Intraocular implant with high prostatin loading

Abstract

Biodegradable intraocular implants with high prostatinamide compound loadings are described for immediate and sustained reduction of intraocular pressure in a patient's eye and for the treatment of glaucoma.

Description

[0001] Cross Reference to Related Applications

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 054,620, filed July 21, 2021, the entire contents of which are incorporated herein by reference in their entirety. TECHNICAL FIELD

[0003] Described herein are intraocular implants with high prostatic amide loading. In particular, described herein are devices and methods for treating an eye of a patient, and more particularly, intraocular implants that provide prolonged release of a therapeutic agent to an eye in which the implant is placed to treat ocular hypertension, such as by reducing or at least maintaining intraocular pressure (IOP), as well as methods of making and using such implants. BACKGROUND

[0004] Intraocular pressure-lowering agents can be used to treat many different ocular hypertensive conditions, such as post-surgical and post-laser trabeculectomy episodes of ocular hypertension, glaucoma, and are useful as preoperative adjunct medications.

[0005] Glaucoma is an eye disease that is usually characterized by increased intraocular pressure. Glaucoma is classified as primary or secondary based on its etiology. For example, primary glaucoma in adults (congenital glaucoma) can be open-angle or acute or chronic angle-closure. Secondary glaucoma results from pre-existing ocular disease such as uveitis, intraocular tumors, or expanding cataracts.

[0006] The increased intraocular pressure of glaucoma is due to obstruction of aqueous outflow. In chronic open-angle glaucoma, the anterior chamber and its anatomy appear essentially normal, but the drainage of aqueous humor is obstructed. In acute or chronic angle-closure glaucoma, the anterior chamber is shallow, the angle of the iris narrows, and the iris can obstruct the trabecular meshwork at the entrance to the canal of Schlemm. Dilation of the pupil can push the root of the iris forward toward the angle and can cause pupillary block, and thus contribute to acute attacks. Eyes with narrow anterior chamber angles are predisposed to acute angle-closure glaucoma attacks of varying severity.

[0007] Secondary glaucoma results from any interference with the flow of aqueous humor from the posterior chamber into the anterior chamber and then into the canal of Schlemm. Inflammatory disease of the anterior segment of the eye can prevent aqueous humor from escaping by causing complete posterior synechiae at the iris hump and can plug the drainage channels with exudates. Other common causes are intraocular tumors, expanding cataracts, central retinal vein occlusion, trauma to the eye, surgical procedures, and intraocular hemorrhage.

[0008] Lowering intraocular pressure can help prevent glaucoma or vision loss due to glaucoma. Currently, many patients are given eye drops containing a therapeutically active agent for lowering intraocular pressure, which they can use one or more times per day to lower the elevated intraocular pressure associated with glaucoma.

[0009] It would be advantageous to provide ocularly implantable drug delivery systems, such as intraocular implants, and methods of using such systems, that are capable of releasing a therapeutic agent, such as a pressure-lowering (or IOP-lowering) agent, at a sustained or controlled rate for a prolonged period of time and in an amount that is little or no negative side effects (i.e., extended release rather than burst release), thereby lowering the intraocular pressure of a patient's eye, including but not limited to a patient who has glaucoma or is at risk of developing glaucoma. The therapeutic agent can be delivered in the intracameral space or in the vitreous humor, where it can be effective at the anterior segment or posterior segment of the human eye. It would also be advantageous to obtain a linear drug release profile for a prolonged period of time. Implant delivery systems with relatively high loading amounts would be desirable, as the size of the implant can be reduced without reducing the effective amount of drug delivered.

[0010] Additional parameters to consider when formulating an implant delivery system include the rate and extent of drug release from the sustained release implant, the extent of swelling of the sustained release implant when placed in an aqueous medium (compared to the initial size), and the time of biodegradation of the implant after drug release is complete.

[0011] To minimize implant mass, size, and injection frequency, it is desirable to maximize the duration of drug loading, polymer erosion rate, and drug release time simultaneously. This is often difficult to achieve in practice, as typically optimizing one component / factor compromises the others. SUMMARY

[0012] The present disclosure relates to the prolonged, long-term lowering of intraocular pressure of an eye provided by the intraocular administration of one or more biodegradable intraocular implants. The biodegradable intraocular implant comprises or consists of a biodegradable polymeric material and a therapeutic agent associated with the biodegradable polymeric material. The one or more implants can be administered to the eye as a monotherapy and can provide the therapeutic agent directly to the ocular region of the eye in an amount effective to lower elevated intraocular pressure (ocular hypertension) in the eye over an extended period of time. The implants can also be used to treat or prevent glaucoma or other medical conditions of the eye associated with elevated intraocular pressure.

[0013] The therapeutic agent contained by the intraocular implants of the present disclosure can comprise, consist essentially of, or consist of a compound effective to lower intraocular pressure in a hypertensive eye. In some embodiments, the therapeutic agent comprises or consists of Compound 1:

[0014]

[0015] Accordingly, the present disclosure describes a biodegradable intraocular implant effective to reduce intraocular pressure of a patient's eye over an extended period of time, wherein the implant comprises or consists of a biodegradable polymeric material and Compound 1, or a pharmaceutically acceptable salt thereof, and wherein Compound 1 is present in an amount greater than 8 wt% of the implant, such as between 8 and 20 wt% (including 20 wt%, such as 9 to 18%, 9 to 17%, 9 to 16%, 9 to 15%, and 10 to 15%), 11 wt%, 12 wt%, or 15 wt%.

[0016] In some embodiments, the biodegradable intraocular implant comprises a biodegradable polymeric material and Compound 1 as a pharmaceutically active agent, wherein the intraocular implant does not comprise a pharmaceutically active agent or IOP-reducing agent other than Compound 1.

[0017] Compound 1 can be associated with the biodegradable polymeric material. Thus, the compound can be mixed with, dissolved and / or dispersed within, encapsulated by, or coupled to the biodegradable polymeric material. Compound 1 can be uniformly or non-uniformly dispersed or distributed throughout the biodegradable polymeric material. Upon placement of the implant in the eye, release of Compound 1 from the implant can occur by diffusion of Compound 1, erosion or degradation of the polymeric material, dissolution, permeation, or any combination thereof.

[0018] The biodegradable intraocular implants described herein can be specifically designed and formulated for placement in an ocular region of an eye, such as the vitreous or anterior chamber of the eye, to treat glaucoma and reduce intraocular pressure, including, for example, elevated intraocular pressure in the eye (or ocular hypertension).

[0019] In some embodiments, the intraocular biodegradable implant can continuously release Compound 1, or a pharmaceutically acceptable salt thereof, in the eye in vitro and / or in vivo for more than one month, such as between about 1 and about 3 months or longer, about 3 to about 6 months, or about 6 months or longer, after placement in the patient's eye.

[0020] The implants of the present disclosure are designed to release Compound 1 in a controlled manner. In some forms, the implant will provide a linear or near-constant release rate of Compound 1 for more than 1 month, such as more than 2 months, between 1 and 3 months, 3 to 6 months, or 6 to 12 months or longer.

[0021] One embodiment is an extruded intraocular implant comprising between about 8% and about 20% by weight (including 20% by weight, such as about 9 to about 18% by weight, about 9 to about 17% by weight, about 9 to about 16% by weight, about 9 to about 15% by weight, and about 10 to about 15% by weight), such as about 11% by weight, about 12% by weight, or about 15% by weight, of Compound 1, and optionally about 2% to about 6% by weight of hexadecan-1-ol (cetyl alcohol), wherein the implant continuously releases Compound 1 in vitro in phosphate buffered saline at 37 °C for 2 to 5 months.

[0022] A biodegradable intraocular implant can comprise a biodegradable polymeric material and Compound 1, wherein i) Compound 1 is in an amount of between about 8% and about 20% by weight (including 20% by weight, such as about 9 to about 18% by weight, about 9 to about 17% by weight, about 9 to about 16% by weight, about 9 to about 15% by weight, and about 10 to about 15% by weight) of the implant, 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 comprise polyethylene glycol.

[0023] In some forms of the implant herein, the biodegradable polymeric material comprises poly(D,L-lactide) having acid end groups and an intrinsic viscosity of 0.16-0.24 dl / g (Polymer 1) and poly(D,L-lactide) having ester end groups and an intrinsic viscosity of 0.25-0.35 dl / g (Polymer 2), and poly(D,L-lactide-co-glycolide) copolymer having ester end groups, a D,L-lactide to glycolide molar ratio of about 75:25 (e.g., 73:27 to 77:23), and an intrinsic viscosity of 0.16-0.24 dl / g (Polymer 3), wherein the intrinsic viscosity of each polymer and copolymer is measured at 25°C for a 0.1% solution of the polymer or copolymer in chloroform. In some forms of the implant herein, Polymer 1 is present in an amount of about 0 to about 20 wt% (such as about 4 to about 10 wt% or about 4 to about 20 wt%, 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 wt%). In some forms of the implant herein, Polymer 2 is present in an amount less than Polymer 3, which is present in an amount of about 20 to about 40 wt% (such as about 20 to about 30 wt%, e.g., about 20, about 25, about 30, about 35, or about 40 wt%). In some forms of the implant herein, Polymer 3 is present in an amount of about 30 to about 70 wt% (such as about 35 to about 50 wt%, e.g., about 30, about 35, about 40, about 45 wt%). In some forms of the implant herein, the weight ratio of Polymer 2 to Polymer 3 is 2:5 to 4:3, such as 1:2 to 1:1, 1:2, 5:9, 5:8, 2:3, 3:4, 6:7, or 1:1.

[0024] The biodegradable implant can be formulated to comprise at least about 3 to about 10 pg (e.g., about 5 or about 7.5 pg) of Compound 1 in an implant of about 100 to about 200 pm diameter (e.g., an implant of about 150 pm diameter).

[0025] One embodiment provides a method of reducing intraocular pressure in a patient in need thereof comprising administering to the eye of the patient a pharmaceutical composition comprising a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof. Some embodiments provide a method of reducing intraocular pressure in a patient in need thereof comprising administering to the eye of the patient a pharmaceutical composition comprising a therapeutically effective amount of Compound 1. The pharmaceutical composition for reducing intraocular pressure will generally be biologically compatible with the eye and will contain a therapeutically effective amount of Compound 1 and a pharmaceutically acceptable excipient. Biocompatible implants and polymers produce little or no toxic effects, are non-harmful or non-physiologically reactive, and do not elicit an immune response.

[0026] Other embodiments provide a method of manufacturing a biodegradable intraocular implant effective to reduce intraocular pressure in a patient, the implant comprising or consisting of a therapeutic agent, a biodegradable polymeric material, and optionally one or more excipients, the method comprising in order a) blending the therapeutic agent with the biodegradable polymer or two 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 into a length suitable for placement in an eye of a patient having elevated intraocular pressure, thereby forming the intraocular implant. In particular embodiments, the filament is cut into a length suitable for placement in the anterior chamber of the eye. The therapeutic agent can comprise Compound 1 as defined herein. In some cases, the therapeutic agent used for blending with the one or more polymers (step a) can be in solid form. The mixture can be extruded at a temperature of from about 60 °C to about 150 °C.

