Intraocular implants highly filled with prostamide

Abstract

Biodegradable intraocular implants highly loaded with prostamide compounds for immediate and sustained reduction of intraocular pressure and treatment of glaucoma in a patient's eye are described.

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims priority to U.S. Provisional Patent Application No. 63 / 054,620, filed on July 21, 2021, the entire content of which is incorporated herein by reference. Intraocular implants highly filled with prostamide are described herein. In particular, devices and methods for treating a patient's eye, more specifically, intraocular implants that provide extended release of a therapeutic agent in an eye in which an implant is placed to treat glaucoma, such as by reducing or at least maintaining intraocular pressure (IOP), and methods of manufacturing and using such implants are described herein.

Background Art

[0002] Agents for reducing intraocular pressure are useful in many different glaucoma conditions, such as the onset of glaucoma after surgery and after laser trabeculoplasty, in the treatment of glaucoma, and as preoperative adjuvants. Glaucoma is an eye disease often characterized by elevated intraocular pressure. Glaucoma is classified as primary or secondary based on its etiology. For example, primary glaucoma in adults (congenital glaucoma) can be either open - angle or acute or chronic closed - angle glaucoma. Secondary glaucoma results from existing eye diseases such as uveitis, intraocular tumors, or advanced cataracts. The elevated intraocular pressure in glaucoma is due to the obstruction of the outflow of aqueous humor. In chronic open - angle glaucoma, the anterior chamber and its anatomical structures appear essentially normal, but the drainage of aqueous humor is obstructed. In acute or chronic closed - angle glaucoma, the anterior chamber is shallow, the filtration angle is narrow, and the iris can block the trabecular meshwork at the entrance of Schlemm's canal. Dilation of the pupil can push the root of the iris forward against the angle, causing pupillary block and thus an acute attack. Eyes with a narrow anterior chamber angle are prone to acute closed - angle glaucoma attacks of various severities.

[0003] Secondary glaucoma is caused by obstruction of the flow of aqueous humor from the posterior chamber to the anterior chamber and then to Schlemm's canal. Inflammatory diseases of the anterior segment can obstruct aqueous humor outflow by causing complete posterior synechiae in the bulging iris, and the drainage channels can be blocked by exudate. Other common causes include intraocular tumors, advanced cataracts, central retinal vein occlusion, eye trauma, surgery, and intraocular hemorrhage. Lowering intraocular pressure can help prevent glaucoma or blindness caused by glaucoma. Currently, eye drops containing therapeutic agents to lower intraocular pressure are prescribed to many patients, who may instill them once or multiple times a day to reduce the elevated intraocular pressure associated with glaucoma.

[0004] It is advantageous to provide an intraocular drug delivery system, such as an intraocular implant, and a method of using such a system, which can deliver therapeutic agents, such as antihypertensive agents (or IOP-lowering agents), at a sustained or controlled rate over an extended period, with little or no negative side effects, in a certain amount (i.e., extended release rather than burst release), thereby lowering intraocular pressure in the eyes of patients, including but not limited to those with glaucoma or at risk of developing glaucoma. The therapeutic agent can be delivered into the anterior chamber space or vitreous fluid and may be effective in the anterior or posterior part of the human eye. It is also advantageous to obtain a linear drug release profile over an extended period. Relatively high-fill implant delivery systems are desirable because they allow for a smaller implant size without reducing the effective amount of drug delivered. Additional parameters to consider when formulating an implantable delivery system include the rate and extent of drug release from the sustained-release implant, the degree to which the sustained-release implant swells when placed in an aqueous medium (compared to its initial size), and the biodegradation time of the implant after drug release is complete. To minimize the mass, dimensions, and injection frequency of the implant, it is necessary to simultaneously maximize drug filling, polymer erosion rate, and drug release duration. Typically, optimizing one component / factor often compromises others, making this practically challenging. [Overview of the project]

[0005] This disclosure relates to an extended, long-term reduction of intraocular pressure in an eye provided by the intraocular administration of one or more biodegradable intraocular implants. The biodegradable intraocular implants comprise or consist of biodegradable polymer materials and therapeutic agents associated with biodegradable polymer materials. The implants can be administered to the eye as monotherapy and can deliver a therapeutic agent directly to the ocular region of the eye in an amount effective in reducing elevated intraocular pressure (ocular hypertension) in the eye over an extended period. The implants can also be used to treat or prevent glaucoma or other medical conditions of the eye associated with elevated intraocular pressure. The therapeutic agents included in the intraocular implants of this disclosure contain, are essentially, or can be essentially, compounds that are effective in lowering intraocular pressure in eyes with high intraocular pressure. In some embodiments, the therapeutic agent contains or consists of compound 1.

[0006] [ka] compound 1 Accordingly, the present disclosure describes a biodegradable intraocular implant effective in reducing intraocular pressure in a patient's eye over an extended period of time, wherein the implant comprises or consists of a biodegradable polymer material and compound 1 or a pharmaceutically acceptable salt thereof, wherein compound 1 is present in an amount greater than 8% by mass, for example, 8-20% by mass (including 20% ​​by mass, for example, 9-18%, 9-17%, 9-16%, 9-15%, and 10-15%), greater than 11% by mass, greater than 12% by mass, or greater than 15% by mass of the implant. In some embodiments, the biodegradable intraocular implant comprises a biodegradable polymer material and compound 1 as a pharmaceutically active agent, and the intraocular implant does not contain any other pharmaceutically active agents or IOP-reducing agents other than compound 1.

[0007] Compound 1 can be associated with biodegradable polymer materials. Therefore, the compound can be mixed with biodegradable polymer materials, dissolved and / or dispersed within the material, encapsulated by the material, or bonded to the material. Compound 1 can be uniformly or non-uniformly dispersed within the biodegradable polymer material, or distributed throughout the material. Release of compound 1 from the implant after placement in the eye may occur by diffusion of compound 1, erosion or degradation of the polymer material, solubility, permeability, or any combination thereof.

[0008] The biodegradable intraocular implants described herein can be specifically sized and formulated for placement in an ocular region of the eye, such as the vitreous humor or anterior chamber, for the treatment of glaucoma and for reducing intraocular pressure, including elevated intraocular pressure (or ocular hypertension) in the eye. In some embodiments, after placement in the patient's eye, the biodegradable intraocular implant can continuously release compound 1 or a pharmaceutically acceptable salt thereof into the eye in vitro and / or in vivo for more than one month, for example, about 1 to about 3 months or more, about 3 to about 6 months or more. The implants of this disclosure are designed to release compound 1 in a controlled manner. In some embodiments, the implant provides a linear or substantially constant release rate of compound 1 over a period of more than one month, e.g., more than two months, one to three months, three to six months, or six to twelve months or longer.

[0009] One embodiment is an extruded pre-orbital biodegradable implant comprising about 8 to about 20% by mass (including 20%, for example, about 9 to about 18%, about 9 to about 17%, about 9 to 16%, about 9 to about 15%, and about 10 to about 15%) of compound 1, for example, about 11% by mass, about 12% by mass, or about 15% by mass, and optionally about 2 to about 6% by mass of hexadecane-1-ol (hexadecanol), the implant continuously releases compound 1 in vitro over a period of 2 to 5 months at 37°C in phosphate-buffered saline.

[0010] A biodegradable intraocular implant may contain a biodegradable polymer material and compound 1, i) compound 1 in an amount of about 8 to about 20% by mass of the implant (including 20%, for example, about 9 to about 18%, about 9 to about 17%, about 9 to about 16%, about 9 to about 15%, and about 10 to about 15% by mass), ii) the implant continuously releases compound 1 in the eye in vitro and / or in vivo for more than one month, and iii) the implant does not contain polyethylene glycol.

[0011] In some forms of this implant, the biodegradable polymer material comprises poly(D,L-lactide) (polymer 1) having acid-terminated groups and an intrinsic viscosity of 0.16–0.24 dl / g, poly(D,L-lactide) (polymer 2) having ester groups and an intrinsic viscosity of 0.25–0.35 dl / g, and poly(D,L-lactide-co-glycolide) copolymer (polymer 3) having ester-terminated groups, a molar ratio of D,L-lactide to glycolide of approximately 75:25 (e.g., 73:27–77:23), and an intrinsic viscosity of 0.16–0.24 dl / g, where the intrinsic viscosity of each polymer and copolymer is measured for a 0.1% solution of the polymer or copolymer in chloroform at 25°C. In some forms of this implant, polymer 1 is present in an amount of about 0 to about 20% by mass (e.g., about 4 to about 10% by mass or about 4 to about 20% by mass, e.g., about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, or about 20% by mass). In some forms of this implant, polymer 2 is present in a smaller amount than polymer 3, in an amount of about 20 to about 40% by mass (e.g., about 20 to about 30% by mass, e.g., about 20, about 25, about 30, about 35, or about 40% by mass). In some forms of this implant, polymer 3 is present in an amount of about 30 to about 70% by mass (e.g., about 35 to about 50% by mass, e.g., about 30, about 35, about 40, or about 45% by mass). In some forms of this implant, the mass ratio of polymer 2 to polymer 3 is 2:5 to 4:3, for example, 1:2 to 1:1, 1:2, 5:9, 5:8, 2:3, 3:4, 6:7, or 1:1. Biodegradable implants can be formulated to contain at least about 3 to about 10 μg (e.g., about 5 or about 7.5 μg) of compound 1 in an implant with a diameter of about 100 to about 200 μm (e.g., an implant with a diameter of about 150 μm).

[0012] One embodiment provides a method for lowering intraocular pressure in a patient requiring a reduction in intraocular pressure, comprising administering a pharmaceutical composition to the patient's eye, wherein the pharmaceutical composition comprises a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof. Several embodiments provide a method for lowering intraocular pressure in a patient requiring a reduction in intraocular pressure, comprising administering a pharmaceutical composition comprising a therapeutically effective amount of compound 1 to the patient's eye. Pharmaceutical compositions for lowering intraocular pressure are generally biocompatible with the eye and contain a therapeutically effective amount of compound 1 and pharmaceutically acceptable excipients. Biocompatible implants and polymers produce little to no toxic effects, are non-harmful or physiologically non-reactive, and do not induce an immune response.

[0013] Other embodiments provide a method for producing a biodegradable intraocular implant effective in lowering a patient's intraocular pressure, the implant comprising or consisting of a therapeutic agent, a biodegradable polymer material, and optionally one or more excipients, the method comprising, in order, a) blending the therapeutic agent with one or more biodegradable polymers and, if present, one or more excipients to form a mixture, b) extruding the mixture to form a filament, and c) cutting the filament to a length suitable for placement in the eye of a patient suffering from elevated intraocular pressure, thereby forming an intraocular implant. In certain embodiments, the filament is cut to a length suitable for placement in the anterior chamber of the eye. The therapeutic agent may include compound 1 as defined herein. In some cases, the therapeutic agent used in blending with the polymer (step a) may be in solid form. The mixture can be extruded at a temperature of about 60°C to about 150°C.

[0014] Further embodiments provide a device for implanting or injecting a biodegradable intraocular implant according to any embodiment described herein into the ocular region of the eye of a patient suffering from glaucoma or ocular hypertension (i.e., elevated intraocular pressure), wherein the device comprises an elongated housing having a longitudinal axis and a cannula extending longitudinally from the housing, the cannula having a lumen extending through the cannula, the lumen being configured to receive an intraocular implant, and the device further comprises an intraocular implant according to any embodiment described herein. The implant can be placed in or near the lumen of the cannula. In certain embodiments of the device, the dimensions of the cannula are the same as or less than those of a 21, 22, 25, 27, 28, or 30 gauge needle, and the cannula has an oblique or sharp tip to facilitate penetration of ocular tissue. In some embodiments, the outer and inner diameters of the cannula are less than or equal to the outer and inner diameters of a 25 or 27 gauge needle.

