Compositions and methods for treating eye diseases

Abstract

To provide an implant suitable for being inserted into the anterior chamber of the eye, with dimensions small enough to fit into the iridocorneal angle of the eye during its insertion, and provide a method for treating ocular diseases using the implant.SOLUTION: An intracameral implant comprises: a biodegradable hydrogel, wherein the hydrogel comprises one or more units of polyalkylene glycol, and travoprost particles; the travoprost particles in the form of travoprost intermixed with a biodegradable polymer; and the travoprost particles dispersed within the hydrogel.SELECTED DRAWING: Figure 1a

Description

[Technical Field]

[0001] The present invention provides a therapeutic approach in human subjects with ocular disease and a corresponding intracameral implant. The present invention also relates to a method for treating intraocular pressure in a human subject and a corresponding intracameral impactor. The present invention also relates to a method for treating ocular hypertension or glaucoma, such as open-angle glaucoma. The present invention also relates to the treatment of intraocular pressure in a human subject. This invention relates to intracameral administration of sustained-release biodegradable intracameral implants. [Background technology]

[0002] Glaucoma is usually a progressive, chronic disease that affects millions of people (Simmo ns,S.,T.,Ophthalmic Formulation.Glaucom a Today Supplement to Advanced Ocular Ca re, 2010;The Eye Disease Prevalence Grou p.,Prevalence of open-angle glaucoma amo ng adults in the United States.Arch Opht halmol, 2004.122:p.532-538). In fact, glaucoma is an irreversible disease. It is reported to be one of the leading causes of blindness and the second leading cause of blindness worldwide (Q uigley,HAand ATBroman,The number of people with glaucoma worldwide in 2010 a nd 2020.Br.J.Ophthalmol,2006.90(3):p.262 -7) It is predicted that by 2040, over 110 million people will be diagnosed with glaucoma. Some people believe this (Tham, Y.-C., et al., Global Prevalence e of Glaucoma and Projections of Glaucom a Burden through 2040.8, Ophthalmology, 20 14.121(11):p.2081-2090).

[0003] Glaucoma leads to the loss of retinal ganglion cells and their axons, which later progresses to visual field loss. It is defined as optic nerve damage that, in very advanced cases, leads to loss of central vision. Radial-angle glaucoma is the most common form of the disease and is classified as primary open-angle glaucoma (POAG). ) refers to eyes with a dilated anterior chamber drainage angle and elevated IOP.

[0004] The main risk factor for glaucoma is increased fluid pressure within the eye (i.e., elevated intraocular pressure (IOP)). It is defined as a pressure above the normal range of 10-21 mmHg. Individuals with elevated IOP levels without ocular damage are diagnosed with ocular hypertension as opposed to glaucoma. However, people with ocular hypertension are at risk for progressive damage to the optic nerve (glaucoma). obtain.

[0005] For both glaucoma and ocular hypertension (OHT), the most important factors for effective treatment are The goal is to lower IOP, which slows the progression of the disease as well as the rate of visual field loss. Drugs classified as prostaglandins can effectively lower IOP. (AAO, Glaucoma Preferred Practice) ice Pattern. 2015). AAO Preferred Practice Pattern recommends prostaglandins as the first choice for the treatment of POAG and OHT. The most commonly prescribed topical medication for the treatment of glaucoma in the United States is promethazine. It is a staglandin analogue.

[0006] Travoprost, for example, is a suitable synthetic prostaglandin F2α analog. The chemical name is (isopropyl(Z)-7-[(1R,2R,3R,5S)-3,5-dihydro 2-[(1E,3R)-3-hydroxy-4-[(α,α,α-trifluoro-m -isopropyl-tolyl)oxy]-1-butenyl]-cyclopentyl]-5-hepteno This prodrug is a synthetic ester that is enzymatically converted to the free acid form in the human cornea. (Al-Jazzaf, A.M., L. DeSant is,and PANetland,Travoprost:a potent o cular hypotensive agent.Drugs Today(Barc ), 2003.39(1):pp.61-74). As with all prostaglandins, Travoprost free acid reduces intraocular pressure by increasing outflow through the trabecular meshwork and uveosclera. It is a selective FP prostanoid receptor agonist that is thought to reduce KS,et al.,Mechanism of action of bimat oprost, latanoprost, and travoprost in hea lthy subjects.A crossover study.Ophthalm ology,2008.115(5):p.790-795 e4 and Toris ,CB,BATGabelt,and PLKaufman,Updat e on the Mechanism of Action of Topical Prostaglandins for Intraocular Pressure Reduction.Survey of Ophthalmology,2008.5 3(6,Supplement):p.S107-S120). Travoprost is vatan®, Travatan Z® (Appendix A: Package Insert), and and Izba™ (all trademarks of Alcon Laboratories, Inc., Ft Worth, T×), all of which are intended to suppress an increase in IOP. The dosage is usually 0.0 mg / day applied to the affected eye(s). One drop per day of a 0.04% or 0.003% solution.

[0007] Successful treatment of glaucoma requires daily self-administered treatment with topical eye drops. While topical antihypertensive drugs can be effective in treating glaucoma, any one of the available treatments is only as effective as the individual patient's adherence to the medication. Known limitations associated with eye drops include (1) difficulty in administering the drops and (2) accuracy of the drops entering the eye. (3) the possibility of washout of the eye drops by tearing or subsequent administration of other eye drops; (4) the need for a caregiver to administer the eye drops and (5) poor subject compliance. Examples include Toris, CB, BAT Gabelt, and PLKa ufman,Update on the Mechanism of Action of Topical Prostaglandins for Intraocula r Pressure Reduction.Survey of Ophthalmo logy,2008.53(6,Supplement):p.S107-S120). Kholdebarin,et al.(Kholdebarin,R.,et al. ,Multicenter study of compliance and dro p administration in glaucoma.Can.J.Ophth almol, 2008.43(4):p.454-61) reported that 34% of patients received inappropriate reported using a technique for administering eye drops. For some patients, multiple eye drops were required. This can lead to a situation due to the washout effect. Nearly 9% of patients who required more than one medication were able to wait at least 3 minutes between doses. Importantly, regardless of the number of drugs, patients are expected to remain on treatment indefinitely. Therefore, the motivation to do so plays an important role. Therefore, it is recommended to use an alternative to daily administration of single or multiple eye drops, especially in elderly people with this condition. You need to provide something different.

[0008] Poorly controlled cases of glaucoma have a long-term effect that can potentially lead to blindness. Patient compliance becomes a major issue. Studies have shown that fewer than 50% of glaucoma patients receive treatment. Continue taking the prescribed medication and refill it as needed (Friedman, DS, et al., Using Pharmacy Claims Data to Study Adhe rence to Glaucoma Medications:Methodlog y and Findings of the Glaucoma Adherence and Persistency Study(GAPS).Investigati ve Ophthalmology & Visual Science,2007.4 8(11):pp.5052-5057), most patients follow their health insurance claims. Patients were likely to discontinue topical therapy use within 1.2 years of filling their first prescription (N ordstrom,BL,et al.,Persistence and Adh. erence With Topical Glaucoma Therapy.Ame rican Journal of Ophthalmology,2005.140( 4): p.598.e1-598.e11). Therefore, 24-hour long-term control of IOP The delivery system provides a number of benefits, including addressing multiple issues and potentially reducing vision loss due to glaucoma in patients. This can potentially delay or prevent the

[0009] Anterior segment drug delivery improves patient compliance and provides a superior safety profile This is a challenge with the ultimate goal of achieving sustained delivery over a long period of time. Continue (Yellepeddi, V.K. and S.Palakurthi, Rec ent Advances in Topical Ocular Drug Deli very.Journal of Ocular Pharmacology and Therapeutics,2015.32(2):p.67-82).

