Compositions and methods for treating eye disorders

Abstract

The present invention relates to the treatment of ocular diseases in human subjects. In particular, the present invention relates to the anterior intraventricular administration of a sustained release biodegradable anterior intraventricular implant.

Description

[0001] This application is a divisional application based on a patent application with an application date of February 5, 2021, application number 202180012836.1 (PCT / US2021 / 016889), and invention name: "Compositions and methods for treating eye diseases". Technical Field

[0002] The present invention relates to methods of treatment in human subjects suffering from eye diseases and corresponding intracameral implants. The present invention also relates to the treatment of intraocular pressure in human subjects and corresponding intracameral implants. The present invention also relates to the treatment of intraocular pressure in human subjects suffering from ocular hypertension or glaucoma, such as open-angle glaucoma. In certain embodiments, the present invention relates to the intracameral administration of a biodegradable intracameral implant for sustained release of travoprost. Background Art

[0003] Glaucoma is usually a progressive chronic disease that affects 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: 532-538 pages). In fact, it is reported that glaucoma is one of the main causes of irreversible blindness, and worldwide, it is the second leading cause of blindness (Quigley, HA and ATBroman, The number of people with glaucoma worldwide in 2010 and 2020. Br J Ophthalmol, 2006. 90 (3): 262-7 pages). It is predicted that by 2040, more than 110 million people will 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): pp. 2081-2090).

[0004] Glaucoma is defined as an optic neuropathy that results in loss of retinal ganglion cells and their axons, which progresses to loss of visual fields and, in advanced cases, central vision. Open-angle glaucoma is the most common form of the disease, and primary open-angle glaucoma (POAG) refers to eyes with an open anterior eye drainage angle and elevated intraocular pressure.

[0005] The main risk factor for glaucoma is increased fluid pressure within the eye (i.e., elevated intraocular pressure (IOP)), defined as pressure above the normal range of 10 to 21 mmHg. In contrast to glaucoma, people who have increased eye pressure but do not currently have any optic nerve damage are diagnosed as having ocular hypertension. However, people with ocular hypertension may be at risk for developing progressive damage to the optic nerve (glaucoma).

[0006] For glaucoma and ocular hypertension (OHT), the most critical factor for effective treatment is to lower IOP, which may slow the progression of the disease and the rate of visual field loss. It has been shown that drugs classified as prostaglandins can effectively lower IOP (AAO, Glaucoma Preferred Practice Pattern. 2015). The AAO's Preferred Practice Patterns recommend prostaglandins as the first-line treatment for POAG and OHT. In the United States, the most commonly prescribed topical medication for the treatment of glaucoma is a prostaglandin analog.

[0007] For example, Travoprost is a suitable synthetic prostaglandin F 2α analog. Its chemical name is ((Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(1E,3R)-3-hydroxy-4-[(α,α,α-trifluoro-m-isopropyl-tolyl)oxy]-1-butenyl]-cyclopentyl]-5-heptenoic acid isopropyl ester. This prodrug is a synthetic prostaglandin analog that is enzymatically converted to the free acid form in the human cornea (Al-Jazzaf, AM, L. DeSantis, and PA 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 prostaglandin receptor agonist that is believed to reduce intraocular pressure by increasing trabecular meshwork and uveoscleral outflow (Lim, KS et al., Mechanism of action of bimatoprost, latanoprost, and travoprost in healthy subjects. A crossover study. Ophthalmology, 2008. 115(5): pp. 790-795 e4 and Toris, CB, BAT Gabelt, and PL Kaufman, Update on the Mechanism of Action of Topical Prostaglandins for Intraocular Pressure Reduction. Survey of Ophthalmology, 2008. 53(6, Supplement): pp. S107-S120). Travoprost is (Appendix A: Package insert) and Izba TM (both Alcon Laboratories, Ft Worth, TX), are topical ophthalmic solutions designed to lower elevated IOP. Dosage is typically one drop per day of a 0.004% or 0.003% solution applied to the affected eye.

[0008] Successful treatment of glaucoma requires daily self-administered treatment with topical eye drops. Although topical antihypertensive drugs may be effective in treating glaucoma, any available therapy is only effective if the individual patient adheres to the regimen. Known limitations associated with the application of topical eye drops include: (1) difficulty in applying the eye drops; (2) limited accuracy of eye drops into the eye; (3) potential washout of the eye drops by tearing or subsequent application of other eye drops; (4) the need for a caregiver to apply the eye drops; and (5) poor subject compliance (Toris, CB, BAT Gabelt, and PL Kaufman, Update on the Mechanism of Action of Topical Prostaglandins for Intraocular Pressure Reduction. Survey of Ophthalmology, 2008. 53(6, Supplement): pages 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 application techniques. For some patients, multiple drops are required, which may be further complicated by the washout effect. In one study, nearly 9% of patients who required more than one medication in the same eye were unable to wait at least three minutes between two applications. Importantly, regardless of the medication used, patients are expected to continue treatment indefinitely, and the motivation to do so is also important. Therefore, there is a need to provide an alternative for daily administration of single or multiple drops of eye drops to treat glaucoma, especially in the aging population with the disease.

[0009] In cases where glaucoma is not managed properly, the long-term effects increase the risk of potential blindness, and patient compliance becomes a significant issue. Studies have shown that less than 50% of glaucoma patients continue therapy and refill prescriptions as needed (Friedman, DS 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 stop using topical therapy within 1.2 years of filling their first prescription according to health insurance claims (Nordstrom, BL et al., Persistence and Adherence With Topical Glaucoma Therapy. American Journal of Ophthalmology, 2005. 140 (4): p. 598.e1-598.e11). Therefore, a delivery system that would provide long-term, 24-hour control of IOP could solve many problems and potentially delay or prevent vision loss caused by glaucoma in patients.

[0010] Drug delivery to the anterior segment has always been a challenge, with the ultimate goal of improving patient compliance, achieving excellent safety characteristics and providing sustained delivery over a long period of time (Yellepeddi, VK and S. Palakurthi, Recent Advances in Topical Ocular Drug Delivery. Journal of Ocular Pharmacology and Therapeutics, 2015. 32(2): pp. 67-82).

[0011] DURYSTA is an FDA-approved bimatoprost intracameral implant indicated to reduce intraocular pressure in patients with open-angle glaucoma or ocular hypertension. Due to the potential for loss of corneal endothelial cells and corneal adverse reactions, the implant is limited to a single implant per eye, cannot be retreated, and should be used with caution in patients with narrow angles or anatomical angle blockages. In patients with open-angle glaucoma or ocular hypertension, the efficacy of DURYSTA was evaluated in two multicenter, randomized, parallel-group, controlled studies lasting 20 months (including an 8-month extended follow-up) compared to twice-daily topical timolol 0.5% eye drops. DURYSTA demonstrated an approximately 5-8 mmHg reduction in IOP in patients with a mean baseline IOP of 24.5 mmHg. Data showed that after Week 12, IOP was higher in the DURYSTA group than in the timolol group. It is an intracameral implant containing 10 μg of bimatoprost in a solid polymer sustained-release drug delivery system. The drug delivery system is composed of poly(D,L-lactide), poly(D,L-lactide-co-glycolide), poly(D,L-lactide) acid ends, and polyethylene glycol 3350. (Prescribing information revised on 11 / 2020). Summary of the invention

[0012] An object of certain embodiments of the present invention is to provide an implant suitable for insertion into the anterior chamber of the eye (anterior chamber implant) that is small enough to fit the iridocorneal angle of the eye when inserted. Specifically, the implant is small enough to fit a variety of iridocorneal angle sizes, including narrow angles.

[0013] It is an object of certain embodiments of the present invention to provide an implant suitable for insertion into the anterior chamber of the eye (anterior chamber implant) that is small enough to fit into the iridocorneal angle of the eye and remain fixed in the iridocorneal angle during treatment and / or until it biodegrades.

[0014] It is an object of certain embodiments of the present invention to provide an implant adapted for insertion into the anterior chamber of the eye (anterior chamber implant) which, after insertion, swells due to absorption of aqueous humor and becomes increasingly soft before it dissolves and completely degrades.

[0015] Another object of certain embodiments of the present invention is to provide a biodegradable intracameral implant for sustained release of travoprost and a corresponding method of treatment, wherein migration of the implant is limited.

[0016] It is another object of certain embodiments of the present invention to provide a biodegradable intracameral implant for sustained release of travoprost that is gentle to the endothelium.

[0017] It is an object of certain embodiments of the present invention to provide a method and corresponding use for treating an eye disease in a human subject over an extended period of time, for example in the range of about 1 month to about 24 months.

[0018] It is an object of certain embodiments of the present invention to provide a method and corresponding use for treating an eye disease in a human subject for an indefinite period of time.

[0019] It is an object of certain embodiments of the present invention to provide a method and corresponding use for safely and effectively treating intraocular pressure in human subjects for a long period of time, for example in the range of about 2 months to about 12 months or 3 months to about 9 months, for example for about 3 months to about 4 months or about 3 months to about 6 months or for about 6 months to about 9 months.

[0020] It is an object of certain embodiments of the present invention to provide a method and corresponding use for safely and effectively treating intraocular pressure in a human subject for an indefinite period of time.

[0021] An object of certain embodiments of the present invention is to provide a method and corresponding use for safely and effectively treating intraocular pressure in a human subject suffering from ocular hypertension or glaucoma, such as open-angle glaucoma, for a long period of time, such as in the range of about 2 months to about 12 months or about 3 months to about 9 months, for example, for about 3 months to about 4 months or about 3 months to about 9 months, for about 6 months to about 9 months.

[0022] It is an object of certain embodiments of the present invention to provide a method and corresponding use for safely and effectively treating intraocular pressure in a human subject suffering from ocular hypertension or glaucoma, such as open-angle glaucoma, for an indefinite period of time.

[0023] Another object of certain embodiments of the present invention is to provide a biodegradable intracameral implant for sustained release of a prostaglandin antagonist (e.g., travoprost) that provides a constant or substantially constant release of the prostaglandin antagonist with only a limited burst release at the beginning to safely and effectively treat intraocular pressure in human subjects suffering from ocular hypertension or glaucoma, such as open-angle glaucoma.

[0024] Another object of certain embodiments of the present invention is to provide a biodegradable intracameral implant and corresponding treatment method for sustained release of a prostaglandin antagonist (e.g., travoprost) that, once implanted in the anterior chamber of the eye of a human subject, does not cause inconvenience or discomfort, such as a foreign body sensation in the eye or eye pain.

[0025] It is another object of certain embodiments of the present invention to provide a method for treating intraocular pressure in a human subject in the absence of a preservative.

[0026] Another object of certain embodiments of the present invention is to provide a biodegradable intracameral implant for sustained release of travoprost and a corresponding method of treatment, wherein the implant is invisible through cosmetic means.

[0027] Another object of certain embodiments of the present invention is to provide a biodegradable intracameral implant for sustained release of travoprost and a corresponding method of treatment, wherein the implant can be monitored in the eye.

[0028] It is another object of certain embodiments of the present invention to provide a prostaglandin antagonist (eg, travoprost) releasing biodegradable intracameral implant that is easily inserted into the eye of a human subject, eg, the anterior chamber or the posterior chamber of the eye of a human subject.

[0029] It is another object of certain embodiments of the present invention to provide a biodegradable intracameral implant for sustained release of a prostaglandin antagonist (eg, travoprost) that is small enough to be inserted into the eye of a human subject, eg, the anterior chamber or the posterior chamber of the eye of a human subject.

[0030] Another object of certain embodiments of the present invention is to provide a biodegradable intracameral implant for sustained release of travoprost and a corresponding method of treatment which, once inserted into the anterior chamber of the eye of a human subject, biodegrades in a residue-free manner and does not require surgical removal, i.e., the implant is completely biodegradable.

[0031] Another object of certain embodiments of the present invention is to provide a biodegradable intracameral implant for sustained release of travoprost and a corresponding method of treatment that can be used to continuously treat intraocular pressure associated with open-angle glaucoma and / or ocular hypertension in a human subject.

[0032] Another object of certain embodiments of the present invention is to provide a biodegradable intracameral implant for sustained release of travoprost and a corresponding method of treatment, wherein the implant provides a long-term therapeutic effect.

[0033] Another object of certain embodiments of the present invention is to provide a biodegradable intracameral implant for sustained release of travoprost and a corresponding method of treatment, wherein the implant provides a long-term therapeutic effect and does not cause changes in corneal thickness measurement and endothelial cell count. One or more embodiments disclosed and claimed herein address one or more of these and other objects of the present invention.

[0034] Individual aspects of the invention are disclosed in the specification and claimed in the independent claims, while the dependent claims claim specific embodiments and variations of these aspects of the invention.Details of various aspects of the invention are provided in the following detailed description. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Figure 1a Graph of in vitro release of formulations 1a, 1b, 2 and 3 measured at 37°C.

[0036] Figure 1b Graph of in vitro release of formulations 1a, 1b, 2 and 3 measured at 40°C.

[0037] Figure 1c Implant integrity grade versus time (weeks)

[0038] Figure 1d Typical Karl Fischer plot of a blank obtained using the method disclosed herein.

[0039] Figure 1e A typical Karl Fischer plot of a water standard obtained using the methods disclosed herein.

[0040] Figure 1f A typical Karl Fischer plot of an OTX-TP sample obtained using the methods disclosed herein.

[0041] Figure 2 Graphic representation of the Phase 1 clinical study design.

[0042] Figure 3a Mean corneal thickness measurements from baseline to month 22 in cohort 1 of the Phase 1 clinical study.

[0043] Figure 3b Mean corneal thickness measurements from baseline to month 9 in cohort 2 of the Phase 1 clinical study.

[0044] Figure 3c Mean corneal thickness measurements from baseline to month 9 in cohort 3 of the Phase 1 clinical study.

[0045] Figure 3d Mean corneal thickness measurements from baseline to month 6 in cohort 4 of the Phase 1 clinical study.

[0046] Figure 4a Mean ECC from baseline to month 9 in cohort 1 of the Phase 1 clinical study.

[0047] Figure 4b Mean ECC from baseline to month 9 in cohort 2 of the Phase 1 clinical study.

[0048] Figure 4c Mean ECC from baseline to month 6 in cohort 3 of the Phase 1 clinical study.

[0049] Figure 5a Change from baseline in mean IOP in Cohort 1 of the Phase 1 clinical study.

[0050] Figure 5b Change from baseline in mean IOP in cohort 2 of the Phase 1 clinical study.

[0051] Figure 5c Change in mean IOP from baseline in Cohort 3 of the Phase 1 clinical study.

[0052] Figure 5d Change from baseline in mean IOP in Phase 1 clinical study.

[0053] Figure 6 Photographs of one human subject's inserted implant between day 1 and month 7.

[0054] Figure 7 Syringe assembly for administration of the OTX-TIC travoprost implant.

[0055] definition

[0056] As used herein, the term "intracameral implant" is used interchangeably with the term "intracameral insert" and refers to an object containing an API, such as a prostaglandin antagonist (e.g., travoprost), which is suitable for administration, i.e., insertion into the anterior segment of the eye for a period of time while releasing the active agent into the surrounding environment, such as aqueous humor. The implant can also be inserted into the posterior segment. The implant is in the form of a fiber before insertion, and although the implant may change in size (e.g., length and / or diameter) after administration due to hydration as further disclosed herein, its shape can be maintained to a certain extent after the implant is placed in the desired position. In other words, the object inserted into the eye is not a solution or suspension, but a shaped, defined object. Prior to administration, the implant is fully formed, for example, according to the methods disclosed herein. The intracameral implant can be designed to be biodegradable over a period of time (as disclosed below), thereby softening, changing its shape and / or reducing its size, and ultimately being eliminated / biodegraded by complete dissolution or disintegration. In the present invention, the term "implant" is used to refer to an implant in a hydrated (also called "swollen") state when it contains water (e.g. after (re)hydration of the implant once applied to the eye or otherwise immersed in an aqueous environment); and in a dry (dried / dehydrated) state, e.g. when it has been dried to a low water content, e.g. up to 1 wt. % or when the preparation results in a low water content without a drying step. The water content of the implant is measured using Karl Fischer coulometric analysis, e.g. as shown in Example 2c.

[0057] The term "insertion" is used interchangeably herein with the terms "placement" or "injection" or "administration" or "implantation." Each term describes the intracameral implantation of the OTX-TIC implant into the anterior chamber of the eye, where it then resides in the iridocorneal angle.

[0058] The term "ocular" as used in the present invention generally refers to the eye, or any part or portion of the eye (since an "ocular implant" can in principle be applied to any part or portion of the eye). As further disclosed below, the present invention is directed in certain embodiments to intracameral injection of an ocular implant, and to the reduction of intraocular pressure in a subject suffering from glaucoma and / or ocular hypertension.

[0059] The term "biodegradable" refers to a material or object (e.g., an intracameral implant according to the present invention) that degrades in vivo (i.e., when placed in the human body). In the context of certain embodiments of the present invention, as disclosed in detail below, an implant comprising a hydrogel containing an active ingredient in the middle, once applied to the anterior segment of the eye, slowly biodegrades over time and resides in the corneal iris angle of the eye. In certain embodiments, biodegradation occurs at least in part via ester hydrolysis in the aqueous environment of the anterior segment of the eye. The implant slowly softens and disintegrates, thereby being cleared by liquefaction and cleared by the aqueous fluid outflow pathway.

[0060] A "hydrogel" is a three-dimensional network of one or more natural or synthetic hydrophilic polymers (as disclosed herein) that can swell in water and hold a certain amount of water while maintaining or substantially maintaining its structure due to, for example, chemical or physical crosslinking of individual polymer chains. Due to the high water content, the hydrogel is soft and elastic, which makes it similar to natural tissue. In the present invention, the term "hydrogel" is used to refer to a hydrogel in a hydrated state when it contains water (for example after the hydrogel has been formed in an aqueous solution, or after the hydrogel is hydrated or (re)hydrated once inserted into the eye or otherwise immersed in an aqueous environment); and a hydrogel in a dry (dried / dehydrated) state, for example when it has been dried to a low water content, for example up to 1% by weight, or when the preparation results in a low water content without the need for a drying step. In the present invention, wherein the active ingredient is contained (for example dispersed) in the hydrogel, the hydrogel may also be referred to as a "matrix".

[0061] The term "polymer network" describes a structure formed by polymer chains (having the same or different molecular structures and having the same or different molecular weights) that are cross-linked to each other. The types of polymers suitable for achieving the purpose of the present invention are disclosed below. The polymer network can be obtained by reacting a multi-arm polymer precursor containing an electrophilic group with a cross-linking agent containing a nucleophilic group.

[0062] The term "fiber" as disclosed herein refers to a shape that is substantially cylindrical and characterized by a diameter and a length.

[0063] The term "amorphous" refers to a polymer or polymer network that does not exhibit a crystalline structure in X-ray or electron scattering experiments.

[0064] The term "semi-crystalline" refers to a polymer or polymer network that has some crystalline properties, ie, exhibits some crystalline properties in X-ray or electron scattering experiments.

[0065] As used herein, "homogeneously dispersed" means that the components, for example, travoprost or travoprost particles, are evenly dispersed throughout the hydrogel or polymer network.

[0066] The term "precursor" herein refers to those molecules or compounds that react with each other and thus connect via cross-linking to form a polymer network and thus a hydrogel matrix. Although other substances may be present in the hydrogel, such as API or buffer, they are not referred to as "precursors".

[0067] The parts of the precursor molecules that are still present in the final polymer network are also referred to herein as "units". Thus, a "unit" is a building block or component of a polymer network that forms a hydrogel. For example, a polymer network suitable for use in the present invention may contain the same or different polyethylene glycol units, as further disclosed herein.

[0068] For the purposes of the present invention, the term "sustained release" is intended to characterize that the product is formulated so that the API can be used over a long period of time, thereby reducing the frequency of administration compared to an immediate release dosage form, such as an API solution applied topically to the eye (e.g., eye drops containing travoprost). Other terms that may be used interchangeably with "sustained release" herein are "extended release" or "controlled release". Within the meaning of the present invention, the term "sustained release" encompasses a constant release of the API in vitro.

[0069] The term "blend of particles" defines a mixture of particles wherein each component of the mixture has a separate composition.

[0070] As used herein, the term "repeated dose", "repeated application" or "repeated use" refers to re-treatment by inserting an intracameral implant containing the API of the present invention into the anterior chamber of the eye after the same eye has been previously treated with an equivalent or similar intracameral implant according to the present invention, before biodegradation in the eye after the use of the intracameral implant. This includes continued treatment by repeated application, such as indefinite treatment.

[0071] As used herein, the term "polylactide" generally refers to a homopolymer obtained by polycondensation of lactic acid. In other words, polylactide is composed of lactic acid monomer units. Such polylactides may have acid end groups or ester end groups, but are not composed of other monomer units in the polymer backbone, such as poly(lactic acid-co-glycolic acid). Polylactide can be formed by polymerization of D-lactic acid, L-lactic acid, or any mixture of D-lactic acid and L-lactic acid. In the latter case, the final polylactide may be referred to as D,L-polylactide.

[0072] The term "intrinsic viscosity" is used to refer to the physical parameters of polylactide (PLA) as used herein. Polymers of different molecular weights are referred to as 4A, 7A, 9A, and 5.5E PLA, where the numerical value represents the target intrinsic viscosity (IV) of the polymer in chloroform, related to the PLA molecular weight, and the letter suffix represents the acid (A) or ester (E) end group. The intrinsic viscosity specification of 4A PLA is 0.35 to 0.45 dl / g when measured in 0.5% w / v chloroform at 30°C; the intrinsic viscosity specification of 7A PLA is 0.60 to 0.80 dl / g or less, and the intrinsic viscosity specification of 9A PLA is 0.80 to 1.0 dl / g. The intrinsic viscosity specification of 5.5E PLA is 0.55 to 0.75 dl / g when measured in 0.1% w / v chloroform at 25°C.

[0073] As used herein, the term "travoprost burst release" refers to the initial rapid release of travoprost from an implant within a relatively short time interval after implantation, such as on the first day after insertion. The travoprost burst release may have a travoprost burst release of between 10% and 20%, such as about 10% to about 15% or less than 15%, based on the total weight of travoprost in the intracameral implant, within one day, such as day 1, measured in vitro under physiological conditions as described herein, such as in 50 mL of 1x PBS, 0.5% castor oil, 0.01% sodium fluoride buffer, pH 7.2-7.4, at 37°C under simulated physiological sedimentation conditions. The term "burst release" may also be applied to other active agents disclosed herein. According to the present invention, the burst release is minimized.

[0074] As used herein, the term "long-term period of time" refers to any period of time that one of ordinary skill in the art considers to be long-term in treating a disease, and particularly refers to, for example, a period of at least about 1 week, or at least about 1 month or longer, such as a period of up to about 24 months, or, for example, any intermediate period of time specifically mentioned herein, such as about 2 months to 12 months or 3 months to about 9 months, about 4 months to about 7 months, about 3 months to about 6 months.

[0075] As used herein, the term "visualizing agent" refers to a molecule or composition contained in the hydrogel of an implant that facilitates visual inspection of the implant when the implant is inserted into the anterior segment of the eye. The visualizing agent can be a fluorophore, such as fluorescein, rhodamine, coumarin, and cyanine. In certain embodiments, the visualizing agent is fluorescein or includes a fluorescein moiety.

[0076] As used herein, the term "aqueous humor" or "AH" refers to the fluid in the anterior chamber.

[0077] As used herein, in the context of administering the implant of the present invention, the term "contralateral" or "contralateral" means that the implant is administered to both eyes of the patient. Each eye is independent.

[0078] The term "intracameral implant" refers to an implant that can be applied to the anterior segment of the eye and located within the iridocorneal angle.

[0079] The terms "API", "active (pharmaceutical) ingredient", "active (pharmaceutical) agent", "active (pharmaceutical) ingredient", "(active) therapeutic agent", "active agent" and "drug" are used interchangeably herein to refer to substances used in finished pharmaceutical products (FPPs) and substances used to prepare such finished pharmaceutical products, which are intended to provide pharmacological activity or have a direct effect on the diagnosis, cure, alleviation, treatment or prevention of disease, or have a direct effect on restoring, correcting or altering the physiological function of a patient. In embodiments where the API is a prostaglandin antagonist, the agent may be, for example, travoprost, bimatoprost or latanoprost.

[0080] As described herein, the terms "treat," "treating," or "treatment" are used interchangeably and refer to reversing, alleviating, delaying onset, or inhibiting progression of a disclosed disorder (e.g., ocular hypertension or glaucoma) or one or more symptoms thereof. In other aspects, treatment may be administered in the absence of symptoms. For example, treatment may be administered to susceptible individuals prior to the onset of symptoms (e.g., based on a history of symptoms and / or based on exposure to a particular organism or other predisposing factor), i.e., prophylactic treatment. Treatment may also be continued after symptom relief, e.g., to delay its recurrence.

[0081] The terms "subject" and "patient" are used interchangeably and refer to mammals in need of treatment, such as companion animals (e.g., dogs, cats, etc.), farm animals (e.g., cows, pigs, horses, sheep, goats, etc.), and experimental animals (e.g., rats, mice, guinea pigs, etc.). Preferably, the subject is a human in need of treatment.

[0082] According to certain embodiments of the present invention, the API is travoprost. Travoprost is a prostaglandin F2α analog and a highly selective full agonist that has a high affinity for prostaglandin FP receptors and reduces intraocular pressure by increasing the outflow of aqueous humor via the trabecular meshwork and uveoscleral pathways. Travoprost is the isopropyl ester of a single enantiomer of the selective FP prostaglandin agonist fluprostenol. Travoprost belongs to the class of prostaglandin F2α analog prodrug esters (including latanoprost, bimatoprost, tafluprost), which promote corneal penetration and can deliver active carboxylic acids (travoprost acid) to the aqueous humor. It is believed that the prodrug ester is hydrolyzed by esterases in the cornea to a biologically active free acid in which carbons 17-20 are substituted by m-trifluoromethylphenoxy. The free acid of travoprost was observed to have higher potency and greater selectivity for the FP prostanoid receptor compared to latanoprost based on the results of in vitro binding affinity studies.

[0083]

[0084] As used herein, the term "therapeutically effective" refers to the amount of an API, such as travoprost, required to produce a desired therapeutic outcome following administration. For example, in the context of the present invention, one desired therapeutic outcome is lowering IOP, for example as measured by in vivo tests known to those of ordinary skill in the art. The amounts and dosages of travoprost as provided herein refer to the isopropyl ester.

[0085] As used herein, the term "intraocular pressure" (IOP) is the pressure of the fluid inside the eye. Tonometry, such as Goldmann tonometry (eg, described in detail in Example 3 below), is a method used by eye care professionals to determine IOP.

[0086] As used herein, "corneal pachymetry" is a method for measuring the thickness of the central cornea of ​​a subject. Measurement of central corneal thickness is performed using an ultrasonic pachymeter, such as defined in detail in Example 3 below.

[0087] As used herein, "endothelial cell count" or "ECC" is determined by microscopy of the corneal endothelium as defined in Example 3 below.

[0088] As used herein, the term "glaucoma" may encompass forms of open-angle glaucoma and closed-angle glaucoma. The subtypes of open-angle glaucoma disclosed herein may encompass normal-tension glaucoma, congenital glaucoma, secondary glaucoma, pigmentary glaucoma, pseudoexfoliation glaucoma, traumatic glaucoma, neovascular glaucoma, iridocorneal endothelial syndrome (ICE) and / or uveal glaucoma.

[0089] As used herein, "endothelial cell counts did not change in the treated eye during the treatment period and / or throughout the treatment period" means that the endothelial cell count value did not decrease clinically meaningfully. A single decrease of up to 20% from baseline in a subject during the treatment period and / or a sustained decrease of up to 10% from baseline in a subject during the treatment period is clinically acceptable.

[0090] As used herein, "no change in corneal thickness or corneal thickness measurement in the treated eye during the treatment period and / or throughout the treatment period" means that the corneal thickness measurement value has not decreased clinically meaningfully. A single decrease of up to 20% from baseline in a subject during the treatment period and / or a sustained decrease of up to 10% from baseline in a subject during the treatment period is clinically acceptable.

[0091] As used herein, the term "open-angle glaucoma" is classified by ICD-10 code H40. Open-angle glaucoma can be broadly classified as mild, moderate, or severe open-angle glaucoma.

[0092] As used herein, "ocular hypertension" generally refers to any condition in which the intraocular pressure, i.e., the IOP, is higher than normal pressure. Intraocular pressure is measured in millimeters of mercury (mm Hg). Normal intraocular pressure is below 21 mm Hg, with an average of 16 mm Hg. Ocular hypertension is generally an intraocular pressure above 21 mm Hg. Intraocular pressure is related to the thickness of the cornea of ​​an individual subject. A subject with a thin cornea may still have ocular hypertension despite an intraocular pressure below 21 mm Hg; an individual with a thick cornea may still have normal intraocular pressure despite an intraocular pressure above 21 mm Hg. Therefore, a correction factor is also generally applied for changes in corneal thickness.

[0093] As used herein, the term "about" in relation to a measured amount refers to the normal variation of the measured amount as would be expected by one of ordinary skill in the art making the measurements and exercising a level of care commensurate with the objective of the measurement and the precision of the measuring device.

[0094] The term "at least about" with respect to a measured amount refers to the normal variation in the measured amount, and any amount above this amount, as would be expected by one of ordinary skill in the art making the measurements and exercising a level of care commensurate with the measurement objective and the precision of the measuring equipment.

[0095] As used herein, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise.

[0096] The term "and / or" as used herein in phrases such as "A and / or B" is intended to include both "A and B" and "A or B."

[0097] For example, open terminology such as “include / including,” “contain / containing,” etc. means “comprising.” These open transitional phrases are used to introduce an open list of elements, method steps, etc. that does not exclude additional, unrecited elements or method steps. DETAILED DESCRIPTION

[0098] Prostaglandin antagonist particles

[0099] The prostaglandin antagonist (eg travoprost) particles according to the present invention are in the form of a prostaglandin antagonist (eg travoprost) intermixed with a biodegradable polymer. For example, the particles are microparticles. Such particles can be prepared by microencapsulation.

[0100] In a specific embodiment, the prostaglandin antagonist (e.g., travoprost) particles have a diameter in the range of about 1 to about 150 μm as determined by sieving, or have an average diameter in the range of 1 to 150 μm as determined by laser diffraction. In a more specific embodiment, the particles have a diameter in the range of about 1 to about 100 μm, about 20 to about 75 μm, about 20 to about 106 μm, or about 20 to about 55 μm as determined by sieving, or have an average diameter in the range of about 1 to about 100 μm, about 20 to about 75 μm, about 20 to about 106 μm, or about 20 to about 55 μm as determined by laser diffraction. In a specific embodiment, the average particle diameter is 36 μm as determined by laser diffraction.

[0101] In a specific embodiment, the biodegradable polymer comprises polylactide. More specifically, the polylactide has acid end groups or ester end groups.

[0102] In one embodiment, the prostaglandin antagonist (e.g., travoprost) particles are a blend of different types of particles, such as particles in the form of a prostaglandin antagonist (e.g., travoprost) intermixed with a first polylactide and particles in the form of a prostaglandin antagonist (e.g., travoprost) intermixed with a second polylactide. More specifically, the first polylactide and the second polylactide each have an acid end group. In a more specific embodiment, the first polylactide has an intrinsic viscosity specification in the range of about 0.05 to less than 0.5 dl / g, or in the range of about 0.35 to about 0.45 dl / g. Additionally or alternatively, the second polylactide has an intrinsic viscosity specification in the range of about 0.5 to less than about 0.80 dl / g, or in the range of about 0.6 to less than about 0.8 dl / g.

[0103] In a certain embodiment, the prostaglandin antagonist (e.g., travoprost) particles are composed of a blend of two types of particles, a first type of particles in the form of a prostaglandin antagonist (e.g., travoprost) intermixed with a biodegradable polymer composed of a first polylactide and a second type of particles in the form of a prostaglandin antagonist (e.g., travoprost) intermixed with a biodegradable polymer composed of a second polylactide.

[0104] In one embodiment, the first polylactide and the second polylactide have a mass ratio of about 1.5:1 to about 1:1.5, or about 1:1 in the particle blend.

[0105] In one embodiment, the prostaglandin antagonist (e.g. travoprost) particles are a blend of different types of particles, including particles in the form of a prostaglandin antagonist (e.g. travoprost) intermixed with a first polylactide, particles in the form of a prostaglandin antagonist (e.g. travoprost) intermixed with a second polylactide, and particles in the form of a prostaglandin antagonist (e.g. travoprost) intermixed with a third polylactide, wherein each of the polylactides has an acid end group. Specifically, the first polylactide has an intrinsic viscosity specification in the range of about 0.05 to less than about 0.5 dl / g, or in the range of about 0.35 to about 0.45 dl / g, the second polylactide has an intrinsic viscosity specification in the range of about 0.5 to less than about 0.80 dl / g, or in the range of about 0.6 to less than about 0.8 dl / g, and the third polylactide has an intrinsic viscosity specification in the range of about 0.8 to about 1.7 dl / g, or in the range of about 0.8 to about 1.0 dl / g.

