Methods of making drug delivery systems for the treatment of ocular diseases

Abstract

The present disclosure relates to methods of making biodegradable ocular implants containing idronexant or a pharmaceutically acceptable salt thereof. The present disclosure also relates to biodegradable ocular implants generally comprising a biodegradable polymer and idronexant or a pharmaceutically acceptable salt thereof.

Description

[0001] Cross-reference to related applications

[0002] This application claims the benefit and priority of U.S. Patent Application No. 63 / 612,918, filed December 20, 2023, the contents of which are incorporated herein by reference in their entirety. Background Technology

[0003] Examples of debilitating eye diseases include glaucoma, diabetic retinopathy (DR), retinal vein occlusion (RVO), retinopathy of prematurity (ROP), geographic atrophy (GA), and age-related macular degeneration (AMD). These eye diseases cause varying degrees of long-term damage to the eyes and can ultimately lead to blindness. While newborns, young adults, adults of all ages, and the elderly can be affected, currently only a limited number of treatments are available. These treatments target only a portion of the eye disease and can slow, but not prevent, blindness. The economic burden in the United States alone exceeds $100 billion annually.

[0004] The options for treating eye diseases remain very limited, largely due to a lack of therapeutic efficacy. Efforts have been made to improve drug efficacy while minimizing side effects in the treatment or improvement of eye diseases. One such effort involves developing novel biodegradable ocular implants that offer better permeability, therapeutic capability, and controlled release at the target site.

[0005] Edonentan is a highly selective and potent endothelin A receptor antagonist. It was developed as a second-generation analogue after the first clinical candidate, BMS-193884 (originally developed for the treatment of congestive heart failure (CHF)), was discontinued. As of April 2002, edonentan was in Phase I clinical trials, but its development was halted.

[0006] There is still a need to more effectively reduce the incidence of glaucoma, DR, GA, AMD, RVO, and ROP, and to treat or improve these diseases. Summary of the Invention

[0007] This disclosure provides biodegradable ocular implants designed to deliver an effective amount of edonantan to ocular tissue. Such biodegradable ocular implants can be used to treat ocular diseases such as glaucoma, diabetic retinopathy (DR), retinal vein occlusion (RVO), retinopathy of prematurity (ROP), geographic atrophy (GA), and age-related macular degeneration (AMD). Methods for preparing biodegradable ocular implants containing an effective amount of edonantan are also provided herein.

[0008] In one respect, this article provides biodegradable ocular implants comprising:

[0009] (i) Adonantan or a pharmaceutically acceptable salt thereof; and

[0010] (ii) Biodegradable polymers,

[0011] The particle size distribution of edonantane or its pharmaceutically acceptable salt is characterized by a D90 of about 9 µm to about 250 µm.

[0012] In some embodiments, the particle size distribution of edonanthan or a pharmaceutically acceptable salt thereof is characterized by a D90 of about 9 µm to about 125 µm. In some embodiments, the particle size distribution of edonanthan or a pharmaceutically acceptable salt thereof is characterized by a D90 of about 10 µm to about 15 µm. In some embodiments, the particle size distribution of edonanthan or a pharmaceutically acceptable salt thereof is further characterized by a D50 of about 2.5 µm to about 150 µm. In some embodiments, the particle size distribution of edonanthan or a pharmaceutically acceptable salt thereof is further characterized by a D50 of about 2.5 µm to about 40 µm. In some embodiments, the particle size distribution of edonanthan or a pharmaceutically acceptable salt thereof is further characterized by a D50 of about 2.5 µm to about 6 µm. In some embodiments, the particle size distribution of edonanthan or a pharmaceutically acceptable salt thereof is further characterized by a D10 of about 0.5 µm to about 90 µm. In some embodiments, the particle size distribution of edonantan or a pharmaceutically acceptable salt thereof is further characterized by a D10 of about 0.5 µm to about 10 µm. In some embodiments, the particle size distribution of edonantan or a pharmaceutically acceptable salt thereof is further characterized by a D10 of about 0.5 µm to about 2 µm.

[0013] In some embodiments, the biodegradable ocular implant comprises about 20% w / w to about 60% w / w edonantan or a pharmaceutically acceptable salt thereof. In some embodiments, the biodegradable ocular implant comprises about 40% w / w to about 50% w / w edonantan or a pharmaceutically acceptable salt thereof. In some embodiments, the biodegradable ocular implant comprises about 45% w / w edonantan or a pharmaceutically acceptable salt thereof. In some embodiments, edonantan is present as an anhydrous crystalline form in its free base form.

[0014] In some embodiments, the biodegradable ocular implant comprises about 40% w / w to about 80% w / w of a biodegradable polymer. In some embodiments, the biodegradable ocular implant comprises about 50% w / w to about 60% w / w of a biodegradable polymer. In some embodiments, the biodegradable ocular implant comprises about 55% w / w of a biodegradable polymer.

[0015] In some embodiments, the biodegradable polymer comprises one or more poly(lactic-co-glycolic acid) (PLGA) polymers. In some embodiments, the one or more PLGA polymers are selected from RG502, RG503, RG753S, DLG5002E, DLG5003E, DLG7505E, and combinations thereof. In some embodiments, the biodegradable polymer comprises PLGARG503 and PLGARG753S. In some embodiments, the biodegradable ocular implant comprises approximately 16.5% w / w PLGARG503 and approximately 38.5% w / w PLGARG753S. In some embodiments, the biodegradable polymer comprises PLGARG502, PLGARG503, and PLGARG753S. In some embodiments, the biodegradable ocular implant comprises approximately 5.5% w / w PLGARG502, approximately 27.5% w / w PLGARG503, and approximately 22% w / w PLGARG753S. In some embodiments, the biodegradable polymer comprises PLGA DLG5002E, PLGA DLG5003E, and PLGA DLG7505E. In some embodiments, approximately 5.5% w / w of PLGA DLG5002E, approximately 27.5% w / w of PLGA DLG5003E, and approximately 22% w / w of PLGA DLG7505E are present. In some embodiments, each of one or more PLGA polymers present in the biodegradable ocular implant contains no more than approximately 0.5% w / w of residual monomer.

[0016] In some embodiments, the biodegradable ocular implant has a length of about 4 mm. In some embodiments, the biodegradable ocular implant has a diameter of about 300 µm to about 360 µm. In some embodiments, the biodegradable ocular implant contains about 180 µg to about 250 µg of adonantan.

[0017] On the other hand, this article provides a method for preparing a biodegradable ocular implant comprising edonantan or a pharmaceutically acceptable salt thereof and a biodegradable polymer, the method comprising:

[0018] (a) Grinding biodegradable polymers;

[0019] (b) Reduce the particle size of edonantan or a pharmaceutically acceptable salt thereof to form treated edonantan or a pharmaceutically acceptable salt thereof;

[0020] (c) The milled biodegradable polymer is mixed with treated adonantan or a pharmaceutically acceptable salt thereof to form a blend;

[0021] (d) The blend is hot-melted and extruded to form a biodegradable ocular implant.

[0022] In some embodiments, in step (a), the biodegradable polymer is cryogenically milled. In some embodiments, in step (a), the biodegradable polymer comprises one or more PLGA polymers. In some embodiments, the one or more PLGA polymers are selected from RG502, RG503, RG753S, DLG5002E, DLG5003E, DLG7505E, and combinations thereof. In some embodiments, in step (a), the biodegradable polymer comprises PLGA RG503 and PLGA RG753S. In some embodiments, in step (a), the biodegradable polymer comprises about 30% w / w PLGA RG503 and about 70% w / w PLGA RG753S. In some embodiments, in step (a), the biodegradable polymer comprises PLGA RG502, PLGA RG503, and PLGA RG753S. In some embodiments, in step (a), the biodegradable polymer comprises about 10% w / w PLGA RG502, about 50% w / w PLGA RG503, and about 40% w / w PLGA RG753S. In some embodiments, in step (a), the biodegradable polymer comprises PLGA DLG5002E, PLGA DLG5003E, and PLGA DLG7505E. In some embodiments, in step (a), the biodegradable polymer comprises about 10% w / w PLGA DLG5002E, about 50% w / w PLGA DLG5003E, and about 40% w / w PLGA DLG7505E.

[0023] In some embodiments, in step (b), reducing the particle size of edonanthan or a pharmaceutically acceptable salt thereof includes passing edonanthan or a pharmaceutically acceptable salt thereof through a 100-mesh sieve. In some embodiments, in step (b), reducing the particle size of edonanthan or a pharmaceutically acceptable salt thereof includes grinding edonanthan or a pharmaceutically acceptable salt thereof. In some embodiments, in step (b), reducing the particle size of edonanthan or a pharmaceutically acceptable salt thereof includes micronizing edonanthan or a pharmaceutically acceptable salt thereof. In some embodiments, in step (b), the particle size distribution of the treated edonanthan or a pharmaceutically acceptable salt thereof is characterized by a D90 of about 10 µm to about 250 µm. In some embodiments, in step (b), the particle size distribution of the treated edonanthan or a pharmaceutically acceptable salt thereof is characterized by a D50 of about 2.5 µm to about 150 µm. In some embodiments, in step (b), the particle size distribution of the treated edonantan or its pharmaceutically acceptable salt is characterized by a D10 of about 0.5 µm to about 90 µm. In some embodiments, in step (b), edonantan exists as a free base as anhydrous crystals both before and after milling.

[0024] In some embodiments, step (d) of hot melt extrusion of the blend includes:

[0025] (i) The blend is hot-melt extruded at a temperature of about 95°C to form a first extrudate;

[0026] (ii) The first extrudate is hot-melt extruded at a temperature of about 100°C to about 120°C to form extruded filaments; and

[0027] (iii) Cut the extruded filaments to form a biodegradable ocular implant.

[0028] In some embodiments, step (d) of hot melt extrusion of the blend includes:

[0029] (i) The blend is hot-melt extruded at a temperature of about 85°C to about 90°C to form a first extrudate;

[0030] (ii) The first extrudate is hot-melt extruded at a temperature of about 88°C to about 90°C to form the second extrudate;

[0031] (iii) The second extrudate is hot-melt extruded at a temperature of about 71°C to about 74°C to form extruded filaments; and

[0032] (iv) Cut the extruded filaments to form a biodegradable ocular implant.

[0033] On the other hand, this article provides a method for treating eye diseases in subjects who require this treatment, which involves bringing the subject's eye tissue into contact with the biodegradable eye implant disclosed herein.

[0034] In some implementations, the eye disease is selected from glaucoma, DR, GA, AMD, RVO, and ROP.

[0035] Details of one or more embodiments of this disclosure are set forth in the description below. Other features, objects, and advantages of this disclosure will become apparent from the following drawings, specification, and claims. Attached Figure Description

[0036] Figure 1 The effect of particle size on the release rate of edonantane in implant formulations 2, 3 and 5 was depicted.

[0037] Figure 2 The effect of the weight percentage (%w / w) of residual monomers in the polymer on the release rate of edonantan from the PLGA matrix in implant formulations 1–4 was depicted.

[0038] Figure 3 In vitro drug release profiles for implant formulations 1–5 were depicted.

[0039] Figure 4 The daily washout rates for implant formulations 1–5 were depicted.

[0040] Figure 5 The in vivo edonantane release curves of implant formulations 1–3, 5, 6 and the implant formulation prepared using the solvent method described in Example 4 are compared.

[0041] Figure 6 and Figure 7 The study depicted intravitreal sustained-release delivery of 45% adonantan in Viatel™ and RESOMER® implants in rabbit retina. Figure 6 ) and retinal pigment epithelium / choroid ( Figure 7 The therapeutic target tissue level of edonantan in )

[0042] Figure 8 and Figure 9 The study describes the intravitreal sustained-release delivery of 45% edonantane in micronized and milled implants in rabbit retina. Figure 8 ) and retinal pigment epithelium / choroid ( Figure 9 The therapeutic target tissue level of edonantan in )

[0043] Figure 10 and Figure 11The intravitreal sustained-release delivery of 45% edonantane in a 50 / 10 / 40 twin-screw extruded implant was described, and the retinal activity in rabbits over 10 weeks was assessed. Figure 10 ) and retinal pigment epithelium / choroid ( Figure 11 The therapeutic target tissue level of edonantan in )

[0044] Figure 12 An exemplary overlay of XRPD plots depicting crystal forms 1–4 is shown.

[0045] Figure 13 An exemplary XRPD diagram of crystal form 1 is depicted.

[0046] Figure 14 An exemplary XRPD diagram of crystal form 2 is depicted.

[0047] Figure 15 An exemplary XRPD diagram of crystal form 3 is depicted.

[0048] Figure 16 An exemplary XRPD diagram of crystal form 4 is depicted.

[0049] Figure 17 An exemplary DSC curve for crystal form 1 is shown.

[0050] Figure 18 An exemplary DSC curve for crystal form 2 is shown.

[0051] Figure 19 An exemplary DSC curve for crystal form 3 is depicted.

[0052] Figure 20 An exemplary DSC curve for crystal form 4 is shown. Detailed Implementation

[0053] This invention stems from the discovery that certain biodegradable ocular implants comprising edonantan or a pharmaceutically acceptable salt thereof are suitable for the prevention, treatment, or otherwise improvement of eye diseases, including but not limited to glaucoma, diabetic retinopathy (DR), retinal vein occlusion (RVO), retinopathy of prematurity (ROP), geographic atrophy (GA), and age-related macular degeneration (AMD). This document provides biodegradable ocular implants that typically comprise edonantan or a pharmaceutically acceptable salt thereof, along with a biodegradable polymer. Methods for preparing the biodegradable ocular implants described herein are also provided. This disclosure is further described below.

[0054] compound

[0055] The biodegradable ocular implants described herein include compounds that can be used to treat ocular diseases such as glaucoma, DR, RVO, ROP, GA, and AMD. It is understood that compounds intended for use in treating ocular diseases include, but are not limited to, endothelin receptor agonists (e.g., endothelin A receptor agonists).

[0056] In some embodiments, the compound that can be used to treat eye diseases is a compound of formula I or a pharmaceutically acceptable salt thereof:

[0057] (I).

[0058] The compound of Formula I is also referred to herein as edonantane. The chemical name of edonantane is N-[[2'-[[(4,5-dimethyl-3-isoxazolyl)amino]sulfonyl]-4-(2-oxazolyl)[1,1'-biphenyl]-2-yl]methyl]-N,3,3-trimethylbutyramide (molecular weight 536.6 g / mol). Methods for preparing edonantane are well known to those skilled in the art. Suitable methods are disclosed, for example, in U.S. Patent No. 6,043,265.

[0059] In some embodiments, the biodegradable ocular implant described herein comprises about 20% w / w to about 60% w / w (e.g., about 20% w / w, about 25% w / w, about 30% w / w, about 35% w / w, about 40% w / w, about 45% w / w, about 50% w / w, about 55% w / w, or 60% w / w) of edonantan or a pharmaceutically acceptable salt thereof. In some embodiments, the biodegradable ocular implant described herein comprises about 35% w / w to about 55% w / w (e.g., about 35% w / w, about 40% w / w, about 45% w / w, about 50% w / w, or about 55% w / w) of edonantan or a pharmaceutically acceptable salt thereof. In some embodiments, the biodegradable ocular implants described herein comprise about 40% w / w to about 50% w / w (e.g., about 40% w / w, about 41% w / w, about 42% w / w, about 43% w / w, about 44% w / w, about 45% w / w, about 46% w / w, about 47% w / w, about 48% w / w, about 49% w / w, and about 50% w / w) of edonantan or a pharmaceutically acceptable salt thereof. In some embodiments, the biodegradable ocular implants described herein comprise about 45% w / w of edonantan or a pharmaceutically acceptable salt thereof.

[0060] In some embodiments, the biodegradable ocular implants described herein comprise about 150 µg to about 300 µg (e.g., about 150 µg, about 160 µg, about 170 µg, about 180 µg, about 190 µg, 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, and about 300 µg) of edonantan or a pharmaceutically acceptable salt thereof. In some embodiments, the biodegradable ocular implants described herein comprise about 150 µg to about 250 µg (e.g., 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, about 230 µg, about 235 µg, about 240 µg, about 245 µg, and about 250 µg) of edonantantan or a pharmaceutically acceptable salt thereof. In some embodiments, the amount of Formula I compound in the biodegradable ocular implant is from about 180 µg to about 250 µg (e.g., 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, about 230 µg, about 235 µg, about 240 µg, about 245 µg, and about 250 µg). In some embodiments, the biodegradable ocular implant described herein comprises about 185 µg to about 225 µg of edonantan or a pharmaceutically acceptable salt thereof. In some embodiments, the biodegradable ocular implant described herein comprises about 210 µg to about 240 µg of edonantan or a pharmaceutically acceptable salt thereof.

