, and about 450 μg). In various embodiments, the implant has a total weight of about 300 μg to about 450 μg. In various embodiments, the implant has a total weight of about 350 μg to about 450 μg. In some embodiments, the implant has a total weight of about 380 μg.

[0061] In some embodiments, the biodegradable ocular implant initially comprises at least about 95% to about 99% (e.g., about 95%, about 96%, about 97%, about 98%, and about 99%) of the biodegradable polymer and compound matrix. In some embodiments, the biodegradable ocular implant initially comprises at least 95% of the biodegradable polymer and compound matrix. In some embodiments, the biodegradable ocular implant initially comprises at least about 80% to about 95% (e.g., about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, and about 95%) of the biodegradable polymer and compound matrix.

[0062] In certain embodiments, the biodegradable ocular implant comprises about .

[0063] The rate of therapeutic agent (e.g., a compound of Formula I) release from an intravitreal implant or particle suspension (e.g., a biodegradable ocular implant of the present disclosure) can depend on several factors, including, but not limited to, the surface area of ​​the implant, the therapeutic agent content, and the aqueous solubility of the therapeutic agent, as well as the rate of polymer degradation.

[0064] In some embodiments, less than 40% (e.g., about 40%, about 35%, about 30%, about 25%, about 20%, about 15%, about 10%, and about 5%) of the compound is released from the biodegradable ocular implant when placed in phosphate buffered saline (PBS) for about one month. In some embodiments, less than 90% (e.g., about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, about 45%, about 40%, about 35%, about 30%, about 25%, about 20%, about 15%, about 10%, and about 5%) of the compound is released from the biodegradable ocular implant when placed in phosphate buffered saline (PBS) for about 1 month to about 12 months (about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months).

[0065] In various embodiments, the implant is administered as an intravitreal administration. Intravitreal administration refers to drug administration into the vitreous humor of the eye. In some embodiments, the implant is administered locally to the back of the eye. In some embodiments, the implant is injected into the intravitreal space using a needle and applicator. In some embodiments, the biodegradable ocular implant is administered in a range of about 1 μg to about 1 mg (e.g., about 1 μg, about 10 μg, about 25 μg, about 50 μg, about 75 μg, about 100 μg, about 125 μg, about 150 μg, about 175 μg, about 200 μg, about 225 μg, about 250 μg, about 275 μg, about 300 μg, about 325 μg, about 350 μg, about 375 μg, about 400 μg, about 425 μg, about 450 μg, about 460 μg, about 470 μg, about 480 μg, about 490 μg, about 500 μg, about 510 μg, about 520 μg, about 530 μg, about 540 μg, about 550 μg, about 560 μg, about 570 μg, about 580 μg, about 590 μg, about 600 μg, about 610 μg, about 620 μg, about 630 μg, about 640 μg, about 650 μg, about 660 μg, about 670 μg, about 680 μg, about 690 μg, about 700 μg, about 710 μg, about 720 μg, about 750 μg, about 760 μg, about 770 μg, about 780 μg, about In some embodiments, the biodegradable ocular implant comprises a dose of the compound (e.g., a compound of Formula I) ranging from about 10 μg to about 100 μg. In some embodiments, the biodegradable ocular implant comprises a dose of the compound (e.g., a compound of formula I) in the range of about 500 μg to about 4 mg (e.g., about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, and about 3.5 mg). In some embodiments, the dose is about 150 μg to about 250 μg. In certain embodiments, the dose is about 165 μg to about 220 μg (e.g., about 165 μg, about 170 μg, about 175 μg, about 180 μg, about 185 μg, about 190 μg, about 195 μg, about 200 μg, about 205 μg, about 210 μg, about 215 μg, and about 220 μg). In some embodiments, the dose is about 300 μg to about 500 μg. In some embodiments, the dose is about 300 μg to about 550 μg, In some embodiments, the dose is about 300 μg to about 600 μg.In certain embodiments, the dose is from about 330 μg to about 500 μg (e.g., about 330 μg, about 335 μg, about 340 μg, about 345 μg, about 350 μg, about 355 μg, about 360 μg, about 365 μg, about 370 μg, about 375 μg, about 380 μg, about 385 μg, about 390 μg, about 395 μg, about 400 μg, about 4 05 μg, about 410 μg, about 415 μg, about 420 μg, about 425 μg, about 430 μg, about 435 μg, about 440 μg, about 445 μg, about 450 μg, about 455 μg, about 460 μg, about 465 μg, about 470 μg, about 475 μg, about 480 μg, about 485 μg, about 490 μg, about 495 μg, and about 500 μg). In some embodiments, the dose is about 200 μg to about 400 μg (e.g., about 200 μg, about 210 μg, about 220 μg, about 230 μg, about 240 μg, about 250 μg, about 260 μg, about 270 μg, about 280 μg, about 290 μg, about 300 μg, about 310 μg, about 320 μg, about 330 μg, about 340 μg, about 350 μg, about 360 μg, about 370 μg, about 380 μg, about 390 μg, about 400 μg). In some embodiments, the dose is about 175 μg.

[0066] In some embodiments, the biodegradable ocular implant is a sterile biodegradable ocular implant. As used herein, "sterile" refers to a composition that meets the requirements for sterility enforced by drug regulatory authorities (e.g., MCA in the UK or FDA in the US). Tests are included within current versions of compendia (e.g., British Pharmacopoeia and United States Pharmacopoeia). In some embodiments, the biodegradable ocular implant is a substantially pure biodegradable ocular implant. In some embodiments, the biodegradable ocular implant is a medical grade biodegradable ocular implant. In some embodiments, the biodegradable ocular implant is administered into the intravitreal space every 3-12 months.

[0067] In some embodiments, provided herein is a biodegradable ocular implant comprising a biodegradable polymer comprising a compound incorporated therein: wherein the compound is a compound of formula I or a pharma- ceutically acceptable salt thereof, wherein the concentration of the compound in the biodegradable polymer is about 45% w / w; and the biodegradable polymer comprises RG503, RG502 and RG753S in a ratio of about 50%:about 10%:about 40%.

[0068] In certain embodiments, provided herein is a biodegradable ocular implant comprising a biodegradable polymer comprising a compound incorporated therein: wherein said compound is a compound of formula I or a pharma- ceutically acceptable salt thereof, wherein the concentration of said compound in said biodegradable polymer is about 45% w / w; and said biodegradable polymer comprises RG503, RG502 and RG753S in a ratio of about 20%:about 20%:about 60%.

[0069] Method of preparation The method of making the biodegradable ocular implant described herein comprises subjecting a biodegradable polymer containing a compound to solvent casting, injection molding, or extrusion, wherein the compound is a compound of Formula I: [ka] or a pharma- ceutically acceptable salt thereof.

[0070] Prior to implant fabrication, the blend of the polymer matrix and therapeutic agent can be dissolved and mixed with a solvent to produce a therapeutic agent that is homogeneously dispersed throughout the body of the implant. The blends prepared can each contain multiple, for example, three, different PLGA polymers in various ratios. The PLGA polymers used to produce the pharmaceutical compositions of the present invention can include, but are not limited to, RESOMER® RG502, RG503, RG752S, RG753S, and 65 / 35 PLA / PLG, all of which are commercially available.

[0071] The following is an exemplary procedure used to prepare the compositions of the present invention: For example, the polymer is dissolved in an organic solvent (e.g., methylene chloride) in a specific ratio. The therapeutic agent (e.g., edonentan) is then added to the polymer solution and dissolved. The methylene chloride is then evaporated at room temperature in a polytetrafluoroethylene (PTFE) dish. After the methylene chloride is evaporated, a thin film of homogeneous material remains. In one embodiment, the thin film ranges in thickness from 200 μm to 300 μm.

[0072] The remaining homogenous film is then ground into a powder using a cryogenic mill. A small portion of the film is added to a stainless steel cryogenic mill vessel containing 2-3 appropriately sized grinding balls and pre-cooled using liquid nitrogen at 5 Hz for 2-3 minutes. The material is then milled for 1 minute at 20 Hz-25 Hz and rested for 1 minute at 5 Hz. This mill / rest cycle is repeated 2-5 times. The resulting material is a coarse to fine powder of homogenous material.

[0073] In one embodiment, the implant of the present invention can be prepared using the homogenous material described above. In one embodiment, the implant is formed by injection molding. Injection molding can be performed, for example, by a suitable injection molding machine, such as a modified Haake MiniJet (ThermoFisher Scientific). The following is an exemplary procedure used to prepare the implant of the present invention.

[0074] The homogenous powder is loaded and injected into a mould consisting of a suitable sized channel (e.g. 300 μm×12 mm). The powder is loaded into a barrel leading to the mould and the mould is placed under vacuum. The temperature of the mould is held at 15° C. to 75° C. The cylinder around the barrel loaded with the powder is held at 145° C. to 220° C. for 10 to 15 minutes to melt the powder blend. Injection is carried out using an injection pressure of 220 bar to 330 bar, held for 2 to 10 minutes. The post-injection pressure is held at 50 bar for 2 to 10 minutes. The mould is then cooled to 15 to 23° C., after which the mould is removed from the injection moulding machine. The moulded fibre is then removed from the mould and then cut into implants of the target weight and length. In some embodiments, the implant is 4 mm in length and contains about 165 μg to about 220 μg of active ingredient (eg, edonentan).