[0106] More specifically, the biodegradable polymer comprises a blend of three types of particles, for example, consists of a blend of three types of particles, the first type of particles being in the form of a prostaglandin antagonist (e.g., travoprost) intermixed with a biodegradable polymer consisting of a first polylactide, and the second type of particles being in the form of a prostaglandin antagonist (e.g., travoprost) intermixed with a biodegradable polymer consisting of a second polylactide and the third type of particles being in the form of a prostaglandin antagonist (e.g., travoprost) intermixed with a biodegradable polymer consisting of a third polylactide.

[0107] In another embodiment, the mass ratio of the first polylactide to the second polylactide in the particle blend is from about 2:1 to about 1:2 or about 1:1.6.

[0108] In another embodiment, the mass ratio of the first polylactide to the third polylactide in the particle blend is from about 2:1 to about 1:2, or about 1:1.4.

[0109] In another embodiment, the prostaglandin antagonist (e.g. travoprost) particles are a blend of different types of particles, including particles in the form of a prostaglandin antagonist (e.g. travoprost) intermixed with a first polylactide, particles in the form of a prostaglandin antagonist (e.g. travoprost) intermixed with a second polylactide, particles in the form of a prostaglandin antagonist (e.g. travoprost) intermixed with a third polylactide, and particles in the form of a prostaglandin antagonist (e.g. travoprost) intermixed with a fourth polylactide.

[0110] More specifically, the first polylactide has an intrinsic viscosity specification in the range of about 0.05 to less than about 0.5 dl / g, or in the range of about 0.35 to about 0.45 dl / g, and has acid end groups, the second polylactide has an intrinsic viscosity specification in the range of about 0.5 to less than about 0.80 dl / g, or in the range of about 0.6 to less than about 0.8 dl / g, and has acid end groups, the third polylactide has an intrinsic viscosity specification in the range of about 0.8 to about 1.7 dl / g, or in the range of about 0.8 to about 1.0 dl / g, and has acid end groups, and the fourth polylactide has an intrinsic viscosity specification in the range of about 0.05 to about 1.7 dl / g, for example, in the range of about 0.55 to about 0.75 dl / g, and has ester end groups.

[0111] Even more specifically, the prostaglandin antagonist (e.g. travoprost) particles may comprise, for example consist of, a blend of four types of particles, a first type of particles in the form of a prostaglandin antagonist (e.g. travoprost) intermixed with a biodegradable polymer consisting of a first polylactide, a second type of particles in the form of a prostaglandin antagonist (e.g. travoprost) intermixed with a biodegradable polymer consisting of a second polylactide, a third type of particles in the form of a prostaglandin antagonist (e.g. travoprost) intermixed with a biodegradable polymer consisting of a third polylactide and a fourth type of particles in the form of a prostaglandin antagonist (e.g. travoprost) intermixed with a biodegradable polymer consisting of a fourth polylactide.

[0112] In another embodiment, the mass ratio of the first polylactide to the second polylactide in the particle blend is from about 1.25:1 to about 1:1.25 or about 1:1.

[0113] In another embodiment, the mass ratio of the first polylactide to the third polylactide in the particle blend is from about 3:1 to about 1:1, or about 2:1.

[0114] In another embodiment, the mass ratio of the first polylactide to the fourth polylactide in the particle blend is from about 1:1 to about 1:3, or about 1:2.5, or about 1:2.6.

[0115] In certain embodiments, the mass ratio between the total amount of prostaglandin antagonist (eg, travoprost) and biodegradable polymer in the prostaglandin antagonist (eg, travoprost) particles is about 2:1 to 1:2 or about 0.77:1.

[0116] In a certain embodiment, the prostaglandin antagonist (eg, travoprost) particles comprise, consist of, or consist essentially of a prostaglandin antagonist (eg, travoprost) and a biodegradable polymer and other pharmaceutically acceptable residual amounts of manufacturing components.

[0117] In a certain embodiment, the travoprost particles are a blend of at least two types of travoprost particles selected from the group consisting of:

[0118] 1) A first type of travoprost particles made from a mixture of:

[0119] - travoprost, and

[0120] - a biodegradable polymer consisting of one or more polylactides having acid end groups and an intrinsic viscosity specification in the range of about 0.05 to less than about 0.5 dl / g, such as about 0.35 to about 0.45 dl / g,

[0121] For example wherein the first type of particles contains about 40 wt.-% to about 50 wt.-%, such as about 43 wt.-% to about 45 wt.-% of travoprost, based on the total mass of particles of the first type;

[0122] 2) A second type of travoprost particles made from a mixture of:

[0123] - travoprost, and

[0124] - a biodegradable polymer consisting of one or more polylactides having acid end groups and an intrinsic viscosity specification in the range of about 0.5 to less than about 0.80 dl / g, such as in the range of about 0.6 to less than about 0.80 dl / g,

[0125] For example wherein the second type of particles contains from about 40 wt.-% to about 50 wt.-%, such as greater than about 45 wt.-% to about 47 wt.-% of travoprost, based on the total mass of particles of the second type;

[0126] 3) A third type of travoprost particles made from a mixture of:

[0127] - travoprost, and

[0128] - a biodegradable polymer consisting of one or more polylactides having acid end groups and an intrinsic viscosity specification in the range of about 0.8 to about 1.7 dl / g, such as in the range of about 0.8 to about 1.0 dl / g,

[0129] For example wherein the third type of particles contains about 40 wt.-% to about 50 wt.-%, such as about 41 wt.-% to about 43 wt.-% of travoprost, based on the total mass of particles of the third type;

[0130] 4) A fourth type of travoprost particles made from a mixture of:

[0131] - travoprost, and

[0132] - a biodegradable polymer consisting of one or more polylactides having ester end groups and an intrinsic viscosity specification in the range of about 0.05 to about 1.7 dl / g, such as in the range of about 0.55 to about 0.75 dl / g,

[0133] For example wherein the fourth type of particles contains about 40 wt.-% to about 50 wt.-%, such as about 41 wt.-% to about 43 wt.-% of travoprost, based on the total mass of particles of the fourth type.

[0134] In a certain embodiment, the travoprost particles are a blend of at least two types of travoprost particles selected from:

[0135] 1) A first type of travoprost particles comprising:

[0136] - travoprost, and

[0137] - a biodegradable polymer comprising one or more polylactides having acid end groups and an intrinsic viscosity specification in the range of about 0.05 to less than about 0.5 dl / g,

[0138] wherein the first type of particles comprises from about 40 wt.-% to about 50 wt.-% of travoprost, based on the total mass of particles of the first type;

[0139] 2) A second type of travoprost particles comprising:

[0140] - travoprost, and

[0141] - a biodegradable polymer comprising one or more polylactides having acid end groups and an intrinsic viscosity specification in the range of about 0.5 to less than about 0.80 dl / g,

[0142] wherein the second type of particles comprises from about 40 wt.-% to about 50 wt.-% of travoprost, based on the total mass of the second type of particles;

[0143] 3) A third type of travoprost particles comprising:

[0144] - travoprost, and

[0145] - a biodegradable polymer comprising one or more polylactides having acid end groups and an intrinsic viscosity specification in the range of about 0.8 to about 1.7 dl / g,

[0146] wherein the third type of particles comprises from about 40 wt.-% to about 50 wt.-% of travoprost, based on the total mass of particles of the third type;

[0147] 4) A fourth type of travoprost particles comprising:

[0148] - travoprost, and

[0149] - a biodegradable polymer comprising one or more polylactides having ester end groups and an intrinsic viscosity specification in the range of about 0.05 to about 1.7 dl / g,

[0150] Wherein the fourth type of particles comprises about 40 wt.-% to about 50 wt.-% travoprost, based on the total mass of particles of the fourth type.

[0151] In a certain embodiment, the travoprost particles are a blend of particles made from:

[0152] 1) a first type of travoprost particles made from a mixture of travoprost and a biodegradable polymer consisting of one or more polylactides having acid end groups and an intrinsic viscosity specification in the range of about 0.05 to less than about 0.5 dl / g, such as about 0.35 to about 0.45 dl / g, wherein the first type of particles contains about 40 wt.-% to about 50 wt.-%, such as about 43 wt.-% to about 45 wt.-% of travoprost based on the total mass of the first type of particles; and

[0153] 2) a second type of travoprost particles made from a mixture of travoprost and a biodegradable polymer consisting of one or more polylactides having acid end groups and an intrinsic viscosity specification in the range of about 0.5 to less than about 0.80 dl / g, such as in the range of about 0.6 to less than about 0.80 dl / g, wherein the second type of particles contains about 40 wt.-% to about 50 wt.-%, such as greater than about 45 wt.-% to about 47 wt.-% of travoprost based on the total mass of the second type of particles,

[0154] For example wherein the blend contains from about 35 wt.-% to about 55 wt.-% of particles of the first type of particles and from about 35 wt.-% to about 55 wt.-% of particles of the second type of particles, based on the total amount of the blend; or

[0155] For example 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,

[0156] Wherein optionally, the polymer network is formed by reacting a multi-arm polymer precursor containing an electrophilic group with a cross-linking agent containing a nucleophilic group, wherein the electrophilic group is a succinimidyl glutarate (SG) group and the multi-arm polymer precursor is 8-arm-15K-SG polyethylene glycol; and the cross-linking agent containing a nucleophilic group is trilysine, or the polymer network comprises cross-linked 8-arm-polyethylene glycol, wherein the 8-arm-polyethylene glycol comprises a group represented by the formula:

[0157]

[0158] Where m is 2.

[0159] In a certain embodiment, the travoprost particles are a blend of particles made from:

[0160] 1) a first type of particles made from a mixture of travoprost and a biodegradable polymer consisting of one or more polylactides having acid end groups and an intrinsic viscosity specification in the range of about 0.05 to less than about 0.5 dl / g, such as about 0.35 to about 0.45 dl / g, wherein the first type of particles contains about 40 wt.-% to about 50 wt.-%, such as about 43 wt.-% to about 45 wt.-% of travoprost, based on the total mass of the first type of particles,

[0161] 2) a second type of travoprost particles made from a mixture of travoprost and a biodegradable polymer consisting of one or more polylactides having acid end groups and an intrinsic viscosity specification in the range of about 0.5 to less than about 0.80 dl / g, such as in the range of 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 greater than about 45 wt.-% to about 47 wt.-% of travoprost, based on the total mass of the second type of particles, and

[0162] 3) a third type of travoprost particles made from a mixture of travoprost and a biodegradable polymer consisting of one or more polylactides having acid end groups and an intrinsic viscosity specification in the range of about 0.8 to about 1.7 dl / g, such as in the range of about 0.8 to about 1.0 dl / g, wherein the third type of particles contains about 40 wt.-% to about 50 wt.-%, such as about 41 wt.-% to about 43 wt.-% of travoprost, based on the total mass of the third type of particles,

[0163] For example wherein the blend contains from about 20 wt.-% to about 35 wt.-% of particles of the first type of particles and from about 30 wt.-% to about 50 wt.-% of particles of the second type of particles and from about 25 wt.-% to about 45 wt.-% of particles of the third type of particles, based on the total amount of the blend; or

[0164] For example wherein about 20 wt.-% to about 35 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 30 wt.-% to about 50 wt.-% of the total amount of travoprost in the implant is present in the form of particles of the second type of particles, and about 25 wt.-% to about 45 wt.-% of the total amount of travoprost in the implant is present in the form of particles of the third type of particles,

[0165] Wherein optionally, the polymer network is formed by reacting a multi-arm polymer precursor containing an electrophilic group with a cross-linking agent containing a nucleophilic group, wherein the electrophilic group is a succinimidyl glutarate (SG) group and the multi-arm polymer precursor is 8-arm-15K-SG polyethylene glycol; and the cross-linking agent containing a nucleophilic group is trilysine, or the polymer network comprises cross-linked 8-arm-polyethylene glycol, wherein the 8-arm-polyethylene glycol comprises a group represented by the formula:

[0166]

[0167] Where m is 2.

[0168] In certain embodiments, the travoprost particles are a blend of particles made from:

[0169] 1) a first type of particles made from a mixture of travoprost and a biodegradable polymer consisting of one or more polylactides having acid end groups and an intrinsic viscosity specification in the range of about 0.05 to less than about 0.5 dl / g, such as about 0.35 to about 0.45 dl / g, wherein the first type of particles contains about 40 wt.-% to about 50 wt.-%, such as about 43 wt.-% to about 45 wt.-% of travoprost, based on the total mass of the first type of particles,

[0170] 2) a second type of particles made from a mixture of travoprost and a biodegradable polymer consisting of one or more polylactides having acid end groups and an intrinsic viscosity specification in the range of about 0.5 to less than about 0.80 dl / g, such as in the range of about 0.6 to less than about 0.80 dl / g, wherein the second type of particles contains about 40 wt.-% to about 50 wt.-%, such as greater than about 45 wt.-% to about 47 wt.-% of travoprost based on the total mass of the second type of particles,

[0171] 3) a third type of particles made of travoprost and a biodegradable polymer consisting of one or more polylactides having acid end groups and an intrinsic viscosity specification in the range of about 0.8 to about 1.7 dl / g, such as in the range of about 0.8 to about 1.0 dl / g, wherein the third type of particles contains about 40 wt.-% to about 50 wt.-%, such as about 41 wt.-% to about 43 wt.-% of travoprost, based on the total mass of the third type of particles, and

[0172] 4) a fourth type of particles made of travoprost and a biodegradable polymer consisting of one or more polylactides having ester end groups and an intrinsic viscosity specification in the range of about 0.05 to about 1.7 dl / g, such as in the range of about 0.55 to about 0.75 dl / g, wherein the fourth type of particles contains about 40 wt.-% to about 50 wt.-%,

[0173] For example wherein the blend contains from about 15 wt.-% to about 25 wt.-% of particles of the first type of particles and from about 15 wt.-% to about 25 wt.-% of particles of the second type of particles and from about 5 wt.-% to about 15 wt.-% of particles of the third type of particles and from about 40 wt.-% to about 60 wt.-% of particles of the fourth type of particles, based on the total amount of the blend; or

[0174] for example wherein about 15 wt.-% to about 25 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 15 wt.-% to about 25 wt.-% of the total amount of travoprost in the implant is present in the form of particles of the second type of particles and about 5 wt.-% to about 15 wt.-% of the total amount of travoprost in the implant is present in the form of particles of the third type of particles and about 40 wt.-% to about 60 wt.-% of the total amount of travoprost in the implant is present in the form of particles of the fourth type of particles,

[0175] Wherein optionally, the polymer network is formed by reacting a multi-arm polymer precursor containing an electrophilic group with a cross-linking agent containing a nucleophilic group, the electrophilic group is a succinimidyl azelate (SAZ) group, and the multi-arm polymer precursor is 8-arm-15K-SAZ polyethylene glycol; and the cross-linking agent containing a nucleophilic group is trilysine, or the polymer network comprises cross-linked 8-arm-polyethylene glycol, and the 8-arm-polyethylene glycol comprises a group represented by the following formula:

[0176]

[0177] Where m is 6.

[0178] In certain embodiments, the travoprost particles comprise a blend of particles comprising

[0179] 1) a first type of travoprost particles comprising a mixture of travoprost and a biodegradable polymer comprising one or more polylactides having acid end groups and an intrinsic viscosity specification in the range of about 0.05 to less than about 0.5 dl / g, wherein the first type of particles contains about 40 wt.-% to about 50 wt.-% travoprost based on the total mass of the first type of particles; and

[0180] 2) a second type of travoprost particles comprising a mixture of travoprost and a biodegradable polymer comprising one or more polylactides having acid end groups and an intrinsic viscosity specification in the range of about 0.5 to less than about 0.80 dl / g, wherein the second type of particles contains about 40 wt.-% to about 50 wt.-% travoprost based on the total mass of the second type of particles,

[0181] wherein the blend comprises about 35 wt.-% to about 55 wt.-% of particles of the first type of particles and about 35 wt.-% to about 55 wt.-% of particles of the second type of particles, based on the total amount of the blend.

[0182] In a certain embodiment, the travoprost particles comprise a blend of particles comprising

[0183] 1) a first type of particles comprising a mixture of travoprost and a biodegradable polymer comprising one or more polylactides having acid end groups and an intrinsic viscosity specification in the range of about 0.05 to less than about 0.5 dl / g, wherein the first type of particles contains about 40 wt.-% to about 50 wt.-% of travoprost based on the total mass of the first type of particles,

[0184] 2) a second type of travoprost particles comprising a mixture of travoprost and a biodegradable polymer comprising one or more polylactides having acid end groups and an intrinsic viscosity specification in the range of about 0.5 to less than about 0.80 dl / g, wherein the second type of particles contains about 40 wt.-% to about 50 wt.-% travoprost, based on the total mass of the second type of particles, and

[0185] 3) a third type of travoprost particles comprising a mixture of travoprost and a biodegradable polymer comprising one or more polylactides having acid end groups and an intrinsic viscosity specification in the range of about 0.8 to about 1.7 dl / g, wherein the third type of particles contains about 40 wt.-% to about 50 wt.-% travoprost based on the total mass of the third type of particles,

[0186] wherein the blend comprises from about 20 wt.-% to about 35 wt.-% of particles of the first type of particles, from about 30 wt.-% to about 50 wt.-% of particles of the second type of particles and from about 25 wt.-% to about 45 wt.-% of particles of the third type of particles, based on the total amount of the blend.

[0187] In certain embodiments, the travoprost particles comprise a blend of particles comprising

[0188] 1) a first type of particles comprising a mixture of travoprost and a biodegradable polymer comprising one or more polylactides having acid end groups and an intrinsic viscosity specification in the range of about 0.05 to less than about 0.5 dl / g, wherein the first type of particles contains about 40 wt.-% to about 50 wt. % travoprost based on the total mass of the first type of particles,

[0189] 2) a second type of particles comprising a mixture of travoprost and a biodegradable polymer comprising one or more polylactides having acid end groups and an intrinsic viscosity specification in the range of about 0.5 to less than about 0.80 dl / g, wherein the second type of particles contains about 40 wt.-% to about 50 wt.-% travoprost based on the total mass of the second type of particles,

[0190] 3) a third type of particles comprising travoprost and a biodegradable polymer comprising one or more polylactides having acid end groups and an intrinsic viscosity specification in the range of about 0.8 to about 1.7 dl / g, wherein the third type of particles contains about 40 wt.-% to about 50 wt.-% travoprost, based on the total mass of the third type of particles, and

[0191] 4) a fourth type of particles comprising travoprost and said biodegradable polymer, comprising one or more polylactides having ester end groups and an intrinsic viscosity specification in the range of about 0.05 to about 1.7 dl / g, wherein said fourth type of particles contains about 40 wt.-% to about 50 wt.-%,

[0192] wherein the blend contains from about 15 wt.-% to about 25 wt.-% of particles of the first type of particles, from about 15 wt.-% to about 25 wt.-% of particles of the second type of particles, from about 5 wt.-% to about 15 wt.-% of particles of the third type of particles, and from about 40 wt.-% to about 60 wt.-% of particles of the fourth type of particles, based on the total amount of the blend.

[0193] In another embodiment, the particles are spherical particles.

[0194] According to a first specific aspect, the present invention is directed to prostaglandin antagonist (e.g. travoprost) particles made from a mixture consisting of:

[0195] - Prostaglandin antagonists (eg, travoprost) and

[0196] - a biodegradable polymer consisting of polylactide having acid end groups and an intrinsic 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,

[0197] The mixture contains about 40 wt.-% to about 50 wt.-%, such as about 43 wt.-% to about 45 wt.-% of the prostaglandin antagonist (eg travoprost), based on the total mass of the mixture.

[0198] According to a second specific aspect, the present invention is directed to prostaglandin antagonist (e.g. travoprost) particles made from a mixture consisting of:

[0199] - Prostaglandin antagonists (eg, travoprost) and

[0200] - a biodegradable polymer consisting of polylactide having acid end groups and an intrinsic viscosity specification in the range of about 0.5 to less than about 0.80 dl / g, such as in the range of about 0.6 to less than about 0.80 dl / g,

[0201] The mixture contains about 40 wt.-% to about 50 wt.-%, such as greater than about 45 wt.-% to about 47 wt.-% of the prostaglandin antagonist (eg travoprost), based on the total mass of the mixture.

[0202] According to a third specific aspect, the present invention is directed to prostaglandin antagonist (e.g. travoprost) particles that are a mixture of:

[0203] - Prostaglandin antagonists (eg, travoprost) and

[0204] - a biodegradable polymer consisting of polylactide having acid end groups and an intrinsic viscosity specification in the range of about 0.8 to about 1.7 dl / g, such as in the range of about 0.8 to about 1.0 dl / g,

[0205] The mixture contains about 40 wt.-% to about 50 wt.-%, such as about 41 wt.-% to about 43 wt.-% of the prostaglandin antagonist (eg travoprost), based on the total mass of the mixture.

[0206] According to a fourth aspect, the present invention is directed to prostaglandin antagonist (e.g. travoprost) particles made from a mixture consisting of:

[0207] - Prostaglandin antagonists (eg, travoprost) and

[0208] - a biodegradable polymer consisting of polylactide having ester end groups and an intrinsic viscosity specification in the range of about 0.05 to about 1.7 dl / g, such as in the range of about 0.55 to about 0.75 dl / g,

[0209] The mixture contains about 40 wt.-% to about 50 wt.-%, such as about 41 wt.-% to about 43 wt.-% of the prostaglandin antagonist (eg travoprost), based on the total mass of the mixture.

[0210] According to aspect (a), the present invention is directed to travoprost particles made from a mixture of:

[0211] - travoprost, and

[0212] - a biodegradable polymer consisting of polylactide having acid end groups and an intrinsic 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,

[0213] Wherein the mixture contains about 40 wt.-% to about 50 wt.-%, such as about 43 wt.-% to about 45 wt.-% of travoprost, based on the total mass of the mixture.

[0214] According to aspect (b), the present invention is directed to travoprost particles made from a mixture of:

[0215] - travoprost, and

[0216] - a biodegradable polymer consisting of polylactide having acid end groups and an intrinsic viscosity specification in the range of about 0.5 to less than about 0.80 dl / g, such as in the range of about 0.6 to less than about 0.80 dl / g,

[0217] Wherein the mixture contains from about 40 wt.-% to about 50 wt.-%, such as greater than about 45 wt.-% to about 47 wt.-% of travoprost, based on the total mass of the mixture.

[0218] According to aspect (c), the present invention is directed to travoprost particles made from a mixture of:

[0219] - travoprost, and

[0220] - a biodegradable polymer consisting of polylactide having acid end groups and an intrinsic viscosity specification in the range of about 0.8 to about 1.7 dl / g, such as in the range of about 0.8 to about 1.0 dl / g,

[0221] Wherein the mixture contains about 40 wt.-% to about 50 wt.-%, such as about 41 wt.-% to about 43 wt.-% of travoprost, based on the total mass of the mixture.

[0222] According to aspect (c), the present invention is directed to travoprost particles made from a mixture of:

[0223] - travoprost, and

[0224] - a biodegradable polymer consisting of polylactide having ester end groups and an intrinsic viscosity specification in the range of about 0.05 to about 1.7 dl / g, such as in the range of about 0.55 to about 0.75 dl / g,

[0225] Wherein the mixture contains about 40 wt.-% to about 50 wt.-%, such as about 41 wt.-% to about 43 wt.-% of travoprost, based on the total mass of the mixture.

[0226] As part of one embodiment, the travoprost in the disclosed implant is microencapsulated, wherein the remainder of the implant is as described herein. Alternatively, the travoprost in the disclosed implant is microencapsulated with poly(lactic-co-glycolic acid) (PLGA) or poly(lactic acid) (PLA) or a combination thereof, wherein the remainder of the implant is as described herein. In another alternative, the travoprost in the disclosed implant is microencapsulated with PLA, wherein the remainder of the implant is as described herein.

[0227] Biodegradable hydrogel

[0228] In certain embodiments of the invention, the prostaglandin antagonist (e.g., travoprost) particles as defined above are dispersed in the biodegradable hydrogel. In other words, in certain embodiments of this type, the prostaglandin antagonist (e.g., travoprost) particles are distributed within the matrix constituted by the hydrogel. In a specific embodiment, the prostaglandin antagonist (e.g., travoprost) particles are uniformly dispersed in the biodegradable polymer. PEG hydrogel

[0229] In certain embodiments, the hydrogel comprises a polymer network comprising one or more polyethylene glycol units.

[0230] In a certain embodiment of the invention, the polymer network forming the hydrogel contains polyethylene glycol (PEG) units. It is known in the art that PEG forms hydrogels when cross-linked, and these PEG hydrogels are suitable for pharmaceutical applications, for example as a matrix for drugs intended to be administered to all parts of the human or animal body.

[0231] The polymer network of the hydrogel implant of the present invention can comprise one or more multi-arm PEG units having 2 to 10 arms, or 4 to 8 arms, or 4, 5, 6, 7 or 8 arms. In certain embodiments, the PEG units used in the hydrogel of the present invention have 8 arms. In certain specific embodiments, 8-arm PEG is utilized.

[0232] In certain embodiments, the polyethylene glycol unit is a 4- to 10-arm polyethylene glycol unit, or an 8-arm polyethylene glycol unit.

[0233] The molecular weight of polyethylene glycol refers to an average molecular weight, which can be selected from various average values ​​known to those of ordinary skill in the art, including number average molecular weight (Mn), weight average molecular weight (Mw) and peak average molecular weight. Any of these average values, in particular the above three average molecular weights, can be used in the context of the present invention. In certain embodiments, the average molecular weight of polyethylene glycol units and precursors as disclosed herein is given as a number average molecular weight.

[0234] As used herein, a multi-arm PEG unit of a specified molecular weight may be abbreviated in the form, for example, 8al5kPEG, which refers to an 8-arm PEG with a molecular weight of 15,000 Daltons.

[0235] In 4-arm PEG, each arm may have an average arm length (or molecular weight) of the total molecular weight of PEG divided by 4. 4a20kPEG precursor is a particularly suitable precursor for the present invention, so it has 4 arms, and the average molecular weight of each arm is about 5,000 Daltons. The 8a20k PEG precursor, which can also be combined with or replace the 4a20kPEG precursor in the present invention, therefore has 8 arms, and the average molecular weight of each arm is 2,500 Daltons. Compared with shorter arms, longer arms can provide increased flexibility. Compared with PEG with shorter arms, PEG with longer arms may swell more. PEG with fewer arm numbers may also swell more and be more flexible than PEG with higher arm numbers. In certain specific embodiments, only 4-arm PEG precursors are used in the present invention. In certain specific embodiments, two different 4-arm PEG precursors are used in the present invention. In certain other embodiments, a combination of 4-arm PEG precursors and 8-arm precursors is used in the present invention. In addition, longer PEG arms have higher melting temperatures when dried, which may provide greater dimensional stability during storage.

[0236] In certain embodiments, the polymer network is formed by reacting a multi-arm polymer precursor containing an electrophilic group with a cross-linking agent containing a nucleophilic group. In certain specific embodiments, the multi-arm polymer precursor is a 4 to 10-arm polyethylene glycol precursor, or an 8-arm polyethylene glycol precursor.

[0237] In certain embodiments, the electrophilic end group of the PEG precursor used to prepare the hydrogels of the present invention is an N-hydroxysuccinimidyl (NHS) ester, including but not limited to NHS dicarboxylates, such as succinimidyl malonate, succinimidyl maleate, succinimidyl fumarate, "SAZ" refers to a succinimidyl azelate end group, "SAP" refers to a succinimidyl adipate end group, "SG" refers to a succinimidyl glutarate end group, and "SS" refers to a succinimidyl succinate end group.

[0238] In certain embodiments, 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.

[0239] In certain embodiments, the electrophilic group is selected from the group consisting of a succinimidyl glutarate (SG) group and a succinimidyl azelaate (SAZ) group.

[0240] In certain embodiments of the present invention, the polymer network is formed by reacting a multi-arm polymer precursor containing an electrophilic group with a cross-linking agent containing a nucleophilic group, wherein the electrophilic group is selected from the group consisting of a succinimidyl glutarate (SG) group and a succinimidyl azelaate (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 cross-linking agent containing a nucleophilic group is trilysine, or 8-arm-15K-SAZ polyethylene glycol; and the cross-linking agent containing a nucleophilic group is trilysine, or the polymer network comprises cross-linked 8-arm-polyethylene glycol, and the 8-arm-polyethylene glycol comprises a group represented by the following formula:

[0241]

[0242] Where m is 2 or 6.

[0243] Thus, in certain embodiments, the PEG-precursor is an NHS dicarboxylate terminated multi-arm PEG precursor which can be represented by the formula:

[0244]

[0245] Where n is determined by the molecular weight of the individual PEG arms, m is an integer from 0 to 10, and specifically, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, and x is the number of arms (and thus can be, for example, 2, 4, 8, etc., see above). Where m is 1, each arm is terminated with a succinimidyl succinate (SS) end group, where m is 2, each arm is terminated with a succinimidyl glutarate (SG) group, where m is 3, each arm is terminated with a succinimidyl adipate (SAP) group, and where m is 6, each arm is terminated with a succinimidyl azelaate (SAZ) group. Under these specific electrophilic end groups, the multi-arm PEG unit can be abbreviated, for example, to the form 4a20kPEG-SAP, referring to a 4-arm PEG with a succinimidyl adipate end group and a molecular weight of 20,000. In the above formula, R is a core structure suitable for providing the desired number of arms. For 4-arm PEG units and precursors, R may be a pentaerythritol structure, and for 8-arm PEG units and precursors, R may be a hexaglycerol structure.

[0246] In certain embodiments, the multi-arm polymer precursor has a mass average molecular weight in the range of about 10,000 to about 20,000 Daltons. In a more specific embodiment, the multi-arm polymer precursor has a mass average molecular weight of 15,000 ± 10% Daltons.

[0247] The molecular weight of polyethylene glycol and polyethylene glycol derivatives can be measured by several methods, including gel electrophoresis, gel permeation chromatography (GPC), GPC combined with dynamic light scattering (DLS) and matrix-assisted laser desorption / ionization time of flight (MALDI-TOF) spectroscopy of, for example, SDS-PAGE (sodium dodecyl sulfate-polyacrylamide gel electrophoresis). The molecular weight of polyethylene glycol precursors as disclosed herein can be measured by any method known to those of ordinary skill in the art, including SDS-PAGE, GPC and MALDI-TOF, especially by GPC using PEG standards with known molecular weight (e.g., measured by MALDI-TOF) and polydispersity (e.g., measured by GPC). If high accuracy is required, MALDI-TOF can be used.

[0248] In certain embodiments, for example, the reaction of a cross-linking agent containing a nucleophilic group with a PEG unit containing an electrophilic group, such as the reaction of an amine-containing cross-linking agent with a PEG unit containing an activated ester group, produces multiple PEG units cross-linked by the cross-linking agent via amide groups.

[0249] In the case of PEG with NHS-ester end groups, such as succinimidyl azelaate (SAZ)-, succinimidyl adipate (SAP)-, or succinimidyl glutarate- (SG)-terminated PEG units (see above), reaction with an amine-containing cross-linking agent results in multiple PEG units cross-linked by the cross-linking agent via a hydrolyzable linker having the formula:

[0250]

[0251] wherein m is an integer from 0 to 10, and specifically, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10. For SAZ-terminal groups, m will be 6. For SAP-terminal groups, m will be 3, for SG-terminal groups, m will be 2 and for SS-terminal groups, m will be 1.

[0252] In a certain embodiment, the nucleophilic group-containing cross-linking agent is an amine.

[0253] In another embodiment, the cross-linking agent containing a nucleophilic group is a small amine having a molecular weight of less than 1,000 Da and containing two or more aliphatic primary amine groups.

[0254] In a certain embodiment, the cross-linking agent containing a nucleophilic group is a small molecule amine selected from the group consisting of dilysine, trilysine, tetralysine, ethylenediamine, 1,3-diaminopropane, 1,3-diaminopropane, diethylenetriamine and trimethylhexanediamine.

[0255] In one embodiment, the cross-linking agent containing a nucleophilic group is trilysine. In a specific embodiment, the cross-linking agent containing a nucleophilic group is trilysine acetate.

[0256] In another embodiment, the trilysine is labeled with a visualizer selected from the group consisting of a fluorophore, such as fluorescein, rhodamine, coumarin, and cyanine. Specifically, the cross-linking agent containing a nucleophilic group is a fluorescein-conjugated trilysine. More specifically, the fluorescein-conjugated trilysine is obtained by reacting trilysine acetate with N-hydroxysuccinimide (NHS)-fluorescein. Even more specifically, wherein the trilysine is labeled by conjugating to a visualizer moiety.