[0010] DURYSTA, an FDA-approved bimatoprost intracameral implant ) is indicated for the reduction of intraocular pressure in patients with open-angle glaucoma or ocular hypertension. Because of the potential for endothelial cell loss and adverse corneal reactions, the implant can be used in one eye without retreatment. Limited to a single implant per patient and patients with narrow or anatomic angle obstruction It should be used with caution. Efficacy has been demonstrated in patients with open-angle glaucoma or ocular hypertension. Compared with twice-daily topical timolol 0.5% eye drops, DURYSTA was The study was conducted in a randomized, parallel-group, controlled, 20-month trial (including an 8-month extension period). YSTA is a measure of intraocular pressure (IOP) of approximately 5 to 8 mmHg in patients with a mean baseline IOP of 24.5 mmHg. The data showed that after 12 weeks, intraocular pressure in the DURYSTA group increased more than in the timolol group. DURYSTA® is a solid polymer sustained release drug delivery system. It is an intracameral implant containing 10 μg of bimatoprost in the stem. The stem is made of poly(D,L lactide), poly(D,L-lactide-co-glycolide), poly(D,L-lactide-co-glycolide), It consists of poly(D,L-lactide) acid terminal and polyethylene glycol 3350. (Formulation Information last updated November 2020). Summary of the Invention

[0011] The objective of certain embodiments of the present invention is to provide a device that is sufficiently conformable to the iridocorneal angle of the eye when inserted. implants having relatively small dimensions suitable for insertion into the anterior chamber of the eye (intracameral implants) In particular, the implant provides a wide range of iris angles, including narrow angles. It should have a size small enough to fit the size of the membrane angle.

[0012] The objective of certain embodiments of the present invention is to provide a lens that is small enough in size to fit the iridocorneal angle of the eye. and remains stable in the iridocorneal angle for the duration of treatment and / or until it biodegrades. To provide an implant (intracameral implant) suitable for insertion into the anterior chamber of the eye. do.

[0013] The objective of certain embodiments of the present invention is to provide a device that, after insertion, swells due to the uptake of aqueous humor, which dissolves. The implant is suitable for insertion into the anterior chamber of the eye and becomes increasingly soft before completely disintegrating. The goal is to provide a rant (intracameral implant).

[0014] Another object of certain embodiments of the present invention is to provide a travoprost sustained-release biodegradable intracameral implant. The objective of the present invention is to provide a corresponding treatment method with limited movement of the implant and the implant.

[0015] Another object of certain embodiments of the present invention is to provide an endothelium-friendly, sustained-release biodegradable pre-gelatinized formulation of travoprost. The present invention provides an intracameral implant.

[0016] It is an object of certain embodiments of the present invention to treat ocular diseases in human subjects over an extended period of time, for example, from about 1 month to about The present invention provides a method of treatment and corresponding uses for a period of 24 months.

[0017] An object of certain embodiments of the present invention is a method for treating an ocular disease in a human subject for an unlimited period of time. and providing corresponding uses.

[0018] It is an object of certain embodiments of the present invention to safely and effectively control intraocular pressure in human subjects over an extended period of time, e.g. For example, about 2 to 12 months or 3 to about 9 months, for example, about 3 to about 4 months or about 3 to about 6 months. The present invention provides a method of treatment for a period of about 6 to about 9 months and corresponding uses.

[0019] An object of certain embodiments of the present invention is to safely and effectively control intraocular pressure in human subjects without restriction. The present invention provides a method for treating and corresponding uses of the disease.

[0020] It is an object of certain embodiments of the present invention to provide a method for treating ocular hypertension or glaucoma, e.g., open-angle glaucoma. The present invention relates to a method for safely and effectively controlling intraocular pressure in a human subject over an extended period of time, for example, about 2 to 12 months or about 3 to 12 months. About 9 months, for example, about 3 to about 4 months, about 3 to about 9 months, or about 6 to about 9 months and to provide methods for treating and corresponding uses.

[0021] It is an object of certain embodiments of the present invention to provide a method for treating ocular hypertension or glaucoma, e.g., open-angle glaucoma. Methods and corresponding methods for safely and effectively treating intraocular pressure in a human subject for an unlimited period of time The purpose is to provide a use that

[0022] Another object of certain embodiments of the present invention is to provide a method for treating ocular hypertension or glaucoma, such as open-angle glaucoma. First limited burst to safely and effectively treat intraocular pressure in human subjects A prostaglandin antagonist that provides a constant or substantially constant release of the prostaglandin antagonist. Staglandin antagonist (e.g., travoprost) sustained-release biodegradable intracameral implant Provide the runt.

[0023] Another object of certain embodiments of the present invention is to provide prostaglandin antagonists (e.g., A biodegradable intracameral implant for sustained release of travoprost and its use in the anterior chamber of a human subject. If swallowed, it may cause inconvenience or discomfort, such as a feeling of having a foreign body in the eye or eye pain. The objective of the present invention is to provide a suitable treatment method.

[0024] Another object of certain embodiments of the present invention is to provide a preservative-free method for treating intraocular pressure in a human subject. The purpose of this study is to provide a method for

[0025] Another object of certain embodiments of the present invention is to provide a travoprost sustained-release biodegradable intracameral implant. The present invention aims to provide an implant and a corresponding treatment method, wherein the implant is visible to the naked eye. It doesn't stick.

[0026] Another object of certain embodiments of the present invention is to provide a travoprost sustained-release biodegradable intracameral implant. and a corresponding method of treatment, wherein the implant is monitored by the eye. It may be possible to do so.

[0027] Another object of certain embodiments of the present invention is to provide a method for treating a human ocular tissue injury, such as the anterior or posterior chamber of the eye of a human subject. A prostaglandin antagonist (e.g., Trabo) that is easily inserted into the subject's eye The present invention provides a biodegradable intracameral implant that releases hydroxybenzoates (HBD).

[0028] Another object of certain embodiments of the present invention is to provide a method for treating a human ocular tissue injury, such as the anterior or posterior chamber of the eye of a human subject. A prostaglandin antagonist (e.g., a steroid) small enough to be inserted into the subject's eye The present invention provides a biodegradable intracameral implant for sustained release of raboprost.

[0029] Another object of certain embodiments of the present invention is to provide a method for treating a vitreous ocular tract infection, comprising administering to a subject a vitreous ocular tract infection, comprising administering to the ... biodegradable in a way that does not require surgical removal, i.e., implants A fully biodegradable travoprost sustained-release biodegradable intracameral implant and corresponding and to provide a method of treatment.

[0030] Another object of certain embodiments of the present invention is to provide a method for treating open-angle glaucoma and / or hyperostosis in a human subject. -release biodegradable travoprost for the continuous treatment of intraocular pressure related hypertension - Patents.com The present invention provides a novel intracameral implant and a corresponding treatment method.

[0031] Another object of certain embodiments of the present invention is to provide a travoprost sustained-release biodegradable intracameral implant. and a corresponding method of treatment, wherein the implant provides long-term Provides therapeutic benefits.

[0032] Another object of certain embodiments of the present invention is to provide a travoprost sustained-release biodegradable intracameral implant. and a corresponding method of treatment, wherein the implant provides long-term The present invention provides a therapeutic effect and does not cause changes in corneal thickness or endothelial cell count. One or more of these objects, and others, are achieved by one or more of the methods disclosed and claimed herein. The present invention is solved by the embodiments.