[0075] In one embodiment, the implant of the present invention can be prepared using the homogenous material. In one embodiment, the implant is formed by extrusion, for example, hot melt extrusion. Hot melt extrusion can be performed using ThermoFisher Pharma mini HME Micro Compounder, ThermoFisher FP-Pharma-11-Twin-230x100, ThermoFisher Pharma 11 Twin-Screw Extruder, ThermoFisher FP-Pharma-16-230x100, ThermoFisher Pharma 16 Twin-Screw Extruder, or Barrell Engineering Micro Syringe Type Extruder.

[0076] Crystal morphology In another aspect, the biodegradable ocular implants and methods of use described herein include a biodegradable polymer comprising a solid form of the compound of Formula I.

[0077] In certain embodiments, the compound of formula I: [ka] is an anhydrous crystalline form (Form 4) having an X-ray powder diffraction pattern comprising at least three characterizing peaks selected from those at 5.6±0.2°, 11.4±0.2°, 17.7±0.2°, 19.3±0.2°, 21.1±0.2°, and 21.9±0.2° in terms of 2θ.

[0078] In some embodiments of the solid form, the anhydrous crystalline Form 4 has the following X-ray powder diffraction pattern expressed in terms of diffraction angles (2θ): 5.6±0.2°, 11.4±0.2°, 17.7±0.2°, 19.3±0.2°, and 21.9±0.2°. In some embodiments of the solid form, the anhydrous crystalline Form 4 has the following X-ray powder diffraction pattern expressed in terms of diffraction angles (2θ): 11.4±0.2°, 17.7±0.2°, and 19.3±0.2°. In some embodiments of the solid form, the anhydrous crystalline Form 4 has a T of about 163° C. by DSC analysis. m In some embodiments of the solid form, the anhydrous crystalline Form 4 has the following X-ray powder diffraction pattern expressed in terms of diffraction angles (2θ): 5.6±0.2°, 11.4±0.2°, 17.7±0.2°, 19.3±0.2°, and 21.9±0.2°. In some embodiments of the solid form, the anhydrous crystalline Form 4 has the following X-ray powder diffraction pattern expressed in terms of diffraction angles (2θ): 11.4±0.2°, 17.7±0.2°, and 19.3±0.2°. In some embodiments of the solid form, the anhydrous crystalline Form 4 has a T of about 163° C. by DSC analysis. m Shows.

[0079] In some embodiments, the compound is 90% or more by weight in crystalline form 4 based on the total weight of the compounds present in the composition. In some embodiments, the compound of formula I is 95% or more by weight in crystalline form 4 based on the total weight of the compounds present in the composition. In some embodiments, the compound of formula I is 96% or more by weight in crystalline form 4 based on the total weight of the compounds present in the composition. In some embodiments, the compound of formula I is 97% or more by weight in crystalline form 4 based on the total weight of the compounds present in the composition. In some embodiments, the compound of formula I is 98% or more by weight in crystalline form 4 based on the total weight of the compounds present in the composition. In some embodiments, the compound of formula I is 99% or more by weight in crystalline form 4 based on the total weight of the compounds present in the composition.

[0080] In certain embodiments, the compound of Formula I is in an anhydrous crystalline form (Form 1), wherein the anhydrous crystalline Form 1 has an X-ray powder diffraction pattern comprising at least three characterizing peaks selected from those at 6.3±0.2°, 7.5±0.2°, 11.7±0.2°, 15.1±0.2°, and 17.3±0.2° in terms of 2θ; the compound is 90% by weight or more in crystalline Form 1, based on the total weight of compound present in the composition.

[0081] In certain embodiments, the compound of Formula I is a monohydrate crystalline form (Form 2), wherein the monohydrate crystalline Form 2 has an X-ray powder diffraction pattern comprising at least three characterizing peaks selected from those at 9.6±0.2°, 10.4±0.2°, 19.6±0.2°, 19.7±0.2°, 22.0±0.2°, 22.9±0.2°, and 23.7±0.2° in terms of 2θ; the compound is 90% by weight or more in crystalline Form 2, based on the total weight of compound present in the composition.

[0082] In certain embodiments, the compound of Formula I is anhydrous crystalline (Form 3), wherein the anhydrous crystalline Form 3 has an X-ray powder diffraction pattern comprising at least three characterizing peaks selected from those at 7.8±0.2°, 9.0±0.2°, 11.6±0.2°, 15.8±0.2°, and 19.1±0.2° in terms of 2θ; the compound is 90% by weight or more in crystalline Form 3, based on the total weight of compound present in the composition.

[0083] As used herein, the term "amorphous" refers to a solid material that does not have long-range order in the position of its molecules. Amorphous solids are generally supercooled liquids in which the molecules are arranged in a random manner, resulting in neither a well-defined arrangement (e.g., molecular packing) nor long-range order. Amorphous solids are generally isotropic, i.e., they exhibit similar properties in all directions, and do not have a distinct melting point. For example, an amorphous material is a solid material that does not have a sharp characteristic crystalline peak in its X-ray powder diffraction (XRPD) pattern (i.e., it is not crystalline as determined by XRPD). Instead, one or several broad peaks (e.g., halos) appear in its XRPD pattern.

[0084] Hydrate forms of crystalline edonentan are contemplated (e.g., edonentan·(HO) m (where m is a fraction or integer between about 0 and about 4, inclusive). For example, anhydrous or monohydrate forms of crystalline edonentan are contemplated herein. In one embodiment, the disclosed crystalline forms of edonentan may have a water level of about 1-10% by weight (e.g., 3-9% by weight or 5-8% by weight).

[0085] eye disease The methods of the present disclosure include the use of biodegradable ocular implants comprising edonentan as described above in the treatment and amelioration of ocular diseases selected from glaucoma, diabetic retinopathy (DR), retinal vein occlusion (RVO), and retinopathy of prematurity (ROP), which are described below.

[0086] Glaucoma In the treatment of glaucoma using compositions comprising edonentan as described herein, a "therapeutically effective amount" can be determined by evaluating the improvement of retinal blood flow (RBF) beyond that which can be achieved by standard care (reduction of intraocular pressure (IOP)). For glaucoma indications, the improvement of blood flow in a healthy rabbit eye model can be used as a predictor of pharmacodynamic response (PD) in humans. Rabbits are commonly used to evaluate the ocular PK / PD relationship for compounds targeting human ocular diseases due to the anatomical and functional similarities between rabbit and human eyes. Previously, intravitreal administration of ET-1 to rabbit eyes has been shown to induce significant vasoconstriction and optic nerve damage (Sasaoka M. et al., Exp Eye Res 2006; Sugiyama T. et al., Arch Ophthalmol 2009). Efficacy in this model is based on reversal of perfusion defect induced by intravitreal ET-1 administration at concentrations equivalent to levels observed in the plasma and aqueous humor of human glaucoma patients (Li S. et al., Journal of Ophthalmology 2016).

[0087] Other examples of relevant animal glaucoma models are the Morrison rat model of acutely elevated IOP and the laser-induced non-human primate (NHP) glaucoma model. Glaucoma in the Morrison rat model is induced by sustained elevation of IOP with administration of hypertonic saline via the episcleral vein. In the laser-induced NHP glaucoma model, it has been shown that optic nerve head blood flow is reduced after sustained elevation of IOP (Wang L. et al., Invest Ophthalmol Vis Sci 2012). Furthermore, it has been shown that reduction of optic nerve head blood flow correlates with long-term structural changes in the optic nerve (Cull G. et al., Invest Ophthalmol Vis Sci 2013).

[0088] Efficacy in the above glaucoma models is defined as a reduction in IOP, improvement in optic nerve head or retinal blood flow from baseline, prevention or slowing of progression of structural neurodegenerative changes (e.g., retinal nerve fiber layer thickness as measured by optical coherence tomography (OCT) or retinal ganglion cell count on flat mounts), and functional changes (electroretinography (ERG) or contrast sensitivity after treatment with edonentan).

[0089] It is believed that the effect of a composition containing edonentan on retinal blood flow can be evaluated by the vessel radius (r) in Boiseuille's law. An increase in (r) with an endothelin antagonist induces a more significant increase in blood flow than can be achieved by increasing the perfusion pressure via IOP reduction: Blood flow = (perfusion pressure × πr 4 ) / (8ηl) where l: Blood vessel length r: vessel radius η: Blood viscosity Perfusion pressure: Mean arterial pressure - IOP Furthermore, compositions containing edonentan can reduce IOP and / or prevent RGC death through mechanisms unrelated to the improvement in retinal / optic nerve head tissue perfusion.Therefore, by using a certain specific edonentan, one (r) or more of the above parameters (IOP) can be altered to improve RBF, thereby achieving therapeutic effectiveness in treating glaucoma.