[0257] In certain embodiments, the implant does not include a visualization agent, eg, trilysine is not labeled with a visualization agent.

[0258] As part of one embodiment, provided herein is a sustained-release biodegradable intracameral hydrogel implant comprising travoprost and a polymer network.

[0259] As part of another embodiment, the polymer network of the disclosed hydrogel implant (eg, as in the first embodiment) comprises a plurality of polyethylene glycol (PEG) units.

[0260] As part of another embodiment, the multiple polyethylene glycol (PEG) units included in the disclosed implant are cross-linked to form a polymer network comprising multiple multi-arm PEG units having at least 2 arms, wherein the remaining features of the implant are as described herein, for example, as described in the first or second embodiment. Alternatively, as part of a third embodiment, the polymer network of the disclosed implant comprises multiple multi-arm PEG units having 2 to 10 arms, wherein the remaining features of the implant are as described herein, for example, as described in the above embodiments. In another alternative, the polymer network of the disclosed implant comprises multiple multi-arm PEG units having 4 to 8 arms, wherein the remaining features of the implant are as described herein, for example, as described above. In another alternative, the polymer network of the disclosed implant comprises multiple 4-arm PEG units, wherein the remaining features of the implant are as described herein, for example, as described above. In another alternative, the polymer network of the disclosed implant comprises multiple 8-arm PEG units, wherein the remaining features of the implant are as described above.

[0261] As part of another embodiment, the polymer network of the disclosed implant comprises multiple PEG units with a number average molecular weight (Mn) in the range of about 5KDa to about 50KDa, wherein the remaining features of the implant are as described herein. Alternatively, the polymer network of the disclosed implant comprises multiple PEG units with a number average molecular weight (Mn) in the range of about 5KDa to about 40KDa, wherein the remaining features of the implant are as described. In another alternative, the polymer network of the disclosed implant comprises multiple PEG units with a number average molecular weight (Mn) in the range of about 5KDa to about 30KDa, wherein the remaining features of the implant are as described herein. In another alternative, the polymer network of the disclosed implant comprises multiple PEG units with a number average molecular weight (Mn) in the range of about 10KDa to about 50KDa, wherein the remaining features of the implant are as described herein. In another alternative, the polymer network of the disclosed implant comprises multiple PEG units with a number average molecular weight (Mn) in the range of about 10KDa to about 40KDa, wherein the remaining features of the implant are as described herein. In another alternative, the polymer network of the disclosed implant comprises multiple PEG units with a number average molecular weight (Mn) in the range of about 10KDa to about 30KDa, wherein the remaining features of the implant are as described herein. In another alternative, the polymer network of the disclosed implant comprises multiple PEG units with a number average molecular weight (Mn) in the range of about 10KDa to about 20KDa, wherein the remaining features of the implant are as described herein. In another alternative, the polymer network of the disclosed implant comprises multiple PEG units with a number average molecular weight (Mn) in the range of about 30KDa to about 50KDa, wherein the remaining features of the implant are as described herein. In another alternative, the polymer network of the disclosed implant comprises multiple PEG units with a number average molecular weight (Mn) in the range of about 35KDa to about 45KDa, wherein the remaining features of the implant are as described herein. In another alternative, the polymer network of the disclosed implant comprises a plurality of PEG units with a number average molecular weight (Mn) in the range of about 15KDa to about 30KDa, wherein the remaining features of the implant are as described herein. In another alternative, the polymer network of the disclosed implant comprises a plurality of PEG units with a number average molecular weight (Mn) in the range of about 15KDa to about 25KDa, wherein the remaining features of the implant are as described herein. In another alternative, the polymer network of the disclosed implant comprises a plurality of PEG units with a number average molecular weight (Mn) of at least about 5KDa, wherein the remaining features of the implant are as described herein.In another alternative, the polymer network of the disclosed implant comprises multiple PEG units with a number average molecular weight (Mn) of at least about 10KDa, wherein the remaining features of the implant are as described herein. In another alternative, the polymer network of the disclosed implant comprises multiple PEG units with a number average molecular weight (Mn) of at least 15 about KDa, wherein the remaining features of the implant are as described herein. In another alternative, the polymer network of the disclosed implant comprises multiple PEG units with a number average molecular weight (Mn) of at least about 20KDa, wherein the remaining features of the implant are as described herein. In another alternative, the polymer network of the disclosed implant comprises multiple PEG units with a number average molecular weight (Mn) of at least about 30KDa, wherein the remaining features of the implant are as described herein. In another alternative, the polymer network of the disclosed implant comprises multiple PEG units with a number average molecular weight (Mn) of at least about 40KDa, wherein the remaining features of the implant are as described herein. In another alternative, the polymer network of the disclosed implant comprises a plurality of PEG units with a number average molecular weight (Mn) of about 10KDa, wherein the remaining features of the implant are as described herein. In another alternative, the polymer network of the disclosed implant comprises a plurality of PEG units with a number average molecular weight (Mn) of about 15KDa, wherein the remaining features of the implant are as described herein. In another alternative, the polymer network of the disclosed implant comprises a plurality of PEG units with a number average molecular weight (Mn) of about 20KDa, wherein the remaining features of the implant are as described herein. In another alternative, the polymer network of the disclosed implant comprises a plurality of PEG units with a number average molecular weight (Mn) of about 40KDa, wherein the remaining features of the implant are as described herein.

[0262] In another embodiment, the polymer network of the disclosed implant comprises a plurality of PEG units cross-linked by a hydrolyzable linker, wherein the remaining features of the disclosed implant are as described herein. Alternatively, the polymer network of the disclosed implant comprises a plurality of PEG units cross-linked by a hydrolyzable linker having the formula:

[0263]

[0264] wherein m is an integer from 1 to 9 and wherein the remaining features of the implant are as described herein. In another alternative, the polymer network of the disclosed implant comprises a plurality of PEG units cross-linked by a hydrolyzable linker having the formula

[0265]

[0266] wherein m is an integer from 2 to 6 and wherein the remaining features of the implant are as described herein. In another alternative, the polymer network of the disclosed implant comprises a plurality of PEG units having the formula:

[0267]

[0268] Wherein n represents ethylene oxide repeating unit and wavy line represents repeating unit point of polymer network, and the remaining characteristics of implant are as described herein.In another alternative, the polymer network of disclosed implant comprises multiple PEG units with the formula set forth above, but with 8-arm PEG backbone, and the remaining characteristics of implant are as described herein.

[0269] In another embodiment, the polymer network of the disclosed hydrogel implant is formed by reacting a plurality of polyethylene glycol (PEG) units comprising a group susceptible to nucleophilic attack with one or more nucleophilic groups to form a polymer network, wherein the remaining features of the hydrogel are as described herein. Examples of suitable groups susceptible to nucleophilic attack include, but are not limited to, activated esters (e.g., thioester succinimidyl esters, benzotriazolyl esters, acrylates, etc.). Examples of suitable nucleophilic groups include, but are not limited to, amines and thiols.

[0270] In another embodiment, the polymer network of the disclosed hydrogel implant is formed by reacting a plurality of polyethylene glycol (PEG) units, each having a molecular weight as described above in the fourth embodiment and comprising a group susceptible to nucleophilic attack, with one or more nucleophilic groups to form a polymer network, wherein the remaining features of the hydrogel are as described herein, e.g., as described in the first to sixth embodiments. Alternatively, as part of the seventh embodiment, the polymer network of the disclosed hydrogel implant is formed by reacting a plurality of polyethylene glycol (PEG) units, each having a molecular weight as described above in the fourth embodiment and comprising a succinimidyl ester group, with one or more nucleophilic groups to form a polymer network, wherein the remaining features of the hydrogel are as described herein, e.g., as described in the first to sixth embodiments. In another alternative, as part of a seventh embodiment, the polymer network of the disclosed hydrogel implant is formed by reacting a plurality of polyethylene glycol (PEG) units selected from 4a20K PEG SAZ, 4a20K PEG SAP, 4a20K PEG SG, 4a20K PEG SS, 8a20K PEG SAZ, 8a20K PEG SAP, 8a20K PEG SG, 8a20K PEG SS, wherein the remainder of the hydrogel is as described herein, e.g., as described in the first to sixth embodiments.

[0271] In another embodiment, the polymer network of the disclosed hydrogel implant is formed by reacting a plurality of polyethylene glycol (PEG) units comprising a group susceptible to nucleophilic attack with one or more amine groups to form a polymer network, wherein the remaining features of the hydrogel are as described herein. Alternatively, the polymer network of the disclosed hydrogel implant is formed by reacting a plurality of polyethylene glycol (PEG) units comprising a group susceptible to nucleophilic attack with one or more PEG or trilysine-based amine groups to form a polymer network, wherein the remaining features of the hydrogel are as described herein. In another alternative, the polymer network of the disclosed hydrogel implant is formed by reacting a plurality of polyethylene glycol (PEG) units comprising a group susceptible to nucleophilic attack with one or more PEG or trilysine-based amine groups selected from 4a20K PEG NH2, 8a20K PEG NH2 and trilysine or its salt, wherein the remaining features of the hydrogel are as described herein.

[0272] As part of another embodiment, the polymer network of the disclosed implant is amorphous (eg, under aqueous conditions, such as in vivo), wherein the remainder of the features of the implant are as described herein.

[0273] Alternatively, as part of another embodiment, the polymer network of the disclosed implant is semi-crystalline (eg, in the absence of water), wherein the remainder of the composition is as described herein.

[0274] As part of another embodiment, an implant is disclosed having travoprost homogeneously dispersed within a polymer network, wherein the remainder of the features of the implant are as described herein.

[0275] Various prostaglandin antagonists (e.g. travoprost) particles

[0276] In one aspect, the invention is directed to a plurality of prostaglandin antagonist (e.g., travoprost) particles formed from a blend of particles comprising, e.g., consisting of, a mixture of:

[0277] -Prostaglandin antagonists (e.g., travoprost);

[0278] - a biodegradable polymer consisting of a polylactide as defined in the above embodiments having acid end groups, and

[0279] - Optionally, other pharmaceutically acceptable residual amounts of manufacturing components.

[0280] In certain embodiments, the blend of particles is comprised of three types of particles, wherein the three types of particles differ from one another by including polylactide components having different intrinsic viscosities.

[0281] More specifically, the three polylactides respectively have the following inherent viscosity specifications: in the range of about 0.05 to less than about 0.5 dl / g, for example, about 0.35 to about 0.45 dl / g; in the range of about 0.5 to less than about 0.80 dl / g, for example, about 0.6 to less than about 0.8 dl / g; and in the range of about 0.8 to about 1.7, for example, about 0.8 to about 1.0 dl / g.

[0282] In another embodiment, the blend of particles is composed of two types of particles, wherein the two types of particles differ from each other in that they include polylactide components with different intrinsic viscosities. More specifically, the two polylactides have the following intrinsic viscosity specifications: in the range of about 0.05 to less than about 0.5 dl / g, such as about 0.35 to about 0.45 dl / g; and in the range of about 0.5 dl / g to about 1.7 dl / g, such as about 0.6 to about 0.8 dl / g.

[0283] In certain embodiments, the travoprost particles have a diameter in the range of 1 to 100 μm, 20 to 75 μm, 20 to 106 μm, or 20 to 55 μm as determined by sieving, or have an average diameter in the range of 1 to 100 μm, 20 to 75 μm, 20 to 106 μm, or 20 to 55 μm as determined by laser diffraction.

[0284] In a specific aspect, the present invention is directed to a plurality of prostaglandin antagonist (e.g. travoprost) particles formed from a blend of particles according to the first to fourth specific aspects of the "Prostaglandin antagonist (e.g. travoprost) particles" section, said particles, for example, about 15 to about 25 wt.-% of particles according to the first specific aspect of the "Prostaglandin antagonist (e.g. travoprost) particles" section and about 15 to about 25 wt.-% of particles according to the second specific aspect of the "Prostaglandin antagonist (e.g. travoprost) particles" section and about 5 to about 15% of particles according to the third aspect of the "Prostaglandin antagonist (e.g. travoprost) particles" section and about 40 to about 60 wt.-% of particles according to the fourth aspect of the "Prostaglandin antagonist (e.g. travoprost) particles" section, based on the total amount of particles; or wherein the prostaglandin antagonist (e.g. travoprost) particles ) is present in the form of particles according to the first specific aspect of the “Prostaglandin antagonist (e.g. travoprost) particles” of the section and about 15 wt.-% to about 25 wt.-% of the total amount of prostaglandin antagonist (e.g. travoprost) is present in the form of particles according to the second specific aspect of the “Prostaglandin antagonist (e.g. travoprost) particles” of the section and about 5 wt.-% to about 15 wt.-% of the total amount of prostaglandin antagonist (e.g. travoprost) is present in the form of particles according to the third specific aspect of the “Prostaglandin antagonist (e.g. travoprost) microparticles” of the section and about 40 wt.-% to about 60 wt.-% of the total amount of prostaglandin antagonist (e.g. travoprost) is present in the form of particles according to the fourth specific aspect of the “Prostaglandin antagonist (e.g. travoprost) particles” of the section.

[0285] In another specific aspect, the present invention is directed to a plurality of prostaglandin antagonist (e.g. travoprost) particles formed from a blend of particles according to the first to third specific aspects of the “Prostaglandin antagonist (e.g. travoprost) particles” section, said particles comprising, for example, about 20 to about 35 wt.-% of particles according to the first specific aspect of the “Prostaglandin antagonist (e.g. travoprost) particles” section and about 30 to about 50 wt.-% of particles according to the second specific aspect of the “Prostaglandin antagonist (e.g. travoprost) particles” section and about 25 to about 45 wt.-% of particles according to the third specific aspect of the “Prostaglandin antagonist (e.g. travoprost) particles” section, based on the total amount of particles; or wherein about 20 wt.-% to about 35 wt.-% of the total amount of the prostaglandin antagonist (e.g. travoprost) is present in the form of particles according to the first specific aspect of the “Prostaglandin antagonist (e.g. travoprost) particles” section and about 30 wt.-% to about 50 wt.-% of the total amount of the prostaglandin antagonist (e.g. travoprost) is present in the form of particles according to the second specific aspect of the “Prostaglandin antagonist (e.g. travoprost) particles” section, and about 25 wt.-% to about 45 wt.-% of the total amount of the prostaglandin antagonist (e.g. travoprost) is present in the form of particles according to the third specific aspect of the “Prostaglandin antagonist (e.g. travoprost) particles” section.

[0286] In another specific aspect, the present invention is directed to a plurality of prostaglandin antagonist (e.g. travoprost) particles formed from a blend of particles according to the first and second specific aspects of the "Prostaglandin antagonist (e.g. travoprost) particles" section, said particles comprising, for example, about 35 to about 55 wt.-% of particles according to the first specific aspect of the "Prostaglandin antagonist (e.g. travoprost) particles" section and about 35 to about 55 wt.-% of particles according to the second specific aspect of the "Prostaglandin antagonist (e.g. travoprost) particles" section, based on the total amount of particles; or wherein about 35 wt.-% to about 55 wt.-% of the total amount of prostaglandin antagonist (e.g. travoprost) is present in the form of particles according to the first specific aspect of the "Prostaglandin antagonist (e.g. travoprost) particles" section and about 35 wt.-% to about 55 wt.-% of the total amount of prostaglandin antagonist (e.g. travoprost) is present in the form of particles according to the second specific aspect of the "Prostaglandin antagonist (e.g. travoprost) particles" section.

[0287] According to one aspect, the present invention is directed to a plurality of travoprost particles formed from a blend of particles of aspects (a) to (d) disclosed herein, such as about 15 to about 25 wt.-% of particles of aspect (a) disclosed herein and about 15 to about 25 wt.-% of particles of aspect (b) disclosed herein and about 5 to about 15% of particles of aspect (c) disclosed herein and about 40 to about 60 wt.-% of particles of aspect (d) disclosed herein, based on the total amount of particles; or wherein the total amount of travoprost is about 15 to about 25 wt.-% of particles of aspect (a) disclosed herein and about 15 to about 25 wt.-% of particles of aspect (b) disclosed herein and about 5 to about 15% of particles of aspect (c) disclosed herein and about 40 to about 60 wt.-% of particles of aspect (d) disclosed herein, based on the total amount of particles; From about 15 wt.-% to about 25 wt.-% of the total amount of travoprost is present in the form of particles of aspect (a) disclosed herein and from about 15 wt.-% to about 25 wt.-% of the total amount of travoprost is present in the form of particles of aspect (b) disclosed herein and from about 5 wt.-% to about 15 wt.-% of the total amount of travoprost is present in the form of particles of aspect (c) disclosed herein and from about 40 wt.-% to about 60 wt.-% of the total amount of travoprost is present in the form of particles of aspect (d) disclosed herein.

[0288] According to one aspect, the present invention is directed to a plurality of travoprost particles formed from a blend of particles of aspects (a) to (c) disclosed herein, such particles comprising, for example, about 20 to about 35 wt.-% of particles of aspect (a) disclosed herein and about 30 to about 50 wt.-% of particles of aspect (b) disclosed herein and about 25 to about 45 wt.-% of particles of aspect (c) disclosed herein, based on the total amount of particles; or wherein about 20 wt.-% to about 35 wt.-% of the total amount of travoprost is in the form of particles of aspect (a) disclosed herein and about 30 wt.-% to about 50 wt.-% of the total amount of travoprost is in the form of particles of aspect (b) disclosed herein, and about 25 wt.-% to about 45 wt.-% of the total amount of travoprost is in the form of particles of aspect (c) disclosed herein.

[0289] According to one aspect, the present invention is directed to a plurality of travoprost particles formed from a blend of particles of aspects (a) and (b), such particles comprising, for example, about 35 to about 55 wt.-% of particles of aspect (a) and about 35 to about 55 wt.-% of particles of aspect (b), based on the total amount of particles; or wherein about 35 wt.-% to about 55 wt.-% of the total amount of travoprost is in the form of particles of aspect (a) and about 35 wt.-% to about 55 wt.-% of the total amount of travoprost is in the form of particles of aspect (b).

[0290] In another aspect, the present invention is directed to a plurality of travoprost particles formed from a blend of particles consisting of a mixture of:

[0291] -Travoprost;

[0292] - a biodegradable polymer consisting of polylactide having acid end groups, and

[0293] - Optionally, other pharmaceutically acceptable residual amounts of manufacturing components.

[0294] Biodegradable intracameral implant for sustained release of prostaglandin antagonists (eg, travoprost)

[0295] According to one aspect, the present invention provides a sustained-release biodegradable intracameral implant for sustained release of a prostaglandin antagonist (e.g., travoprost), comprising, for example, consisting of:

[0296] - a plurality of prostaglandin antagonist (eg travoprost) particles as defined in the preceding section and / or in the section "Prostaglandin antagonist (eg travoprost) particles" above; and

[0297] - A biodegradable hydrogel as defined in the above section "Biodegradable hydrogel", wherein a plurality of prostaglandin antagonist (eg travoprost) particles are dispersed within the hydrogel.

[0298] According to another aspect, the present invention provides a sustained-release biodegradable intracameral implant for sustained release of a prostaglandin antagonist (e.g., travoprost), comprising, for example, consisting of:

[0299] - a biodegradable hydrogel as defined above in the section "Biodegradable hydrogel" and prostaglandin antagonist (eg travoprost) particles as defined above in the section "Prostaglandin antagonist (eg travoprost) particles",

[0300] - particles of a prostaglandin antagonist (eg travoprost) in the form of a prostaglandin antagonist (eg travoprost) intermixed with polylactide.

[0301] - The prostaglandin antagonist (eg, travoprost) particles are dispersed within the hydrogel, wherein the hydrogel comprises a polymer network formed by reacting 8-Arm-15K-SG or 8-Arm-15K-SAZ polyethylene glycol, each having a mass average molecular weight of 15,000±10% Daltons, with trilysine acetate.

[0302] According to another aspect, the present invention is directed to an intracameral implant comprising:

[0303] - a biodegradable hydrogel, wherein the hydrogel comprises a polymer network comprising one or more polyalkylene glycol units, and travoprost particles,

[0304] - the travoprost particles are in the form of travoprost intermixed with a biodegradable polymer, and

[0305] -Travoprost particles are dispersed in the hydrogel.

[0306] According to another aspect, the present invention is directed to a biodegradable intracameral implant for sustained release of travoprost, comprising:

[0307] - a biodegradable hydrogel, wherein the hydrogel comprises a polymer network comprising one or more polyalkylene glycol units, and travoprost particles,

[0308] - the travoprost particles are in the form of travoprost intermixed with a biodegradable polymer, and

[0309] - Travoprost particles are dispersed in the hydrogel,

[0310] The implant has a length of about 1.00 mm to about 2.50 mm and a diameter of no more than 0.30 mm in its dry state.

[0311] According to another aspect, the present invention is directed to an intracameral implant comprising:

[0312] - a biodegradable hydrogel comprising (i) a polymer network comprising one or more polyalkylene glycol units, and (ii) sustained-release travoprost particles,

[0313] - sustained-release travoprost particles comprising travoprost and at least one biodegradable polymer, and

[0314] -Sustained release travoprost particles dispersed in the hydrogel.

[0315] In certain embodiments, the implant has a length in its dry state of about 1 mm to about 2.5 mm, a diameter in its dry state of no more than 0.3 mm and a total weight in its dry state of about 20 μg to about 110 μg.

[0316] In certain embodiments, the implant has a diameter of less than 0.5 mm after hydration in phosphate buffered saline, pH 7.4 at 37°C for 24 hours in vitro.

[0317] In certain embodiments, the implant has a diameter in the range of about 0.3 mm to 0.49 mm after hydration in phosphate buffered saline, pH 7.4 at 37°C for 24 hours in vitro.

[0318] In certain embodiments, the implant is modified to be an intracameral implant.

[0319] In certain embodiments, the hydrogel dissolves within 2 to 4 months when implanted in the eye.

[0320] In certain embodiments, the hydrogel dissolves within 6 to 8 months when implanted in the eye.

[0321] Without wishing to be bound by any theory, it is believed that the hydrogel implant is small enough to sink into the iridocorneal angle (e.g., below Schwalbe's line) when inserted into the anterior chamber of the eye and then swell sufficiently by absorbing aqueous humor to be fixed in the iridocorneal angle and thus not move during the entire placement process. During the treatment period, the implant becomes increasingly soft and thus can further adapt to the anatomical conditions, thereby further preventing any movement of the hydrogel before it is completely degraded. The prevention of movement and its soft, tissue-like texture provide assurance for its gentleness to the endothelium and the overall safety of the implant, thereby allowing repeated applications. It is further believed that due to the possibility of size reduction, such implants are suitable for a wide range of anatomical conditions, including narrow iridocorneal angles.

[0322] The following embodiments relate to each of the aspects described in the preceding paragraphs.

[0323] In one embodiment, the prostaglandin antagonist (e.g. travoprost) particles comprise, e.g. consist of, a blend of two types of particles, a first type of particles in the form of a prostaglandin antagonist (e.g. travoprost) intermixed with a biodegradable polymer consisting of a first polylactide as defined above and a second type of particles in the form of a prostaglandin antagonist (e.g. travoprost) intermixed with a biodegradable polymer consisting of a second polylactide as defined above, and optionally the intracameral implant does not comprise a further polylactide.

[0324] In another embodiment, the prostaglandin antagonist (e.g. travoprost) particles or a blend of particles comprising different types, for example particles in the form of a prostaglandin antagonist (e.g. travoprost) intermixed with a first polylactide as defined above and particles in the form of a prostaglandin antagonist (e.g. travoprost) intermixed with a second polylactide as defined above, and optionally the intracameral implant does not include other polylactides.

[0325] In a certain embodiment, the travoprost particles as described herein are a blend of at least two types of travoprost particles selected from the group consisting of:

[0326] 1) A blend of particles made from:

[0327] a first type of travoprost particles made from a mixture of travoprost and a biodegradable polymer consisting of one or more polylactides having acid end groups and an intrinsic viscosity specification in the range of about 0.05 to less than about 0.5 dl / g, such as about 0.35 to about 0.45 dl / g, wherein the first type of particles contains about 40 wt.-% to about 50 wt.-%, such as about 43 wt.-% to about 45 wt.-% of travoprost, based on the total mass of the first type of particles; and

[0328] a second type of travoprost particles made from a mixture of travoprost and a biodegradable polymer consisting of one or more polylactides having acid end groups and an intrinsic viscosity specification in the range of about 0.5 to less than about 0.80 dl / g, such as in the range of about 0.6 to less than about 0.80 dl / g, wherein the second type of particles contains about 40 wt.-% to about 50 wt.-%, such as greater than about 45 wt.-% to about 47 wt.-% of travoprost, based on the total mass of the second type of particles,

[0329] For example wherein the blend contains from about 35 wt.-% to about 55 wt.-% of particles of the first type of particles and from about 35 wt.-% to about 55 wt.-% of particles of the second type of particles, based on the total amount of the blend; or

[0330] For example 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 a multi-arm polymer precursor containing electrophilic groups with a cross-linker containing nucleophilic groups, the electrophilic groups are succinimidyl glutarate (SG) groups and the multi-arm polymer precursor is 8-arm-15K-SG polyethylene glycol; and the cross-linker containing nucleophilic groups is trilysine;

[0331] 2) A blend of particles made from:

[0332] a first type of particles made from a mixture of travoprost and a biodegradable polymer consisting of one or more polylactides having acid end groups and an intrinsic viscosity specification in the range of about 0.05 to less than about 0.5 dl / g, such as about 0.35 to about 0.45 dl / g, wherein the first type of particles contains about 40 wt.-% to about 50 wt.-%, such as about 43 wt.-% to about 45 wt.-% of travoprost, based on the total mass of the first type of particles,

[0333] a second type of travoprost particles made from a mixture of travoprost and a biodegradable polymer consisting of one or more polylactides having acid end groups and an intrinsic viscosity specification in the range of about 0.5 to less than about 0.80 dl / g, such as in the range of 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 greater than about 45 wt.-% to about 47 wt.-% of travoprost, based on the total mass of the second type of particles, and

[0334] a third type of travoprost particles made from a mixture of travoprost and a biodegradable polymer consisting of one or more polylactides having acid end groups and an intrinsic viscosity specification in the range of about 0.8 to about 1.7 dl / g, such as in the range of about 0.8 to about 1.0 dl / g, wherein the third type of particles contains about 40 wt.-% to about 50 wt.-%, such as about 41 wt.-% to about 43 wt.-% of travoprost, based on the total mass of the third type of particles,

[0335] For example wherein the blend contains from about 20 wt.-% to about 35 wt.-% of particles of the first type of particles and from about 30 wt.-% to about 50 wt.-% of particles of the second type of particles and from about 25 wt.-% to about 45 wt.-% of particles of the third type of particles, based on the total amount of the blend; or

[0336] For example wherein about 20 wt.-% to about 35 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 30 wt.-% to about 50 wt.-% of the total amount of travoprost in the implant is present in the form of particles of the second type of particles, and about 25 wt.-% to about 45 wt.-% of the total amount of travoprost in the implant is present in the form of particles of the third type of particles,

[0337] wherein optionally, the polymer network is formed by reacting a multi-arm polymer precursor containing an electrophilic group with a cross-linking agent containing a nucleophilic group, wherein the electrophilic group is a succinimidyl glutarate (SG) group and the multi-arm polymer precursor is 8-arm-15K-SG polyethylene glycol; and the cross-linking agent containing a nucleophilic group is trilysine; and

[0338] 3) A blend of particles made from:

[0339] a first type of particles made from a mixture of travoprost and a biodegradable polymer consisting of one or more polylactides having acid end groups and an intrinsic viscosity specification in the range of about 0.05 to less than about 0.5 dl / g, such as about 0.35 to about 0.45 dl / g, wherein the first type of particles contains about 40 wt.-% to about 50 wt.-%, such as about 43 wt.-% to about 45 wt.-% of travoprost, based on the total mass of the first type of particles,

[0340] a second type of particles made from a mixture of travoprost and a biodegradable polymer consisting of one or more polylactides having acid end groups and an intrinsic viscosity specification in the range of about 0.5 to less than about 0.80 dl / g, such as in the range of about 0.6 to less than about 0.80 dl / g, wherein the second type of particles contains about 40 wt.-% to about 50 wt.-%, such as greater than about 45 wt.-% to about 47 wt.-% of travoprost, based on the total mass of the second type of particles,

[0341] a third type of particles made of travoprost and a biodegradable polymer consisting of one or more polylactides having acid end groups and an intrinsic viscosity specification in the range of about 0.8 to about 1.7 dl / g, such as in the range of about 0.8 to about 1.0 dl / g, wherein the third type of particles contains about 40 wt.-% to about 50 wt.-%, such as about 41 wt.-% to about 43 wt.-% of travoprost, based on the total mass of the third type of particles, and

[0342] - a fourth type of particles made of travoprost and a biodegradable polymer consisting of one or more polylactides having ester end groups and an intrinsic viscosity specification in the range of about 0.05 to about 1.7 dl / g, such as in the range of about 0.55 to about 0.75 dl / g, wherein the fourth type of particles contains about 40 wt.-% to about 50 wt.-%,

[0343] For example wherein the blend contains from about 15 wt.-% to about 25 wt.-% of particles of the first type of particles and from about 15 wt.-% to about 25 wt.-% of particles of the second type of particles and from about 5 wt.-% to about 15 wt.-% of particles of the third type of particles and from about 40 wt.-% to about 60 wt.-% of particles of the fourth type of particles, based on the total amount of the blend; or

[0344] for example wherein about 15 wt.-% to about 25 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 15 wt.-% to about 25 wt.-% of the total amount of travoprost in the implant is present in the form of particles of the second type of particles and about 5 wt.-% to about 15 wt.-% of the total amount of travoprost in the implant is present in the form of particles of the third type of particles and about 40 wt.-% to about 60 wt.-% of the total amount of travoprost in the implant is present in the form of particles of the fourth type of particles,

[0345] Optionally, the polymer network is formed by reacting a multi-arm polymer precursor containing an electrophilic group with a cross-linking agent containing a nucleophilic group, wherein the electrophilic group is a succinimidyl azelaic acid ester (SAZ) group, and the multi-arm polymer precursor is 8-arm-15K-SAZ polyethylene glycol; and the cross-linking agent containing a nucleophilic group is trilysine.

[0346] In another embodiment, the intracameral implant has an in vitro release with a mean prostaglandin antagonist (e.g., travoprost) release ranging from about 65% to about 85% and a mean absolute deviation of at most 5%, based on the amount % released every 70 days from day 1 to day 84 when measured under sedimentation conditions in PBS at pH 7.2 to 7.4 at 37°C.

[0347] In certain embodiments, the implant exhibits a burst release of less than 15% of the total weight of travoprost in the anterior chamber implant as measured in vitro on day 1 under simulated physiological sedimentation conditions in 50 mL of 1 x PBS, 0.5% castor oil, 0.01% sodium fluoride buffer, pH 7.2-7.4 at 37°C.

[0348] In another embodiment, the implant has an in vitro release with a mean prostaglandin antagonist (e.g. travoprost) release in the range of about 800 to about 1100 ng / week and a standard deviation in the range of 450 to 550 ng / week, wherein the mean is based on weekly prostaglandin antagonist (e.g. travoprost) release values ​​between day 7 and day 98 when measured under sedimentation conditions in PBS at pH 7.2 to 7.4 at 37°C, excluding the burst release on day 1 after administration; or wherein the weekly prostaglandin antagonist (e.g. travoprost) release when measured at time intervals between day 7 and day 98 when measured under sedimentation conditions in PBS at pH 7.2 to 7.4 at 37°C, is in the range of about 100 to about 2300 ng, excluding the burst release on day 1 after administration.

[0349] In another embodiment, the prostaglandin antagonist (e.g. travoprost) particles comprise or are a blend of different types of particles, including particles in the form of a prostaglandin antagonist (e.g. travoprost) intermixed with a first polylactide as defined above, particles in the form of a prostaglandin antagonist (e.g. travoprost) intermixed with a second polylactide as defined above, and particles in the form of a prostaglandin antagonist (e.g. travoprost) intermixed with a third polylactide as defined above, wherein each of the polylactides has an acid end group, and optionally the intracameral implant does not include other polylactides.

[0350] In one embodiment, the prostaglandin antagonist (e.g. travoprost) particles comprise or consist of a blend of three types of particles, a first type of particles being in the form of a prostaglandin antagonist (e.g. travoprost) intermixed with a biodegradable polymer consisting of a first polylactide as defined above, and a second type of particles being in the form of a prostaglandin antagonist (e.g. travoprost) intermixed with a biodegradable polymer consisting of a second polylactide as defined above and a third type of particles being in the form of a prostaglandin antagonist (e.g. travoprost) intermixed with a biodegradable polymer consisting of a third polylactide as defined above, wherein optionally the intracameral implant does not comprise a further polylactide.