[0033] Individual aspects of the invention are disclosed herein and claimed in independent claims, while dependent claims The claims claim specific embodiments and variations of these aspects of the invention. Further details are provided in the detailed description below. [Brief explanation of the drawings]

[0034] [Figure 1a] FIG. 1 shows the in vitro release of formulations 1a, 1b, 2, and 3 measured at 37° C. [Figure 1b] FIG. 1 shows the in vitro release of formulations 1a, 1b, 2, and 3 measured at 40° C. [Figure 1c] FIG. 1 shows grading of implant integrity over time (weeks). [Figure 1d] FIG. 1 shows a typical Karl Fischer plot of a blank obtained using the methods disclosed herein. [Figure 1e]FIG. 1 shows a typical Karl Fischer plot of a water standard obtained using the methods disclosed herein. [Figure 1f] FIG. 1 shows a typical Karl Fischer plot of an OTX-TP sample obtained using the methods disclosed herein. [Figure 2] FIG. 1 shows the design of a phase 1 clinical trial. [Figure 3a] FIG. 1 shows mean corneal thickness measurements for Cohort 1 of a Phase 1 clinical trial from baseline to Month 22. [Figure 3b] FIG. 1 shows mean corneal thickness measurements for Cohort 2 of a Phase 1 clinical trial from baseline to Month 9. [Figure 3c] FIG. 1 shows mean corneal thickness measurements for Cohort 3 of a Phase 1 clinical trial from baseline to Month 9. [Figure 3d] FIG. 1 shows mean corneal thickness measurements for Cohort 4 of a Phase 1 clinical trial from baseline to 6 months. [Figure 4a] FIG. 1 shows the mean ECC for Cohort 1 of a Phase 1 clinical trial from baseline to Month 9. [Figure 4b] FIG. 1 shows the mean ECC for Cohort 2 of a Phase 1 clinical trial from baseline to month 9. [Figure 4c] FIG. 1 shows the mean ECC for Cohort 3 of a Phase 1 clinical trial from baseline to 6 months. [Figure 5a] FIG. 1 shows the mean IOP change from baseline in Cohort 1 of a Phase 1 clinical study. [Figure 5b] FIG. 1 shows the mean IOP change from baseline in Cohort 2 of a Phase 1 clinical study. [Figure 5c] FIG. 1 shows the mean IOP change from baseline in Cohort 3 of a Phase 1 clinical study. [Figure 5d] FIG. 1 shows the mean IOP change from baseline in a Phase 1 clinical study. [Figure 6] Photographs of inserted implants in one human subject from day 1 to month 7. [Figure 7] FIG. 1 shows a syringe construction for administering an OTX-TIC travoprost implant. DETAILED DESCRIPTION OF THE INVENTION

[0035] definition As used herein, the term "intracameral implant" means an "intracameral insert." The term is used interchangeably with prostaglandin antagonists (e.g., trabeculopeptides ... and is suitable for administration, i.e., as a retention agent for a period of time. Suitable for insertion into the anterior segment of the eye while releasing the active agent into the surrounding environment, such as aqueous humor. The implant may also be inserted into the posterior segment of the eye. Prior to insertion, the fibers are in the form of fibers, which undergo hydration as further disclosed herein. The dimensions (e.g., length and / or diameter) of the implant may vary after administration to achieve Once the implant is placed in the desired position, it can maintain its shape to some extent. What is inserted into the eye is not a solution or suspension, but a preformed, defined object. Before administration, the implant may be thoroughly purified, e.g., according to the methods disclosed herein. The intracameral implant is designed to biodegrade over time. (as disclosed below) thereby softening and changing its shape. The particles may be condensed and / or reduced in size, eventually resulting in either complete dissolution or disintegration. In the present invention, the term "implant" refers to If it contains water (e.g., the implant will be (re)hydrated once administered to the eye), hydrated (referred to as "swollen") after being exposed to an aqueous environment or otherwise immersed in an aqueous environment. Implants in a dry state (also called dry state) and those dried to a low moisture content, e.g., 1% by weight or less. or when the preparation results in a low moisture content insert without the need for a drying step. The term is used to refer to both implants in their dry (dry / dehydrated) state and implants in their dry (dry / dehydrated) state. The water content of the sample was measured using the Karl Fischer coulometric method as shown in Example 2c. will be done.

[0036] The term "inserted" is used herein in the same sense as "placed" or "injected" or "placed on" or "inserted on". The terms "administered" and "implanted" are used interchangeably. The term describes the intracameral implantation of the OTX-TIC implant into the anterior chamber of the eye, and then It is present in the iridocorneal angle.

[0037] The term "eye" as used herein refers to the eye in general, or any part of the eye or (An "ocular implant" is, in principle, a device administered to any part or portion of the eye. In certain embodiments, the present invention provides a method for treating ophthalmic Intracameral injection of the implant and the reduction of intraocular pressure in subjects with glaucoma and / or ocular hypertension Targets decline.

[0038] The term "biodegradable" refers to materials that are biodegradable, i.e., when placed in the human body. The term "intracameral implant" refers to a material or object (e.g., an intracameral implant according to the present invention). In the context of the form, as disclosed in detail below, the active ingredient is contained therein. When administered to the anterior segment of the eye, the implant containing the hydrogel slowly degrades over time. In certain embodiments, biodegradation occurs within the anterior corneal area of ​​the eye. This occurs at least in part via ester hydrolysis in the aqueous environment of the implant. The spheroid slowly softens, disintegrates, and passes through the aqueous humor outflow pathways to the crystalline lens via liquefaction and clearing. brings about clearance.

[0039] "Hydrogels" are, for example, polymers formed by chemical or physical crosslinking of individual polymer chains. It swells in water and retains a certain amount of water while maintaining or substantially maintaining its structure. one or more hydrophilic natural or synthetic polymers (as disclosed herein) that can Due to their high water content, hydrogels are soft and It is flexible and resembles natural tissue. In the present invention, the term "hydrogel" refers to Once the hydrogel contains water (e.g., after the hydrogel is formed in an aqueous solution, or Once inserted into the eye, after hydration or (re)hydration, or otherwise hydrogels in a hydrated state (after immersion in an aqueous environment, if any), and e.g. When the preparation is dried to a low moisture content of less than 100%, or when the preparation has a low moisture content without the need for a drying step. This refers to both the hydrogel in its dry (dry / dehydrated) state when the insert is formed. In the present invention, where the active ingredient is contained (e.g., dispersed) in the hydrogel, , the hydrogel may also be referred to as a "matrix."

[0040] The term "polymer network" refers to polymers that are cross-linked to each other (either the same or different molecules). The present invention describes structures formed from polymer chains (of the same or different molecular weights) and polymer structures. Suitable polymer types for clarity purposes are disclosed herein below. Polymer Nets The work involves reacting an electrophilic multi-arm polymer precursor with a nucleophilic crosslinker. It may be obtained by

[0041] The term "fiber" as disclosed herein refers to a fiber that is essentially cylindrical and has a diameter It refers to a shape characterized by its length and width.

[0042] The term "amorphous" refers to a polymer or polymers that do not exhibit crystalline structure in X-ray or electron scattering experiments. or polymer network.

[0043] The term "semicrystalline" refers to a material that has some crystalline characteristics, i.e., is crystalline when viewed by X-ray or electron Refers to a polymer or polymer network that exhibits some crystalline properties in scattering experiments. vinegar.

[0044] As used herein, "homogeneously dispersed" means that the travoprost or travoprost Components such as prost particles are distributed uniformly throughout the hydrogel or polymer network. This means that the information is uniformly distributed.

[0045] The term "precursors" as used herein refers to compounds that react with each other and thus bond through crosslinking. The molecules or molecules are connected to form a polymer network and thus a hydrogel matrix. refers to the compound, while other materials such as APIs and buffers may be present in the hydrogel. , they are not called "precursors."

[0046] The portion of the precursor molecule that is still present in the final polymer network is referred to herein as a "uniform polymer." Therefore, the "units" are polymer networks that form the hydrogel. For example, polymers suitable for use in the present invention are The networks may be made of the same or different polyethylenes, as further disclosed herein. It may contain units of ethylene glycol.

[0047] For purposes of this invention, the term "sustained release" refers to the availability of an API over an extended period of time. and thereby forming a solution of the API that is applied topically to the eye (e.g., Allows for reduced dosing frequency compared to immediate release formulations such as travoprost-containing eye drops It is meant to characterize a product that provides sustained release. Other terms that may be used are "extended release" or "controlled release." The term "sustained release" includes constant release of API in vitro.

[0048] The term "particle blend" defines a mixture of particles, where each component of the mixture is an individual component. It has a structure.

[0049] As used herein, the terms "repeated administration," "repeated application," or "repeated use" The intracameral implant is biodegradable in the eye and is used before use, and the same or equivalent of the present invention is used after use. in the anterior chamber of the eye after the same eye had been treated before with a similar intracameral implant. Refers to further treatment by inserting a clear API-containing intracameral implant into the anterior chamber. This includes continuous treatment, such as treatment for an unlimited period of time with repeated applications. can be.