[0061] In some embodiments, the particle size distribution of edonantan or its pharmaceutically acceptable salt present in biodegradable ocular implants is characterized by a D90 of about 9 µm to about 250 µm (e.g., about 9 µm, about 10 µm, about 20 µm, about 30 µm, about 40 µm, about 50 µm, about 60 µm, about 70 µm, about 80 µm, about 90 µm, about 100 µm, about 110 µm, about 120 µm, about 130 µm, about 140 µm, about 150 µm, about 160 µm, about 170 µm, about 180 µm, about 190 µm, about 200 µm, about 210 µm, about 220 µm, about 230 µm, about 240 µm, or about 250 µm). In some embodiments, the particle size distribution of edonantan or its pharmaceutically acceptable salt present in biodegradable ocular implants is characterized by a D90 of about 9 µm to about 125 µm (e.g., about 9 µm, about 10 µm, about 15 µm, about 20 µm, about 25 µm, about 30 µm, about 35 µm, about 40 µm, about 45 µm, about 50 µm, about 55 µm, about 60 µm, about 65 µm, about 70 µm, about 75 µm, about 80 µm, about 85 µm, about 90 µm, about 95 µm, about 100 µm, about 105 µm, about 110 µm, about 115 µm, about 120 µm, or about 125 µm). In some embodiments, the particle size distribution of edonantan or a pharmaceutically acceptable salt thereof present in biodegradable ocular implants is characterized by a D90 of about 9 µm to about 15 µm (e.g., about 9 µm, about 9.25 µm, about 9.5 µm, about 9.75 µm, about 10 µm, about 10.25 µm, about 10.5 µm, about 10.75 µm, about 11 µm, about 11.25 µm, about 11.5 µm, about 11.75 µm, about 12 µm, about 12.25 µm, about 12.5 µm, about 12.75 µm, about 13 µm, about 13.25 µm, about 13.5 µm, about 13.75 µm, about 14 µm, about 14.25 µm, about 14.5 µm, about 14.75 µm, or about 15 µm).

[0062] In some embodiments, the particle size distribution of edonantan or its pharmaceutically acceptable salt present in biodegradable ocular implants is characterized by a D50 of about 2.5 µm to about 150 µm (e.g., about 2.5 µm, about 10 µm, about 20 µm, about 30 µm, about 40 µm, about 50 µm, about 60 µm, about 70 µm, about 80 µm, about 90 µm, about 100 µm, about 110 µm, about 120 µm, about 130 µm, about 140 µm, or about 150 µm). In some embodiments, the particle size distribution of edonantan or its pharmaceutically acceptable salt present in biodegradable ocular implants is characterized by a D50 of about 2.5 µm to about 40 µm (e.g., about 2.5 µm, about 5 µm, about 7.5 µm, about 10 µm, about 12.5 µm, about 15 µm, about 17.5 µm, about 20 µm, about 22.5 µm, about 25 µm, about 27.5 µm, about 30 µm, about 32.5 µm, about 35 µm, about 37.5 µm, or about 40 µm). In some embodiments, the particle size distribution of edonantan or its pharmaceutically acceptable salt present in biodegradable ocular implants is characterized by a D50 of about 2.5 µm to about 6 µm (e.g., about 2.5 µm, about 2.75 µm, about 3 µm, about 3.25 µm, about 3.5 µm, about 3.75 µm, about 4 µm, about 4.25 µm, about 4.5 µm, about 4.75 µm, about 5 µm, about 5.25 µm, about 5.5 µm, about 5.75 µm, or about 6 µm).

[0063] In some embodiments, the particle size distribution of edonantan or its pharmaceutically acceptable salt present in biodegradable ocular implants is characterized by a D10 of about 0.5 µm to about 90 µm (e.g., about 0.5 µm, about 5 µm, about 10 µm, about 15 µm, about 20 µm, about 25 µm, about 30 µm, about 35 µm, about 40 µm, about 45 µm, about 50 µm, about 55 µm, about 60 µm, about 65 µm, about 70 µm, about 75 µm, about 80 µm, about 85 µm, or about 90 µm). In some embodiments, the particle size distribution of edonantan or its pharmaceutically acceptable salt present in biodegradable ocular implants is characterized by a D10 of about 0.5 µm to about 10 µm (e.g., about 0.5 µm, about 1 µm, about 1.5 µm, about 2 µm, about 2.5 µm, about 3 µm, about 3.5 µm, about 4 µm, about 4.5 µm, about 5 µm, about 5.5 µm, about 6 µm, about 6.5 µm, about 7 µm, about 7.5 µm, about 8 µm, about 8.5 µm, about 9 µm, about 9.5 µm, or about 10 µm). In some embodiments, the particle size distribution of edonantan or its pharmaceutically acceptable salt present in biodegradable ocular implants is characterized by a D10 of about 0.5 µm to about 2 µm (e.g., about 0.5 µm, about 0.6 µm, about 0.7 µm, about 0.8 µm, about 0.9 µm, about 1 µm, about 1.1 µm, about 1.2 µm, about 1.3 µm, about 1.4 µm, about 1.5 µm, about 1.6 µm, about 1.7 µm, about 1.8 µm, about 1.9 µm, or about 2 µm).

[0064] In some embodiments, the particle size distribution of edonantan or a pharmaceutically acceptable salt thereof present in the biodegradable ocular implant is characterized by one or more of the following: (i) D10 of about 0.5 µm to about 90 µm; (ii) D50 of about 2.5 µm to about 150 µm; and (iii) D90 of about 9 µm to about 250 µm. In some embodiments, the particle size distribution of edonantan or a pharmaceutically acceptable salt thereof present in the biodegradable ocular implant is characterized by one or more of the following: (i) D10 of about 0.5 µm to about 10 µm; (ii) D50 of about 2.5 µm to about 40 µm; and (iii) D90 of about 9 µm to about 125 µm. In some embodiments, the particle size distribution of edonantan or its pharmaceutically acceptable salt present in biodegradable ocular implants is characterized by one or more of the following: (i) D10 is about 0.5 µm to about 2 µm; (ii) D50 is about 2.5 µm to about 6 µm; and (iii) D90 is about 9 µm to about 15 µm.

[0065] In some embodiments, the particle size distribution of edonantan or a pharmaceutically acceptable salt thereof present in a biodegradable ocular implant is characterized by a D10 of about 0.5 µm to about 90 µm, a D50 of about 2.5 µm to about 150 µm, and a D90 of about 9 µm to about 250 µm. In some embodiments, the particle size distribution of edonantan or a pharmaceutically acceptable salt thereof present in a biodegradable ocular implant is characterized by a D10 of about 0.5 µm to about 10 µm, a D50 of about 2.5 µm to about 40 µm, and a D90 of about 9 µm to about 125 µm. In some embodiments, the particle size distribution of edonantan or a pharmaceutically acceptable salt thereof present in a biodegradable ocular implant is characterized by a D10 of about 0.5 µm to about 2 µm, a D50 of about 2.5 µm to about 6 µm, and a D90 of about 9 µm to about 15 µm.

[0066] In some embodiments, the particle size distribution of edonantan or its pharmaceutically acceptable salt present in biodegradable ocular implants is characterized by a D90 of less than about 250 µm (e.g., about 9 µm, about 10 µm, about 20 µm, about 30 µm, about 40 µm, about 50 µm, about 60 µm, about 70 µm, about 80 µm, about 90 µm, about 100 µm, about 110 µm, about 120 µm, about 130 µm, about 140 µm, about 150 µm, about 160 µm, about 170 µm, about 180 µm, about 190 µm, about 200 µm, about 210 µm, about 220 µm, about 230 µm, or about 240 µm). In some embodiments, the particle size distribution of edonantan or its pharmaceutically acceptable salt present in biodegradable ocular implants is characterized by a D90 of less than about 125 µm (e.g., about 9 µm, about 10 µm, about 15 µm, about 20 µm, about 25 µm, about 30 µm, about 35 µm, about 40 µm, about 45 µm, about 50 µm, about 55 µm, about 60 µm, about 65 µm, about 70 µm, about 75 µm, about 80 µm, about 85 µm, about 90 µm, about 95 µm, about 100 µm, about 105 µm, about 110 µm, about 115 µm, or about 120 µm). In some embodiments, the particle size distribution of edonantan or its pharmaceutically acceptable salt present in biodegradable ocular implants is characterized by a D90 of less than about 15 µm (e.g., about 9 µm, about 9.25 µm, about 9.5 µm, about 9.75 µm, about 10 µm, about 10.25 µm, about 10.5 µm, about 10.75 µm, about 11 µm, about 11.25 µm, about 11.5 µm, about 11.75 µm, about 12 µm, about 12.25 µm, about 12.5 µm, about 12.75 µm, about 13 µm, about 13.25 µm, about 13.5 µm, about 13.75 µm, about 14 µm, about 14.25 µm, about 14.5 µm, or about 14.75 µm).

[0067] In some embodiments, the particle size distribution of edonantan or its pharmaceutically acceptable salt present in biodegradable ocular implants is characterized by a D50 of less than about 150 µm (e.g., about 2.5 µm, about 10 µm, about 20 µm, about 30 µm, about 40 µm, about 50 µm, about 60 µm, about 70 µm, about 80 µm, about 90 µm, about 100 µm, about 110 µm, about 120 µm, about 130 µm, or about 140 µm). In some embodiments, the particle size distribution of edonantan or its pharmaceutically acceptable salt present in biodegradable ocular implants is characterized by a D50 of less than about 40 µm (e.g., about 2.5 µm, about 5 µm, about 7.5 µm, about 10 µm, about 12.5 µm, about 15 µm, about 17.5 µm, about 20 µm, about 22.5 µm, about 25 µm, about 27.5 µm, about 30 µm, about 32.5 µm, about 35 µm, or about 37.5 µm). In some embodiments, the particle size distribution of edonantan or its pharmaceutically acceptable salt present in biodegradable ocular implants is characterized by a D50 of less than about 6 µm (e.g., about 2.5 µm, about 2.75 µm, about 3 µm, about 3.25 µm, about 3.5 µm, about 3.75 µm, about 4 µm, about 4.25 µm, about 4.5 µm, about 4.75 µm, about 5 µm, about 5.25 µm, about 5.5 µm, or about 5.75 µm).

[0068] In some embodiments, the particle size distribution of edonantan or its pharmaceutically acceptable salt present in biodegradable ocular implants is characterized by a D10 of less than about 90 µm (e.g., about 0.5 µm, about 5 µm, about 10 µm, about 15 µm, about 20 µm, about 25 µm, about 30 µm, about 35 µm, about 40 µm, about 45 µm, about 50 µm, about 55 µm, about 60 µm, about 65 µm, about 70 µm, about 75 µm, about 80 µm, or about 85 µm). In some embodiments, the particle size distribution of edonantan or its pharmaceutically acceptable salt present in biodegradable ocular implants is characterized by a D10 of less than about 10 µm (e.g., about 0.5 µm, about 1 µm, about 1.5 µm, about 2 µm, about 2.5 µm, about 3 µm, about 3.5 µm, about 4 µm, about 4.5 µm, about 5 µm, about 5.5 µm, about 6 µm, about 6.5 µm, about 7 µm, about 7.5 µm, about 8 µm, about 8.5 µm, about 9 µm, or about 9.5 µm). In some embodiments, the particle size distribution of edonantan or its pharmaceutically acceptable salt present in biodegradable ocular implants is characterized by a D10 of less than about 2 µm (e.g., about 0.5 µm, about 0.6 µm, about 0.7 µm, about 0.8 µm, about 0.9 µm, about 1 µm, about 1.1 µm, about 1.2 µm, about 1.3 µm, about 1.4 µm, about 1.5 µm, about 1.6 µm, about 1.7 µm, about 1.8 µm, or about 1.9 µm).

[0069] In some embodiments, the particle size distribution of edonantan or a pharmaceutically acceptable salt thereof present in the biodegradable ocular implant is characterized by one or more of the following: (i) D10 less than about 90 µm; (ii) D50 less than about 150 µm; and (iii) D90 less than about 250 µm. In some embodiments, the particle size distribution of edonantan or a pharmaceutically acceptable salt thereof present in the biodegradable ocular implant is characterized by one or more of the following: (i) D10 less than about 10 µm; (ii) D50 less than about 40 µm; and (iii) D90 less than about 125 µm. In some embodiments, the particle size distribution of edonantan or a pharmaceutically acceptable salt thereof present in the biodegradable ocular implant is characterized by one or more of the following: (i) D10 less than about 2 µm; (ii) D50 less than about 6 µm; and (iii) D90 less than about 15 µm.

[0070] In some embodiments, the particle size distribution of edonantan or a pharmaceutically acceptable salt thereof present in the biodegradable ocular implant is characterized by a D10 less than about 90 µm, a D50 less than about 150 µm, and a D90 less than about 250 µm. In some embodiments, the particle size distribution of edonantan or a pharmaceutically acceptable salt thereof present in the biodegradable ocular implant is characterized by a D10 less than about 10 µm, a D50 less than about 40 µm, and a D90 less than about 125 µm. In some embodiments, the particle size distribution of edonantan or a pharmaceutically acceptable salt thereof present in the biodegradable ocular implant is characterized by a D10 less than about 2 µm, a D50 less than about 6 µm, and a D90 less than about 15 µm.

[0071] In some embodiments, the particle size distribution described herein is measured using laser diffraction techniques. In some embodiments, the instrument described herein for measuring the particle size distribution is a Malvern Mastersizer (e.g., Mastersizer 3000), a HELOS particle size analyzer, or an LS-909 laser particle size analyzer.

[0072] In some embodiments, edonanthant is present in the biodegradable ocular implant as its free base. In some embodiments, edonanthant is present in the biodegradable ocular implant as a crystalline solid in its free base form. In some embodiments, the crystalline solid is the crystal form described herein. In some embodiments, edonanthant is present in the biodegradable ocular implant as an anhydrous crystalline form as its free base. In some embodiments, edonanthant is present in the biodegradable ocular implant as edonanthant amorphous form 4.

[0073] Biodegradable polymers

[0074] Suitable polymeric materials or compositions used in the biodegradable ocular implants described herein include those that are compatible with the eye (i.e., biocompatible) without materially interfering with the function or physiology of the eye. Such polymeric materials may be biodegradable, biodegradable, or both.

[0075] As used herein, the terms “biodegradable” or “biodegradable” generally refer to the bio-assisted degradation process that the polymers constituting the implant undergo in a biological environment (such as within a subject's body). It should be understood that biodegradation encompasses the processes by which the implant is absorbed, dissolved, broken down, degraded, assimilated, or otherwise removed by the body (a biological environment).

[0076] As used herein, the term "polymer" encompasses both homopolymers (polymers having only one type of repeating unit) and copolymers (polymers having more than one type of repeating unit).

[0077] As used herein, the term "biodegradable polymer" refers to one or more polymers that degrade in vivo under physiological conditions. The release of the therapeutic agent and the degradation of the biodegradable polymer over time may occur simultaneously or sequentially.

[0078] In a preferred embodiment, the biodegradable polymer is PLGA (poly(lactic-co-glycolic acid)). PLGA polymers are known to degrade via backbone hydrolysis (overall degradation), with the final degradation products being lactic acid and glycolic acid. These degradation products are non-toxic and are considered natural metabolic compounds. Lactic acid and glycolic acid can be safely eliminated via the Krebs cycle by conversion to carbon dioxide and water.

[0079] PLGA is synthesized through random ring-opening copolymerization of glycolic acid and lactic acid cyclic dimers. Continuous glycolic acid or lactic acid monomer units are linked together by ester bonds. The ratio of lactide to glycolide can be varied, thereby altering the biodegradability of the product. By changing this ratio, the polymer degradation time can be tuned. Importantly, drug release characteristics are influenced by the biodegradation rate, molecular weight, and crystallinity of the drug delivery system. Drug delivery characteristics can be modified by altering and customizing the biodegradable polymer matrix.

[0080] In the presence of water in surrounding tissues, PLGA primarily cleaves through non-enzymatic hydrolysis of its ester bonds throughout the polymer matrix. PLGA polymers are biocompatible because they hydrolyze in vivo to produce the initial monomers lactic acid and / or glycolic acid. Lactic acid and glycolic acid are non-toxic and can be safely eliminated via the Krebs cycle by conversion to carbon dioxide and water. The biocompatibility of PLGA polymers has been further tested in both non-ocular and ocular tissues in animals and humans. The results indicate that the polymer is well tolerated.

[0081] Examples of PLGA polymers that may be used in embodiments of this disclosure include the RESOMER® product line from Evonik Industries and the VIATEL™ product line from Ashland Inc., which are identified as, but not limited to, RG502, RG502H, RG503, RG503H, RG504, RG504H, RG505, RG653H, RG750S, RG752H, RG752S, RG753H, RG753S, RG755S, RG756S, RG757S, RG858S, DLG 5003E, DLG 5002E, and DLG7505E.

[0082] Such PLGA polymers include both acid- and ester-terminated polymers, with intrinsic viscosities ranging from about 0.14 dL / g to about 1.7 dL / g when measured at 0.1% w / v in CHCl3 at 25°C using a Ubbelhode size 0c glass capillary viscometer. Exemplary polymers used in various embodiments of this disclosure may include D,L-lactide and glycolide in molar ratios ranging from about 50:50 to about 85:15 (including, but not limited to, 50:50, 65:35, 75:25, and 85:15).