[0351] In another embodiment, the intracameral implant has a mean prostaglandin antagonist (e.g., travoprost) release ranging from about 60% to about 80% and a mean absolute deviation of at most 5%, or an in vitro release of a prostaglandin antagonist (e.g., travoprost) release ranging from 60% to 80%, based on the amount % released every 70 days from day 1 to day 98 when measured under sedimentation conditions in PBS at pH 7.2 to 7.4 at 37°C.

[0352] In certain embodiments, the implant has an in vitro release with a mean prostaglandin antagonist (e.g., travoprost) release in the range of about 800 to about 1100 ng / week and a standard deviation in the range of 450 to 550 ng / week, wherein the mean is based on weekly prostaglandin antagonist (e.g., travoprost) release values ​​between day 7 and day 98 when measured under sedimentation conditions in PBS at pH 7.2 to 7.4 at 37°C, excluding the burst release on day 1 after administration; or wherein the weekly prostaglandin antagonist (e.g., travoprost) release when measured at time intervals between day 7 and day 98 when measured under sedimentation conditions in PBS at pH 7.2 to 7.4 at 37°C, is in the range of about 100 to about 2300 ng, excluding the burst release on day 1 after administration.

[0353] In certain embodiments, the prostaglandin antagonist (e.g. travoprost) particles comprise or are a blend of different types of particles, including particles in the form of a prostaglandin antagonist (e.g. travoprost) intermixed with a first polylactide as defined above, particles in the form of a prostaglandin antagonist (e.g. travoprost) intermixed with a second polylactide as defined above, particles in the form of a prostaglandin antagonist (e.g. travoprost) intermixed with a third polylactide as defined above, and particles in the form of a prostaglandin antagonist (e.g. travoprost) intermixed with a fourth polylactide as defined above, and optionally the intracameral implant does not include additional polylactides.

[0354] In another embodiment, the prostaglandin antagonist (e.g. travoprost) particles comprise or consist of a blend of four types of particles, a first type of particles being in the form of a prostaglandin antagonist (e.g. travoprost) intermixed with a biodegradable polymer consisting of a first polylactide as defined above, a second type of particles being in the form of a prostaglandin antagonist (e.g. travoprost) intermixed with a biodegradable polymer consisting of a second polylactide as defined above, a third type of particles being in the form of a prostaglandin antagonist (e.g. travoprost) intermixed with a biodegradable polymer consisting of a third polylactide as defined above and a fourth type of particles being in the form of a prostaglandin antagonist (e.g. travoprost) intermixed with a biodegradable polymer consisting of a fourth polylactide as defined above, and optionally the intracameral implant comprises no further polylactide.

[0355] In a certain embodiment, the intracameral implant has an in vitro release with a mean prostaglandin antagonist (e.g., travoprost) release ranging from about 5% to about 15% and a mean absolute deviation of at most 3%, based on the amount % released every 14 days from day 1 to day 112 when measured under sedimentation conditions in PBS at pH 7.2 to 7.4 at 37°C.

[0356] In another embodiment, the content of the biodegradable polymer relative to the total weight of the biodegradable intracameral implant for sustained release of travoprost is from about 10 wt.-% to about 35 wt.-%, or from about 23 to about 27 wt.-%, or from about 12 to about 17 wt.-%, or from about 30 to about 35 wt.-%, or about 25 wt.-%, or about 15 wt.-%, or about 34 wt.-%.

[0357] In another embodiment, the content of the biodegradable hydrogel relative to the total weight of a sustained-release biodegradable intracameral implant is about 30 to about 70 wt.-%, or about 32 to about 37 wt.-%, or about 45 to about 55 wt.-%, or about 60 to about 70 wt.-%, or about 49.3 wt.-% or about 37.5 wt.-% or about 50.1 wt.-% or about 66.8 wt.-%.

[0358] According to another embodiment, the content of the cross-linking agent containing a nucleophilic group relative to the total weight of a sustained-release biodegradable anterior chamber implant is about 1 to about 5 wt.-% or 1 to about 3 wt.-%, or 2 to about 4 wt.-% or 4 to about 5 wt.-%, or about 3.2 wt.-%, or about 2.3 wt.-%, or about 4.3 wt.-%.

[0359] In a certain embodiment, the visualization agent is present in an amount of about 0.1 to about 0.5 wt.-%, or 0.2 wt.-%, or 0.3 wt.-% relative to the total weight of a sustained-release biodegradable intracameral implant.

[0360] In another embodiment, the implant contains a dose of about 2 μg to about 30 μg, or about 21 μg to about 30 μg, or about 11 μg to about 20 μg, or about 2 μg to about 10 μg of travoprost. In a specific embodiment, the implant contains a dose of about 5 μg of travoprost. In another specific embodiment, the implant contains a dose of about 15 μg of travoprost. In an alternative specific embodiment, the implant contains a dose of about 26 μg of travoprost.

[0361] In a certain embodiment, the total mass of the biodegradable polymer in the implant is less than 34 μg, less than 30 μg, less than 20 μg, or less than 10 μg.

[0362] In a certain embodiment, the amount of travoprost in the implant is less than 25 μg, or less than 20 μg, or less than 10 μg.

[0363] In certain embodiments, the total mass of the implant in its dry state is less than 103 μg, less than 80 μg, or less than 50 μg.

[0364] In certain embodiments, the implant contains a dose of about 5 μg of travoprost and the multi-arm polymer precursor is 8-arm-15K-SG polyethylene glycol and the nucleophilic group-containing cross-linker is trilysine.

[0365] In certain embodiments, the implant contains a dose of about 15 μg of travoprost and the multi-arm polymer precursor is 8-arm-15K-SG polyethylene glycol and the nucleophilic group-containing cross-linker is trilysine.

[0366] In certain embodiments, the implant contains a dose of about 15 μg of travoprost and the multi-arm polymer precursor is 8-arm-15K-SAZ polyethylene glycol and the nucleophilic group-containing cross-linker is trilysine.

[0367] In certain embodiments, the implant contains a dose of about 26 μg of travoprost and the multi-arm polymer precursor is 8-arm-15K-SAZ polyethylene glycol and the nucleophilic group-containing cross-linker is trilysine.

[0368] In certain embodiments, the implant has a diameter of less than 0.50 mm after hydration in vitro in phosphate buffered saline (PBS) at pH 7.4 at 37° C. for 24 hours. Specifically, the volume of PBS added to the sample tube for such hydration is 5 ml. The sample tube is equilibrated at 37° C., in particular, before adding 5 ml of PBS. More specifically, the implant has a diameter in the range of about 0.30 mm to 0.49 mm, or about 0.40 mm to about 0.49 mm, after hydration in vitro in phosphate buffered saline at pH 7.4 at 37° C. for 24 hours.

[0369] In certain embodiments, the ratio of the diameter of the implant after hydration in vitro in phosphate buffered saline at pH 7.4 at 37° C. for 24 hours to the diameter of the implant in its dry state is less than 2.5. Specifically, the volume of PBS added to the sample tube for such hydration is 5 ml. The sample tube is equilibrated, in particular, at 37° C. before the addition of 5 ml of PBS.

[0370] In a particular embodiment, the implant is in the form of a fiber. Specifically, the implant is in the form of a fiber having a length of less than about 2.5 mm or about 1.0 mm to about 2.5 mm in its dry state and a diameter of no more than 0.3 mm or 0.14 mm to about 0.29 mm. Alternatively, the implant is in the form of a fiber having a diameter of 0.6 mm or less and a length of 3.0 mm or less in a balanced state after hydration in phosphate buffered saline at pH 7.4 at 37° C. for 24 hours in vitro.

[0371] In certain embodiments, the implant has a length of about 1.00 mm to about 2.50 mm in its dry state and a diameter of no more than 0.30 mm.

[0372] In certain embodiments, the implant is a fiber having, in its dry state, a length of about 1.5 mm to about 2.5 mm, or about 1.8 mm to about 2.2 mm; and a diameter of about 0.14 mm to about 0.29 mm, or about 0.20 mm to about 0.24 mm, or about 0.24 mm to about 0.28 mm, or about 0.19 mm to about 0.23 mm, or about 0.15 mm to about 0.19 mm.

[0373] In certain embodiments, the implant in its dry form has a total weight of about 20 to about 150 μg, or about 70 μg to about 80 μg, or about 40 μg to about 50 μg, or about 90 μg to 110 μg. In another embodiment, the implant in its dry form has a total weight of about 20 μg to about 110 μg, or about 30 μg to about 105 μg.

[0374] In certain embodiments, the amount of travoprost in the implant is less than 25 μg, or less than 20 μg, or less than 10 μg.

[0375] According to certain embodiments, the implant has an in vitro release with a mean prostaglandin antagonist (e.g. travoprost) travoprost release in the range of about 500 to about 900 ng / week and a standard deviation in the range of 150 to 250 ng / week, wherein the mean is based on weekly prostaglandin antagonist (e.g. travoprost) travoprost release values ​​between day 7 and day 119 when measured under sedimentation conditions in PBS at pH 7.2 to 7.4 at 37°C, excluding the 1st day post-dose burst release; or wherein the weekly prostaglandin antagonist (e.g. travoprost) travoprost release when measured at time intervals between day 7 and day 119, excluding the 1st day post-dose burst release; when measured under sedimentation conditions in PBS at pH 7.2 to 7.2 at 37°C.

[0376] According to another aspect, the present invention is directed to an intracameral implant comprising

[0377] - a plurality of travoprost particles according to any one of aspects (a) to (d) disclosed herein; and

[0378] -Biodegradable hydrogel,

[0379] The plurality of travoprost particles are dispersed in the hydrogel.

[0380] According to another aspect, the present invention is directed to an intracameral implant comprising

[0381] -Biodegradable hydrogel and travoprost particles,

[0382] - the travoprost particles are in the form of travoprost intermixed with polylactide,

[0383] - Travoprost particles are dispersed in a hydrogel, wherein the hydrogel comprises a polymer network formed by reacting 8-arm-15K-SG or 8-arm-15K-SAZ polyethylene glycol, each having a mass average molecular weight of 15,000±10% Dalton, with trilysine acetate; or the polymer network comprises cross-linked 8-arm-polyethylene glycol comprising a group represented by the formula:

[0384]

[0385] Where m is 2 or 6.

[0386] Manufacturing of a biodegradable intracameral implant for sustained release of a prostaglandin antagonist such as travoprost method

[0387] In another aspect, the present invention is directed to a method for manufacturing a sustained release biodegradable intracameral implant for sustained release of a prostaglandin antagonist (e.g., travoprost), the method comprising the steps of:

[0388] a) preparing travoprost particles in the form of a prostaglandin antagonist (e.g. travoprost) intermixed with a biodegradable polymer,

[0389] b) preparing a precursor mixture containing a hydrogel precursor and prostaglandin antagonist (e.g. travoprost) particles,

[0390] c) cross-linking the precursor mixture using a cross-linking agent to form a polymer network and obtain a hydrogel mixture comprising the polymer network, and

[0391] d) drying the hydrogel mixture to provide the implant.

[0392] The component types, component contents and mass ratios described in the aforementioned sections “Prostaglandin antagonist (e.g. travoprost) particles”, “Biodegradable hydrogel”, “Multiple prostaglandin antagonist (e.g. travoprost) particles” and “Biodegradable intracameral implant for sustained release of prostaglandin antagonist (e.g. travoprost)” are also correspondingly applicable to the manufacturing method of the present invention.

[0393] In another aspect, the present invention is directed to a sustained-release biodegradable intracameral implant obtainable by the method as described in the section "Method for producing a sustained-release biodegradable implant of a prostaglandin antagonist (eg, travoprost)".

[0394] In another aspect, the present invention is directed to a method of making an intracameral implant, the method comprising the steps of:

[0395] a) preparing travoprost particles in the form of travoprost intermixed with a biodegradable polymer,

[0396] b) preparing a precursor mixture containing a hydrogel precursor and said travoprost particles,

[0397] c) cross-linking the precursor mixture using a cross-linking agent to form a polymer network and obtain a hydrogel mixture comprising the polymer network, and

[0398] d) drying the hydrogel mixture to provide the implant.

[0399] In another aspect, the present invention is directed to an intracameral implant obtainable by the method of the preceding paragraph.

[0400] Syringes for intracameral injections

[0401] According to one aspect, the present invention is directed to a syringe for intracameral injection comprising a biodegradable intracameral implant for sustained release of a prostaglandin antagonist (eg travoprost) as defined above.

[0402] According to one aspect, the present invention is directed to a syringe for intracameral injection comprising an implant as disclosed herein.

[0403] A specific embodiment of the syringe is shown in Example 4.

[0404] Methods of treating intraocular pressure in a human subject

[0405] One aspect of the invention is directed to a method of treating intraocular pressure in a human subject suffering from ocular hypertension or suffering from glaucoma, such as open-angle glaucoma, by treating each eye in need of treatment with a single prostaglandin antagonist (e.g. travoprost) sustained-release biodegradable intracameral implant as defined in the above section for a period ranging from about 2 months to about 12 months or from about 3 months to about 9 months, the method comprising treating each eye:

[0406] Step 1: Providing a biodegradable intracameral implant for sustained release of a prostaglandin antagonist (e.g. travoprost) as defined in the above section, providing treatment for a period ranging from about 2 months to about 12 months or from about 3 months to about 9 months, said implant comprising:

[0407] - a biodegradable hydrogel as defined in the above section and prostaglandin antagonist (eg travoprost) particles as defined in the above section,

[0408] - the prostaglandin antagonist (eg travoprost) particles are in the form of a prostaglandin antagonist (eg travoprost) intermixed with a biodegradable polymer, and

[0409] - the prostaglandin antagonist (eg travoprost) particles are dispersed within the hydrogel; and

[0410] Step 2: Inserting a sustained-release biodegradable intracameral implant of step 1 into the anterior segment of the eye so as to place it within the iridocorneal angle of the eye.

[0411] One aspect of the invention is directed to a method of treating intraocular pressure in a human subject suffering from ocular hypertension or suffering from glaucoma, such as open-angle glaucoma, wherein each eye in need of treatment is treated with a single prostaglandin antagonist (e.g., travoprost) sustained-release biodegradable intracameral implant as defined in the above section for a period of time ranging from about 2 months to about 12 months or from about 3 months to about 9 months, the method comprising inserting one sustained-release biodegradable intracameral implant into the anterior segment of the eye of each eye so as to place it within the iridocorneal angle of the eye, wherein the implant is as defined in the above section, provides treatment for a period of time ranging from about 2 months to about 12 months or from about 3 months to about 9 months, the implant comprising:

[0412] - a biodegradable hydrogel as defined in the above section and prostaglandin antagonist (eg travoprost) particles as defined in the above section,

[0413] - the prostaglandin antagonist (eg travoprost) particles are in the form of a prostaglandin antagonist (eg travoprost) intermixed with a biodegradable polymer, and

[0414] - The prostaglandin antagonist (eg travoprost) particles are dispersed within the hydrogel.

[0415] Another aspect of the present invention is directed to a travoprost sustained-release biodegradable intracameral implant as described herein for use in a method of treating intraocular pressure in a human subject suffering from ocular hypertension and / or glaucoma, wherein each eye in need of treatment is treated with a single travoprost sustained-release biodegradable implant for a period of time ranging from about 1 month to about 24 months, such as about 3 months to about 9 months.

[0416] Another aspect of the present invention is directed to a method for treating intraocular pressure in a human subject suffering from ocular hypertension and / or glaucoma, wherein each eye in need of treatment is treated with a single intracameral implant according to any one of technical solutions 1 to 20 for a period of time ranging from about 1 month to about 24 months, for example, from about 3 months to about 9 months.

[0417] According to some embodiments of the present invention, the implant is in a dry state prior to insertion and becomes hydrated once inserted into the eye. In some embodiments, hydration occurs in less than 2 minutes.

[0418] In certain embodiments of the present invention, the treatment period is about 6 months to about 9 months and the biodegradable intracameral implant with sustained release of a prostaglandin antagonist (e.g., travoprost) provides treatment for about 6 months to about 9 months. In another embodiment, the treatment period is about 4 months to about 7 months and the biodegradable intracameral implant with sustained release of a prostaglandin antagonist (e.g., travoprost) provides treatment for about 4 months to about 7 months. In an alternative embodiment, the treatment period is about 3 months to about 6 months and the biodegradable intracameral implant with sustained release of a prostaglandin antagonist (e.g., travoprost) provides treatment for about 3 months to about 6 months. In an alternative embodiment, the treatment period is about 3 months to about 4 months and the biodegradable intracameral implant with sustained release of a prostaglandin antagonist (e.g., travoprost) provides treatment for about 3 months to about 4 months. In another embodiment, the treatment period is about 7 months to about 8 months, or about 7 months to about 9 months, or about 4 months, or about 5 months, or about 6 months, or about 7 months, or about 8 months, or about 9 months and the biodegradable intracameral implant with sustained release of the prostaglandin antagonist (e.g., travoprost) provides treatment for about 7 months to about 8 months, or about 7 months to about 9 months, or about 4 months, or about 5 months, or about 6 months, or about 7 months, or about 8 months, or about 9 months, respectively.

[0419] In certain embodiments,

[0420] - an intracameral implant having an in vitro release of a mean travoprost release ranging from about 65% to about 85% and a mean absolute deviation of at most 5% based on the amount % released every 70 days from day 1 to day 84 when measured under sedimentation conditions in PBS at pH 7.2 to 7.4 at 37°C, wherein the treatment period is from about 3 months to about 6 months or from about 3 months to 4 months; or

[0421] - based on the amount % released every 70 days from day 1 to day 98 when measured under sedimentation conditions at 37°C in PBS at pH 7.2 to 7.4, wherein the intracameral implant has an in vitro release with a mean travoprost release ranging from about 60% to about 80% and a mean absolute deviation of at most 5%, wherein the treatment period is from about 3 months to about 7 months or from about 4 months to 7 months; or

[0422] - wherein the intracameral implant has an in vitro release with a mean travoprost release ranging from about 5% to about 15% and a mean absolute deviation of at most 3% based on the amount % released every 14 days from day 1 to day 112 when measured under sedimentation conditions in PBS at pH 7.2 to 7.4 at 37°C, wherein the treatment period is from about 6 months to about 9 months or from about 6 months to about 12 months.

[0423] In certain embodiments of the invention, the treatment period is from about 3 months to about 7 months or from about 4 months to 7 months or from about 3 months to about 6 months or from about 3 months to 4 months and the biodegradable intracameral implant for sustained release of travoprost provides treatment for from about 3 months to about 7 months or from about 4 months to 7 months or from about 3 months to about 6 months or from 3 months to 4 months, wherein the polymer network is formed by reacting a multi-arm polymer precursor containing an electrophilic group with a cross-linker containing a nucleophilic group, the electrophilic group is a succinimidyl glutarate (SG) group and the multi-arm polymer precursor is 8-arm-15K-SG polyethylene glycol; and the cross-linker containing a nucleophilic group is trilysine and the hydrogel dissolves within 2 months to 4 months.

[0424] In certain embodiments, the treatment period is about 6 months to about 9 months or about 6 months to about 12 months and the biodegradable intracameral implant with sustained release of travoprost provides treatment for about 6 months to 9 months or about 6 months to about 12 months, wherein the polymer network is formed by reacting a multi-arm polymer precursor containing an electrophilic group with a cross-linker containing a nucleophilic group, the electrophilic group is a succinimidyl azelaic acid ester (SAZ) group, and the multi-arm polymer precursor is 8-arm-15K-SAZ polyethylene glycol; and the cross-linker containing a nucleophilic group is trilysine and the hydrogel dissolves within 6 months to 8 months.

[0425] In certain embodiments, treatment is continued by repeating steps 1 and 2 after said treatment period in the range of about 2 months to about 12 months, in the range of about 3 months to about 9 months. More specifically, treatment is continued by repeating steps 1 and 2 until treatment is no longer needed. Even more specifically, treatment comprises repeating steps 1 and 2 once a year, twice a year, three times a year, or four times a year at approximately equal time intervals with: a prostaglandin antagonist (e.g., travoprost) sustained-release biodegradable intracameral implant providing treatment once a year for about 12 months, providing treatment twice a year for 6 months to 9 months; and a prostaglandin antagonist (e.g., travoprost) sustained-release biodegradable intracameral implant providing treatment three times a year or four times a year for 3 months to 4 months.

[0426] In another embodiment, the first treatment period is 3 to 4 months and the biodegradable intracameral implant for sustained release of a prostaglandin antagonist (e.g., travoprost) provides treatment for 3 to 4 months, and treatment with the biodegradable intracameral implant for sustained release of a prostaglandin antagonist (e.g., travoprost) is continued for a treatment period of 6 to 9 months, providing treatment for 6 to 9 months.

[0427] In certain embodiments, the travoprost sustained-release biodegradable intracameral implant or hydrogel dissolves / completely biodegrades within 5 to 7 months or within 3 to 5 months.

[0428] In certain embodiments, the treatment period ranges from 6 months to 9 months or 6 months to 12 months and the travoprost sustained-release biodegradable intracameral implant or hydrogel dissolves / completely biodegrades within 5 months to 7 months. In certain embodiments, the treatment period ranges from 3 months to 6 months and the travoprost sustained-release biodegradable intracameral implant or hydrogel dissolves / completely biodegrades within 3 months to 5 months.

[0429] In certain embodiments, "glaucoma" may encompass forms of open-angle glaucoma and angle-closure glaucoma. The subtypes of open-angle glaucoma disclosed herein may encompass normal-tension glaucoma, congenital glaucoma, secondary glaucoma, pigmentary glaucoma, pseudoexfoliation glaucoma, traumatic glaucoma, neovascular glaucoma, iridocorneal endothelial syndrome (ICE), and / or uveal glaucoma.

[0430] In certain embodiments, the treatments of the invention are for mild, moderate or severe open-angle glaucoma.

[0431] In certain embodiments, in the treatment of the present invention, the intraocular pressure is reduced by at least 4 mmHg, or at least 5 mmHg from the baseline intraocular pressure, during a treatment period of, for example, about 1 month to about 12 months, or about 2 months to about 12 months, or about 3 months to about 9 months, for example, about 6 months to about 12 months, or for example, about 6 months to about 9 months, or during repeated administration of sustained treatment. According to certain embodiments, the intraocular pressure is reduced by as much as 7 to 11 mmHg. Alternatively, in the treatment of the present invention, the intraocular pressure is reduced by at least 20%, or at least 25%, or at least about 30%, or about 20% to about 35%, or about 20% to about 30% relative to the baseline intraocular pressure, during a treatment period of, for example, about 1 month to about 12 months, or about 2 months to about 12 months, or about 3 months to about 9 months, for example, about 6 months to about 12 months, or for example, about 6 months to about 9 months, or during repeated administration of sustained treatment. Reductions were measured at 2 weeks, 6 weeks, 12 weeks, 4 months, 6 months, 9 months and 12 months, with any time point applicable for each treatment period. Measurements were made at 8am, 10am and 4pm at each relevant time point. Alternatively, treatment was performed with a different IOP medication (e.g. travoprost eye drops) for each treatment period at each time point, non-inferiority, with a non-inferiority margin of 1.5 mm Hg.

[0432] In certain embodiments, treatment prevents vision loss, such as peripheral vision loss.

[0433] In certain embodiments, the treatment prevents optic nerve fiber loss.

[0434] In certain embodiments, the treatment prevents retinal ganglion cell death.

[0435] In certain embodiments, the treatment prevents optic nerve damage.

[0436] In certain embodiments, in the treatment of the invention, intraocular pressure has been significantly reduced at least five days, or at least three days, or at least two days after administration.

[0437] In certain embodiments, during the treatment of the present invention, intraocular pressure is reduced to a level comparable to topical travoprost therapy.

[0438] In certain embodiments, the number of endothelial cells in the treated eye does not change during and / or throughout the treatment period.

[0439] In certain embodiments, there is no change in corneal thickness in the treated eye or during the treatment period and / or over the entire treatment period.

[0440] In certain embodiments, there is substantially no movement of the implant as monitored, for example, by keratoscopy and slit lamp examination.

[0441] In certain embodiments, the implant is invisible through makeup.

[0442] In certain embodiments, the treatment period is from about 3 months to about 6 months or from about 3 months to 4 months and the travoprost sustained release biodegradable intracameral implant provides treatment for about 3 months to about 6 months or from 3 months to 4 months, wherein the travoprost particles are a blend of particles made of:

[0443] a first type of travoprost particles made from a mixture of travoprost and a biodegradable polymer consisting of one or more polylactides having acid end groups and an intrinsic viscosity specification in the range of about 0.05 to less than about 0.5 dl / g, such as about 0.35 to about 0.45 dl / g, wherein the first type of particles contains about 40 wt.-% to about 50 wt.-%, such as about 43 wt.-% to about 45 wt.-% of travoprost, based on the total mass of the first type of particles; and

[0444] a second type of travoprost particles made from a mixture of travoprost and a biodegradable polymer consisting of one or more polylactides having acid end groups and an intrinsic viscosity specification in the range of about 0.5 to less than about 0.80 dl / g, such as in the range of about 0.6 to less than about 0.80 dl / g, wherein the second type of particles contains about 40 wt.-% to about 50 wt.-%, such as greater than about 45 wt.-% to about 47 wt.-% of travoprost, based on the total mass of the second type of particles,

[0445] wherein the blend contains, based on the total amount of particles, about 35 wt.-% to about 55 wt.-% of particles of the first type of particles and about 35 wt.-% to about 55 wt.-% of particles of the second type of particles; or 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.

[0446] In certain embodiments, the treatment period is 4 to 7 months and the travoprost sustained release biodegradable intracameral implant provides treatment for about 4 to about 7 months, wherein the travoprost particles are a blend of particles made of:

[0447] a first type of particles made from a mixture of travoprost and a biodegradable polymer consisting of one or more polylactides having acid end groups and an intrinsic viscosity specification in the range of about 0.05 to less than about 0.5 dl / g, such as about 0.35 to about 0.45 dl / g, wherein the first type of particles contains about 40 wt.-% to about 50 wt.-%, such as about 43 wt.-% to about 45 wt.-% of travoprost, based on the total mass of the first type of particles,

[0448] a second type of particles made from a mixture of travoprost and said biodegradable polymer consisting of one or more polylactides having acid end groups and an intrinsic viscosity specification in the range of about 0.5 to less than about 0.80 dl / g, such as in the range of about 0.6 to less than about 0.80 dl / g, wherein said second type of particles contains from about 40 wt.-% to about 50 wt.-%, such as greater than about 45 wt.-% to about 47 wt.-% of travoprost, based on the total mass of the second type of particles, and

[0449] a third type of particles made from a mixture of travoprost and said biodegradable polymer, said biodegradable polymer consisting of one or more polylactides having acid end groups and an intrinsic viscosity specification in the range of about 0.8 to about 1.7 dl / g, such as in the range of about 0.8 to about 1.0 dl / g, wherein said third type of particles contains about 40 wt.-% to about 50 wt.-%, such as about 41 wt.-% to about 43 wt.-% of travoprost, based on the total mass of the third type of particles,

[0450] wherein the blend contains, based on the total amount of particles, about 20 wt.-% to about 35 wt.-% of particles of the first type of particles and about 30 wt.-% to about 50 wt.-% of particles of the second type of particles and about 25 wt.-% to about 45 wt.-% of particles of the third type of particles; or wherein about 20 wt.-% to about 35 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 30 wt.-% to about 50 wt.-% of the total amount of travoprost in the implant is present in the form of particles of the second type of particles and about 25 wt.-% to about 45 wt.-% of the total amount of travoprost in the implant is present in the form of particles of the third type of particles.

[0451] In certain embodiments, the treatment period is from about 6 months to about 12 months, from about 6 months to about 9 months and the travoprost sustained-release biodegradable intracameral implant provides treatment for about 6 months to 12 months or about 6 months to 9 months, wherein the travoprost particles are a blend of particles made of:

[0452] a first type of particles made from a mixture of travoprost and a biodegradable polymer consisting of one or more polylactides having acid end groups and an intrinsic viscosity specification in the range of about 0.05 to less than about 0.5 dl / g, such as about 0.35 to about 0.45 dl / g, wherein the first type of particles contains about 40 wt.-% to about 50 wt.-%, such as about 43 wt.-% to about 45 wt.-% of travoprost, based on the total mass of the first type of particles,

[0453] a second type of particles made from a mixture of travoprost and said biodegradable polymer consisting of one or more polylactides having acid end groups and an intrinsic viscosity specification in the range of about 0.5 to less than about 0.80 dl / g, such as in the range of about 0.6 to less than about 0.80 dl / g, wherein said second type of particles contains about 40 wt.-% to about 50 wt.-%, such as greater than about 45 wt.-% to about 47 wt.-% of travoprost, based on the total mass of the second type of particles,

[0454] a third type of particles made of travoprost and a biodegradable polymer consisting of one or more polylactides having acid end groups and an intrinsic viscosity specification in the range of about 0.8 to about 1.7 dl / g, such as in the range of about 0.8 to about 1.0 dl / g, wherein the third type of particles contains about 40 wt.-% to about 50 wt.-%, such as about 41 wt.-% to about 43 wt.-% of travoprost, based on the total mass of the third type of particles, and

[0455] a fourth type of particles made of travoprost and a biodegradable polymer consisting of one or more polylactides having ester end groups and an intrinsic viscosity specification in the range of about 0.05 to about 1.7 dl / g, such as in the range of about 0.55 to about 0.75 dl / g, wherein the fourth type of particles contains about 40 wt.-% to about 50 wt.-%, such as about 41 wt.-% to about 43 wt.-% of travoprost, based on the total mass of the fourth type of particles,

[0456] wherein the blend contains, based on the total amount of particles, about 15 wt.-% to about 25 wt.-% of particles of the first type of particles and about 15 wt.-% to about 25 wt.-% of particles of the second type of particles and about 5 wt.-% to about 15 wt.-% of particles of the third type of particles and about 40 wt.-% to about 60 wt.-% of particles of the fourth type of particles; or wherein about 15 wt.-% to about 25 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 15 wt.-% to about 25 wt.-% of the total amount of travoprost in the implant is present in the form of particles of the second type of particles and about 5 wt.-% to about 15 wt.-% of the total amount of travoprost in the implant is present in the form of particles of the third type of particles and about 40 wt.-% to about 60 wt.-% of the total amount of travoprost in the implant is present in the form of particles of the fourth type of particles.

[0457] In certain embodiments, the treatment period is from about 3 months to about 6 months or from about 3 months to 4 months, the implant contains a dose of about 5 μg of travoprost, and wherein the implant has an in vitro release with a mean travoprost release in the range of about 300 to about 500 ng / week and a standard deviation in the range of 100 to 200 ng / week, wherein the mean travoprost release is based on weekly travoprost release values ​​between day 7 and day 84 when measured under sedimentation conditions in PBS at pH 7.2 to 7.4 at 37°C, excluding the burst release on day 1 after administration; or wherein the weekly travoprost release when measured at time intervals between day 7 and day 84 when measured under sedimentation conditions in PBS at pH 7.2 to 7.4 at 37°C, excluding the burst release on day 1 after administration, is in the range of about 10 to about 700 ng, excluding the burst release on day 1 after administration.

[0458] In certain embodiments, the treatment period is from about 3 months to about 7 months or from about 4 months to 7 months, the implant contains a dose of about 15 μg of travoprost, and the implant has an in vitro release with a mean travoprost release in the range of about 800 to about 1100 ng / week and a standard deviation in the range of 450 to 550 ng / week, wherein the mean is based on weekly travoprost release values ​​between day 7 and day 98 when measured under sedimentation conditions st in PBS at pH 7.2 to 7.4 at 37°C, excluding the burst release on day 1 after administration; or wherein the weekly travoprost release when measured at time intervals between day 7 and day 98 when measured under sedimentation conditions st in PBS at pH 7.2 to 7.4 at 37°C, excluding the burst release on day 1 after administration, is in the range of about 100 to about 2300 ng, excluding the burst release on day 1 after administration.

[0459] In certain embodiments, the treatment period is from about 6 months to about 9 months or from about 6 months to about 12 months, the implant contains a dose of about 15 μg of travoprost, and wherein the implant has an in vitro release with a mean travoprost release in the range of about 500 to about 900 ng / week and a standard deviation in the range of 150 to 250 ng / week, wherein the mean is based on weekly travoprost release values ​​between day 7 and day 119 when measured under sedimentation conditions in PBS at pH 7.2 to 7.4 at 37°C, excluding the burst release on day 1 after dosing; or wherein the weekly travoprost release when measured at time intervals between day 7 and day 119, excluding the burst release on day 1 after dosing; when measured under sedimentation conditions in PBS at pH 7.2 to 7.2 at 37°C.