[0090] In some embodiments, the glaucoma patient is started on treatment as soon as they are diagnosed. In some embodiments, a biodegradable ocular implant containing the compound of formula I (edonentan) is administered locally to the back of the eye (e.g., using an intravitreal biodegradable ocular implant) at a frequency of every 3 to 12 months (e.g., every 4 to 12 months, every 5 to 12 months, every 6 to 12 months, every 7 to 12 months, every 8 to 12 months, every 9 to 12 months, every 10 to 12 months, every 11 to 12 months, every 3 to 4 months, every 3 to 5 months, every 3 to 6 months, every 3 to 7 months, every 3 to 8 months, every 3 to 9 months, every 3 to 10 months, or every 3 to 11 months).

[0091] In some embodiments, the biodegradable ocular implant for treating glaucoma in a subject in need thereof comprises a biodegradable polymer (e.g., PLGA) that substantially biodegrades in about 1 month to about 24 months (e.g., about 2 months to about 24 months, about 5 months to about 24 months, about 7 months to about 10 months, about 10 months to about 24 months, about 12 months to about 24 months, about 15 months to about 24 months, about 17 months to about 24 months, about 20 months to about 24 months, and about 22 months to about 24 months). In some embodiments, the biodegradable polymer (e.g., PLGA) is substantially biodegraded in about 3 months to about 12 months (e.g., about 4 months to about 12 months, about 5 months to about 12 months, about 5 months to about 12 months, about 6 months to about 12 months, about 7 months to about 12 months, about 8 months to about 12 months, about 9 months to about 12 months, about 10 months to about 12 months, and about 11 months to about 12 months). In some embodiments, the biodegradable polymer (e.g., PLGA) is substantially biodegraded in about 12 months to about 18 months (e.g., about 13 months to about 18 months, about 14 months to about 18 months, about 15 months to about 18 months, about 16 months to about 18 months, and about 17 months to about 18 months). In some embodiments, the biodegradable polymer (eg, PLGA) substantially biodegrades in about 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months.

[0092] Diabetic retinopathy (DR) Diabetes can cause serious late complications classified as microangiopathic (retinopathy, neuropathy, and diabetic nephropathy) and macroangiopathic (cardiovascular disease). Diabetic retinopathy is the result of damage to the small blood vessels and neurons of the retina. The earliest changes resulting in diabetic retinopathy include narrowing of the retinal arteries associated with reduced retinal blood flow; dysfunction of neurons of the inner retina, followed by later stages by altered function of the outer retina (associated with subtle changes in visual function); dysfunction of the blood-retinal barrier (which protects the retina from many substances in the blood, including toxins and immune cells), resulting in leakage of blood components into the retinal neuropile. Later, the basement membrane of the retinal blood vessels thickens, the capillaries degenerate, and lose cells, especially pericytes and vascular smooth muscle cells. This results in loss of blood flow and progressive ischemia, and microscopic aneurysms that appear as balloon-like structures protruding from the capillary wall, which recruit inflammatory cells; leading to progressive dysfunction and degeneration of retinal neurons and glial cells.

[0093] The ischemia and oxidant injury observed in DR impairs blood flow, and the inventors have found that tissue ischemia can be reversed by a composition containing edonentan.With respect to DR indications, improvements in retinal perfusion are expected to reduce hypoxia and inhibit vascular endothelial growth factor (VEGF) upregulation, with the resulting benefits of slowing down various proliferative changes, neovascularization and / or macular edema complications.

[0094] A preclinical mouse model of retinopathy of prematurity (ROP) can be used as a surrogate model for the ischemic retinopathy changes observed in DR. Oxygen-induced retinopathy in mice is a reproducible and quantifiable proliferative retinal neovascularization model suitable for testing the pathogenesis and therapeutic interventions for retinal neovascularization in ROP and other vascular pathologies, including DR. The model is induced by exposing 1-week-old C57BL / 6J mice to 75% oxygen for 5 days followed by room air as previously described (Smith LEH et al., Invest Ophthalmol Vis Sci 1994). The efficacy of this preclinical model of ROP can be evaluated by testing retinal hypoxia and neovascularization. The current standard of care in DR includes anti-VEGF treatment, which only addresses advanced vascular complications of the disease.

[0095] In some embodiments, patients with DR are initiated into this treatment during the non-proliferative stage of the disease. In some embodiments, a biodegradable ocular implant comprising the compound of formula I (edonentan) is administered locally to the back of the eye (e.g., using an intravitreal biodegradable ocular implant) at a frequency of every 3-12 months (e.g., every 4-12 months, every 5-12 months, every 6-12 months, every 7-12 months, every 8-12 months, every 9-12 months, every 10-12 months, every 11-12 months, every 3-4 months, every 3-5 months, every 3-6 months, every 3-7 months, every 3-8 months, every 3-9 months, every 3-10 months, or every 3-11 months).

[0096] In some embodiments, the biodegradable ocular implant for treating DR in a subject in need thereof comprises a biodegradable polymer (e.g., PLGA) that substantially biodegrades in about 1 month to about 24 months (e.g., about 2 months to about 24 months, about 5 months to about 24 months, about 7 months to about 10 months, about 10 months to about 24 months, about 12 months to about 24 months, about 15 months to about 24 months, about 17 months to about 24 months, about 20 months to about 24 months, and about 22 months to about 24 months). In some embodiments, the biodegradable polymer (e.g., PLGA) is substantially biodegraded in about 3 months to about 12 months (e.g., about 4 months to about 12 months, about 5 months to about 12 months, about 5 months to about 12 months, about 6 months to about 12 months, about 7 months to about 12 months, about 8 months to about 12 months, about 9 months to about 12 months, about 10 months to about 12 months, and about 11 months to about 12 months). In some embodiments, the biodegradable polymer (e.g., PLGA) is substantially biodegraded in about 12 months to about 18 months (e.g., about 13 months to about 18 months, about 14 months to about 18 months, about 15 months to about 18 months, about 16 months to about 18 months, and about 17 months to about 18 months). In some embodiments, the biodegradable polymer (eg, PLGA) substantially biodegrades in about 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months.

[0097] Retinal vein occlusion (RVO) Retinal vein occlusion (RVO) (vascular disease of the retina) is currently treated with intravitreal injections of anti-VEGF drugs that inhibit the growth factors that cause macular edema and corticosteroids that combat the inflammatory components that lead to edema. It is highly desirable to use a composition containing edonentan to treat RVO by improving tissue perfusion and reducing inflammation while avoiding the unwanted effects of systemic immunosuppression and / or the local adverse effects of steroids.

[0098] RVO is currently treated with intravitreal steroids and anti-VEGF agents. We hypothesize that improving perfusion of existing vessels will reduce the extent of macular edema and VEGF upregulation, as well as downstream maladaptive changes manifested as RVO. To test efficacy, a preclinical mouse model of ischemic retinopathy can be used. Oxygen-induced retinopathy in mice is a reproducible and quantifiable proliferative retinal neovascularization model suitable for testing the pathogenesis and therapeutic interventions for retinal neovascularization in many ischemic retinopathies, including RVO. The model is induced by exposing 1-week-old C57BL / 6J mice to 75% oxygen for 5 days followed by room air, as previously described (Smith LEH et al., Invest Ophthalmol Vis Sci 1994). The efficacy of this preclinical model of ischemic retinopathy can be evaluated by testing retinal hypoxia and neovascularization. The "therapeutically effective amount" of the composition comprising edonentan described herein can be additive to the current standard of care by improving tissue perfusion and reducing ET-1-mediated inflammation while avoiding the unwanted effects of topical steroids. In some embodiments of the treatment of RVO, the biodegradable ocular implant comprising the compound of formula I (edonentan) is administered locally to the back of the eye using an intravitreal biodegradable ocular implant. The frequency of administration varies based on the patient's disease course and response to treatment.

[0099] In some embodiments, a biodegradable ocular implant comprising a compound of formula I (edonentan) is administered locally to the back of the eye (e.g., using an intravitreal biodegradable ocular implant) at a frequency of every 3 to 12 months (e.g., every 4 to 12 months, every 5 to 12 months, every 6 to 12 months, every 7 to 12 months, every 8 to 12 months, every 9 to 12 months, every 10 to 12 months, every 11 to 12 months, every 3 to 4 months, every 3 to 5 months, every 3 to 6 months, every 3 to 7 months, every 3 to 8 months, every 3 to 9 months, every 3 to 10 months, or every 3 to 11 months).