[0015] A method for delivering an intraocular implant to the eye of a patient suffering from glaucoma or elevated intraocular pressure using the above-described device, the device comprising a cannula having a proximal end, a distal sharp end, and a lumen extending through them, an intraocular implant selected from any of those described herein, and an actuator by which the operation of the actuator ejects the implant from the device, the cannula lumen being sized to receive the intraocular implant and to allow the implant to move through the lumen, the method also within the scope of the disclosure comprising the steps of inserting the cannula into the ocular region of the patient's eye and pressing down or activating the actuator to eject the implant from the cannula into the patient's eye. In some embodiments, the ocular region of the eye into which the implant is injected may be the anterior chamber or the vitreous humor. Some non-limiting illustrative embodiments are shown below. Exemplary Embodiment 1: A biodegradable intraocular implant comprising a biodegradable polymer material and compound 1,

[0016] [ka] Compound 1 A biodegradable intraocular implant in which Compound 1 is present in an amount of 10 - 20% by mass of the implant, and the implant continuously releases Compound 1 in vitro over a period of 2 - 6 months. Exemplary Embodiment 2: A biodegradable intraocular implant comprising a biodegradable polymer material and Compound 1,

[0017] [Chemical formula] Compound 1 A biodegradable intraocular implant in which Compound 1 is present in an amount of 10 - 20% by mass of the implant, and the implant releases less than 30% of Compound 1 in vitro during the first 24 hours.

[0018] Exemplary Embodiment 3: The biodegradable intraocular implant of Exemplary Embodiment 2, in which the implant releases less than 35% of Compound 1 in vitro during the first 24 hours. Exemplary Embodiment 4: The biodegradable intraocular implant of Exemplary Embodiment 2, in which the implant releases less than 20% of Compound 1 in vitro during the first 24 hours. Exemplary Embodiment 5: The biodegradable intraocular implant of Exemplary Embodiment 2, in which the implant releases less than 15% of Compound 1 in vitro during the first 24 hours. Exemplary Embodiment 6: The in vitro release of Compound 1 is measured in a phosphate buffered saline (PBS) solution at pH 7.4 ± 0.05 and 37°C, and the PBS solution contains no magnesium and calcium and has a pH of 7.4 ± 0.05 at 25°C. The biodegradable intraocular implant according to any one of Exemplary Embodiments 1 - 5. Exemplary Embodiment 7: A biodegradable intraocular implant comprising a biodegradable polymer material and Compound 1,

[0019] [Chemical formula] Compound 1 i) Compound 1 is present in an amount of 10-20% by mass of the implant; ii) the implant continuously releases Compound 1 in the eye for more than one month in vitro and / or in vivo; and iii) the implant is a biodegradable intraocular implant that does not contain polyethylene glycol.

[0020] Exemplary Embodiment 8: A biodegradable intraocular implant according to any one of Exemplary Embodiments 1 to 7, wherein the biodegradable polymer material comprises a first polymer which is poly(D,L-lactide) having acid-terminated groups and an intrinsic viscosity of about 0.16 to 0.24 dl / g; a second polymer which is poly(D,L-lactide) having ester-terminated groups and an intrinsic viscosity of about 0.25 to 0.35 dl / g; and a third polymer which is poly(D,L-lactide-co-glycolide) having ester-terminated groups, an intrinsic viscosity of about 0.16 to 0.24 dl / g, and a D,L-lactide:glycolide ratio of about 75:25, wherein the intrinsic viscosity of each polymer and copolymer is measured for a 0.1% solution of the polymer or copolymer in chloroform at 25°C. Exemplary Embodiment 9: A biodegradable intraocular implant comprising a biodegradable polymer material and compound 1,

[0021] [ka] compound 1 i) Compound 1 is present in an amount of 10-20% by mass of the implant; ii) The biodegradable polymer material comprises a first polymer which is poly(D,L-lactide) with acid-terminated groups and an intrinsic viscosity of about 0.16-0.24 dl / g; a second polymer which is poly(D,L-lactide) with ester-terminated groups and an intrinsic viscosity of about 0.25-0.35 dl / g; and a third polymer which is poly(D,L-lactide-co-glycolide) with ester-terminated groups, an intrinsic viscosity of about 0.16-0.24 dl / g, and a D,L-lactide:glycolide ratio of about 75:25, wherein the intrinsic viscosity of each polymer and copolymer is measured for a 0.1% solution of the polymer or copolymer in chloroform at 25°C; and (iii) the amount of the second polymer is less than or equal to the amount of the third polymer and is present in an amount of 20-40% by mass. Exemplary Embodiment 10: A biodegradable intraocular implant comprising a biodegradable polymer material and compound 1,

[0022] [ka] compound 1 i) Compound 1 is present in an amount of 10-20% by mass of the implant; ii) The biodegradable polymer material comprises a first polymer which is poly(D,L-lactide) with acid-terminated groups and an intrinsic viscosity of about 0.16-0.24 dl / g; a second polymer which is poly(D,L-lactide) with ester-terminated groups and an intrinsic viscosity of about 0.25-0.35 dl / g; and a third polymer which is poly(D,L-lactide-co-glycolide) with ester-terminated groups, an intrinsic viscosity of about 0.16-0.24 dl / g, and a D,L-lactide:glycolide ratio of about 75:25, wherein the intrinsic viscosity of each polymer and copolymer is measured for a 0.1% solution of the polymer or copolymer in chloroform at 25°C; and (iii) the mass ratio of the second polymer to the third polymer is 2:5-4:3.

[0023] Exemplary Embodiment 11: A biodegradable intraocular implant of Exemplary Embodiment 10, wherein the third polymer is present in an amount of about 30-70% by mass. Exemplary Embodiment 12: A biodegradable intraocular implant according to Exemplary Embodiment 10 or 11, wherein the first polymer is present in an amount of about 4 to 20% by mass. Exemplary Embodiment 13: A biodegradable intraocular implant according to any one of the Exemplary Embodiments 9-12, wherein the implant releases less than 30% of compound 1 in vitro during the first 24 hours. Exemplary Embodiment 14: A biodegradable intraocular implant of Exemplary Embodiment 13, wherein the implant releases less than 25% of compound 1 in vitro during the first 24 hours.

[0024] Exemplary Embodiment 15: A biodegradable intraocular implant of Exemplary Embodiment 13, wherein the implant releases less than 20% of compound 1 in vitro during the first 24 hours. Exemplary Embodiment 16: A biodegradable intraocular implant of Exemplary Embodiment 13, wherein the implant releases less than 15% of compound 1 in vitro during the first 24 hours. Exemplary Embodiment 17: A biodegradable intraocular implant according to any of Exemplary Embodiments 1 to 16, wherein the implant further comprises cetyl alcohol. Exemplary Embodiment 18: A biodegradable intraocular implant according to any of Exemplary Embodiments 1 to 17, wherein the implant further comprises butylated hydroxyanisole. Exemplary Embodiment 19: A biodegradable intraocular implant according to any of Exemplary Embodiments 1 to 19, wherein compound 1 is present in an amount of 11, 12, or 15% by mass of the implant. Exemplary Embodiment 20: Compound 1 in approximately 12% by mass,

[0025] [ka] compound 1 A biodegradable intraocular implant according to any one of the exemplary embodiments 1 to 19, comprising: a first polymer which is poly(D,L-lactide) having acid-terminated groups and an intrinsic viscosity of about 0.16 to 0.24 dl / g, a second polymer which is poly(D,L-lactide) having ester-terminated groups and an intrinsic viscosity of about 0.25 to 0.35 dl / g, a third polymer which is poly(D,L-lactide-co-glycolide) having ester-terminated groups and an intrinsic viscosity of about 0.16 to 0.24 dl / g and a D,L-lactide:glycolide ratio of about 75:25, about 5% by mass of cetyl alcohol, and about 2% by mass of butylated hydroxyanisole, wherein the intrinsic viscosities of the first, second, and third polymers correspond to those measured for a 0.1% solution of the polymers in chloroform at 25°C. Exemplary Embodiment 21: Compound 1 in approximately 12% by mass,

[0026] [ka] compound 1 A biodegradable intraocular implant comprising any one of the exemplary embodiments 1 to 20, wherein the intrinsic viscosities of the first, second, and third polymers correspond to those measured for a 0.1% solution of the polymers in chloroform at 25°C, comprising: a first polymer which is poly(D,L-lactide) having acid-terminated groups and an intrinsic viscosity of about 0.16 to 0.24 dl / g; a second polymer which is poly(D,L-lactide) having ester-terminated groups and an intrinsic viscosity of about 0.25 to 0.35 dl / g; a third polymer which is poly(D,L-lactide-co-glycolide) having ester-terminated groups and an intrinsic viscosity of about 0.16 to 0.24 dl / g and a D,L-lactide:glycolide ratio of about 75:25; about 5% by mass of cetyl alcohol; and about 2% by mass of butylated hydroxyanisole. Exemplary Embodiment 22: Approximately 15% by mass of compound 1,

[0027] [ka] compound 1 A biodegradable intraocular implant according to any one of the exemplary embodiments 1 to 21, comprising: a first polymer which is poly(D,L-lactide) having acid-terminated groups and an intrinsic viscosity of about 0.16 to 0.24 dl / g, a second polymer which is poly(D,L-lactide) having ester-terminated groups and an intrinsic viscosity of about 0.25 to 0.35 dl / g, a third polymer which is poly(D,L-lactide-co-glycolide) having ester-terminated groups and an intrinsic viscosity of about 0.16 to 0.24 dl / g and a D,L-lactide:glycolide ratio of about 75:25, about 3% by mass of cetyl alcohol, and about 2% by mass of butylated hydroxyanisole, wherein the intrinsic viscosities of the first, second, and third polymers correspond to those measured for a 0.1% solution of the polymers in chloroform at 25°C. Exemplary Embodiment 23: Compound 1 in approximately 15% by mass,

[0028] [ka] compound 1 A biodegradable intraocular implant according to any one of exemplary embodiments 1 to 22, comprising: a first polymer which is poly(D,L-lactide) having acid-terminated groups and an intrinsic viscosity of about 5% by mass; a second polymer which is poly(D,L-lactide) having ester-terminated groups and an intrinsic viscosity of about 0.25 to 0.35 dl / g; a third polymer which is poly(D,L-lactide-co-glycolide) having ester-terminated groups and an intrinsic viscosity of about 0.16 to 0.24 dl / g and a D,L-lactide:glycolide ratio of about 75:25; about 3% by mass of cetyl alcohol; and about 2% by mass of butylated hydroxyanisole, wherein the intrinsic viscosities of the first, second, and third polymers correspond to those measured for a 0.1% solution of the polymers in chloroform at 25°C. Exemplary Embodiment 24: Compound 1 in approximately 11% by mass,

[0029] [ka] compound 1 A biodegradable intraocular implant according to any one of the exemplary embodiments 1 to 23, comprising: a first polymer which is poly(D,L-lactide) having acid-terminated groups and an intrinsic viscosity of about 0.16 to 0.24 dl / g, a second polymer which is poly(D,L-lactide) having ester-terminated groups and an intrinsic viscosity of about 0.25 to 0.35 dl / g, a third polymer which is poly(D,L-lactide-co-glycolide) having ester-terminated groups and an intrinsic viscosity of about 0.16 to 0.24 dl / g and a D,L-lactide:glycolide ratio of about 75:25, about 3% by mass of cetyl alcohol, and about 2% by mass of butylated hydroxyanisole, wherein the intrinsic viscosities of the first, second, and third polymers correspond to those measured for a 0.1% solution of the polymers in chloroform at 25°C. Exemplary Embodiment 25: Compound 1 in approximately 11% by mass,

[0030] [ka] compound 1 A biodegradable intraocular implant according to any one of exemplary embodiments 1 to 24, comprising: a first polymer which is poly(D,L-lactide) having acid-terminated groups and an intrinsic viscosity of about 0.16 to 0.24 dl / g, a second polymer which is poly(D,L-lactide) having ester-terminated groups and an intrinsic viscosity of about 0.25 to 0.35 dl / g, a third polymer which is poly(D,L-lactide-co-glycolide) having ester-terminated groups and an intrinsic viscosity of about 0.16 to 0.24 dl / g and a D,L-lactide:glycolide ratio of about 75:25, about 5% by mass of cetyl alcohol, and about 2% by mass of butylated hydroxyanisole, wherein the intrinsic viscosities of the first, second, and third polymers correspond to those measured for a 0.1% solution of the polymers in chloroform at 25°C.

