Patent Application Titled “Compositions And Methods For Treating Ocular Diseases” Published Online (USPTO 20220218643): Patent Application

2022 AUG 02 (NewsRx) -- By a News Reporter-Staff News Editor at Insurance Daily News -- According to news reporting originating from Washington, D.C., by NewsRx journalists, a patent application by the inventors Blizzard, Charles D. (Nashua, NH, US); Desai, Ankita (Reading, MA, US); Driscoll, Arthur (Reading, MA, US); Goldstein, Michael (Cambridge, MA, US), filed on February 16, 2022, was made available online on July 14, 2022.

No assignee for this patent application has been made.

Reporters obtained the following quote from the background information supplied by the inventors: “Glaucoma is typically a progressive, chronic disease affecting millions of people (Simmons, S., T., Ophthalmic Formulations. Glaucoma Today Supplement to Advanced Ocular Care, 2010; The Eye Disease Prevalence Group., Prevalence of open-angle glaucoma among adults in the United States. Arch Ophthalmol, 2004. 122: p. 532-538). In fact, glaucoma has been reported to be one of the leading causes of irreversible blindness, and worldwide it is the second leading cause of blindness (Quigley, H. A. and A. T. Broman, The number of people with glaucoma worldwide in 2010 and 2020. Br J Ophthalmol, 2006. 90(3): p. 262-7). Some have projected that by the year 2040 more than 110 million people would be diagnosed with glaucoma (Tham, Y.-C., et al., Global Prevalence of Glaucoma and Projections of Glaucoma Burden through 2040. 8 Ophthalmology, 2014. 121(11): p. 2081-2090).

“Glaucoma is defined as optic neuropathy leading to the loss of retinal ganglion cells and their axons and progressing in later stages to loss of visual field and, in very advanced cases, central visual acuity. Open-angle glaucoma is the most common form of the disease and primary open angle glaucoma (POAG) refers to eyes with open anterior drainage angles and elevated IOP.

“Elevated fluid pressure within the eye (i.e., elevated intraocular pressure (IOP)), defined as pressures above the normal range of 10 to 21 mmHg, is the main risk factor for glaucoma. People with elevated IOP levels without any current optic-nerve damage are diagnosed with ocular hypertension, as opposed to glaucoma. However, people with ocular hypertension may be at risk of progressive damage to the optic nerve (glaucoma).

“For both glaucoma and ocular hypertension (OHT), the most critical factor for effective therapy is to lower the IOP, and in doing so, the disease progression may be slowed along with the rate of visual field loss. Drugs that are classified as prostaglandins have been shown to effectively lower IOP (AAO, Glaucoma Preferred Practice Pattern. 2015). The Preferred Practice Patterns of the AAO recommend prostaglandins as the first line of therapy for POAG and OHT.

“The most commonly prescribed topical medications for the treatment of glaucoma in the United States are the prostaglandin analogues.

“Travoprost is for example a suitable synthetic prostaglandin F 2a analogue. Its chemical name is (isopropyl (Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(1E,3R)-3-hydroxy-4-[(a,a,a-trifluoro-m-isopropyl-tolyl)oxy]-1-butenyl]-cyclopentyl]-5-heptenoate. This prodrug is a synthetic prostaglandin analogue that is enzymatically converted to a free acid form in human cornea (Al-Jazzaf, A. M., L. DeSantis, and P. A. Netland, Travoprost: a potent ocular hypotensive agent. Drugs Today (Barc), 2003. 39(1): p. 61-74). Travoprost free acid like all prostaglandins is a selective FP prostanoid receptor agonist which is believed to reduce intraocular pressure by increasing trabecular meshwork and uveoscleral outflow (Lim, K S., et al., Mechanism of action of bimatoprost, latanoprost, and travoprost in healthy subjects. A crossover study. Ophthalmology, 2008. 115(5): p. 790-795 e4 and Tons, C. B., B. A. T. Gabelt, and P. L. Kaufman, Update on the Mechanism of Action of Topical Prostaglandins for Intraocular Pressure Reduction. Survey of Ophthalmology, 2008. 53(6, Supplement): p. S107-S120). Travoprost is the active ingredient in Travatan®, Travatan Z® (Appendix A: package insert), and Izba™ (all Alcon Laboratories, Inc., Ft Worth, TX), which are all topical ophthalmic solutions intended to reduce elevated IOP. The dosage is typically one drop daily of a 0.004% or 0.003% solution applied daily to the affected eye(s).