[0027] Still other embodiments provide an apparatus for implanting or injecting a biodegradable intraocular implant according to any of the embodiments described herein into an ocular region of an eye of a patient having glaucoma or ocular hypertension (i.e., elevated intraocular pressure), the apparatus comprising an elongated housing having a longitudinal axis and a cannula extending longitudinally from the housing, the cannula having a lumen extending therethrough, the lumen configured to receive the intraocular implant, the apparatus further comprising the intraocular implant according to any of the embodiments described herein. The implant can be located within the cannula lumen or at a location proximal of the cannula lumen. In specific forms of the apparatus, the cannula is sized equal to or no larger than a size of a 21, 22, 25, 27, 28, or 30 gauge needle, and the cannula will have a beveled or sharp tip to facilitate penetration of ocular tissue. In some forms, the outer and inner diameters of the cannula are no larger than the outer and inner diameters of a 25 or 27 gauge needle.

[0028] Methods for delivering an intraocular implant into an eye of a patient having glaucoma or elevated intraocular pressure using an apparatus as described above, the apparatus comprising a cannula having a proximal end, a distal sharp end, and a lumen extending therethrough, an intraocular implant selected from any of the intraocular implants described herein, and an actuator whose movement causes the implant to be ejected from the apparatus, the cannula lumen sized to receive the intraocular implant and allow the implant to translate therethrough, the method comprising the steps of inserting the cannula into an ocular region of the patient’s eye and pressing or activating the actuator, thereby ejecting 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 can be the anterior chamber or the vitreous of the eye.

[0029] Some non-limiting example embodiments are set forth below.

[0030] Example Embodiment 1 : A biodegradable intraocular implant comprising a biodegradable polymeric material and Compound 1 :

[0031]

[0032] wherein Compound 1 is present in an amount between 10 and 20% by weight of the implant, and wherein the implant releases Compound 1 continuously in vitro for 2 to 6 months.

[0033] Example Embodiment 2: A biodegradable intraocular implant comprising a biodegradable polymeric material and Compound 1:

[0034]

[0035] wherein Compound 1 is present in an amount between 10 and 20% by weight of the implant, and wherein the implant releases less than 30% of Compound 1 in vitro during the first 24 hours.

[0036] Example Embodiment 3: The biodegradable intraocular implant according to Example Embodiment 2, wherein the implant releases less than 35% of Compound 1 in vitro during the first 24 hours.

[0037] Example Embodiment 4: The biodegradable intraocular implant according to Example Embodiment 2, wherein the implant releases less than 20% of Compound 1 in vitro during the first 24 hours.

[0038] Example Embodiment 5: The biodegradable intraocular implant according to Example Embodiment 2, wherein the implant releases less than 15% of Compound 1 in vitro during the first 24 hours.

[0039] Example Embodiment 6: The biodegradable intraocular implant according to any of the preceding example embodiments, 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 wherein the PBS solution is a PBS solution that is free of magnesium and calcium and has a pH of 7.4 ± 0.05 at 25 °C.

[0040] Example Embodiment 7: A biodegradable intraocular implant comprising a biodegradable polymeric material and Compound 1:

[0041]

[0042] wherein i) Compound 1 is present in an amount between 10 and 20% by weight of the implant, ii) the implant releases Compound 1 continuously in vitro and / or in vivo in an eye for more than one month, and iii) the implant does not comprise polyethylene glycol.

[0043] Example Embodiment 8: The biodegradable intraocular implant of any of the preceding example embodiments, wherein the biodegradable polymeric material comprises a first polymer that is poly(D,L-lactide) having acid end groups and an intrinsic viscosity of about 0.16 to 0.24 dl / g; a second polymer that is poly(D,L-lactide) having ester end groups and an intrinsic viscosity of about 0.25 to 0.35 dl / g; and a third polymer that is poly(D,L-lactide-co-glycolide) having ester end 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, wherein the intrinsic viscosity of each polymer and copolymer is measured at 25 °C for a 0.1% solution of the polymer or copolymer in chloroform.

[0044] Example Embodiment 9: A biodegradable intraocular implant comprising a biodegradable polymeric material and Compound 1:

[0045]

[0046] wherein i) Compound 1 is in an amount between 10 and 20 weight percent of the implant, ii) the biodegradable polymeric material comprises a first polymer that is poly(D,L-lactide) having acid end groups and an intrinsic viscosity of about 0.16 to 0.24 dl / g; a second polymer that is poly(D,L-lactide) having ester end groups and an intrinsic viscosity of about 0.25 to 0.35 dl / g; and a third polymer that is poly(D,L-lactide-co-glycolide) having ester end 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, wherein the intrinsic viscosity of each polymer and copolymer is measured at 25 °C for a 0.1% solution of the polymer or copolymer in chloroform, and (iii) the amount of the second polymer is less than or equal to the amount of the third polymer, the second polymer being present in an amount of 20 to 40 wt%.

[0047] Example Embodiment 10: A biodegradable intraocular implant comprising a biodegradable polymeric material and Compound 1:

[0048]

[0049] wherein i) Compound 1 is present in an amount between 10 and 20 weight percent of the implant, ii) the biodegradable polymeric material comprises a first polymer that is poly(D,L-lactide) having acid end groups and an intrinsic viscosity of about 0.16 to 0.24 dl / g; a second polymer that is poly(D,L-lactide) having ester end groups and an intrinsic viscosity of about 0.25 to 0.35 dl / g; and a third polymer that is poly(D,L-lactide-co-glycolide) having ester end 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, wherein the intrinsic viscosity of each polymer and copolymer is measured at 25°C for a 0.1% solution of the polymer or copolymer in chloroform, and (iii) the weight ratio of the second polymer to the third polymer is 2:5 to 4:3.

[0050] Example Embodiment 11: The biodegradable intraocular implant of Example Embodiment 10, wherein the third polymer is present in an amount of about 30 to 70 wt%.

[0051] Example Embodiment 12: The biodegradable intraocular implant of Example Embodiment 10 or 11, wherein the first polymer is present in an amount of about 4 to 20 wt%.

[0052] Example Embodiment 13: The biodegradable intraocular implant of any one of Example Embodiments 9 to 12, wherein the implant releases less than 30% of Compound 1 in vitro during the initial 24 hours.

[0053] Example Embodiment 14: The biodegradable intraocular implant of Example Embodiment 13, wherein the implant releases less than 25% of Compound 1 in vitro during the initial 24 hours.

[0054] Example Embodiment 15: The biodegradable intraocular implant of Example Embodiment 13, wherein the implant releases less than 20% of Compound 1 in vitro during the initial 24 hours.

[0055] Example Embodiment 16: The biodegradable intraocular implant of Example Embodiment 13, wherein the implant releases less than 15% of Compound 1 in vitro during the initial 24 hours.

[0056] Example Embodiment 17: The biodegradable intraocular implant of any one of the preceding Example Embodiments, wherein the implant additionally comprises cetyl alcohol.

[0057] Example Embodiment 18: The biodegradable intraocular implant according to any one of the preceding example embodiments, wherein the implant further comprises butylated hydroxyanisole.

[0058] Exemplary Embodiment 19: The biodegradable intraocular implant according to any one of the preceding exemplary embodiments, wherein Compound 1 is present in an amount of 11, 12, or 15 wt% of the implant.

[0059] Example 20: The biodegradable intraocular implant according to any one of the preceding example embodiments, comprising about 12% by weight of Compound 1:

[0060]

[0061] about 16 weight percent of a first polymer, the first polymer being a poly(D,L-lactide) having acid end groups and an intrinsic viscosity of about 0.16 to 0.24 dl / g; about 25 weight percent of a second polymer, the second polymer being a poly(D,L-lactide) having ester end groups and an intrinsic viscosity of about 0.25 to 0.35 dl / g; about 40 weight percent of a third polymer, the third polymer being a poly(D,L-lactide-co-glycolide) having ester end 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 weight percent of cetyl alcohol and about 2 weight percent of butylated hydroxyanisole, wherein the intrinsic viscosities of the first, second, and third polymers correspond to the intrinsic viscosities measured for a 0.1% solution of the polymer in chloroform at 25°C.

[0062] Example 21: The biodegradable intraocular implant according to any of the preceding example embodiments, comprising about 12% by weight of Compound 1:

[0063]

[0064] about 6 wt.% of a first polymer that is poly(D,L-lactide) having acid end groups and an intrinsic viscosity of about 0.16 to 0.24 dl / g; about 30 wt.% of a second polymer that is poly(D,L-lactide) having ester end groups and an intrinsic viscosity of about 0.25 to 0.35 dl / g; about 45 wt.% of a third polymer that is poly(D,L-lactide-co-glycolide) having ester end 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 wt.% cetyl alcohol, and about 2 wt.% butylated hydroxyanisole, wherein the intrinsic viscosity of the first, second, and third polymers corresponds to the intrinsic viscosity measured at 25°C for a 0.1% solution of the polymer in chloroform.

[0065] Example Embodiment 22: The biodegradable intraocular implant of any of the preceding example embodiments, comprising about 15 wt.% of Compound 1:

[0066]

[0067] about 6 wt.% of a first polymer that is poly(D,L-lactide) having acid end groups and an intrinsic viscosity of about 0.16 to 0.24 dl / g; about 30 wt.% of a second polymer that is poly(D,L-lactide) having ester end groups and an intrinsic viscosity of about 0.25 to 0.35 dl / g; about 45 wt.% of a third polymer that is poly(D,L-lactide-co-glycolide) having ester end 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 wt.% cetyl alcohol, and about 2 wt.% butylated hydroxyanisole, wherein the intrinsic viscosity of the first, second, and third polymers corresponds to the intrinsic viscosity measured at 25°C for a 0.1% solution of the polymer in chloroform.

[0068] Example Embodiment 23: The biodegradable intraocular implant of any of the preceding example embodiments, comprising about 15 wt.% of Compound 1:

[0069]

[0070] about 5 weight percent of a first polymer that is poly(D,L-lactide) having acid end groups and an intrinsic viscosity of about 0.16 to 0.24 dl / g; about 30 weight percent of a second polymer that is poly(D,L-lactide) having ester end groups and an intrinsic viscosity of about 0.25 to 0.35 dl / g; about 45 weight percent of a third polymer that is poly(D,L-lactide-co-glycolide) having ester end 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 weight percent of cetyl alcohol and about 2 weight percent of butylated hydroxyanisole, wherein the intrinsic viscosity of the first, second, and third polymers corresponds to the intrinsic viscosity measured at 25°C for a 0.1% solution of the polymer in chloroform.

[0071] Example 24: The biodegradable intraocular implant of any of the preceding example embodiments, comprising about 11 weight percent of Compound 1:

[0072]

[0073] about 5 weight percent of a first polymer that is poly(D,L-lactide) having acid end groups and an intrinsic viscosity of about 0.16 to 0.24 dl / g; about 30 weight percent of a second polymer that is poly(D,L-lactide) having ester end groups and an intrinsic viscosity of about 0.25 to 0.35 dl / g; about 45 weight percent of a third polymer that is poly(D,L-lactide-co-glycolide) having ester end 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 weight percent of cetyl alcohol and about 2 weight percent of butylated hydroxyanisole, wherein the intrinsic viscosity of the first, second, and third polymers corresponds to the intrinsic viscosity measured at 25°C for a 0.1% solution of the polymer in chloroform.