[0031] Exemplary Embodiment 26: A biodegradable intraocular implant according to any one of the exemplary embodiments 20-25, wherein the implant releases less than 30% of compound 1 in vitro during the first 24 hours. Exemplary Embodiment 27: A biodegradable intraocular implant of Exemplary Embodiment 26, wherein the implant releases less than 25% of compound 1 in vitro during the first 24 hours. Exemplary Embodiment 28: A biodegradable intraocular implant of Exemplary Embodiment 26, wherein the implant releases less than 20% of compound 1 in vitro during the first 24 hours. Exemplary Embodiment 29: A biodegradable intraocular implant of Exemplary Embodiment 26, wherein the implant releases less than 15% of compound 1 in vitro during the first 24 hours.

[0032] Exemplary Embodiment 30: A biodegradable intraocular implant according to any one of Exemplary Embodiments 7, 13-16, and 26-29, wherein the in vitro release of compound 1 is measured in a phosphate-buffered saline (PBS) solution at pH 7.4 ± 0.05 and 37°C, and the PBS solution is a magnesium and calcium-free PBS solution having a pH of 7.4 ± 0.05 at 25°C. Exemplary Embodiment 31: A biodegradable intraocular implant from any one of Exemplary Embodiments 1 to 30, wherein the implant is sized for placement in the anterior chamber of the eye. Exemplary Embodiment 32: A biodegradable intraocular implant according to any one of Exemplary Embodiments 1 to 31, wherein the implant has a diameter of approximately 150 μm and the implant contains approximately 5 μg or approximately 7.5 μg of compound 1. Exemplary Embodiment 33: A method for lowering a patient's intraocular pressure, comprising implanting a biodegradable intraocular implant of any one of Exemplary Embodiments 1 to 32 into the patient's eye. Exemplary Embodiment 34: The method of Exemplary Embodiment 33, wherein the patient has, is diagnosed with, or is at risk of developing, elevated intraocular pressure or glaucoma.

[0033] Exemplary Embodiment 35: The method of Exemplary Embodiment 33 or 34, wherein the intraocular implant is placed in the anterior chamber of the patient's eye. Exemplary Embodiment 36: Any one of the exemplary embodiments 33 to 35, wherein the patient is a human. Exemplary Embodiment 37: A biodegradable intraocular implant according to any one of the exemplary embodiments 1 to 32 for use in a method of lowering a patient's intraocular pressure, wherein the method comprises placing the intraocular implant in the patient's eye. Exemplary Embodiment 38: A biodegradable intraocular implant for use in Exemplary Embodiment 37, wherein the patient has, has been diagnosed with, or is at risk of developing, elevated intraocular pressure or glaucoma. Exemplary Embodiment 39: A biodegradable intraocular implant for use in Exemplary Embodiment 37 or 38, wherein the intraocular implant is placed in the anterior chamber of the patient's eye.

[0034] Exemplary Embodiment 40: A biodegradable intraocular implant for use in any one of the exemplary embodiments 37-39, wherein the patient is human. Exemplary Embodiment 41: Use of any one of the exemplary embodiments 1 to 32 of a biodegradable intraocular implant in the manufacture of a pharmaceutical product for lowering a patient's intraocular pressure. Exemplary Embodiment 42: Use of Exemplary Embodiment 41 in which the patient has, is diagnosed with, or is at risk of developing elevated intraocular pressure or glaucoma. Exemplary Embodiment 43: Use of Exemplary Embodiment 41 or 42, wherein the biodegradable intraocular implant is placed in the anterior chamber of the patient's eye when administered to the patient. Exemplary Embodiment 44: Use of any one of the exemplary embodiments 41-43, wherein the patient is human.

[0035] Exemplary Embodiment 45: Use of any one of the Exemplary Embodiments 1 to 32 of a biodegradable intraocular implant in a method for lowering a patient's intraocular pressure, wherein the method comprises placing the intraocular implant in the patient's eye. Exemplary Embodiment 46: Use of Exemplary Embodiment 45 in which the patient has, is diagnosed with, or is at risk of developing elevated intraocular pressure or glaucoma. Exemplary Embodiment 47: Use of Exemplary Embodiment 45 or 46, in which a biodegradable intraocular implant is placed in the anterior chamber of the patient's eye. Exemplary Embodiment 48: Use of any one of the exemplary embodiments 45-47, wherein the patient is human. Exemplary Embodiment 49: A biodegradable intraocular implant substantially as described herein. Exemplary Embodiment 50: Compound 1:

[0036] [ka] compound 1 A biodegradable intraocular implant substantially as described herein, including the following. [Brief explanation of the drawing]

[0037] [Figure 1] Figure 1 shows a cross-section of a mammalian eye. [Figure 2] Figure 2 shows the in vitro cumulative total release percentage of compound 1 over time into phosphate-buffered saline (0.01 M; pH 7.4) at 37°C for six distinct implants (implants 1-6). The composition of each implant is listed in Table 2. [Figure 3] Figure 3 shows the in vitro cumulative total release percentage of compound 1 over time into phosphate-buffered saline (0.01 M; pH 7.4) at 37°C for implants 1, 2, 4, and 7. The composition of each implant is shown in Table 2. [Figure 4] Figure 4 shows the in vitro cumulative total release percentage of compound 1 over time into phosphate-buffered saline (0.01 M; pH 7.4) at 37°C for implants 1 and 5. The composition of each implant is shown in Table 2. [Figure 5] Figure 5 shows the in vitro 1-day release rate of compound 1 in phosphate-buffered saline (0.01 M; pH 7.4) at 37°C for implants 1 and 5. The composition of each implant is shown in Table 2. [Figure 6]Figure 6 shows the in vitro cumulative total release percentage of compound 1 (API) in R202H implants with different filling (mass%) of compound 1. [Figure 7] Figure 7 shows the results of swelling studies for implants 1 and 5 in images. [Figure 8] Figure 8 shows the results of the swelling study for implants 1 and 5 in graph form. [Modes for carrying out the invention]

[0038] definition "Cumulative release profile" refers to the cumulative total percentage of compound 1 released from the implant over time into the ocular region in vivo, or into a specific release medium (e.g., PBS) in vitro. A "prodrug" refers to a compound (e.g., a drug precursor) that is converted in vivo to produce the active form of a compound. This conversion can occur through various mechanisms of action (e.g., metabolism or chemical processes), such as hydrolysis.

[0039] "Intraocular implant" refers to a device or element configured to be implanted in the eye. Examples include extruded filaments containing a biodegradable polymer material and a pharmaceutically active agent such as compound 1 associated with the polymer material, and cut to a length suitable for implantation in the eye. Intraocular implants are generally biocompatible with the physiological state of the eye and do not cause adverse reactions in the eye. In certain embodiments described herein, intraocular implants can be sized and formulated for implantation in the anterior chamber or vitreous humor of the eye. Intraocular implants can be implanted in the eye without significantly impairing the eye's vision. Intraocular implants containing one or more biodegradable polymers and compound 1 or a pharmaceutically acceptable salt thereof are examples of intraocular implants (drug delivery systems) within the scope of this disclosure.

[0040] An "intra-aortic" implant is an intraocular implant that is sized and formulated for placement in the anterior chamber of the eye. Non-limiting examples include implants 2-6 listed in Table 2. "Intravitreal" implants are intraocular implants that are sized and formulated for placement in the vitreous humor of the eye. With respect to implants, "suitable, constructed, sized, or structured for insertion, implantation, or placement in (or therein) the ocular region or part of the eye" means an implant having a size (e.g., dimensions and mass) such that it can be inserted, implanted, or placed in an ocular region, such as the anterior chamber or vitreous humor of the eye, without causing excessive tissue damage or significantly impairing the existing vision of the patient into which the implant is implanted or inserted.

[0041] As used herein, “to treat” and “to treat” include any beneficial effects on the patient’s eye brought about by this method. By treating an eye condition such as ocular hypertension or elevated intraocular pressure or glaucoma, the eye condition may be alleviated or resolved, or the progression of one or more signs, symptoms, or risk factors of the eye condition or related thereto may be reduced or slowed. The signs or symptoms that are positively affected by treatment vary depending on the specific condition. Examples of beneficial (and therefore positive) effects brought about by this method may include a reduction in intraocular pressure, eye pain (i.e., eye pain), eye swelling, and / or eye inflammation. Treatment by any of the methods described herein using one or more of the intraocular implants described herein may, in some cases, also improve the general health, comfort, and / or visual performance of the eye.

[0042] The terms "activator," "drug," "therapeutic agent," "therapeutic activator," and "pharmaceutical activator" all refer to Compound 1. A "patient" may be a human or non-human mammal requiring treatment. The term "eye" includes the eyeball or globe, which is a sensory organ of vision that receives light and transmits visual information to the central nervous system. Roughly speaking, the eye includes the eyeball, the ocular region that makes up the eyeball, tissues and fluids, the muscles around the eye (such as the oblique and rectus muscles), and the optic nerve portion within or adjacent to the eyeball. The terms "therapeutic dose" or "effective dose" generally refer to the level or amount of active agent necessary to treat an eye condition without causing significant negative or adverse side effects in the eye or area of ​​the eye to which the drug is administered. The term "biodegradable polymer" refers to one or more polymers that degrade in vivo, with the degradation of one or more polymers occurring simultaneously with or after the release of the therapeutic agent. Biodegradable polymers may be homopolymers, copolymers, or polymers containing two or more different structural repeating units.

[0043] The term “ocular region” or “ocular area” generally refers to any region of the eyeball, including the anterior and posterior parts of the eye, and generally includes, but is not limited to, any functional (e.g., visual) or structural tissues found in the eyeball, or tissues or cell layers that partially or completely cover the inside or outside of the eyeball. Specific examples of ocular regions of the eye include the anterior chamber, posterior chamber, vitreous cavity (vitreous body or vitreous), choroid, suprachoroidal space, conjunctiva, subconjunctival space, sub-Tenon space, episcleral space, intracorneal space, epicorneal space, sclera, ciliary body squamata, surgically induced avascular areas, macula, and retina. As used herein, “eye condition” means a disease, illness, or condition affecting or involving the eye, or one of the parts or areas of the eye. Broadly speaking, the eye includes the eyeball, the tissues and fluids that make up the eyeball, the muscles around the eye (such as the oblique and rectus muscles), and the portion of the optic nerve within or adjacent to the eyeball.