“Successful treatment for glaucoma requires daily self-administered treatment with topical eye drops. While topical antihypertensive medication may be effective in treating glaucoma, any one of the available therapies will only be as effective as the adherence to administration by individual patients. Known limitations associated with the application of topical eye drops include: (1) difficulty in administering drops, (2) limited accuracy of drops getting into the eye, (3) potential washout of drops by lacrimation or subsequent administration of other drops, (4) the need for a caregiver to administer drops and (5) poor subject compliance (Toris, C. B., B. A. T. Gabelt, and P. L. Kaufman, Update on the Mechanism of Action of Topical Prostaglandins for Intraocular Pressure Reduction. Survey of Ophthalmology, 2008. 53(6, Supplement): p. S107-S120). Kholdebarin, et al (Kholdebarin, R., et al., Multicenter study of compliance and drop administration in glaucoma. Can J Ophthalmol, 2008. 43(4): p. 454-61) reported that 34% of patients used improper administration technique. For some patients there is the need to administer multiple drops and this may compound the situation due to washout effects. In one study, nearly 9% of the patients who required more than one medication in the same eye failed to wait at least three minutes between administrations. Importantly, regardless of the number of medications, patients are expected to remain on treatment indefinitely and motivation to do so plays an important role. Accordingly, there is a need to provide an alternative to the daily administration of single or multiple eye drops for the treatment of glaucoma, especially in an aging population with the disease.

“The risk of potential blindness as a long-term effect increases in cases of poorly managed glaucoma, and patient compliance becomes an important issue. Studies have shown that less than 50% of glaucoma patients continue therapy and refill prescriptions as required (Friedman, D. S., et al., Using Pharmacy Claims Data to Study Adherence to Glaucoma Medications: Methodology and Findings of the Glaucoma Adherence and Persistency Study (GAPS). Investigative Ophthalmology & Visual Science, 2007. 48(11): p. 5052-5057), and most patients are likely to discontinue use of a topical therapy within 1.2 years after filling their first prescription according to health insurance claims (Nordstrom, B. L., et al., Persistence and Adherence With Topical Glaucoma Therapy. American Journal of Ophthalmology, 2005. 140(4): p. 598.e1-598.e11). Thus, a delivery system that would provide long-term, 24 hour control of IOP could address a multitude of issues and potentially delay or prevent loss of vision resulting from glaucoma for a patient.

“Drug delivery to the anterior segment continues to be a challenge with the ultimate goal of improving patient compliance, achieving an excellent safety profile and providing for sustained delivery over an extended period of time (Yellepeddi, V. K. and S. Palakurthi, Recent Advances in Topical Ocular Drug Delivery. Journal of Ocular Pharmacology and Therapeutics, 2015. 32(2): p. 67-82).”

In addition to obtaining background information on this patent application, NewsRx editors also obtained the inventors’ summary information for this patent application: “It is an object of certain embodiments of the present invention to provide an implant suitable for being inserted into the anterior chamber of the eye (intracameral implant) with dimensions small enough to fit into the iridocomeal angle of the eye when inserted. In particular the implant should have a size small enough to fit a wide range of iridocomeal angle sizes including narrow angels.

“It is an object of certain embodiments of the present invention to provide an implant suitable for being inserted into the anterior chamber of the eye (intracameral implant) with dimensions small enough to fit into the iridocomeal angle of the eye and gets fixated in the iridocorneal angle during the period of treatment and/or until it is biodegraded.

“It is an object of certain embodiments of the present invention to provide an implant suitable for being inserted into the anterior chamber of the eye (intracameral implant) which after insertion swells due to the uptake of aqueous humor and becomes increasingly soft before it dissolves and fully degrades.