[0074] Example 25: The biodegradable intraocular implant of any of the preceding example embodiments, comprising about 11 weight percent of Compound 1:

[0075]

[0076] about 12 wt% of a first polymer that is poly(D,L-lactide) having acid end groups and an intrinsic viscosity of about 0.16 to 0.24 dl / g; about 30 wt% of a second polymer that is poly(D,L-lactide) having ester end groups and an intrinsic viscosity of about 0.25 to 0.35 dl / g; about 40 wt% of a third polymer that is poly(D,L-lactide-co-glycolide) having ester end 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 wt% cetyl alcohol and about 2 wt% butylated hydroxyanisole, wherein the intrinsic viscosity of the first, second, and third polymers corresponds to the intrinsic viscosity measured at 25°C for a 0.1% solution of the polymer in chloroform.

[0077] Example Embodiment 26: The biodegradable intraocular implant of any one of Example Embodiments 20-25, wherein the implant releases less than 30% of Compound 1 in vitro during the initial 24 hours.

[0078] Example Embodiment 27: The biodegradable intraocular implant of Example Embodiment 26, wherein the implant releases less than 25% of Compound 1 in vitro during the initial 24 hours.

[0079] Example Embodiment 28: The biodegradable intraocular implant of Example Embodiment 26, wherein the implant releases less than 20% of Compound 1 in vitro during the initial 24 hours.

[0080] Example Embodiment 29: The biodegradable intraocular implant of Example Embodiment 26, wherein the implant releases less than 15% of Compound 1 in vitro during the initial 24 hours.

[0081] Example Embodiment 30: The biodegradable intraocular implant of any one of Example 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 wherein the PBS solution is a PBS solution that is free of magnesium and calcium and has a pH of 7.4 ± 0.05 at 25°C.

[0082] Example Embodiment 31 : The biodegradable intraocular implant of any one of the preceding Example Embodiments, wherein the implant is sized for placement in the anterior chamber of an eye.

[0083] Example 32: The biodegradable intraocular implant of any of the preceding example embodiments, wherein the implant has a diameter of about 150 pm and the implant contains about 5 pg or about 7.5 pg of Compound 1.

[0084] Example 33: A method for reducing intraocular pressure in a patient comprising placing a biodegradable intraocular implant according to any of example embodiments 1-32 in the eye of the patient.

[0085] Example 34: The method of example embodiment 33, wherein the patient has, is diagnosed with, or is at risk of developing elevated intraocular pressure or glaucoma.

[0086] Example 35: The method of example embodiment 33 or 34, wherein the intraocular implant is placed in the anterior chamber of the eye of the patient.

[0087] Example 36: The method of any of example embodiments 33-35, wherein the patient is a human.

[0088] Example 37: The biodegradable intraocular implant of any of example embodiments 1-32 for use in a method of reducing intraocular pressure in a patient, the method comprising placing the intraocular implant in the eye of the patient.

[0089] Example 38: The biodegradable intraocular implant for use of example embodiment 37, wherein the patient has, is diagnosed with, or is at risk of developing elevated intraocular pressure or glaucoma.

[0090] Example 39: The biodegradable intraocular implant for use of example embodiment 37 or 38, wherein the intraocular implant is placed in the anterior chamber of the eye of the patient.

[0091] Example 40: The biodegradable intraocular implant for use of any of example embodiments 37-39, wherein the patient is a human.

[0092] Example 41: Use of a biodegradable intraocular implant according to any of example embodiments 1-32 in the manufacture of a medicament for reducing intraocular pressure in a patient.

[0093] Example 42: The use of example embodiment 41, wherein the patient has, is diagnosed with, or is at risk of developing elevated intraocular pressure or glaucoma.

[0094] Example 45: Use of a biodegradable intraocular implant according to any one of Examples 1-32 in a method of reducing intraocular pressure in a patient, the method comprising placing the intraocular implant in the eye of the patient.

[0095] Example 44: Use according to any one of Examples 41-43, wherein the patient is a human.

[0096] Example 45: Use of a biodegradable intraocular implant according to any one of Examples 1-32 in a method of reducing intraocular pressure in a patient, the method comprising placing the intraocular implant in the eye of the patient.

[0097] Example 46: Use according to Example 45, wherein the patient has, is diagnosed with, or is at risk of developing elevated intraocular pressure or glaucoma.

[0098] Example 47: Use according to Example 45 or 46, wherein the biodegradable intraocular implant is placed in the anterior chamber of the eye of the patient.

[0099] Example 48: Use according to any one of Examples 45-47, wherein the patient is a human.

[0100] Example 49: A biodegradable intraocular implant substantially as described herein.

[0101] Example 50: A biodegradable intraocular implant comprising Compound 1 substantially as described herein:

[0102] BRIEF DESCRIPTION OF DRAWINGS

[0103] Figure 1 A cross-section of a mammalian eye is shown.

[0104] Figure 2 In vitro cumulative total percent release of Compound 1 into phosphate buffered saline (0.01 M; pH 7.4) at 37 °C over time is shown for six (6) individual implants (Implants 1-6). The composition of each implant is described in Table 2.

[0105] Figure 3 In vitro cumulative total percent release of Compound 1 into phosphate buffered saline (0.01 M; pH 7.4) at 37 °C over time is shown for Implants 1, 2 4, and 7. The composition of each implant is described in Table 2.

[0106] Figure 4In vitro cumulative total percent release of Compound 1 into phosphate buffered saline (0.01 M; pH 7.4) over time at 37 °C is shown for implants 1 and 5. The composition of each implant is set forth in Table 2.

[0107] Figure 5 In vitro daily release rate of Compound 1 into phosphate buffered saline (0.01 M; pH 7.4) over time at 37 °C is shown for implants 1 and 5. The composition of each implant is set forth in Table 2.

[0108] Figure 6 In vitro cumulative total percent release of Compound 1 (API) in R202H implants at different loading of Compound 1 (wt %) is shown.

[0109] Figure 7 Swelling study results for implants 1 and 5 are shown by image.

[0110] Figure 8 Swelling study results for implants 1 and 5 are shown by graph. DETAILED DESCRIPTION

[0111] DEFINITIONS

[0112] “Cumulative release profile” means the cumulative total percent of Compound 1 released from an implant in vivo into the ocular region over time or released in vitro into a particular release medium (e.g., PBS) over time.

[0113] “Prodrug” means a compound that is converted by the in vivo mechanisms (e.g., by metabolism or a chemical process) to produce the active form of the compound, e.g., a drug precursor. The conversion can occur by different mechanisms, e.g., by hydrolysis.

[0114] “Intraocular implant” means a device or element configured to be placed in the eye. Examples include an extruded filament comprising a biodegradable polymeric material and a pharmaceutically active agent, such as Compound 1, associated with the polymeric material, and the filament is cut to a length suitable for placement in the eye. The intraocular implant is generally biocompatible with the physiological conditions of the eye and does not cause adverse reactions in the eye. In certain embodiments described herein, the intraocular implant can be designed and formulated for placement in the anterior chamber or the vitreous of the eye. The intraocular implant can be placed in the eye without significantly impairing vision of the eye. An intraocular implant comprising one or more biodegradable polymers and Compound 1 or a pharmaceutically acceptable salt thereof is an example of an intraocular implant (drug delivery system) within the scope of the present disclosure.

[0115] An “intracameral” implant is an intraocular implant sized and formulated for placement in the anterior chamber of the eye. Non-limiting examples include implants 2-6 described in Table 2.

[0116] An “intravitreal” implant is an intraocular implant sized and formulated for placement in the vitreous of the eye.

[0117] With respect to implants, “adapted for, sized for, or structured for insertion, implantation, or placement in (or to) an ocular region or site” means that the implant has a size (e.g., dimensions and weight) such that it can be inserted, implanted, or placed in an ocular region, such as the anterior chamber or vitreous of the eye, without causing undue tissue damage or significantly impairing the existing vision of the patient into which the implant is implanted or inserted.

[0118] As used herein, “treating” and “treatment” include any beneficial effect on the eye of a patient resulting from the methods of the present application. Treating an ocular condition, such as ocular hypertension or elevated intraocular pressure, or glaucoma, can reduce or resolve the ocular condition, or can reduce or delay the progression of one or more signs, symptoms, or risk factors of the ocular condition or one or more signs, symptoms, or risk factors associated with the ocular condition. The sign or signs or the symptom or symptoms that are positively affected by the treatment will depend on the particular condition. Examples of beneficial (and thus positive) effects resulting from the methods of the present application can include reducing intraocular pressure, ocular pain (i.e., eye pain), ocular swelling, and / or ocular inflammation. In some cases, treatment by any of the methods described herein using one or more of the intraocular implants described herein can also improve the overall health, comfort, and / or visual performance of the eye.

[0119] “Active agent,” “drug,” “therapeutic agent,” “therapeutically active agent,” and “pharmaceutically active agent” refer to Compound 1.

[0120] A “patient” can be a human or non-human mammal in need of treatment.

[0121] An “eye” is the organ of sight and includes the eyeball or globe, which is the orbital sensory organ that receives light and transmits visual information to the central nervous system. Broadly, the eye includes the eyeball and the ocular regions, tissues, and fluids that make up the eyeball, the extraocular muscles (such as the oblique and rectus muscles), and the portion of the optic nerve that is within or near the eyeball.

[0122] The term “therapeutically effective amount” or “effective amount” refers to the level or amount of active agent that is typically required to treat an ocular condition without causing significant negative or adverse side effects to the eye or region of the eye to which the agent is administered.

[0123] The term "biodegradable polymer" refers to one or more polymers that degrade in vivo, and wherein the degradation of the one or more polymers over time occurs concurrently with or subsequent to the release of the therapeutic agent. The biodegradable polymer can be a homopolymer, a copolymer, or a polymer comprising more than two different structural repeating units.

[0124] The term "ocular region" or "ocular site" generally refers to any region of the eyeball, including the anterior and posterior segments of the eye, and generally includes, but is not limited to, any functional (e.g., visual) or structural tissue found in the eyeball, or a layer of tissue or cells that is partially or completely disposed within or outside the eyeball. Particular examples of ocular regions in the eye include the anterior chamber, posterior chamber, vitreous chamber (vitreous or vitreous body), choroid, suprachoroidal space, conjunctiva, subconjunctival space, subtenon's space, episcleral space, intracorneal space, supracorneal space, sclera, pars plana, surgically created avascular regions, macula, and retina.

[0125] As used herein, an "ocular condition" is a disease, ailment, or condition that affects or involves the eye or one part or region of the eye. Broadly, the eye includes the eyeball and the tissues and fluids that make up the eyeball, the periocular muscles (such as the oblique and rectus muscles), and the portion of the optic nerve that is within or near the eyeball.

[0126] Unless otherwise indicated herein, the term "about," as used in reference to a value (e.g., a weight percent) is intended to include values that are near to (and / or within an acceptable error range of) the recited value (and / or range of values) that are equivalent in function to the recited value (and / or range of values) (e.g., that are bioequivalent). Furthermore, as will be understood by those in the art, all numbers, including numerical ranges, expressed either herein as a group of individual values, or as a range of values, are approximate values, and are understood to be optionally modified by the term "about," to encompass equivalent values that are within an acceptable error range of the recited value (and / or range of values). It is also understood that such values inherently contain variability due to, for example, standard deviation found in their respective testing measurements, and that some values and amounts can be rounded off to the nearest whole number, or to the nearest tenth or hundredth, so that, for example, they will be the "same" as another value or amount. It is further understood that some values and amounts can be rounded off to the nearest whole number, or to the nearest tenth or hundredth, so that, for example, they will be the "same" as another value or amount.