[0044] Unless otherwise indicated herein, the term “about” when used with respect to values ​​(e.g., mass percentages) includes values ​​close to the stated values ​​(and / or ranges of values) that are equivalent (e.g., biologically equivalent) with respect to the function of individual components (e.g., active ingredients or excipients), compositions, or embodiments. Furthermore, as will be understood by those skilled in the art, all figures, including those representing the amount of components, properties such as molecular weight, reaction conditions, etc., are approximations and are in all cases optionally modified by the term “about.” These values ​​may vary depending on the desired properties that those skilled in the art seek to obtain using the teachings of this description. It will also be understood that such values ​​inherently include variations that inevitably arise from the standard deviation found in each test measurement, and that some values ​​and quantities may be rounded up or down to be “approximately the same” as other values ​​or quantities.

[0045] An anterior segment condition is a disease, illness, or condition affecting or involving the anterior region or part of the eye (i.e., the front of the eye), such as the muscles around the eye, eyelids, or tissues or fluids of the eyeball located anterior to the posterior wall of the lens capsule or the ciliary muscle. Therefore, anterior segment conditions primarily affect or involve the conjunctiva, cornea, anterior chamber, iris, posterior chamber (behind the retina but anterior to the posterior wall of the lens capsule), lens or lens capsule, and the blood vessels and nerves that generate new blood vessels or develop nerves in the anterior segment region or part. Since the clinical goal of glaucoma treatment is to reduce the pressure of aqueous humor in the anterior chamber of the eye (i.e., to reduce intraocular pressure), glaucoma can be considered an anterior segment condition. A posterior segment condition is a disease, illness, or condition that primarily affects or involves the posterior segment of the eye, including the choroid or sclera (located posterior to the plane passing through the posterior wall of the lens capsule), the vitreous humor, the vitreous chamber, the retina, the optic nerve (i.e., the optic disc), and blood vessels and nerves that generate new blood vessels or develop nerves in the posterior segment or area. Glaucoma can also be considered a posterior segment condition because the treatment goal is to prevent or reduce the occurrence of vision loss due to damage or loss of retinal or optic nerve cells (i.e., neuroprotection).

[0046] Size and composition of biodegradable intraocular implants A biodegradable implant containing compound 1, sized and formulated for placement in a patient's eye (intraocular implant) and dispersed in a biodegradable polymer material (or matrix), may be useful for lowering intraocular pressure and treating glaucoma. Compound 1 is particularly effective in lowering intraocular pressure in the eye when administered directly to the anterior chamber. Biodegradable implants may provide a safe, non-toxic, and effective means of administering this compound into the anterior chamber.

[0047] In accordance with this delivery site, the implants described herein can be sized and formulated to be received in the anterior chamber of the eye (e.g., the human eye), particularly in the anterior chamber angle of the eye, with little to no adverse effects on the eye, in particular the corneal endothelium, and without impairing or significantly reducing the patient's vision. The patient receiving the implant receives a therapeutically effective dose of compound 1 and, ideally, experiences little to no redness or inflammation of the eye after the implant is placed in the eye. In this regard, intraocular implants are disclosed herein that are sized and formulated for placement in the anterior chamber of the eye, are biocompatible with the eye, cause little to no immune response or inflammation in the eye, and may be effective in reducing intraocular pressure in the eye over an extended period of time. For example, the very high potency of compound 1 in reducing IOP allows for a reduction in the size of the intraocular implant required to deliver a therapeutically effective dose of the IOP-reducing agent to target tissues and sites of the eye, such as the anterior chamber. This minimizes the potential for irritation or damage to ocular tissues and, more generally, provides patients with greater safety, overall benefit, and comfort. Furthermore, using smaller implants reduces the time required for the intraocular implant to completely disintegrate after drug release. In addition, the ability to fill the implant with a larger amount of compound 1 (e.g., 15% by mass, rather than small amounts such as 8% by mass or less) without the initial burst release of compound 1 seen in other implants containing compound 1 also allows for the creation of more beneficial, smaller implants.

[0048] The implant may have a size suitable for insertion, placement, or embedding in an ocular region or part of the eye, such as the anterior chamber, posterior chamber, or vitreous humor. The size of the implant may affect the release rate, treatment duration, and concentration of compound 1 in the treatment tissue. Assuming equal activator filling, a larger implant can deliver a proportionally larger dose.

[0049] Implants sized for placement in the anterior chamber (anterior chamber implants) can generally have a diameter of about 100 to about 400 μm (or other dimensions suitable for non-cylindrical filaments) and a length of about 0.5 to about 6 mm. Implants can generally be formed by a uniaxial or biaxial extrusion process, can be cylindrical or non-cylindrical, and can have a total mass in the range of about 10 μg to about 500 μg. The mass may be partially dependent on the desired dose. In some embodiments, implants suitable for placement in the anterior chamber of the eye and suitable for use according to this disclosure can have a diameter of about 100 μm to about 300 μm, a length of about 0.5 mm to about 3 mm (e.g., about 2 mm), and a total mass of about 10 μg to about 200 μg or about 10 μg to about 100 μg. In some cases, an anterior chamber implant for reducing IOP has a total mass of about 10 μg to about 100 μg, more specifically about 30 μg to about 100 μg, and the dose of the active compound (e.g., compound 1) depends on the mass percentage of the active compound described herein (for example, if the mass percentage of compound 1 is about 15%, an implant of about 33.3 μg contains about 5 μg of compound 1, and an implant of about 50 μg contains about 7.5 μg of compound 1). One embodiment is an extruded biodegradable intraocular implant suitable for placement in the anterior chamber of the eye and having a diameter of about 200 μm or about 150 μm and a length of about 1.5 mm or about 2 mm.

[0050] The eyes of some patients with glaucoma or, more generally, ocular hypertension, may be more tolerant of the placement of biodegradable implants in the vitreous humor of the eye. The vitreous humor can accept larger implants of the same general formulation. For example, intravitreal implants can have a length of approximately 1 mm to approximately 10 mm, a diameter of approximately 0.5 mm to approximately 1.5 mm, and a total mass of approximately 50 μg to approximately 5000 μg. The scale of the implants can be increased or decreased depending on the administration site of the eye and the size of the patient or vitreous volume. In most cases, a single implant is found to reduce intraocular pressure in the eye over a sustained period, but in some cases, medical professionals may find it useful to place two or more of the implants described herein in the ocular region of the eye to improve the therapeutic effect. Regarding the configuration, the intraocular implant may be in the form of an extruded rod having the dimensions described above or a non-cylindrical filament. Wafers, sheets, or films, and in some cases compressed tablets, may also find applications according to this disclosure.

[0051] Biodegradable polymer materials and other implant components Generally, the implants according to this disclosure comprise or consist of a biodegradable polymer material and compound 1 or a pharmaceutically acceptable salt thereof. The polymer material may comprise, consist of, or essentially consist of one, two, three, or more biodegradable polymers and optionally one or more excipients in order to further improve the stability and / or release properties of the implant.

[0052] Examples of useful biodegradable polymers include polylactide (lactic acid) and polyglycolide (glycolic acid) polymers, and their copolymers (e.g., poly(lactide-co-glycolide) copolymers). In some embodiments, the biodegradable polymer material may include polylactide, poly(lactide-co-glycolide), a mixture of two or more polylactide polymers (e.g., a first and a second polylactide polymer), a mixture of two or more poly(lactide-co-glycolide) copolymers, or a mixture of polylactide and poly(lactide-co-glycolide) polymers. In any particular form of these implants, the polylactide polymer may be poly(D,L-lactide), and the poly(lactide-co-glycolide) copolymer may be poly(D,L-lactide-co-glycolide). In any of the aforementioned combinations, the two or more polymers may differ from one another based on their end groups (e.g., acid and ester end groups), repeating units, intrinsic viscosity, or any combination thereof. The polylactide and poly(lactide-co-glycolide) polymers used in the implants of the present invention may have either a carboxyl (-COOH) or ester-terminated group. Furthermore, two or more poly(lactide-co-glycolide) polymers may have different lactide:glycolide ratios in each polymer, and this ratio may vary depending on the polymer from about 85:15 to about 50:50 to about 75:25. Poly(D,L-lactide) or PLA can be identified by CAS number 26680-10-4 and can be expressed as follows:

[0053] [ka] Poly(D,L-lactide-co-glycolide) or PLGA can be identified by CAS number 26780-50-7 and can be expressed as follows:

[0054] [ka] In the formula, x is the number of D,L-lactide repeating units, y is the number of glycolide repeating units, and n is the number of D,L-lactide-co-glycolide repeating units. Therefore, poly(D,L-lactide-co-glycolide) (PLGA) contains one or more blocks of D,L-lactide repeating units and one or more blocks of glycolide repeating units, and the size and number of each block may vary.

[0055] The molar percentage of each monomer or repeating unit in the PLGA copolymer may be 0–100%, about 15–85%, about 25–75%, or about 35–65%. In some embodiments, D,L-lactide may be about 50%–75%, about 48%–52%, or about 50%, about 73%–77%, or about 75% of the PLGA polymer on a molar basis. The remainder of the polymer may essentially be glycolide repeating units. For example, glycolide may be about 25%–50%, about 23%–27%, or about 25%, about 48%–52%, or about 50% of the PLGA polymer on a molar basis. Other groups, such as terminal groups or capping groups, may be present in small amounts. As described above, in some embodiments, the PLGA copolymer is used in combination with a PLA polymer. Some implants use 75 / 25PLGA polymer with ester-terminated groups.

[0056] The hydrophilicity or hydrophobicity of end groups can be useful in differently determining the degradation of polymer materials. Polymers with hydrophilic end groups can degrade faster than polymers with hydrophobic end groups because the hydrophilic groups can absorb water. Suitable examples of hydrophilic end groups include, but are not limited to, carboxyl (acid end group), hydroxyl, and polyethylene glycol. These groups can be introduced using appropriate initiators. End groups can also be introduced after polymerization is complete to convert end hydroxyl groups to other end groups. For example, ethylene oxide can convert hydroxyl to polyethylene glycol. Hydrophobic end (also called capped or end-capped) polymers have inherently hydrophobic ester bonds at the polymer ends. Other polymers in question include, or can be selected from, hydroxyaliphatic carboxylic acids, homopolymers or copolymers, hyaluronic acid, sodium hyaluronate, polycaprolactone, polysaccharides, polyethers, calcium alginate, cellulose, carboxymethylcellulose, polyvinyl alcohol, polyesters, and combinations thereof. Useful polysaccharides may include, but are not limited to, calcium alginate and functionalized celluloses such as carboxymethylcellulose esters, which are characterized by being water-insoluble and having a molecular weight of approximately 5 kD to approximately 500 kD.

[0057] The release of drugs from biodegradable polymer materials is the result of several mechanisms of action or combinations thereof. Some of these mechanisms of action include detachment from the implant surface, dissolution, diffusion of polymer hydrates through porous channels, and erosion of the polymer constituting the matrix. Erosion may occur in the bulk, on the surface, or a combination of both. The polymer matrix can release the therapeutic agent at a rate effective enough to sustain the release of a certain amount of drug (e.g., compound 1) for more than one month, two to three months, three to six months, or more than six months after implantation in the eye. For example, the implant may contain compound 1, and the polymer material (or matrix) of the implant can degrade at a rate effective enough to sustain the release of a therapeutically effective amount of compound 1 for more than one month, for example, two, three, four, five, or six months, either in vitro or after implantation in the eye, or more specifically after implantation in the anterior chamber of the eye.

[0058] One or more biodegradable polymers used to form the matrix (polymer material of the implant) preferably enjoy instability by enzymatic or hydrolysis. Additional features of the polymer include biocompatibility, compatibility with therapeutic components, ease of use of the polymer in the manufacture of the implant of this disclosure, a half-life of at least about 6 hours, e.g., more than about 1 day, in a physiological environment, and water insolubility.