“Another object of certain embodiments of the present invention is to provide a travoprost sustained release biodegradable intracameral implant and corresponding method of treatment with limited movement of the implant.

“Another object of certain embodiments of the present invention is to provide a travoprost sustained release biodegradable intracameral implant which is gentle to the endothelium.

“It is an object of certain embodiments of the present invention to provide a method and corresponding use of treating ocular diseases in human subjects for an extended period of time, e.g. ranging from about 1 to about 24 months.

“It is an object of certain embodiments of the present invention to provide a method and corresponding use of treating ocular diseases in human subjects for an unlimited period of time.

“It is an object of certain embodiments of the present invention to provide a method and corresponding use for safely and effectively treating the intraocular pressure in human subjects for an extended period of time, e.g. ranging from about 2 to about 12 months or 3 to about 9 months, e.g. for about 3 to about 4 months or for about 3 to about 6 months or for about 6 to about 9 months.

“It is an object of certain embodiments of the present invention to provide a method and corresponding use for safely and effectively treating the intraocular pressure in human subjects for an unlimited period of time.

“It is an object of certain embodiments of the present invention to provide a method and corresponding use for safely and effectively treating the intraocular pressure in human subjects with ocular hypertension or glaucoma, e.g. open angle glaucoma, for an extended period of time, e.g. ranging from about 2 to about 12 months or from about 3 to about 9 months, e.g. for about 3 to about 4 months or about 3 to about 9 months for about 6 to about 9 months.

“It is an object of certain embodiments of the present invention to provide a method and corresponding use for safely and effectively treating the intraocular pressure in human subjects with ocular hypertension or glaucoma, e.g. open angle glaucoma, for an unlimited period of time.

“Another object of certain embodiments of the present invention to provide a prostaglandin antagonist (e.g., travoprost) sustained release biodegradable intracameral implant which provides a constant or substantially constant prostaglandin antagonist release with limited burst at the beginning for safely and effectively treating the intraocular pressure in human subjects with ocular hypertension or glaucoma, e.g. open angle glaucoma.

“Another object of certain embodiments of the present invention is to provide a prostaglandin antagonist (e.g., travoprost) sustained release biodegradable intracameral implant and corresponding method of treatment which do not cause inconvenience or discomfort once implanted into the anterior chamber of the human subject’s eye, such as a sensation of having a foreign object in the eye or eye pain.

“Another object of certain embodiments of the present invention is to provide a method for preservative free treating the intraocular pressure in human subjects.

“Another object of certain embodiments of the present invention is to provide a travoprost sustained release biodegradable intracameral implant and corresponding method of treatment and wherein the implant is cosmetically invisible.

“Another object of certain embodiments of the present invention is to provide a travoprost sustained release biodegradable intracameral implant and corresponding method of treatment wherein the implant can be monitored in the eye.

“Another object of certain embodiments of the invention is to provide a prostaglandin antagonist (e.g., travoprost) release biodegradable intracameral implant which is easily insertable into the human subject’s eye, such as the anterior chamber or the posterior chamber of the human subject’s eye.

“Another object of certain embodiments of the present invention is to provide a prostaglandin antagonist (e.g., travoprost) sustained release biodegradable intracameral implant which is sufficiently small to be inserted into the human subject’s eye, such as the anterior chamber or the posterior chamber of the human subject’s eye.

“Another object of certain embodiments of the present invention is to provide a travoprost sustained release biodegradable intracameral implant and corresponding method of treatment which is biodegradable in a residual-free manner once inserted into the anterior chamber of the human subject’s eye and does not need to be removed by a surgery, i.e. the implant is fully biodegradable.

“Another object of certain embodiments of the present invention is to provide a travoprost sustained release biodegradable intracameral implant and corresponding method of treatment which can be used for a continuous treatment of the intraocular pressure associated with open angle glaucoma and/or ocular hypertension in a human subject.

“Another object of certain embodiments of the present invention is to provide a travoprost sustained release biodegradable intracameral implant and corresponding method of treatment, wherein said implant provides a long-term treatment effect.