[0127] A anterior ocular condition is a disease, ailment, or condition that affects or involves the anterior ocular region or site (i.e., the front of the eye), which is the area or site such as the periocular muscles, the eyelids, or the globe tissue or fluid located anterior to the posterior wall of the lens capsule or ciliary muscle. Thus, an anterior ocular condition primarily affects or involves the conjunctiva, cornea, anterior chamber, iris, posterior chamber (behind the retina but in front of the posterior wall of the lens capsule), lens or lens capsule, and the blood vessels and nerves that vascularize or innervate the anterior ocular region or site. Glaucoma can be considered an anterior ocular condition because the clinical goal of glaucoma treatment can be to reduce the high pressure of aqueous humor in the anterior chamber of the eye (i.e., to lower intraocular pressure).

[0128] A posterior ocular condition is a disease, ailment, or condition that primarily affects or involves the posterior ocular region or site (i.e., the back of the eye), which is the area or site such as the choroid or sclera (located posterior to the plane that passes through the posterior wall of the lens capsule), vitreous, vitreous chamber, retina, optic nerve (i.e., optic disc), and the blood vessels and nerves that vascularize or innervate the posterior ocular region or site. Glaucoma can also be considered a posterior ocular condition because the goal of treatment is to prevent vision loss or reduce the occurrence of vision loss due to damage or loss of retinal cells or optic nerve cells (i.e., neuroprotection).

[0129] Size and configuration of biodegradable intraocular implants

[0130] A biodegradable implant sized and configured for placement in the eye of a patient (intraocular implant) and containing Compound 1 dispersed in a biodegradable polymeric material (or matrix) can be used to reduce intraocular pressure and treat glaucoma. Compound 1 is particularly effective at reducing intraocular pressure of the eye when administered directly to the anterior chamber of the eye. The biodegradable implant can be a safe, non-toxic, and effective means by which this compound can be administered to the anterior chamber.

[0131] Consistent with this delivery site, the size of the implant described herein can be designed and formulated to be received in the anterior chamber of an eye (e.g., a human eye), and particularly in the anterior chamber angle of the eye, with little or no adverse effect on the eye, particularly the corneal endothelium, and without obstructing or significantly damaging the patient's vision. The patient receiving the implant will receive a therapeutically effective amount of Compound 1, and ideally will experience little or no congestion or inflammation of the eye after the implant is placed in the eye. Then, in this regard, intraocular implants are disclosed herein, which are sized and formulated for placement in the anterior chamber of the eye, are biocompatible with the eye, cause little or no immune response or inflammation in the eye, and can effectively reduce the intraocular pressure of the eye for an extended period of time. For example, the excellent efficacy of Compound 1 for reducing IOP makes it possible to reduce the size of the intraocular implant required for delivering a therapeutically effective dose of IOP lowering agents to the target tissues and positions in the eye, such as the anterior chamber, to minimize potential irritation or damage to the tissues in the eye, and more generally provide increased safety and greater overall benefits and comfort to the patient. In addition, the use of smaller implants can reduce the time required for the implant to completely degrade in the eye after drug release. In addition, the ability to load the implant with a larger amount of Compound 1 (e.g., 15 wt % rather than a lower amount like 8 wt % or less) can also lead to more beneficial smaller implants without the initial burst release of Compound 1 seen in other implants with Compound 1.

[0132] The implant can be of a size suitable for insertion, placement, or implantation into an ocular region or site, such as the anterior chamber, posterior chamber, or vitreous body of the eye. The size of the implant can affect the release rate, treatment period, and concentration of Compound 1 in the treated tissue. At the same active agent loading, a larger implant can deliver a proportionally larger dose.

[0133] Implants designed to be placed in the anterior chamber (anterior chamber implants) can generally have a diameter (or other dimensions appropriate for non-cylindrical filaments) of about 100 to about 400 pm and a length of about 0.5 to about 6 mm. The implants can generally be formed by a single or double extrusion process, can be cylindrical or non-cylindrical, and can have a total weight in the range of about 10 pg to about 500 pg. The weight can depend in part on the desired dosage. In some embodiments, implants suitable for placement in the anterior chamber of the eye and suitable for use according to the present disclosure can have a diameter of between about 100 pm and about 300 pm, a length of between about 0.5 mm and about 3 mm (e.g., about 2 mm), and a total weight of between about 10 pg and about 200 pg or between about 10 pg and about 100 pg. In some cases, the total weight of an anterior chamber implant for reducing IOP is about 10 pg to about 100 pg, or more specifically about 30 to about 100 pg, where the dosage of active compound (e.g., Compound 1) depends on the weight percent of active compound as described herein (e.g., a weight percent of Compound 1 of about 15%, about 33.3 pg of the implant will contain about 5 pg amount of Compound 1, and about 50 pg of the implant will contain about 7.5 pg amount 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 pm or about 150 pm and a length of about 1.5 mm or about 2 mm.

[0134] The eyes of some patients with glaucoma or more generally ocular hypertension can be more amenable to placement of biodegradable implants in the vitreous of the eye. The vitreous can accept larger implants of the same general formulation. For example, intravitreal implants can have a length of about 1 mm to about 10 mm, a diameter of about 0.5 mm to about 1.5 mm, and a total weight of about 50 pg to about 5000 pg. The implants can be scaled up or down depending on the site of administration in the eye and the size or vitreous volume of the patient. While in most cases a single implant can be found to reduce intraocular pressure of the eye for a sustained period of time, in some cases the practitioner can 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.

[0135] With regard to configuration, the intraocular implants can be in the form of an extruded rod or in the form of a non-cylindrical filament, having the dimensions described above. According to the present disclosure, wafers, sheets or films and in some cases compressed tablets can also find use.

[0136] Biodegradable polymeric materials and other implant components

[0137] Generally, implants according to the present disclosure will comprise or consist of a biodegradable polymeric material and Compound 1 or a pharmaceutically acceptable salt thereof. The polymeric material can comprise, consist of, or consist essentially of one, two, three, or more biodegradable polymers and optionally one or more excipients to further improve the stability and / or release characteristics of the implant.

[0138] Examples of useful biodegradable polymers include poly(lactide) (lactic acid) and poly(glycolide) (glycolic acid) polymers and copolymers thereof (e.g., poly(lactide-co-glycolide) copolymers). In some embodiments, the biodegradable polymeric material can comprise poly(lactide), poly(lactide-co-glycolide), a mixture of two or more poly(lactide) polymers (e.g., a first and a second poly(lactide) polymer), a mixture of two or more poly(lactide-co-glycolide) copolymers, or a mixture of poly(lactide) and poly(lactide-co-glycolide) polymers. In particular forms of any of these implants, the poly(lactide) polymer can be poly(D,L-lactide) and the poly(lactide-co-glycolide) copolymer can be poly(D,L-lactide-co-glycolide). In any of the above combinations, the two or more polymers can differ from one another based on their end groups (e.g., acid and ester end groups), repeat units, intrinsic viscosity, or any combination thereof. The poly(lactide) and poly(lactide-co-glycolide) polymers used in the present implants can have carboxyl (-COOH) or ester end groups. Further, the two or more poly(lactide-co-glycolide) polymers can differ from one another due to the lactide:glycolide ratio in each polymer, which can vary between about 85:15 to about 50:50 to about 75:25, depending on the polymer.

[0139] Poly(D,L-lactide) or PLA can be identified by CAS Number 26680-10-4 and can be represented as:

[0140]

[0141] Poly(D,L-lactide-co-glycolide) or PLGA can be identified by CAS Number 26780-50-7 and can be represented as:

[0142]

[0143] where x is the number of D,L-lactide repeat units and y is the number of glycolide repeat units and n is the number of D,L-lactide-co-glycolide repeat units. Thus, poly(D,L-lactide-co-glycolide) (PLGA) comprises one or more blocks of D,L-lactide repeat units and one or more blocks of glycolide repeat units, where the size and number of individual blocks can vary.

[0144] The mole percentage of each monomer or repeating unit in the PLGA copolymer can be 0-100%, about 15-85%, about 25-75%, or about 35-65%. In some embodiments, D,L-lactide can be about 50% to about 75%, about 48% to about 52%, or about 50%; about 73% to about 77%, or about 75% by mole of the PLGA polymer. The remainder of the polymer can be substantially glycolide repeating units. For example, glycolide can be about 25% to about 50%, about 23% to about 27%, or about 25%; about 48% to about 52%, or about 50% by mole of the PLGA polymer. Other groups such as terminal or endcapping groups (end groups) can be present in small amounts. As noted above, in some embodiments, the PLGA copolymer is used in conjunction with a PLA polymer. In some implants, a 75 / 25 PLGA polymer with ester end groups is used.

[0145] The hydrophilic or hydrophobic nature of the end groups can be useful in the degradation of different polymer materials. Polymers with hydrophilic end groups can degrade faster than polymers with hydrophobic end groups because the hydrophilic groups can absorb water. Examples of suitable hydrophilic end groups include, but are not limited to, carboxyl (acid end groups), hydroxyl, and polyethylene glycol. These groups can be introduced by using a suitable initiator. End groups can also be introduced after polymerization is complete to convert terminal hydroxyl groups to other end groups. For example, ethylene oxide can convert hydroxyl groups to polyethylene glycol. Hydrophobic terminal (also known as endcapped or end-terminated) polymers have ester linkages at the end of the polymer that are intrinsically hydrophobic.

[0146] Other polymers of interest include or can be selected from the group consisting of hydroxyaliphatic carboxylic acids, homopolymers or copolymers, hyaluronic acid, sodium hyaluronate, polycaprolactone, polysaccharides, polyethers, calcium alginate, cellulose, carboxymethylcellulose, polyvinyl alcohol, polyesters, and combinations thereof.

[0147] Useful polysaccharides can include, but are not limited to, calcium alginate and functionalized cellulose such as carboxymethyl cellulose esters characterized, for example, by being insoluble in water and having a molecular weight of about 5 kD to about 500 kD.

[0148] Release of a drug from a biodegradable polymeric material is the result of several mechanisms or a combination of various mechanisms. Some of these mechanisms include desorption from the surface of the implant, dissolution, diffusion through porous channels of the hydrated polymer, and erosion of one or more polymers that make up the matrix. Erosion can be bulk erosion or surface erosion or a combination of both. The polymeric matrix can release the therapeutic agent at a rate effective to release an amount of the agent (e.g., Compound 1) for a duration of more than one month, 2-3 months, 3-6 months, or 6 months or more after implantation in the eye. For example, the implant can include Compound 1, and the polymeric material (or matrix) of the implant can degrade at a rate effective to release a therapeutically effective amount of Compound 1 for a duration of more than one month, e.g., two, three, four, five, or six months, in vitro or after placement in the eye, or more specifically, after placement in the anterior chamber of the eye.

[0149] The one or more biodegradable polymers used to form the matrix (polymeric material of the implant) desirably are subject to the effects of enzymatic or hydrolytic instability. Additional properties of the one or more polymers include biocompatibility, compatibility with the therapeutic component, ease of use of the polymer in the manufacture of the implant of the disclosure, a half-life of at least about 6 hours, e.g., more than about one day, in a physiological environment, and water insolubility.

[0150] The biodegradable polymeric material degrades in vivo in a manner that provides release of a therapeutically effective amount of the therapeutic agent for a period of time that is significantly longer than the in vivo lifetime of the agent when administered in an eye drop formulation. As discussed previously, the polymeric material can be a single polymer or copolymer, or in some cases, a combination or blend of biodegradable polymers and / or copolymers.