[0059] Biodegradable polymer materials degrade in vivo in a manner that releases a therapeutically effective amount of the therapeutic agent over a period significantly longer than the in vivo lifespan of the drug when administered as eye drops. As discussed above, the polymer material may be a single polymer or copolymer, or in some cases, a combination or blend of biodegradable polymers and / or copolymers. In addition to the biodegradable polymer and compound 1 or a pharmaceutically acceptable salt thereof, the intraocular implant according to this disclosure may include one or more excipients to improve the stability of the therapeutic agent in the final implant (e.g., shelf life), the ease of manufacture and handling of the implant, and / or the release properties of the implant. For example, compound 1 is susceptible to oxidative degradation under various manufacturing, formulation, and storage conditions. The inventors believe that the main degradation product is the C-15 ketone. Examples of excipients for any of these purposes may include preservatives, antioxidants, chelating agents, electrolytes, or other excipients. Generally, excipients, if present, may constitute 0.001 to 10% by mass or up to 15% by mass of the implant and may be selected from any of the following:

[0060] Useful water-soluble preservatives may include sodium bisulfite, sodium bisulfate, sodium thiosulfate, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercury acetate, phenylmercury nitrate, methylparaben, benzyl alcohol, polyvinyl alcohol, and phenylethyl alcohol. Suitable electrolytes may include sodium chloride, potassium chloride, and others containing MgCl2. Zinc salts may also be suitable. Examples of antioxidants include ascorbates, ascorbic acid, L-ascorbic acid, melatonin, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), thiols, polyphenols, tocopherols such as α-tocopherol, mannitol, reduced glutathione, various carotenoids, cysteine, taurine, tyrosine, superoxide dismutase, lutein, zeaxanthin, cryptoxanthin, astaxanthin, lycopene, N-acetylcysteine, carnosine, γ-glutamylcysteine, quercitin, lactoferrin, vitamin E or esters of vitamin E, retinyl palmitate, and their derivatives.

[0061] Useful chelating agents can be selected from, for example, ethylenediaminetetraacetic acid (EDTA), ethylenediamine, porfin, and vitamin B-12. Other excipients may include alcohols such as hexadecanol (also known as cetyl alcohol and hexadecane-1-ol, sometimes indicated as C16-OH). In some embodiments, the implant may contain linear or branched alcohols with a length of more than 10 carbon atoms. The implants described herein may include combinations of two or more of the above-mentioned excipients. Oxygen can be a crucial component in the degradation pathway of therapeutic agents such as compound 1. Other or additional means to extend the shelf life of manufactured implants and maintain their efficacy may include the step of storing the implants in an oxygen-depleted or oxygen-deficient atmosphere, such as in a sealed pouch (e.g., an aluminum pouch) containing an oxygen absorber pack. An additional step may include filling the pouch with nitrogen or argon gas or other inert gas before sealing the pouch to further remove oxygen from the pouch.

[0062] One embodiment is an intraocular implant according to the present disclosure comprising an antioxidant that retains at least about 85%, at least about 90%, or more than about 95%, or at least about 98% of its initial potency (or loses about 5% or less, or about 2% or less, of its initial potency) after being stored at 25°C for one or three months in a sealed pouch containing an oxygen absorber and / or an inert gas. The initial potency may be based on the actual or theoretical amount of activator compound 1 on a mass-to-mass basis (w / w) present in the implant immediately after implant manufacturing. In some embodiments, the implant may further be included in an ophthalmic implant delivery device having a needle-tipped tip in the pouch, and the pouch may further contain a desiccant.

[0063] In one embodiment, the biodegradable polymer material comprises, essentially consists of, or comprises first, second, and third biodegradable polymers. The first and second polymers may be poly(D,L-lactide) polymers with different terminal groups (ester or acid) and / or intrinsic viscosity (determined for a 0.1% solution in chloroform at 25°C), and the third polymer may be poly(D,L-lactide-co-glycolide). The implant may optionally further contain hexadecanol and / or butylated hydroxyanisole (BHA).

[0064] In one embodiment, the first polymer is poly(D,L-lactide) (e.g., R203S) having ester-terminated groups and an intrinsic viscosity of 0.25-0.35 dl / g (measured for a 0.1% w / v solution in chloroform at 25°C), the second polymer is poly(D,L-lactide) (e.g., R203H) having acid-terminated groups (i.e., carboxyl-terminated groups) and an intrinsic viscosity of 0.25-0.35 dl / g (measured for a 0.1% w / v solution in chloroform at 25°C), and the third polymer is poly(D,L-lactide-co-glycolide) (e.g., RG752S) having ester-terminated groups, an intrinsic viscosity of 0.16-0.24 dl / g (measured for a 0.1% w / v solution in chloroform at 25°C), and a D,L-lactide:glycolide ratio of about 75:25.

[0065] In some embodiments, the first, second, and third biodegradable polymers are independently selected from the group consisting of: R202H is a poly(D,L-lactide) with acid-terminated groups and an intrinsic viscosity of 0.16-0.24 dl / g as measured in a 0.1% solution in chloroform at 25°C. R202S is a poly(D,L-lactide) with ester-terminated groups and an intrinsic viscosity of 0.16-0.24 dl / g as measured in a 0.1% solution in chloroform at 25°C. R203H is a poly(D,L-lactide) with acid terminal groups and an intrinsic viscosity of 0.25-0.35 dl / g as measured in a 0.1% solution in chloroform at 25°C. R203S is a poly(D,L-lactide) with ester-terminated groups and an intrinsic viscosity of 0.25-0.35 dl / g as measured for a 0.1% solution in chloroform at 25°C; and RG752S is a poly(D,L-lactide-co-glycolide) having an ester-terminated group, an intrinsic viscosity of 0.16-0.24 dl / g (measured for a 0.1% solution in chloroform at 25°C), and a molar ratio of approximately 75:25 for D,L-lactide:glycolide. The above-mentioned R202H, R202S, R203H, R203S, and RG752S PLA and PLGA polymers are from the RESOMER® polymer product line, manufactured by Evonik Industries AG (Germany) and available from chemical suppliers such as Sigma-Aldrich / Millipore Sigma, and others that can be identified to those skilled in the art by reading this disclosure.

[0066] In one embodiment, the first polymer is a poly(D,L-lactide) having ester-terminated groups and an intrinsic viscosity of 0.25 to 0.35 dl / g; the second polymer is a poly(D,L-lactide) having acid-terminated groups and an intrinsic viscosity of 0.16 to 0.24 dl / g; and the third polymer is a poly(D,L-lactide-co-glycolide) having ester-terminated groups, an intrinsic viscosity of 0.16 to 0.24 dl / g, and a D,L-lactide:glycolide ratio of approximately 75:25. The intrinsic viscosity of each polymer or copolymer is measured for a 0.1% solution of the polymer or copolymer in chloroform at 25°C.

[0067] In one particular embodiment, the first polymer is R203S, the second polymer is R202H, and the third polymer is RG752S, and the implant further comprises hexadecane-1-ol and / or BHA as excipients. In a particular form, the implant contains 0.001% to 10% by mass of hexadecane-1-ol. In another embodiment, the biodegradable polymer material comprises, essentially consists of, or consists of first and second biodegradable polymers, the first polymer being poly(D,L-lactide) (e.g., R203S) having ester-terminated groups and an intrinsic viscosity of 0.25-0.35 dl / g (measured for a 0.1% w / v solution in chloroform at 25°C), and the second polymer being poly(D,L-lactide) (e.g., R203H) having acid-terminated groups (e.g., carboxyl) and an intrinsic viscosity of 0.25-0.35 dl / g (measured for a 0.1% w / v solution in chloroform at 25°C).

[0068] In another embodiment, the biodegradable polymer material comprises, essentially consists of, or comprises poly(D,L-lactide) (e.g., R2O2H) having acid-terminated groups (i.e., carboxyl-terminated groups) and an intrinsic viscosity of 0.16 to 0.24 dl / g (measured for a 0.1% w / v solution in chloroform at 25°C). In another embodiment, the biodegradable polymer material comprises, is essentially, or consists of poly(D,L-lactide) (e.g., R2O3H)) having acid-terminated groups (i.e., carboxyl-terminated groups) and an intrinsic viscosity of 0.25 to 0.35 dl / g (measured for a 0.1% w / v solution in chloroform at 25°C).

[0069] One embodiment is an extruded biodegradable anterior chamber implant comprising compound 1, hexadecane-1-ol (hexadecanol), and a biodegradable polymer material, wherein the biodegradable polymer material comprises, essentially consists of, or comprises first, second, and third polymers, the first polymer being R203S, the second polymer being R202H, and the third polymer being RG752S. The implant may further contain antioxidants. Non-limiting examples include implants 2-7, the formulations of which are listed in Table 2 below. One embodiment comprises a biodegradable polymer material, hexadecane-1-ol, BHA, and about 15% by mass of compound 1:

[0070] [ka] compound 1 The biodegradable intraocular implant comprises a biodegradable polymer material including i) poly(D,L-lactide) (e.g., R203S) having ester-terminated groups and an intrinsic viscosity of about 0.25–0.35 dl / g, ii) poly(D,L-lactide) (e.g., R202H) having acid-terminated groups and an intrinsic viscosity of about 0.16–0.24 dl / g, and iii) poly(D,L-lactide-co-glycolide) (e.g., R752S) having ester-terminated groups, an intrinsic viscosity of about 0.16–0.24 dl / g, and a D,L-lactide:glycolide ratio of about 75:25, wherein the intrinsic viscosity of each of the poly(D,L-lactide) and poly(D,L-lactide-co-glycolide) described above is measured for a 0.1% solution of the polymer in chloroform at 25°C. In some embodiments, the implant is an extruded implant.

[0071] In one embodiment, the implant further comprises an antioxidant, a chelating agent, or both an antioxidant and a chelating agent. In certain forms, the antioxidant is butylated hydroxyanisole or ascorbic acid, and the chelating agent is EDTA. The intraocular implant can be sized for placement in the anterior chamber of the eye. An implant according to any of the embodiments listed above may contain compound 1 in an amount greater than about 8% by mass but less than or equal to about 20% by mass. For example, compound 1 may be present in the implant in an amount of about 11%, about 12%, or about 15% by mass of the implant. The implant may contain about 15% by mass of compound 1. One exemplary embodiment is an intraocular implant comprising about 12% by mass of compound 1, about 16% by mass of a first polymer which is poly(D,L-lactide) having acid-terminated groups and an intrinsic viscosity of about 0.16-0.24 dl / g, about 25% by mass of a second polymer which is poly(D,L-lactide) having ester-terminated groups and an intrinsic viscosity of about 0.25-0.35 dl / g, about 40% by mass of a third polymer which is poly(D,L-lactide-co-glycolide) having ester-terminated groups, an intrinsic viscosity of about 0.16-0.24 dl / g and a D,L-lactide:glycolide ratio of about 75:25, about 5% by mass of cetyl alcohol, and about 2% by mass of butylated hydroxyanisole, wherein the intrinsic viscosities of the first, second, and third polymers correspond to those measured for a 0.1% solution of the polymer in chloroform at 25°C.

[0072] Another exemplary embodiment is an implant comprising about 12% by mass of compound 1, about 6% by mass of a first polymer which is poly(D,L-lactide) having acid-terminated groups and an intrinsic viscosity of about 0.16-0.24 dl / g, about 30% by mass of a second polymer which is poly(D,L-lactide) having ester-terminated groups and an intrinsic viscosity of about 0.25-0.35 dl / g, about 45% by mass of a third polymer which is poly(D,L-lactide-co-glycolide) having ester-terminated groups, an intrinsic viscosity of about 0.16-0.24 dl / g, and a D,L-lactide:glycolide ratio of about 75:25, about 5% by mass of cetyl alcohol, and about 2% by mass of butylated hydroxyanisole, wherein the intrinsic viscosities of the first, second, and third polymers correspond to those measured for a 0.1% solution of the polymer in chloroform at 25°C.