[0460] In certain embodiments, the treatment period is from about 6 months to about 9 months or from about 6 months to about 12 months, the implant contains a dose of about 26 μg of travoprost, and wherein the implant has an in vitro release with a mean travoprost release in the range of about 1000 to about 1500 ng / week and a standard deviation in the range of 100 to 400 ng / week, wherein the mean is based on weekly travoprost release values ​​between day 7 and day 119 when measured under sedimentation conditions in PBS at pH 7.2 to 7.4 at 37°C, excluding the burst release on day 1 after administration; or wherein the weekly travoprost release when measured at time intervals between day 7 and day 119 when measured under sedimentation conditions in PBS at pH 7.2 to 7.4 at 37°C, excluding the burst release on day 1 after administration, is in the range of about 100 to about 2000 ng, excluding the burst release on day 1 after administration.

[0461] In certain embodiments, the implant can be monitored in the eye, for example, by keratoscopy and slit lamp examination.

[0462] In a specific aspect, the invention is directed to a method of treating intraocular pressure in a human subject suffering from ocular hypertension or glaucoma, such as open-angle glaucoma, by treating each eye in need of such treatment with a single prostaglandin antagonist (e.g., travoprost) sustained-release biodegradable intracameral implant for a period of about 2 months to about 12 months or about 6 months to about 9 months, the method comprising treating each eye:

[0463] Step 1: Providing a prostaglandin antagonist (e.g. travoprost) sustained-release biodegradable intracameral implant as defined above, said implant containing 21 to 30 μg of a prostaglandin antagonist (e.g. travoprost), wherein said implant is in the form of a fiber having a length of about 1.0 mm to about 2.5 mm and a diameter of not more than 0.3 mm in its dry state, said implant comprising:

[0464] a biodegradable hydrogel as defined above, and a prostaglandin antagonist (e.g. travoprost) particle as defined above,

[0465] The prostaglandin antagonist (e.g. travoprost) particles are in the form of a prostaglandin antagonist (e.g. travoprost) intermixed with a biodegradable polymer, wherein the prostaglandin antagonist (e.g. travoprost) particles contain a blend of four types of particles, a first type of particles are in the form of a prostaglandin antagonist (e.g. travoprost) intermixed with a biodegradable polymer, the biodegradable polymer consisting of a first polylactide having an intrinsic viscosity specification in the range of about 0.05 to less than 5 dl / g, for example, about 0.35 to about 0.45 dl / g and having acid end groups; and a second type of particles are in the form of a prostaglandin antagonist (e.g. travoprost) intermixed with a biodegradable polymer, the biodegradable polymer consisting of a first polylactide having an intrinsic viscosity specification in the range of about 0.5 to less than about 0.8 dl / g, for example, about 0.6 to less than about 0.8 dl / g and having acid end groups; and a third type of particles is in the form of a prostaglandin antagonist (e.g., travoprost) intermixed with a biodegradable polymer, the biodegradable polymer consisting of a third polylactide having an intrinsic viscosity specification in the range of about 0.8 to about 1.7 dl / g, for example, 0.8 to about 1.0 dl / g and having acid end groups; and a fourth type of particles is in the form of a prostaglandin antagonist (e.g., travoprost) intermixed with a biodegradable polymer, the biodegradable polymer consisting of a fourth polylactide having an intrinsic viscosity specification in the range of about 0.05 to about 1.7 dl / g, for example, about 0.55 to 0.75 dl / g and having ester end groups; and

[0466] The prostaglandin antagonist (e.g., travoprost) particles are dispersed within the hydrogel, wherein the hydrogel comprises a polymer network formed by reacting 8-arm-15K-SAZ polyethylene glycol having a mass average molecular weight of 15,000±10% Daltons with trilysine acetate; and

[0467] Step 2: Inserting a sustained-release biodegradable intracameral implant of step 1 into the anterior segment of the eye so as to place it within the iridocorneal angle of the eye.

[0468] In a specific aspect, the present invention is directed to a method of treating intraocular pressure in a human subject suffering from ocular hypertension or glaucoma, such as open-angle glaucoma, by treating each eye in need of such treatment with a single prostaglandin antagonist (e.g. travoprost) sustained-release biodegradable intracameral implant for a period of about 2 months to about 12 months or about 6 months to about 9 months, the method comprising treating each eye, wherein the implant is as defined above, containing 21 to 30 μg of the prostaglandin antagonist (e.g. travoprost), wherein the implant is in the form of a fiber having a length of about 1.0 mm to about 2.5 mm in its dry state and a diameter of not more than 0.3 mm, comprising:

[0469] - a biodegradable hydrogel as defined above, and prostaglandin antagonist (e.g. travoprost) particles as defined above,

[0470] - the prostaglandin antagonist (e.g. travoprost) particles are in the form of a prostaglandin antagonist (e.g. travoprost) intermixed with a biodegradable polymer, wherein the prostaglandin antagonist (e.g. travoprost) particles contain a blend of four types of particles, a first type of particles are in the form of a prostaglandin antagonist (e.g. travoprost) intermixed with a biodegradable polymer, the biodegradable polymer consisting of a first polylactide having an intrinsic viscosity specification in the range of about 0.05 to less than 5 dl / g, such as about 0.35 to about 0.45 dl / g and having acid end groups; and a second type of particles are in the form of a prostaglandin antagonist (e.g. travoprost) intermixed with a biodegradable polymer consisting of a first polylactide having an intrinsic viscosity specification in the range of about 0.5 to less than about 0.8 dl / g, for example, about 0.6 to less than about 0.8 dl / g and having acid end groups; and a third type of particles is in the form of a prostaglandin antagonist (e.g., travoprost) intermixed with a biodegradable polymer, the biodegradable polymer consisting of a third polylactide having an intrinsic viscosity specification in the range of about 0.8 to about 1.7 dl / g, for example, 0.8 to about 1.0 dl / g and having acid end groups; and a fourth type of particles is in the form of a prostaglandin antagonist (e.g., travoprost) intermixed with a biodegradable polymer, the biodegradable polymer consisting of a fourth polylactide having an intrinsic viscosity specification in the range of about 0.05 to about 1.7 dl / g, for example, about 0.55 to 0.75 dl / g and having ester end groups; and

[0471] - The prostaglandin antagonist (eg, travoprost) particles are dispersed within the hydrogel, wherein the hydrogel comprises a polymer network formed by reacting 8-arm-15K-SAZ polyethylene glycol having a mass average molecular weight of 15,000±10% Daltons with trilysine acetate.

[0472] In another specific aspect, the present invention is directed to a method of treating intraocular pressure in a human subject suffering from ocular hypertension or glaucoma, such as open-angle glaucoma, by treating each eye in need of such treatment with a single prostaglandin antagonist (e.g., travoprost) sustained-release biodegradable intracameral implant for a period of about 2 months to about 12 months or about 6 months to about 9 months, the method comprising treating each eye:

[0473] Step 1: Providing a prostaglandin antagonist (e.g. travoprost) sustained-release biodegradable intracameral implant as defined above, said implant containing 11 to 20 μg of a prostaglandin antagonist (e.g. travoprost), wherein said implant is in the form of a fiber having a length of about 1.0 mm to about 2.5 mm and a diameter of not more than 0.3 mm in its dry state, said implant comprising:

[0474] - a biodegradable hydrogel as defined above, and prostaglandin antagonist (e.g. travoprost) particles as defined above,

[0475] - the prostaglandin antagonist (e.g. travoprost) particles are in the form of a prostaglandin antagonist (e.g. travoprost) intermixed with a biodegradable polymer, wherein the prostaglandin antagonist (e.g. travoprost) particles contain a blend of four types of particles, a first type of particles are in the form of a prostaglandin antagonist (e.g. travoprost) intermixed with a biodegradable polymer, the biodegradable polymer consisting of a first polylactide having an intrinsic viscosity specification in the range of about 0.05 to less than about 0.5 dl / g, for example, about 0.35 to about 0.45 dl / g and having acid end groups; and a second type of particles are in the form of a prostaglandin antagonist (e.g. travoprost) intermixed with a biodegradable polymer, the biodegradable polymer consisting of a first polylactide having an intrinsic viscosity specification in the range of about 0.5 to less than about 0.8 dl / g, for example, about 0.6 to less than about 0.8 dl / g, and having acid end groups; and a third type of particles is in the form of a prostaglandin antagonist (e.g., travoprost) intermixed with a biodegradable polymer, the biodegradable polymer consisting of a third polylactide having an intrinsic viscosity specification in the range of about 0.8 to about 1.7 dl / g, for example, about 0.8 to about 1.0 dl / g, and having acid end groups; and a fourth type of particles is in the form of a prostaglandin antagonist (e.g., travoprost) intermixed with a biodegradable polymer, the biodegradable polymer consisting of a fourth polylactide having an intrinsic viscosity specification of about 0.55 to 0.75 dl / g and having ester end groups, and

[0476] The prostaglandin antagonist (e.g., travoprost) particles are dispersed within the hydrogel, wherein the hydrogel comprises a polymer network formed by reacting 8-arm-15K-SAZ polyethylene glycol having a mass average molecular weight of 15,000±10% Daltons with trilysine acetate; and

[0477] Step 2: Inserting a sustained-release biodegradable intracameral implant of step 1 into the anterior segment of the eye so as to place it within the iridocorneal angle of the eye.

[0478] In another specific aspect, the present invention is directed to a method for treating intraocular pressure in a human subject suffering from ocular hypertension or glaucoma, such as open-angle glaucoma, by treating each eye in need of such treatment with a single sustained-release biodegradable intracameral implant of a prostaglandin antagonist (e.g., travoprost) for a period of about 2 months to about 12 months or about 6 months to about 9 months, the method comprising inserting one sustained-release biodegradable intracameral implant into the anterior segment of the eye of each eye so as to place it within the iridocorneal angle of the eye, wherein the implant is as defined above, containing 11 to 20 μg of a prostaglandin antagonist (e.g., travoprost), wherein the implant is in the form of a fiber having a length of about 1.0 mm to about 2.5 mm and a diameter of not more than 0.3 mm in its dry state, comprising:

[0479] - a biodegradable hydrogel as defined above, and prostaglandin antagonist (e.g. travoprost) particles as defined above,

[0480] - the prostaglandin antagonist (e.g. travoprost) particles are in the form of a prostaglandin antagonist (e.g. travoprost) intermixed with a biodegradable polymer, wherein the prostaglandin antagonist (e.g. travoprost) particles contain a blend of four types of particles, a first type of particles are in the form of a prostaglandin antagonist (e.g. travoprost) intermixed with a biodegradable polymer, the biodegradable polymer consisting of a first polylactide having an intrinsic viscosity specification in the range of about 0.05 to less than about 0.5 dl / g, for example, about 0.35 to about 0.45 dl / g and having acid end groups; and a second type of particles are in the form of a prostaglandin antagonist (e.g. travoprost) intermixed with a biodegradable polymer, the biodegradable polymer consisting of a first polylactide having an intrinsic viscosity specification in the range of about 0.5 to less than about 0.8 dl / g, for example, about 0.6 to less than about 0.8 dl / g, and having acid end groups; and a third type of particles is in the form of a prostaglandin antagonist (e.g., travoprost) intermixed with a biodegradable polymer, the biodegradable polymer consisting of a third polylactide having an intrinsic viscosity specification in the range of about 0.8 to about 1.7 dl / g, for example, about 0.8 to about 1.0 dl / g, and having acid end groups; and a fourth type of particles is in the form of a prostaglandin antagonist (e.g., travoprost) intermixed with a biodegradable polymer, the biodegradable polymer consisting of a fourth polylactide having an intrinsic viscosity specification of about 0.55 to 0.75 dl / g and having ester end groups, and

[0481] - The prostaglandin antagonist (eg, travoprost) particles are dispersed within the hydrogel, wherein the hydrogel comprises a polymer network formed by reacting 8-arm-15K-SAZ polyethylene glycol having a mass average molecular weight of 15,000±10% Daltons with trilysine acetate.

[0482] In another specific aspect, the present invention is directed to a method of treating intraocular pressure in a human subject suffering from ocular hypertension or glaucoma, such as open-angle glaucoma, by treating each eye in need of such treatment with a single prostaglandin antagonist (e.g., travoprost) sustained-release biodegradable intracameral implant for a period of about 3 months to about 6 months or about 3 months to about 4 months, the method comprising treating each eye:

[0483] Step 1: Providing a prostaglandin antagonist (e.g. travoprost) sustained-release biodegradable intracameral implant as defined above, said implant containing 11 to 20 μg of a prostaglandin antagonist (e.g. travoprost), wherein said implant is in the form of a fiber having a length of about 1.0 mm to about 2.5 mm and a diameter of not more than 0.3 mm in its dry state, comprising:

[0484] - a biodegradable hydrogel as defined above, and prostaglandin antagonist (e.g. travoprost) particles as defined above,

[0485] - the prostaglandin antagonist (e.g. travoprost) particles are in the form of a prostaglandin antagonist (e.g. travoprost) intermixed with a biodegradable polymer, wherein the prostaglandin antagonist (e.g. travoprost) particles contain a blend of three types of particles, a first type of particles are in the form of a prostaglandin antagonist (e.g. travoprost) intermixed with a biodegradable polymer, the biodegradable polymer consisting of a first polylactide having an intrinsic viscosity specification in the range of about 0.05 to less than about 0.5 dl / g, for example about 0.35 to about 0.45 dl / g and having acid end groups; and a second type of particles are in the form of a prostaglandin antagonist (e.g. travoprost) intermixed with a biodegradable polymer consisting of a first polylactide having an intrinsic viscosity specification in the range of about 0.05 to less than about 0.5 dl / g, for example about 0.35 to about 0.45 dl / g and having acid end groups; in the form of a prostaglandin antagonist (e.g., travoprost) intermixed with a biodegradable polymer consisting of a second polylactide having an intrinsic viscosity specification in the range of about 0.5 to about 1.7 dl / g, such as about 0.6 to less than about 0.8 dl / g, and having acid end groups; and a third type of particle is in the form of a prostaglandin antagonist (e.g., travoprost) intermixed with a biodegradable polymer consisting of a third polylactide having an intrinsic viscosity specification in the range of about 0.8 to about 1.7 dl / g, such as 0.8 to about 1.0 dl / g, and having acid end groups; and

[0486] - the prostaglandin antagonist (e.g., travoprost) particles are dispersed within the hydrogel, wherein the hydrogel comprises a polymer network formed by reacting 8-arm-15K-SG polyethylene glycol having a mass average molecular weight of 15,000±10% Daltons with trilysine acetate; and

[0487] Step 2: Inserting a sustained-release biodegradable intracameral implant of step 1 into the anterior segment of the eye so as to place it within the iridocorneal angle of the eye.

[0488] In another specific aspect, the present invention is directed to a method of treating intraocular pressure in a human subject suffering from ocular hypertension or glaucoma, such as open-angle glaucoma, by treating each eye in need of such treatment with a single sustained-release biodegradable intracameral implant of a prostaglandin antagonist (e.g., travoprost) for a period of about 3 months to about 6 months or about 3 months to about 4 months, the method comprising inserting one sustained-release biodegradable intracameral implant into the anterior segment of the eye of each eye so as to place it within the iridocorneal angle of the eye, wherein the implant is as defined above, containing 11 to 20 μg of a prostaglandin antagonist (e.g., travoprost), wherein the implant is in the form of a fiber having a length of about 1.0 mm to about 2.5 mm and a diameter of not more than 0.3 mm in its dry state, comprising:

[0489] - a biodegradable hydrogel as defined above, and prostaglandin antagonist (e.g. travoprost) particles as defined above,

[0490] - the prostaglandin antagonist (e.g. travoprost) particles are in the form of a prostaglandin antagonist (e.g. travoprost) intermixed with a biodegradable polymer, wherein the prostaglandin antagonist (e.g. travoprost) particles contain a blend of three types of particles, a first type of particles are in the form of a prostaglandin antagonist (e.g. travoprost) intermixed with a biodegradable polymer, the biodegradable polymer consisting of a first polylactide having an intrinsic viscosity specification in the range of about 0.05 to less than about 0.5 dl / g, for example about 0.35 to about 0.45 dl / g and having acid end groups; and a second type of particles are in the form of a prostaglandin antagonist (e.g. travoprost) intermixed with a biodegradable polymer consisting of a first polylactide having an intrinsic viscosity specification in the range of about 0.05 to less than about 0.5 dl / g, for example about 0.35 to about 0.45 dl / g and having acid end groups; in the form of a prostaglandin antagonist (e.g., travoprost) intermixed with a biodegradable polymer consisting of a second polylactide having an intrinsic viscosity specification in the range of about 0.5 to about 1.7 dl / g, such as about 0.6 to less than about 0.8 dl / g, and having acid end groups; and a third type of particle is in the form of a prostaglandin antagonist (e.g., travoprost) intermixed with a biodegradable polymer consisting of a third polylactide having an intrinsic viscosity specification in the range of about 0.8 to about 1.7 dl / g, such as 0.8 to about 1.0 dl / g, and having acid end groups; and

[0491] - The prostaglandin antagonist (eg, travoprost) particles are dispersed within the hydrogel, wherein the hydrogel comprises a polymer network formed by reacting 8-arm-15K-SG polyethylene glycol having a mass average molecular weight of 15,000±10% Daltons with trilysine acetate.

[0492] In another specific aspect, the present invention is directed to a method of treating intraocular pressure in a human subject suffering from ocular hypertension or glaucoma, such as open-angle glaucoma, by treating each eye in need of such treatment with a single prostaglandin antagonist (e.g., travoprost) sustained-release biodegradable intracameral implant for a period of about 3 months to about 6 months or about 3 months to about 4 months, the method comprising treating each eye:

[0493] Step 1: providing a prostaglandin antagonist (e.g. travoprost) sustained-release biodegradable intracameral implant as defined above, said implant containing 2 to 10 μg of a prostaglandin antagonist (e.g. travoprost), wherein said implant is in the form of a fiber having a length of about 1.0 mm to about 2.5 mm and a diameter of not more than 0.3 mm in its dry state, said implant comprising: a biodegradable hydrogel as defined above, and prostaglandin antagonist (e.g. travoprost) particles as defined above,

[0494] The prostaglandin antagonist (e.g. travoprost) particles are in the form of a prostaglandin antagonist (e.g. travoprost) intermixed with a biodegradable polymer, wherein the prostaglandin antagonist (e.g. travoprost) particles contain a blend of two types of particles, a first type of particles being in the form of a prostaglandin antagonist (e.g. travoprost) intermixed with a biodegradable polymer consisting of a first polylactide having an intrinsic viscosity specification in the range of 0.05 to less than about 0.5 dl / g, such as about 0.35 to about 0.45 dl / g, and having acid end groups; and a second type of particles being in the form of a prostaglandin antagonist (e.g. travoprost) intermixed with a biodegradable polymer consisting of a second polylactide having an intrinsic viscosity specification in the range of about 0.5 to about 1.7 dl / g, such as about 0.6 to about 0.8 dl / g, and having acid end groups; and

[0495] The prostaglandin antagonist (e.g., travoprost) particles are dispersed within the hydrogel, wherein the hydrogel comprises a polymer network formed by reacting 8-arm-15K-SG polyethylene glycol having a mass average molecular weight of 15,000±10% Daltons with trilysine acetate; and

[0496] Step 2: Inserting a sustained-release biodegradable intracameral implant of step 1 into the anterior segment of the eye so as to place it within the iridocorneal angle of the eye.

[0497] In another specific aspect, the present invention is directed to a method of treating intraocular pressure in a human subject suffering from ocular hypertension or glaucoma, such as open-angle glaucoma, by treating each eye in need of such treatment with a single sustained-release biodegradable intracameral implant of a prostaglandin antagonist (e.g. travoprost) for a period of about 3 months to about 6 months or about 3 months to about 4 months, the method comprising inserting one sustained-release biodegradable intracameral implant into the anterior segment of the eye of each eye so as to place it within the iridocorneal angle of the eye, wherein the implant is as defined above, containing 2 to 10 μg of a prostaglandin antagonist (e.g. travoprost), wherein the implant is in the form of a fiber having a length of about 1.0 mm to about 2.5 mm and a diameter of not more than 0.3 mm in its dry state, the implant comprising: a biodegradable hydrogel as defined above, and prostaglandin antagonist (e.g. travoprost) particles as defined above,

[0498] The prostaglandin antagonist (e.g. travoprost) particles are in the form of a prostaglandin antagonist (e.g. travoprost) intermixed with a biodegradable polymer, wherein the prostaglandin antagonist (e.g. travoprost) particles contain a blend of two types of particles, a first type of particles being in the form of a prostaglandin antagonist (e.g. travoprost) intermixed with a biodegradable polymer consisting of a first polylactide having an intrinsic viscosity specification in the range of 0.05 to less than about 0.5 dl / g, such as about 0.35 to about 0.45 dl / g, and having acid end groups; and a second type of particles being in the form of a prostaglandin antagonist (e.g. travoprost) intermixed with a biodegradable polymer consisting of a second polylactide having an intrinsic viscosity specification in the range of about 0.5 to about 1.7 dl / g, such as about 0.6 to about 0.8 dl / g, and having acid end groups; and

[0499] The prostaglandin antagonist (eg, travoprost) particles are dispersed within the hydrogel, wherein the hydrogel comprises a polymer network formed by reacting 8-arm-15K-SG polyethylene glycol having a mass average molecular weight of 15,000±10% Daltons with trilysine acetate.

[0500] In another specific aspect, the present invention is directed to a method of treating intraocular pressure in a human subject suffering from ocular hypertension or glaucoma, such as open-angle glaucoma, by treating each eye in need of such treatment with a single prostaglandin antagonist (e.g., travoprost) sustained-release biodegradable intracameral implant for a period of about 2 months to about 12 months or about 6 months to about 9 months, the method comprising treating each eye:

[0501] Step 1: providing a prostaglandin antagonist (e.g. travoprost) sustained-release biodegradable intracameral implant as defined above, said implant containing 21 to 30 μg of prostaglandin antagonist (e.g. travoprost), wherein said implant is in the form of a fiber having a length of about 1.0 mm to about 2.5 mm and a diameter of not more than 0.3 mm in its dry state, said implant comprising a biodegradable hydrogel as defined above, and prostaglandin antagonist (e.g. travoprost) particles as defined above dispersed therein, wherein based on the pH value when at sedimentation conditions 7.2 to 7.4% released every 14 days from day 1 to day 112 when measured in PBS at 37°C, the intracameral implant has a mean prostaglandin antagonist (e.g. travoprost) release in the range of about 5% to about 15% and a mean absolute deviation of at most 3%, or an in vitro release of the prostaglandin antagonist (e.g. travoprost) release in the range of 5% to 15%, and the hydrogel dissolves / completely biodegrades within 6 to 8 months or within 5 to 7 months; and

[0502] Step 2: Inserting a sustained-release biodegradable intracameral implant of step 1 into the anterior segment of the eye so as to place it within the iridocorneal angle of the eye.

[0503] In another specific aspect, the present invention is directed to a method of treating intraocular pressure in a human subject suffering from ocular hypertension or glaucoma, such as open-angle glaucoma, by treating each eye in need of such treatment with a single sustained-release biodegradable intracameral implant of a prostaglandin antagonist (e.g., travoprost) for a period of about 2 months to about 12 months or about 6 months to about 9 months, the method comprising inserting one sustained-release biodegradable intracameral implant into the anterior segment of the eye of each eye so as to place it within the iridocorneal angle of the eye, wherein the implant is as defined above, containing 21 to 30 μg of the prostaglandin antagonist (e.g., travoprost), wherein the implant is in the form of a fiber having a length of about 1.0 mm to about 2.5 mm and a diameter of no more than 0.3 mm in its dry state, the implant comprising a biodegradable hydrogel as defined above, and particles of a prostaglandin antagonist (e.g., travoprost) as defined above dispersed therein, wherein based on the pH value when at sedimentation conditions, the implant is approximately 1.0 to 1.2 μg of the prostaglandin antagonist (e.g., travoprost) particles are approximately 1.0 to 2.5 ... The intracameral implant has a mean prostaglandin antagonist (e.g. travoprost) release in the range of about 5% to about 15% and a mean absolute deviation of at most 3%, or an in vitro release of the prostaglandin antagonist (e.g. travoprost) in the range of 5% to 15%, and the hydrogel dissolves within 6 to 8 months.

[0504] In another specific aspect, the present invention is directed to a method of treating intraocular pressure in a human subject suffering from ocular hypertension or glaucoma, such as open-angle glaucoma, by treating each eye in need of such treatment with a single prostaglandin antagonist (e.g., travoprost) sustained-release biodegradable intracameral implant for a period of about 3 months to about 6 months or about 3 months to about 4 months, the method comprising treating each eye:

[0505] Step 1: providing a prostaglandin antagonist (e.g. travoprost) sustained-release biodegradable intracameral implant as defined above, said implant containing 11 to 20 μg of a prostaglandin antagonist (e.g. travoprost), wherein said implant is in the form of a fiber having a length of about 1.0 mm to about 2.5 mm and a diameter of not more than 0.3 mm in its dry state, said implant comprising a biodegradable hydrogel as defined above, and prostaglandin antagonist (e.g. travoprost) particles as defined above dispersed therein, wherein based on the pH value when at sedimentation conditions 7.2 to 7.4% released every 70 days from day 1 to day 84 when measured in PBS at 37°C, the intracameral implant has a mean prostaglandin antagonist (e.g. travoprost) release in the range of about 65% to about 85% and a mean absolute deviation of at most 5%, or an in vitro release of the prostaglandin antagonist (e.g. travoprost) release in the range of 65% to 85%, and the hydrogel dissolves / completely biodegrades within 2 to 4 months or within 3 to 5 months; and

[0506] Step 2: Inserting a sustained-release biodegradable intracameral implant of step 1 into the anterior segment of the eye so as to place it within the iridocorneal angle of the eye.

[0507] In another specific aspect, the present invention is directed to a method of treating intraocular pressure in a human subject suffering from ocular hypertension or glaucoma, such as open-angle glaucoma, by treating each eye in need of such treatment with a single sustained-release biodegradable intracameral implant of a prostaglandin antagonist (e.g., travoprost) for a period of about 3 months to about 6 months or about 3 months to about 4 months, the method comprising inserting one sustained-release biodegradable intracameral implant into the anterior segment of the eye of the eye so as to place it within the iridocorneal angle of the eye, wherein the insert is as defined above, containing 11 to 20 μg of the prostaglandin antagonist (e.g., travoprost), wherein the implant is in the form of a fiber having a length of about 1.0 mm to about 2.5 mm and a diameter of no more than 0.3 mm in its dry state, the implant comprising a biodegradable hydrogel as defined above, and particles of a prostaglandin antagonist (e.g., travoprost) as defined above dispersed therein, wherein based on the pH value when at sedimentation conditions, the prostaglandin antagonist (e.g., travoprost) particles are present in the anterior segment of the eye. The intracameral implant has a mean prostaglandin antagonist (e.g. travoprost) release in the range of about 65% to about 85% and a mean absolute deviation of at most 5%, or an in vitro release of the prostaglandin antagonist (e.g. travoprost) in the range of 65% to 85%, and the hydrogel dissolves / completely biodegrades within 2 to 4 months or within 3 to 5 months.

[0508] In another specific aspect, the present invention is directed to a method of treating intraocular pressure in a human subject suffering from ocular hypertension or glaucoma, such as open-angle glaucoma, by treating each eye in need of such treatment with a single prostaglandin antagonist (e.g., travoprost) sustained-release biodegradable intracameral implant for a period of about 3 months to about 6 months or about 3 months to about 4 months, the method comprising treating each eye:

[0509] Step 1: providing a prostaglandin antagonist (e.g. travoprost) sustained-release biodegradable intracameral implant as defined above, the implant containing 2 to 10 μg of the prostaglandin antagonist (e.g. travoprost), wherein the implant is in the form of a fiber having a length of about 1.0 mm to about 2.5 mm and a diameter of not more than 0.3 mm in its dry state, the implant comprising a biodegradable hydrogel as defined above, and prostaglandin antagonist (e.g. travoprost) particles as defined above dispersed therein, wherein based on the pH value when the prostaglandin antagonist (e.g. travoprost) is released under sedimentation conditions, 7.2 to 7.4% released every 70 days from day 1 to day 98 when measured in PBS at 37°C, the intracameral implant has a mean prostaglandin antagonist (e.g., travoprost) release in the range of about 60% to about 80% and a mean absolute deviation of at most 5%, or an in vitro release of a prostaglandin antagonist (e.g., travoprost) release in the range of 60% to 80%, and the hydrogel dissolves within 2 to 4 months; and

[0510] Step 2: Inserting a sustained-release biodegradable intracameral implant of step 1 into the anterior segment of the eye so as to place it within the iridocorneal angle of the eye.

[0511] In another specific aspect, the present invention is directed to a method for treating intraocular pressure in a human subject suffering from ocular hypertension or glaucoma, such as open-angle glaucoma, by treating each eye in need of such treatment with a single sustained-release biodegradable intracameral implant of a prostaglandin antagonist (e.g., travoprost) for a period of about 3 months to about 6 months or about 3 months to about 4 months, the method comprising inserting one sustained-release biodegradable intracameral implant into the anterior segment of the eye of each eye so as to place it within the iridocorneal angle of the eye, wherein the implant is as defined above, containing 2 to 10 μg of the prostaglandin antagonist (e.g., travoprost), wherein the implant is in the form of a fiber having a length of about 1.0 mm to about 2.5 mm and a diameter of not more than 0.3 mm in its dry state, the implant comprising a biodegradable hydrogel as defined above, and particles of a prostaglandin antagonist (e.g., travoprost) as defined above dispersed therein, wherein the prostaglandin antagonist (e.g., travoprost) particles as defined above are dispersed therein, wherein the prostaglandin antagonist (e.g., travoprost) particles are dispersed therein, wherein the prostaglandin antagonist (e.g., travoprost) particles are dispersed therein, wherein the prostaglandin antagonist (e.g., travoprost) particles are dispersed therein, and ... The intracameral implant has a mean prostaglandin antagonist (e.g., travoprost) release in the range of about 60% to about 80% and a mean absolute deviation of at most 5%, or an in vitro release of the prostaglandin antagonist (e.g., travoprost) in the range of 60% to 80%, and the hydrogel dissolves within 2 to 4 months.

[0512] Implants of the present invention can be provided by the physician performing the surgery. In certain embodiments, the implant will be in a device such as a syringe packaged in a sterile package, and the medical professional will unwrap the implant before surgery and provide the implant for the implantation / insertion method described herein.

[0513] The disclosed implants can be used to reduce intraocular pressure. Thus, provided herein are methods of reducing intraocular pressure in a subject in need thereof, the methods comprising administering a hydrogel implant as described herein. Also disclosed are uses of the disclosed implants for reducing intraocular pressure in a subject. Also provided are uses of the disclosed implants in the manufacture of a medicament for reducing intraocular pressure.

[0514] Also provided is a method of treating ocular hypertension in a subject in need thereof, the method comprising administering the hydrogel implant described herein. Also disclosed is the use of the disclosed implant to treat ocular hypertension in a subject. Further provided is the use of the disclosed implant in the manufacture of a medicament for treating ocular hypertension.

[0515] Also provided are methods of treating glaucoma (open-angle glaucoma) in a subject in need thereof, the methods comprising administering the hydrogel implant described herein. Also disclosed are uses of the disclosed implants for treating glaucoma (open-angle glaucoma) in a subject. Further provided are uses of the disclosed implants in the manufacture of a medicament for treating glaucoma (open-angle glaucoma).

[0516] As part of another embodiment, travoprost is delivered to the eye in a sustained manner for a period of time in the range of about 1 month to about 1 year, wherein the remaining characteristics of the implant are as described herein. Alternatively, as part of other embodiments, travoprost is delivered to the eye in a sustained manner for a period of time in the range of about 1 month to about 11 months, wherein the remaining characteristics of the implant are as described herein. In another alternative, as part of this embodiment, travoprost is delivered to the eye in a sustained manner for a period of time in the range of about 1 month to about 10 months, wherein the remaining characteristics of the implant are as described herein. In another alternative, as part of this embodiment, travoprost is delivered to the eye in a sustained manner for a period of time in the range of about 1 month to about 9 months, wherein the remaining characteristics of the implant are as described herein. In another alternative, as part of this embodiment, travoprost is delivered to the eye in a sustained manner for a period of time in the range of about 1 month to about 8 months, wherein the remaining characteristics of the implant are as described herein. In another alternative, as part of this embodiment, travoprost is delivered to the eye in a sustained manner for a period of time in the range of about 2 months to about 8 months, wherein the remaining characteristics of the implant are as described herein. In another alternative, as part of this embodiment, travoprost is delivered to the eye in a sustained manner for a period of time in the range of about 3 months to about 7 months, wherein the remaining characteristics of the implant are as described herein. In another alternative, as part of this embodiment, travoprost is delivered to the eye in a sustained manner for a period of time in the range of about 4 months to about 6 months, wherein the remaining characteristics of the implant are as described herein. In another alternative, as part of this embodiment, travoprost is delivered to the eye in a sustained manner for a period of time in the range of about 1 month, wherein the remaining characteristics of the implant are as described herein. In another alternative, as part of this embodiment, travoprost is delivered to the eye in a sustained manner for a period of time in the range of about 2 months, wherein the remaining characteristics of the implant are as described herein. In another alternative, as part of this embodiment, travoprost is delivered to the eye in a sustained manner for a period of about 3 months, wherein the remaining characteristics of the implant are as described herein. In another alternative, as part of this embodiment, travoprost is delivered to the eye in a sustained manner for a period of about 4 months, wherein the remaining characteristics of the implant are as described herein. In another alternative, as part of this embodiment, travoprost is delivered to the eye in a sustained manner for a period of about 5 months, wherein the remaining characteristics of the implant are as described herein. In another alternative, as part of this embodiment, travoprost is delivered to the eye in a sustained manner for a period of about 6 months, wherein the remaining characteristics of the implant are as described herein.