[0151] In addition to the one or more biodegradable polymers and Compound 1 or a pharmaceutically acceptable salt thereof, the intraocular implant according to the disclosure can include one or more excipients to improve the stability (e.g., shelf life) of the therapeutic agent in the final implant, ease of manufacture and handling of the implant, and / or release properties of the implant. For example, Compound 1 is susceptible to oxidative degradation under different manufacturing, formulation, and storage conditions. The present inventors believe that the primary degradation product is the C-15 ketone.

[0152] Examples of excipients for any of these purposes can include preservatives, antioxidants, chelating agents, electrolytes, or other excipients. Generally, when present, the excipients can constitute 0.001 to 10% or up to 15% by weight of the implant, and can be selected from any of the excipients mentioned below.

[0153] Useful water-soluble preservatives can include sodium bisulfite, sodium bisulfate, sodium thiosulfate, benzalkonium chloride, chlorobutanol, thiomersal, phenylmercuric acetate, phenylmercuric nitrate, methyl paraben, benzyl alcohol, polyvinyl alcohol, and phenethyl alcohol.

[0154] Suitable electrolytes can include sodium chloride, potassium chloride, and the like, including MgCh. Zinc salts can also be of interest.

[0155] Examples of antioxidants include ascorbate salts, ascorbic acid, L-ascorbic acid, melatonin, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), thiols, polyphenols, tocopherols such as a-tocopherol, mannitol, reduced glutathione, various carotenoids, cysteine, taurine, tyrosine, superoxide dismutase, lutein, zeaxanthin, cryptoxanthin, astaxanthin, lycopene, N-acetyl cysteine, carnosine, gamma-glutamylcysteine, quercetin, lactoferrin, vitamin E or esters of vitamin E, retinyl palmitate, and derivatives thereof.

[0156] Useful chelating agents can be selected from, for example, ethylenediaminetetraacetic acid (EDTA), ethylenediamine, porphyrins, and vitamin B-12.

[0157] Other excipients can include alcohols, such as cetyl alcohol (also known as spermaceti alcohol and hexadecan-1-ol, and sometimes denoted as C16-OH). In some embodiments, the implant can comprise a straight-chain or branched-chain alcohol having a length of greater than 10 carbons.

[0158] The implants described herein can comprise a combination of two or more of the above-mentioned excipients.

[0159] Oxygen can be an important element in the degradation pathway of therapeutic agents such as Compound 1. Other or additional means for extending the shelf life of the implant and maintaining the potency of the implant once manufactured can include storing the implant in an oxygen-free or oxygen-poor atmosphere, such as a step in a sealed bag (e.g., an aluminum bag) that includes an oxygen adsorbent packet. An additional step can include filling the bag with nitrogen or argon or some other inert gas prior to sealing the bag to additionally remove oxygen from the bag.

[0160] 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 greater than about 95%, or at least about 98% (or loses no more than about 5% or no more than about 2% of its initial potency) of its initial potency of the active agent Compound 1 in a sealed bag comprising an oxygen adsorbent and / or an inert gas at 25°C after one month or three months of storage of the extruded implant, based on the actual or theoretical amount of active agent Compound 1 present in the implant immediately after manufacture of the implant in weight by weight (w / w). In some embodiments, the implant can additionally comprise a needle tip ophthalmic implant delivery device in the bag, and the bag can additionally contain a desiccant.

[0161] In one embodiment, the biodegradable polymeric material comprises, consists essentially of, or consists of a first, second, and third biodegradable polymers. The first and second polymers can be poly(D,L-lactide) polymers that differ from one another due to their end groups (ester or acid) and / or their intrinsic viscosity (as determined at 25 °C for a 0.1% solution in chloroform), and the third polymer can be poly(D,L-lactide-co-glycolide). The implant can optionally additionally comprise cetyl alcohol and / or butylated hydroxyanisole (BHA).

[0162] In one embodiment, the first polymer is poly(D,L-lactide) having ester end groups and an intrinsic viscosity of 0.25-0.35 dl / g (as measured at 25 °C for a 0.1% w / v solution in chloroform) (e.g., R203S); the second polymer is poly(D,L-lactide) having acid end groups (i.e., carboxyl end groups) and an intrinsic viscosity of 0.25-0.35 dl / g (as measured at 25 °C for a 0.1% w / v solution in chloroform) (e.g., R203H); and the third polymer is poly(D,L-lactide-co-glycolide) having ester end groups, an intrinsic viscosity of 0.16-0.24 dl / g (as measured at 25 °C for a 0.1% w / v solution in chloroform), and a D,L-lactide:glycolide ratio of about 75:25 (e.g., RG752S).

[0163] In some embodiments, the first, second, and third biodegradable polymers are independently selected from the group consisting of:

[0164] R202H, which is poly(D,L-lactide) having acid end groups and an intrinsic viscosity of 0.16-0.24 dl / g as measured at 25 °C for a 0.1% solution in chloroform;

[0165] R202S, which is poly(D,L-lactide) having ester end groups and an intrinsic viscosity of 0.16-0.24 dl / g as measured at 25 °C for a 0.1% solution in chloroform;

[0166] R203H, which is poly(D,L-lactide) having acid end groups and an intrinsic viscosity of 0.25-0.35 dl / g as measured at 25 °C for a 0.1% solution in chloroform;

[0167] R203S, which is poly(D,L-lactide) having ester end groups and an intrinsic viscosity of 0.25-0.35 dl / g as measured at 25 °C for a 0.1% solution in chloroform; and

[0168] RG752S, which is a poly(D,L-lactide-co-glycolide) having ester end groups and an inherent viscosity of 0.16-0.24 dl / g (as measured at 25 °C for a 0.1% solution in chloroform) and a D,L-lactide:glycolide molar ratio of about 75:25.

[0169] The above-mentioned R202H, R202S, R203H, R203S, and RG752S PLA and PLGA polymers are from the RESOMER® polymer product line produced by Evonik Industries AG, Germany and are available from chemical suppliers such as Sigma-Aldrich / Millipore Sigma and other suppliers that can be identified by the skilled person upon reading the present disclosure. The above-mentioned R202H, R202S, R203H, R203S, and RG752S PLA and PLGA polymers are from the RESOMER® polymer product line produced by Evonik Industries AG, Germany and are available from chemical suppliers such as Sigma-Aldrich / Millipore Sigma and other suppliers that can be identified by the skilled person upon reading the present disclosure.

[0170] In one embodiment, the first polymer is a poly(D,L-lactide) having ester end groups and an inherent viscosity of 0.25-0.35 dl / g, the second polymer is a poly(D,L-lactide) having acid end groups and an inherent viscosity of 0.16-0.24 dl / g, and the third polymer is a poly(D,L-lactide-co-glycolide) having ester end groups and an inherent viscosity of 0.16-0.24 dl / g and a D,L-lactide:glycolide ratio of about 75:25, wherein the inherent viscosity of each polymer or copolymer is measured at 25 °C for a 0.1% solution of the polymer or copolymer in chloroform.

[0171] In one specific embodiment, the first polymer is R203S, the second polymer is R202H, and the third polymer is RG752S, and the implant additionally comprises the excipients hexadecan-1-ol and / or BHA. In a specific form, the implant comprises 0.001% to 10% by weight of hexadecan-1-ol.

[0172] In another embodiment, the biodegradable polymeric material comprises, consists essentially of, or consists of a first and a second biodegradable polymer, wherein the first polymer is a poly(D,L-lactide) having ester end groups and an inherent viscosity of 0.25-0.35 dl / g (as measured at 25 °C for a 0.1% w / v solution in chloroform) (e.g., R203S), and the second polymer is a poly(D,L-lactide) having acid end groups (i.e., carboxyl groups) and an inherent viscosity of 0.25-0.35 dl / g (as measured at 25 °C for a 0.1% w / v solution in chloroform) (e.g., R203H).

[0173] In another embodiment, the biodegradable polymeric material comprises, consists essentially of, or consists of poly(D,L-lactide) having acid end groups (i.e., carboxyl end groups) and an intrinsic viscosity of 0.16-0.24 dl / g (as measured at 25 °C for a 0.1% w / v solution in chloroform) (e.g., R202H).

[0174] In another embodiment, the biodegradable polymeric material comprises, consists essentially of, or consists of poly(D,L-lactide) having acid end groups (i.e., carboxyl end groups) and an intrinsic viscosity of 0.25-0.35 dl / g (as measured at 25 °C for a 0.1% w / v solution in chloroform) (e.g., R203H).

[0175] One embodiment is an extruded biodegradable intracameral implant comprising Compound 1, hexadecan-1-ol (cetyl alcohol), and a biodegradable polymeric material, wherein the biodegradable polymeric material comprises, consists essentially of, or consists of a first, second, and third polymer, wherein the first polymer is R203S, the second polymer is R202H, and the third polymer is RG752S. The implant can additionally comprise an antioxidant. Non-limiting examples include implants 2-7, the formulations of which are listed in Table 2 below.

[0176] One embodiment is a biodegradable intraocular implant comprising a biodegradable polymeric material, hexadecan-1-ol, BHA, and about 15 wt% of Compound 1:

[0177]

[0178] wherein the biodegradable polymeric material comprises i) poly(D,L-lactide) having ester end groups and an intrinsic viscosity of about 0.25-0.35 dl / g (e.g., R203S), ii) poly(D,L-lactide) having acid end groups and an intrinsic viscosity of about 0.16-0.24 dl / g (e.g., R202H), and iii) poly(D,L-lactide-co-glycolide) having ester end groups, an intrinsic viscosity of about 0.16-0.24 dl / g, and a D,L-lactide:glycolide ratio of about 75:25 (e.g., R752S), wherein the intrinsic viscosity of each poly(D,L-lactide) and poly(D,L-lactide-co-glycolide) as given above is measured at 25 °C for a 0.1% solution of the polymer in chloroform. In some embodiments, the implant is an extruded implant.

[0179] In one embodiment, the implant additionally comprises an antioxidant, a chelating agent, or both an antioxidant and a chelating agent. In a particular form, the antioxidant is butylated hydroxyanisole or ascorbic acid, and the chelating agent is EDTA. The intraocular implant can be sized to be placed in the anterior chamber of the eye.

[0180] The implant according to any of the embodiments listed above can comprise more than about 8 wt% but no more than about 20 wt% of Compound 1. For example, Compound 1 can be present in the implant in an amount of about 11, about 12, or about 15 wt% of the implant. The implant can contain about 15 wt% of Compound 1.

[0181] One example embodiment is an intraocular implant comprising: about 12 wt% of Compound 1; about 16 wt% of a first polymer that is poly(D,L-lactide) having acid end groups and an intrinsic viscosity of about 0.16-0.24 dl / g; about 25 wt% of a second polymer that is poly(D,L-lactide) having ester end groups and an intrinsic viscosity of about 0.25-0.35 dl / g; about 40 wt% of a third polymer that is poly(D,L-lactide-co-glycolide) having ester end groups and an intrinsic viscosity of about 0.16-0.24 dl / g and a D,L-lactide:glycolide ratio of about 75:25; about 5 wt% of cetyl alcohol; and about 2 wt% of butylated hydroxyanisole, wherein the intrinsic viscosities of the first, second, and third polymers correspond to the intrinsic viscosities measured at 25°C for a 0.1% solution of the polymer in chloroform.