[0050] As used herein, the term "polylactide" generally refers to a compound produced by the polycondensation of lactic acid. In other words, polylactide is a homopolymer obtained from lactic acid monomer units. Such polylactides may have acid or ester end groups, but Consisting of other monomer units in the polymer backbone, such as poly(lactic acid-co-glycolic acid), Polylactide is a polymer made from D-lactic acid, L-lactic acid, or any combination of D-lactic acid and L-lactic acid. In the latter case, the final polylactide is D, It may also be called L-polylactide.

[0051] The term "intrinsic viscosity" as used herein refers to the physical viscosity of polylactide (PLA). Polymers of different molecular weights are used to indicate the mechanical parameters. and 5.5E PLA, where the numbers are chloroforms that correlate to the PLA molecular weight. indicates the target intrinsic viscosity (IV) of the polymer in formaldehyde, and the letter suffix indicates the acid (A) end group or or ester (E) end groups. Measured in 0.5% w / v chloroform at 30°C. In this case, 4A PLA has an intrinsic viscosity of 0.35-0.45 dl / g; 7A PLA has an intrinsic viscosity of 0. 60~0.80dL / g; 9A PLA has an intrinsic viscosity of 0.80~1.0dL / g It has an intrinsic viscosity of 5.5E when measured in 0.1% w / v chloroform at 25°C. PLA has an intrinsic viscosity of 0.55 to 0.75 dl / g.

[0052] As used herein, the term "travoprost burst" refers to a relatively rapid burst of Travoprost from the implant within a short interval, e.g., on the first day after insertion Travoprost burst refers to the rapid initial release of travoprost as described herein. Under physiological conditions, e.g., 50 mL of 1x PBS, 0.5% castor oil, 0.01% fluoride Sodium fluoride buffer, pH 7.2-7.4, under simulated physiological sink conditions at 37°C. When measured in vitro, the decrease is between 10-20% within 1 day, e.g., within 1 day, e.g., about 1 0 to approximately 15% or less than 15% of travoprost release (intracameral implant) The term "burst" as used herein may include a It may also be used with other disclosed active agents. It will be reduced as it comes.

[0053] As used herein, the term "extended period" refers to an extended period of time in relation to the treatment of a disease. It refers to any period of time that would be considered by one skilled in the art to be sufficient, particularly at least about one week, and for at least about 1 month or more, for example, up to about 24 months, or as specifically mentioned herein. Any intermediate period as may be considered, for example, about 2 to 12 months, or 3 to about 9 months, or about 4 to about 7 months. It refers to a period such as a month, or about 3 to 6 months.

[0054] As used herein, the term "visualization agent" refers to a visualizing agent that, when inserted into the anterior segment of the eye, Contained within the implant's hydrogel, providing the possibility to easily visualize the implant Visualization agents refer to molecules or compositions that are capable of producing visible light. Visualization agents include fluoresceins, rhodamines, coumarins, and In certain embodiments, the visualization agent may be a fluorescent dye molecule such as a fluorescent dye or a cyanine. is a fluorescein or contains a fluorescein moiety.

[0055] As used herein, the term "aqueous humor" or "AH" refers to the fluid in the anterior chamber .

[0056] As used herein, the terms "bilaterally" or "bilateral" refer to the In the context of administering an implant, it refers to administering an implant to both eyes of a patient. Independent of the eyes.

[0057] The term "intracameral implant" refers to an implant that can be administered to the anterior segment of the eye and that penetrates the iridocorneal angle. This refers to implants that are present within the

[0058] "API", "active pharmaceutical ingredient", "active pharmaceutical agent", "active pharmaceutical ingredient" The terms "(active) therapeutic agent", "active", and "drug" are used interchangeably herein. Used interchangeably, and refer to any compound or compound that provides pharmacological activity or that diagnoses, cures, or alleviates disease, Having a direct effect on the treatment or prevention of disease or on the physiological function of a patient Used in finished pharmaceutical products (FPPs) that are intended to have a direct effect on the recovery, correction or modification of API refers to any substance used in the preparation of such a finished drug product, as well as any substance used in the preparation of such a finished drug product. In embodiments that are prostaglandin antagonists, the agent may be, for example, travoprostaglandin. The compound may be methadone, bimatoprost, or latanoprost.

[0059] The terms "treat," "treating," or "treatment" are used interchangeably. and conditions disclosed herein (e.g., ocular hypertension or glaucoma), or refers to the reversal, alleviation, delay in onset, or inhibition of progression of one or more of the symptoms of In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered after the onset of symptoms. before the disease (e.g., taking into account the history of symptoms and / or exposure to specific organisms, or other susceptibility factors), i.e., It may also be preventative treatment. Treatment may be continued after symptoms have resolved, for example to delay recurrence. It may be continued.

[0060] The terms "subject" and "patient" may be used interchangeably and refer to a person in need of treatment. mammals, such as pets (e.g., dogs, cats, etc.), livestock (e.g., cows, pigs, horses, etc.) "means animals (e.g., sheep, goats, etc.) and laboratory animals (e.g., rats, mice, guinea pigs, etc.) Preferably, the subject is a human in need of treatment.

[0061] According to a particular embodiment of the present invention, the API is travoprost. Travoprost, a prostaglandin F2α analogue, has high affinity for the prostaglandin FP receptor. It has anti-inflammatory properties and increases the outflow of aqueous humor through the trabecular meshwork and uveoscleral pathways. Travoprost is a highly selective full agonist that reduces intraocular pressure. Single enantiomers of fluprostenol, a selective FP prostaglandin agonist Travoprost is an isopropyl ester of prostaglandin F2α analogues. Class of drug esters (including latanoprost, bimatoprost, and tafluprost) It promotes penetration into the cornea and delivery of the active carboxylic acid (travoprost acid) to the aqueous humor. The prodrug ester is a compound that is cleaved by esterase in the cornea at carbons 17 to 20. Addition to the biologically active free acid substituted with a meta-trifluoromethylphenoxy group Compared to latanoprost, the free acid of travoprost is Based on the results of in vitro binding affinity studies, it was found that FP binds to the prostanoid receptor with even higher affinity. It was observed that the compound had high potency and even high selectivity. [ka]

[0062] As used herein, the term "therapeutically effective" refers to a compound that, after administration, produces a desired therapeutic result. This refers to the amount of API, e.g., travoprost, required to produce a desired effect. In the context of the invention, one desired therapeutic result may be, for example, a therapeutic effect measured in an in vivo test known to one skilled in the art. The reduction in IOP as measured by the trabecular pressure (TP) of the present invention is The amounts and doses of Prost refer to the isopropyl ester.

[0063] As used herein, the term "intraocular pressure" (IOP) is the fluid pressure within the eye. Intraocular pressure measurements, such as Goldmann tonometry, as detailed in Example 3 below. The conventional method is the method used by ophthalmic professionals to determine IOP.

[0064] As used herein, "corneal pachymetry" refers to a method used to measure the central corneal thickness of a subject. The central corneal thickness is measured using a method as defined in detail in Example 3 below. This is performed using an ultrasound pachymeter.

[0065] As used herein, "endothelial cell count" or "ECC" is defined in Example 3 below. The luminance is determined by specular microscopy as described above.

[0066] As used herein, the term "glaucoma" includes open-angle glaucoma and closed-angle glaucoma. The subtypes of open-angle glaucoma disclosed herein include: Normal tension glaucoma, congenital glaucoma, secondary glaucoma, pigmentary glaucoma, pseudoexfoliative glaucoma, traumatic glaucoma glaucoma, neovascular glaucoma, iridocorneal endothelial syndrome (ICE), and / or uveitis glaucoma may be included.

[0067] As used herein, "in the treated eye during the treatment period and / or the entire treatment" "No change in endothelial cell count" means that there is no clinically significant decrease in endothelial cell count. A single decrease of up to 20% from baseline in subjects during the treatment period and / or a sustained reduction of up to 10% from baseline in subjects during treatment is clinically acceptable.