[0073] Another exemplary embodiment is an implant comprising about 15% by mass of compound 1, about 15% by mass of a first polymer which is poly(D,L-lactide) having acid-terminated groups and an intrinsic viscosity of about 0.16-0.24 dl / g, about 25% by mass of a second polymer which is poly(D,L-lactide) having ester-terminated groups and an intrinsic viscosity of about 0.25-0.35 dl / g, about 40% by mass of a third polymer which is poly(D,L-lactide-co-glycolide) having ester-terminated groups, an intrinsic viscosity of about 0.16-0.24 dl / g, and a D,L-lactide:glycolide ratio of about 75:25, about 3% by mass of cetyl alcohol, and about 2% by mass of butylated hydroxyanisole, wherein the intrinsic viscosities of the first, second, and third polymers correspond to those measured for a 0.1% solution of the polymer in chloroform at 25°C.

[0074] Another exemplary embodiment is an implant comprising about 15% by mass of compound 1, about 5% by mass of a first polymer which is poly(D,L-lactide) having acid-terminated groups and an intrinsic viscosity of about 0.16-0.24 dl / g, about 30% by mass of a second polymer which is poly(D,L-lactide) having ester-terminated groups and an intrinsic viscosity of about 0.25-0.35 dl / g, about 45% by mass of a third polymer which is poly(D,L-lactide-co-glycolide) having ester-terminated groups, an intrinsic viscosity of about 0.16-0.24 dl / g, and a D,L-lactide:glycolide ratio of about 75:25, about 3% by mass of cetyl alcohol, and about 2% by mass of butylated hydroxyanisole, wherein the intrinsic viscosities of the first, second, and third polymers correspond to those measured for a 0.1% solution of the polymer in chloroform at 25°C.

[0075] Another exemplary embodiment is an implant comprising about 11% by mass of compound 1, about 14% by mass of a first polymer which is poly(D,L-lactide) having acid-terminated groups and an intrinsic viscosity of about 0.16-0.24 dl / g, about 35% by mass of a second polymer which is poly(D,L-lactide) having ester-terminated groups and an intrinsic viscosity of about 0.25-0.35 dl / g, about 35% by mass of a third polymer which is poly(D,L-lactide-co-glycolide) having ester-terminated groups, an intrinsic viscosity of about 0.16-0.24 dl / g, and a D,L-lactide:glycolide ratio of about 75:25, about 3% by mass of cetyl alcohol, and about 2% by mass of butylated hydroxyanisole, wherein the intrinsic viscosities of the first, second, and third polymers correspond to those measured for a 0.1% solution of the polymer in chloroform at 25°C.

[0076] Another exemplary embodiment is an implant comprising about 11% by mass of compound 1, about 12% by mass of a first polymer which is poly(D,L-lactide) having acid-terminated groups and an intrinsic viscosity of about 0.16-0.24 dl / g, about 30% by mass of a second polymer which is poly(D,L-lactide) having ester-terminated groups and an intrinsic viscosity of about 0.25-0.35 dl / g, about 40% by mass of a third polymer which is poly(D,L-lactide-co-glycolide) having ester-terminated groups, an intrinsic viscosity of about 0.16-0.24 dl / g, and a D,L-lactide:glycolide ratio of about 75:25, about 5% by mass of cetyl alcohol, and about 2% by mass of butylated hydroxyanisole, wherein the intrinsic viscosities of the first, second, and third polymers correspond to those measured for a 0.1% solution of the polymer in chloroform at 25°C.

[0077] Therapeutic drugs Compound 1 can be prepared by methods known in the art. See, for example, U.S. Patents 6,602,900, 6,124,344, 5,741,810, and 5,834,498. This disclosure includes a biodegradable intraocular implant manufactured by an extrusion process, which may be effective in reducing intraocular pressure in a patient's eye over an extended period. Generally, the implant contains, is essentially, or consists of a biodegradable polymer material and a therapeutic agent comprising compound 1, and the intraocular implant is suitable for placement in the anterior chamber of the eye. The intraocular implant can release about 10 to about 50 ng of the therapeutic agent per day in vitro for at least one month.

[0078] Generally, the therapeutic agent in an implant can constitute 1% to about 90% of the total mass of the implant. In some embodiments, the therapeutic agent can account for more than 8% to 20% of the total mass of the implant. In some embodiments, the amount of compound 1 in the implant on a mass-to-mass basis (w / w) is 15% or less of the total mass of the implant. Therefore, in an implant containing compound 1, compound 1 can constitute more than 8% to 15% by mass of the implant, and in certain forms, 11, 12, or 15% by mass of the implant. These predetermined levels (e.g., 15%) of compound 1 in the implant can avoid undesirable rapid or burst-like release of the drug when the implant is placed in a liquid environment such as the eye. In the implant according to this disclosure, compound 1 may be dispersed or distributed within a biodegradable polymer material and / or surrounded and / or incorporated thereby. When the implant comes into contact with a physiological fluid such as ophthalmic fluid (e.g., aqueous humor) in vivo, the physiological fluid may come into contact with portions of compound 1 on the surface of the implant, but not with portions of the compound dispersed within the polymer material. Upon implantation, the biodegradable polymer may begin to hydrate. Hydration of the implant can improve the diffusion and release of compound 1. Furthermore, the implant may begin to degrade or erode over time. Degradation increases hydration, enhances the mobility of the polymer chains, and creates pores for faster diffusion. Thus, the implant can be configured such that the compound is released from the polymer material as the polymer material hydrates and / or degrades in vivo. The hydration and / or degradation of the implant can take a considerable amount of time, which can be significantly longer than the normal disintegration life of the compound when administered by conventional eye drops, and the implant can provide sustained release. The sustained release can continue as long as at least a portion of the biodegradable polymer material containing at least a portion of compound 1 remains intact.

[0079] The rate at which compound 1 is released from the implant, and the duration for which the implant releases compound 1, may depend on a variety of factors, including but not limited to the size and shape of the implant, the particle size of the compound, the solubility of the compound, the ratio of the compound to the polymer material, the polymer used (including the monomer ratio in the polymer used, the polymer end groups, and the polymer molecular weight), the crystallinity of the polymer, the manufacturing method, the exposed surface area, the erosion rate of the polymer material, and the biological environment in which the implant exists after administration. Implants containing the above-described type of biodegradable polymer material can provide a constant and stable release of compound 1 over extended periods exceeding one month, such as two, three, four to five, or six months. Remarkably, the inventors have found that the implant formulations described herein provide a low-burst, controlled release of compound 1, for example, when drug-filled at 15% (w / w).

[0080] In particular, the biodegradable intraocular implant comprises a biodegradable polymer material and compound 1, wherein compound 1 is present in an amount of about 8 to about 20% by mass of the implant (e.g., about 9 to about 18% by mass, about 9 to about 17% by mass, about 9 to about 16% by mass, about 9 to about 15% by mass, and about 10 to about 15% by mass), and the implant is less than about 30% on day 1 (e.g., the first 24 hours after implantation), e.g., less than about 1%, less than about 2%, less than about 3%, less than about 4%, and less than 5%. Drug fills in vitro are released in amounts of full, less than approximately 6%, less than approximately 7%, less than approximately 8%, less than approximately 9%, less than approximately 10%, less than approximately 11%, less than approximately 12%, less than approximately 13%, less than approximately 14%, less than approximately 15%, less than approximately 16%, less than approximately 17%, less than approximately 18%, less than approximately 19%, less than approximately 20%, less than approximately 21%, less than approximately 22%, less than approximately 23%, less than approximately 24%, less than approximately 25%, less than approximately 26%, less than approximately 27%, less than approximately 28%, less than approximately 29%, and in the range between these amounts. In vitro release of more than approximately 30% drug fill on day 1 is considered a burst release.

[0081] Therefore, in some embodiments, the in vitro release rates of the drug filling on day 1 are approximately 1% to 30%, approximately 2% to 30%, approximately 3% to 30%, approximately 4% to 30%, approximately 5% to 30%, approximately 6% to 30%, approximately 7% to 30%, approximately 8% to 30%, approximately 9% to 30%, approximately 10% to 30%, approximately 11% to 30%, approximately 12% to 30%, approximately 13% to 30%, and approximately 14% to 30%. , approximately 15% to 30%, approximately 16% to 30%, approximately 17% to 30%, approximately 18% to 30%, approximately 19% to 30%, approximately 20% to 30%, approximately 21% to 30%, approximately 22% to 30%, approximately 23% to 30%, approximately 24% to 30%, approximately 25% to 30%, approximately 26% to 30%, approximately 27% to 30%, approximately 28% to 30%, approximately 29% to 30%, and any range in between.

[0082] In other embodiments, the in vitro release rates of the drug filling on day 1 are approximately 1% to 25%, 2% to 25%, 3% to 25%, 4% to 25%, 5% to 25%, 6% to 25%, 7% to 25%, 8% to 25%, 9% to 25%, 10% to 25%, 11% to 25%, and 12% to 25%. This could be a percentage, approximately 13% to 25%, approximately 14% to 25%, approximately 15% to 25%, approximately 16% to 25%, approximately 17% to 25%, approximately 18% to 25%, approximately 19% to 25%, approximately 20% to 25%, approximately 21% to 25%, approximately 22% to 25%, approximately 23% to 25%, approximately 24% to 25%, and any range in between. In other embodiments, the in vitro release rate of the drug filling on day 1 may be in the range of approximately 1% to approximately 20%, approximately 2% to approximately 20%, approximately 3% to approximately 20%, approximately 4% to approximately 20%, approximately 5% to approximately 20%, approximately 6% to approximately 20%, approximately 7% to approximately 20%, approximately 8% to approximately 20%, approximately 9% to approximately 20%, approximately 10% to approximately 20%, approximately 11% to approximately 20%, approximately 12% to approximately 20%, approximately 13% to approximately 20%, approximately 14% to approximately 20%, approximately 15% to approximately 20%, approximately 16% to approximately 20%, approximately 17% to approximately 20%, approximately 18% to approximately 20%, approximately 19% to approximately 20%, and in the range between these. In other embodiments, the in vitro release rate of the drug filling on day 1 may be in the range of approximately 1% to 15%, approximately 2% to 15%, approximately 3% to 15%, approximately 4% to 15%, approximately 5% to 15%, approximately 6% to 15%, approximately 7% to 15%, approximately 8% to 15%, approximately 9% to 15%, approximately 10% to 15%, approximately 11% to 15%, approximately 12% to 15%, approximately 13% to 15%, approximately 14% to 15%, and in the range between these.

[0083] U.S. Patent No. 9,889,142 ('142 Patent) describes an extended, long-term reduction in intraocular pressure in an eye provided by intraocular administration of one or more biodegradable intraocular implants containing compound 1. However, compared to implants containing compound 1 in amounts of 8.0% by mass or less, implants containing more than 8.0% by mass of the therapeutic agent along with the amount of biodegradable polymer described in the '142 Patent exhibit a significant initial burst release of compound 1 and / or provide a very rapid release rate (e.g., about 55% release on day 1 for implants with 12% drug filling), which are generally considered unsuitable for the intended therapeutic use. Surprisingly, such initial burst release was not observed in the implant formulations described herein, even with drug fillings exceeding 8% by mass (e.g., 15% by mass).