[0100] In some embodiments, the biodegradable ocular implant for treating RVO in a subject in need thereof comprises a biodegradable polymer (e.g., PLGA) that substantially biodegrades in about 1 month to about 24 months (e.g., about 2 months to about 24 months, about 5 months to about 24 months, about 7 months to about 10 months, about 10 months to about 24 months, about 12 months to about 24 months, about 15 months to about 24 months, about 17 months to about 24 months, about 20 months to about 24 months, and about 22 months to about 24 months). In some embodiments, the biodegradable polymer (e.g., PLGA) is substantially biodegraded in about 3 months to about 12 months (e.g., about 4 months to about 12 months, about 5 months to about 12 months, about 5 months to about 12 months, about 6 months to about 12 months, about 7 months to about 12 months, about 8 months to about 12 months, about 9 months to about 12 months, about 10 months to about 12 months, and about 11 months to about 12 months). In some embodiments, the biodegradable polymer (e.g., PLGA) is substantially biodegraded in about 12 months to about 18 months (e.g., about 13 months to about 18 months, about 14 months to about 18 months, about 15 months to about 18 months, about 16 months to about 18 months, and about 17 months to about 18 months). In some embodiments, the biodegradable polymer (eg, PLGA) substantially biodegrades in about 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months.

[0101] Retinopathy of Prematurity (ROP) Retinopathy of prematurity (ROP) is a retinal vascular proliferative disorder that affects preterm infants. ROP remains the leading preventable cause of blindness and visual impairment worldwide. With improvements in perinatal care, improved survival of moderately preterm infants, and limited resources for oxygen delivery and monitoring, more mature preterm infants are developing severe ROP in developing countries.

[0102] The pathophysiology of ROP is characterized by two stages. Stage I ROP results from vaso-obliteration beginning shortly after birth secondary to a marked decrease in vascular endothelial growth factor (VEGF) and insulin-like growth factor-1 (IGF-1). Stage II begins at approximately 33 weeks postmenstrual age (PMA). During this stage, VEGF levels increase, especially in the presence of retinal hypoxia, as retinal metabolism and oxygen demand increase, leading to abnormal vascular proliferation. For advanced stages of ROP, laser ablation of the avascular retina, Early Treatment of ROP (ETROP) protocols, intravitreal injections of anti-VEGF antibodies (e.g., bevacizumab), and vitrectomy are used to protect central vision and prevent retinal detachment. Long-term complications (e.g., refractory error, risk of recurrence of ROP and retinal detachment) require continued follow-up by an ophthalmologist during adolescence and beyond.

[0103] ROP is induced by severe ischemia due to underdevelopment of retinal blood vessels secondary to premature birth. Thus, as an aspect of the present disclosure, the inventors believe that improving perfusion of existing blood vessels with a composition comprising edonentan will reduce the degree of ischemia and VEGF upregulation, as well as downstream maladaptive changes manifested as ROP. To test efficacy, a preclinical mouse model of ROP can be used. Oxygen-induced retinopathy in mice is a reproducible and quantifiable proliferative retinal neovascularization model suitable for testing pathogenesis and therapeutic interventions related to retinal neovascularization in ROP. The model is induced by exposing 1-week-old C57BL / 6J mice to 75% oxygen for 5 days followed by room air, as previously described (Smith LEH et al., Invest Ophthalmol Vis Sci 1994). The efficacy of this preclinical model of ROP can be evaluated by testing retinal hypoxia and neovascularization. The "therapeutically effective amount" of the composition comprising edonentan described herein is additive to the current standard of care by improving tissue perfusion and reducing pathological neovascularization induced by VEGF. In some embodiments, the drug therapy is administered locally to the back of the eye using an intravitreal biodegradable ocular implant every 4-6 weeks, as needed, based on the patient's disease history and response to treatment. For example, the intravitreal biodegradable ocular implant is administered locally to the back of the eye using an intravitreal injection every 5 weeks, as needed, based on the patient's disease history and response to treatment.

[0104] In some embodiments, patients with ROP are initiated into this treatment during the non-proliferative stage of the disease. In some embodiments, a biodegradable ocular implant comprising a compound of formula I (edonentan) is administered locally to the back of the eye (e.g., using an intravitreal biodegradable ocular implant) at a frequency of every 3-12 months (e.g., every 4-12 months, every 5-12 months, every 6-12 months, every 7-12 months, every 8-12 months, every 9-12 months, every 10-12 months, every 11-12 months, every 3-4 months, every 3-5 months, every 3-6 months, every 3-7 months, every 3-8 months, every 3-9 months, every 3-10 months, or every 3-11 months).

[0105] In some embodiments, the biodegradable ocular implant for treating ROP in a subject in need thereof comprises a biodegradable polymer (e.g., PLGA) that substantially biodegrades in about 1 month to about 24 months (e.g., about 2 months to about 24 months, about 5 months to about 24 months, about 7 months to about 10 months, about 10 months to about 24 months, about 12 months to about 24 months, about 15 months to about 24 months, about 17 months to about 24 months, about 20 months to about 24 months, and about 22 months to about 24 months). In some embodiments, the biodegradable polymer (e.g., PLGA) is substantially biodegraded in about 3 months to about 12 months (e.g., about 4 months to about 12 months, about 5 months to about 12 months, about 5 months to about 12 months, about 6 months to about 12 months, about 7 months to about 12 months, about 8 months to about 12 months, about 9 months to about 12 months, about 10 months to about 12 months, and about 11 months to about 12 months). In some embodiments, the biodegradable polymer (e.g., PLGA) is substantially biodegraded in about 12 months to about 18 months (e.g., about 13 months to about 18 months, about 14 months to about 18 months, about 15 months to about 18 months, about 16 months to about 18 months, and about 17 months to about 18 months). In some embodiments, the biodegradable polymer (eg, PLGA) substantially biodegrades in about 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months.

[0106] In various embodiments, the biodegradable ocular implant for treating an ocular disease described herein releases at least 10% edonentane after 14 days. In some embodiments, the implant releases about 16% edonentane after 14 days. In various embodiments, the biodegradable ocular implant for treating an ocular disease described herein releases at least 25% edonentane after 28 days. In some embodiments, the implant releases about 30% edonentane after 28 days. In various embodiments, the biodegradable ocular implant for treating an ocular disease described herein releases at least 40% edonentane after 56 days. In some embodiments, the implant releases about 48% edonentane after 56 days. In various embodiments, the biodegradable ocular implant for treating an ocular disease described herein releases at least 90% edonentane after 84 days. In some embodiments, the implant releases about 100% of edonentan after 84 days.

[0107] Pharmaceutical Compositions Some embodiments described herein relate to pharmaceutical compositions that may include a therapeutically effective amount of edonentan (as described herein), or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier, diluent, excipient, or combination thereof.

[0108] The term "pharmaceutical composition" refers to a mixture of one or both compounds disclosed herein with other chemical components (e.g., diluents or carriers). The pharmaceutical composition facilitates administration of the compound to an organism. Pharmaceutical compositions are generally tailored for a particular intended route of administration.

[0109] Some pharmaceutical compositions involve preparing pharma- ceutically acceptable salts, including salts of acidic or basic groups present in the compounds of the present disclosure. Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)). Certain compounds of the present disclosure may form pharma- ceutically acceptable salts with various amino acids. Suitable base salts include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, and diethanolamine salts. For a review of pharma- ceutically acceptable salts, see Berge et al., 66 J. PHARM. SCI., 1-19 (1977).

[0110] The term "pharmacologically acceptable" defines a carrier, diluent, excipient, salt, or composition that is safe and effective for its intended use and possesses the desired biological and pharmacological activity.

[0111] As used herein, "carrier" refers to a compound that facilitates the incorporation of a compound into cells or tissues. For example, and without limitation, dimethylsulfoxide (DMSO) is a commonly used carrier that facilitates the incorporation of many organic compounds into cells or tissues of a subject.

[0112] As used herein, "diluent" refers to an ingredient in a pharmaceutical composition that lacks pharmacological activity but may be pharmacologic necessary or desirable. For example, a diluent may be used to increase the bulk of a potent drug whose mass is too small for manufacture and / or administration. It may also be a liquid for dissolving a drug to be administered by injection, ingestion, or inhalation. A common form of diluent in the art is a buffered aqueous solution, including but not limited to phosphate buffered saline, which mimics the composition of human blood.

[0113] As used herein, "excipient" refers to an inert substance added to a pharmaceutical composition to provide the composition with, without limitation, bulk, consistency, stability, binding ability, lubrication, disintegration ability, delayed dissolution, etc. A "diluent" is a type of excipient.

[0114] definition As used herein, "about" will be understood by one of ordinary skill in the art and will vary to some extent depending on the context in which it is used. If there are uses of the term that are not clear to persons of ordinary skill in the art given the context in which it is used, then "about" will mean up to ±10% of that particular term.

[0115] As used herein, the term "effective amount" refers to an amount of a compound sufficient to produce a beneficial or desired result. An effective amount can be administered in one or more administrations, applications or dosages, and is not intended to be limited to a specific formulation or route of administration. As used herein, the term "treat" includes any effect that results in the improvement of the condition, disease, disorder, etc., such as reducing, reducing, regulating, improving or eliminating the condition, disease, disorder, etc., or improving its symptoms.

[0116] "Individual", "patient" or "subject" are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, or primates, and most preferably humans. Compounds of the present disclosure can be administered to mammals, such as humans, but also to other mammals, such as animals in need of veterinary treatment, including domestic animals (e.g., dogs, cats, etc.), livestock animals (e.g., cows, sheep, pigs, horses, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.). "Modulation" includes antagonism (e.g., inhibition), agonism, partial antagonism, and / or partial agonism.