[0068] As used herein, "in the treated eye during the treatment period and / or the entire treatment" "No change in corneal thickness or pachymetry due to the treatment" means that the pachymetry values ​​are clinically meaningful. This means that there is no significant decrease in the maximum A single decrease of 20% and / or up to 1% from baseline in subjects during the treatment period A sustained reduction of 0% is clinically acceptable.

[0069] As used herein, the term "open-angle glaucoma" refers to glaucoma classified under the ICD-10 code H Open-angle glaucoma is classified as mild, moderate, or severe. These can be broadly classified into four types:

[0070] As used herein, "ocular hypertension" generally refers to pressure within the eye, or IOP, that is abnormal. Refers to any condition that is higher than normal. Intraocular pressure is measured in millimeters of mercury (mmHg). Normal intraocular pressure is below 21mmHg, with an average of 16mmHg. Ocular hypertension is usually Intraocular pressure is greater than 21 mmHg. Intraocular pressure is related to the thickness of the cornea of ​​each individual. Even though the pressure is less than mmHg, people with thin corneas may have ocular hypertension, which means that the pressure in the eye A person with a thick cornea can have normal intraocular pressure despite having a blood pressure of over 21 mmHg. Therefore, it is common to apply a correction factor for variations in corneal thickness.

[0071] The term "about" when used herein in reference to a measured quantity by a person skilled in the art making the measurements and using a level of care commensurate with the purpose of the measurements and the precision of the measuring equipment. The normal variation in a measured quantity that is expected from a given condition.

[0072] The term "at least about" refers to the quantity measured and is used for the purpose and purpose of the measurement. The accuracy of the measuring equipment and the amount of care that would be expected by a person skilled in the art The term "normal" refers to the normal variation in the quantity measured, as measured by the normal

[0073] As used herein, the singular forms "a," "an," and "the" are used where the context clearly indicates. Unless otherwise indicated, plural references are included.

[0074] The term "and / or" as used in expressions such as "A and / or B" in this specification The term is intended to include both "A and B" and "A or B."

[0075] "include," "including," "contai" Open terms such as "contain" and "containing" are used as "c These open-ended transitional expressions mean Openness of elements, method steps, etc. that do not exclude additional, unrecited elements or method steps Used to introduce end lists.

[0076] Detailed Description Prostaglandin antagonist particles The prostaglandin antagonist (e.g., travoprost) particles of the present invention comprise: Prostaglandin antagonists (e.g., travoprostaglandins) mixed with biodegradable polymers For example, the particles are microparticles. Such particles are called microcapsules. It can be prepared by chemistry.

[0077] In specific embodiments, a prostaglandin antagonist (e.g., travoprost) The particles have a diameter in the range of about 1 to about 150 μm as determined by sieving, or or have an average diameter in the range of 1 to 150 μm as determined by laser diffraction. In a specific embodiment, the particles are from about 1 to about 100 μm, about having a diameter in the range of 20 to about 75 μm, about 20 to about 106 μm, or about 20 to about 55 μm. or about 1 to about 100 μm, about 20 to about 75 μm, as determined by laser diffraction; The average diameter ranges from about 20 to about 106 μm, or from about 20 to about 55 μm. In an embodiment, the average particle size is 36 μm as determined by laser diffraction.

[0078] In particular embodiments, the biodegradable polymer comprises polylactide. The relactide has acid or ester end groups.

[0079] In one embodiment, prostaglandin antagonist (e.g., travoprost) particles For example, a prostaglandin antagonist (e.g., prostaglandin A (e.g., travoprost) and a second polylactide. Various types of particles such as gin antagonists (e.g., travoprost) in the form of More specifically, the first and second polylactides are each a blend of acid powder. In a more specific embodiment, the first polylactide has an end group of about 0.05 to about 0 Intrinsic viscosity specifications in the range of 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 a viscosity of about 0.5 to about 0.80 dl / min. or having an intrinsic viscosity specification in the range of about 0.6 to about 0.80 dl / g. .

[0080] In certain embodiments, a prostaglandin antagonist (e.g., travoprost) The particles consist of two types of particles: first, a protease inhibitor mixed with a biodegradable polymer consisting of polylactide; A first type of particle is in the form of a staglandin antagonist (e.g., travoprost). and a prostaglandin A compound mixed with a second biodegradable polymer consisting of polylactide. a blend with a second type of particle in the form of an antagonist (e.g., travoprost) It consists of.

[0081] In one embodiment, the first and second polylactides are in a ratio of about 1.5:1 to about 1:1.5; have a mass ratio in the particle blend of about 1:1.

[0082] In one embodiment, prostaglandin antagonist (e.g., travoprost) particles The first polylactide is mixed with a prostaglandin antagonist (e.g., thiazol-3-yl). prostaglandin A (prostaglandin B) in the form of particles mixed with a second polylactide. and a third polylactide in the form of particles of an agonist (e.g., travoprost). and particles in the form of a prostaglandin antagonist (e.g., travoprost). , a blend of various types of particles, each of which has an acid end group. Specifically, the first polylactide has a viscosity in the range of about 0.05 to less than about 0.5 dL / g. or an intrinsic viscosity specification in the range of about 0.35 to about 0.45 dl / g, and the second polylactate The concentration is in the range of about 0.5 to less than about 0.80 dL / g or 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 has an intrinsic viscosity specification in the range of about 0.8 to about 1.0 dl / g.

[0083] More specifically, the biodegradable polymer consists of three types of particles: first, polylactide; Prostaglandin antagonists (e.g., travoprostaglandins) mixed with biodegradable polymers a first type of particle in the form of a granule, and a second type of biodegradable polymer comprising polylactide. In the form of a prostaglandin antagonist (e.g., travoprost) mixed with The second type of particles is made of a biodegradable polymer, and the third type is made of a biodegradable polymer, polylactide. A third type of particle is a form of staglandin antagonist (e.g., travoprost). It includes a blend of three types of particles, e.g., consisting of them.

[0084] In a further embodiment, the mass ratio of the first to second polylactides in the particle blend is: It is about 2:1 to about 1:2, or about 1:1.6.

[0085] In another embodiment, the weight ratio of the first and third polylactides in the particle blend is about 2 :1 to about 1:2, or about 1:1.4.

[0086] In another embodiment, prostaglandin antagonist (e.g., travoprost) particles The child is a prostaglandin antagonist (e.g., thiamin) mixed with a first polylactide. particles in the form of laboprost and a prostaglandin A compound mixed with a second polylactide. and a third polylactide in the form of particles of a steroid antagonist (e.g., travoprost). particles in the form of a prostaglandin antagonist (e.g., travoprost) and Prostaglandin antagonists (e.g., travoprostaglandins) mixed with polylactides of 4 It is a blend of various types of particles, including particles in the form of granules (stone).

[0087] More specifically, the first polylactide has a viscosity in the range of about 0.05 to less than about 0.5 dL / g; or having an intrinsic viscosity specification in the range of about 0.35 to about 0.45 dL / g and having an acid end group. and the second polylactide has a viscosity in the range of about 0.5 to less than about 0.80 dL / g or about 0.6 to about a third polylactate having an intrinsic viscosity specification in the range of less than 0.8 dl / g and having acid end groups; The concentration is 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. The fourth polylactide has an intrinsic viscosity specification and has an acid end group. dL / g, for example, in the range of about 0.55 to about 0.75 dL / g, and It has a ster end group.

[0088] Even more particularly, prostaglandin antagonists (e.g., travoprost) The particles consist of four types: first, a polymer blended with a biodegradable polymer consisting of polylactide; The first type is in the form of a prostaglandin antagonist (e.g., travoprost). particles and a prostaglandin mixed with a second biodegradable polymer comprising polylactide. a second type of particle in the form of an antagonist (e.g., travoprost) and a third type of particle Prostaglandin antagonists ( A third type of particle is in the form of a drug (e.g., travoprost), and a fourth type is composed of polylactide. prostaglandin antagonists (e.g., trabeculopeptides) mixed with biodegradable polymers The blend may also include a fourth type of particle in the form of a powder (lost particles), e.g. It may also consist of:

[0089] In another embodiment, the weight ratio of the first and second polylactides in the particle blend is about 1 .25:1 to about 1:1.25, or about 1:1.