[0182] Another example embodiment is an implant comprising: about 12 wt% of Compound 1; about 6 wt% of a first polymer that is poly(D,L-lactide) having acid end groups and an intrinsic viscosity of about 0.16-0.24 dl / g; about 30 wt% of a second polymer that is poly(D,L-lactide) having ester end groups and an intrinsic viscosity of about 0.25-0.35 dl / g; about 45 wt% of a third polymer that is poly(D,L-lactide-co-glycolide) having ester end groups and an intrinsic viscosity of about 0.16-0.24 dl / g and a D,L-lactide:glycolide ratio of about 75:25; about 5 wt% of cetyl alcohol; and about 2 wt% of butylated hydroxyanisole, wherein the intrinsic viscosities of the first, second, and third polymers correspond to the intrinsic viscosities measured at 25°C for a 0.1% solution of the polymer in chloroform.

[0183] Another example embodiment is an implant comprising: about 15 wt% of Compound 1; about 15 wt% of a first polymer that is poly(D,L-lactide) having acid end groups and an intrinsic viscosity of about 0.16-0.24 dl / g; about 25 wt% of a second polymer that is poly(D,L-lactide) having ester end groups and an intrinsic viscosity of about 0.25-0.35 dl / g; about 40 wt% of a third polymer that is poly(D,L-lactide-co-glycolide) having ester end groups and an intrinsic viscosity of about 0.16-0.24 dl / g and a D,L-lactide:glycolide ratio of about 75:25; about 3 wt% of cetyl alcohol; and about 2 wt% of butylated hydroxyanisole, wherein the intrinsic viscosities of the first, second, and third polymers correspond to the intrinsic viscosities measured at 25°C for a 0.1% solution of the polymer in chloroform.

[0184] Another example embodiment is an implant comprising: about 15 wt% of Compound 1; about 5 wt% of a first polymer that is poly(D,L-lactide) having acid end groups and an intrinsic viscosity of about 0.16-0.24 dl / g; about 30 wt% of a second polymer that is poly(D,L-lactide) having ester end groups and an intrinsic viscosity of about 0.25-0.35 dl / g; about 45 wt% of a third polymer that is poly(D,L-lactide-co-glycolide) having ester end groups and an intrinsic viscosity of about 0.16-0.24 dl / g and a D,L-lactide:glycolide ratio of about 75:25; about 3 wt% of cetyl alcohol; and about 2 wt% of butylated hydroxyanisole, wherein the intrinsic viscosities of the first, second, and third polymers correspond to the intrinsic viscosities measured at 25°C for a 0.1% solution of the polymer in chloroform.

[0185] Another example embodiment is an implant comprising: about 15 wt% of Compound 1; about 5 wt% of a first polymer that is poly(D,L-lactide) having acid end groups and an intrinsic viscosity of about 0.16-0.24 dl / g; about 30 wt% of a second polymer that is poly(D,L-lactide) having ester end groups and an intrinsic viscosity of about 0.25-0.35 dl / g; about 45 wt% of a third polymer that is poly(D,L-lactide-co-glycolide) having ester end groups and an intrinsic viscosity of about 0.16-0.24 dl / g and a D,L-lactide:glycolide ratio of about 75:25; about 3 wt% of cetyl alcohol; and about 2 wt% of butylated hydroxyanisole, wherein the intrinsic viscosities of the first, second, and third polymers correspond to the intrinsic viscosities measured at 25°C for a 0.1% solution of the polymer in chloroform.

[0186] Another example embodiment is an implant comprising: about 11 wt% of Compound 1; about 12 wt% of a first polymer that is poly(D,L-lactide) having acid end groups and an intrinsic viscosity of about 0.16-0.24 dl / g; about 30 wt% of a second polymer that is poly(D,L-lactide) having ester end groups and an intrinsic viscosity of about 0.25-0.35 dl / g; about 40 wt% of a third polymer that is poly(D,L-lactide-co-glycolide) having ester end groups and an intrinsic viscosity of about 0.16-0.24 dl / g and a D,L-lactide:glycolide ratio of about 75:25; about 5 wt% of cetyl alcohol and about 2 wt% of butylated hydroxyanisole, wherein the intrinsic viscosities of the first, second, and third polymers correspond to the intrinsic viscosities measured at 25°C for a 0.1% solution of the polymer in chloroform.

[0187] therapeutic agent

[0188] Compound 1 can be prepared by methods known in the art. See, for example, U.S. Patent Nos. 6,602,900, 6,124,344, 5,741,810, and 5,834,498.

[0189] The present disclosure includes biodegradable intraocular implants made by an extrusion process that can effectively reduce intraocular pressure of a patient’s eye over an extended period of time. Generally, the implant comprises, consists essentially of, or consists of a biodegradable polymeric 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.

[0190] Generally, the therapeutic agent of the implant can constitute 1% to about 90% of the total weight of the implant. In some embodiments, the therapeutic agent can constitute more than 8% to 20% of the total weight of the implant. In some embodiments, Compound 1 is in the implant in an amount that does not exceed 15% of the total weight of the implant on a weight by weight (w / w) basis. Thus, in implants comprising Compound 1, Compound 1 can constitute greater than 8% to 15% by weight of the implant, and particular forms thereof constitute 11, 12, or 15% by weight of the implant. The weight percent of Compound 1 in the implant at these prescribed levels (e.g., 15%) can avoid an undesirable rapid or burst release of the drug after placement of the implant in a liquid environment, such as the eye.

[0191] In implants according to the present disclosure, Compound 1 can be dispersed or distributed in and / or covered by and / or surrounded by biodegradable polymeric material. When the implant is in contact with physiological fluid, such as intraocular fluid (e.g., aqueous humor), in the body, the physiological fluid can contact portions of Compound 1 on the surface of the implant, but can not contact portions of the Compound dispersed within the interior of the polymeric material. Once implanted, the biodegradable polymer can begin to hydrate. Hydration of the implant can improve diffusion and release of Compound 1. In addition, the implant can begin to degrade or erode over time. Degradation can increase hydration, increase the mobility of the polymer chains, and create pores that diffuse more quickly. Thus, the implant can be configured such that Compound is released from the polymeric material as the polymeric material hydrates and / or degrades in the body. Because hydration breakdown and / or degradation of the implant can take a significant amount of time - and can be significantly longer than the normal decay period of the Compound when administered in a normal eye drop formulation - the implant can provide sustained release. Sustained release can continue as long as at least some of the biodegradable polymeric material containing at least a portion of Compound 1 remains intact.

[0192] The rate at which Compound 1 is released from the implant and the duration of time that the implant releases Compound 1 can depend on a variety of factors, including but not limited to implant size and shape, particle size of the Compound, solubility of the Compound, ratio of Compound to polymeric material, the polymer(s) used (including the ratio of monomers in the polymer used, polymer end groups, and polymer molecular weight), polymer crystallinity, manufacturing method, surface area exposed, rate of erosion of the polymeric material, and the biological environment in which the implant is placed after administration, among others.

[0193] Implants comprising biodegradable polymeric material of the type described above can provide a sustained, prolonged period of constant, steady release of Compound 1, such as over 1 month, such as 2, 3, 4-5, or 6 months. In particular, the present inventors have surprisingly found that the implant formulations described herein provide controlled release and low burst of Compound 1 with, for example, a drug loading of 15% (w / w).

[0194] In particular, the biodegradable intraocular implant comprises a biodegradable polymeric material and Compound 1, wherein Compound 1 is in an amount between about 8 and about 20 weight percent of the implant (such as about 9 to about 18 weight percent, about 9 to about 17 weight percent, about 9 to about 16 weight percent, about 9 to about 15 weight percent, and about 10 to about 15 weight percent), and wherein the implant releases less than about 30% of the drug load in vitro on day 1 (e.g., in the first 24 hours after implantation), such as less than about 1%, less than about 2%, less than about 3%, less than about 4%, less than about 5%, less than about 6%, less than about 7%, less than about 8%, less than about 9%, less than about 10%, less than about 11%, less than about 12%, less than about 13%, less than about 14%, less than about 15%, less than about 16%, less than about 17%, less than about 18%, less than about 19%, less than about 20%, less than about 21%, less than about 22%, less than about 23%, less than about 24%, less than about 25%, less than about 26%, less than about 27%, less than about 28%, less than about 29%, and ranges between these amounts. In vitro release of more than about 30% of the drug load on day 1 will be considered a burst release.

[0195] Thus, in some embodiments, the in vitro release rate of the drug load on day 1 can be between about 1% and about 30%, between about 2% and about 30%, between about 3% and about 30%, between about 4% and about 30%, between about 5% and about 30%, between about 6% and about 30%, between about 7% and about 30%, between about 8% and about 30%, between about 9% and about 30%, between about 10% and about 30%, between about 11% and about 30%, between about 12% and about 30%, between about 13% and about 30%, between about 14% and about 30%, between about 15% and about 30%, between about 16% and about 30%, between about 17% and about 30%, between about 18% and about 30%, between about 19% and about 30%, between about 20% and about 30%, between about 21% and about 30%, between about 22% and about 30%, between about 23% and about 30%, between about 24% and about 30%, between about 25% and about 30%, between about 26% and about 30%, between about 27% and about 30%, between about 28% and about 30%, between about 29% and about 30%, and ranges between these amounts.

[0196] In other embodiments, the in vitro release rate of the drug load at day 1 can be between about 1% and about 25%, between about 2% and about 25%, between about 3% and about 25%, between about 4% and about 25%, between about 5% and about 25%, between about 6% and about 25%, between about 7% and about 25%, between about 8% and about 25%, between about 9% and about 25%, between about 10% and about 25%, between about 11% and about 25%, between about 12% and about 25%, between about 13% and about 25%, between about 14% and about 25%, between about 15% and about 25%, between about 16% and about 25%, between about 17% and about 25%, between about 18% and about 25%, between about 19% and about 25%, between about 20% and about 25%, between about 21% and about 25%, between about 22% and about 25%, between about 23% and about 25%, between about 24% and about 25%, and ranges between.

[0197] In other embodiments, the in vitro release rate of the drug load at day 1 can be between about 1% and about 20%, between about 2% and about 20%, between about 3% and about 20%, between about 4% and about 20%, between about 5% and about 20%, between about 6% and about 20%, between about 7% and about 20%, between about 8% and about 20%, between about 9% and about 20%, between about 10% and about 20%, between about 11% and about 20%, between about 12% and about 20%, between about 13% and about 20%, between about 14% and about 20%, between about 15% and about 20%, between about 16% and about 20%, between about 17% and about 20%, between about 18% and about 20%, between about 19% and about 20%, and ranges between.

[0198] In other embodiments, the in vitro release rate of the drug load at day 1 can be between about 1% and about 15%, between about 2% and about 15%, between about 3% and about 15%, between about 4% and about 15%, between about 5% and about 15%, between about 6% and about 15%, between about 7% and about 15%, between about 8% and about 15%, between about 9% and about 15%, between about 10% and about 15%, between about 11% and about 15%, between about 12% and about 15%, between about 13% and about 15%, between about 14% and about 15%, and ranges between.

[0199] U.S. Patent No. 9,889,142 (the '142 patent) describes the prolonged, long-term reduction of intraocular pressure of the eye provided by intraocular administration of one or more of biodegradable intraocular implants comprising Compound 1. However, the '142 patent describes that implants comprising therapeutic agents in amounts greater than 8.0 wt% along with the amounts of biodegradable polymers described in the '142 patent show a significant initial burst release of Compound 1 and / or provide very fast release rates (e.g., about 55% released on day 1 for implants with 12% drug loading) compared to implants comprising Compound 1 in amounts less than or equal to 8.0 wt%, which are generally considered unsuitable for the intended therapeutic use. Surprisingly, no such initial burst release was seen in the implant formulations described herein even at drug loadings exceeding 8 wt% (e.g., 15 wt%).