[0083] Other examples of PLGA polymers that can be used in the embodiments of this disclosure include those produced by Lakeshore Biomaterials, which are identified as, but not limited to, DLG 1A, DLG 3A, or DLG 4A. Such DLG polymers comprise both acid (A) and ester (E)-terminated polymers, with an intrinsic viscosity ranging from about 0.5 dL / g to about 1.0 dL / g when measured at 0.1% w / v in CHCl3 at 25°C using a Ubbelhode size 0c glass capillary viscometer. Exemplary polymers used in the various embodiments of this disclosure may include D,L-lactide and glycolide in molar ratios ranging from about 1:99 to about 99:1 (including, but not limited to, 50:50, 65:35, 75:25, and 85:15).

[0084] RESOMERS® and / or viatel™ (identified in product names as “RG” or “DLG”, such as RG752S) are poly(D,L-lactide-co-glycolic acid) or PLGA having the following general formula (V):

[0085] .

[0086] DLGs with different molecular weights and different D,L-lactide-glycol ratios can be synthesized. In one embodiment, a DLG with an intrinsic viscosity of about 0.05 dL / g to about 0.15 dL / g, such as 1A, can be used. In another embodiment, a DLG with an intrinsic viscosity of about 0.15 dL / g to about 0.25 dL / g, such as 2A, can be used.

[0087] Poly(D,L-lactide-co-glycolic acid) or PLGA copolymers can be synthesized with different lactide to glycolide ratios, such as a 75:25 lactide:glycolic acid ratio. These copolymers can be ester-terminated PLGA copolymers, as indicated by the "S" at the end of the product name, or acid-terminated PLGA copolymers, as indicated by the "H" at the end of the product name.

[0088] The “RG502” used in this article refers to poly(D,L-lactide-co-glycolic acid) (RESOMER®) developed by Evonik, with a lactic acid to glycolic acid ratio of approximately 50:50 and a molecular weight (M... w The number is approximately 7,000 to 17,000.

[0089] The “RG503” used in this article refers to poly(D,L-lactide-co-glycolic acid) (RESOMER®) developed by Evonik, with a lactic acid to glycolic acid ratio of approximately 50:50 and a molecular weight (M... w The number is approximately 24,000 to approximately 38,000.

[0090] As used in this article, "RG753S" refers to poly(D,L-lactide-co-glycolic acid) (RESOMER®) developed by Evonik, with a lactic acid to glycolic acid ratio of approximately 75:25.

[0091] As used in this article, "DLG 5002E" refers to poly(D,L-lactide-co-glycolic acid) developed by Ashland (viatel). TM Its lactic acid to glycolic acid ratio is approximately 50:50, and its intrinsic viscosity (dl / g) is approximately 0.10 – 0.30.

[0092] As used in this article, "DLG 5003E" refers to poly(D,L-lactide-co-glycolic acid) developed by Ashland (viatel). TM Its lactic acid to glycolic acid ratio is approximately 50:50, and its intrinsic viscosity (dl / g) is approximately 0.20 – 0.40.

[0093] As used in this article, "DLG 7505E" refers to poly(D,L-lactide-co-glycolic acid) developed by Ashland (viatel). TM Its lactic acid to glycolic acid ratio is approximately 75:25, and its intrinsic viscosity (dl / g) is approximately 0.40 – 0.60.

[0094] In some embodiments, the biodegradable ocular implants described herein comprise about 40% w / w to about 80% w / w (e.g., about 40% w / w, about 45% w / w, about 50% w / w, about 55% w / w, about 60% w / w, about 65% w / w, about 70% w / w, about 75% w / w, or about 80% w / w) of a biodegradable polymer. In some embodiments, the biodegradable ocular implants described herein comprise about 45% w / w to about 65% w / w (e.g., about 45% w / w, about 50% w / w, about 55% w / w, about 60% w / w, or about 65% w / w) of a biodegradable polymer. In some embodiments, the biodegradable ocular implants described herein comprise about 50% w / w to about 60% w / w (e.g., about 50% w / w, about 51% w / w, about 52% w / w, about 53% w / w, about 54% w / w, about 55% w / w, about 56% w / w, about 57% w / w, about 58% w / w, about 59% w / w, or about 60% w / w) of a biodegradable polymer. In some embodiments, the biodegradable ocular implants described herein comprise about 55% w / w of a biodegradable polymer.

[0095] In some embodiments, the biodegradable polymer comprises one or more PLGA polymers. In some embodiments, the biodegradable polymer comprises two or more PLGA polymers. In some embodiments, the biodegradable polymer comprises three or more PLGA polymers.

[0096] In some embodiments, one or more PLGA polymers are selected from RG502, RG503, RG753S, DLG5002E, DLG5003E, DLG7505E, and combinations thereof. In some embodiments, two or more PLGA polymers are selected from RG502, RG503, RG753S, DLG5002E, DLG5003E, DLG7505E, and combinations thereof. In some embodiments, three or more PLGA polymers are selected from RG502, RG503, RG753S, DLG5002E, DLG5003E, DLG7505E, and combinations thereof.

[0097] In some embodiments, the biodegradable polymer comprises PLGA RG503 and PLGA RG753S. In some embodiments, the biodegradable ocular implant described herein comprises approximately 16.5% w / w PLGA RG503 and approximately 38.5% w / w PLGA RG753S.

[0098] In some embodiments, the biodegradable polymer comprises PLGA RG502, PLGA RG503, and PLGA RG753S. In some embodiments, the biodegradable ocular implant described herein comprises approximately 5.5% w / w PLGA RG502, approximately 27.5% w / w PLGA RG503, and approximately 22% w / w PLGA RG753S.

[0099] In some embodiments, the biodegradable polymers comprise PLGA DLG5002E, PLGA DLG5003E, and PLGA DLG7505E. In some embodiments, the biodegradable ocular implants described herein comprise approximately 5.5% w / w PLGA DLG5002E, approximately 27.5% w / w PLGA DLG5003E, and approximately 22% w / w PLGA DLG7505E.

[0100] In some embodiments, each of one or more PLGA polymers present in the biodegradable ocular implant comprises from about 0.2% w / w to about 2.5% w / w (e.g., about 0.2% w / w, about 0.3% w / w, about 0.4% w / w, about 0.5% w / w, about 0.6% w / w, about 0.7% w / w, about 0.8% w / w, about 0.9% w / w, about 1% w / w, about 1.1% w / w, about 1.2% w / w, about 1.3% w / w, about 1.4% w / w, about 1.5% w / w, about 1.6% w / w, about 1.7% w / w, about 1.8% w / w, about 1.9% w / w, about 2% w / w, about 2.1% w / w, about 2.2% w / w, about 2.3% w / w, about 2.4%). Residual monomers (w / w, or about 2.5% w / w). In some embodiments, each of the one or more PLGA polymers present in the biodegradable ocular implant contains about 0.2% w / w to about 2.2% w / w residual monomers. In some embodiments, each of the one or more PLGA polymers present in the biodegradable ocular implant contains about 1.3% w / w to about 2.2% w / w residual monomers. In some embodiments, each of the one or more PLGA polymers present in the biodegradable ocular implant contains about 0.2% w / w to about 0.4% w / w residual monomers.

[0101] In some embodiments, each of the one or more PLGA polymers present in the biodegradable ocular implant contains no more than about 2.5% w / w of residual monomer. In some embodiments, each of the one or more PLGA polymers present in the biodegradable ocular implant contains no more than about 2.4% w / w of residual monomer. In some embodiments, each of the one or more PLGA polymers present in the biodegradable ocular implant contains no more than about 2.3% w / w of residual monomer. In some embodiments, each of the one or more PLGA polymers present in the biodegradable ocular implant contains no more than about 2.2% w / w of residual monomer. In some embodiments, each of the one or more PLGA polymers present in the biodegradable ocular implant contains no more than about 2.1% w / w of residual monomer. In some embodiments, each of the one or more PLGA polymers present in the biodegradable ocular implant contains no more than about 2% w / w of residual monomer. In some embodiments, each of the one or more PLGA polymers present in the biodegradable ocular implant contains no more than about 1.5% w / w of residual monomer. In some embodiments, each of the one or more PLGA polymers present in the biodegradable ocular implant contains no more than about 1.4% w / w of residual monomer. In some embodiments, each of the one or more PLGA polymers present in the biodegradable ocular implant contains no more than about 1.3% w / w of residual monomer. In some embodiments, each of the one or more PLGA polymers present in the biodegradable ocular implant contains no more than about 1.2% w / w of residual monomer. In some embodiments, each of the one or more PLGA polymers present in the biodegradable ocular implant contains no more than about 1.1% w / w of residual monomer. In some embodiments, each of the one or more PLGA polymers present in the biodegradable ocular implant contains no more than about 0.5% w / w of residual monomer. In some embodiments, each of the one or more PLGA polymers present in the biodegradable ocular implant contains no more than about 0.4% w / w of residual monomer. In some embodiments, each of the one or more PLGA polymers present in the biodegradable ocular implant contains no more than about 0.35% w / w of residual monomer. In some embodiments, each of the one or more PLGA polymers present in the biodegradable ocular implant contains no more than about 0.3% w / w of residual monomer. In some embodiments, each of the one or more PLGA polymers present in the biodegradable ocular implant contains no more than about 0.25% w / w of residual monomer.

[0102] In some embodiments, the biodegradable polymer (e.g., PLGA) biodegrades substantially within about 1 month to about 12 months (e.g., about 1 month to about 11 months, about 1 month to about 10 months, about 1 month to about 9 months, about 1 month to about 8 months, about 1 month to about 7 months, about 1 month to about 6 months, about 1 month to about 5 months, about 1 month to about 4 months, about 1 month to about 3 months, and about 1 month to about 2 months). In some embodiments, the biodegradable polymer (e.g., PLGA) biodegrades substantially within 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, or about 12 months. In some embodiments, the biodegradable polymer (e.g., PLGA) biodegrades substantially within about 1 month. In some embodiments, the biodegradable polymer (e.g., PLGA) biodegrades substantially within about 2 months. In some embodiments, the biodegradable polymer (e.g., PLGA) biodegrades substantially within about 3 months. In some embodiments, the biodegradable polymer (e.g., PLGA) biodegrades substantially within approximately 4 months. In some embodiments, the biodegradable polymer (e.g., PLGA) biodegrades substantially within approximately 5 months. In some embodiments, the biodegradable polymer (e.g., PLGA) biodegrades substantially within approximately 6 months.

[0103] Biodegradable eye implants

[0104] The biodegradable ocular implants described herein typically comprise edonantan or a pharmaceutically acceptable salt thereof, along with a biodegradable polymer. In a preferred embodiment, the compound is a compound of formula I.

[0105] In one respect, this article provides biodegradable ocular implants comprising:

[0106] (i) Adonantan or a pharmaceutically acceptable salt thereof; and

[0107] (ii) Biodegradable polymers,

[0108] The particle size distribution of edonantane or its pharmaceutically acceptable salt is characterized by a D90 of about 10 µm to about 250 µm.

[0109] On the other hand, this article provides biodegradable ocular implants comprising:

[0110] (i) Adonantan or a pharmaceutically acceptable salt thereof; and

[0111] (ii) One or more poly(lactic acid-co-glycolic acid) (PLGA) polymers,

[0112] Each of the one or more PLGA polymers present in biodegradable ocular implants contains no more than about 0.5% w / w of residual monomer.

[0113] In various embodiments, the diameter of the biodegradable ocular implant is from about 200 µm to about 500 µm (e.g., about 200 µm, about 225 µm, about 250 µm, about 275 µm, about 300 µm, about 325 µm, about 350 µm, about 375 µm, about 400 µm, about 425 µm, about 450 µm, about 475 µm and about 500 µm). In various embodiments, the diameter of the biodegradable ocular implant is from about 300 µm to about 400 µm (e.g., about 300 µm, about 305 µm, about 310 µm, about 315 µm, about 320 µm, about 325 µm, about 330 µm, about 335 µm, about 340 µm, about 345 µm, about 350 µm, about 355 µm, about 360 µm, about 365 µm, about 370 µm, about 375 µm, 380 µm, 385 µm, 390 µm, 395 µm, and 400 µm). In various embodiments, the diameter of the biodegradable ocular implant is from about 300 µm to about 360 µm. In some implementations, the diameter of the biodegradable ocular implant is about 310 µm, about 321 µm, about 325 µm, about 330 µm, about 345 µm, or about 356 µm.

[0114] In various embodiments, the length of the implant is from about 3 mm to about 6 mm (e.g., 3 mm, 3.1 mm, 3.2 mm, 3.3 mm, 3.4 mm, 3.5 mm, 3.6 mm, 3.7 mm, 3.8 mm, 3.9 mm, 4.0 mm, 4.1 mm, 4.2 mm, 4.3 mm, 4.4 mm, 4.5 mm, 4.6 mm, 4.7 mm, 4.8 mm, 4.9 mm, 5 mm, 5.1 mm, 5.2 mm, 5.3 mm, 5.4 mm, 5.5 mm, 5.6 mm, 5.7 mm, 5.8 mm, 5.9 mm, 6.0 mm). In various embodiments, the length of the implant is from 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 some implementations, the implant is approximately 4 mm in length.

[0115] In each embodiment, the total weight of the implant is from about 300 µg to about 600 µg (e.g., about 300 µg, about 325 µg, about 350 µg, about 375 µg, about 400 µg, about 425 µg, about 450 µg, about 475 µg, about 500 µg, about 525 µg, about 550 µg, about 575 µg and 600 µg). In each embodiment, the total weight of the implant is from approximately 400 µg to approximately 600 µg (e.g., approximately 400 µg, approximately 405 µg, approximately 410 µg, approximately 415 µg, approximately 420 µg, approximately 425 µg, approximately 430 µg, approximately 435 µg, approximately 440 µg, approximately 445 µg, approximately 450 µg, approximately 455 µg, approximately 460 µg, approximately 465 µg, approximately 470 µg, approximately 475 µg, approximately 480 µg, approximately 485 µg, approximately 490 µg, approximately 495 µg, approximately 500 µg, approximately 505 µg, approximately 510 µg, approximately 515 µg, approximately 520 µg, approximately 525 µg, approximately 530 µg, approximately 535 µg, approximately 540 µg, approximately 545 µg, approximately 550 µg, approximately 555 µg, approximately 555 µg, approximately 555 µg, approximately 555 µg, approximately 550 ... (approximately 560 µg, 565 µg, 570 µg, 575 µg, 580 µg, 585 µg, 590 µg, 595 µg, and 600 µg). In some embodiments, the total weight of the implant is approximately 415 µg, 440 µg, 501 µg, 523 µg, 526 µg, or 529 µg.

[0116] The release rate of therapeutic agents (e.g., edonantan) from intravitreal implants or particulate suspensions (e.g., the biodegradable ocular implants of this disclosure) may depend on a number of factors, including but not limited to the surface area of ​​the implant, the content of the therapeutic agent, the water solubility of the therapeutic agent, and the degradation rate of the polymer.

[0117] In some embodiments, after incubating the biodegradable ocular implant in 3 mL of phosphate-buffered saline (PBS) at pH 7.4 and containing 0.1% Tween in a shaking incubator at 39°C and 50 rpm for 28 days, approximately 5% to approximately 40% (e.g., approximately 5%, approximately 10%, approximately 15%, approximately 20%, approximately 25%, approximately 30%, approximately 35%, or approximately 40%) of edonantan is released from the biodegradable ocular implant. In some embodiments, after incubating the biodegradable ocular implant in 3 mL of phosphate-buffered saline (PBS) at pH 7.4 and containing 0.1% Tween in a shaking incubator at 39°C and 50 rpm for 28 days, approximately 40% or less of edonantan is released from the biodegradable ocular implant.

[0118] In some embodiments, after incubating the biodegradable ocular implant in 3 mL of phosphate-buffered saline (PBS) at pH 7.4 and containing 0.1% Tween in a shaking incubator at 39°C and 50 rpm for 42 days, approximately 20% to approximately 60% (e.g., approximately 20%, approximately 25%, approximately 30%, approximately 35%, approximately 40%, approximately 45%, approximately 50%, approximately 55%, or approximately 60%) of edonantan is released from the biodegradable ocular implant. In some embodiments, after incubating the biodegradable ocular implant in 3 mL of phosphate-buffered saline (PBS) at pH 7.4 and containing 0.1% Tween in a shaking incubator at 39°C and 50 rpm for 42 days, approximately 60% or less of edonantan is released from the biodegradable ocular implant.

[0119] In some embodiments, after incubating the biodegradable ocular implant in 3 mL of phosphate-buffered saline (PBS) at pH 7.4 and containing 0.1% Tween in a shaking incubator at 39°C and 50 rpm for 70 days, approximately 35% to approximately 80% (e.g., approximately 35%, approximately 40%, approximately 45%, approximately 50%, approximately 55%, approximately 60%, approximately 65%, approximately 70%, approximately 75%, or approximately 80%) of edonantan is released from the biodegradable ocular implant. In some embodiments, after incubating the biodegradable ocular implant in 3 mL of phosphate-buffered saline (PBS) at pH 7.4 and containing 0.1% Tween in a shaking incubator at 39°C and 50 rpm for 70 days, approximately 80% or less of edonantan is released from the biodegradable ocular implant.

