US-12622894-B2 - Pharmaceutical compositions and intravitreal drug delivery systems for the treatment of ocular diseases

Abstract

The present disclosure relates to a biodegradable ocular implant comprising a biodegradable polymer containing a compound such as Edonentan, or a pharmaceutically acceptable salt thereof. Also disclosed are methods of treatment of ocular diseases with the biodegradable ocular implant and methods of preparation of the same.

Inventors

• Cheng-Wen Lin
• Angela Dawn Glendenning
• Sevgi Gurkan

Assignees

• PERFUSE THERAPEUTICS, INC.

Dates

Publication Date

20260512

Application Date

20230907

Claims (8)

1. 1 . A biodegradable ocular implant comprising a biodegradable polymer containing a compound incorporated therein, wherein: the compound is a compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein: the concentration of the compound in the biodegradable polymer is about 45% w/w; and the biodegradable polymer is [about 20% of RG503]: [about 20% of RG502]: [about 60% of RG753S], wherein said RG503 or RG502 is a poly (D,L-lactide-co-glycolide) synthesized at about 50:50 ratio of lactide to glycolide, and said RG753S is a poly (D,L-lactide-co-glycolide) synthesized at about 75:25 ratio of lactide to glycolide.
2. 2 . The biodegradable ocular implant of claim 1 , wherein the implant has a diameter of about 300 μm to about 400 μm and a length of about 4 mm to about 5 mm.
3. 3 . The biodegradable ocular implant of claim 1 , wherein the implant is suitable for administration as an intravitreal administration.
4. 4 . The biodegradable ocular implant of claim 1 , wherein the implant is suitable for administration into the back of an eye.
5. 5 . A biodegradable ocular implant comprising: a biodegradable polymer containing a compound incorporated therein, wherein: the compound is a compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein: the concentration of the compound in the biodegradable polymer is about 45% w/w; and the biodegradable polymer is [about 30% of RG503]: [about 20% of RG502]: [about 30% of RG753S]: [about 20% of R203S], wherein said RG503 or RG502 is a poly (D,L-lactide-co-glycolide) synthesized at about 50:50 ratio of lactide to glycolide, said RG753S is a poly (D,L-lactide-co-glycolide) synthesized at about 75:25 ratio of lactide to glycolide, and said R203S is a poly (D,L-lactide).
6. 6 . The biodegradable ocular implant of claim 5 , wherein the implant has a diameter of about 300 μm to about 400 μm and a length of about 4 mm to about 5 mm.
7. 7 . The biodegradable ocular implant of claim 5 , wherein the implant is suitable for administration as an intravitreal administration.
8. 8 . The biodegradable ocular implant of claim 5 , wherein the implant is suitable for administration into the back of an eye.

Description

RELATED APPLICATIONS This application is a divisional of U.S. Non-provisional patent application Ser. No. 18/060,503, filed on Nov. 30, 2022, which is a continuation of International Application No. PCT/US2022/027048, filed on Apr. 29, 2022, which claims priority to U.S. Provisional Patent Application No. 63/182,559, filed on Apr. 30, 2021, and 63/287,737, filed on Dec. 9, 2021, the entire contents of each of which are hereby incorporated by reference for all purposes. BACKGROUND Examples of debilitating ocular diseases include glaucoma, diabetic retinopathy (DR), retinal vein occlusion (RVO), and retinopathy of prematurity (ROP). These ocular diseases can variously cause long-term damage to the eye and, ultimately, blindness. While neonates, the young, adults of all ages and the elderly are affected, only a handful of treatments exist. These treatments are only for a subset of ocular diseases and slow, but do not prevent, blindness. The annual economic burden on the U.S. alone is over $100 billion. Options for treating the ocular diseases are still very limited largely due to lack of therapeutic efficacy. Efforts have been devoted to enhancing drug therapeutic effectiveness while minimizing side effects in the treatment or amelioration of ocular diseases. One such effort involves development of novel biodegradable ocular implants providing better permeability, treatability, and controlled release at target site. Edonentan is a highly selective and very potent endothelin A receptor antagonist. Edonentan was developed as a second-generation analog following the discontinuation of the first clinical candidate, BMS-193884, which was being developed for the treatment of congestive heart failure (CHF). Edonentan was in phase I trials by April 2002, but its development was discontinued. There remains a need to more effectively reduce the incidence of, treat or otherwise ameliorate glaucoma, DR, RVO, and ROP. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 depicts drug release profiles of Edonentan in disk punches of exemplary formulations each containing a polymer matrix incorporating Edonentan. Up to 70% of Edonentan was released from most formulations within 100 days as determined by high-performance liquid chromatography (HPLC). The in vitro release results show that the amount of Edonentan released decreases with the increase of the ratio of poly-lactic acid (PLA) to poly-glycolic acid (PGA) as well as the increase of molecular weight of the polymer. Formulation 1 (50/50 RG503/RG503H) has a faster release compared to Formulation 2 (65/35 PLA/PGA) due to the lower ratio of PLG to PGA. Formulation 4 (50/50 502/502H) has a faster release compared to Formulation 1 (50/50 503/503H) due to the lower molecular weight of the polymer. The results also showed that RG753S has the slowest release profile among the formulations tested, and the mixtures of RG753S with other faster-releasing formulations provide a long period of sustained drug release while maintaining sufficient drug release at earlier time points. FIG. 2 depicts elution rate profiles of Edonentan in disk punches of exemplary formulations each containing a polymer matrix incorporating Edonentan. The in vitro release results show that for each polymer matrix there is a peak Edonentan release from 10 to 35 days followed by a decrease in elution rate, with a sustained steady-state release for some matrices as determined by HPLC. FIG. 3 depicts drug release profiles of Edonentan in implants of exemplary formulations each containing a polymer matrix incorporating Edonentan. The in vitro release results show that the combination of polymer matrix with Edonentan provides sustained release of active as determined by HPLC. FIG. 4 depicts elution rate profiles of Edonentan in implants of exemplary formulations each containing a polymer matrix incorporating Edonentan. The in vitro release results show that the polymer matrix controls the initial release of Edonentan with the peak release ranging from day 17 to day 92, as determined by HPLC. The in vitro release results show that the amount of Edonentan released decreases with the increase of the ratio of poly-lactic acid (PLA) to poly-glycolic acid (PGA) as well as the increase of molecular weight of the polymer. The mixtures of RG753S with other faster-releasing formulations provide a long period of sustained drug release while maintaining sufficient drug release at earlier time points. FIG. 5 depicts a time course of the Edonentan plasma levels during 8-week single-dose intravitreal ocular toxicity study in Dutch-belted rabbits in 2 and 3 implant groups. FIG. 6 depicts a time course of Edonentan retina levels during 12-week single dose intravitreal ocular pharmacokinetic study in Dutch-belted rabbits dosed with 2 implants of injection molded and ram extruded product. FIG. 7 depicts a time course of Edonentan RPE/choroid levels during 12-week single dose intravitreal ocular pharmacokinetic study in Dutch-belted rabbits dos