[0200] In vitro release rates of Compound 1 from implants can be measured by following the USP approved method for dissolution or release testing (USP 23; NF 18 (1995) pp. 1790-1798). For example, using the infinite sink method, a weighed implant sample is added to a measured volume of solution (release medium) containing 0.9% NaCl (aqueous solution) or phosphate buffered saline, where the solution volume will be such that the concentration of the therapeutically active agent after release is less than 20% of the saturation, and in some embodiments, less than 5% of the saturation. The mixture is maintained at 37 °C and slowly stirred or shaken to ensure diffusion of the therapeutically active agent from the implant. The appearance of the therapeutically active agent in the solution or release medium as a function of time can be confirmed by various methods known in the art such as spectrophotometry, HPLC, mass spectrometry, etc.

[0201] 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, wherein the PBS solution is a PBS solution that is free of magnesium and calcium 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 solution containing disodium hydrogen phosphate, sodium chloride, potassium chloride, and potassium dihydrogen phosphate. In addition to the sodium chloride and potassium chloride described above, PBS can be prepared to contain calcium chloride and magnesium chloride, or can be prepared to be free of calcium chloride and magnesium chloride (i.e., free of magnesium and calcium). PBS is a buffer that can mimic an approximate physiological pH of about 7.4 (e.g., 7.4 ± 0.05) and approximate osmotic pressure and ionic concentrations of many physiological fluids, including fluids in the eye. Thus, the PBS used to measure the in vitro release rate of Compound 1 is a PBS containing disodium hydrogen phosphate, sodium chloride, potassium chloride, and potassium dihydrogen phosphate that is free of magnesium and calcium and has a pH of 7.4 ± 0.05 at 25°C, and can be prepared according to known formulations such as the Cold Spring Harbor formulation (see, e.g., www web page cshprotocols.cshlp.org / content / 2006 / 1 / pdb.rec8247), or it can be purchased as a powder (or other solid mixture of non-aqueous ingredients) that can be reconstituted in water according to the manufacturer’s instructions (see, e.g., Sigma-Aldrich / Millipore Sigma Catalog No. P5368).

[0202] The in vitro release rate of a compound can be measured by incubating an implant in about 1 mL to about 3 mL of the above-described PBS at pH 7.4 under gentle agitation (50 rpm) at 37°C in a glass scintillation vial. At the designated time points, the release medium can be completely removed and replaced with fresh PBS. The amount of drug in the recovered release medium can be analyzed by, e.g., HPLC, which can be analyzed in triplicate if desired.

[0203] An intraocular implant according to the present disclosure can release about 5 to about 100 nanograms, about 5 to about 200 nanograms of Compound 1 per day, about 10 to about 200 nanograms of Compound 1 per day, about 5 to about 100 nanograms of Compound 1 per day, about 10 to about 100 nanograms of Compound 1 per day, about 10 to about 50 nanograms of Compound 1 per day, at least about 10 ng but no more than about 50 ng of Compound 1 per day, about 10 to about 35 ng of Compound 1 per day, or about 20 to about 35 nanograms of Compound 1 per day for more than about 1 month, more than about 2 months, between about 1 and about 3 months, about 3 to about 6 months, or about 6 to about 12 months or more.

[0204] Specific embodiments include, but are not limited to, extruded intraocular implants sized for placement in the anterior chamber of the eye and comprising any of the formulations given in Table 2 for implant numbers 2 to 7.

[0205] Manufacturing methods

[0206] Various techniques can be employed to manufacture the intraocular implants described herein. Useful techniques can include extrusion methods (e.g., hot melt extrusion) for producing rod-shaped implants (or fibers), compression methods for producing tablets, wafers, or granules, and solvent casting methods for producing biodegradable sheets, films, and dry powders. Emulsion methods for producing multiple microspheres can also be used to make biodegradable intraocular drug delivery systems for the sustained release of Compound 1 into a patient’s eye. Accordingly, one embodiment provides a pharmaceutical composition suitable for placement in an ocular region of an eye and comprising a plurality of biodegradable microspheres encapsulating Compound 1 or a pharmaceutically acceptable salt thereof.

[0207] Extruded implants can be made by single or double extrusion methods and can be made, for example, with a piston or twin-screw extruder. The choice of technique and manipulation of the technical parameters for producing the implants can affect the release rate of the drug. As the production temperature is increased, the extrusion method can allow for large-scale manufacturing of the implants and result in the implants gradually more uniformly dispersing the drug within a continuous polymer matrix. The extrusion method can use temperatures of about 50 °C to about 150 °C, or about 70 °C to about 100 °C, or lower if necessary.

[0208] In one embodiment, the intraocular implants according to the present disclosure are produced by an extrusion process. The polymer and excipients, if present, are typically blended with the therapeutic agent and then co-extruded at a selected temperature to form a filament comprising a biodegradable polymer matrix (or material) and the therapeutic agent dispersed in and / or distributed throughout the matrix (or material). If desired, the filament can be comminuted and re-extruded to form a double extruded implant.

[0209] In one variant of the implant produced by an extrusion process, the therapeutic agent, one or more biodegradable polymers, and optionally one or more excipients are first mixed at room temperature (blended in a container) and then heated to a temperature range of 50°C to 150°C for a period of between 1 and 60 minutes, such as 1 to 30 minutes, 5 minutes 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 into the desired length to produce an intraocular implant of a specific weight. The orifice of the nozzle through which the mixture is extruded will generally have a diameter suitable for the desired diameter of the implant, but if necessary, the extruded filament can be pulled from the nozzle to further reduce the diameter of the implant. Extruded implants can generally be cylindrical or non-cylindrical with a length and diameter (or other dimensions suitable for non-cylindrical fibers) suitable for placement in an ocular region of the eye, such as the anterior chamber or vitreous body.

[0210] A possible method for producing intraocular implants of the present disclosure uses a combination of solvent casting and hot melt extrusion. See, for example, US 2010 / 0278897. In this method, a dry powder or film is first prepared by dissolving all materials (active agent, one or more 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., TEFLON.RTM. tray) and then dried overnight in a vacuum oven to form a dry film. The film is then ground into particles, collected and extruded by hot melt extrusion to prepare a filament containing the active agent and one or more biodegradable polymers. The filament can be cut into a length and weight suitable for placement in the eye. The extrusion temperature used for this process can be in the range of 50°C to 150°C.

[0211] Thus, the present disclosure encompasses methods for making and using extruded biodegradable implants (which may generally be referred to as extruded rods or fibers) suitable for placement in an eye of a patient to reduce intraocular pressure, including elevated intraocular pressure in the eye.

[0212] Mode and site of administration and treatment methods

[0213] To provide the desired therapeutic effect (e.g., long-term reduction of intraocular pressure) in a patient, including a patient with glaucoma, an implant according to the present disclosure may be placed in the anterior chamber of the eye. The anterior chamber refers to the space inside the eye between the iris and the innermost corneal surface (endothelium). However, in some patients, it may be desirable to place the implant in the vitreous humor of the eye. The posterior chamber refers to the space inside the eye between the back of the iris and the front of the vitreous humor. The posterior chamber includes the space between the lens and the ciliary processes, which produce the aqueous humor that nourishes the cornea, iris, and lens and maintains intraocular pressure. References Figure 1These and other ocular regions of the eye (100) are shown in cross-section. Specific regions of the eye (100) include the cornea (102) and iris (104) surrounding the anterior chamber (106). Behind the iris (104) is the posterior chamber (108) and lens (110). Within the anterior chamber are the anterior chamber angle (112) and trabecular meshwork (114). Also shown are the corneal epithelium (118), sclera (116), vitreous (119), ciliary zonules (120), and ciliary processes (121). The posterior segment of the eye is the posterior two-thirds of the eyeball (behind the lens) and includes the vitreous, retina, and optic nerve.

[0214] To reduce intraocular pressure in a patient and treat glaucoma, the implants described herein can be implanted into the anterior chamber (or other ocular region) of a mammalian eye as a monotherapy to deliver a therapeutic agent, such as Compound 1, into the anterior chamber of the eye without the need for eye drops. Alternatively, the implants can be used with eye drops as an adjunct therapy. In some embodiments, the insertion of the implants described herein into the anterior chamber of the eye can reduce the intraocular pressure of the eye by at least about, for example, 20% or 30% or more compared to baseline IOP. The patient can be a human or non-human mammal that has elevated intraocular pressure or glaucoma and therefore is in need of treatment. In some embodiments, the implants can release Compound 1 according to linear or pseudo-zero order kinetics for at least one month after the implant is placed in the eye.

[0215] Biodegradable implants can be inserted into the eye by a variety of methods, including placement by forceps, by trocar, or by a handheld delivery device (applicator) equipped with a needle (or needle tip). Some handheld applicators can be used to insert one or more biodegradable implants into the eye. The handheld applicators can include an 18-30 GA (gauge) stainless steel needle, a lever, an actuator, and a plunger or push rod to facilitate ejection of the implant. The implant can be inserted through a scleral, limbal, or corneal approach to access the anterior chamber. Alternatively, the implant can be inserted into the vitreous using an appropriate applicator having a needle or cannula of a length suitable for accessing the target site and delivering the implant. Some methods for inserting the implant include using a needle, trocar, or implantation device to access a target region within an ocular region. Once within the target region, for example, the anterior chamber or vitreous, a lever on the handheld device can be pressed to cause the actuator to drive the plunger or push rod forward. As the plunger moves forward, it can push the device or implant into the target region, such as the vitreous or anterior chamber. One example of an ocular 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.

[0216] Thus, methods for treating glaucoma and reducing intraocular pressure in a patient's eye as discussed herein can include administering a biodegradable intraocular implant of the presently disclosed type to the eye by injection into the anterior chamber of the eye (intracameral injection) or into the vitreous (intravitreal injection). A syringe device including a needle of appropriate size (e.g., a 22, 25, 27, 28, or 30 gauge needle) can be used to inject one or more implants into these regions of the eye. Thus, the width or diameter of the implant can be selected so as to allow the implant to be received in the lumen of the selected needle gauge and translated through the lumen.

[0217] Prior to use in a subject, the implant can be sterilized with a suitable dose of, for example, beta-radiation. 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.

[0218] A daily dose of Compound 1 in the range of about 5 to about 100 nanograms, about 5 to about 200, about 10 to about 100 nanograms, or even about 5 to about 50 nanograms when delivered or released directly into the anterior chamber can be a therapeutically effective amount for reducing intraocular pressure in a patient's eye.

[0219] The patient is typically a human or non-human mammal experiencing or diagnosed with elevated intraocular pressure or ocular hypertension in one or both eyes. The patient can additionally be defined as a patient with glaucoma, as glaucoma generally includes elevated intraocular pressure. Thus, the implants described herein can be generally useful for reducing elevated intraocular pressure in the eye and treating glaucoma in a patient. In this regard, one embodiment is a method of reducing ocular hypertension or elevated intraocular pressure in a patient in need thereof, the method comprising placing a biodegradable intraocular implant according to the present disclosure in the patient's eye.