[0120] In various embodiments, the implant is administered via intravitreal administration. Intravitreal administration refers to administering the drug into the vitreous fluid of the eye. In some embodiments, the implant is administered locally to the posterior part of the eye. In some embodiments, the implant is injected into the vitreous space using a needle and a delivery device.

[0121] In some embodiments, the biodegradable ocular implant is a sterile biodegradable ocular implant. As used herein, "sterile" means a composition that meets the sterility requirements mandated by drug regulatory agencies such as the UK MCA or the US FDA. Test methods are included in current editions of pharmacopoeias, such as the British Pharmacopoeia and the 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 vitreous space every 3 to 12 months.

[0122] Preparation method

[0123] This article provides a method for preparing the biodegradable ocular implant described herein. The method typically involves hot-melt extrusion of a blend of edonantan or a pharmaceutically acceptable salt thereof with a biodegradable polymer to form the biodegradable ocular implant.

[0124] On the one hand, this article provides a method for preparing a biodegradable ocular implant comprising edonantan or a pharmaceutically acceptable salt thereof and a biodegradable polymer, the method comprising;

[0125] (a) Grinding biodegradable polymers;

[0126] (b) Reduce the particle size of edonantan or a pharmaceutically acceptable salt thereof to form treated edonantan or a pharmaceutically acceptable salt thereof;

[0127] (c) The milled biodegradable polymer is mixed with treated adonantan or a pharmaceutically acceptable salt thereof to form a blend;

[0128] (d) The blend is hot-melted and extruded to form a biodegradable ocular implant.

[0129] In some implementations, in step (a), the biodegradable polymer is cryogenically milled.

[0130] In some embodiments, in step (a), the biodegradable polymer comprises one or more PLGA polymers. In some embodiments, the one or more PLGA polymers are selected from RG502, RG503, RG753S, DLG5002E, DLG5003E, DLG7505E, and combinations thereof.

[0131] In some embodiments, in step (a), the biodegradable polymer comprises PLGA RG503 and PLGA RG753S. In some embodiments, in step (a), the biodegradable polymer comprises about 30% w / w PLGA RG503 and about 70% w / w PLGA RG753S.

[0132] In some embodiments, in step (a), the biodegradable polymer comprises PLGA RG502, PLGA RG503, and PLGA RG753S. In some embodiments, in step (a), the biodegradable polymer comprises about 10% w / w PLGA RG502, about 50% w / w PLGA RG503, and about 40% w / w PLGA RG753S.

[0133] In some embodiments, in step (a), the biodegradable polymer comprises PLGA DLG5002E, PLGA DLG5003E, and PLGA DLG7505E. In some embodiments, in step (a), the biodegradable polymer comprises about 10% w / w PLGA DLG5002E, about 50% w / w PLGA DLG5003E, and about 40% w / w PLGA DLG7505E.

[0134] In some embodiments, in step (b), reducing the particle size of edonanthan or a pharmaceutically acceptable salt thereof includes passing edonanthan or a pharmaceutically acceptable salt thereof through a 100-mesh sieve. In some embodiments, in step (b), reducing the particle size of edonanthan or a pharmaceutically acceptable salt thereof includes grinding edonanthan or a pharmaceutically acceptable salt thereof. In some embodiments, in step (b), reducing the particle size of edonanthan or a pharmaceutically acceptable salt thereof includes micronizing edonanthan or a pharmaceutically acceptable salt thereof.

[0135] In some embodiments, in step (b), the particle size distribution of the treated adonantan or its pharmaceutically acceptable salt is characterized by a D90 of about 10 µm to about 250 µm.

[0136] In some embodiments, in step (b), the particle size distribution of the treated edonantan or its pharmaceutically acceptable salt is characterized by a D90 of about 9 µm to about 250 µm (e.g., about 9 µm, about 10 µm, about 20 µm, about 30 µm, about 40 µm, about 50 µm, about 60 µm, about 70 µm, about 80 µm, about 90 µm, about 100 µm, about 110 µm, about 120 µm, about 130 µm, about 140 µm, about 150 µm, about 160 µm, about 170 µm, about 180 µm, about 190 µm, about 200 µm, about 210 µm, about 220 µm, about 230 µm, about 240 µm, or about 250 µm). In some embodiments, in step (b), the particle size distribution of the treated edonantan or its pharmaceutically acceptable salt is characterized by a D90 of about 9 µm to about 125 µm (e.g., about 9 µm, about 10 µm, about 15 µm, about 20 µm, about 25 µm, about 30 µm, about 35 µm, about 40 µm, about 45 µm, about 50 µm, about 55 µm, about 60 µm, about 65 µm, about 70 µm, about 75 µm, about 80 µm, about 85 µm, about 90 µm, about 95 µm, about 100 µm, about 105 µm, about 110 µm, about 115 µm, about 120 µm, or about 125 µm). In some embodiments, in step (b), the particle size distribution of the treated edonantan or its pharmaceutically acceptable salt is characterized by a D90 of about 9 µm to about 15 µm (e.g., about 9 µm, about 9.25 µm, about 9.5 µm, about 9.75 µm, about 10 µm, about 10.25 µm, about 10.5 µm, about 10.75 µm, about 11 µm, about 11.25 µm, about 11.5 µm, about 11.75 µm, about 12 µm, about 12.25 µm, about 12.5 µm, about 12.75 µm, about 13 µm, about 13.25 µm, about 13.5 µm, about 13.75 µm, about 14 µm, about 14.25 µm, about 14.5 µm, about 14.75 µm, or about 15 µm).

[0137] In some embodiments, in step (b), the particle size distribution of the treated edonantan or its pharmaceutically acceptable salt is characterized by a D50 of about 2.5 µm to about 150 µm (e.g., about 2.5 µm, about 10 µm, about 20 µm, about 30 µm, about 40 µm, about 50 µm, about 60 µm, about 70 µm, about 80 µm, about 90 µm, about 100 µm, about 110 µm, about 120 µm, about 130 µm, about 140 µm, or about 150 µm). In some embodiments, in step (b), the particle size distribution of the treated edonantan or its pharmaceutically acceptable salt is characterized by a D50 of about 2.5 µm to about 40 µm (e.g., about 2.5 µm, about 5 µm, about 7.5 µm, about 10 µm, about 12.5 µm, about 15 µm, about 17.5 µm, about 20 µm, about 22.5 µm, about 25 µm, about 27.5 µm, about 30 µm, about 32.5 µm, about 35 µm, about 37.5 µm, or about 40 µm). In some embodiments, in step (b), the particle size distribution of the treated edonantan or its pharmaceutically acceptable salt is characterized by a D50 of about 2.5 µm to about 6 µm (e.g., about 2.5 µm, about 2.75 µm, about 3 µm, about 3.25 µm, about 3.5 µm, about 3.75 µm, about 4 µm, about 4.25 µm, about 4.5 µm, about 4.75 µm, about 5 µm, about 5.25 µm, about 5.5 µm, about 5.75 µm, or about 6 µm).

[0138] In some embodiments, in step (b), the particle size distribution of the treated edonantan or its pharmaceutically acceptable salt is characterized by a D10 of about 0.5 µm to about 90 µm (e.g., about 0.5 µm, about 5 µm, about 10 µm, about 15 µm, about 20 µm, about 25 µm, about 30 µm, about 35 µm, about 40 µm, about 45 µm, about 50 µm, about 55 µm, about 60 µm, about 65 µm, about 70 µm, about 75 µm, about 80 µm, about 85 µm, or about 90 µm). In some embodiments, in step (b), the particle size distribution of the treated edonantan or its pharmaceutically acceptable salt is characterized by a D10 of about 0.5 µm to about 10 µm (e.g., about 0.5 µm, about 1 µm, about 1.5 µm, about 2 µm, about 2.5 µm, about 3 µm, about 3.5 µm, about 4 µm, about 4.5 µm, about 5 µm, about 5.5 µm, about 6 µm, about 6.5 µm, about 7 µm, about 7.5 µm, about 8 µm, about 8.5 µm, about 9 µm, about 9.5 µm, or about 10 µm). In some embodiments, in step (b), the particle size distribution of the treated edonantan or its pharmaceutically acceptable salt is characterized by a D10 of about 0.5 µm to about 2 µm (e.g., about 0.5 µm, about 0.6 µm, about 0.7 µm, about 0.8 µm, about 0.9 µm, about 1 µm, about 1.1 µm, about 1.2 µm, about 1.3 µm, about 1.4 µm, about 1.5 µm, about 1.6 µm, about 1.7 µm, about 1.8 µm, about 1.9 µm, or about 2 µm).

[0139] In some embodiments, in step (b), the particle size distribution of the treated edonantan or a pharmaceutically acceptable salt thereof is characterized by one or more of the following: (i) D10 of about 0.5 µm to about 90 µm; (ii) D50 of about 2.5 µm to about 150 µm; and (iii) D90 of about 9 µm to about 250 µm. In some embodiments, in step (b), the particle size distribution of the treated edonantan or a pharmaceutically acceptable salt thereof is characterized by one or more of the following: (i) D10 of about 0.5 µm to about 10 µm; (ii) D50 of about 2.5 µm to about 40 µm; and (iii) D90 of about 9 µm to about 125 µm. In some embodiments, in step (b), the particle size distribution of the treated adonantan or its pharmaceutically acceptable salt is characterized by one or more of the following: (i) D10 is about 0.5 µm to about 2 µm; (ii) D50 is about 2.5 µm to about 6 µm; and (iii) D90 is about 9 µm to about 15 µm.

[0140] In some embodiments, in step (b), the particle size distribution of the treated edonantan or a pharmaceutically acceptable salt thereof is characterized by a D10 of about 0.5 µm to about 90 µm, a D50 of about 2.5 µm to about 150 µm, and a D90 of about 9 µm to about 250 µm. In some embodiments, in step (b), the particle size distribution of the treated edonantan or a pharmaceutically acceptable salt thereof is characterized by a D10 of about 0.5 µm to about 10 µm, a D50 of about 2.5 µm to about 40 µm, and a D90 of about 9 µm to about 125 µm. In some embodiments, in step (b), the particle size distribution of the treated edonantan or a pharmaceutically acceptable salt thereof is characterized by a D10 of about 0.5 µm to about 2 µm, a D50 of about 2.5 µm to about 6 µm, and a D90 of about 9 µm to about 15 µm.

[0141] In some embodiments, in step (b), the particle size distribution of the treated edonantan or its pharmaceutically acceptable salt is characterized by a D90 of less than about 250 µm (e.g., about 9 µm, about 10 µm, about 20 µm, about 30 µm, about 40 µm, about 50 µm, about 60 µm, about 70 µm, about 80 µm, about 90 µm, about 100 µm, about 110 µm, about 120 µm, about 130 µm, about 140 µm, about 150 µm, about 160 µm, about 170 µm, about 180 µm, about 190 µm, about 200 µm, about 210 µm, about 220 µm, about 230 µm, or about 240 µm). In some embodiments, in step (b), the particle size distribution of the treated edonantan or its pharmaceutically acceptable salt is characterized by a D90 of less than about 125 µm (e.g., about 9 µm, about 10 µm, about 15 µm, about 20 µm, about 25 µm, about 30 µm, about 35 µm, about 40 µm, about 45 µm, about 50 µm, about 55 µm, about 60 µm, about 65 µm, about 70 µm, about 75 µm, about 80 µm, about 85 µm, about 90 µm, about 95 µm, about 100 µm, about 105 µm, about 110 µm, about 115 µm, or about 120 µm). In some embodiments, in step (b), the particle size distribution of the treated edonantan or its pharmaceutically acceptable salt is characterized by a D90 of less than about 15 µm (e.g., about 9 µm, about 9.25 µm, about 9.5 µm, about 9.75 µm, about 10 µm, about 10.25 µm, about 10.5 µm, about 10.75 µm, about 11 µm, about 11.25 µm, about 11.5 µm, about 11.75 µm, about 12 µm, about 12.25 µm, about 12.5 µm, about 12.75 µm, about 13 µm, about 13.25 µm, about 13.5 µm, about 13.75 µm, about 14 µm, about 14.25 µm, about 14.5 µm, or about 14.75 µm).

[0142] In some embodiments, in step (b), the particle size distribution of the treated edonantan or its pharmaceutically acceptable salt is characterized by a D50 of less than about 150 µm (e.g., about 2.5 µm, about 10 µm, about 20 µm, about 30 µm, about 40 µm, about 50 µm, about 60 µm, about 70 µm, about 80 µm, about 90 µm, about 100 µm, about 110 µm, about 120 µm, about 130 µm, or about 140 µm). In step (b), the particle size distribution of the treated edonantan or its pharmaceutically acceptable salt is characterized by a D50 of less than about 40 µm (e.g., about 2.5 µm, about 5 µm, about 7.5 µm, about 10 µm, about 12.5 µm, about 15 µm, about 17.5 µm, about 20 µm, about 22.5 µm, about 25 µm, about 27.5 µm, about 30 µm, about 32.5 µm, about 35 µm, or about 37.5 µm). In some embodiments, in step (b), the particle size distribution of the treated edonantan or its pharmaceutically acceptable salt is characterized by a D50 of less than about 6 µm (e.g., about 2.5 µm, about 2.75 µm, about 3 µm, about 3.25 µm, about 3.5 µm, about 3.75 µm, about 4 µm, about 4.25 µm, about 4.5 µm, about 4.75 µm, about 5 µm, about 5.25 µm, about 5.5 µm, or about 5.75 µm).

[0143] In some embodiments, in step (b), the particle size distribution of the treated edonantan or its pharmaceutically acceptable salt is characterized by a D10 of less than about 90 µm (e.g., about 0.5 µm, about 5 µm, about 10 µm, about 15 µm, about 20 µm, about 25 µm, about 30 µm, about 35 µm, about 40 µm, about 45 µm, about 50 µm, about 55 µm, about 60 µm, about 65 µm, about 70 µm, about 75 µm, about 80 µm, or about 85 µm). In some embodiments, in step (b), the particle size distribution of the treated edonantan or its pharmaceutically acceptable salt is characterized by a D10 of less than about 10 µm (e.g., about 0.5 µm, about 1 µm, about 1.5 µm, about 2 µm, about 2.5 µm, about 3 µm, about 3.5 µm, about 4 µm, about 4.5 µm, about 5 µm, about 5.5 µm, about 6 µm, about 6.5 µm, about 7 µm, about 7.5 µm, about 8 µm, about 8.5 µm, about 9 µm, or about 9.5 µm). In some embodiments, in step (b), the particle size distribution of the treated edonantan or its pharmaceutically acceptable salt is characterized by a D10 of less than about 2 µm (e.g., about 0.5 µm, about 0.6 µm, about 0.7 µm, about 0.8 µm, about 0.9 µm, about 1 µm, about 1.1 µm, about 1.2 µm, about 1.3 µm, about 1.4 µm, about 1.5 µm, about 1.6 µm, about 1.7 µm, about 1.8 µm, or about 1.9 µm).

[0144] In some embodiments, in step (b), the particle size distribution of the treated edonanthan or a pharmaceutically acceptable salt thereof is characterized by one or more of the following: (i) D10 less than about 90 µm; (ii) D50 less than about 150 µm; and (iii) D90 less than about 250 µm. In some embodiments, in step (b), the particle size distribution of the treated edonanthan or a pharmaceutically acceptable salt thereof is characterized by one or more of the following: (i) D10 less than about 10 µm; (ii) D50 less than about 40 µm; and (iii) D90 less than about 125 µm. In some embodiments, in step (b), the particle size distribution of the treated edonanthan or a pharmaceutically acceptable salt thereof is characterized by one or more of the following: (i) D10 less than about 2 µm; (ii) D50 less than about 6 µm; and (iii) D90 less than about 15 µm.

[0145] In some embodiments, in step (b), the particle size distribution of the treated edonantan or a pharmaceutically acceptable salt thereof is characterized by a D10 less than about 90 µm, a D50 less than about 150 µm, and a D90 less than about 250 µm. In some embodiments, in step (b), the particle size distribution of the treated edonantan or a pharmaceutically acceptable salt thereof is characterized by a D10 less than about 10 µm, a D50 less than about 40 µm, and a D90 less than about 125 µm. In some embodiments, in step (b), the particle size distribution of the treated edonantan or a pharmaceutically acceptable salt thereof is characterized by a D10 less than about 2 µm, a D50 less than about 6 µm, and a D90 less than about 15 µm.

[0146] In some embodiments, in step (b), the particle size distribution described herein is measured using laser diffraction techniques. In some embodiments, in step (b), the instrument described herein for measuring the particle size distribution is a Malvern Mastersizer (e.g., Mastersizer 3000), a HELOS particle size analyzer, or an LS-909 laser particle size analyzer.