“Another object of certain embodiments of the present invention is to provide a travoprost sustained release biodegradable intracameral implant and corresponding method of treatment, wherein said implant provides a long-term treatment effect and causes no change of pachymetry and endothelial cell count. One or more of these objects of the present invention and others are solved by one or more embodiments as disclosed and claimed herein.

“The individual aspects of the present invention are disclosed in the specification and claimed in the independent claims, while the dependent claims claim particular embodiments and variations of these aspects of the invention. Details of the various aspects of the present invention are provided in the detailed description below.”

The claims supplied by the inventors are:

“1. A method of treating ocular hypertension comprising: injecting an intracameral implant into the anterior chamber of the eye of a patient in need thereof for the implant to reside in the iridocorneal angle, wherein the intracameral implant has a length of about 1.00 mm to about 2.50 mm and comprises: a biodegradable hydrogel, wherein the hydrogel comprises a polymer network comprising one or more units of polyalkylene glycol, and travoprost particles, the travoprost particles being in the form of travoprost intermixed with a biodegradable polymer, and the travoprost particles being dispersed within the hydrogel; wherein the ocular hypertension is treated.

“2. The method according to claim 1, wherein the implant has a diameter of not more than 0.30 mm in its dried state.

“3. The method according to claim 1, wherein the implant has a diameter of less than 0.50 mm after 24 hours of hydration in vitro in phosphate-buffered saline at a pH of 7.4 at 37° C.

“4. The method according to claim 3, wherein the implant has a diameter ranging from about 0.30 mm to 0.49 mm, after 24 hours of hydration in vitro in phosphate-buffered saline at a pH of 7.4 at 37° C.

“5. The method according to claim 1, wherein a ratio of the diameter of the implant after 24 hours of hydration in vitro in phosphate-buffered saline at a pH of 7.4 at 37° C. to the diameter of the implant in its dried state is less than 2.5.

“6. The method according to claim 1, wherein the implant contains a dose of about 2 mg to about 30 mg of travoprost

“7. The method according to claim 1, wherein the biodegradable polymer comprises a polylactide.

“8. The method according to claim 1, wherein the hydrogel comprises a polymer network comprising one or more units of polyethylene glycol.

“9. The method according claim 1, wherein the treating is for a period ranging from about 3 to about 9 months.

“10. The method according to claim 1, wherein the implant has a total weight of about 20 mg to about 110 mg in its dried state.

“11. The method according to claim 1, wherein the implant shows a burst of less than 15%, based on the total weight of travoprost in the implant, on day 1 measured in vitro under simulated physiological sink conditions in 50 mL of 1 x PBS, 0.5% castor oil, 0.01% sodium fluoride buffer at pH 7.2-7.4 at 37° C.

“12. The method according to claim 1, wherein the total mass of the biodegradable polymer in the implant is less than 34 mg.

“13. The method according to claim 1 wherein the travoprost in the implant is less than 25 mg.

“14. The method according to claim 1 wherein the total mass of the implant is less than 103 mg in its dried state.

“15. The method according to claim 1, wherein the travoprost particles have a diameter ranging from 1 to 100 mm determined by sieving or have an average diameter ranging from 1 to 100 mm determined by laser diffraction.

“16. The method according to claim 1, wherein the polymer network is formed by reacting an electrophilic group-containing multi-arm-polymer precursor with a nucleophilic group-containing cross-linking agent, the electrophilic group is selected from the group consisting of a succinimidylglutarate (SG) group and a succinimidylazelate (SAZ) group, and the multi-arm polymer precursor is selected from the group consisting of 8-arm-15K-SG polyethylene glycol or 8-arm-15K-SAZ polyethylene glycol; and the nucleophilic group-containing cross-linking agent is a trilysine, or the polymer network comprises an 8-arm-polyethylene glycols being cross-linked including a group represented by the following formula wherein m is 2 or 6.