[0117] The term "pharmaceutically acceptable salts" as used herein refers to salts of acidic or basic groups that may be present in the compounds used in the compositions. Compounds included in the compositions of the present invention that are basic in nature can form a wide variety of salts with various inorganic and organic acids. Acids which may be used to prepare pharma- ceutically acceptable acid addition salts of such basic compounds include non-toxic acid addition salts (i.e., salts containing pharma- ceutically acceptable anions, malate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and the like). It is one that forms pamoate salts (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)). Compounds contained in the compositions of the present invention that are acidic in nature can form base salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts, particularly calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts. Compounds contained in the compositions of the present invention that contain a basic or acidic moiety can also form pharma-ceutically acceptable salts with various amino acids. Compounds of the present disclosure can contain both acidic and basic groups; for example, one amino group and one carboxylic acid group. In such cases, the compounds can exist as acid addition salts, zwitterions, or base salts.

[0118] A "therapeutically effective amount" includes an amount of a compound of the present disclosure that is effective when administered alone or in combination to treat a desired condition or disorder. A "therapeutically effective amount" includes an amount of a combination of compounds claimed that is effective to treat a desired condition or disorder. The combination of compounds may be an additive combination, preferably a synergistic combination. Synergism occurs when the effect of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent, as described, for example, by Chou and Talalay, Adv. Enzyme Regul. 1984, 22:27-55. In general, synergism is most clearly demonstrated at suboptimal concentrations of the compounds. Synergism may relate to a lower incidence of adverse side effects and / or toxicity, increased efficacy, or some other beneficial effect of the combination compared to the individual components.

[0119] As used herein, the term "substantially" refers to the complete or nearly complete extent or degree of an action, characteristic, property, state, structure, or result. For example, a polymer that is "substantially" biodegraded means that an object is either completely biodegraded or nearly completely biodegraded. EXAMPLES

[0120] Working Example In order that the disclosure described herein may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this application are provided to illustrate the compounds, pharmaceutical compositions, and methods described herein, and are not to be construed in any way as limiting the scope thereof.

[0121] Abbreviations: w / w: weight / weight; HPLC: high performance liquid chromatography; PBS: phosphate buffered saline; rpm: revolutions per minute; DB: Dutch-belted; DME: diabetic macular edema; DR: diabetic retinopathy; ERG: electroretinogram; GLP: good laboratory practice; IOP: intraocular pressure; IVT: intravitreal; LC-MS: liquid chromatography-mass spectrometry; MS: mass spectrometry; NPDR: non-proliferative diabetic retinopathy; OCT: optical coherence tomography; PDR: proliferative diabetic retinopathy; PLGA: poly(D,L-lactide-co-glycolide); RPE: retinal pigment epithelium; TK: thymidine kinase; UPLC: ultra-performance liquid chromatography.

[0122] Example 1. Preparation and Testing of Exemplary Formulation Punch Discs Small disks of polymer matrix incorporating edonentan were prepared for elution rate evaluation. Polymers at a particular weight ratio (e.g., 50% RG503 and 50% RG503H (50 / 50 RG503 / RG503H) as shown in Table 1 were dissolved in methylene chloride. Edonentane (at 30% w / w with respect to the total weight of the polymer and edonentane) was then added to the polymer solution and dissolved. The methylene chloride solution was then evaporated in a polytetrafluoroethylene (PTFE) dish at room temperature for 72-120 hours. After the methylene chloride was removed, a thin film of a homogenous mixture of polymer and edonentane remained. Discs were prepared by cutting 2 mm diameter discs from each film and using a biopsy punch to yield discs weighing from 900 μg to 1500 μg (yielding drug loadings from 270 μg to 450 μg per disc).

[0123] For in vitro drug release testing, three film discs per formulation were cut from the films and incubated in 3 mL of PBS (pH 7.4) in a shaking incubator set at 37° C. and 50 rpm. Drug release was sampled at the indicated time points and the released edonentan content as a function of time was analyzed by HPLC assay, as shown in FIG. 1. The corresponding elution rate of edonentan from the discs as a function of time is provided in FIG. 2. Drug release samples were analyzed by reversed-phase chromatography using an Agilent Polaris Amide-C18 column at 40° C. and a mobile phase consisting of water and acetonitrile modified with trifluoroacetic acid. Quantitation was performed using an external standard with detection at 275 nm. The release medium was completely replaced with fresh medium between each sampling time point. [Table 1]

[0124] Example 2. Preparation and Testing of Exemplary Implants Additional formulations containing various polymer and drug ratios using the procedure to produce homogenous films in Example 1 are shown in Table 2. The formulations were either evaporated at room temperature for 72-120 hours as described in Example 1 or dried under 25°C and 20 mbar vacuum for 24 hours. The films were then ground into powder using a cryogenic mill. A small portion of the film was added to a stainless steel cryogenic mill vessel containing 2-3 appropriately sized grinding balls and pre-cooled using liquid nitrogen at 5 Hz for 2-3 minutes. The material was then milled at 20 Hz-25 Hz for 1 minute and rested at 5 Hz for 1 minute. This grind / rest cycle was repeated 2-5 times. The resulting material was a coarse to fine powder of homogenous material.

[0125] Implants were formed by injection molding in a modified Haake MiniJet (ThermoFisher Scientific). The homogenous powder was loaded and injected into a mold consisting of channels of appropriate size (e.g., 300 μm×12 mm or 325 μm×12 mm). The powder was loaded into a barrel leading to the mold, and the mold was placed under vacuum. The temperature of the mold was held at 15° C. to 25° C. The cylinder around the barrel loaded with the powder was held at 145° C. to 165° C. for 12 to 15 minutes to melt the powder blend. Injection was performed using an injection pressure of 230 bar to 320 bar, held for 2 to 5 minutes. Post-injection pressure was held at 50 bar for 2 to 5 minutes. The mold was then cooled to 15 to 23° C., after which the mold was removed from the injection machine. The molded fibers were then removed from the mold and they were then cut into 4 mm implants containing 165 μg to 220 μg of edonentan per implant.

[0126] Implants of selected formulations were also formed by ram extrusion using a modified Barrell Micro Extruder (Barrell Engineering). The homogenous powder was loaded into a 3 mm barrel and extruded through a 0.30 μm die maintaining a temperature of 68° C. to 80° C. at a flow rate of 5 μL / min to 6 μL / min. The extruded filaments were then cut into 4 mm implants containing 165 μg to 220 μg of edonentan per implant. The resulting implants have similar performance characteristics to those produced by injection molding.

[0127] For in vitro drug release studies, three implants per formulation were randomly cut from fiber trees and incubated in 3 mL of PBS (pH 7.4) in a shaking incubator set at 37° C. and 50 rpm. The drug release profile of the implants was sampled at the designated time points and the released edonentan content was analyzed by HPLC assay, as shown in FIG. 3. The corresponding elution rate of edonentan from the implants as a function of time is provided in FIG. 4. The release medium was completely replaced with fresh medium between each sampling time point. [Table 2]

[0128] Example 3. Pharmacokinetic study: 12-week ocular and systemic pharmacokinetics of edonentan intravitreal implant in rabbits In a non-GLP 12-week ocular and systemic pharmacokinetic study in DB rabbits, one edonentan intravitreal implant (total implant weight 384 μg / implant; 173 μg edonentan / implant) was administered as one bilateral IVT injection in DB rabbits (2 animals and 4 eyes per time point). The implant contained 45% edonentan in a blend of Resomer® containing 50% RG503, 10% RG502, and 40% RG752S. Rabbits were euthanized at weeks 2, 4, 8, and 12 to determine drug concentrations in the aqueous humor, lens, vitreous humor, retina, RPE / choroid, and plasma.

[0129] Ocular tissue and plasma samples were analyzed for drug content by LC-MS / MS analysis. Reverse phase separation was utilized using a Zorbax Eclipse Plus C18 Rapid Resolution column and a mobile phase of water and acetonitrile modified with 0.1% formic acid. An Agilent 1290 UPLC coupled to an Agilent 6430 triple quadrupole mass spectrometer was used for analysis (mass transition of 537.21→439.4 Da is captured for quantification). A deuterated edonentane internal standard at a fixed concentration of 10.6 ng / mL was used with a concentration range of edonentane from 1 to 200 ng / mL. Ocular tissues were prepared for analysis by protein precipitation and liquid-liquid extraction.

[0130] The IVT sustained delivery of 45% edonentan in this PLGA implant clearly demonstrated the achievement of sustainable therapeutic target tissue levels of edonentan over the duration of the study (Table 3). The results showed that the implants released 16%, 30%, 48%, and 100% cumulative total edonentan at 2, 4, 8, and 12 weeks, respectively. [Table 3]

[0131] Example 4. Distribution Test The in vitro melanin binding of edonentan was evaluated in an in vitro assay with synthetic melanin. A concentration of 200 μM edonentan was added to two separate working solutions with or without melanin (1 mg / mL). A concentration of 200 μM chloroquine was used as a positive control. In this assay, edonentan showed low (6.1% bound) binding to melanin. As for the control, the percentage of chloroquine bound to melanin (99.5%) was comparable to literature values ​​(Rimpela 2016) (92-99.6% bound in 2 mg / mL melanin solution at pH 7.4).