[0517] As part of another embodiment, the sustained release of travoprost is effected in an aqueous humor, wherein the remainder of the features of the implant are as described herein.

[0518] As part of another embodiment, the polymer network of the disclosed hydrogel implant is conjugated to fluorescein, wherein the remaining features of the implant are as described herein.

[0519] As part of another embodiment, the disclosed implant is designed for implantation adjacent to corneal endothelial cells, wherein the remaining features of the implant are as described herein.

[0520] As part of another embodiment, the disclosed implant is designed for implantation in the inferior iridocorneal angle, wherein the remaining features of the implant are as described herein.

[0521] As part of another embodiment, the disclosed implant comprises 5pg, 15pg or 26pg of travoprost, wherein the remaining features of the implant are as described herein as in the first to fifteenth embodiments. Alternatively, as part, the disclosed implant comprises 5pg, 15pg or 26pg of travoprost; and comprises a polymer network formed by reacting a plurality of polyethylene glycol (PEG) units comprising a group susceptible to nucleophilic attack with one or more PEG or trilysine-based amine groups selected from 4a20K PEG NH2, 8a20K PEG NH2 and trilysine, wherein the remaining features of the hydrogel are as described herein.

[0522] As part of another embodiment, the disclosed implant completely degrades after complete release of travoprost, wherein the remaining characteristics of the implant are as described herein. Alternatively, the hydrogel implant completely degrades after about 12 months, about 11 months, about 10 months, about 9 months, about 8 months, about 6 months, about 5 months, about 4 months, about 3 months, about 2 months, about 1 month (i.e., about 30 days) after complete release of travoprost, wherein the remaining characteristics of the implant are as described herein. Alternatively, the hydrogel implant completely degrades after at least 90% (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) of travoprost is released, wherein the remaining characteristics of the implant are as described herein.

[0523] In one aspect, the invention is directed to the methods disclosed herein, wherein intraocular pressure is reduced from baseline intraocular pressure by about 5 to about 7 mmHg, or about 7 to about 9 mmHg, during a treatment period of, e.g., about 2 months to about 12 months, or about 3 months to about 9 months, e.g., about 6 months, or during sustained treatment with repeated administrations.

[0524] Methods of treating eye disease in human subjects

[0525] In one aspect, the invention is directed to a method of treating an ocular disease in a human subject, wherein each eye in need of such treatment is treated with a single sustained-release biodegradable intracameral implant containing an API for a period of time ranging from about 1 month to about 24 months, or from about 2 months to about 12 months, or from about 3 months to about 9 months, the method comprising treating each eye:

[0526] Step 1: Providing a sustained release biodegradable intracameral implant containing an API, providing treatment for a period of time ranging from about 1 month to about 24 months, or from about 2 months to about 12 months, or from about 3 months to about 9 months, the implant comprising:

[0527] - the biodegradable hydrogel and API particles as defined above,

[0528] - the API particles are dispersed within the hydrogel; and

[0529] Step 2: Inserting a sustained-release biodegradable intracameral implant of step 1 into the anterior segment of the eye so as to place it within the iridocorneal angle of the eye.

[0530] In one aspect, the present invention is directed to a method of treating an ocular disease in a human subject, wherein each eye in need of such treatment is treated with a single sustained-release biodegradable intracameral implant containing an API for a period of time ranging from about 1 month to about 24 months, or from about 2 months to about 12 months, or from about 3 months to about 9 months, the method comprising inserting a sustained-release biodegradable intracameral implant into the anterior segment of the eye of each eye so as to place it within the iridocorneal angle of the eye, wherein the implant is a sustained-release biodegradable intracameral implant containing an API providing treatment for a period of time ranging from about 1 month to about 24 months, or from about 2 months to about 12 months, or from about 3 months to about 9 months, the implant comprising:

[0531] - the biodegradable hydrogel and API particles as defined above,

[0532] - The API particles are dispersed in the hydrogel.

[0533] In another aspect, the invention is directed to a method of treating an ocular disease in a human subject in need of treatment with a single implant containing an API for a period of 3 to 9 months.

[0534] In another aspect, the invention is directed to an implant for use in a method of treating an ocular disease in a human subject in need of treatment for a period of 3 months to 9 months with a single implant containing an API.

[0535] In one embodiment, the one API is a prostaglandin antagonist. Specifically, the single API is selected from the group consisting of travoprost, bimatoprost and latanoprost.

[0536] Therapeutic agents also include, for example, agents for treating disorders caused by inflammation or abnormal blood vessel disorders, retinal vein occlusion, geographic atrophy, retinitis pigmentosa, retinoblastoma, etc. For cancer, the agent may be, for example, an anticancer drug, anti-VEGF, or a drug known for cancer treatment.

[0537] The therapeutic agent can be, for example, an anti-VEGF, a drug that blocks VEGFR1, blocks VEGFR2, blocks VEGFR3, an anti-PDGF, an anti-angiogenic drug; Sunitinib, E7080, Takeda-6d, Tivozanib, Regorafenib, Sorafenib, Pazopanib, Axitinib, Nintedanib, Cediranib, Vatalanib, Motesanib, macrolides, sirolimus, everolimus, tyrosine kinase inhibitors (T KI), imatinib (GLEEVAC), gefinitib (IRESSA), toceranib (PALLADIA), erlotinib (TARCEVA), lapatinib (TYKERB), nilotinib, bosutinib, neratinib, lapatinib, vatalanib, dasatinib, erlotinib, gefitinib, imatinib, lapatinib, lestaurine, nilotinib, semaxanib, toceranib, vandetanib.

[0538] The therapeutic agent may comprise a macromolecule, such as an antibody or antibody fragment. The therapeutic macromolecule may comprise a VEGF inhibitor, such as ranibizumab, marketed as Lucentis TMThe active ingredient in VEGF. When released into the vitreous humor of the eye, VEGF (vascular endothelial growth factor) inhibitors cause regression of abnormal blood vessels and improvement in vision. Examples of VEGF inhibitors include Lucentis TM (ranibizumab), Eylea TM (VEGF trap), Avastin TM (bevacizumab), Macugen TM (pegaptanib). Platelet-derived growth factor (PDGF) inhibitors can also be delivered, such as the anti-PGDF aptamer Fovista TM .

[0539] The therapeutic agent may comprise a small molecule, such as a steroid or corticosteroid and its analogs. For example, a therapeutic corticosteroid may comprise one or more of tramacinone, tramacinone acetonide, dexamethasone, dexamethasone acetate, fluocinolone, fluocinolone acetate, loteprednol etabonate or its analogs. Alternatively or in combination, the small molecule of the therapeutic agent may comprise a tyrosine kinase inhibitor.

[0540] The therapeutic agent may comprise an anti-VEGF therapeutic agent. Anti-VEGF therapies and agents can be used to treat certain cancers and age-related macular degeneration. Examples of anti-VEGF therapeutic agents suitable for use in the embodiments described herein include one or more of the following: monoclonal antibodies, such as bevacizumab (Avastin TM ) or antibody derivatives, such as ranibizumab (Lucentis TM ), or small molecules that inhibit VEGF-stimulated tyrosine kinases, such as lapatinib (Tykerb TM ), Sunitinib TM Sorafenib (Nexavar TM ), axitinib, or pazopanib.

[0541] The therapeutic agent may include a therapeutic agent suitable for treating dry AMD, such as Sirolimus TM (Rapamycin), Copaxone TM (Glatiramer Acetate), Othera TM One or more of complement C5aR blocker, ciliary neurotrophic factor, fenretinide or rheopheresis.

[0542] The therapeutic agent may include a therapeutic agent suitable for treating wet AMD, such as REDD14NP (Quark), Sirolimus TM (rapamycin), ATG003; EYELEA (VEGF trap) or one or more of a complement inhibitor (POT-4).

[0543] The therapeutic agent may comprise a kinase inhibitor, such as one or more of BIBW 2992 (a small molecule targeting EGFR / Erb2), imatinib (a small molecule), gefitinib (a small molecule), ranibizumab (a monoclonal antibody), pegaptanib (a small molecule), sorafenib (a small molecule), dasatinib (a small molecule), sunitinib (a small molecule), erlotinib (a small molecule), nilotinib (a small molecule), lapatinib (a small molecule), panitumumab (a monoclonal antibody), vandetanib (a small molecule), or E7080 (a small molecule targeting VEGFR2 / VEGFR2, commercially available from Esai). The therapeutic agent may comprise an antibody drug, such as bevacizumab, trastuzumab, cetuximab, and panitumumab.

[0544] Therapeutic agents may include various classes of drugs. Drugs include, for example, steroids, nonsteroidal anti-inflammatory drugs (NSAIDs), anticancer drugs, antibiotics, anti-inflammatory drugs (e.g., Diclofenac), analgesics (e.g., Bupivacaine), calcium channel blockers (e.g., Nifedipine), antibiotics (e.g., Ciprofloxacin), cell cycle inhibitors (e.g., Simvastatin), proteins (e.g., insulin). Therapeutic agents include the following classes of drugs, including, for example, steroids, NSAIDs, antioxidants, antibiotics, analgesics, vascular endothelial growth factor (VEGF) inhibitors, chemotherapeutic agents, antivirals. Examples of NSAIDs are ibuprofen, meclofenamate sodium, mefanamic acid, salicylates, sulindac, tolmetin sodium, ketoprofen, diflunisal, piroxicam, naproxen, etodolac, flurbiprofen, fenoprofen calcium, indomethacin, celoxib, ketrolac and nepafenac. The drug itself can be a small molecule, protein, RNA fragment, protein, glycosaminoglycan, carbohydrate, nucleic acid, inorganic and organic biologically active compounds, where specific biologically active agents include but are not limited to: enzymes, antibiotics, anti-tumor agents, local anesthetics, hormones, angiogenic agents, anti-angiogenic agents, growth factors, antibodies, neurotransmitters, psychoactive drugs, anti-cancer drugs, chemotherapeutic drugs, drugs that affect reproductive organs, genes and oligonucleotides or other configurations.

[0545] Therapeutic agents may include proteins or other water-soluble biological agents. These include peptides of various molecular weights. Peptides include therapeutic proteins and peptides, antibodies, antibody fragments, short chain variable fragments (scFv), growth factors, angiogenic factors and insulin. Other water-soluble biological agents are carbohydrates, polysaccharides, nucleic acids, antisense nucleic acids, RNA, DNA, small interfering RNA (siRNA) and aptamers.

[0546] The therapeutic agent can be used as part of a method of treating the indicated condition or making a composition for treating the indicated condition. For example, AZOPT (brinzolamide ophthalmic suspension) can be used to treat elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma. BETADINE in povidone-iodine ophthalmic solution can be used to prepare the periocular area and irrigate the ocular surface. BETOPTIC (betaxolol HCl) can be used to reduce intraocular pressure, or for chronic open-angle glaucoma and / or ocular hypertension. CILOXAN (ciprofloxacin hydrochloride ophthalmic solution) can be used to treat infections caused by susceptible microbial strains. NATACYN (Natamycin ophthalmic suspension) can be used to treat fungal blepharitis, conjunctivitis, and keratitis. NEVANAC (Nepanfenac ophthalmic suspension) can be used to treat pain and inflammation associated with cataract surgery. TRAVATAN (travoprost ophthalmic solution) may be used to reduce elevated intraocular pressure in open-angle glaucoma or ocular hypertension. FML FORTE (Fluorometholone ophthalmic suspension) may be used to treat corticosteroid-responsive inflammation of the bulbar conjunctiva, cornea, and anterior segment of the globe. LUMIGAN (bimatoprost ophthalmic solution) may be used to treat elevated intraocular pressure in open-angle glaucoma or ocular hypertension. PRED FORTE (Prednisolone acetate) may be used to treat corticosteroid-responsive inflammation of the bulbar conjunctiva, cornea, and anterior segment of the globe. PROPINE (Dipivefrin hydrochloride) may be used to control intraocular pressure in chronic open-angle glaucoma. RESTASIS (Cyclosporine ophthalmic emulsion) may be used to increase tear production in patients, such as those with ocular inflammation associated with keratoconjunctivitis sicca. ALREX (loteprednol etabonate ophthalmic suspension) may be used to temporarily relieve seasonal allergic conjunctivitis. LOTEMAX (loteprednol etabonate ophthalmic suspension) may be used to treat corticosteroid-responsive inflammation of the bulbar conjunctiva, cornea, and anterior segment of the globe. MACUGEN (pegaptanib sodium injection) may be used to treat neovascular (wet) age-related macular degeneration. OPTIVAR (azelastine hydrochloride) may be used to treat eye itching associated with allergic conjunctivitis. XALATAN (latanoprost ophthalmic solution) may be used to reduce elevated intraocular pressure in patients with, for example, open-angle glaucoma or ocular hypertension. BETIMOL (timolol ophthalmic solution) may be used to treat elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma.Latanoprost is a prodrug in the form of a free acid that is a prostanoid selective FP receptor agonist. Latanoprost reduces intraocular pressure in glaucoma patients with few side effects. Latanoprost has a relatively low solubility in aqueous solution but is readily soluble in organic solvents that are commonly used to make microspheres using solvent evaporation.

[0547] Other embodiments of therapeutic agents for delivery include therapeutic agents that specifically bind to the target peptide in vivo to prevent the target peptide from interacting with its natural receptor or other ligand. AVASTIN is, for example, an antibody that binds VEGF. It is also known to use an IL-1 trap of the extracellular domain of the IL-1 receptor; the trap can block IL-1 from binding to and activating receptors on the surface of stimulating cells. Embodiments of agents for delivery include nucleic acids, such as aptamers. Pegaptanib (MACUGEN), for example, is a pegylated anti-VEGF aptamer. The advantage of the particle and hydrogel delivery process is that the aptamer is protected from the in vivo environment until it is released. Other embodiments of agents for delivery include macromolecular drugs, which term refers to drugs that are significantly larger than classical small molecule drugs, i.e., drugs such as oligonucleotides (aptamers, antisense, RNAi), ribozymes, gene therapy nucleic acids, recombinant peptides and antibodies.

[0548] One embodiment comprises the extended release of the drug for allergic conjunctivitis. For example, ketotifen (ketotifen) (a kind of antihistamine and mast cell stabilizer) can be provided in the form of particles as described herein and released into the eye in an amount effective for treating allergic conjunctivitis. Seasonal allergic conjunctivitis (SAC) and perennial allergic conjunctivitis (PAC) are allergic conjunctivitis. Symptoms include itching and pink to slightly red eyes. These two eye diseases are mediated by mast cells. Conventional non-specific measures to improve symptoms include: cold compresses, washing eyes with tear substitutes and avoiding allergens. Treatment is usually composed of antihistamine mast cell stabilizers, dual mechanism antiallergic agents or topical antihistamines. Corticosteroids may be effective, but due to side effects, they are reserved for more severe forms of allergic conjunctivitis, such as vernal keratoconjunctivitis (VKC) and atopic keratoconjunctivitis (AKC).

[0549] Moxifloxacin is the active ingredient of VIGAMOX, which is a fluoroquinolone approved for the treatment or prevention of bacterial infections of the eye. VKC and AKC are chronic allergic diseases in which eosinophils, conjunctival fibroblasts, epithelial cells, mast cells and / or TH2 lymphocytes aggravate the biochemistry and histology of the conjunctiva. VKC and AKC can be treated with drugs for allergic conjunctivitis. Penetrants are reagents and may also be included in gels, hydrogels, organogels, xerogels and biomaterials as described herein. These are agents that help drugs penetrate into the desired tissue. Penetrants may be selected according to the needs of the tissue, such as penetrants for skin, penetrants for tympanic membranes, penetrants for eyes.

[0550] The agent can treat a posterior ocular disease, for example, wherein the posterior ocular disease is age-related macular degeneration (AMD), cystoid macular edema (CME), diabetic macular edema (DME), posterior uveitis and diabetic retinopathy, or glaucoma.

[0551] The agent may be, for example, an agent comprising anti-VEGF, blocking VEGFR1, blocking VEGFR2, blocking VEGFR3, anti-PDGF, anti-PDGF-R, blocking PDGFRβ; anti-angiogenic agent, sunitinib, E7080, Takeda-6d, tivozanib, regorafenib, sorafenib, pazopanib, axitinib, nindanib, cediranib, vatalanib, motesanib, macrolide, sirolimus, everolimus, tyrosine Acid kinase inhibitors (TKI), imatinib gefitinib, toranib, erlotinib, lapatinib, nilotinib, bosutinib neratinib, lapatinib, vatalanib, including low solubility prostaglandin analogs for glaucoma; nepafenac, macrolide, rapamycin, sirolimus, tacrolimus or for blocking mTOR receptors, for AMD (also known as choroidal neovascularization (CNV). mTOR refers to mammalian rapamycin target). The agent can be, for example, moxifloxacin, dexamethasone, travoprost, steroids, fluoroquinolones, prostaglandin analogs, prostaglandins.

[0552] Ocular diseases include ocular pathologies, among which hyphema, ocular hypertension and glaucoma are conditions treated with anterior chamber drug reservoirs. Many agents are suitable for ocular delivery, such as NSAIDs, steroids, anti-glaucoma drugs, antivirals, antibiotics, mydriatics and antifungals administered via intracameral injection.

[0553] Some disease conditions are diseases behind the eye. The term diseases behind the eye is recognized by technicians in these struggling fields, and generally refers to any eye disease of the rear segment, which affects the vasculature and integrity of the retina, macula or choroid, thereby causing visual impairment, loss of vision or blindness. The disease conditions of the rear segment may be caused by age, trauma, surgical intervention and genetic factors. Some diseases behind the eye are: age-related macular degeneration (AMD) cystoid macular edema (CME), diabetic macular edema (DME), posterior uveitis and diabetic retinopathy. Some diseases behind the eye are caused by undesirable angiogenesis or vascular proliferation, such as macular degeneration or diabetic retinopathy. Drug treatment options for these and other eye diseases can be provided by delivering agents from implants.

[0554] Example

[0555] The following examples are included to illustrate certain aspects and embodiments of the present invention as described in the claims. However, it should be understood by those skilled in the art that the following description is merely illustrative and should not be construed as limiting the present invention in any way.

[0556] Example 1: Manufacture of travoprost implant

[0557] Travoprost implants or "OTX-TIC travoprost implants" for use in the clinical Phase 1 study described in Example 3 were prepared, said implants having the chemical compositions and weights of Formulations 1a, 1b, 2 and 3 (see Tables 1 and 2a), respectively. For the types of components used to make Formulations 1a, 1b, 2 or 3, respectively, as well as the masses and contents of the components, reference is generally made to Table 1, which shows the chemical compositions and contents. In the description of the respective manufacturing methods of Formulations 1a, 1b, 2 and 3 below, said masses and contents of Table 1 will not be repeated in detail or converted to initial masses.

[0558] Table 1: Chemical composition and weight of OTX-TIC (travoprost) implants based on formulations 1a, 1b, 2 and 3

[0559]

[0560]

[0561] Preparation of biodegradable travoprost particles

[0562] To prepare a travoprost implant according to any of formulations 1a, 1b, 2 or 3, travoprost particles in which travoprost was mixed with polylactide (PLA) were first prepared by an oil-in-water emulsion solvent evaporation / extraction technique. Polylactide and travoprost were dissolved in dichloromethane (DCM) to prepare a single-phase solution referred to as the dispersed phase (DP) in the process (see Table 2a). The polymers of different molecular weights were referred to as 4A, 7A, 9A and 5.5E PLA, where the numerical values ​​represent the target intrinsic viscosity (IV) of the polymer in chloroform, which is related to the PLA molecular weight, and the letter suffix represents the acid (A) or ester (E) end group. The intrinsic viscosity specification of 4A PLA is 0.35 to 0.45 dl / g when measured in 0.5% w / v chloroform at 30°C; the intrinsic viscosity specification of 7APLA is 0.60 to 0.80 dl / g or less, and the intrinsic viscosity specification of 9A PLA is 0.80 to 1.0 dl / g. The details of measuring the intrinsic viscosity of polylactide are set forth in Table 2b below. The intrinsic viscosity specification of 5.5E PLA is 0.55 to 0.75 dl / g when measured in 0.1% w / v chloroform at 25°C. DP is injected into a flowing stream of an aqueous solution of about 1% (w / w) polyvinyl alcohol (PVA), referred to as the continuous phase (CP), via a syringe pump, in which the PVA acts as an emulsifier. The injection is performed just before passing through the inline homogenizer to disperse the DP into the primary microparticles. Adding the dispersed phase to the continuous aqueous phase at this introduction stage allows time for the droplets to disperse and then harden to produce a primary emulsion. These nascent microparticles in the CP stream then flow into a stirred CP (quench medium) in a jacketed reactor maintained at a controlled temperature. The emulsion is stirred in the quench medium overnight to extract and evaporate the DCM and harden the microparticles. The resulting microparticles are washed and sieved to an appropriate size using a vibrating screen agitator. The microparticles (4A PLA, 7A PLA, 9A PLA or 5.5E PLA loaded with travoprost) are then collected in glass vials and freeze-dried to produce dry microparticles for the manufacture of OTX-TIC (travoprost) implants. The diameter of the travoprost loaded microparticles ranged from 20 to 53 μm as measured by sieving. The average microparticle diameter measured by laser diffraction was 35 μm.

[0563] Table 2a: Dispersed phase composition used to make travoprost loaded microparticles for different formulations, different mass ratios used to produce microparticles for formulations 1a, 1b, 2 and 3, and the average drug loading of the microparticles actually measured

[0564]

[0565]

[0566] Table 2b: Experimental parameters used to measure the intrinsic viscosity of polylactide

[0567]

[0568] Preparation of travoprost implants

[0569] General Procedures

[0570] The freeze-dried microparticles (4A, 7A, 9A and 5.5E, depending on the formulation set forth in Table 1) were blended and weighed in a syringe at a predetermined ratio (see Table 2a above) and suspended in water for injection (WFI). A blend of 4A (20%), 7A (20%), 9A (10%) and 5.5E (50%) PLA microparticles for 15 μg and 26 μg formulation 1a, 1b OTX-TIC implants, a blend of 4A (25%), 7A (40%), 9A (35%) PLA microparticles for 15 μg formulation 2 OTX-TIC implants, and a blend of 4A (47%), 7A (53%) PLA microparticles for 5 μg formulation 3 OTX-TIC implants were prepared. The multi-arm PEG precursor solution was dissolved in sodium dihydrogen phosphate or WFI in a syringe, respectively. The trilysine acetate or trilysine acetate / NHS-fluorescein buffer solution was transferred to a syringe. All syringes were placed under vacuum. The microparticles and PEG precursor syringes were mixed first and then combined with TLA or TLA / FL buffer solution, which initiated the formation of the hydrogel. The resulting suspension was injected into a small inner diameter tubing. Table 3 highlights the differences between each formulation.

[0571] Table 3: Differences between each formulation used to prepare travoprost implants

[0572]

[0573] Preparation of trilysine acetate / NHS fluorescein (TLA / FL) solutions for 15 μg and 26 μg dose formulations 1a and 1b Fluid and syringe

[0574] The amount of trilysine acetate (TLA) was calculated based on a one to one molar ratio of amine to reactive PEG end groups (forming a PEG hydrogel network when mixed in a buffered aqueous solution).

[0575] Prepare TLA solution in sodium hydrogen phosphate buffer. Adjust the pH of the solution to 8.40 ± 0.05 by adding 1N NaOH to provide an optimal reaction environment for TLA and NHS-fluorescein (FL). After adjustment, add NHS-fluorescein to the TLA solution vial. Cap the vial and vortex to dissolve the NHS-fluorescein. Leave the TLA / FL solution in the foil-covered vial to react at room temperature for 1 to 24 hours.

[0576] At the end of the reaction time, the pH of the solution was measured and a predetermined volume of the TLA / FL solution was pipetted into four separate syringes. The syringes were placed upright in a beaker and transferred to a vacuum chamber to degas the solution.

[0577] Preparation of Trilysine Acetate (TLA) Solution and Syringe for 15 μg Dose Formulation 2 and 5 μg Dose Formulation 3

[0578] The amount of trilysine acetate (TLA) was calculated based on a one-to-one molar ratio of amine to reactive PEG end groups (forming a PEG hydrogel network when mixed in a buffered aqueous solution). TLA solutions were prepared in disodium hydrogen phosphate buffer. At the end of mixing, the pH of the solution was measured and a predetermined volume of TLA solution was pipetted into four separate syringes. The syringes were placed upright in a beaker and transferred to a vacuum chamber to degas the solution.

[0579] Preparation of microparticle syringe

[0580] For the 15 μg and 26 μg doses (Formulations 1a and 1b), each microparticle syringe contained a predetermined ratio of 4A PLA, 7A PLA, 9A PLA, and 5.5E PLA microparticles (see "General Procedure" above). For the 15 μg Formulation 2 dose, each microparticle syringe contained a predetermined ratio of 4A PLA, 7A PLA, and 9A PLA microparticles (see "General Procedure" above). For the 5 μg Formulation 3 dose, each microparticle syringe contained a predetermined ratio of 4A PLA and 7A PLA microparticles (see "General Procedure" above). After weighing the microparticles, WFI was added to each of the four syringes to suspend the microparticles. The syringes were placed upright in a beaker and transferred to a vacuum chamber to degas the suspension.

[0581] Preparation of PEG syringe

[0582] Weigh a predetermined amount of 8a15k PEG and transfer it to four different syringes. For the 15μg and 26μg doses (Formulations 1a and 1b), pipette sodium dihydrogen phosphate solution into each syringe to dissolve the 8a15k PEG-SAZ. For the 15μg Formulation 2 and 5μg Formulation 3, pipette WFI into each syringe to dissolve the 8a15k PEG-SG. Use the PEG solution within 60 minutes of preparation. Place the syringe upright in a beaker and transfer to a vacuum chamber to degas the solution.

[0583] pouring

[0584] For each operation, microparticle syringe and PEG syringe are connected by female to female Luer connector (female to female luer connector).Use slow uniform pressure to make the contents of each syringe pass backward (through 1 time) and forward (through 1 time), totaling 25-50 times, to mix the contents of syringe together.Suspension is pulled into a single syringe and then connected to TLA / FL (15μg and 26μg dosage preparations 1a and 1b) or TLA (15μg dosage preparations 2 and 5μg preparations 3 doses) syringe.When the contents of the syringe are first mixed, the calibrated stopwatch starts to measure the time of suspension gelation.Use slow uniform pressure to make the contents of each syringe pass backward (through 1 time) and forward (through 1 time), totaling 25-50 times, to produce PEG / microparticle / TLA / FL (15ug and 26μg dosage preparations 1) or PEG / microparticle / TLA (15μg dosage preparations 2 and 5μg dosage preparations 3 doses) suspension. The suspension was drawn into a syringe and primed to remove any excess air.

[0585] While the suspension is still in liquid form, connect the syringe to the tube and inject the suspension into the tube. Once the tube is filled, cap it at the bottom end, separate it from the syringe, and cap the pouring end. The remaining 11 tubes are filled in the same way until the gel solidifies.

[0586] Once all the channels of each syringe set are capped, place a small amount of the remaining suspension on a glass slide to monitor gel formation. Tap the suspension with a pipette tip until the suspension begins to tangle (i.e., remain attached to the pipette tip during a complete tapping cycle). Repeat this operation for each syringe set (four operations or four syringe sets in total).

[0587] dry

[0588] The tubing was placed on a drying jig that held the hydrogel bundle taut during drying. Each drying jig could hold up to six bundles at a time. The drying jig was placed horizontally in an incubator set to 33°C with nitrogen flow (10 L / min). The hydrogel bundles remained in the incubator for 48 to 72 hours to dry.

[0589] Cutting and implant inspection

[0590] The dried bundles are removed from the tube and any bundles damaged during the removal process are discarded. The bundles are fed into a cutter which cuts the bundles into implants approximately 2.0 mm long. During the cutting process, each syringe operation is collected in a sterile clear vial, labeled with the lot number, part number, and associated operation number, and marked "uninspected". If the vial of drug implant is not immediately inspected, it is sealed under a blanket of dry nitrogen in a glove box and refrigerated.

[0591] Table 1 shows the final chemical composition and weight of the travoprost implants of Formulations 1a, 1b, 2 and 3. Table 4 shows the physical properties of the travoprost implants of Formulations 1a, 1b, 2 and 3.

[0592] Table 4: Physical characteristics of Formulations 1a, 1b, 2 and 3, such as implant measurements and duration of treatment

[0593]

[0594] _____________________________________________

[0595] The in vitro release in physiological (pH 7.4) dissolution medium under sedimentation conditions at 37°C was approximately the following durations for each formulation:

[0596] a Released for 120 days

[0597] b Released for 90 days

[0598] c Released for 60 days

[0599] d Dry size means that the implant contains less than 1% water as measured using the Karl Fischer coulometric method.

[0600] e Size was measured in vitro in phosphate buffered saline (PBS), pH 7.4, at 37°C after hydration for 24 hours in 5 ml PBS.

[0601] Each individual OTX-TIC drug product was visually inspected by rotating the drug implant 360° and evaluating the cylindrical shape with no visual voids or foreign particles using a vision system or microscope. Implants that passed the visual inspection were dimensionally inspected to the specifications required for the dose and strength (see Table 5).

[0602] Table 5: OTX-TIC process control (IPC) in terms of size

[0603]

[0604] OTX-TIC implants that do not meet process visual, length, or diameter requirements are placed in separate vials clearly marked as “Failed Inspection.”

[0605] The visually and dimensionally inspected OTX-TIC implants were sealed and refrigerated in a glove box under a blanket of dry nitrogen.

[0606] OTX-TIC (travoprost) implant packaging

[0607] OTX-TIC implants that meet all process specifications are ready for packaging. Individual OTX-TIC implants are packaged in syringe (27G (5μg and 15μg dose formulations) or 26G (26μg dose) 1 / 2" ultra-thin wall sterile needle) assemblies and sealed in peelable foil-like LDPE laminated bags.

[0608] Example 2: Characterization

[0609] Example 2a: In vitro release measurements

[0610] In vitro release of travoprost from OTX-TIC was performed under simulated physiological sedimentation conditions using 10 OTX-TIC implants in 60 mL polypropylene bottles in a water bath in 50 mL 1x PBS, 0.5% castor oil, 0.01% sodium fluoride buffer, pH 7.2-7.4 at 37° C. Samples were taken at predetermined time points and analyzed using ultra-high performance liquid chromatography on a C18 reverse phase column with UV detection at 220 nm.

[0611] Figure 1a The results of in vitro travoprost release from OTX-TIC at 37°C are shown. The duration of travoprost release depends on the travoprost-loaded PLA microparticle blends listed in Table 3.

[0612] Table 6 below shows the in vitro release (expressed as a percentage) of implants consisting of formulations 1a, 1b, 2 and 3. Figure 1a Corresponding data points. Table 7 below shows the in vitro release values ​​(in nanograms) per 7 days.

[0613] Table 6: In vitro travoprost release data points measured by OTX-TIC for Formulations 1a, 1b, 2 and 3 respectively

[0614]

[0615]

[0616] a The percentage of travoprost release was calculated based on the maximum measured release.

[0617] b The slope is the increase in the amount of travoprost released every 14 days, and the slope is calculated by subtracting the amount released on day 1 from the amount released on day 14, and by subtracting the amount released on day 7 from the amount released on day 21, and so on.

[0618] c The slope is the increase in the amount of travoprost released every 70 days, and the slope is calculated by subtracting the amount released on day 1 from the amount released on day 70, and by subtracting the amount released on day 7 from the amount released on day 77, and so on.

[0619] Figure 1b Shown is the in vitro release of travoprost from formulations 1a, 1b, 2 and 3 measured under the same conditions as above, except that the release was measured at 40°C.