“17. The method according to claim 1, wherein the travoprost particles comprise a blend of at least two types of travoprost particles selected from the group consisting of 1) a first type of travoprost particles made of a mixture of: travoprost and a biodegradable polymer consisting of a polylactide or polylactides having an acid end group and an inherent viscosity specification ranging from about 0.05 to less than about 0.5 dl/g, such as from about 0.35 to about 0.45 dl/g, such as wherein the first type of particles contains from about 40 wt.-% to about 50 wt.-%, such as from about 43 wt.-% to about 45 wt.-% travoprost, based on the total mass of the first type of particles; 2) a second type of travoprost particles made of a mixture of: travoprost and a biodegradable polymer consisting of a polylactide or polylactides having an acid end group and an inherent viscosity specification ranging from about 0.5 to less than about 0.80 dl/g, such as ranging from about 0.6 to less than about 0.80 dl/g, such as wherein the second type of particles contains from about 40 wt.-% to about 50 wt.-%, such as from more than about 45 wt.-% to about 47 wt.-% travoprost, based on the total mass of the second type of particles; 3) a third type of travoprost particles made of a mixture of: travoprost and a biodegradable polymer consisting of a polylactide or polylactides having an acid end group and an inherent viscosity specification ranging from about 0.8 to about 1.7 dl/g, such as ranging from about 0.8 to about 1.0 dl/g, such as wherein the third type of particles contains from about 40 wt.-% to about 50 wt.-%, such as from about 41 wt.-% to about 43 wt.-% travoprost based on the total mass of third type of particles; 4) a fourth type of travoprost particles made of a mixture of: travoprost and a biodegradable polymer consisting of a polylactide or polylactides having an ester end group and an inherent viscosity specification ranging from about 0.05 to about 1.7 dl/g, such as ranging from about 0.55 to about 0.75 dl/g, such as wherein the fourth type of particles contains from about 40 wt.-% to about 50 wt.-%, such as from about 41 wt.-% to about 43 wt.-% travoprost based on the total mass of the fourth type of particles.

“18. The method according to claim 1, wherein the travoprost particles comprise a blend of particles made of a first type of travoprost particles made of a mixture of travoprost and the biodegradable polymer consisting of a polylactide or polylactides having an acid end group and an inherent viscosity specification ranging from about 0.05 to less than about 0.5 dl/g, such as from about 0.35 to about 0.45 dl/g, wherein the first type of particles contains from about 40 wt.-% to about 50 wt.-%, such as from about 43 wt.-% to about 45 wt.-% travoprost, based on the total mass of the first type of particles; and a second type of travoprost particles made of a mixture of travoprost and the biodegradable polymer consisting of a polylactide or polylactides having an acid end group and an inherent viscosity specification ranging from about 0.5 to less than about 0.80 dl/g, such as ranging from about 0.6 to less than about 0.80 dl/g, wherein the second type of particles contains from about 40 wt.-% to about 50 wt.-%, such as more than from about 45 wt.-% to about 47 wt.-% travoprost, based on the total mass of the second type of particles, such as wherein the blend contains, based on the total amount of the blend, about 35 wt.-% to about 55 wt.-% particles of the first type of particles and about 35 wt.-% to about 55 wt.-% particles of the second type of particles; or such as wherein about 35 wt.-% to about 55 wt.-% of the total amount of travoprost in the implant is present in the form of particles of the first type of particles and about 35 wt.-% to about 55 wt.-% of the total amount of travoprost in the implant is present in the form of particles of the second type of particles, wherein optionally the polymer network is formed by reacting an electrophilic group-containing multi-arm-polymer precursor with a nucleophilic group-containing cross-linking agent, the electrophilic group is a succinimidylglutarate (SG) group and the multi-arm polymer precursor an 8-arm-15K-SG polyethylene glycol; and the nucleophilic group-containing cross-linking agent is a trilysine, or the polymer network comprises an 8-arm-polyethylene glycols being cross-linked including a group represented by the following formula wherein m is 2.”

There are additional claims. Please visit full patent to read further.

For more information, see this patent application: Blizzard, Charles D.; Desai, Ankita; Driscoll, Arthur; Goldstein, Michael. Compositions And Methods For Treating Ocular Diseases. Filed February 16, 2022 and posted July 14, 2022. Patent URL: https://appft.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220220218643%22.PGNR.&OS=DN/20220218643&RS=DN/20220218643

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