[0132] Example 5. Toxicity study: A two-month single-dose intravitreal ocular toxicity study in rabbits In a non-GLP 2-month single-dose IVT ocular dose-ranging toxicity study in DB rabbits (5 males / group), two or three edonentan intravitreal implants (180 μg edonentan / implant; 360 μg and 540 μg / eye total) or two placebo implants were administered over a 56-day evaluation period: total implant mass was 365 μg (approximately 300 μm diameter and 4 mm length), and the implants were Resomer containing 50% RG503 and 50% RG503H. (登録商標) The blend contained 45% edonentan.

[0133] Parameters evaluated included ophthalmologic examination, ocular observations (modified Hackett and McDonald), intraocular pressure measurements, retinal imaging of the implant, optical coherence tomography (OCT), ERG, and toxicokinetics. Animals were euthanized on day 56 and one eye was collected for pharmacokinetics and the other eye for potential histopathology.

[0134] Ophthalmic findings included transient ocular changes (conjunctival redness, aqueous humor flare, vitreous cells) in one of 10 eyes receiving two or three Edentan intravitreal implants (360 μg or 540 μg / eye, respectively) on day 27. These changes completely resolved by the end of the study on day 56. No changes in IOP, ERG, or OCT were observed.

[0135] Ocular tissue and plasma samples were analyzed for drug content by LC-MS / MS. Reverse-phase separation was utilized using a Zorbax Eclipse Plus C18 Rapid Resolution column and a mobile phase of water and acetonitrile modified with 0.1% formic acid. An Agilent 1290 UPLC coupled to an Agilent 6430 triple quadrupole mass spectrometer was used for analysis (mass transition 537.21→439.4 Da captured for quantification). A deuterated edonentane internal standard at a fixed concentration of 10.6 ng / mL was used with a concentration range of edonentane from 0.9 to 200 ng / mL. Ocular tissues were prepared for analysis by protein precipitation and liquid-liquid extraction.

[0136] Results showed that edonentan levels were highest in the lens at day 56 (Table 4). The implants had nearly complete release at day 56, with detectable plasma levels of 3.4 ng / mL and 5.4 ng / mL for two and three edonentan intravitreal implants, respectively. Plasma levels over time are shown in Figure 5. [Table 4]

[0137] Eyes collected for histological examination were processed (n=2 animals / group). Other than a few vitreous cells and occasional retinal folds (which were likely artifacts of sectioning), no histological abnormalities were noted in any of the eyes of the above groups. Based on the examination of these eyes for histology, the placebo implants and the implants containing 360 μg or 540 μg edonentan appeared to be well tolerated.

[0138] Example 6. Toxicity study: A three-month single-dose intravitreal ocular toxicity study in rabbits A formulation of edonentan intravitreal implant (total implant mass 440 μg; 200 μg edonentan with a diameter of 340 μm and a length of 4 mm) is evaluated in a GLP 3-month single-dose IVT ocular toxicity study with 1-month recovery in DB rabbits. The implant is a Resomer formulation containing 50% RG503, 10% RG502, and 40% RG753S. (登録商標) Contains 45% edonentan in the blend.

[0139] Group 1 will receive 3 placebo implants in the left eye (0 μg / eye) and 2 placebo implants in the right eye (0 μg / eye) with a sham injection in the right eye. Group 2 will receive 2 edonentan intravitreal implants in the left eye (400 μg / eye) and the right eye will not be treated. Group 3 will receive 3 edonentan intravitreal implants in the left eye (600 μg / eye) with a sham injection in the right eye. The study design is shown in Table 5 below. [Table 5]

[0140] The 12-week main phase evaluation (4 rabbits / sex / group) was selected based on the observation of detectable drug concentrations of edonentan present in target (RPE / choroid) and non-target (lens) tissues at 12 weeks based on ocular pharmacokinetic studies in rabbits. The 1-month recovery phase is selected based on expected low or absent tissue concentrations at 4 months.

[0141] The high dose of 3 Edentan intravitreal implants represents a 1.5-fold ocular safety margin in terms of implant number compared to the planned highest clinical dose of 2 Edentan intravitreal implants. The high dose of 3 Edentan intravitreal implants (600 μg / eye) also represents a 5-fold ocular dose safety margin compared to the planned highest clinical dose of 2 Edentan implants (400 μg / eye), based on species differences in vitreous volume of 1.4 mL in rabbits (Struble 2014) and 4.6 mL in humans (Caruso 2020, Azhdam 2020). The parameters and frequency of evaluation for this study are listed in Table 6. [Table 6]

[0142] Ocular histopathology includes evaluation of a complete range of ocular tissues. At least three sagittal sections of each eye are prepared, including a complete evaluation of the cone dense retina (visual streak) in one or several sections. In-life toxicity considerations for sectioning and evaluation of the eye are included. The study pathologist ensures that the cone dense visual streak is adequately evaluated.

[0143] Example 7. Toxicity Study: A 6-Month Single-Dose Intravitreal Ocular Toxicity Study in Monkeys The Edentan intravitreal implant formulation and dose selection for the GLP 6-month single-dose IVT ocular toxicity study in cynomolgus monkeys are similar to those described above for the GLP 3-month IVT ocular toxicity study in rabbits. The high dose of three Edentan implants represents a 1.5-fold ocular safety margin of implant number compared to the planned highest clinical dose of two Edentan implants. The high dose of three Edentan implants (600 μg / eye) also represents a 3.5-fold ocular dose safety margin compared to the planned highest clinical dose of two Edentan implants (400 μg / eye) based on species differences in vitreous volume between monkeys (2.0 mL) and humans (4.6 mL) (Caruso 2020, Azhdam 2020). Study details are shown in Table 7. The parameters and frequency of evaluation for this study are listed in Table 8. [Table 7] [Table 8]

[0144] Ocular histopathology involves evaluation of the full range of ocular tissues. At least three horizontal (transverse) sections of each eye are prepared, including a complete evaluation of the cone-dense retina (macula) in one or several sections. Viability toxicity considerations regarding sectioning and evaluation of the eye are included. The study pathologist ensures that the cone-dense macula has been adequately evaluated.

[0145] Example 8. Toxicity study: GLP 1-month oral toxicity study in rats A GLP 1-month oral toxicity study in rats is conducted to evaluate the systemic toxicity of edonentan. This 1-month oral toxicity study in Sprague-Dawley rats consists of a 1-month main phase and a 2-week recovery phase. The highest dose selected in this study is 5 mg / kg / day, and lower doses of 1.5 and 0.5 mg / kg / day are selected to evaluate the dose-response relationship. The high dose selection of 5 mg / kg / day for this study is consistent with the previously tested 0.83 mg / kg human dose (estimate for high dose selection) based on a comparison between BMS-193884 and BMS-207940 literature data, as well as the ICH M3(R2) guideline for high dose selection. The study design is listed in Table 9 below. The parameters and frequency of evaluation are listed in Table 10 below. Safety pharmacology evaluation of central nervous system function was performed using a 0.4-hour oral T max Based on (Murugesan 2003). [Table 9] [Table 10]

[0146] Example 9. Genotoxicity Testing An in vitro genotoxicity group (Ames assay and in vitro micronucleus assay in human thymidine kinase heterozygous (TK6) cells) and an in vivo oral micronucleus test in rats are performed.

[0147] Example 10. A study of the safety, tolerability, pharmacodynamics and pharmacokinetics of the edonentan intravitreal implant The safety, tolerability, pharmacodynamics and pharmacokinetics studies of the edonentan intravitreal implant in patients with diabetic retinopathy and in patients with glaucoma are described in Table 11. [Table 11-1] [Table 11-2]

[0148] Example 11. Pharmacokinetic study: 12-week ocular and systemic pharmacokinetics of edonentan intravitreal implant in rabbits In a non-GLP 12-week ocular and systemic pharmacokinetic study in DB rabbits, two Edentan intravitreal implants (total implant weight IM 423 μg / implant; 380 μg Edentan / 2 implants, RE 461 μg / implant, 415 μg Edentan / 2 implants) from either an injection molding (IM) or ram extrusion (RE) manufacturing process were administered as one bilateral IVT injection (2 animals and 4 eyes per time point) in DB rabbits. The implants contained 45% Edentan in a blend of Resomer® containing 50% RG503, 10% RG502, and 40% RG753S. Rabbits were euthanized at weeks 4, 8, 10, 11, and 12 and drug concentrations were determined in the aqueous humor, lens, vitreous humor, retina, RPE / choroid, and plasma.