[0620] Table 7: Release per 7 days measured in the 37°C release experiment

[0621]

[0622] * Weekly travoprost release after day 1 burst (sampling time point x rounded release percentage between doses)

[0623] Example 2b: Implant integrity / softness

[0624] The integrity of the implant can be considered as a qualitative parameter of the softness of the implant relative to the anterior chamber tissue of the eye, especially the iridocorneal angle. The integrity of the implant was determined based on the criteria shown in the box below. Figure 1c The corresponding results for Formulations 1a, 1b, 2 and 3 of Cohorts 1 to 4 are shown.

[0625]

[0626] Example 2c: Water content of dry implants

[0627] This example describes a protocol for determining the water content of an intracameral implant of the present invention in a dry state.

[0628] 1.0 Purpose

[0629] The procedure used to determine the water content of travoprost intratubular inserts (OTX-TP) using Karl Fischer coulometry is described.

[0630] 2.0 Scope

[0631] This procedure is applicable to OTX-TP travoprost intratubular inserts where water content determination is required.

[0632] Note: This test method has been validated according to TP-1332 / TR-1297 for the determination of the optimal water content of the travoprost vial reservoir.

[0633] Plan / Report

[0634] 3.0 References

[0635] Document Number Title

[0636] SOP-10050Balances

[0637] SOP-10053 Gloveboxes

[0638] SOP-10080Metrohm Karl Fischer Coulometer with 874Oven SampleProcessor using Tiamo software.

[0639] TP-1332Method Validation for Optimized Water Content Determination ofTravoprost Intracanalicular Depots Protocol

[0640] TR-1297Method Validation for Optimized Water Content Determination ofTravoprost Intracanalicular Depots Report

[0641] 4.0 Reagents, Materials, and Equipment

[0642] Hydranal Water Standard - KF Oven 140-160℃

[0643] 4.1.1 Reference Standard. The exact water % is specified on the Statement of Analysis (CoA) for each batch.

[0644] Reagents

[0645] 4.2.1 Hydranal Coulomat AG oven anolyte

[0646] Material

[0647] 4.3.1 0.3nm molecular sieve (VWR P / N: EM-MX1583D-1 or equivalent)

[0648] 4.3.2 Magnetic stirring bar

[0649] 4.3.3 Crimper

[0650] 4.3.4 20 mm Karl Fischer vials with screw caps

[0651] equipment

[0652] 4.4.1 Analytical balance

[0653] 4.4.2 Portable glove box with adjustable nitrogen supply

[0654] 4.4.3 Flow meter, located in series between the regulated nitrogen supply and the glove box.

[0655] 4.4.4 Karl Fischer coulometric titrator equipped with oven sample processor (autosampler) and Dosino bottle dispenser.

[0656] 4.4.5 Karl Fischer Coulometric Titrator with Tiamo Software

[0657] 5.0 Device Setup

[0658] Set up the portable glove box per SOP-10053 Gloveboxes. Make sure the flow meter is vertical. Fully open the valve on the flow meter by turning the dial counterclockwise until a soft stop is reached. Open the valve on the regulated nitrogen supply and adjust the regulator if necessary to achieve a nitrogen flow of at least about 2-3 psi. This is "full flow" nitrogen. Purge the glove box at full flow for at least 30 minutes.

[0659] For instrument setup and analysis procedures, please refer to SOP-10080 Karl Fischer Coulometer with 874 Oven Sample Processor using Tiamo Software.

[0660] 6.0 Blank Preparation

[0661] Bench blank preparation – performed in triplicate (n=3) – system suitability

[0662] blank

[0663] 6.1.1 Allow the empty vials to equilibrate under bench conditions for at least 30 minutes.

[0664] 6.1.2 Crimping seal the empty bottle and then prepare the standard.

[0665] 6.1.3 Place the vial in the autosampler.

[0666] 6.1.4 Analyze the moisture content of the blank according to Section 9.0.

[0667] Glove box blank preparation – performed in triplicate (n=3) – sample blank

[0668] 6.2.1 Allow the empty bottle to equilibrate under full flow of nitrogen for at least 30 minutes.

[0669] 6.2.2 Crimp seal the empty bottle and then prepare the sample.

[0670] 6.2.3 Place the vial in the autosampler.

[0671] 6.2.4 Analyze the moisture content of the blank according to Section 9.0.

[0672] 7.0 Preparation of Standards

[0673] Water standard preparation – performed in triplicate (n=3)

[0674] 7.1.1 Allow the empty vials to equilibrate under bench conditions for at least 30 minutes.

[0675] 7.1.2 Balances according to SOP-10050 Weigh 50.0 ± 5.0 mg of Hydranal water standard using an analytical balance into a vial that has been equilibrated under bench conditions for at least 30 minutes.

[0676] 7.1.3 Record the exact weight and water content (from CoA) of the standard on the appropriate row in the Tiamo software.

[0677] 7.1.4 Crimp seal the vial and place it in the autosampler.

[0678] 7.1.5 Analyze moisture content standards according to Section 9.0.

[0679] Preparation of scaffold standards

[0680] 7.2.2 Allow the empty vials to equilibrate under bench conditions for at least 30 minutes.

[0681] 7.2.2 Weigh 50.0 ± 5.0 mg of Hydranal water standard using an analytical balance as per SOP-10050 into a vial that has been equilibrated under bench conditions for at least 30 minutes.

[0682] 7.2.3 Record the exact weight and water content (from CoA) of the standard on the appropriate row in the Tiamo software.

[0683] 7.2.4 Crimp seal the vial and place it in the autosampler.

[0684] 7.2.5 Analyze moisture content standards according to Section 9.0.

[0685] 8.0 Sample Preparation

[0686] OTX-TP tubule insert sample preparation – performed in triplicate (n=3)

[0687] 8.1.1 Allow the vials and caps to equilibrate for at least 30 minutes under full flow of nitrogen.

[0688] 8.1.3 Place the cap loosely on the vial and remove from the glove box.

[0689] 8.1.3 Obtain the weight of the empty vial and cap for each sample, ensuring that the vial and cap remain matched during sample preparation. Record the exact weight.

[0690] 8.1.4 Return the vial and cap to the glove box. Allow the glove box to re-equilibrate under full flow nitrogen for at least 5 minutes.

[0691] 8.1.5 Before preparing the sample, adjust the dial of the flow meter until 4 ± 1 L / min is achieved. This can be achieved by first turning the dial clockwise until the flow rate is below 4 L / min, then turning the dial counterclockwise back up to 4 L / min. Read the flow rate at the center of the float.

[0692] 8.1.6 For each sample, remove the cap and place 30 OTX-TP vial inserts in a vial.

[0693] 8.1.7 Press the sealing cap onto the vial.

[0694] 8.1.8 Remove the sealed vial from the glove box and obtain the weight of the vial using the insert. Record the exact weight.

[0695] 8.1.9 Calculate sample weight: Sample weight (mg) = weight of vial with insert (mg) – weight of empty vial (mg)

[0696] 8.1.10 Record the exact weight of the sample on the appropriate row in the Tiamo software.

[0697] 8.1.11 Place the sample in the autosampler.

[0698] 8.1.12 Analyze the water content of the samples according to Section 9.0.

[0699] 8.1.13 After preparation, the sample is allowed to stabilize at the ambient conditions of the instrument for four hours.

[0700] 9.0 Analytical Procedure

[0701] Program Reference

[0702] 9.1.1 For a typical Karl Fischer plot of a blank obtained using this procedure, see Figure 1d .

[0703] 9.1.2 For a typical Karl Fischer plot of a water standard obtained using this procedure, see Figure 1e .

[0704] 9.1.3 For a typical Karl Fischer plot of an OTX-TP sample obtained using this procedure, see Figure 1f .

[0705] 9.2 Ensure that the Karl Fischer titrator with oven sample handling system is set to the following parameters:

[0706] Flow rate 75mL / min Oven temperature 140℃ Stirring speed 10 Extraction time 120 seconds* Start drift 20 μg / min Stop drifting 10μg / min Minimum titration rate 15 μg / min

[0707] *Note: The KF Blank and System Suitability Blank methods used an extraction time of 60 seconds.

[0708] Universal variables

[0709] 9.3.1Two general variables are required in the Tiamo software to ensure that appropriate blank values ​​are applied to standard and sample injections. By preparing the blank under ambient conditions, the ambient moisture of standards prepared under ambient conditions can be corrected. By preparing the blank under glove box conditions, the glove box moisture of samples prepared in a glove box under nitrogen can be corrected.

[0710] 9.3.1.1 Universal Variable #1 - System Suitability Blank: This universal variable characterizes the average blank value of the three "System Suitability Blank" injections. This universal variable value is used to determine the water content value of the "System Suitability Standard" and "Standard Standard" injections.

[0711] 9.3.1.2 Universal Variable #2 – Sample Blank: This universal variable characterizes the average blank value of the three “Sample Blank” injections. This universal variable value is used to determine the water content value of the sample injection.

[0712] NOTE: See the following table for an overview of the common variables used:

[0713]

[0714] Karl Fischer analysis

[0715] 9.4.1 Place a previously filled blank vial in the autosampler in position 1 and another in the "Condition" position. These are used for system preparation (equilibration). If it is not possible to use a previously filled blank vial, use a freshly pressed empty vial. Use the "KF System Preparation" method in Tiamo to perform system preparation at the beginning of each operation.

[0716] Note: If it is a freshly compressed empty bottle

[0717] 9.4.2 Perform one injection on each system suitability blank vial (n=3) using the “System Suitability Blank” method in Tiamo.

[0718] 9.4.3 Perform one injection per water standard bottle (n=3) using the "KF Bench Standard" method in Tiamo.

[0719] 9.4.4 Perform one injection on each glove box sample blank vial (n=3) using the “Sample Blank” method in Tiamo.

[0720] 9.4.5 Perform one injection per glove box sample vial using the “KF Glove Box Sample” method in Tiamo.

[0721] 9.4.6 As a system check, inject the vial of the stent standard after every 15 samples and at the end of the analysis using the “KF Bench Standards” method in Tiamo.

[0722] 9.5 Example injection sequence:

[0723] Vial number Injection Name / Description Tiamo Method 1 System Preparation Bottle KF system preparation 2-4 System Suitability Blanks 1-3 System suitability gap 5-7 System suitability criteria 1-3 KF workbench standard 8-10 Sample Blank 1-3 Sample Blank 11-25 Samples 1-15 KF Glove Box Sample 26 Bracket Standard KF workbench standard

[0724] System suitability criteria

[0725] 9.6.1 Calculate the relative standard deviation (%RSD) of the water % for three consecutive injections of the water standard. The RSD of the water % must be less than or equal to 2.0%

[0726] 9.6.2 Tiamo software will calculate the percent recovery of the water content in the standard injection relative to the water content of CoA.

[0727] 9.6.2.1 The total average moisture content percent recovery listed for the third standard must be in the range of 95.0-105.0%.

[0728] 9.6.3, calculate the recovery of the % water of the scaffold standard relative to the total average % water of the three system suitability standards as follows:

[0729]

[0730] 9.6.3.1 The recovery percentage of the standard stent must be within the range of 95.0-105.0%

[0731] 10.0 Sample Calculation

[0732] Tiamo software will automatically calculate the water % for each sample.

[0733] 10.1.1 Each sample with a water % value less than (<) 1.0% shall be reported as “<1.0%”

[0734] 10.1.2 For each sample with a water % value greater than or equal to (≥) 1.0%, report the value to two decimal places. Calculate the average water % of the three samples.

[0735] 10.2.1 If the Water % for all 3 samples is less than 1.0%, report the average Water % result as "< 1.0%".

[0736] 10.2.2 If the Water % of any sample is greater than or equal to 1.0%, the values ​​≥ 1.0% are used to calculate the Average Water %. Any values ​​< 1.0% will not be included in the Average Water % calculation.

[0737] 10.2.2.1 Report the average water % to one decimal place.

[0738] Example 3: Phase 1 Clinical Study

[0739] A prospective, open-label, multicenter, phase 1 study was conducted to evaluate the safety, tolerability, and efficacy of the OTX-TIC (travoprost) intracameral implant in patients with primary open-angle glaucoma (OAG) or ocular hypertension (OHT).

[0740] Research objectives

[0741] The primary study objectives were to evaluate the safety, tolerability, and efficacy of a single-dose OTX-TIC (travoprost) intracameral implant in patients with primary OAG or OHT.

[0742] Study outcome measures

[0743] Safety outcome measures

[0744] The investigator graded the ease of the injection procedure. Safety outcome measures were assessed immediately (within 1 hour) after implant placement and continued throughout the study.

[0745] The safety assessment includes:

[0746] Adverse event reporting (evaluation of adverse events to determine if they are procedure related)

[0747] ·Evaluation of eye comfort of subjects

[0748] Investigator's overall tolerability score

[0749] BCVA

[0750] Slit lamp biomicroscopy

[0751] Gonioscopy

[0752] Fundus examination

[0753] Endothelial cell count using corneal endothelial microscopy

[0754] Corneal thickness measurement

[0755] Anterior segment (AS)-OCT

[0756] Automatic field of view

[0757] OCT Optic Nerve NFL

[0758] Posterior segment OCT

[0759] Efficacy outcome measures

[0760] Efficacy outcome measures were:

[0761] • Check IOP daily (8 AM, 10 AM, 4 PM) at Baseline, Day 14 (Visit 5), Day 42 (Visit 7), Day 85 (Visit 8), Month 4 (Visit 9), and Month 6 (Visit 11).

[0762] In addition, the intraocular pressure was checked at 8:00 AM on the day of injection, on days 3, 7, and 28, and at month 5 (visit 10).

[0763] Exploratory Measurement

[0764] To determine if there was enough space in the iridocorneal angle to safely inject the implant, the investigator determined the size of the iridocorneal angle using gonioscopy. Comparison of angle determination using AS-OCT read by a masked reading center served as an exploratory endpoint.

[0765] Study Design

[0766] This is an open-label, multicenter, Phase 1 clinical study that treated 19 subjects in one of four cohorts:

[0767] Cohort 1 (15 μg, Formulation 1a, as described in Example 1) consisted of 5 subjects, each receiving a single implant in one eye

[0768] • Cohort 2 (26 μg, Formulation 1b, as described in Example 1) consisted of 4 subjects, each subject receiving a single implant in one eye.

[0769] Cohort 3 (15 μg, Formulation 2, as described in Example 1) consisted of 5 subjects, each receiving a single implant in one eye

[0770] Cohort 4 (5 μg, Formulation 3, as described in Example 1) consisted of 5 subjects, each receiving a single implant in one eye

[0771] The subjects were intended to be followed for approximately 7 months (one month washout and 6 month follow-up after injection of the OTX-TIC implant). However, several were followed for longer periods.

[0772] If biological activity or implants were found at the 6-month visit, the subject was followed monthly until their IOP reached within 10% of the baseline measurement or until the investigator deemed the subject clinically stable.

[0773] Subject selection

[0774] Study Group

[0775] Subjects enrolled in this study had stable primary OAG or OHT in the study eye and were either receiving topical medication management or had not received treatment. If applicable, current IOP-lowering medications were stopped at the beginning of the screening visit (Visit 1). Eligible subjects completed a 4- to 6-week washout period before randomization on Day 1. Subjects were considered stable if the investigator did not recommend additional IOP-lowering treatments to the subject in the past 8 weeks prior to the screening visit, and based on the investigator's assessment, there was no sign of functionally significant central visual field loss or documented significant progressive visual field loss in either eye in the past year. After the washout period, eligible subjects must have a baseline IOP as described in the inclusion criteria below. If both eyes are eligible (i.e., both are included and neither meets the exclusion criteria), the eye with the highest baseline IOP after the washout period is the study eye. If both eyes are eligible after the washout period and the baseline IOP of both eyes is the same, the right eye is selected as the study eye.

[0776] Inclusion Criteria

[0777] Subjects of either sex who meet the following criteria are eligible to participate in the study:

[0778] 1. Must be 18 years of age or older at the time of screening

[0779] 2. Documented diagnosis of OHT or primary OAG in the study eye

[0780] 3. IOP is currently under control (assessed by investigator)

[0781] 4. In the study eye, after a 4 to 6 week washout period on current therapy (if necessary), have the following mean baseline IOP:

[0782] 5. T0 ≥ 24 mmHg and ≤ 36 mmHg at the second baseline visit (day 0) after the washout period, and

[0783] 6. (T0+2 hours) ≥22 mmHg

[0784] 7. Normal-appearing anterior chamber angle opening (determined by gonioscopy) in the study eye, sufficient to allow placement of the implant without contact with the corneal endothelium, i.e., angle approaching 20° or greater according to Shaffer-Etienne classification grade 3 (20°-35°, visible scleral protrusion) or grade 4 (35°-45°, visible ciliary body)

[0785] 8. Able to meet all research requirements

[0786] 9. Provide written informed consent

[0787] Exclusion criteria

[0788] Individuals who meet the following criteria are not eligible to participate in the study:

[0789] 1. The study eye has angle-closure glaucoma, narrow-angle glaucoma, pseudoexfoliation syndrome, pseudoexfoliation glaucoma, pigment dispersion or pigmentary glaucoma, glaucoma diagnosed before the age of 15, inflammatory, neovascular or other secondary glaucoma

[0790] 2. Previous history of anterior chamber implants in the study eye

[0791] 3. Unwilling to stop using contact lenses before corneal thickness measurement (3 days) and throughout the study

[0792] 4. Known or suspected allergy and / or anaphylaxis to prostaglandins (e.g., travoprost), fluorescein, or any component of the investigational product

[0793] 5. Any corneal or other ocular or adnexal abnormality that would prevent reliable applanation tonometry in either eye

[0794] 6. Central corneal thickness <480 μm or >620 μm in either eye (or difference between the two eyes >70 μm)

[0795] 7. According to the investigator's assessment, the cup-to-disc ratio in the study eye is >0.8 (measured horizontally or vertically)

[0796] 8. Based on the investigator's assessment, the study eye has functionally significant central visual field loss or documented significant progressive visual field loss in the past year

[0797] 9. Active eyelid or eye disease in either eye within the past 3 months (i.e., moderate or severe blepharitis, tarsus, dry eyes, eye infection (viral, fungal, or recurrent bacterial), scleritis, uveitis, or corneal edema)

[0798] 10. Endothelial cell count in the study eye is <1,800 cells / mm 2 and / or other endothelial abnormalities (based on corneal endothelial microscopy and confirmed by a central reading center)

[0799] 11. Endothelial cell count <1,800 cells / mm in non-study eyes 2 and / or other endothelial abnormalities (based on corneal endothelial microscopy and confirmed by a central reading center)

[0800] 12. History of significant ocular trauma in the study eye in the past six months

[0801] 13. History of peripheral iridotomy / iridectomy in the study eye at 180° below the iris

[0802] 14. Any history of bleeding using medications that, in the investigator's opinion, would place the subject at high risk during implant insertion

[0803] 15. Any ophthalmic surgical procedure (e.g., glaucoma laser, minimally invasive glaucoma surgery, refractive surgery) in the study eye within the past 6 months, or the need for ophthalmic surgery during the study. Subjects who were planned to be treated with the CyPass implant at the time of recruitment or during the study were excluded.

[0804] 16. The study eye has a history of penetrating keratoplasty

[0805] 17. Suffering from proliferative diabetic retinopathy or a history of macular edema in either eye

[0806] 18. Have an uncontrolled systemic or debilitating illness (e.g., cardiovascular disease, hypertension, uncontrolled diabetes, or cystic fibrosis)

[0807] 19. Participated in any research involving investigational drugs in the United States or outside the United States in the past 30 days

[0808] 20. An employee of a location directly involved in the management, administration or support of the research, or an immediate family member of the employee

[0809] 21. Pregnant, breastfeeding, or not using appropriate contraceptive methods during the study and of childbearing potential at the time of recruitment

[0810] Study Data Collection

[0811] Table 8 presents the study period and timeline of events

[0812] Table 8: Timing and event schedule of Phase 1 clinical study

[0813]

[0814]

[0815]

[0816]

[0817]

[0818]

[0819] a: For treatment-naive subjects, the Screening Visit (Visit 1) and Baseline Visit (Day 0) can be combined into one visit.

[0820] b: Medical and ophthalmological history.

[0821] c: Unplanned Visit: The investigator must determine which assessments are required based on the reason for the unplanned visit; not all assessments need to be performed

[0822] d: IOP measurements were performed at 8 AM (±1 hour), 10 AM (±1 hour), and 4 PM (±1 hour) at the baseline visit, day 14 (visit 5), day 42 (visit 7), day 85 (visit 8), months 4 (visit 9), and 6 (visit 11), month 9 (visit 14 if necessary), and at the final visit after month 9 (if necessary).

[0823] e: Fundus examination at Screening (Visit 1) and Month 6 Visit (11) requires expansion.

[0824] f: Complete only for subjects who still have evidence of biological activity or residual implant. These subjects will be followed up monthly until their IOP reaches within 10% of the baseline measurement or until the investigator deems the subject clinically stable. If retained microspheres are observed at Month 12, the subject should be followed up at the discretion of the investigator. For all visits after Month 9, the same assessment schedule as described for the Month 7 visit should be followed. The final study visit will occur after the Visit 11 assessment.

[0825] g: Assessments completed before and after implant placement at Day 1 visit Study Observations and Procedures

[0826] Subject screening and informed consent

[0827] Prior to enrollment in the study, subjects are evaluated to determine potential eligibility. Investigators and study staff determine the subject's willingness and ability to meet follow-up requirements. If a subject wishes to participate in the study, written informed consent is obtained before any study-specific examinations are performed. After completing the screening and baseline assessments, investigators and study staff determine whether the subject meets all eligibility criteria. If the subject meets the eligibility criteria and agrees to participate, the subject is enrolled.

[0828] When the subject signs the informed consent form, the subject is considered to have participated in the study. Once the subject meets the study qualifications and is randomized, he or she must be followed up regardless of whether the subject receives the study-assigned treatment.

[0829] If an OTX-TIC implant injection failed, the reason for the injection failure was recorded on the eCRF as injection failure rather than an AE; the subject was followed up as long as medically appropriate.

[0830] Screening failure

[0831] Subjects who have been recruited, i.e. have signed informed consent, but are determined to be ineligible during the screening assessment or at the baseline visit but before receiving OTX-TIC treatment, are considered screen failures, should be withdrawn from the study, and will not require additional study follow-up. The reason for screen failure will be recorded in the eCRF.

[0832] If a subject who did not meet the eligibility criteria experienced an AE during the screening or baseline visit, they were followed until the AE resolved or stabilized.

[0833] Subject withdrawal

[0834] All subjects treated in the study are required to adhere to the follow-up schedule as described in this protocol.

[0835] Subjects may withdraw from clinical studies at any time and for any reason without risk of harm or prejudice and without prejudice to the investigator’s clinical care. Investigators also have the right to withdraw subjects from the trial in the event of intercurrent illness, AEs, protocol violations, and / or administrative reasons.

[0836] For any subject who withdraws consent after treatment, the reason for withdrawal was recorded on the end-of-study eCRF whenever possible. Prior to withdrawal from the study, subjects were encouraged but not required to return for removal of the intracameral implant (if one had been placed).

[0837] If withdrawal from the study was due to an AE or death, the AE form was also completed. If a subject withdraws from the study due to an AE, the investigator will make every effort to follow up with the subject until the AE resolves or stabilizes.

[0838] Every effort was made to contact subjects who were noncompliant or lost to follow-up, and such attempts were documented in the subject's study record.

[0839] Subjects who withdrew from the study after receiving the OTX-TIC (travoprost) intracameral implant were not replaced.

[0840] Product Failure

[0841] All malfunctions of the OTX-TIC (travoprost) intracameral implant injector are documented on the appropriate eCRF and reported to Ocular Therapeutix within 24 hours. Ocular Therapeutix advises on how to return the intracameral implant for analysis. The incidence of malfunctions will be included in the final analysis.

[0842] Treatment Point

[0843] Once a subject was determined to be eligible for study participation and completed all screening assessments, including the washout period, the investigator confirmed eligibility prior to treatment.

[0844] This study treated 19 subjects (approximately 5 subjects per group) in one of four possible cohorts: 15 μg (Formulation 1a as described in Example 1), 26 μg (Formulation 1b as described in Example 1), 15 μg (Formulation 2 as described in Example 1), and 5 μg (Formulation 3 as described in Example 1).

[0845] As part of this study, subjects may only have 1 eye treated with OTX-TIC; this eye is referred to as study eye SE. If both eyes are eligible for the study, the SE is selected based on the eye with the highest IOP after the washout period as described in the protocol. If the IOP is the same in both eyes after the washout period, the right eye is selected as the SE.

[0846] The Data Safety Monitoring Committee (DSMC) reviewed the safety data from Cohort 1 before enrolling any subjects into Cohort 2.

[0847] Cohort 1 is fully enrolled, and all safety and tolerability data for OTX-TIC are assessed for each subject in Cohort 1 (minimum follow-up of two weeks) before any subject enters Cohort 2. Dose escalation to Cohort 2 is based on the recommendation of the DSMC and is at the discretion of the Medical Monitor (MM) or Sponsor.

[0848] Cohorts 3 and 4 were initiated in parallel because the dose in Cohort 4 was lower and the duration of the implant was shorter than the doses studied in Cohorts 1, 2, and 3.

[0849] If one dose-limiting toxicity (DLT) is identified in the Cohort 2 dose group, enrollment continues; however, if another DLT is identified, the previous dose (lower - Cohort 1) is declared the MTD. However, there is no MTD.

[0850] If necessary, the fellow eye, referred to as the non-study eye (NSE), was treated with Travatan Z (if not contraindicated). Treatment of NSE remained consistent during the study. All ocular assessments were performed in both eyes at each visit.

[0851] Concomitant medications

[0852] Any concurrent use of ophthalmic and systemic medications, prescription or over-the-counter, and the reason for taking medications within the 3 years prior to the screening visit, from the screening visit to the end of the study, were recorded in the subject's medical record and on the corresponding eCRF. Any herbal or vitamin supplements, other than antibiotics, NSAIDs, or steroids, and any use of mydriatic and other standard-of-care drops for ophthalmic evaluations, including IOP measurements and insertion procedures (i.e., betaine or local anesthetics) were not recorded.

[0853] The following restrictions apply in relation to medications and treatments:

[0854] · No topical or systemic antihypertensive medications other than study treatment may be used during the study. For subjects currently taking prostaglandin analogs for OAG / OHT, the medication washout period between the screening and baseline visit (Visit 2, Day 0) is approximately 4 to 6 weeks.

[0855] Note: Subjects’ current ocular hypertension medications may be replaced with medications that require a shorter washout period to minimize potential risk to the subject from elevated IOP during the washout period. (For example, a subject currently taking a prostaglandin that requires a 4-6 week washout period may be switched to a carbonic anhydrase inhibitor for 3 weeks, then allowed a washout period of one week for the carbonic anhydrase inhibitor, and then re-enrolled in the study at Visit 2 (Day 0).

[0856] The use of systemic beta-blockers was allowed, but any initiation or change in systemic therapy containing beta-blockers from 8 weeks before screening to the final study visit was excluded.

[0857] The use of short-term inhaled (using a mouthpiece), local injectable, nasal, and topical skin steroids is permitted and should be recorded in the eCRF if used.

[0858] Any medication or substance used chronically by any route that has not reached a stable dose within 8 weeks prior to screening.

[0859] • Non-diagnostic topical ophthalmic solutions (other than study treatment) should not be used from the baseline visit and throughout the study. Note: The use of artificial tears or ophthalmic lubricants should be avoided but may be used intermittently if necessary.

[0860] Contact lens use must not occur at any time during the study after the screening visit. In addition, contact lens wear must be stopped for at least 3 days before corneal thickness measurement.

[0861] Rescue therapy

[0862] If the investigator determines at any time point during the study that the IOP is not adequately controlled, IOP-lowering drops may be provided as rescue therapy at the investigator's discretion to ensure the subject's safety. Medications to lower the IOP will be recorded on the appropriate eCRF.

[0863] Research Assessment

[0864] Screening assessment: Up to 4 to 6 weeks prior to baseline visit

[0865] At the screening visit, the eligibility of the subject to participate in the study was determined by checking all the inclusion and exclusion criteria as detailed above, respectively. If the subject did not pass one of the inclusion or exclusion criteria, the subject failed the screening and was not further evaluated.

[0866] Details of the procedures for these assessments can be found below, and both eyes were assessed at each visit. The following assessments were performed according to the Reading Center Study Manual: AS-OCT, OCT Optic Nerve NFL, OCT Posterior Segment, Endothelial Cell Count.

[0867] The following procedures and assessments will be completed up to 4 to 6 weeks prior to Baseline Visit 2 (Day 0). Pupil dilation will be performed after the last IOP measurement of the day is completed.

[0868] Screening Visit (1st visit, up to 4 to 6 weeks)

[0869] Obtain written informed consent

[0870] Demographic information, including age, gender, race, ethnicity

[0871] Medical and ophthalmological history, including interventions

[0872] Inclusion and exclusion criteria

[0873] Prior and concomitant medications and procedures

[0874] Vital signs (blood pressure and heart rate)

[0875] BCVA

[0876] Slit lamp biomicroscopy (including external ocular examination)

[0877] Applanation (Goldmann) tonometry to measure IOP

[0878] Gonioscopy

[0879] · Fundus dilation examination

[0880] ·View

[0881] Corneal thickness measurement (contact lens wear must be stopped 3 days before corneal thickness measurement)

[0882] Posterior segment OCT

[0883] OCT Optic Nerve NFL

[0884] Endothelial cell count (microscopic examination of the corneal endothelium confirmed by a central reading center)

[0885] Urine pregnancy test: If the subject is a female of childbearing potential, the investigator shall determine that the subject must use a reliable contraceptive method during the study and have a negative urine pregnancy test.

[0886] At the end of screening, instruct 1 potentially eligible subject to begin a washout from current IOP-lowering medications

[0887] NOTE: For subjects with stable primary OAG or OHT who have not been taking IOP-lowering medications prior to enrollment, the Screening Visit and Baseline Visit may be combined into a single visit.

[0888] For screening failures due to anticipated temporary reasons, the Sponsor will be contacted and a rescreening visit may be scheduled. Rescreened subjects will be assigned a new subject number and will be required to repeat all screening procedures (including signing a new informed consent form).

[0889] For eligible subjects, all information must be recorded in the subject's eCRF. For subjects who do not meet the eligibility criteria, the minimum information to be recorded in the eCRF is as follows: screening date, subject number, and reason for screening failure.

[0890] Baseline Visit (Visit 2, Day 0, Day -4)

[0891] The following assessments were performed on both eyes. The IOP measurement performed on Day 0 was the baseline IOP measurement.

[0892] 8:00 AM (T0)

[0893] Confirmation of inclusion and exclusion criteria

[0894] Concomitant medications

[0895] Adverse event assessment

[0896] BCVA

[0897] Slit lamp biomicroscopy, including external ocular examination

[0898] IOP

[0899] Fundus examination

[0900] Anterior segment OCT

[0901] 10am (T0+2 hours) and 4pm (T0+8 hours)

[0902] Applanation (Goldmann) tonometry to measure IOP

[0903] NOTE: All IOP measurements must be performed within ± 60 minutes of the desired time and at approximately the same time at each visit. IOP was measured using a 2-person masked reading method.

[0904] Intracameral injection day, visit 3 (day 1)

[0905] Pre-procedural evaluation

[0906] The following procedures and assessments are performed prior to treatment:

[0907] Review concomitant medications and procedures

[0908] Adverse events (before injection)

[0909] Vital signs (heart rate and blood pressure)

[0910] · Subjects' eye comfort rating

[0911] Investigator's overall tolerability score

[0912] BCVA

[0913] Slit lamp biomicroscopy, including external ocular examination

[0914] IOP was measured by applanation (Goldmann) tonometry only at 8 a.m. IOP measurements had to be performed within ±60 minutes of the required time.

[0915] Treatment with OTX-TIC intracameral implant

[0916] After all assessments were completed, subjects were assigned study medication (OTX-TIC implant) by the Investigator and Study Staff according to the procedures recommended in the Study Manual. The Investigator recorded the ease of the injection procedure.

[0917] If both eyes are eligible (i.e., both are enrolled and neither meets the exclusion criteria), the study eye must be selected as described above. If necessary, the fellow eye, referred to as the non-study eye (NSE), will be treated with Travatan Z (if there are no contraindications). Treatment of the NSE must remain consistent during the study.

[0918] Approximately 1 hour after the injection and before discharge, the investigators and study staff were responsible for the following:

[0919] · Investigator confirmation of correct placement of the OTX-TIC (travoprost) intracameral implant.

[0920] Investigators documented the presence of anterior chamber implants using slit lamp photographs whenever possible

[0921] Adverse events (after injection)

[0922] ·Evaluation of eye comfort of subjects

[0923] Investigator's overall tolerability assessment

[0924] Discharge Instructions

[0925] Subjects were instructed not to rub their eyes and to contact the investigator if they experienced excessive pain, excessive discomfort, eye redness, vision changes, or vision loss.

[0926] Standard retrobulbar injection therapy consisted of topical broad-spectrum antibiotic drops and topical steroids up to four times a day per week at the discretion of the investigator.