[0084] The in vitro release rate of compound 1 from the implant can be measured according to the USP-approved dissolution or release test method (USP23; NF18 (1995) pp. 1790-1798). For example, using the infinite sink method, a gravimetric sample of the implant is added to a measured volume of solution (release medium) containing 0.9% NaCl (aqueous solution) or phosphate-buffered saline, such that the volume of the solution is such that the concentration of the therapeutic activator after release is less than 20% of saturation, and in some embodiments less than 5% of saturation. The mixture is maintained at 37°C and slowly stirred or shaken to ensure diffusion of the therapeutic activator from the implant. The appearance of the therapeutic activator in the solution or release medium as a function of time can be tracked by various methods known in the art, such as spectrophotometrics, HPLC, and mass spectrometry.

[0085] In particular, in some embodiments, the in vitro release rate of compound 1 is measured in phosphate-buffered saline (PBS) solution at pH 7.4 ± 0.05 and 37°C, where the PBS solution is magnesium- and calcium-free and has a pH of 7.4 ± 0.05 at 25°C. As will be apparent to those skilled in the art, phosphate-buffered saline (PBS) is a buffered saline containing disodium hydrogen phosphate, sodium chloride, potassium chloride, and potassium dihydrogen phosphate. PBS may also be prepared to contain calcium chloride and magnesium chloride in addition to the sodium chloride and potassium chloride mentioned above, or it may be prepared without calcium chloride and magnesium chloride (i.e., without magnesium and calcium). PBS is a buffer that can simulate not only the approximate physiological pH of about 7.4 (e.g., 7.4 ± 0.05), but also the approximate osmotic pressure and ion concentration of many physiological fluids, including intraocular physiological fluids. Therefore, the PBS used to measure the in vitro release rate of compound 1 is either PBS containing disodium hydrogen phosphate, sodium chloride, potassium chloride, and potassium dihydrogen phosphate, free of magnesium and calcium, having a pH of 7.4 ± 0.05 at 25°C, which can be prepared according to a known recipe such as the Cold Spring Harbor recipe (see, for example, www.webpage cshprotocols.cshlp.org / content / 2006 / 1 / pdb.rec8247), or it can be purchased as a powder (or other solid mixture of non-aqueous components) which can be reconstituted with water according to the manufacturer's instructions (see, for example, Sigma-Aldrich / Millipore-Sigma catalog number P5368).

[0086] The in vitro release rate of the compound can be measured by incubating the implant at 37°C with gentle agitation (50 rpm) in approximately 1 mL to 3 mL of the above-mentioned PBS (pH 7.4) in a glass scintillation vial. At the specified time, the release medium can be completely removed and replaced with fresh PBS. The amount of drug in the recovered release medium can be analyzed, for example, by HPLC, up to three times as needed. The intraocular implant according to this disclosure can release compound 1 at a rate of approximately 5 to approximately 100 nanograms, approximately 5 to approximately 200 nanograms per day, approximately 10 to approximately 200 nanograms per day, approximately 5 to approximately 100 nanograms per day, approximately 10 to approximately 100 nanograms per day, approximately 10 to approximately 50 nanograms per day, at least approximately 10 ng but less than or equal to approximately 50 ng per day, approximately 10 to approximately 35 ng per day, or approximately 20 to approximately 35 nanograms per day, over a period of more than approximately 1 month, more than approximately 2 months, approximately 1 month to approximately 3 months, approximately 3 months to approximately 6 months, or approximately 6 months to approximately 12 months or more. Specific embodiments include, but are not limited to, extruded intraocular implants sized for placement in the anterior chamber of the eye and comprising one of the formulations given for implant numbers 2–7 in Table 2.

[0087] Manufacturing method Various techniques can be used to manufacture the intraocular implants described herein. Useful techniques may include extrusion methods (e.g., hot-melt extrusion) for manufacturing rod-shaped (or fibrous) implants, compression methods for manufacturing tablets, wafers, or pellets, and solvent casting methods for manufacturing biodegradable sheets, films, and dry powders. Emulsion methods for generating multiple microspheres can also be used to prepare a biodegradable intraocular drug delivery system for the sustained release of compound 1 into the patient's eye. Accordingly, one embodiment provides a pharmaceutical composition suitable for implantation in the ocular region of the eye and comprising multiple biodegradable microspheres encapsulating compound 1 or a pharmaceutically acceptable salt thereof.

[0088] Extrusion implants can be manufactured by uniscrew or twin-screw extrusion, for example, using a piston or twin-screw extruder. The choice of technology and the manipulation of the technical parameters used in implant manufacturing can affect the drug release rate. Extrusion allows for large-scale production of implants, and implants can be obtained in which the dispersion of the drug in the continuous polymer matrix becomes progressively more uniform as the manufacturing temperature increases. Extrusion can be used at temperatures of approximately 50°C to 150°C, or approximately 70°C to 100°C, or lower if necessary. In one embodiment, the intraocular implant according to the present disclosure is manufactured by an extrusion process. The polymer and, if present, the excipients are generally blended with the therapeutic agent and then co-extruded at a selected temperature to form a filament containing a biodegradable polymer matrix (or material) and the therapeutic agent dispersed within and / or distributed throughout the matrix (or material). If desired, the filament can be crushed and re-extruded to form a twin-screw extruded implant.

[0089] In one form of implant manufacturing by extrusion, the therapeutic agent, biodegradable polymer, and optionally one or more excipients are first mixed (blended in a container) at room temperature, and then heated to a temperature range of 50°C to 150°C for a period of 1 to 60 minutes, for example, 1 to 30 minutes, 5 to 15 minutes, or 10 minutes. The mixture is then extruded through a nozzle at a temperature of 60°C to 130°C, or 80°C. The extruded filament is then cut to the desired length to manufacture an intraocular implant of a specific mass. The opening of the nozzle from which the mixture is extruded generally has a diameter suitable for the desired diameter of the implant, but if necessary, the extruded filament can be withdrawn from the nozzle to further reduce the diameter of the implant. The extruded implant can generally be cylindrical or non-cylindrical and have a length and diameter (or other dimensions suitable for non-cylindrical fibers) suitable for placement in the ocular region of the eye, such as the anterior chamber or vitreous humor.

[0090] One possible method for manufacturing the intraocular implants of this disclosure uses a combination of solvent casting and hot melt extrusion. See, for example, US2010 / 0278897. In this method, a dry powder or film is prepared by first dissolving all materials (activators, polymers, and excipients, if present) in a suitable solvent such as ethyl acetate to form a solution. The solution is then cast into a suitable container (e.g., a TEFLON® dish) and then dried overnight in a vacuum oven to form a dry film. The film is then crushed into particles, collected, and extruded by hot melt extrusion to prepare filaments containing activators and one or more biodegradable polymers. The filaments can be cut to a suitable length and thus a suitable mass for implantation in the eye. The extrusion temperature for this process may be in the range of 50°C to 150°C. Accordingly, this disclosure includes methods for manufacturing and using extruded biodegradable implants (which may generally be referred to as extruded rods or fibers) suitable for placement in a patient's eye to reduce intraocular pressure, including elevated intraocular pressure in the eye.

[0091] Mode and site of administration, and treatment method To provide the intended therapeutic effect (e.g., long-term reduction of intraocular pressure) in patients, including those with glaucoma, the implant according to this disclosure may be placed in the anterior chamber of the eye. The anterior chamber refers to the internal space of the eye between the iris and the innermost surface (endothelium) of the cornea. However, in some patients, the implant may need to be placed in the vitreous humor of the eye. The posterior chamber refers to the internal space of the eye between the posterior part of the iris and the anterior surface of the vitreous humor. The posterior chamber includes the space between the lens and the ciliary process, which produces aqueous humor that nourishes the cornea, iris, and lens and maintains intraocular pressure. Referring to Figure 1, Figure 1 shows these and other ocular regions of the eye (100) in cross-section. A specific region of the eye (100) includes the cornea (102) and iris (104) surrounding the anterior chamber (106). Behind the iris (104) are the posterior chamber (108) and lens (110). The anterior chamber contains the anterior chamber angle (112) and the trabecular network (114). The corneal epithelium (118), sclera (116), vitreous humor (119), ciliary zonules (120), and ciliary process (121) are also shown. The posterior segment is the posterior two-thirds of the eyeball (behind the lens) and includes the vitreous humor, retina, and optic nerve.

[0092] To lower intraocular pressure and treat glaucoma in a patient, the implant described herein can be implanted as monotherapy in the anterior chamber (or other ocular region) of a mammalian eye, allowing the therapeutic agent (such as compound 1) to be delivered to the anterior chamber of the eye without the need for eye drops. Alternatively, the implant can also be used in conjunction with eye drops as adjunctive therapy. In some embodiments, by inserting the implant described herein into the anterior chamber of the eye, intraocular pressure in the eye can be reduced by, for example, at least about 20% or 30% or more compared to baseline IOP. The patient may be a human or non-human mammal suffering from elevated intraocular pressure or glaucoma and therefore requiring treatment. In some embodiments, the implant can release compound 1 linearly or according to pseudo-zero-order dynamics for at least one month after the implant has been placed in the eye.

[0093] Biodegradable implants can be inserted into the eye by various methods, including placement using forceps, trocars, or handheld delivery devices (applicators) equipped with needles (or with needles at their tips). Several handheld applicators can be used to insert one or more biodegradable implants into the eye. Handheld applicators may include an 18-30GA (gauge) stainless steel needle, a lever, an actuator, and a plunger or push rod to facilitate the ejection of the implant. The implant can be inserted via the sclera, corneal margin, or corneal pathway to access the anterior chamber. Alternatively, the implant can be inserted into the vitreous humor using a suitable applicator with a needle or cannula of appropriate length for accessing the target site and delivering the implant. Several methods of implant insertion involve accessing a target area within the ocular region using a needle, trocar, or implantation device. Once placed within the target area, for example, in the anterior chamber or vitreous humor, the lever of the handheld device can be pressed down to push the plunger or push rod forward into the actuator. As the plunger moves forward, it can push the device or implant into a target area (such as the vitreous humor or anterior chamber). One example of an ophthalmic implant delivery device is disclosed in U.S. Patent Application Publication 2004 / 0054374. Another example can be found in U.S. Patent 6,899,717.

[0094] Accordingly, methods for treating glaucoma in the eye of a patient and lowering intraocular pressure as discussed herein may include administering a biodegradable intraocular implant of the type disclosed herein into the eye by injection into the anterior chamber of the eye (intracavitary injection) or into the vitreous humor of the eye (intravitreal injection). A syringe device including a needle of an appropriate size (e.g., 22, 25, 27, 28, or 30 gauge needle) may be useful for injecting one or more implants into these areas within the eye. Thus, the width or diameter of the implant may be selected so that the implant is received within the lumen of the selected needle gauge and is able to move through the lumen. Prior to use in a target area, the implant can be sterilized with a suitable dose, for example, a beta radiation dose. Preferably, the sterilization method does not substantially reduce the therapeutic activity of the therapeutic agent in the implant, or retains at least 50% or 80% or more of the initial activity.

[0095] When delivered or released directly into the anterior chamber, daily doses of compound 1 in the range of approximately 5 to approximately 100 nanograms, approximately 5 to approximately 200 nanograms, approximately 10 to approximately 100 nanograms, or approximately 5 to approximately 50 nanograms may be therapeutically effective in lowering intraocular pressure in a patient's eye. A patient is typically a human or non-human mammal experiencing or diagnosed with elevated intraocular pressure or ocular hypertension in one or both eyes. Since glaucoma often involves elevated intraocular pressure, a patient can be further defined as a patient suffering from glaucoma. Accordingly, the implants described herein can generally be used to reduce elevated intraocular pressure in the eye and to treat glaucoma in a patient. In this regard, one embodiment is a method for reducing ocular hypertension or elevated intraocular pressure in a patient requiring reduction of ocular hypertension or elevated intraocular pressure, the method comprising implanting a biodegradable intraocular implant according to the present disclosure in the patient's eye.