[0149] Ocular tissues and plasma were analyzed for edonentane content using an analytical method based on protein precipitation and liquid-liquid extraction followed by reversed-phase LC-MS / MS analysis. An Agilent 1290 UPLC coupled to an Agilent 6430 triple quadrupole mass spectrometer was used for the analysis. The quantification range for edonentane was 1-250 ng / mL. Tissue and plasma samples were homogenized and extracted with 0.1% formic acid in acetonitrile spiked with deuterated edonentane at approximately 10 ng / mL. The extracts were analyzed using reversed-phase liquid chromatography separation and tandem mass spectrometry detection in positive ion mode following quantitative transitions m / z 537.2-439.1 for edonentane and m / z 540.2-442.1 for deuterated edonentane.

[0150] The IVT sustained delivery of 45% edonentan in the PLGA implants clearly demonstrated the achievement of sustainable therapeutic target tissue levels of edonentan over the duration of the study (Figure 6, Figure 7). The cumulative total edonentan released from the implants was 100% at 8 weeks (Table 12). [Table 12]

[0151] Example 15. Crystalline form of edonentan Exemplary Methods for Preparing Crystalline Form 1 Amorphous edonentan (840 mg) was dissolved in 12 mL of IPA. The resulting solution was filtered and the filter was washed with an additional 2.5 mL of IPA. The filtrate was concentrated to dryness, dissolved in 11.8 mL of IPA and heated to 60° C. with stirring. Then, 18 mL of hot water was added dropwise at 60° C. with vigorous stirring and the solution was stirred at 60° C. for 1 hour. The solution was slowly cooled to 25° C., filtered and dried under vacuum at 25° C. to obtain 660 mg of crystalline Form 1 (XRPD and DSC are in FIG. 9 and FIG. 13, respectively).

[0152] Exemplary Preparations of Crystalline Form 2 Amorphous edonentan (250 mg) was dissolved in 3.5 mL of IPA. The resulting solution was filtered and the filter was washed with an additional 0.25 mL of IPA. The solution was then heated to 60° C., during which 7.5 mL of warm water was added dropwise at 60° C. with vigorous stirring, and then stirred at 60° C. for 1 hour. After slowly cooling to 25° C., the mixture was filtered to obtain crystalline form 2 (XRPD and DSC are in Figures 3 and 7, respectively). Alternatively, a preferred method for preparing crystalline form 2 is as follows: Amorphous edonentan (1 g) was slurried in 20 mL of water at 25° C. for 15 hours. The solution was then filtered to obtain crystalline form 2 (XRPD and DSC are in Figures 10 and 14, respectively).

[0153] Exemplary Preparations of Crystalline Form 3 Amorphous edonentan (250 mg) was dissolved in 0.5 mL of ethyl acetate. The resulting solution was filtered and heated to 60° C., and 1.5 mL of hexane was added dropwise with vigorous stirring at 60° C. To the resulting slightly cloudy solution, 0.1 mL of ethyl acetate was added, resulting in a clear solution. This was then stirred at 60° C. for 1 hour. The solution was slowly cooled to 25° C., and the resulting precipitate was filtered to obtain crystalline Form 3 (XRPD and DSC are in FIG. 11 and FIG. 15, respectively).

[0154] Exemplary Preparations of Crystalline Form 4 Amorphous edonentan (100 mg) was added to 2 mL of water containing 0.2 mL of tetrahydrofuran (THF). The resulting mixture was stirred at 50° C. for 24 hours, cooled, and filtered to obtain Form 4, which was confirmed to be distinct from Forms 1, 2, and 3 by XRPD (FIG. 16) and DSC (FIG. 20).

[0155] In an alternative method, 107 mg of amorphous edonentan was added to 1 mL of water, followed by the equivalent amount of KOH in 1 mL of water. The resulting solution was heated to 60° C. for 20 minutes, filtered warm, and acidified with 1 mL of 0.2 N HCl. The resulting mixture was stirred at 60° C. for 5 hours, cooled, and filtered to obtain Form 4, which was confirmed by XRPD.

[0156] In an alternative method, 150 mg of edonentan (form 3) was added to a mixture of isopropanol and water (1 mL and 2 mL, respectively). The resulting slurry was stirred at 15° C. for 48 hours and then filtered. The sample was confirmed to be form 4 by XRPD analysis. This clearly indicates that form 4 is more thermodynamically stable than form 3 under these conditions.

[0157] In an alternative method, 200 mg of edonentan (form 1) was added to a mixture of isopropanol and water (1.3 mL and 2.6 mL, respectively). The resulting solution was heated to 80° C. and stirred for 24 hours, then cooled and filtered. The sample so obtained was confirmed to be form 4 by XRPD analysis. This clearly indicates that under these conditions, form 4 is more thermodynamically stable than form 1.

[0158] In an alternative method, 100 mg of edonentan (amorphous) was stirred in 10 mL of water and heated to 100° C. for 40 hours. The resulting solution was cooled to ambient temperature and filtered to obtain Form 4. In an alternative method, amorphous (crude) edonentan was dissolved in 8 volumes of isopropanol at 60° C. The resulting solution was cooled to 57° C. and then small crystals of crystalline Form 4 were added. After 2 hours, the solution was cooled to 5° C., held for 15 hours and filtered to obtain crystalline Form 4.

[0159] XRPD pattern of the crystalline form XRPD patterns of crystalline forms 1-4 are shown in Figures 8-12. XRPD patterns of the crystalline forms described herein were recorded using a Polycrystalline X-ray diffractometer (Bruker, D8 ADVANCE). CuKa radiation was operated at a voltage of 40 kv and a current of 40 mA with a 1.0 mm transmission slit and a 0.4° cable-stayed slit. The sample was placed in the center of the sample holder groove, with the surface of the sample holder flush with the surface of the sample holder. Data were collected using a lynxeye detector with a step size of 0.02° and a continuous scan at a rate of 8° / min.

[0160] Tables 13-16 below list certain XRPD characteristic peaks for crystalline forms 1-4, respectively. [Table 13] [Table 14] [Table 15] [Table 16]

[0161] Physicochemical properties of crystalline forms Exemplary physicochemical properties of the crystalline forms are provided herein. The melting points described herein can be measured using the following procedure:

[0162] i. Melting Point Protocol The maximum melting point peak of each crystalline form (T m ) was determined using DSC. DSC of the crystalline forms described herein was measured using a TA Instruments DSC Q2000. Samples (1.3010 mg) were weighed into aluminum crucibles and heated from 30° C. to 300° C. at a heating rate of 10° C. / min. The temperatures of the crystalline melting peak start, peak onset, peak maximum, and peak end were collected.

[0163] The solubility described herein may be measured using the following procedure: ii. Solubility Analysis Protocol 1. 2.0 mg or more of sample was weighed into the lower chamber of a whatman mini uniprep vial (GE Healthcare). 450 μL of buffer was added to each chamber. 2. Place the filter piston of the Mini Uniprep vial and push it down to liquid level to allow buffer and compound contact with the filter during incubation. 3. The samples are vortexed for 2 minutes and then incubated at room temperature (approximately 25±2° C.) for 24 hours with shaking at 500 rpm. 4. Press the Mini Uniprep to prepare the filtrate for injection into the HPLC system. Inspect all vials for visible undissolved material before filtration and for leakage after filtration. 5. Dilute the supernatant 100-fold with buffer to prepare a dilution for analysis by HPLC.

[0164] Exemplary physicochemical properties of crystalline forms 1-4 are provided below in Table 17. The physicochemical properties may be obtained using the methods described above. [Table 17]

[0165] Equivalents and Scope In the claims, articles such as "a," "an," and "the" can mean one or more than one, unless indicated to the contrary or otherwise clear from the context. A claim or detailed description containing "or" between one or more members of a group is considered to be satisfied if one, more than one, or all of the group are present in, used in, or otherwise relevant to a given product or process, unless indicated to the contrary or otherwise clear from the context. The present disclosure includes embodiments in which exactly one member of the group is present in, used in, or otherwise relevant to a given product or process. The present disclosure includes embodiments in which more than one, or all of the members of the group are present in, used in, or otherwise relevant to a given product or process.

[0166] Furthermore, the disclosure encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the enumerated claims are incorporated into another claim. For example, any claim that is dependent on another claim may be modified to include one or more limitations found in any other claim that is dependent on the same base claim. When elements are presented as a list, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element may be removed from the group. In general, when the disclosure or aspects of the disclosure are referred to as comprising certain elements and / or features, it should be understood that certain embodiments of the disclosure or aspects of the disclosure consist of or consist essentially of such elements and / or features. For purposes of simplicity, those embodiments have not been specifically set forth in these terms herein. It is noted that the terms "comprising" and "containing" are intended to be open-ended and permit the inclusion of additional elements or steps. When ranges are given, the endpoints are included. Moreover, unless otherwise indicated or otherwise clear from the context and the understanding of one of ordinary skill in the art, values ​​expressed as ranges can assume any specific value or subrange within the range set forth in different embodiments of this disclosure, down to one-tenth of the unit of the lower limit of said range, unless the context clearly specifies otherwise.

[0167] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. In the event of a conflict between any of the incorporated documents and this specification, this specification shall control. Furthermore, any particular embodiment of the present disclosure that falls within the prior art may be expressly excluded from any one or more of the claims. Since such embodiments are deemed known to those skilled in the art, they may be excluded even if the exclusion is not expressly set forth herein. Any particular embodiment of the present disclosure may be excluded from any claim for any reason, whether related to the existence of prior art or not.