[0090] In a further embodiment, the mass ratio of the first and third polylactides in the particle blend is It is about 3:1 to about 1:1, or about 2:1.

[0091] In a further embodiment, the mass ratio of the first and fourth polylactides in the particle blend is It is about 1:1 to about 1:3, or about 1:2.5 or about 1:2.6.

[0092] In certain embodiments, a prostaglandin antagonist (e.g., travoprost) and biodegradation of prostaglandin antagonist (e.g., travoprost) particles. The mass ratio between the total amount of the hydroxyl group and the total amount of the hydroxyl group is about 2:1 to 1:2, or about 0.77:1.

[0093] In certain embodiments, a prostaglandin antagonist (e.g., travoprost) The particles are composed of a prostaglandin antagonist (e.g., travoprost) and a biodegradable polymer. comprising, consisting of, or consisting essentially of a pharmaceutically acceptable carrier and other pharmaceutically acceptable ingredients. It consists of them.

[0094] In certain embodiments, the travoprost particles comprise: (1) Travoprost acid end groups and about 0.05 to less than about 0.5 dL / g, for example about 0.35 to about 0.45 dL Biodegradable polymers consisting of one or more polylactides with intrinsic viscosity specifications in the range of 1 / g a first type of travoprost particles made of a mixture of In this case, for example, the first type of particles may be about 40% by weight based on the total mass of the first type of particles. A first formulation containing about 43% to about 45% by weight of travoprost. types of travoprost particles and; (2) Travoprost acid end groups and from about 0.5 to less than about 0.80 dl / g, for example from about 0.6 to about 0.80 dl / g Biodegradable polymers comprising one or more polylactides having an intrinsic viscosity specification in the range of less than 1000 g. a second type of travoprost particles made of a mixture with mer, In this case, for example, the second type of particles may be about 40% by weight based on the total mass of the second type of particles. a second formulation containing about 45% to about 47% by weight of travoprost; types of travoprost particles and; (3) Travoprost acid end groups and from about 0.8 to less than about 1.7 dl / g, for example from about 0.8 to about 1.0 dl / g and a biodegradable polymer comprising one or more polylactides having an intrinsic viscosity specification in the range A third type of travoprost particles made of a mixture, In this case, for example, the third type of particles may be about 40% by weight based on the total mass of the third type of particles. a third formulation containing about 41% to about 43% by weight of travoprost; types of travoprost particles and; (4) Travoprost Ester end groups and about 0.05 to about 1.7 dL / g, for example about 0.55 to about 0.75 dL / g Biodegradable polymers consisting of one or more polylactides with intrinsic viscosity specifications in the range of 1 / g. A fourth type of travoprost particles made of a mixture with mer, In this case, for example, the fourth type of particles is about 40% by weight based on the total mass of the fourth type of particles. A fourth formulation containing about 41% to about 43% by weight of travoprost. and at least two types of travoprost particles selected from the group consisting of It is a blend of stone particles.

[0095] In certain embodiments, the travoprost particles comprise: (1) Travoprost One or more polymers having acid end groups and an intrinsic viscosity specification in the range of about 0.05 to less than about 0.5 dl / g A first type of travoprost particles comprising a biodegradable polymer including a plurality of polylactides. , In this case, the first type of particles are about 40% by weight to about 50% by weight based on the total mass of the first type of particles. a first type of travoprost particles comprising travoprost in an amount of 0.01 wt.%; (2) Travoprost - One or more polymers having acid end groups and an intrinsic viscosity specification in the range of about 0.5 to less than about 0.80 dl / g and a second type of travoprost particle comprising a biodegradable polymer containing a plurality of polylactides. , In this case, the second type of particles is about 40% by weight to about 50% by weight based on the total mass of the second type of particles. a second type of travoprost particles comprising travoprost in an amount of 0.01 wt.%; (3) Travoprost one or more polymers having an acid end group and an intrinsic viscosity specification in the range of about 0.8 to about 1.7 dl / g and a biodegradable polymer comprising polylactide; In this case, the third type of particles is about 40% by weight to about 50% by weight based on the total mass of the third type of particles. a third type of travoprost particles comprising travoprost in an amount of 0.01 wt.%; (4) Travoprost 1 or 2 having ester end groups and an intrinsic viscosity specification ranging from about 0.05 to about 1.7 dl / g and a biodegradable polymer containing polylactide. child, In this case, the fourth type of particles is about 40% by weight to about 50% by weight based on the total mass of the fourth type of particles. a fourth type of travoprost particles containing at least 100% by weight of travoprost; Both are blends of two types of travoprost particles.

[0096] In certain embodiments, the travoprost particles comprise: (1) Travoprost and an acid end group and about 0.05 to about less than 0.5 dl / g, for example, about One or more polylactides having an intrinsic viscosity specification in the range of 0.35 to about 0.45 dl / g. A first type of travoprost particles made of a mixture of a biodegradable polymer and a In this case, the first type of particles are about 40% by weight to about 50% by weight based on the total mass of the first type of particles. % by weight, for example, about 43% to about 45% by weight of travoprost. With boprost particles; (2) Travoprost and an acid end group and about 0.5 to about less than 0.80 dL / g, for example, about one or more polylactides having an intrinsic viscosity specification in the range of 0.6 to less than about 0.80 dl / g; a second type of travoprost particles made of a mixture of travoprost and a biodegradable polymer comprising travoprost; In this case, the second type of particles is about 40% by weight to about 50% by weight based on the total mass of the second type of particles. A second type of travoprost containing travoprost in an amount of about 45% to about 47% by weight, for example, about 45% to about 47% by weight. A blend of particles made of boprost particles and In this case, for example, the blend may contain about 35% to about 55% by weight of the total amount of the blend. a first type of particles and about 35% to about 55% by weight of a second type of particles; and teeth For example, about 35% to about 55% by weight of the total amount of travoprost in the implant is The total amount of travoprost in the implant is approximately 35 times that of the original amount of travoprost. % to about 55% by weight are present in the form of a second type of particles; Optionally, the polymer network comprises a multi-arm polymer precursor containing an electrophilic group and a nucleophilic group. The electrophilic group is formed by reacting the crosslinker with succinimidyl glutarate. The multi-arm polymer precursor is an 8-arm-15K-SG polyethylene. the nucleophilic group-containing crosslinker is trilysine, or the polymer network The workpiece is the following formula: [ka] wherein m is 2. Includes recalls.

[0097] In certain embodiments, the travoprost particles comprise: (1) Travoprost and an acid end group and about 0.05 to about less than 0.5 dl / g, for example, about One or more polylactides having an intrinsic viscosity specification in the range of 0.35 to about 0.45 dl / g. A first type of particle made of a mixture of a biodegradable polymer and a polymer comprising a The second type of particles may be present in an amount of about 40% by weight to about 50% by weight, for example, based on the total mass of the first type of particles. a first type of particles containing about 43% to about 45% by weight of travoprost; (2) Travoprost and an acid end group and about 0.5 to about less than 0.80 dL / g, for example, about one or more polylactides having an intrinsic viscosity specification in the range of 0.6 to less than about 0.80 dl / g; a second type of travoprost particles made of a mixture of travoprost and a biodegradable polymer comprising travoprost; In this case, the second type of particles is about 40% by weight to about 50% by weight based on the total mass of the second type of particles. A second type of travoprost containing travoprost in an amount of about 45% to about 47% by weight, for example, about 45% to about 47% by weight. Boprost particles; (3) Travoprost and an acid end group and about 0.8 to about 1.7 dl / g, for example, about 0.8 Consists of one or more polylactides having an intrinsic viscosity specification in the range of about 1.0 dl / g A third type of travoprost particles made of a mixture with a biodegradable polymer, wherein the third The particles of the second kind are about 40% by weight to about 50% by weight based on the total mass of the particles of the third kind, for example For example, a third type of travoprost containing about 41% to about 43% by weight of travoprost. It is a blend of particles made from In this case, for example, the blend may contain about 20% by weight to about 35% by weight of the total amount of the blend. a first type of particles, about 30% to about 50% by weight of a second type of particles, and about 25% to about 50% by weight of a about 45% by weight of a third type of particles; or For example, about 20% by weight to about 35% by weight of the total amount of travoprost in the implant is The total amount of travoprost in the implant is approximately 30 times that of the original amount of travoprost. % to about 50% by weight of the second type of particles are present in the form of particles of the second type, and the second type of particles are present in the implant. about 25% to about 45% by weight of the total amount of voprost is present in the form of a third type of particles; Optionally, the polymer network comprises a multi-arm polymer precursor containing an electrophilic group and a nucleophilic group. The electrophilic group is formed by reacting the crosslinker with succinimidyl glutarate. The multi-arm polymer precursor is an 8-arm-15K-SG polyethylene. the nucleophilic group-containing crosslinker is trilysine, or the polymer network The workpiece is given by the following formula: [ka] wherein m is 2. Includes recalls.