[0927] Follow-up evaluation:

[0928] Visit 4 (Day 3, Day -1)

[0929] Investigators and researchers performed the following procedures on both eyes of each subject at 8 a.m. only:

[0930] Concomitant medications and procedures

[0931] Adverse events

[0932] ·Evaluation of eye comfort of subjects

[0933] Investigator's overall tolerability score

[0934] BCVA

[0935] Slit lamp biomicroscopy, including external ocular examination

[0936] Product visualization and description (via slit lamp)

[0937] IOP measurement

[0938] Visit 4.1 (Day 7, ± 1 day)

[0939] Investigators and researchers performed the following procedures on both eyes of each subject at 8 a.m. only:

[0940] Concomitant medications and procedures

[0941] Adverse events

[0942] · Eye comfort of the subjects

[0943] Investigator's overall tolerability score

[0944] BCVA

[0945] Slit lamp biomicroscopy, including external ocular examination

[0946] Product visualization and description (via slit lamp)

[0947] IOP measurement

[0948] Visit 5 (Day 14, ± 1 day)

[0949] Do the following for both eyes:

[0950] 8:00 AM (T0)

[0951] Concomitant medications

[0952] Adverse events

[0953] · Eye comfort of the subjects

[0954] Investigator's overall tolerability score

[0955] BCVA

[0956] Slit lamp biomicroscopy, including external ocular examination

[0957] Product visualization and description (via slit lamp)

[0958] IOP measurement

[0959] 10am (T0+2 hours) and 4pm (T0+8 hours)

[0960] IOP measurement.

[0961] Visit 6 (Day 28, ±2 days)

[0962] Investigators and researchers performed the following procedures on both eyes of each subject at 8 a.m. only:

[0963] Concomitant medications and procedures

[0964] Adverse events

[0965] · Eye comfort of the subjects

[0966] Investigator's overall tolerability score

[0967] BCVA

[0968] Slit lamp biomicroscopy, including external ocular examination

[0969] Product visualization and description (via slit lamp)

[0970] IOP measurement

[0971] Visit 7 (Day 42, ± 2 days) Do the following for both eyes:

[0972] 8:00 AM (T0)

[0973] Concomitant medications

[0974] Adverse events

[0975] · Eye comfort of the subjects

[0976] Investigator's overall tolerability score

[0977] BCVA

[0978] Slit lamp biomicroscopy, including external ocular examination

[0979] Product visualization and description (via slit lamp)

[0980] IOP measurement

[0981] Corneal thickness measurement

[0982] IOP measurement at 10 am (T0+2 hours) and 4 pm (T0+8 hours).

[0983] Visit 8 (Day 85, ±2 days)

[0984] The following procedures were performed on both eyes at 8:00 AM (T0) during the study visit:

[0985] Concomitant medications

[0986] Adverse events

[0987] · Eye comfort of the subjects

[0988] Investigator's overall tolerability score

[0989] BCVA

[0990] Slit lamp biomicroscopy, including external ocular examination

[0991] Product visualization and description (via slit lamp)

[0992] IOP measurement

[0993] Gonioscopy

[0994] Fundus examination

[0995] Corneal thickness measurement

[0996] Anterior segment OCT

[0997] Posterior segment OCT

[0998] OCT Optic Nerve NFL

[0999] Endothelial cell count (microscopic examination of the corneal endothelium confirmed by a central reading center) at 10 am (T0+2 hours) and 4 pm (T0+8 hours)

[1000] IOP measurement.

[1001] Visit 8 (Day 85, ±2 days)

[1002] The following procedures were performed on both eyes at 8:00 AM (T0) during the study visit:

[1003] Concomitant medications

[1004] Adverse events

[1005] · Eye comfort of the subjects

[1006] Investigator's overall tolerability score

[1007] BCVA

[1008] Slit lamp biomicroscopy, including external ocular examination

[1009] Product visualization and description (via slit lamp)

[1010] IOP measurement

[1011] Gonioscopy

[1012] Fundus examination

[1013] Corneal thickness measurement

[1014] Anterior segment OCT

[1015] Posterior segment OCT

[1016] OCT Optic Nerve NFL

[1017] Endothelial cell count (microscopic examination of the corneal endothelium confirmed by a central reading center) at 10 am (T0+2 hours) and 4 pm (T0+8 hours)

[1018] IOP measurement

[1019] Visit 9 (Month 4, ±3 days)

[1020] Do the following for both eyes:

[1021] 8:00 AM (T0)

[1022] Concomitant medications

[1023] Adverse events

[1024] · Eye comfort of the subjects

[1025] Investigator's overall tolerability score

[1026] BCVA

[1027] Slit lamp biomicroscopy, including external ocular examination

[1028] Product visualization and description (via slit lamp)

[1029] IOP measurement

[1030] 10am (T0+2 hours) and 4pm (T0+8 hours)

[1031] IOP measurement.

[1032] Visit 10 (5th month, ±3 days)

[1033] Investigators and researchers performed the following procedures on both eyes of each subject at 8 a.m. only:

[1034] Concomitant medications and procedures

[1035] Adverse events

[1036] · Eye comfort of the subjects

[1037] Investigator's overall tolerability score

[1038] BCVA

[1039] Slit lamp biomicroscopy, including external ocular examination

[1040] Product visualization and description (via slit lamp)

[1041] IOP measurement

[1042] Final Study Visit: Visit 11 (Month 6, ±3 days) Do the following for both eyes:

[1043] 8:00 AM (T0)

[1044] Concomitant medications

[1045] Adverse events

[1046] Vital signs (heart rate and blood pressure)

[1047] · Eye comfort of the subjects

[1048] Investigator's overall tolerability score

[1049] BCVA

[1050] Slit lamp biomicroscopy, including external ocular examination

[1051] Product visualization and description (via slit lamp)

[1052] IOP measurement

[1053] Gonioscopy

[1054] · Fundus dilation examination

[1055] ·View

[1056] Corneal thickness measurement

[1057] Anterior segment OCT

[1058] Posterior segment OCT

[1059] OCT Optic Nerve NFL

[1060] Endothelial cell count (microscopic examination of the corneal endothelium confirmed by a central reading center)

[1061] Urine pregnancy test (if applicable)

[1062] 10am (T0+2 hours) and 4pm (T0+8 hours)

[1063] IOP measurement

[1064] If biological activity or implants are found at the Month 6 visit, the subject will be followed monthly until their IOP is within 10% of their baseline measurement or until the investigator deems the subject clinically stable (see below). For all visits after Month 9, the same assessment schedule as described for Month 7 must be followed (see below). If residual microspheres are observed at Month 12, the subject should be followed at the discretion of the investigator. The final study visit should follow the Visit 11 assessment.

[1065] Follow-up Visit 12, 7 months (±3 days) and Visit 13, 8 months (±3 days)

[1066] If necessary, investigators and research staff performed the following procedures on both eyes of each subject at 8:00 AM only:

[1067] Concomitant medications and procedures

[1068] Adverse events

[1069] · Eye comfort of the subjects

[1070] Investigator's overall tolerability score

[1071] BCVA

[1072] Slit lamp biomicroscopy, including external ocular examination

[1073] Product visualization and description (via slit lamp)

[1074] IOP measurement

[1075] Follow-up Visit 14, 9 months (±3 days) If necessary, do the following during the study visit:

[1076] Concomitant medications

[1077] Adverse events

[1078] · Eye comfort of the subjects

[1079] Investigator's overall tolerability score

[1080] BCVA

[1081] Slit lamp biomicroscopy, including external ocular examination

[1082] Product visualization and description (via slit lamp)

[1083] IOP measurement

[1084] Gonioscopy

[1085] Fundus examination

[1086] Corneal thickness measurement

[1087] Anterior segment OCT

[1088] Posterior segment OCT

[1089] OCT Optic Nerve NFL

[1090] Endothelial cell count (microscopic examination of the corneal endothelium confirmed by a central reading center)

[1091] 10am (T0+2 hours) and 4pm (T0+8 hours)

[1092] IOP measurement

[1093] Unplanned Visits

[1094] Unscheduled visits may be conducted at any time when the investigator deems it necessary to see a subject outside of the study visit window. These visits may be scheduled as many times as necessary. The investigator may decide whether to perform an examination and evaluation based on the reason for the visit. For example, if there is evidence of clinical corneal edema, the evaluation must include AS-OCT.

[1095] Any unscheduled visits, along with the reason for the visit, are recorded on the “unscheduled” visit electronic case report form.

[1096] Adverse Events

[1097] Throughout the study, every effort was made to remain alert for possible AEs or adverse findings. If an AE occurred, the first focus was on the safety and well-being of the subject. Appropriate medical intervention was performed. Any AE observed by the Investigator or Study Staff or reported by the subject, whether or not attributed to study treatment, was recorded on the subject's Adverse Event eCRF.

[1098] Documentation of AEs must be prepared regarding the nature, onset date, end date, severity and relationship to study drug, actions taken, severity, and outcome of any signs or symptoms observed by the physician or reported by the subject.

[1099] NOTE: Subjects were asked if they had experienced the following ocular complaints: excessive tearing, foreign body sensation, stinging / burning, and itching. Affirmative responses to these standardized ocular complaints should be reported as ocular complaints rather than AEs unless the complaint: (1) meets the criteria for a specific event listed, (2) is outside normal limits, or (3) is associated with clinical sequelae (e.g., adverse slit-lamp findings).

[1100] Definition of Adverse Events

[1101] An AE is any untoward medical event in a subject administered a medicinal product or in a clinical investigation subject that does not necessarily have a causal relationship to the treatment.

[1102] Therefore, an AE may be any unfavorable and unexpected sign (including clinically significant abnormal laboratory findings), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. Inadequate efficacy of the investigational agent does not constitute an adverse event.

[1103] Definition of Serious Adverse Event (SAE)

[1104] A SAE is any adverse medical event at any dose:

[1105] Causes death

[1106] Life-threatening

[1107] - The term "life-threatening" refers to an event in which there is a risk of death for the subject if the event occurs. It does not refer to an event that, if more severe, could result in death.

[1108] · Requirement for hospitalization or prolongation of an existing hospitalization. Hospitalization for elective surgery does not constitute an SAE.

[1109] · Causes persistent or severe disability / incapacity

[1110] Congenital anomalies / birth defects

[1111] Medical and scientific judgment must be exercised in determining whether other circumstances should be considered SAEs, such as medically significant events that may not be immediately life-threatening or result in death or hospitalization but that could endanger the subject or may require intervention to prevent one of the other outcomes listed above.

[1112] Examples of such events are intensive treatment in the emergency department or at home for allergic bronchospasm, blood dyscrasias, tumors, or seizures that do not result in hospitalization.

[1113] AEs assessed as 'severe' should not be confused with SAEs. The term 'severe' is often used to describe the intensity (ie, severity) of a specific event (eg, mild, moderate, or severe myocardial infarction); however, the event itself may be of relatively minor medical significance (eg, severe headache). This is distinct from 'serious', which is based on outcome or behavioral criteria typically associated with events that are threatening to life or function. Severity (not severity) and causality are used as guides for defining regulatory reporting responsibilities.

[1114] Severity

[1115] The severity of an AE is defined as a qualitative assessment of the intensity of the AE as determined by the investigator or reported to the investigator by the subject. Severity is assessed without regard to the relationship to the study drug or the severity of the event and should be assessed according to the following scale:

[1116] Mild events are noticeable to the subject but are well tolerated and do not interfere with the subject's daily activities

[1117] Moderate events are disturbing, may require additional treatment, and may interfere with the subject's daily activities

[1118] Severe events are unbearable, require additional therapy or changes in therapy, and interfere with the subject's daily activities

[1119] For AEs of varying intensity, the start and end dates for each intensity should be recorded.

[1120] Relationship to intracameral implants or surgery

[1121] For each (S)AE, the treating investigator must determine whether the event is related to the injection procedure or the intracameral implant. To do this, the investigator must determine, based on their medical judgment, whether the event was likely caused by the intracameral implant or the injection procedure.

[1122] The following are guidelines that investigators must use when assessing the causality of a (S)AE: A causal relationship to the injection procedure or intracameral implant should be established in the CRF.

[1123] The No Suspected Relationship category applies to those (S)AEs that, after careful consideration, are clearly and indisputably caused by an external cause (disease, environment, etc.); there is no reasonable possibility that the (S)AE may have been caused by the injection procedure or the intracameral implant. If the investigator determines that the AE is unlikely to be related to the study drug, then this would be the appropriate category.

[1124] Suspicious Relationships When considering the inclusion of a (S)AE in this category, the following criteria must be applied:

[1125] 1) Has a reasonable temporal relationship to the injection procedure or the presence of an intracameral implant.

[1126] 2) cannot be reasonably explained by the known characteristics of the subject's clinical status, environmental or toxic factors, or other factors (such as the disease being studied, concurrent diseases, and concomitant medications) and the treatment pattern of the subject.

[1127] 3) Disappear or decrease after removal of the anterior chamber implant.

[1128] 4) Follow known patterns of response to injection procedures or intracameral implants.

[1129] A suspected AE is any event with a reasonable probability that the study drug caused the AE. "Reasonable probability" means that there is evidence of a causal relationship between the study drug and the AE. Types of evidence that may suggest a causal relationship between the study drug and the AE include: a single occurrence of an event that is uncommon and known to be closely related to drug exposure; one or more occurrences of an event that is not usually associated with drug exposure but is uncommon in the drug-exposed population (e.g., tendon rupture); and a pooled analysis of specific events observed in clinical trials (e.g., known consequences of the underlying disease or condition under study or other common events in the study population that are not related to drug treatment) showing that these events occurred more frequently in the drug-treated group than in the same period or historical control groups.

[1130] Anticipation

[1131] The expected nature of an (S)AE must be determined based on the available safety information on the study drug using the following criteria:

[1132] Unanticipated and not described in the study protocol, investigator's brochure, or registered formulation of travoprost AEs listed in the prescribing information for or not listed under specificity or severity observed

[1133] AEs that are expected to be listed under observed specificity or severity in the study protocol, investigator's brochure, or travoprost prescribing information

[1134] AEs that were mentioned in the Investigator's Brochure as occurring with a class of drugs or as expected from the pharmacological properties of that drug, but were not specifically mentioned as occurring with the specific drug being studied, were considered expected.

[1135] The investigator should initially categorize the AE as prospective, but the final categorization is determined by the medical monitor.

[1136] Clarification

[1137] diagnosis

[1138] Whenever possible, the event to be recorded and reported will be the event diagnosis rather than the event signs or symptoms.

[1139] Hospitalization

[1140] Hospitalization for elective treatment of a pre-existing condition (i.e., a condition that existed before the subject signed informed consent) that was not exacerbated during the study was not considered an SAE. Complications that occurred during hospitalization were AEs. Complications were SAEs if they prolonged hospitalization or met any other SAE criteria.

[1141] Pre-existing medical conditions, including glaucoma

[1142] Expected daily fluctuations in pre-existing conditions that were not worsening relative to baseline were not considered (S)AEs.

[1143] Glaucoma worsening or progression was considered “lack of efficacy” or “failure of expected pharmacological action” per the protocol and was recorded as part of the efficacy evaluation and therefore did not need to be recorded as an (S)AE.

[1144] Medical or surgical procedures

[1145] In the case of an elective medical or surgical procedure, or a pre-study planned medical or surgical procedure for a pre-existing condition (i.e., a condition that existed before the subject signed informed consent) that was not exacerbated during the study, the condition resulting from the procedure need not be reported as an (S)AE.

[1146] die

[1147] Death is not an SAE. The illness that caused the death is an SAE.

[1148] Abnormal laboratory values

[1149] Abnormal laboratory values ​​that are clinically significant in the judgment of the investigator must be recorded as (S)AEs. Abnormal laboratory findings of clinical significance that were present at baseline and significantly worsened after the start of the study are also recorded as (S)AEs. The investigator should review, sign, date, and determine clinical significance within 24 to 48 hours of receipt of these values.

[1150] AE time selection

[1151] All AEs observed during the study, regardless of severity or relationship to the injection or intracameral implant, were recorded on the appropriate eCRF starting from the time the subject signed the informed consent.

[1152] Procedures for reporting adverse events

[1153] Report all "suspected" and "unexpected" AEs to Ocular Therapeutix and the IRB as required by the IRB / IEC, local regulations, and health authorities. Unexpected events will be reported to the Salus IRB within 10 business days of event identification. Serious unexpected suspected adverse events will be reported to the Food and Drug Administration within 7 days for fatal and life-threatening events; all others within 15 days.

[1154] any serious Adverse events or any severe AEs, whether or not attributable to study treatment, are communicated to Ocular Therapeutix by fax or telephone within 24 hours. The Investigator must obtain all relevant medical records, information, and medical judgment from colleagues assisting with the subject's treatment and follow-up and maintain them in their files; provide Ocular Therapeutix with a complete medical history, including a statement as to whether the event is suspected to be related to the use of the study drug; and notify the IRB / IEC of the AE in accordance with the IRB / IEC guidelines for reporting SAEs. A written report signed by the Investigator describing the event in detail must be submitted to the Sponsor within 5 business days. All subjects who experience a SAE must be followed until the event is resolved or stabilized and the results are reported in the CRF.

[1155] Type and duration of adverse event follow-up

[1156] Track AE until:

[1157] · Resolution of the event, i.e. return to baseline value or state or ‘normal’

[1158] - AEs may be determined to be completely resolved or resolved with sequelae

[1159] For an event that is not resolved (e.g., metastasis), the principal investigator determines that the condition is chronic; the event may be determined to be resolved or resolved with sequelae

[1160] The incident has stabilized, i.e., the investigators do not expect it to worsen

[1161] All AEs were recorded in the CRF. For subjects who reached the final scheduled visit (i.e., Visit 11 [Month 6]), unscheduled visits were allowed thereafter to follow up on any AEs that the investigator considered to be unresolved or stable.

[1162] Study Supervision

[1163] Data Safety Monitoring Committee (DSMC)

[1164] The sponsor appoints the DSMC to monitor the safety of study subjects during the trial. The DSMC is composed of a group of independent glaucoma physician experts from the field of ophthalmology. For safety monitoring, the DSMC establishes a charter that includes a mission statement, operating procedures, and monitoring criteria for study proposals, including any supplemental proposed study stopping rules in addition to the criteria listed in the next section. The DSMC reviews the safety data from Cohort 1 before enrolling any subjects into Cohort 2; Cohorts 3 and 4 are not reviewed ex ante because the doses are lower than those in Cohort 2 and the duration of therapy is shorter than that studied in Cohorts 1 and 2.

[1165] Written minutes of all meetings must be prepared following each DSMC meeting, and the major conclusions (ie, assessment to continue the study versus recommendation to stop the study) must be recorded.

[1166] Statistical analysis

[1167] Statistics and Analysis Program

[1168] This study was not designed to show statistical significance, therefore, no statistical analysis was completed. A general statistical plan exists which will briefly outline how the data will be presented, i.e. descriptive statistics etc.

[1169] Determination of sample size

[1170] A formal sample size calculation has not been performed for this Phase 1 study. A sample size of 5 subjects is considered sufficient to inform on the safety of the product.

[1171] Analyze the dataset

[1172] The safety population consisted of all subjects who received the OTX-TIC implant. All safety and efficacy analyses were performed on the safety population.

[1173] Demographics and baseline data

[1174] Present subject disposition, including the number of subjects screened, enrolled, and treated. Summarize the number of subjects who completed the study and the reasons for discontinuation.

[1175] Demographics and baseline characteristics (including diseases and medical history) were summarized.

[1176] Security Analysis

[1177] Safety was assessed by adverse events, subject ocular comfort assessment, investigator global tolerability score, and other ocular-related outcomes.

[1178] Adverse events were coded by system organ class and preferred terms using the Medical Dictionary for Regulatory Activities (MedDRA). Adverse events related to the injection procedure and intracameral implants were summarized separately. In addition, serious adverse events were summarized.

[1179] An overview of other safety-related findings is provided.

[1180] Efficacy analysis

[1181] Efficacy was assessed based on daily IOP. Measures taken at baseline, day 14 (visit 5), day 42 (visit 7), day 85 (visit 8), month 4 (visit 9), and month 6 (visit 11) were summarized (8 a.m., 10 a.m., 4 p.m.). If biological activity was noted at month 6, IOP measurements continued (see below). In addition, intraocular pressure at 8 a.m. on the day of insertion, day 3, day 7, day 28, and month 5 (visit 10) was summarized.

[1182] Exploratory analysis

[1183] Angle size was assessed by two methods. Angle size was determined by the investigator using gonioscopy. Additionally, angle size was assessed using AS-OCT read by a masked reading center. An overview of the angle sizes assessed by the obtained methods is provided.

[1184] General Information

[1185] Study Termination

[1186] Ocular Therapeutix reserves the right to discontinue a study at any stage and, where appropriate, provide appropriate written notice to the Investigator, IRB / IEC and other regulatory authorities. Similarly, an Investigator may withdraw from participation as a research subject by providing written notice of his / her intent to withdraw to Ocular Therapeutix within 30 days. However, Ocular Therapeutix and the Investigator are obligated to complete follow-up of subjects who have been treated in a clinical study. Subjects must be followed up according to the clinical protocol and information obtained during subject follow-up must be reported on the CRF.

[1187] All serious AEs will be evaluated and if the Sponsor determines that an unreasonable risk to the subject may result, the study will be terminated and all regulatory authorities and participating investigators will be notified no later than 5 working days after the Sponsor makes this determination and no later than 15 working days after the Sponsor is first notified of the effect.

[1188] A terminated investigation cannot be reopened without approval from the local research ethics committee or regulatory authority, as required.

[1189] Supervision

[1190] The Investigator and Sites allow the Ocular Therapeutix-assigned, authorized Clinical Investigator and Clinical Study Monitor to review completed CRFs, IRB / IEC decisions, and Investigator and Clinical Site records periodically throughout the study. In addition, subject charts and clinical records are requested and reviewed to verify protocol compliance and source documentation. In cases where data protection regulations and / or hospital policies prohibit the Study Sponsor or designee from directly inspecting hospital records, the Investigator collaborates with the Sponsor in a source data verification system. Further details of the study monitoring procedures are outlined in the Monitoring Plan.

[1191] If the monitor finds that the investigator is not complying with the signed investigator agreement, the investigational plan, or other applicable regulations, or reviewing any approval conditions imposed by the IRB / IEC, the monitor will report to the sponsor and take such steps as are necessary to promptly ensure compliance. If compliance cannot be ensured, shipments of study product to the investigator may be stopped and the investigator’s participation in the clinical study terminated. The monitor must also require such investigator to dispose of or return unused product unless doing so would compromise the rights, safety, or well-being of the subjects.

[1192] Retention of Documents

[1193] The Investigator maintains all study-related documentation, including all correspondence, records of financial interests, individual subject records, informed consent forms, all drug liability records, the protocol with any / all amendments, all correspondence and approvals with the IRB / IEC, the budget agreement, the Investigator Agreement, and copies of the CRF for up to 2 years after the later of the following dates:

[1194] 1. The date on which the marketing application for the drug was approved for the indication for which it was investigated, or

[1195] 2. The date on which the records are no longer required to support an application to the regulatory authority.

[1196] These documents may be discarded only upon notification from Ocular Therapeutix. To avoid errors, investigators should contact Ocular Therapeutix prior to destroying any records and reports related to the study to ensure that they are no longer necessary.

[1197] Slit lamp photos

[1198] The investigator will capture correct placement of the OTX-TIC (travoprost) intracameral implant via slit-lamp photographs on Day 1 and at any subsequent visits after injection. Photographs must be identified using the subject number and subject initials and may not include any identifiers, such as subject name or date of birth. Photographs document continued correct placement of the implant. Photographs may also be used for training, advertising, or publication in scientific meetings, journals, or magazines.

[1199] Compliance with good clinical practice, ethical considerations and administrative issues

[1200] The study was conducted according to the protocol of the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines and was consistent with the 1996 version of the Declaration of Helsinki.

[1201] Study Inspection Procedure

[1202] Best corrected visual acuity

[1203] Visual acuity must be assessed at the beginning of each study visit, before other tests (e.g., Goldmann tonometry and gonioscopy) and before pupil dilation (i.e., before slit-lamp examination). Every effort must be made to have the same BCVA assessor throughout the study. Visual acuity testing must be performed from the most recent correction.

[1204] B...

Claims

1. Travoprost particles made from a mixture of: - travoprost, and - a biodegradable polymer consisting of polylactide having acid end groups and an intrinsic viscosity specification in the range of 0.05 dl / g to less than about 0.5 dl / g, wherein the mixture contains 40 wt.-% to 50 wt.-% of travoprost, based on the total mass of the mixture, and The travoprost particles have an average diameter in the range of 1 to 75 μm as determined by laser diffraction.

2. Travoprost particles according to claim 1, wherein the intrinsic viscosity specification is in the range of 0.35 to 0.45 dl / g.

3. Travoprost particles according to claim 1 or 2, wherein the mixture contains 43 wt.-% to 45 wt.-% of travoprost, based on the total mass of the mixture.

4. The travoprost particles according to any one of claims 1 to 3, wherein the travoprost particles have an average diameter in the range of 20 to 75 μm or in the range of 20 to 55 μm as determined by laser diffraction.

5. The travoprost particles according to any one of claims 1 to 4, wherein the particles are spherical particles.

6. Travoprost particles made from a mixture of: - travoprost, and - a biodegradable polymer consisting of polylactide having acid end groups and an intrinsic viscosity specification ranging from 0.5 to less than 0.80 dl / g, wherein the mixture contains 40 wt.-% to 50 wt.-% of travoprost, based on the total mass of the mixture, and The travoprost particles have an average diameter in the range of 1 to 75 μm as determined by laser diffraction.

7. The travoprost particles of claim 6, wherein the intrinsic viscosity specification is in the range of 0.6 to less than about 0.80 dl / g.

8. The travoprost particles according to claim 6 or 7, wherein The mixture contains 45 to 47 wt.-% travoprost, based on the total mass of the mixture.

9. The travoprost particles according to any one of claims 6 to 8, wherein The travoprost particles have an average diameter in the range of 20 to 75 μm or in the range of 20 to 55 μm as determined by laser diffraction.

10. The travoprost particles according to any one of claims 6 to 9, wherein the particles are spherical particles.

11. Travoprost particles made from a mixture of: - travoprost, and - a biodegradable polymer consisting of polylactide having acid end groups and an intrinsic viscosity specification ranging from 0.8 to 1.7 dl / g, wherein the mixture contains 40 wt.-% to 50 wt.-% of travoprost, based on the total mass of the mixture, and The travoprost particles have an average diameter in the range of 1 to 75 μm as determined by laser diffraction.

12. Travoprost particles according to claim 11, wherein the intrinsic viscosity specification is in the range of 0.8 to 1.0 dl / g.

13. The travoprost particles according to claim 11 or 12, wherein The mixture contains 41 to 43 wt.-% travoprost, based on the total mass of the mixture.

14. The travoprost particles according to any one of claims 11 to 13, wherein The travoprost particles have an average diameter in the range of 20 to 75 μm or in the range of 20 to 55 μm as determined by laser diffraction.

15. The travoprost particles according to any one of claims 11 to 14, wherein the particles are spherical particles.

16. Travoprost particles made from a mixture of: - travoprost, and - a biodegradable polymer consisting of polylactide having ester end groups and an intrinsic viscosity specification ranging from 0.05 to 1.7 dl / g, wherein the mixture contains 40 wt.-% to 50 wt.-% of travoprost, based on the total mass of the mixture, and The travoprost particles have an average diameter in the range of 1 to 75 μm as determined by laser diffraction.

17. Travoprost particles according to claim 16, wherein the intrinsic viscosity specification is in the range of 0.55 to 0.75 dl / g.

18. The travoprost particles according to claim 16 or 17, wherein The mixture contains 41 to 43 wt.-% travoprost, based on the total mass of the mixture.

19. The travoprost particles according to any one of claims 16 to 18, wherein The travoprost particles have an average diameter in the range of 20 to 75 μm or in the range of 20 to 55 μm as determined by laser diffraction.

20. The travoprost particle according to any one of claims 16 to 19, wherein the particle is a spherical particle.

21. A plurality of travoprost particles formed from a blend of at least two types of travoprost particles selected from the group consisting of: a first type of travoprost particles, a second type of travoprost particles, a third type of travoprost particles and a fourth type of travoprost particles, wherein the first type of travoprost particles are particles according to any one of claims 1 to 5, the second type of travoprost particles are particles according to any one of claims 6 to 10, the third type of travoprost particles are particles according to any one of claims 11 to 15, and the fourth type of travoprost particles are particles according to any one of claims 16 to 20.

22. A plurality of travoprost particles formed by a blend of a first type of travoprost particles, a second type of travoprost particles, a third type of travoprost particles and a fourth type of travoprost particles, wherein the first type of travoprost particles are particles according to any one of claims 1 to 5, the second type of travoprost particles are particles according to any one of claims 6 to 10, the third type of travoprost particles are particles according to any one of claims 11 to 15, and the fourth type of travoprost particles are particles according to any one of claims 16 to 20.

23. A plurality of travoprost particles according to claim 22, wherein the particles, based on the total amount of particles, comprise 15 to 25 wt.-% of the first type of particles and 15 to 25 wt.-% of the second type of particles and 5 to 15 wt.-% of the third type of particles and 40 to 60 wt.-% of the fourth type of particles; or wherein 15 to 25 wt.-% of the total amount of travoprost is present in the form of particles of the first type and 15 to 25 wt.-% of the total amount of travoprost is present in the form of particles of the second type and 5 to 15 wt.-% of the total amount of travoprost is present in the form of particles of the third type and 40 to 60 wt.-% of the total amount of travoprost is present in the form of particles of the fourth type.

24. A plurality of travoprost particles formed from a blend of a first type of travoprost particles, a second type of travoprost particles and a third type of travoprost particles, wherein the first type of travoprost particles are particles according to any one of claims 1 to 5, the second type of travoprost particles are particles according to any one of claims 6 to 10, and the third type of travoprost particles are particles according to any one of claims 11 to 15.

25. A plurality of travoprost particles according to claim 24, wherein 20 to 35 wt.-% of the particles, based on the total amount of particles, are particles of the first type and 30 to 50 wt.-% are particles of the second type and 25 to 45 wt.-% are particles of the third type; or wherein 20 to 35 wt.-% of the total amount of travoprost is present in the form of particles of the first type and 30 to 50 wt.-% of the total amount of travoprost is present in the form of particles of the second type and 25 to 45 wt.-% of the total amount of travoprost is present in the form of particles of the third type.

26. A plurality of travoprost particles formed from a blend of a first type of travoprost particles and a second type of travoprost particles, wherein the first type of travoprost particles are particles according to any one of claims 1 to 5 and the second type of travoprost particles are particles according to any one of claims 6 to 10.

27. A plurality of travoprost particles according to claim 26, wherein 35 to 55 wt.-% of the particles, based on the total amount of particles, are particles of the first type and 35 to 55 wt.-% are particles of the second type; or wherein 35 to 55 wt.-% of the total amount of travoprost is in the form of particles of the first type and 35 to 55 wt.-% of the total amount of travoprost is in the form of particles of the second type.

28. Use of the travoprost particles according to any one of claims 1 to 20 or a plurality of travoprost particles according to any one of claims 21 to 27 for the preparation of an intracameral implant, wherein the intracameral implant comprises a biodegradable hydrogel, wherein the hydrogel comprises a polymer network comprising one or more polyalkylene glycol units, and the plurality of travoprost particles are dispersed within the hydrogel.

29. A method for manufacturing a biodegradable intracameral implant for sustained release of travoprost, the method comprising the following steps: a) preparing travoprost particles according to any one of claims 1 to 20 or a plurality of travoprost particles according to any one of claims 21 to 27, b) preparing a precursor mixture containing a hydrogel precursor and the travoprost particles or the plurality of travoprost particles, c) cross-linking the precursor mixture using a cross-linking agent to form a polymer network and obtain a hydrogel mixture comprising the polymer network, and d) drying the hydrogel mixture to provide the intracameral implant.

30. The use according to claim 28 or the method according to claim 29, wherein the polymer network is formed by reacting a multi-arm polymer precursor containing electrophilic groups with a cross-linking agent containing nucleophilic groups.

31. The use or method according to claim 30, wherein the multi-arm polymer precursor containing electrophilic groups is a 4 to 10-arm polyethylene glycol precursor, and the cross-linking agent containing nucleophilic groups is an amine.

32. The use or method according to claim 30 or 31, wherein the electrophilic group is selected from succinimidyl glutarate (SG) group and succinimidyl azelaic acid (SAZ) group, the multi-arm polymer precursor is selected from 8-arm-15K-SG polyethylene glycol or 8-arm-15K-SAZ polyethylene glycol; and the cross-linking agent containing a nucleophilic group is trilysine.

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