[0096] Patients who can be effectively treated with a biodegradable anterior chamber implant containing Compound 1 or a pharmaceutically acceptable salt thereof may include patients who have, suffer from, or have been diagnosed with glaucoma, open-angle glaucoma, closed-angle glaucoma, chronic closed-angle glaucoma, glaucoma, iridotomy, ocular hypertension, elevated intraocular pressure, pseudoexfoliation glaucoma, or pigmentary glaucoma. The implants according to this disclosure may be effective in lowering intraocular pressure in eyes with low, normal, or elevated intraocular pressure. Thus, the implants according to this disclosure may be effective in treating all forms of glaucoma, including glaucoma characterized by elevated intraocular pressure and glaucoma with low or normal intraocular pressure, because these patients may also potentially benefit from a further reduction in intraocular pressure. Because it is possible to release a therapeutically effective amount of a potent intraocular pressure-lowering agent such as Compound 1 over a sustained period, the implants of this disclosure are expected to lower the intraocular pressure of these patients over the long term without requiring frequent intraocular injections or regular drops of eye drops that may be necessary with topical treatment. Furthermore, the greater potency of Compound 1 in lowering IOP compared to several other prostamides and antiglaucoma agents makes it possible to manufacture smaller implants with a safer and better-than-average duration of administration for the eye and, consequently, the patient.

[0097] Accordingly, one embodiment of the present disclosure is a method for reducing intraocular pressure (IOP) in an eye, the method comprising implanting a biodegradable intraocular implant disclosed herein into the eye, wherein the implant reduces the intraocular pressure of the eye over an extended period of time. The implant can be implanted in the ocular region of the eye and can therefore be sized for implantation in the ocular region of the eye. The patient may have low or normal intraocular pressure, or have elevated intraocular pressure sometimes referred to as ocular hypertension, or the patient may have glaucoma. In a more specific embodiment, the patient has or has been diagnosed with glaucoma or elevated intraocular pressure, and the implant is implanted in the anterior chamber or vitreous humor of the affected eye. In a particular embodiment, the implant is implanted in the anterior chamber angle (or iridocorneal angle) of the affected eye, more specifically in the inferior iridocorneal angle of the affected eye. In any of these methods, the compound in the implant (i.e., the therapeutic agent) may contain, essentially consist of, or comprise compound 1, a pharmaceutically acceptable salt of compound 1, or any mixture thereof, and the implant may be placed in the anterior chamber or vitreous humor of the eye by intra-anterior chamber or intravitreous injection. In certain embodiments, the implant is placed in the anterior chamber angle (or iris-corneal angle) of the eye. The implant may also be placed in the subconjunctival region of the eye.

[0098] Accordingly, this disclosure provides a method for treating glaucoma in a patient, comprising the step of implanting a biodegradable intraocular implant described herein into the patient's eye. The implant is implanted in the anterior chamber of the eye or in another ocular region of the eye, thereby treating glaucoma. Some embodiments include a method for administering compound 1 without eye drops, which involves inserting an implant described herein into the eye of a patient requiring it. The implant can be placed in the anterior chamber of the eye. In certain forms of the treatment method, one or more intraocular implants containing compound 1 or a pharmaceutically acceptable salt thereof can be placed in the anterior chamber of the eye, or more specifically, injected therein, thereby reducing intraocular pressure and ocular hypertension in the eye. Therefore, intraocular implants can be sized and formulated, for example, for placement in the anterior chamber of the eye. Such implants may be referred to as “anterior chamber” implants.

[0099] The implants of this disclosure are designed to provide a long-lasting reduction of elevated intraocular pressure (or ocular hypertension) by directly and continuously releasing a therapeutically effective amount of compound 1 or any pharmaceutically acceptable salt thereof to an affected area of ​​the eye, such as the anterior chamber of the eye. In this regard, the therapeutically effective amount of compound 1 may be a dose of about 5 to about 100 ng / day, about 5 to about 200 ng / day, about 10 to about 200 ng / day, about 5 to about 50 ng / day, or more specifically about 10 to about 50 ng / day, or even more specifically about 15 ng / day, about 20 ng / day, about 30 ng / day, about 40 ng / day, or about 50 ng / day. The patient may be a human or non-human mammal requiring treatment for ocular hypertension (elevated intraocular pressure) or glaucoma. The implants may be in the form of an extruded filament or a compressed tablet. Other forms may include wafers, films, or sheets. The extruded filament may be a cylindrical or non-cylindrical rod having a diameter suitable for placement in the eye, such as the anterior chamber or vitreous humor, and cut to a suitable length. [Examples]

[0100] The following embodiments are intended solely to illustrate the methods of the Disclosure and should not be construed as limiting the methods of the Disclosure.

[0101] (Example 1) Implant manufacturing Implants 1-6 in Table 2 were manufactured as follows: The drug substance, polymer, and additives were added to a stainless steel (SS) container containing two 10 mm SS balls. The powder was blended in a Turbula mixer for 15 minutes, then mixed by hand using a spatula, and then blended again in the Turbula mixer for another 15 minutes. The resulting powder blend was then processed into filaments using a twin-screw microcompounder / extruder. Extrusion was performed using the process settings summarized in Table 1. [Table 1]

[0102] The formulation composition and references are summarized in Table 2. [Table 2] Extruded filaments were randomly selected and cut using an autocutter to produce implants of a specific mass. A total of 50 implants were cut for each implant number. The target implant mass for a 150 μm diameter filament was 50 ± 2.5 μg (5%). The implants were stored in glass vials, sealed in foil pouches containing a desiccant, and sterilized with an electron beam at 25 ± 10% kGy before testing.

[0103] (Example 2) In vitro drug release assay In vitro drug release studies were conducted by placing each implant in 2 ml of aqueous incubation buffer (release medium) in a 10 ml glass vial. The vials were maintained at 37°C and 50 rpm in a shaking water bath. The incubation buffer consisted of pH 7.4 phosphate-buffered saline (PBS) (137 mM NaCl, 2.7 mM KCl, and 10 mM phosphate buffer). At each specified time point, all of the 2 ml of release medium in each vial was sampled and replaced with an equal volume of fresh release medium. The sedimentation conditions in the release medium were maintained throughout the study.

[0104] The drug release profiles of the Table 2 implants extruded under the conditions specified in Table 1 are shown in Figures 2 and 3. These figures also include Implant 1 formulation containing 8 mass% of compound 1 as a comparison implant. Data points represent the average release of three replicate implant samples that are not normalized to relative mass. Implant 5, with 15% drug filling, had a similar release profile to Implant 1 (Figure 4), with a 1-day release rate similar to or higher than Implant 1 (Figure 5), and less than 30% release of compound 1 on day 1. However, Implant 5 showed the absence of this burst release, while being able to contain nearly twice the amount of compound 1 within the implant. As can be seen in comparison with implants manufactured using only R202H as the polymer (Figure 6), the Table 2 implants showed a better release profile in that they did not exhibit the initial burst release seen in R202H implants with drug fillings exceeding 8 (mass)% (Figure 6). For example, as seen in Figure 6, in contrast to the polymer mixtures in Table 2, when R202H alone was used in implants with 15% drug loading, the release rate on day 1 was approximately 28%. On the other hand, as can be seen in Figures 3 and 4, implants 4 and 5 (both with 15% drug loading) showed a release rate of approximately 12% on day 1. Furthermore, see U.S. Patent No. 9,889,142, which also shows burst release in implants with more than 8% filling, which can be as high as approximately 55% drug release on day 1.

[0105] Based on the above, while a similar acceptable drug release profile (e.g., no initial burst release and very stable release) can be observed in implant formulations described herein with 8% by mass implants, the implants of the present invention exhibit this acceptable release at significantly higher drug fills than 8% by mass (e.g., 15% by mass).

[0106] (Example 3) Implant swelling Swelling studies were conducted according to the instructions for polymer implant swelling procedures. The physical appearance and dimensional measurements of implant samples were studied using a Keyence digital microscope (model VHX-600). Images were acquired for extruded implants at 100x and 150x magnification. The culture medium used in this study was 0.01 MPBS, pH 7.4, 37°C. The swelling behavior of all implants is summarized in Figure 7. A comparison of the maximum swelling diameters of implant 1 and implant 5 is shown in Figure 8. The maximum swelling diameter of implant 5 is smaller than that of implant 1, and is approximately 75% to 85% of the maximum swelling diameter of implant 1.

[0107] (Example 4) In vitro polymer degradation The in vitro polymer lifespan of implants 2-6 was compared to that of implant 1. The study was conducted over 24 weeks at 37°C in a buffered aqueous solution (0.01 M PBS, pH 7.4). The degradation rate constant was defined as the average molecular weight (MW) of the polymer matrix over time. peak The decrease in ) was estimated by fitting it to the primary dynamics. The total dynamic rate constant and estimated in vitro lifetime (MW at 1000 g / mol) were estimated. peak t is the time to reach that point. 1000 Table 3 summarizes the ranking of formulations based on the following criteria. The reported molecular weight data is relative to the polystyrene standard. [Table 3]

[0108] Throughout this specification, references are made to publications such as U.S. and foreign patent applications, journal articles, and book chapters. All such publications, including any supplementary / supporting information sections published with their corresponding bibliographies, are expressly incorporated by reference for all purposes unless otherwise indicated.

[0109] While many exemplary embodiments and designs have been discussed above, those skilled in the art will recognize specific modifications, alterations, additions, and subcombinations thereof. Therefore, the claims accompanying and set forth below are intended to be interpreted as encompassing all such modifications, alterations, additions, and subcombinations within their intent and scope.

Claims

1. Compound 1 in approximately 15% by mass, 【Chemistry 9】 compound 1 A biodegradable intraocular implant comprising: a first polymer, which is poly(D,L-lactide) having acid-terminated groups and an intrinsic viscosity of about 0.16 to 0.24 dl / g, in approximately 5% by mass; a second polymer, which is poly(D,L-lactide) having ester-terminated groups and an intrinsic viscosity of about 0.25 to 0.35 dl / g, in approximately 30% by mass; a third polymer, which is poly(D,L-lactide-co-glycolide) having ester-terminated groups, an intrinsic viscosity of about 0.16 to 0.24 dl / g, and a D,L-lactide:glycolide ratio of about 75:25; about 3% by mass of cetyl alcohol; and about 2% by mass of butylated hydroxyanisole, wherein the intrinsic viscosities of the first, second, and third polymers correspond to those measured for a 0.1% solution of the polymers in chloroform at 25°C.

2. The biodegradable intraocular implant according to claim 1, wherein the implant releases less than 30% of compound 1 in vitro during the first 24 hours.

3. The biodegradable intraocular implant according to claim 2, wherein the implant releases less than 25% of compound 1 in vitro during the first 24 hours.

4. The biodegradable intraocular implant according to claim 2, wherein the implant releases less than 20% of compound 1 in vitro during the first 24 hours.

5. The biodegradable intraocular implant according to claim 2, wherein the implant releases less than 15% of compound 1 in vitro during the first 24 hours.

6. The biodegradable intraocular implant according to any one of claims 1 to 5, wherein the implant is sized for placement in the anterior chamber of the eye.

7. The biodegradable intraocular implant according to any one of claims 1 to 6, wherein the diameter of the implant is approximately 150 μm, and the implant contains approximately 5 μg or approximately 7.5 μg of compound 1.

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