[0147] In some embodiments, in step (b), edonanthantan exists as an anhydrous crystalline form in its free base form both before and after milling. In some embodiments, in step (b), edonanthantan exists as the amorphous form described herein in its free base form both before and after milling. In some embodiments, in step (b), edonanthantan exists as amorphous form 4 in its free base form both before and after milling.

[0148] In some embodiments, step (d) of hot melt extrusion of the blend includes:

[0149] (i) The blend is hot-melt extruded at a temperature of about 95°C to form a first extrudate;

[0150] (ii) The first extrudate is hot-melt extruded at a temperature of about 100°C to about 120°C to form extruded filaments; and

[0151] (iii) Cut the extruded filaments to form a biodegradable ocular implant.

[0152] In some embodiments, in step (i), the blend is hot-melt extruded using a Thermo Haake conical twin-screw extruder equipped with a 1.96 mm die. In some embodiments, in step (i), the blend is hot-melt extruded using a screw speed of approximately 10 rpm.

[0153] In some embodiments, in step (ii), the first extrudate is hot-melt extruded using a Thermo Haake conical twin-screw extruder equipped with a 0.31 mm – 0.33 mm die. In some embodiments, in step (i), the blend is hot-melt extruded using a screw speed of about 4 to about 10 rpm.

[0154] In some embodiments, step (d) of hot melt extrusion of the blend includes:

[0155] (i) The blend is hot-melt extruded at a temperature of about 85°C to about 90°C to form a first extrudate;

[0156] (ii) The first extrudate is hot-melt extruded at a temperature of about 88°C to about 90°C to form the second extrudate;

[0157] (iii) The second extrudate is hot-melt extruded at a temperature of about 71°C to about 74°C to form extruded filaments; and

[0158] (iv) Cut the extruded filaments to form a biodegradable ocular implant.

[0159] In some implementations, in step (i), the blend is hot-melt extruded using a ThermoHaake conical twin-screw extruder equipped with a 3 mm die.

[0160] In some implementations, in step (ii), the first extrudate is hot-melt extruded using a Thermo Haake conical twin-screw extruder equipped with a 1.54 mm die.

[0161] In some implementations, in step (iii), the second extrudate is hot-melt extruded using a Barrell custom plunger extruder equipped with a 0.325 mm die.

[0162] The crystal form of Adonantan

[0163] On the one hand, the biodegradable ocular implants described herein contain one or more solid forms of edonantan or a pharmaceutically acceptable salt thereof.

[0164] On the other hand, the biodegradable ocular implants described herein comprise one or more solid forms of adonantan.

[0165] In some embodiments, the solid form of adonantan is amorphous (crystal form 4), the X-ray powder diffraction (XRPD) pattern of which contains at least three characteristic peaks (denoted by 2θ) selected from the 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°.

[0166] In some embodiments of the solid form, the crystal-free type 4 has the following XRPD patterns expressed in diffraction angles (2θ): 5.6 ± 0.2°, 11.4 ± 0.2°, 17.7 ± 0.2°, 19.3 ± 0.2°, and 21.9 ± 0.2°.

[0167] In some embodiments of the solid form, the crystal-free type 4 is characterized in that its XRPD pattern includes one or more diffraction angles (2θ) selected from the following: 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 crystal-free type 4 is characterized in that its XRPD pattern includes one or more diffraction angles (2θ) selected from the following: 11.4 ± 0.2°, 17.7 ± 0.2°, and 19.3 ± 0.2°.

[0168] In some embodiments in solid form, the melting temperature (T0) of amorphous type 4 was determined by differential scanning calorimetry (DSC). m The temperature is approximately 163°C.

[0169] In some embodiments of the solid form, the crystal-amorphous type 4 is characterized by having an XRPD pattern containing one or more diffraction angles (2θ) selected from the following: 5.6 ± 0.2°, 11.4 ± 0.2°, 17.7 ± 0.2°, 19.3 ± 0.2°, and 21.9 ± 0.2°; and having a T0 determined by DSC analysis. m The temperature is approximately 163°C. In some embodiments in solid form, the crystal-free type 4 is characterized by having an XRPD pattern containing one or more diffraction angles (2θ) selected from the following: 11.4 ± 0.2°, 17.7 ± 0.2°, and 19.3 ± 0.2°; and its To is determined by DSC analysis. m It is approximately 163°C.

[0170] In some embodiments, based on the total weight of edonantan present in the biodegradable ocular implant, edonantan comprises at least about 90% by weight of crystal-free type 4. In some embodiments, based on the total weight of edonantan present in the biodegradable ocular implant, edonantan comprises at least about 95% by weight of crystal-free type 4. In some embodiments, based on the total weight of edonantan present in the biodegradable ocular implant, edonantan comprises at least about 96% by weight of crystal-free type 4. In some embodiments, based on the total weight of edonantan present in the biodegradable ocular implant, edonantan comprises at least about 97% by weight of crystal-free type 4. In some embodiments, based on the total weight of edonantan present in the biodegradable ocular implant, edonantan comprises at least about 98% by weight of crystal-free type 4. In some embodiments, based on the total weight of edonantan present in the biodegradable ocular implant, edonantan comprises at least about 99% by weight of crystal-free type 4.

[0171] In some embodiments, the solid form of edonantan is amorphous (crystalline form 1), wherein the XRPD pattern of amorphous form 1 contains at least three diffraction peaks (denoted by 2θ) selected from peaks at 6.3±0.2°, 7.5±0.2°, 11.7±0.2°, 15.1±0.2°, and 17.3±0.2°; based on the total weight of edonantan present in the biodegradable ocular implant, edonantan contains at least about 90% by weight of amorphous form 1.

[0172] In some embodiments, edonantan in solid form is a monohydrate crystal form (crystal form 2), wherein the XRPD pattern of the monohydrate crystal form 2 contains at least three diffraction peaks (denoted by 2θ) selected from peaks 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°; based on the total weight of edonantan present in the biodegradable ocular implant, edonantan comprises at least about 90% by weight of the monohydrate crystal form 2.

[0173] In some embodiments, the solid form of edonantan is amorphous (crystal form 3), wherein the XRPD pattern of amorphous form 3 contains at least three diffraction peaks (denoted by 2θ) selected from peaks at 7.8±0.2°, 9.0±0.2°, 11.6±0.2°, 15.8±0.2°, and 19.1±0.2°; based on the total weight of edonantan present in the biodegradable ocular implant, edonantan contains at least about 90% by weight of amorphous form 3.

[0174] In some embodiments, edonantan in solid form is an amorphous solid. As used herein, the term "amorphous" refers to a solid material whose molecular positions do not exhibit long-range order. Amorphous solids are typically supercooled liquids in which molecules are arranged randomly, thus lacking a definite arrangement (e.g., molecular packing) and long-range order. Amorphous solids are generally isotropic, exhibiting similar properties in all directions and without a definite melting point. For example, an amorphous material is a solid material whose XRPD spectrum does not contain sharp, characteristic crystalline peaks (i.e., determined to be amorphous by XRPD). Instead, its XRPD spectrum shows one or more broad peaks (e.g., halo peaks).

[0175] Eye diseases

[0176] The methods disclosed herein generally involve treating and improving eye diseases selected from those of glaucoma, diabetic retinopathy (DR), retinal vein occlusion (RVO), retinopathy of preterm birth (ROP), geographic atrophy (GA), and age-related macular degeneration (AMD), as described herein.

[0177] glaucoma

[0178] In glaucoma treatment using the biodegradable ocular implants containing edonantan described herein, the “therapeutic effective dose” can be determined by assessing the achievable improvement in retinal blood flow (RBF) relative to standard treatment (reduction of intraocular pressure (IOP)). For the glaucoma indication, improvements in blood flow in healthy rabbit eye models can be used to predict drug efficacy response (PD) in humans. Rabbits are commonly used to assess ocular PK / PD relationships for compounds targeting human eye diseases due to the anatomical and functional similarities between rabbit and human eyes. Previously, intravitreal administration of ET-1 in 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 Ophasemol 2009). Efficacy in this model was based on reversing perfusion damage induced by intravitreal administration of ET-1 at concentrations comparable to those observed in the plasma and aqueous humor of human glaucoma patients (Li S. et al., Journal of Ophthalmology 2016).

[0179] Other examples of relevant animal glaucoma models include the Morrison rat model of acute intraocular pressure elevation and the laser-induced non-human primate (NHP) glaucoma model. Glaucoma in the Morrison rat model was induced by sustained elevation of intraocular pressure via episcleral intravenous administration of hypertonic saline. In the laser-induced NHP glaucoma model, reduced optic nerve head blood flow has been observed after sustained elevation of IOP (Wang L. et al., Invest Ophamol Vis Sci 2012). Furthermore, this reduction in optic nerve head blood flow has been shown to be associated with long-term structural changes in the optic nerve (Cull G. et al., Invest Ophasemol Vis Sci 2013).

[0180] In the aforementioned glaucoma model, efficacy was defined as: compared to baseline, after treatment with edonantan, a reduction in intraocular pressure, improved blood flow to the optic nerve head or retina, prevention or slowing of the progression of structural neurodegenerative changes (e.g., retinal nerve fiber layer thickness measured by optical coherence tomography (OCT), or ganglion cell counts in retinal patches); and improvement in functional changes (e.g., electroretinography (ERG) or contrast sensitivity).

[0181] It is believed that the effects of compositions containing edonantan on retinal blood flow can be assessed using Poiseuille's law via vessel radius (r). The increase in blood flow induced by increasing (r) with an endothelin antagonist will be more significant than the increase in blood flow achieved by increasing perfusion pressure through decreasing IOP.

[0182] Blood flow = (perfusion pressure × πr) 4 ) / (8ηl)

[0183] in

[0184] l: Blood vessel length

[0185] r: radius of blood vessel

[0186] η: Blood viscosity

[0187] Perfusion pressure: Mean arterial pressure - IOP

[0188] Furthermore, the biodegradable ocular implants containing edonantan described herein can reduce IOP and / or prevent RGC death through mechanisms independent of retinal / optic nerve head tissue perfusion improvement. Therefore, by using certain specific edonantans, one or more of the aforementioned parameters (IOP) can be altered to improve RBF, thereby achieving therapeutic efficacy for glaucoma.

[0189] In some implementations, glaucoma patients begin treatment immediately upon diagnosis. In some implementations, the biodegradable ocular implant containing edonantan described herein is administered topically to the posterior part of the eye (e.g., using an intravitreal biodegradable ocular implant) at the following frequencies: 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).

[0190] In some embodiments, the biodegradable ocular implant described herein for treating glaucoma in subjects with this need comprises a biodegradable polymer (e.g., PLGA) that biodegrades substantially over the following time periods: approximately 1 month to approximately 24 months (e.g., approximately 2 months to approximately 24 months, approximately 5 months to approximately 24 months, approximately 7 months to approximately 10 months, approximately 10 months to approximately 24 months, approximately 12 months to approximately 24 months, approximately 15 months to approximately 24 months, approximately 17 months to approximately 24 months, approximately 20 months to approximately 24 months, and approximately 22 months to approximately 24 months). In some embodiments, the biodegradable polymer (e.g., PLGA) biodegrades substantially over the following time periods: approximately 3 months to approximately 12 months (e.g., approximately 4 months to approximately 12 months, 5 months to approximately 12 months, approximately 5 months to approximately 12 months, approximately 6 months to approximately 12 months, approximately 7 months to approximately 12 months, approximately 8 months to approximately 12 months, approximately 9 months to approximately 12 months, approximately 10 months to approximately 12 months, and approximately 11 months to approximately 12 months). In some embodiments, the biodegradable polymer (e.g., PLGA) biodegrades substantially within the following timeframes: approximately 12 months to approximately 18 months (e.g., approximately 13 months to approximately 18 months, approximately 14 months to approximately 18 months, approximately 15 months to approximately 18 months, approximately 16 months to approximately 18 months, approximately 17 months to approximately 18 months). In some embodiments, the biodegradable polymer (e.g., PLGA) biodegrades substantially within the following timeframes: approximately 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months.

[0191] Diabetic retinopathy (DR)

[0192] Diabetes can cause serious late-stage complications, which are classified as microvascular complications (retinopathy, neuropathy, and diabetic nephropathy) and macrovascular complications (cardiovascular disease). DR results from damage to the small blood vessels and neurons of the retina. The earliest changes leading to DR include narrowing of the retinal arteries associated with reduced retinal blood flow; dysfunction of the inner retinal neurons, followed later by changes in the function of the outer retina, associated with subtle changes in visual function; and dysfunction of the blood-retinal barrier (which protects the retina from many substances in the blood, including toxins and immune cells), leading to leakage of blood components into the retinal plexus. Subsequently, the basement membrane of the retinal vessels thickens, capillaries degenerate and lose cells, particularly pericytes and vascular smooth muscle cells. This leads to reduced blood flow and progressive ischemia, as well as microscopic aneurysms manifesting as balloon-like structures protruding from the capillary walls, which recruit inflammatory cells; and late-stage dysfunction and degeneration of retinal neurons and glial cells.

[0193] The ischemic and oxidative damage observed in DR affects blood flow and tissue ischemia, which can be reversed by the biodegradable ocular implant containing edonantan described herein. For the DR indication, improved retinal perfusion is expected to reduce hypoxia and inhibit the upregulation of vascular endothelial growth factor (VEGF), thereby helping to mitigate proliferative changes, neovascularization, and / or macular edema complications.

[0194] As an alternative model for ischemic retinopathy changes observed in DR, a preclinical mouse model of retinopathy of prematurity (ROP) can be used. Oxygen-induced mouse retinopathy is a reproducible and quantifiable model of proliferative retinal angiogenesis, suitable for examining the pathogenesis and therapeutic interventions of retinal neovascularization in ROP and other vascular pathologies, including DR. This model was induced, as previously described, by exposing one-week-old C57BL / 6J mice to 75% oxygen for 5 days, followed by exposure to room air (Smith LEH et al., Invest Ophthalmol Vis Sci 1994). The efficacy of this preclinical ROP model can be evaluated by studying retinal hypoxia and neovascularization. Current standard treatment for DR includes anti-VEGF therapy targeting only late vascular complications of the disease.

[0195] In some implementations, this treatment is initiated in patients with DR during the non-proliferative phase of the disease. In some implementations, the biodegradable ocular implant containing edonantan described herein is administered topically to the posterior part of the eye (e.g., using an intravitreal biodegradable ocular implant) at the following frequencies: 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).

[0196] In some embodiments, the biodegradable ocular implant described herein for treating DR in subjects with this need comprises a biodegradable polymer (e.g., PLGA) that biodegrades substantially over the following time periods: approximately 1 month to approximately 24 months (e.g., approximately 2 months to approximately 24 months, approximately 5 months to approximately 24 months, approximately 7 months to approximately 10 months, approximately 10 months to approximately 24 months, approximately 12 months to approximately 24 months, approximately 15 months to approximately 24 months, approximately 17 months to approximately 24 months, approximately 20 months to approximately 24 months, and approximately 22 months to approximately 24 months). In some embodiments, the biodegradable polymer (e.g., PLGA) biodegrades substantially over the following time periods: approximately 3 months to approximately 12 months (e.g., approximately 4 months to approximately 12 months, 5 months to approximately 12 months, approximately 5 months to approximately 12 months, approximately 6 months to approximately 12 months, approximately 7 months to approximately 12 months, approximately 8 months to approximately 12 months, approximately 9 months to approximately 12 months, approximately 10 months to approximately 12 months, and approximately 11 months to approximately 12 months). In some embodiments, the biodegradable polymer (e.g., PLGA) biodegrades substantially within the following timeframes: approximately 12 months to approximately 18 months (e.g., approximately 13 months to approximately 18 months, approximately 14 months to approximately 18 months, approximately 15 months to approximately 18 months, approximately 16 months to approximately 18 months, approximately 17 months to approximately 18 months). In some embodiments, the biodegradable polymer (e.g., PLGA) biodegrades substantially within the following timeframes: approximately 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months.

[0197] Retinal vein occlusion (RVO)

[0198] Retinal vein occlusion (RVO) is a retinal vascular disease currently treated with intravitreal injections of anti-VEGF drugs to inhibit growth factors that cause macular edema, and intravitreal injections of corticosteroids to combat the inflammatory components that cause edema. Ideally, RVO should be treated with the biodegradable ocular implants containing edonantan described herein, which improve tissue perfusion and reduce inflammation, while avoiding the adverse effects of systemic immunosuppression and / or the local adverse reactions of steroids.