[0098] In certain embodiments, the travoprost particles comprise: (1) Travoprost and an acid end group and about 0.05 to about less than 0.5 dl / g, for example, about One or more polylactides having an intrinsic viscosity specification in the range of 0.35 to about 0.45 dl / g. A first type of particle made of a mixture of a biodegradable polymer and a polymer comprising a The second type of particles may be present in an amount of about 40% by weight to about 50% by weight, for example, based on the total mass of the first type of particles. a first type of particles containing about 43% to about 45% by weight of travoprost; (2) Travoprost and an acid end group and about 0.5 to about less than 0.80 dL / g, for example, about one or more polylactides having an intrinsic viscosity specification in the range of 0.6 to less than about 0.80 dl / g; A second type of particle is made of a mixture of a biodegradable polymer and a tide, wherein the second The particles of one type are present in an amount of about 40% by weight to about 50% by weight, based on the total mass of the particles of the second type, for example a second type of particles containing about 45% to about 47% by weight of travoprost; (3) Travoprost and an acid end group and about 0.8 to about 1.7 dl / g, for example, about 0.8 Consists of one or more polylactides having an intrinsic viscosity specification in the range of about 1.0 dl / g a third type of particle made of a biodegradable polymer, wherein the third type of particle is a third type of About 40% by weight to about 50% by weight, for example, about 41% by weight to about 40% by weight based on the total mass of the particles. a third type of particles containing 3% by weight of travoprost; (4) Travoprost and an ester end group and about 0.05 to about 1.7 dl / g, for example, one or more polylactides having an intrinsic viscosity specification in the range of about 0.55 to about 0.75 dl / g; and a biodegradable polymer comprising a tide, wherein the fourth type of particle The blend of particles is made of a fourth type of particles containing about 40% to about 50% by weight of the fourth type of particles. It is In this case, for example, the blend may contain about 15% to about 25% by weight of the total amount of the blend. the first type of particles, about 15% to about 25% by weight of the second type of particles, and about 5% to about 1 Contains 5% by weight of a third type of particles and about 40% to about 60% by weight of a fourth type of particles. or For example, about 15% by weight to about 25% by weight of the total amount of travoprost in the implant is The total amount of travoprost in the implant is approximately 15 times that of the original amount of travoprost. % to about 25% by weight are present in the form of a second type of particles, About 5% by weight to about 15% by weight of the total amount of the resin is present in the form of a third type of particles, and Approximately 40% to 60% by weight of the total amount of travoprost in the plant is the fourth type of particles. exists in the form of a child, Optionally, the polymer network comprises a multi-arm polymer precursor containing an electrophilic group and a nucleophilic group. The electrophilic group is formed by reacting the crosslinker with succinimidyl azelate. The multi-arm polymer precursor is an 8-arm-15K-SAZ polyester. the nucleophilic group-containing crosslinker is trilysine, or the polymer network The network is based on the following formula: [ka] wherein m is 6. Includes recalls.

[0099] In certain embodiments, the travoprost particles comprise: (1) Travoprost and its acid end groups and intrinsic hydroxyl groups in the range of about 0.05 to less than about 0.5 dl / g Contains a mixture of one or more polylactides with a biodegradable polymer having a viscosity specification a first type of travoprost particles, wherein the first type of particles is a total mass of the first type of particles; A first type of travoprost containing about 40% to about 50% by weight of travoprost based on the amount of travoprost. Laboprost particles and; (2) Travoprost and its acid end groups and intrinsic hydroxybenzoates in the range of about 0.5 to less than about 0.80 dL / g Contains a mixture of one or more polylactides with a biodegradable polymer having a viscosity specification a second type of travoprost particles, wherein the second type of particles is a total mass of the second type of particles; A second type of travoprost containing about 40% to about 50% by weight of travoprost based on the amount of travoprost. a blend of particles comprising: In this case, the blend may contain from about 35% to about 55% by weight of the first species, based on the total weight of the blend. The composition comprises a first type of particles and about 35% to about 55% by weight of a second type of particles.

[0100] In certain embodiments, the travoprost particles comprise: (1) Travoprost and its acid end groups and intrinsic hydroxyl groups in the range of about 0.05 to less than about 0.5 dl / g Contains a mixture of one or more polylactides with a biodegradable polymer having a viscosity specification a first type of particle, wherein the first type of particle is, based on the total mass of the first type of particle, a first type of particles containing about 40% to about 50% by weight of travoprost; (2) Travoprost and its acid end groups and intrinsic hydroxybenzoates in the range of about 0.5 to less than about 0.80 dL / g Contains a mixture of one or more polylactides with a biodegradable polymer having a viscosity specification a second type of travoprost particles, wherein the second type of particles is a total mass of the second type of particles; A second type of travoprost containing about 40% to about 50% by weight of travoprost based on the amount of travoprost. Prost particles and (3) Travoprost and a copolymer having an acid end group and an intrinsic viscosity in the range of about 0.8 to about 1.7 dl / g. a third polymer containing a mixture of one or more biodegradable polymers containing polylactide having a hydroxyl group; type of travoprost particles, wherein the third type of particles is based on the total mass of the third type of particles. and a third type of travoprost containing about 40% by weight to about 50% by weight of travoprost. a blend of particles comprising: In this case, the blend may contain from about 20% to about 35% by weight of the first species, based on the total weight of the blend. a first type of particles, about 30% to about 50% by weight of a second type of particles, and about 25% to about 45% by weight of a % by volume of a third type of particle.

[0101] In certain embodiments, the travoprost particles comprise: (1) Travoprost and its acid end groups and intrinsic hydroxyl groups in the range of about 0.05 to less than about 0.5 dl / g Contains a mixture of one or more polylactides with a biodegradable polymer having a viscosity specification a first type of particle, wherein the first type of particle is about 100% by mass based on the total mass of the first type of particle; a first type of particles containing 40% to about 50% by weight of travoprost; (2) Travoprost and its acid end groups and intrinsic hydroxybenzoates in the range of about 0.5 to less than about 0.80 dL / g Contains a mixture of one or more polylactides with a biodegradable polymer having a viscosity specification a second type of particle, wherein the second type of particle is, based on the total mass of the second type of particle, a second type of particles containing about 40% to about 50% by weight of travoprost; (3) Travoprost and a copolymer having an acid end group and an intrinsic viscosity in the range of about 0.8 to about 1.7 dl / g. a third type of particle comprising one or more biodegradable polymers including polylactide having a granular structure; In this case, the third type of particles is about 40% by weight to about 40% by weight based on the total mass of the third type of particles. a third type of particles containing about 50% by weight of travoprost; (4) Travoprost and a compound having an ester end group and a solid content in the range of about 0.05 to about 1.7 dl / g and a fourth biodegradable polymer comprising one or more polylactides having a viscosity rating. a fourth type of particles, wherein the fourth type of particles comprises about 40% to about 50% by weight; and a blend of particles including: In this case, the blend may contain from about 15% to about 25% by weight of the first species, based on the total weight of the blend. a first type of particles, about 15% to about 25% by weight; a second type of particles, about 5% to about 15% by weight; The third type of particles and about 40% to about 60% by weight of the fourth type of particles.

[0102] In another embodiment, the particles are spherical particles.