[0220] Patients that can be effectively treated using biodegradable intra- anterior chamber implants comprising Compound 1, or a pharmaceutically acceptable salt thereof, can include patients having, suffering from, or diagnosed with glaucoma, open-angle glaucoma, angle closure glaucoma, chronic angle closure glaucoma, open iridotomy, ocular hypertension, elevated intraocular pressure, pseudo-exfoliation glaucoma, or pigmentary glaucoma. Implants according to the present disclosure can be effective in reducing intraocular pressure in eyes having low, normal, or elevated intraocular pressure. Thus, implants according to the present disclosure can be effective in treating all forms of glaucoma, including glaucoma characterized by elevated intraocular pressure, as well as glaucoma with low or normal intraocular pressure, as these patients can also potentially benefit from additional reductions in intraocular pressure. Because of their ability to release a therapeutically effective amount of a potent intraocular pressure reducing agent, such as Compound 1, over a sustained period of time, implants of the present disclosure are expected to be able to reduce intraocular pressure in these patients over a long period of time, without the need for frequent intraocular injections or regular instillation of eye drops to the visual field as is necessary with topical therapies. Furthermore, the greater potency of Compound 1 for reducing IOP relative to some other pro-cathamic and anti-glaucoma agents makes it possible to produce smaller implants over longer periods of administration, which are safer and better for the eye, and thus the patient.

[0221] Accordingly, one embodiment of the present disclosure is a method for reducing intraocular pressure (IOP) in an eye, the method comprising placing a biodegradable intraocular implant as disclosed herein in the eye, wherein the implant reduces intraocular pressure in the eye over an extended period of time. The implant can be placed in the ocular region of the eye, and thus can be sized for placement in the ocular region of the eye. The patient can have low or normal intraocular pressure, or can have elevated intraocular pressure, sometimes referred to as ocular hypertension, or the patient can have glaucoma. In more specific forms, the patient has or is diagnosed with glaucoma or elevated intraocular pressure, and the implant is placed in the anterior chamber or vitreous of the affected eye. In specific embodiments, the implant is placed in the anterior chamber angle (or iridocorneal angle) of the affected eye, and even more specifically in the inferior iridocorneal angle. In any of these methods, the compound (i.e., the therapeutic agent) in the implant can comprise, consist essentially of, or consist of Compound 1, a pharmaceutically acceptable salt of Compound 1, or any mixture thereof, and the implant can be placed in the anterior chamber or vitreous of the eye via an intra- anterior chamber or intra-vitreous injection. In particular embodiments, the implant is placed in the anterior chamber angle (or iridocorneal angle) of the eye. The implant can also be placed in the subconjunctival region of the eye.

[0222] Accordingly, the present disclosure provides a method of treating glaucoma in a patient, comprising the step of placing a biodegradable intraocular implant as described herein in the eye of the patient. The implant can be placed in the anterior chamber of the eye or other ocular region of the eye, thereby treating the glaucoma.

[0223] Some embodiments include methods of administering Compound 1 without eye drops, the methods comprising inserting an implant described herein into the eye of a patient in need thereof. The implant can be placed in the anterior chamber of the eye.

[0224] In a particular form of the method of treatment, one or more intraocular implants comprising Compound 1, or a pharmaceutically acceptable salt thereof, can be placed or more specifically injected into the anterior chamber of the eye, thereby reducing intraocular pressure of the eye and ocular hypertension. Thus, the intraocular implant can be sized and formulated, for example, for placement in the anterior chamber of the eye. Such implants can be referred to as “intracameral” implants.

[0225] The implants of the present disclosure are designed to provide sustained remission of elevated intraocular pressure (or ocular hypertension) by providing a sustained, continuous release of a therapeutically effective amount of Compound 1, or any pharmaceutically acceptable salt thereof, directly to the affected area of the eye, such as the anterior chamber of the eye. In this context, the therapeutically effective amount of Compound 1 can be at a dosage of between about 5 and about 100 nanograms / day, about 5 to about 200 nanograms / day, about 10 to about 200 nanograms / day, about 5 to about 50 nanograms / day, or more specifically about 10 to about 50 nanograms / day, or even more specifically about 15 nanograms / day, about 20 nanograms / day, about 30 nanograms / day, about 40 nanograms / day, or about 50 nanograms / day. The patient can be a human or non-human mammal in need of treatment for ocular hypertension (elevated intraocular pressure) or glaucoma. The implant can be in the form of an extruded filament or a compressed tablet. Other forms can include a wafer, a film, or a sheet. The extruded filament can be a cylindrical or non-cylindrical rod having a certain diameter and cut to a length suitable for placement in the eye, such as the anterior chamber of the eye or the vitreous.

[0226] Example

[0227] The following examples are merely intended to illustrate the methods of the present disclosure and are in no way to be interpreted as limiting the methods of the present disclosure.

[0228] Example 1

[0229] Manufacture of implants

[0230] Manufacture of implants 1-6 in Table 2 was 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, mixed by hand using a spatula, and then blended again in a Turbula mixer for another 15 minutes. The resulting powder blend was then processed into filaments using a twin-screw microcompounder / extruder. Extrusion was performed under the process settings summarized in Table 1.

[0231]

[0232] The formulation compositions and notebook references are summarized in Table 2.

[0233]

[0234] The extruded filaments were randomly selected and cut using an automated cutter to produce implants of a specific weight. A total of 50 implants were cut per implant number. The target implant weight for 150 μιη diameter filaments was 50 ± 2.5 μg (5%). Implants were stored in glass vials, sealed in foil pouches with desiccant, and e-beam sterilized at 25 ± 10% kGy prior to testing.

[0235] Example 2

[0236] In vitro drug release rate determination

[0237] In vitro drug release studies were performed by placing each implant in 2 ml of aqueous incubation buffer (release medium) in a 10 ml glass vial. The vials were maintained in a shaking water bath at 37 °C and 50 rpm. The incubation buffer consisted of phosphate buffered saline (PBS) with a pH of 7.4 (137 mM NaCl, 2.7 mM KCl, and 10 mM phosphate buffer). At each designated time point, 2 ml of release medium was sampled from each vial and replaced with an equal volume of fresh release medium. Sink conditions were maintained in the release medium throughout the study.

[0238] Drug release profiles for the implants of Table 2, extruded under the conditions specified in Table 1, are shown in Figure 2 and 3 The plots also include Implant 1 formulation containing 8 wt% Compound 1 as a comparative implant. The data points represent the average release of 3 replicate implant samples, which were not normalized to their relative weights. Implant 5, with a drug loading of 15%, has a similar release profile to Implant 1 Figure 4 ), and a daily release rate similar to or higher than that of Implant 1 Figure 5 ), where less than 30% of Compound 1 is released on day 1. However, Implant 5 shows a lack of this burst release while being able to contain nearly twice the amount of Compound 1 in the implant. As can be seen in Figure 6 ), the implants of Table 2 show a better release profile than implants made using only R202H as the polymer, as they do not show the initial burst release seen in R202H implants at drug loadings greater than 8% (w / w). For example, as seen in Figure 6 , when using only R202H in an implant with a 15% drug loading, the release rate on day 1 is approximately 28%; on the other hand, as seen in Figure 3 and4 As can be seen, implants 4 and 5 (both also having a drug loading of 15%) show a release rate of about 12% at day 1. Further, see also U.S. Patent No. 9,889,142, which also shows a burst release in implants having a loading higher than 8%, which can be as high as about 55% drug release at day 1.

[0239] Based on the above, it can be seen that for the implant formulations described herein, an acceptable drug release profile similar to that of an 8 wt% implant (e.g., a fairly steady release without an initial burst release) can be seen, but the implants of the present application show this acceptable release at a drug loading significantly higher than 8 wt% (e.g., 15 wt%).

[0240] Example 3

[0241] Implant Swelling

[0242] Swelling studies were performed according to the Polymer Implant Swelling Working Guide. A Keyence digital microscope (Model VHX-600) was used to study the physical appearance and dimensional measurements of samples of the implants. Images of the extruded implants were taken at 100X and 150X magnification. The media used for this study was 0.01 M PBS, pH 7.4, at 37 °C. The swelling behavior of all implants is summarized in Table 2. Figure 7 A comparison of the maximum swollen diameters of Implant 1 and Implant 5 is shown in Table 3. Figure 8 The maximum swollen diameter of Implant 5 was less than the maximum swollen diameter of Implant 1, where the maximum swollen diameter of Implant 5 was about 75% to about 85% of the maximum swollen diameter of Implant 1.

[0243] Example 4

[0244] In Vitro Polymer Degradation

[0245] The in vitro polymer lifetimes of Implants 2-6 were compared to Implant 1. The studies were performed in buffered aqueous solution (0.01 M PBS, pH 7.4) at 37 °C for 24 weeks. The degradation rate constant was estimated by fitting the decrease in the average molecular weight (Mw 峰 ) of the polymer matrix over time to first order kinetics. The ranking order of the formulations based on the overall kinetic rate constant and the estimated in vitro lifetime (t 1000 , which is the time to reach a Mw 峰 of 1000 g / mol) is summarized in Table 3. The reported molecular weight data are relative to polystyrene standards.

[0246]

[0247] Throughout this specification, references are made to publications such as U.S. and foreign patents, journal articles, book chapters, and the like. All such publications are hereby expressly incorporated by reference, in their entireties, for all purposes, including supplemental / supporting information disclosed with the corresponding reference.

[0248] While numerous example aspects and embodiments have been discussed above, those of skill in the art will recognize certain modifications, permutations, additions and subcombinations thereof. It is therefore intended that the following appended claims be construed to include all such modifications, permutations, additions and subcombinations as fall within the true spirit and scope of the claims.

Claims

1. A biodegradable intraocular implant comprising 15% by weight of Compound 1; 5 wt% of a first polymer, the first polymer being a poly(D,L-lactide) having acid end groups and an intrinsic viscosity of 0.16 to 0.24 dl / g; 30 wt% of a second polymer, the second polymer being a poly(D,L-lactide) having ester end groups and an intrinsic viscosity of 0.25 to 0.35 dl / g; 45 wt% of a third polymer, the third polymer being a poly(D,L-lactide-co-glycolide) having ester end groups and an intrinsic viscosity of 0.16 to 0.24 dl / g and a D,L-lactide:glycolide ratio of 75:25; 3 wt% of cetyl alcohol and 2 wt% 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; And wherein the implant releases less than 30% of Compound 1 in vitro during the first 24 hours, wherein the in vitro release of Compound 1 is measured in phosphate buffered saline (PBS) solution at a pH of 7.4±0.05 and 37°C, and wherein the PBS solution is a PBS solution without magnesium and calcium and having a pH of 7.4±0.05 at 25°C.

2. The biodegradable intraocular implant of claim 1, wherein the implant is sized for placement in the anterior chamber of the eye. 3 . The biodegradable intraocular implant according to claim 1 , wherein the diameter of the implant is 150 μm and the implant contains 5 μg or 7.5 μg of Compound 1. 4 .

4. The biodegradable intraocular implant according to claim 1 or 2, wherein the diameter of the implant is 200 μm and the implant contains 5 μg or 7.5 μg of Compound 1.

5. Use of the biodegradable intraocular implant according to any one of claims 1 to 4 for the manufacture of a medicament for reducing intraocular pressure in a patient.

6. The use according to claim 5, wherein the patient suffers from, is diagnosed with, or is at risk of developing elevated intraocular pressure or glaucoma.

7. The use according to claim 5 or 6, wherein the biodegradable intraocular implant is placed in the anterior chamber of the patient's eye when administered to the patient.

8. The use according to claim 5 or 6, wherein the patient is a human.

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