[0199] RVO is currently treated with intravitreal steroids and anti-VEGF drugs. We believe that improving perfusion of existing vessels will reduce macular edema and the degree of VEGF upregulation, as well as the downstream maladaptive changes manifested as in RVO. To test efficacy, a preclinical mouse model of ischemic retinopathy can be used. Mouse oxygen-induced retinopathy is a reproducible and quantifiable model of proliferative retinal neovascularization suitable for examining the pathogenesis and therapeutic interventions of retinal neovascularization in many ischemic retinopathy diseases, including RVO. This model is induced by exposing 1-week-old C57BL / 6J mice to 75% oxygen for 5 days, followed by exposure to room air (as previously described) (Smith LEH et al., Invest OphasemolVis Sci 1994). The efficacy of this preclinical model of ischemic retinopathy can be evaluated by studying retinal hypoxia and neovascularization. The biodegradable ocular implant described in this article, containing a “therapeutic effective dose” of edonantan, could be added to current standards of care by improving tissue perfusion and reducing ET-1-mediated inflammation while avoiding the adverse effects of topical steroids. In some implementations of treatment for RVO, the biodegradable ocular implant described herein, containing edonantan, is administered topically to the posterior part of the eye using an intravitreal biodegradable ocular implant. The frequency of administration will vary depending on the patient's disease course and response to treatment.

[0200] In some embodiments, the biodegradable ocular implant containing edonantan described herein is administered topically to the posterior part of the eye at the following frequencies (e.g., using an intravitreal biodegradable ocular implant): 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).

[0201] In some embodiments, the biodegradable ocular implant described herein for treating RVOs in subjects requiring this treatment comprises a biodegradable polymer (e.g., PLGA) that biodegrades substantially over the following time periods: approximately 1 month to approximately 24 months (e.g., approximately 2 months to approximately 24 months, approximately 5 months to approximately 24 months, approximately 7 months to approximately 10 months, approximately 10 months to approximately 24 months, approximately 12 months to approximately 24 months, approximately 15 months to approximately 24 months, approximately 17 months to approximately 24 months, approximately 20 months to approximately 24 months, and approximately 22 months to approximately 24 months). In some embodiments, the biodegradable polymer (e.g., PLGA) biodegrades substantially over the following time periods: approximately 3 months to approximately 12 months (e.g., approximately 4 months to approximately 12 months, 5 months to approximately 12 months, approximately 5 months to approximately 12 months, approximately 6 months to approximately 12 months, approximately 7 months to approximately 12 months, approximately 8 months to approximately 12 months, approximately 9 months to approximately 12 months, approximately 10 months to approximately 12 months, and approximately 11 months to approximately 12 months). In some embodiments, the biodegradable polymer (e.g., PLGA) biodegrades substantially within the following timeframes: approximately 12 months to approximately 18 months (e.g., approximately 13 months to approximately 18 months, approximately 14 months to approximately 18 months, approximately 15 months to approximately 18 months, approximately 16 months to approximately 18 months, approximately 17 months to approximately 18 months). In some embodiments, the biodegradable polymer (e.g., PLGA) biodegrades substantially within the following timeframes: approximately 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months.

[0202] Retinopathy of prematurity (ROP)

[0203] Retinal vascular proliferative disorder (ROP) is a preterm retinal vascular proliferative disease. ROP remains a leading preventable cause of blindness and visual impairment worldwide. With improvements in perinatal care, increased survival rates for moderately preterm infants, and limited resources for oxygen delivery and monitoring, more mature preterm infants are developing severe ROP in developing countries.

[0204] The pathophysiology of retinopathy of prematurity (ROP) is characterized by two phases. Stage I ROP is caused by vascular occlusion that begins immediately after birth, secondary to a significant reduction in vascular endothelial growth factor (VEGF) and insulin-like growth factor-1 (IGF-1). Stage II begins around 33 weeks of postmenstrual age (PMA). In this stage, VEGF levels increase, especially when there is retinal hypoxia, increased retinal metabolism, and increased oxygen demand, leading to abnormal angiogenesis. For late-stage ROP, laser ablation of avascular retina, early treatment for ROP (ETROP), intravitreal injection of anti-VEGF antibodies (such as bevacizumab), and vitrectomy can be used to protect central vision and prevent retinal detachment. Long-term complications, such as refractory errors, ROP recurrence, and the risk of retinal detachment, require continuous follow-up by an ophthalmologist during adolescence and beyond.

[0205] ROP is caused by severe ischemia resulting from retinal vascular dysplasia secondary to preterm birth. Therefore, as an aspect of this invention, we believe that improving perfusion of existing vessels with the biodegradable ocular implant containing edonantan described herein will reduce ischemia and the degree of VEGF upregulation, as well as the downstream maladaptive changes manifested as in ROP. To test efficacy, a preclinical mouse model of ROP can be used. Mouse oxygen-induced retinopathy is a reproducible and quantifiable model of proliferative retinal neovascularization suitable for examining the pathogenesis and therapeutic interventions of ROP retinal neovascularization. This model is induced by exposing 1-week-old C57BL / 6J mice to 75% oxygen for 5 days, followed by exposure to room air (as previously described) (Smith LEH et al., Invest Ophasemol Vis Sci 1994). The efficacy of this preclinical ROP model can be evaluated by studying retinal hypoxia and neovascularization. The biodegradable ocular implant described herein, containing a "therapeutic effective dose" of edonantan, will complement current standards of care by improving tissue perfusion and reducing VEGF-induced pathological neovascularization. In some embodiments, the medication is administered topically to the posterior segment of the eye via intravitreal injection as needed, every 4 to 6 weeks, depending on the patient's disease course and response to treatment. For example, the intravitreal biodegradable ocular implant may be administered topically to the posterior segment of the eye via intravitreal injection as needed, every 5 weeks, depending on the patient's disease course and response to treatment.

[0206] In some implementations, patients with ROP begin this treatment during the non-proliferative phase of the disease. In some implementations, the biodegradable ocular implant containing edonantan described herein is administered topically to the posterior part of the eye (e.g., using an intravitreal biodegradable ocular implant) at the following frequencies: 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).

[0207] In some embodiments, the biodegradable ocular implant described herein for treating a subject with this need comprises a biodegradable polymer (e.g., PLGA) that biodegrades substantially over the following time periods: approximately 1 month to approximately 24 months (e.g., approximately 2 months to approximately 24 months, approximately 5 months to approximately 24 months, approximately 7 months to approximately 10 months, approximately 10 months to approximately 24 months, approximately 12 months to approximately 24 months, approximately 15 months to approximately 24 months, approximately 17 months to approximately 24 months, approximately 20 months to approximately 24 months, and approximately 22 months to approximately 24 months). In some embodiments, the biodegradable polymer (e.g., PLGA) biodegrades substantially over the following time periods: approximately 3 months to approximately 12 months (e.g., approximately 4 months to approximately 12 months, 5 months to approximately 12 months, approximately 5 months to approximately 12 months, approximately 6 months to approximately 12 months, approximately 7 months to approximately 12 months, approximately 8 months to approximately 12 months, approximately 9 months to approximately 12 months, approximately 10 months to approximately 12 months, and approximately 11 months to approximately 12 months). In some embodiments, the biodegradable polymer (e.g., PLGA) biodegrades substantially within the following timeframes: approximately 12 months to approximately 18 months (e.g., approximately 13 months to approximately 18 months, approximately 14 months to approximately 18 months, approximately 15 months to approximately 18 months, approximately 16 months to approximately 18 months, approximately 17 months to approximately 18 months). In some embodiments, the biodegradable polymer (e.g., PLGA) biodegrades substantially within the following timeframes: approximately 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months.

[0208] Age-related macular degeneration (AMD)

[0209] Age-related macular degeneration (AMD), also known as macular degeneration, is a degenerative disease affecting the central portion of the retina, leading to severe and irreversible vision loss. AMD is a common cause of vision loss in older adults, and its prevalence is increasing due to increased life expectancy. Clinically, AMD is classified from early (intermediate-sized drusen and retinitis pigmentosa) to late (neovascular and atrophic). AMD is a multifactorial disease involving complex interactions between aging, environmental risk factors, and genetic susceptibility. Chronic inflammation, lipid deposition, oxidative stress, and impaired maintenance of the extracellular matrix are closely related to the pathogenesis of AMD. However, the exact interactions of the pathophysiological events that ultimately lead to drusen formation and the associated degenerative processes remain to be elucidated. Despite significant advances in clinical care and the elucidation of pathophysiological mechanisms, unmet medical needs related to AMD remain substantial.

[0210] In some implementations, AMD is wet AMD. In some implementations, AMD is dry AMD.

[0211] Wet AMD is characterized by the presence of new blood vessels in the macula. Wet AMD occurs when abnormal blood vessels appear in the retina and under the macula. These vessels leak blood and fluid. Vision loss caused by wet AMD often progresses faster than that caused by dry AMD. Wet AMD can cause rapid and severe loss of central vision.

[0212] Dry AMD accounts for nearly 90% of all cases. It is caused by tiny yellow protein deposits called drusen forming beneath the macula. The accumulated deposits dry out and thin the macula. Vision loss caused by dry macular degeneration often occurs gradually.

[0213] Drusen are a characteristic manifestation of age-related macular degeneration (AMD). They are tiny, yellowish or white accumulations of extracellular material located between Bruch's membrane and the retinal pigment epithelium (RPE) in the eye. Drusen contain proteins and lipids (lipids are naturally occurring molecules, including fats). Patients with drusen deposits or other protein exudates in the eye are at risk of developing AMD. The deposition of drusen reduces the efficiency of oxygen, nutrient, and waste exchange between the RPE and the retinal choroidal plexus. Given the extremely high energy consumption of the retina and photoreceptor cells and their requirement for efficient oxygenation, a decrease in the RPE's ability to support photoreceptor cells and neural tissue can lead to stress on the retinal tissue and increase the risk of AMD.

[0214] In some implementations, patients with AMD begin this treatment during the non-proliferative phase of the disease. In some implementations, the biodegradable ocular implant containing edonantan described herein is administered topically to the posterior part of the eye (e.g., using an intravitreal biodegradable ocular implant) at the following frequencies: 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).

[0215] In some embodiments, the biodegradable ocular implant described herein for treating age-related macular degeneration in subjects with this need comprises a biodegradable polymer (e.g., PLGA) that biodegrades substantially over the following time periods: approximately 1 month to approximately 24 months (e.g., approximately 2 months to approximately 24 months, approximately 5 months to approximately 24 months, approximately 7 months to approximately 10 months, approximately 10 months to approximately 24 months, approximately 12 months to approximately 24 months, approximately 15 months to approximately 24 months, approximately 17 months to approximately 24 months, approximately 20 months to approximately 24 months, and approximately 22 months to approximately 24 months). In some embodiments, the biodegradable polymer (e.g., PLGA) biodegrades substantially over the following time periods: approximately 3 months to approximately 12 months (e.g., approximately 4 months to approximately 12 months, 5 months to approximately 12 months, approximately 5 months to approximately 12 months, approximately 6 months to approximately 12 months, approximately 7 months to approximately 12 months, approximately 8 months to approximately 12 months, approximately 9 months to approximately 12 months, approximately 10 months to approximately 12 months, and approximately 11 months to approximately 12 months). In some embodiments, the biodegradable polymer (e.g., PLGA) biodegrades substantially within the following timeframes: approximately 12 months to approximately 18 months (e.g., approximately 13 months to approximately 18 months, approximately 14 months to approximately 18 months, approximately 15 months to approximately 18 months, approximately 16 months to approximately 18 months, approximately 17 months to approximately 18 months). In some embodiments, the biodegradable polymer (e.g., PLGA) biodegrades substantially within the following timeframes: approximately 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months.

[0216] Map-like atrophy (GA)

[0217] Geographic atrophy (GA) is a medical term referring to a late-stage case of dry AMD. Symptoms of GA include, but are not limited to: decreased vision (reduced visual acuity), difficulty reading, difficulty driving, difficulty performing manual activities or any other activity that relies on central vision, scotomas or blind spots in central vision, difficulty seeing objects in dim light, and colors becoming dull or less vibrant.

[0218] GA is clinically easy to identify because it presents as a well-defined area of ​​retinal thinning compared to the surrounding retina, with a relative change in color, making the underlying choroidal vessels easier to observe. Pigmentation changes may occur around macular atrophy, manifesting as hypopigmentation or hyperpigmentation.

[0219] In some implementations, patients with GA begin this treatment during the non-proliferative phase of the disease. In some implementations, the biodegradable ocular implant containing edonantan described herein is administered topically to the posterior part of the eye (e.g., using an intravitreal biodegradable ocular implant) at the following frequencies: 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).

[0220] In some embodiments, the biodegradable ocular implant described herein for treating geographic atrophy in subjects with this need comprises a biodegradable polymer (e.g., PLGA) that biodegrades substantially over the following time periods: approximately 1 month to approximately 24 months (e.g., approximately 2 months to approximately 24 months, approximately 5 months to approximately 24 months, approximately 7 months to approximately 10 months, approximately 10 months to approximately 24 months, approximately 12 months to approximately 24 months, approximately 15 months to approximately 24 months, approximately 17 months to approximately 24 months, approximately 20 months to approximately 24 months, and approximately 22 months to approximately 24 months). In some embodiments, the biodegradable polymer (e.g., PLGA) biodegrades substantially over the following time periods: approximately 3 months to approximately 12 months (e.g., approximately 4 months to approximately 12 months, 5 months to approximately 12 months, approximately 5 months to approximately 12 months, approximately 6 months to approximately 12 months, approximately 7 months to approximately 12 months, approximately 8 months to approximately 12 months, approximately 9 months to approximately 12 months, approximately 10 months to approximately 12 months, and approximately 11 months to approximately 12 months). In some embodiments, the biodegradable polymer (e.g., PLGA) biodegrades substantially within the following timeframes: approximately 12 months to approximately 18 months (e.g., approximately 13 months to approximately 18 months, approximately 14 months to approximately 18 months, approximately 15 months to approximately 18 months, approximately 16 months to approximately 18 months, approximately 17 months to approximately 18 months). In some embodiments, the biodegradable polymer (e.g., PLGA) biodegrades substantially within the following timeframes: approximately 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months.

[0221] definition

[0222] As used herein, “about” will be understood by those skilled in the art and will vary to some extent depending on the context in which it is used. Where there is a usage of the term that is not clear to those skilled in the art, “about” will mean a particular term by a maximum of ±10%, given the context in which it is used.

[0223] As used herein, the term "effective amount" means an amount of compound sufficient to achieve a beneficial or desired result. An effective amount may be administered once or multiple times in an application or dose and is not intended to be limited to a particular formulation or route of administration. As used herein, the term "treatment" includes any effect, such as relief, reduction, regulation, improvement, or elimination, that results in improvement of a symptom, disease, disorder, etc., or improvement of its symptoms.

[0224] The terms "individual," "patient," or "subject" are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, with humans being the most preferred. The compounds of this invention can be administered to mammals, such as humans, but can also be administered to other mammals, such as animals requiring veterinary treatment, such as livestock (e.g., dogs, cats, etc.), farm animals (e.g., cattle, sheep, pigs, horses, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.). "Regulation" includes antagonism (e.g., inhibition), agonism, partial antagonism, and / or partial agonism.

[0225] As used herein, the term "pharmaceutically acceptable salt" refers to a salt in which an acidic or basic group may be present in the compound used in the composition. Basic compounds included in the compositions of this invention are capable of forming various salts with a variety of inorganic and organic acids. Pharmaceutically acceptable acid addition salts that can be used to prepare such basic compounds are those acids that form non-toxic acid addition salts, i.e., salts containing pharmaceutically acceptable anions, including but not limited to malates, oxalates, chlorides, bromides, iodides, nitrates, sulfates, hydrogen sulfates, phosphates, acid phosphates, isonicotinates, acetates, lactates, salicylates, citrates, tartrates, oleates, tannates, pantothenates, hydrogen tartrates, ascorbic acid salts, succinates, maleates, gentianates, fumarates, gluconates, glucurons, sucrose salts, formates, benzoates, glutamates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, and bis(hydroxynaphthyl)ate (i.e., 1,1'-methylene-di-(2-hydroxy-3-naphthylcarboxylate)). The acidic compounds contained in the compositions of the present invention are capable of forming basic salts with a variety of 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, including basic or acidic moieties, can also form pharmaceutically acceptable salts with various amino acids. The compounds disclosed herein can contain both acidic and basic groups; for example, an amino group and a carboxylic acid group. In this case, the compound can exist as an acid addition salt, a zwitterion, or a basic salt.

[0226] "Therapeutic effective amount" refers to the amount of the compound of the invention that is effective in treating the desired condition or disorder when administered alone or in combination. "Therapeutic effective amount" also refers to the amount of the claimed combination of compounds that is effective in treating the desired condition or disorder. Combinations of compounds can be additive, and are preferably synergistic. Synergistic effects, as described, for example, by Chou and Talalay, Adv. Enzyme Regul. 1984, 22:27-55, occur when the effect of the combined administration of compounds is greater than the additive effect of the compounds administered alone as single agents. Generally, synergistic effects are most pronounced at suboptimal concentrations of the compounds. Synergistic effects can manifest as a lower incidence of adverse side effects and / or toxicity, increased efficacy, or other beneficial effects compared to the individual components.

[0227] As used herein, the term “substantially” refers to the complete or near-complete extent or degree of an action, characteristic, property, state, structure, or result. For example, a “substantially” biodegradable polymer means that the object is completely or almost completely biodegradable.