[0168] Those skilled in the art will recognize, or ascertain using no more than routine experimentation, many equivalents to the specific embodiments described herein. The scope of the embodiments of the invention described herein is not intended to be limited to the above detailed description, but rather as set forth in the appended claims. Those skilled in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present disclosure, as defined in the following claims.

Claims

1. 1. A biodegradable ocular implant, comprising: Biodegradable polymers having compounds incorporated therein wherein said compound is selected from the group consisting of edonentan, tezosentan, A-182086, clazosentan, S1255, ACT-132577, enrasentan, and sparsentan, or a pharma-ceutically acceptable salt thereof. Biodegradable eye implants.

2. 1. A biodegradable ocular implant, comprising: Biodegradable polymers having compounds incorporated therein wherein said compound is a compound of formula I: 【Chemistry 8】 or a pharma- ceutically acceptable salt thereof.

3. 3. The biodegradable ocular implant of claim 1 or 2, wherein the concentration of said compound in said biodegradable polymer is from about 20% w / w to about 60% w / w.

4. 3. The biodegradable ocular implant of claim 1 or 2, wherein the concentration of said compound in said biodegradable polymer is from about 40% w / w to about 50% w / w.

5. 3. The biodegradable ocular implant of claim 1 or 2, wherein the concentration of said compound in said biodegradable polymer is about 45% w / w.

6. 3. The biodegradable ocular implant of claim 1 or 2, wherein the compound is present in the biodegradable polymer in an amount of about 100 μg to about 500 μg.

7. 3. The biodegradable ocular implant of claim 1 or 2, wherein the compound is present in the biodegradable polymer in an amount of about 200 μg to about 400 μg.

8. 3. The biodegradable ocular implant of claim 1 or 2, wherein the compound is present in the biodegradable polymer in an amount of about 150 μg to about 250 μg.

9. 3. The biodegradable ocular implant of claim 1 or 2, wherein the concentration of the biodegradable polymer is from about 40% w / w to about 80% w / w.

10. 3. The biodegradable ocular implant of claim 1 or 2, wherein the concentration of the biodegradable polymer is about 60% w / w.

11. 10. The biodegradable ocular implant of claim 1, wherein the biodegradable polymer comprises at least one poly(lactic-co-glycolic acid) (PLGA).

12. The biodegradable ocular implant of claim 2, wherein the biodegradable polymer comprises at least one type of poly(lactic-co-glycolic acid) (PLGA).

13. The biodegradable ocular implant of claim 11 or 12, wherein each PLGA is independently selected from the group consisting of RG502, RG502H, RG503, RG503H, RG504, RG504H, RG505, RG653H, RG752H, RG752S, RG753H, RG753S, RG755, RG756, RG757S, RG750S, RG858, and RG858S.

14. 13. The biodegradable ocular implant of claim 11 or 12, wherein each PLGA is independently selected from the group consisting of RG503, RG502 and RG753S.

15. 3. The biodegradable ocular implant of claim 1 or 2, wherein the biodegradable polymer comprises at least two types of PLGA in a ratio of about 1:1 to about 3:

1.

16. 3. The biodegradable ocular implant of claim 1 or 2, wherein the biodegradable polymer comprises at least two types of PLGA in a ratio of about 1:

1.

17. 3. The biodegradable ocular implant of claim 1 or 2, wherein the biodegradable polymer comprises at least three types of PLGA in a ratio of about 1:6:13 to about 1:5:

14.

18. 3. The biodegradable ocular implant of claim 1 or 2, wherein the biodegradable polymer comprises at least three types of PLGA in a ratio of about 1:6:13 to about 2:7:

1.

19. 3. The biodegradable ocular implant of claim 1 or 2, wherein the biodegradable polymer comprises at least three types of PLGA in a ratio of about 5:1:

4.

20. 3. The biodegradable ocular implant of claim 1 or 2, wherein the biodegradable polymer comprises at least four types of PLGA in a ratio of about 2:3:3:

2.

21. 3. The biodegradable ocular implant of claim 1 or 2, wherein the biodegradable polymer comprises at least four types of PLGA in a ratio of about 1:5:3:

1.

22. 3. The biodegradable ocular implant of claim 1 or 2, wherein the biodegradable polymer comprises RG503, RG502 and RG753S in a ratio of about 5:1:

4.

23. 3. The biodegradable ocular implant of claim 1 or 2, wherein the biodegradable polymer substantially biodegrades in about 3 months to about 12 months.

24. 3. The biodegradable ocular implant of claim 1 or 2, wherein the biodegradable polymer substantially biodegrades in about 6 months to about 12 months.

25. 3. The biodegradable ocular implant of claim 1 or 2, wherein the biodegradable polymer substantially biodegrades in about 12 months to about 18 months.

26. 3. The biodegradable ocular implant of claim 1 or 2, wherein the biodegradable ocular implant initially comprises a matrix of at least 95% of the biodegradable polymer and the compound.

27. 3. The biodegradable ocular implant of claim 1 or 2, wherein less than 40% of the compound is released from the biodegradable ocular implant when placed in phosphate buffered saline (PBS) for about one month.

28. 3. The biodegradable ocular implant of claim 1 or 2, wherein the implant is maintained in a subject for about 3 months to about 12 months after implantation of the implant.

29. 3. The biodegradable ocular implant of claim 1 or 2, wherein the implant has a diameter of about 300 μm to about 400 μm and a length of about 4 mm to about 5 mm.

30. The biodegradable ocular implant of claim 1 or 2, wherein the implant is suitable for intravitreal administration.

31. 3. The biodegradable ocular implant of claim 1 or 2, wherein the implant is administered to the back of the eye.

32. 3. The biodegradable ocular implant of claim 1 or 2, wherein the edonentan or the compound of formula I is in an anhydrous crystalline form (Form 4) having an X-ray powder diffraction pattern comprising at least three characterizing peaks selected from peaks at 5.6±0.2°, 11.4±0.2°, 17.7±0.2°, 19.3±0.2°, 21.1±0.2°, and 21.9±0.2° in terms of 2θ.

33. The biodegradable ocular implant of claim 1 for use in treating an ocular disease selected from the group consisting of glaucoma, diabetic retinopathy (DR), retinal vein occlusion (RVO), and retinopathy of prematurity (ROP), wherein the compound is present in an amount therapeutically effective to treat the ocular disease.

34. The biodegradable ocular implant of claim 2 for use in treating an ocular disease selected from the group consisting of glaucoma, diabetic retinopathy (DR), retinal vein occlusion (RVO), and retinopathy of prematurity (ROP), wherein the compound is present in an amount therapeutically effective to treat the ocular disease.

35. 35. The biodegradable ocular implant of claim 33 or 34, wherein the eye disease is glaucoma.

36. 35. The biodegradable ocular implant of claim 33 or 34, wherein the ocular disease is diabetic retinopathy (DR).

37. 35. The biodegradable ocular implant of claim 33 or 34, wherein the ocular disease is retinal vein occlusion (RVO).

38. 35. The biodegradable ocular implant of claim 33 or 34, wherein the ocular disease is retinopathy of prematurity (ROP).

39. 35. The biodegradable ocular implant of any one of claims 33 or 34, wherein the implant releases at least 10% of edonentan 14 days after contact with the ocular tissue of a subject.

40. 35. The biodegradable ocular implant of any one of claims 33 or 34, wherein the implant releases at least 25% of edonentan 28 days after contact with the ocular tissue of a subject.

41. 35. The biodegradable ocular implant of claim 33 or 34, wherein the implant releases at least 40% of edonentan 56 days after contact with the ocular tissue of a subject.

42. 35. The biodegradable ocular implant of any one of claims 33 or 34, wherein the implant releases at least 90% of the edonentan after 84 days of contact with the ocular tissue of a subject.

43. 10. A method of making a biodegradable ocular implant according to claim 1, comprising subjecting a biodegradable polymer containing a compound to solvent casting, injection molding, or extrusion, wherein the compound is a compound of formula I: 【Chemistry 9】 or a pharma- ceutically acceptable salt thereof.

44. 44. The method of claim 43, wherein the biodegradable polymer is PLGA.

45. 1. A biodegradable ocular implant, comprising: A biodegradable polymer having incorporated therein a compound of formula I: 【Chemistry 10】 or a pharma- ceutically acceptable salt thereof, wherein the concentration of said compound in said biodegradable polymer is about 45% w / w; and said biodegradable polymer comprises RG503, RG502 and RG753S in a ratio of about 5:1:

4.

46. 1. A biodegradable ocular implant, comprising: A biodegradable polymer having incorporated therein a compound of formula I: 【Chemistry 11】 or a pharma- ceutically acceptable salt thereof, wherein the concentration of said compound in said biodegradable polymer is about 45% w / w; and said biodegradable polymer comprises RG503, RG502 and RG753S in a ratio of about 2:2:5.

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