[0228] Example

[0229] To provide a more complete understanding of the disclosure herein, the following embodiments are illustrated. The synthetic and biological embodiments described in this application are provided to illustrate the compounds, pharmaceutical compositions, and methods provided herein, and should not be construed as limiting their scope in any way.

[0230] Abbreviations: D: Distribution; DSC: Differential Scanning Calorimetry; LC: Standardized Amount; w / w: Weight Ratio; HPLC: High Performance Liquid Chromatography; PBS: Phosphate Buffered Saline; rpm: Revolutions per Minute; DR: Diabetic Retinopathy; GLP: Good Laboratory Practice; IVT: In Vitreous Body; IPA: Isopropanol; LC-MS: Liquid Chromatography-Mass Spectrometry; MS: Mass Spectrometer; PLGA: Poly(D,L-lactide-co-glycolic acid); RPE: Retinal Pigment Epithelial Cells; THF: Tetrahydrofuran; UPLC: Ultra-High Performance Liquid Chromatography; XRPD: X-ray Powder Diffraction.

[0231] Example 1. Preparation of Adonantan Implant I

[0232] The polymer (PLGA) was cryogenically ground to reduce particle size and achieve uniformity. Adonantan was prepared using, for example, a method disclosed in U.S. Patent No. 6,043,265. Then, crystalline form 4 of edonantan was prepared according to the method described in Example 6 herein. The edonantan was further sieved, ground, or micronized to adjust its particle size. The polymer and edonantan were mixed in a specific ratio, and the resulting powder mixture was fed into a heated Thermo Haake conical twin-screw extruder (85–88°C) equipped with a 3 mm die, and the extrudate was collected. The specific ratio of polymer to edonantan is shown in Table 1. The extrudate was broken into pieces of approximately 0.5 inches and placed in wide-mouth bottles. The pieces in the wide-mouth bottles were manually mixed and then fed a second time into a heated Thermo Haake conical twin-screw extruder (88–90°C) and extruded through a 1.54 mm die. The resulting extrudate was granulated and mixed. The mixed material is fed into the barrel of a Barrell custom plunger extruder, heated to the appropriate temperature (71 – 74°C), and then extruded through a 0.325 mm die (actual filament diameter 0.345 mm). The die diameter can be adjusted according to processing conditions to achieve the target filament diameter. The extruded filament is then cut into 4 mm implants, each containing approximately 210 µg to 240 µg of edonantan.

[0233] Table 1. Edonantan formulations 1-5

[0234]

[0235] 1The total weight of the polymer in the implant is 55% w / w.

[0236] Edonantan particle size

[0237] The effect of edonanthant particle size on the release rate of implants prepared by the above processes (including twin-screw blending and plunger extrusion) was investigated. Three different particle size ranges were studied: (1) edonanthant passed through a 100-mesh sieve (150 µm); (2) milled edonanthant; and (3) micronized edonanthant. Tables 2a, 2b, and 2c summarize the particle size ranges. Figure 1 The effect of particle size on the release rate of edonantan in implant formulations 2, 3, and 5 was shown. The effect of edonantan particle size on the release rate remained consistent for each different PLGA composition tested.

[0238] Table 2a. a Particle size distribution of edonantan particles prepared by sieving

[0239]

[0240] a “D” refers to the distribution.

[0241] b Particle size distribution was analyzed using a Mastersizer 3000 medium-volume sample cell. 80 mg of edonantane was added to 120 mL of dispersant (0.1% Span 80 in hexane solution), and the results were calculated as the average of 5 measurements.

[0242] c Only materials that pass through a 100-mesh sieve are used to prepare the biodegradable ocular implant.

[0243] Table 2b. a Particle size distribution of edonantan particles prepared by grinding

[0244]

[0245] a “D” refers to the distribution.

[0246] b Particle size distribution was analyzed using a Mastersizer 3000 small-volume sample cell. 1 mL of dispersant (0.1% Span 80 in hexane solution) was added to 10 mg of edonantane, and the results were calculated as the average of 5 measurements.

[0247] Table 2c. a Particle size distribution of adonantan particles prepared by micronization

[0248]

[0249] a “D” refers to the distribution.

[0250] b Particle size distribution analyzed using an LS-909 laser particle size analyzer.

[0251] PLGA % Residual Monomer

[0252] The effect of the percentage of residual monomers in PLGAs with similar viscosities was investigated. The particle size, PLGA composition, PLGA ratio, and percentage of residual monomers in each PLGA for formulations 1-5 are described in Tables 3a and 3b. The study found that differences in the percentage of residual monomers in the polymers affected the release rate of idonanthan from the PLGA matrix. Figure 2 As shown, maintaining the percentage of residual monomers at ≤ 0.5% is crucial for sustaining the release duration of edonantan implants.

[0253] Table 3a. Particle size and PLGA of edonantane in formulations 1, 3, and 5

[0254]

[0255] 1 The total weight of the polymer in the implant is 55% w / w.

[0256] a The approximate monomer composition of D,L-lactide + glycolide.

[0257] Table 3b. Particle size and PLGA of edonantane in formulations 2 and 4

[0258]

[0259] 1 The total weight of the polymer in the implant is 55% w / w.

[0260] a The approximate monomer composition of D,L-lactide + glycolide.

[0261] Example 2. In vitro drug release characteristics of formulations 1-5

[0262] For in vitro drug release testing, six implants were randomly cut from the extruded filaments of each formulation in Table 1 and placed in 3 mL of PBS containing 0.1% Tween at pH 7.4. The implants were incubated in a constant-temperature shaking incubator at 39°C and 50 rpm. Drug release profiles of the implants were sampled at specified time points, and the released edonantan content was analyzed using the HPLC method described below. At each sampling time point, the release medium was completely replaced with fresh medium. Figure 3 The in vitro drug release curves are shown. Figure 4 The daily release rate is displayed.

[0263] HPLC determination

[0264] The samples were analyzed by reversed-phase chromatography using a Waters XBridge C18 column and a mobile phase of 0.1% formic acid in aqueous solution and 0.1% formic acid in acetonitrile. Detection was performed over 2.5 minutes using a linear gradient of aqueous solution from 55% to 5%, at a detection wavelength of 275 nm. The samples were evaluated using an external standard prepared from the analytical reference material.

[0265] Example 3. Preparation of Erdonantan Implant II

[0266] The polymer was cryogenically ground to reduce particle size. Adonantan was prepared using, for example, the method disclosed in U.S. Patent No. 6,043,265, and the adonantan was further micronized to adjust the particle size. The polymer and adonantan were mixed in a specific ratio, and the resulting powder mixture was fed into a heated Thermo Haake twin-screw extruder (95°C, 10 rpm screw speed) equipped with a 1.96 mm die, and the extrudate was collected. The specific ratio of polymer to adonantan is shown in Table 4. The extrudate was broken into small pieces of about 1 / 8 inch and placed in a wide-mouth bottle. The small pieces in the wide-mouth bottle were manually mixed and then fed a second time into a heated twin-screw extruder (110°C) and extruded through a 0.31–0.33 mm die at 100–120°C and a screw speed of 4–10 rpm (actual filament diameter 0.321–0.356 mm). The die diameter can be adjusted according to processing conditions to obtain the target filament diameter. The extruded filament is then cut into 4 mm implants, each containing approximately 185 µg to 225 µg of adonantan.

[0267] Table 4. Eldonantan formulations 6-7

[0268]

[0269] 1 The total weight of the polymer in the implant is 55% w / w.

[0270] a The approximate monomer composition of D,L-lactide + glycolide.

[0271] Edonantan particle size

[0272] Table 5 summarizes the particle size distribution of edonantane in formulations 6–7.

[0273] Table 5. a Particle size distribution of adonantan particles prepared by micronization

[0274]

[0275] a “D” refers to the distribution.

[0276] b Particle size distribution analyzed using the HELOS particle size analyzer.

[0277] Example 4. Comparative study

[0278] The in vivo edonantan release profile of the biodegradable ocular implant (“solvent-cast implant”) prepared by solvent casting, disclosed in U.S. Patent Application No. 18 / 060,503 (“503 application”), was compared with the release profile of the biodegradable implant prepared by the methods described in Examples 1 and 3 herein. In this study, the solvent-cast implant (in… Figure 5 The solvent-cast implants (referred to as the "solvent process") consist of 45% w / w edonantan and a polymer matrix composed of 10% RG502, 50% RG503, and 40% RG753S. These solvent-cast implants were prepared using the solvent casting process as described in application '503, followed by cryogenic grinding and injection molding. The implants were then implanted into the ocular tissue of rabbits (see Example 5 for the rabbit model used in the test). The implants were removed from the vitreous body at different time points, soaked in acetonitrile overnight, and then analyzed by HPLC. The samples were analyzed by reversed-phase chromatography using a Waters XBridge C18 column with a mobile phase of 0.1% formic acid in aqueous solution and 0.1% formic acid in acetonitrile. Detection was performed over 2.5 minutes using a linear gradient of aqueous solution from 55% to 5% at a detection wavelength of 275 nm. The samples were evaluated using an external standard prepared from an analytical reference material. Comparison of in vivo edonantan release curves for different implants, as follows: Figure 5 As shown.

[0279] Example 5. Pharmacokinetic studies

[0280] I. 10-week ocular pharmacokinetic study of edonantan intravitreal implant in rabbits

[0281] In a 10-week non-GLP ocular pharmacokinetic study in rabbits, two edonantan intravitreal implants prepared using polymers derived from RESOMER or VIATEL (RESOMER polymer implant total weight 526 µg / implant, 474 µg / 2 implants; VIATEL polymer implant total weight 489 µg / implant, 440 µg / 2 implants) were administered via a single bilateral intravitreal (IVT) injection (2 animals and 4 eyes at each time point). The implant contained 45% edonantan, mixed with RESOMER® containing 50% RG503, 10% RG502 and 40% RG753S, or VIATEL™ containing 50% DLG 5003E, 10% DLG 5002E and 40% DLG 7505E. Rabbits were euthanized at weeks 4, 7, 8, and 10 (week 7 only for the VIATEL group and week 10 only for the RESOMER group), and drug concentrations in the aqueous humor, lens, retina, and RPE / choroid were measured.

[0282] The content of edonantan in ocular tissues was analyzed using an analytical method based on protein precipitation and liquid-liquid extraction, followed by reversed-phase LC-MS / MS analysis. Analysis was performed using an Agilent 1290UPLC coupled with an Agilent 6430 triple quadrupole mass spectrometer. The quantitative range for edonantan was 0.1 to 350 ng / mL. Tissue samples were homogenized and extracted with acetonitrile in 0.1% formic acid, which contained approximately 10 ng / mL of deuterated edonantan. After quantitative conversion of edonantan (m / z 537.2 to 439.1) and deuterated edonantan (m / z 540.2 to 442.1), the extracts were separated by reversed-phase liquid chromatography and detected by tandem mass spectrometry in positive ion mode.

[0283] In RESOMER® implants, intravitreal sustained-release delivery of 45% edonantan has demonstrated sustained therapeutic target tissue levels of edonantan during the study period. Figure 6 and Figure 7 At week 10, 99% of the cumulative amount of edonantan released from the implant was achieved (Table 6). In Viatel TM In implants, intravitreal sustained-release delivery of 45% edonantan demonstrated sustained therapeutic target tissue levels of edonantan within 8 weeks. Figure 6 and Figure 7 At week 8, the cumulative total amount of edonantan released from the implant was 100% (Table 6).

[0284] Table 6. Cumulative release of edonantan from the intravitreal implant during 10 weeks of ocular pharmacokinetics in rabbits.

[0285]

[0286] II. 12-week ocular pharmacokinetic study of edonantan intravitreal implant in rabbits

[0287] In a 12-week non-GLP ocular pharmacokinetic study in rabbits, two edonantan intravitreal implants prepared using the method described in Example 1 with ground or micronized API particles (total weight of micronized implants: 529 µg edonantan / implant, 476 µg edonantan / 2 implants; total weight of ground implants: 523 µg edonantan / implant, 470 µg edonantan / 2 implants) were administered via a single bilateral intravitreal injection (2 animals and 4 eyes at each time point, and 4 animals and 8 eyes at week 10 of the micronization study). The implants contained 45% edonantan (micronized or ground) mixed in RESOMER® containing 50% RG503, 10% RG502, and 40% RG753S. Rabbits were euthanized at weeks 4, 8, and 12, and drug concentrations in the aqueous humor, lens, retina, and RPE / choroid were measured.

[0288] The content of edonantan in ocular tissues was analyzed using an analytical method based on protein precipitation and liquid-liquid extraction, followed by reversed-phase LC-MS / MS analysis. Analysis was performed using an Agilent 1290UPLC coupled with an Agilent 6430 triple quadrupole mass spectrometer. The quantitative range for edonantan was 0.1 to 350 ng / mL. Tissue samples were homogenized and extracted with acetonitrile in 0.1% formic acid, which contained approximately 10 ng / mL of deuterated edonantan. After quantitative conversion of edonantan (m / z 537.2 to 439.1) and deuterated edonantan (m / z 540.2 to 442.1), the extracts were separated by reversed-phase liquid chromatography and detected by tandem mass spectrometry in positive ion mode.

[0289] Intravitreal sustained-release delivery of 45% edonantan (micronized) implants demonstrated sustained therapeutic target tissue levels of edonantan during the study period. Figure 8 and Figure 9 At week 11, the cumulative total amount of edonantan released from the (micronized) implant was 100% (Table 7). Intravitreal sustained-release delivery of 45% edonantan (micronized) implants demonstrated sustained therapeutic target tissue levels of edonantan within 10 weeks. Figure 8 and Figure 9At week 10, the cumulative total amount of edonantan released from the (ground) implant was 100% (Table 7).

[0290] Table 7. Cumulative release of edonantan from the intravitreal implant during 12 weeks of ocular pharmacokinetics in rabbits.

[0291]

[0292] III. 12-week ocular pharmacokinetic study of edonantan intravitreal implant in rabbits

[0293] In a 12-week non-GLP ocular pharmacokinetic study in rabbits, two edonantane intravitreal implants (containing polymer ratios of 50 / 10 / 40 RG503 / RG502 / RG753S or 30 / 70 RG503 / RG753S) prepared by twin-screw extrusion according to the method described in Example 3 (total weight of 50 / 10 / 40 RG503 / RG502 / RG753S implants: 415 µg edonantane / implant, 374 µg edonantane / 2 implants; total weight of 30 / 70 RG503 / RG753S implants: 501 µg edonantane / implant, 451 µg edonantane / 2 implants) were administered via a single bilateral intravitreal injection (2 animals and 4 eyes at each time point; 4 animals and 8 eyes in the 50 / 10 / 40 polymer ratio group at week 10). The implant contains 45% micronized edonantan, mixed with either 50% RG503, 10% RG502 and 40% RG753S in RESOMER® or 30% RG503 and 70% RG753S. Rabbits were euthanized at weeks 4, 6, 7, 8, 10 and 12, and drug concentrations in the aqueous humor, lens, retina and RPE / choroid were measured.

[0294] The content of edonantan in ocular tissues was analyzed using an analytical method based on protein precipitation and liquid-liquid extraction, followed by reversed-phase LC-MS / MS analysis. Analysis was performed using an Agilent 1290UPLC coupled with an Agilent 6430 triple quadrupole mass spectrometer. The quantitative range for edonantan was 0.1 to 350 ng / mL. Tissue samples were homogenized and extracted with acetonitrile in 0.1% formic acid, which contained approximately 10 ng / mL of deuterated edonantan. After quantitative conversion of edonantan (m / z 537.2 to 439.1) and deuterated edonantan (m / z 540.2 to 442.1), the extracts were separated by reversed-phase liquid chromatography and detected by tandem mass spectrometry in positive ion mode.

[0295] Intravitreal sustained-release delivery of 45% edonantan (50 / 10 / 40 polymer ratio) implants has demonstrated sustained therapeutic target tissue levels of edonantan within 10 weeks. Figure 10 and Figure 11 At week 10, the cumulative amount of edonantan released from the (50 / 10 / 40 polymer ratio) implant was 99.7% (Table 8).

[0296] Table 8. Cumulative release of edonantan from the intravitreal implant during 12 weeks of ocular pharmacokinetics in rabbits.

[0297]

[0298] Example 6. The crystal form of Adonantan

[0299] Exemplary method for preparing crystal form 1

[0300] Amorphous edonantan (840 mg) was dissolved in 12 mL IPA. The resulting solution was filtered and the filter was washed with another 2.5 mL of IPA. The filtrate was concentrated to dryness, dissolved in 11.8 mL IPA, and heated to 60 °C with stirring. Then, while stirring vigorously, 18 mL of warm water was added dropwise at 60 °C, 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 provide 660 mg of crystal form 1 (XRPD and DSC were respectively...). Figure 13 and Figure 17 middle).

[0301] Exemplary method for preparing crystal form 2

[0302] Amorphous edonantan (250 mg) was dissolved in 3.5 mL IPA. The resulting solution was filtered and the filter was washed with another 0.25 mL IPA. The solution was then heated to 60 °C, followed by the addition of 7.5 mL of warm water at 60 °C with vigorous stirring, and then stirred at 60 °C for 1 hour. After slow cooling to 25 °C, the mixture was filtered to provide crystal form 2 (XRPD and DSC were respectively dissolved in...). Figure 14 and Figure 18 (Middle). Alternatively, a preferred method for preparing crystal form 2 is as follows: Amorphous edonanthantan (1 g) is slurried in 20 mL of water at 25°C for 15 hours. The solution is then filtered to obtain crystal form 2 (XRPD and DSC are respectively ). Figure 14 and Figure 18 middle).

[0303] Exemplary method for preparing crystal form 3

[0304] Amorphous edonantan (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 at 60 °C while stirring vigorously. 0.1 mL of ethyl acetate was added to the slightly turbid solution to obtain a clear solution, which was then stirred at 60 °C for 1 hour. The solution was slowly cooled to 25 °C and the resulting precipitate was filtered to provide crystal form 3 (XRPD and DSC were respectively in…). Figure 15 and Figure 19 middle).

[0305] Exemplary method for preparing crystal form 4

[0306] Amorphous edonantane (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 provide crystal form 4, via XRPD (…). Figure 16 ) and DSC ( Figure 20 This confirms that the crystal form is different from crystal forms 1, 2 and 3.

[0307] In an alternative method, 107 mg of amorphous edonantane was added to 1 mL of water, followed by an equivalent amount of KOH in 1 mL of water. The resulting solution was heated to 60 °C and held for 20 minutes, then warm-filtered 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 crystal form 4, which was confirmed by XRPD.

[0308] In an alternative method, 150 mg of edonantan (crystal 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. XRPD analysis confirmed that the sample was crystal form 4, indicating that crystal form 4 is thermodynamically more stable than crystal form 3 under these conditions.

[0309] In an alternative method, 200 mg of edonantane (crystal 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 resulting sample was confirmed as crystal form 4 by XRPD analysis, demonstrating that crystal form 4 is thermodynamically more stable than crystal form 1 under these conditions.

[0310] In an alternative method, 100 mg of amorphous edonantane 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 crystal form 4. In another method, amorphous (crude) edonantane was dissolved in 8 volumes of isopropanol at 60°C. The resulting solution was cooled to 57°C, and then small crystals of crystal form 4 were added. After 2 hours, the solution was cooled to 5°C, allowed to stand for 15 hours, and filtered to obtain crystal form 4.

[0311] XRPD diagram of crystal form

[0312] XRPD spectra of crystal forms 1–4 are shown in Figure 12 – 16. XRPD patterns of the crystal form described herein were recorded using a polycrystalline X-ray diffractometer (Bruker, D8 ADVANCE). The CuKa radiation was applied at a voltage of 40 kV and a current of 40 mA, with a transmission slit of 1.0 mm and a cable-stayed slit angle of 0.4°. The sample was placed in the center of the sample holder recess, with the sample holder surface flush with the sample holder surface. Data were collected using a LynxEye detector with continuous scanning at 0.02° steps and a rate of 8° / min.

[0313] Tables 9-12 below list some XRPD characteristic peaks for crystal forms 1-4, respectively.

[0314] Table 9. Exemplary XRPD diagrams of crystal form 1

[0315]

[0316] Table 10. Exemplary XRPD diagrams of crystal form 2

[0317]

[0318] Table 11. Exemplary XRPD diagrams of crystal form 3

[0319]

[0320] Table 12. Exemplary XRPD diagrams of crystal form 4

[0321]

[0322] Physicochemical properties of crystal form

[0323] This article provides exemplary physicochemical properties of the crystal form. The melting point described herein can be measured using the following procedure:

[0324] i. Melting point scheme

[0325] The maximum melting point peak (T) of each crystal form was determined using DSC. m The DSC of the crystal form described herein was measured using a TA instrument DSC Q2000. A sample (1.3010 mg) was weighed into an aluminum crucible and heated from 30°C to 300°C at a heating rate of 10°C / min. The onset, peak initiation, peak maximum, and peak end temperatures of the crystal melting peak were collected.

[0326] The solubility described in this article can be measured using the following procedure:

[0327] ii. Solubility Analysis Scheme

[0328] 1. Weigh at least 2.0 mg of sample into the lower chamber of a Whatman Mini Uniprep vial (GE Healthcare). Add 450 µL of buffer to each chamber.

[0329] 2. Place the filter stopcock of the miniuniprep vial and press it to the liquid level position to allow the buffer and compound to come into contact with the filter during incubation.

[0330] 3. Vortex the sample for 2 minutes, then incubate at room temperature (approximately 25±2℃) with shaking at 500 rpm for 24 hours.

[0331] 4. Pressurize the miniunipreps to prepare the filtrate for injection into the HPLC system. Before filtration, check all vials for visible undissolved substances; after filtration, check for leaks.

[0332] 5. Dilute the supernatant 100 times with buffer solution to prepare a diluted solution, and analyze it by HPLC.

[0333] Table 13 below provides exemplary physicochemical properties for crystal forms 1–4. These physicochemical properties can be obtained using the methods described above.

[0334] Table 13. Exemplary physicochemical properties of crystal forms 1–4

[0335]

[0336] Equivalents and scope

[0337] In the claims, articles such as “a,” “an,” and “the” may indicate one or more, unless indicated to the contrary or clearly apparent from the context. The presence or use of, or association with, one, more, or all members of a product or method not explicitly shown, constitutes a satisfaction of a claim or description including “or” among one or more members of the group. The invention includes the presence, use, or other association of exactly one member of the group with a given product or method. The invention also includes the presence, use, or other association of one or more or all members of the group with a given product or method.

[0338] Furthermore, this invention includes all variations, combinations, and arrangements of one or more of the listed claims that introduce one or more limitations, elements, clauses, and descriptive terms different from other claims. For example, any claim dependent on another claim may be modified to include one or more limitations found in any other claim dependent on the same basic claim. Where elements are presented in list form (e.g., in Markush group format), each subgroup of elements is also disclosed, and any element may be removed from the group. It should be understood that where a particular embodiment or aspect of the invention is generally described as including a specific element and / or feature, that particular embodiment or aspect of the invention is constituted by, or erroneously constituted by, such element and / or feature. For simplicity, such embodiments are not specifically described in this specification. Furthermore, it should be noted that the terms “comprising” and “containing” are intended to be open-ended and allow for the inclusion of additional elements or steps. The given scope includes endpoints. Furthermore, values ​​expressed as scopes may take any specific value or lower limit range up to one-tenth of the lower unit in other embodiments of the invention (scopes not explicitly indicated by the context), unless otherwise stated or clearly understood by one of the art from the context.

[0339] This application relates to various granted patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference in their entirety. In the event of any conflict between any incorporated reference and this specification, this specification shall prevail. Furthermore, any particular embodiment of the invention falling within the scope of the prior art may be expressly excluded from any one or more claims. This is because such embodiments are considered known to those skilled in the art, and may be excluded even if not expressly stated in this specification. Any particular embodiment of the invention may be excluded from the claims for any reason, regardless of the presence or absence of prior art.

[0340] Those skilled in the art can identify and confirm various equivalents of the specific embodiments described in this specification through routine experiments. The scope of the specific embodiments described herein is not intended to be limited to the foregoing description, but rather depends on the appended claims. Those skilled in the art will understand that various changes and modifications can be made to this description without departing from the spirit or scope of the invention as defined in the appended claims.

Claims

1. Biodegradable ocular implants, comprising: (i) Adonantan or a pharmaceutically acceptable salt thereof; and (ii) Biodegradable polymers, The particle size distribution of said adonantan or its pharmaceutically acceptable salt is characterized by a D90 of about 9 µm to about 250 µm.

2. The biodegradable ocular implant of claim 1, wherein the particle size distribution of said adonantan or a pharmaceutically acceptable salt thereof is characterized by a D90 of about 9 µm to about 125 µm.

3. The biodegradable ocular implant according to claim 1 or 2, wherein the particle size distribution of said adonantan or its pharmaceutically acceptable salt is characterized by a D90 of about 9 µm to about 15 µm.

4. The biodegradable ocular implant according to any one of claims 1-3, wherein the particle size distribution of said adonantan or a pharmaceutically acceptable salt thereof is further characterized in that the D50 is from about 2.5 µm to about 150 µm.

5. The biodegradable ocular implant according to any one of claims 1–4, wherein the particle size distribution of said adonantan or a pharmaceutically acceptable salt thereof is further characterized by a D50 of about 2.5 µm to about 40 µm.

6. The biodegradable ocular implant according to any one of claims 1–5, wherein the particle size distribution of said adonantan or a pharmaceutically acceptable salt thereof is further characterized in that the D50 is about 2.5 µm to about 6 µm.

7. The biodegradable ocular implant according to any one of claims 1–6, wherein the particle size distribution of said adonantan or a pharmaceutically acceptable salt thereof is further characterized in that the D10 is from about 0.5 µm to about 90 µm.

8. The biodegradable ocular implant according to any one of claims 1–7, wherein the particle size distribution of said adonantan or a pharmaceutically acceptable salt thereof is further characterized in that the D10 is from about 0.5 µm to about 10 µm.

9. The biodegradable ocular implant according to any one of claims 1-8, wherein the particle size distribution of said adonantan or a pharmaceutically acceptable salt thereof is further characterized in that the D10 is from about 0.5 µm to about 2 µm.

10. A biodegradable ocular implant according to any one of claims 1–9, comprising about 20% w / w to about 60% w / w edonantan or a pharmaceutically acceptable salt thereof.

11. A biodegradable ocular implant according to any one of claims 1-10, comprising about 40% w / w to about 50% w / w of edonantan or a pharmaceutically acceptable salt thereof.

12. A biodegradable ocular implant according to any one of claims 1–11, comprising about 45% w / w edonantan or a pharmaceutically acceptable salt thereof.

13. The biodegradable ocular implant according to any one of claims 1-12, wherein the adonantan exists as a crystalline anhydrous form in its free base form.

14. A biodegradable ocular implant according to any one of claims 1-13, comprising about 40% w / w to about 80% w / w of the biodegradable polymer.

15. A biodegradable ocular implant according to any one of claims 1-14, comprising about 50% w / w to about 60% w / w of the biodegradable polymer.

16. A biodegradable ocular implant according to any one of claims 1-15, comprising about 55% w / w of the biodegradable polymer.

17. A biodegradable ocular implant according to any one of claims 1-16, wherein the biodegradable polymer comprises one or more poly(lactic-co-glycolic acid) (PLGA) polymers.

18. The biodegradable ocular implant of claim 17, wherein the one or more PLGA polymers are selected from RG502, RG503, RG753S, DLG5002E, DLG5003E, DLG7505E and combinations thereof.

19. A biodegradable ocular implant according to any one of claims 1-18, wherein the biodegradable polymer comprises PLGA RG503 and PLGA RG753S.

20. The biodegradable ocular implant of claim 19, comprising about 16.5% w / w PLGA RG503 and about 38.5% w / w PLGA RG753S.

21. A biodegradable ocular implant according to any one of claims 1-18, wherein the biodegradable polymer comprises PLGA RG502, PLGA RG503 and PLGA RG753S.

22. The biodegradable ocular implant of claim 21, comprising about 5.5% w / w PLGA RG502, about 27.5% w / w PLGA RG503 and about 22% w / w PLGA RG753S.

23. The biodegradable ocular implant according to any one of claims 1-18, wherein the biodegradable polymer comprises PLGA DLG5002E, PLGA DLG5003E and PLGA DLG7505E.

24. The biodegradable ocular implant of claim 23, comprising about 5.5% w / w PLGA DLG5002E, about 27.5% w / w PLGA DLG5003E and about 22% w / w PLGA DLG7505E.

25. A biodegradable ocular implant according to any one of claims 17-24, wherein each of one or more PLGA polymers present in the biodegradable ocular implant contains no more than about 0.5% w / w of residual monomer.

26. The biodegradable ocular implant according to any one of claims 1-25, wherein the biodegradable ocular implant is about 4 mm in length.

27. A biodegradable ocular implant according to any one of claims 1–26, wherein the diameter of the biodegradable ocular implant is from about 300 µm to about 360 µm.

28. A biodegradable ocular implant according to any one of claims 1–26, wherein the biodegradable ocular implant comprises about 180 µg to about 250 µg of adonantan.

29. A method for preparing a biodegradable ocular implant, said biodegradable ocular implant comprising edonantan or a pharmaceutically acceptable salt thereof and a biodegradable polymer, said method comprising: (a) Grinding the biodegradable polymer; (b) Reduce the particle size of the edonantan or a pharmaceutically acceptable salt thereof to form treated edonantan or a pharmaceutically acceptable salt thereof; (c) The milled biodegradable polymer is mixed with treated adonantan or a pharmaceutically acceptable salt thereof to form a blend; (d) The blend is hot-melt extruded to form the biodegradable ocular implant.

30. The method of claim 29, wherein in step (a), the biodegradable polymer is cryogenically milled.

31. The method of claim 29 or 30, wherein in step (a), the biodegradable polymer comprises one or more PLGA polymers.

32. The method of claim 31, wherein the one or more PLGA polymers are selected from RG502, RG503, RG753S, DLG5002E, DLG5003E, DLG7505E and combinations thereof.

33. The method according to any one of claims 29-32, wherein in step (a), the biodegradable polymer comprises PLGA RG503 and PLGA RG753S.

34. The method of claim 33, wherein in step (a), the biodegradable polymer comprises about 30% w / w PLGA RG503 and about 70% w / w PLGA RG753S.

35. The method of any one of claims 29-32, wherein in step (a), the biodegradable polymer comprises PLGA RG502, PLGA RG503 and PLGA RG753S.

36. The method of claim 35, wherein in step (a), the biodegradable polymer comprises about 10% w / w PLGA RG502, about 50% w / w PLGA RG503 and about 40% w / w PLGA RG753S.

37. The method of any one of claims 29-32, wherein in step (a), the biodegradable polymer comprises PLGA DLG5002E, PLGA DLG5003E and PLGA DLG7505E.

38. The method of claim 37, wherein in step (a), the biodegradable polymer comprises about 10% w / w PLGA DLG5002E, about 50% w / w PLGA DLG5003E and about 40% w / w PLGA DLG7505E.

39. The method of any one of claims 29-38, wherein in step (b), reducing the particle size of the edonantan or a pharmaceutically acceptable salt thereof comprises passing the edonantan or a pharmaceutically acceptable salt thereof through a 100-mesh sieve.

40. The method of any one of claims 29-38, wherein in step (b), reducing the particle size of the edonantan or a pharmaceutically acceptable salt thereof comprises grinding the edonantan or a pharmaceutically acceptable salt thereof.

41. The method of any one of claims 29-38, wherein in step (b), reducing the particle size of the edonantan or a pharmaceutically acceptable salt thereof comprises micronizing the edonantan or a pharmaceutically acceptable salt thereof.

42. The method according to any one of claims 29-41, wherein in step (b), the particle size distribution of the treated adonantan or its pharmaceutically acceptable salt is characterized by a D90 of about 10 µm to about 250 µm.

43. The method according to any one of claims 29-42, wherein in step (b), the particle size distribution of the treated adonantan or its pharmaceutically acceptable salt is characterized by a D50 of about 2.5 µm to about 150 µm.

44. The method according to any one of claims 29-43, wherein in step (b), the particle size distribution of the treated adonantan or its pharmaceutically acceptable salt is characterized by a D10 of about 0.5 µm to about 90 µm.

45. The method according to any one of claims 29-44, wherein in step (b), the adonantan exists as a free base as an anhydrous crystalline substance both before and after grinding.

46. ​​The method according to any one of claims 29-45, wherein in step (d), hot-melt extrusion of the blend comprises: (i) The blend is hot-melt extruded at a temperature of about 95°C to form a first extrudate; (ii) The first extrudate is heat-melted and extruded at a temperature of about 100°C to about 120°C to form an extruded filament; and (iii) Cut the extruded filament to form the biodegradable ocular implant.

47. The method according to any one of claims 29-45, wherein in step (d), hot-melt extrusion of the blend comprises: (i) The blend is hot-melt extruded at a temperature of about 85°C to about 90°C to form a first extrudate; (ii) The first extrudate is hot-melt extruded at a temperature of about 88°C to about 90°C to form a second extrudate; (iii) The second extrudate is hot-melt extruded at a temperature of about 71°C to about 74°C to form an extruded filament; and (iv) Cut the extruded filament to form the biodegradable ocular implant.

48. A method for treating an eye disease in a subject with such need, the method comprising contacting the subject's ocular tissue with a biodegradable ocular implant according to any one of claims 1-28.

49. The method of claim 48, wherein the eye disease is selected from glaucoma, diabetic retinopathy, retinal vein occlusion, retinopathy of prematurity, geographic atrophy, and age-related macular degeneration.

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