[0103] According to a first particular aspect, the present invention provides a method for producing a cellular membrane comprising: Prostaglandin antagonists (e.g., travoprost), acid end groups and about 0.05 to less than about 0.5 dL / g, for example about 0.35 to about 0.45 dL / g and a biodegradable polymer consisting of polylactide having an intrinsic viscosity specification in the range of The prostaglandin antagonist (e.g., travoprost) particles are targeted , In this case, the mixture is about 40% by weight to about 50% by weight, for example, about 4 3% to about 45% by weight of a prostaglandin antagonist (e.g., travoprost ) contains.

[0104] According to a second specific aspect, the present invention provides a method for producing a medicament for the treatment of a pulmonary arthritis, comprising: Prostaglandin antagonists (e.g., travoprost), acid end groups and from about 0.5 to less than about 0.80 dl / g, for example from about 0.6 to about 0.80 dl / g and a biodegradable polymer comprising polylactide having an intrinsic viscosity specification in the range of less than 1000 g. Prostaglandin antagonist (e.g., travoprost) granules made from a mixture of Aimed at children, In this case, the mixture is about 40% by weight to about 50% by weight, for example, about 4 5% to about 47% by weight of a prostaglandin antagonist (e.g., travoprost ) contains.

[0105] According to a third specific aspect, the present invention provides a method for producing a medicament for the treatment of a pulmonary arthritis, comprising: Prostaglandin antagonists (e.g., travoprost) and acid end groups and a range of about 0.8 to about 1.7 dl / g, for example, about 0.8 to about 1.0 dl / g A polymer made of a mixture of a biodegradable polymer and a polylactide having an intrinsic viscosity specification of Prostaglandin antagonist (e.g., travoprost) particles are targeted In this case, the mixture is about 40% by weight to about 50% by weight, for example, about 4 1% to about 43% by weight of a prostaglandin antagonist (e.g., travoprost ) contains.

[0106] According to a fourth aspect, the present invention provides a method for producing a medicament for the treatment of a pulmonary arthritis, comprising Prostaglandin antagonists (e.g., travoprost), Ester end groups and about 0.05 to about 1.7 dL / g, for example about 0.55 to about 0.75 dL / g and a biodegradable polymer consisting of polylactide having an intrinsic viscosity specification in the range of 1 / g. Prostaglandin antagonist (e.g., travoprost) granules made from a mixture of Aimed at children, In this case, the mixture is about 40% by weight to about 50% by weight, for example, about 4 1% to about 43% by weight of a prostaglandin antagonist (e.g., travoprost ) contains.

[0107] According to aspect (a), the present invention provides a method for producing a pharmaceutical composition comprising: Travoprost and acid end groups and about 0.05 to less than about 0.5 dL / g, for example about 0.35 to about 0.45 dL / g and a biodegradable polymer consisting of polylactide having an intrinsic viscosity specification in the range of The target is the travoprost particles produced, In this case, the mixture is about 40% by weight to about 50% by weight, for example, about 4 It contains 3% to about 45% by weight of travoprost.

[0108] According to aspect (b), the present invention provides a method for producing a composition comprising: Travoprost and acid end groups and from about 0.5 to less than about 0.80 dl / g, for example from about 0.6 to about 0.80 dl / g Blends of biodegradable polymers with polylactides having intrinsic viscosity specifications in the range of less than 1000 g The target is travoprost particles made of In this case, the mixture is about 40% by weight to about 50% by weight, for example, about 4 It contains 5% to about 47% by weight of travoprost.

[0109] According to aspect (c), the present invention provides a method for producing a composition comprising: Travoprost and acid end groups and in the range of about 0.8 to about 1.7 dl / g, for example, about 0.8 to about 1.0 dl / g The mixture is made of a biodegradable polymer consisting of polylactide having an intrinsic viscosity specification in the range of The target is travoprost particles, In this case, the mixture is about 40% by weight to about 50% by weight, for example, about 4 It contains 1% to about 43% by weight of travoprost.

[0110] According to aspect (c), the present invention provides a method for producing a composition comprising: Travoprost and Ester end groups and a range of about 0.05 to about 1.7 dl / g, for example, about 0.55 to about 0. and biodegradable polymers consisting of polylactide with intrinsic viscosity specifications in the range of 75 dl / g. The present invention is directed to travoprost particles made of a mixture, In this case, the mixture is about 40% by weight to about 50% by weight, for example, about 4 It contains 1% to about 43% by weight of travoprost.

[0111] As part of one embodiment, the travoprost in the disclosed implant is The remaining features of the implant are described herein. Alternatively, the travoprost in the disclosed implant may be poly(lactic acid-co- poly(lactic acid) (PLGA) or poly(lactic acid) (PLA), or a combination thereof microencapsulated, and the remaining characteristics of the implant are described herein. In another alternative, the travoprost in the disclosed implants is PL A, and the remaining characteristics of the implant are as described herein. There are.

[0112] Biodegradable hydrogels In certain embodiments of the present invention, prostaglandin antagonists (e.g., trabeculopeptides) are used. The (lost) particles are dispersed in a biodegradable hydrogel, as defined above. Therefore, prostaglandin antagonist (e.g., travoprost) particles are In certain embodiments, the hydrogel is distributed within a matrix of the hydrogel. In certain embodiments, prostaglandin antagonist (e.g., travoprost) particles is uniformly dispersed in the biodegradable polymer.

[0113] In certain embodiments, the hydrogel comprises one or more units of polyethylene glycol. It includes a polymer network.

[0114] In certain embodiments of the present invention, the polymer network forming the hydrogel is polyethylene. It contains ethylene glycol (PEG) units, which form a hydrogel when crosslinked. These PEG hydrogels are known in the art to be biocompatible, e.g., in the human body. or as a matrix for a drug intended to be administered to all parts of the animal's body. It is suitable for medicinal use.

[0115] The polymer network of the hydrogel implant of the present invention may have 2 to 10 arms, or 4 to 8 arms, or one or more multi-arm Ps with 4, 5, 6, 7, or 8 arms In certain embodiments, the P used in the hydrogels of the present invention may contain EG units. The EG unit has eight arms. In certain particular embodiments, the eight-armed PEG is It will be used.

[0116] In certain embodiments, the polyethylene glycol unit is a 4- to 10-arm polyethylene glycol unit. It is an eight-arm polyethylene glycol unit, or an eight-arm polyethylene glycol unit.

[0117] The molecular weight of polyethylene glycol refers to the average molecular weight, which is the number average molecular weight (Mn) Various average molecular weights known to those skilled in the art, including weight average molecular weight (Mw) and peak average molecular weight (PWM), are also known. Any of such average values, and in particular the three aforementioned average values, may be selected. In certain embodiments, the molecular weights disclosed herein can be used in the context of the present invention. The average molecular weight of the polyethylene glycol unit and precursor is the number average molecular weight. and is given.

[0118] As used herein, a multi-arm PEG unit having a particular molecular weight is, for example, For example, 8a15kPEG refers to an 8-arm PEG with a molecular weight of 1,5000 daltons. This may be done.

[0119] In a 4-arm PEG, each arm has an average arm length (also The precursor 4a20kP is particularly suitable for use in the present invention. The EG precursor thus contains four arms, each with an average molecular weight of approximately 5,000 daltons. The compound may be used in combination with or in place of the 4a20kPEG precursor in the present invention. The 8a20kPEG precursors may thus each have an average molecular weight of 2,500 daltons. It has eight arms with different weights. The longer arms offer improved flexibility compared to the shorter arms. PEG with long arms swells more than PEG with short arms. PEG with fewer arms swells and is more flexible than PEG with more arms. In certain particular embodiments, only four-arm PEG precursors are utilized in the present invention. In certain particular embodiments, two different four-arm PEG precursors are utilized in the present invention. In certain other embodiments, a combination of a 4-arm PEG precursor and an 8-arm precursor is used. In addition, the longer the PEG arm, the higher the melting temperature when dried. This may provide additional dimensional stability during storage.

[0120] In certain embodiments, the polymer network is an electrophilic group-containing multi-arm polymer. They are formed by reacting a precursor with a cross-linking agent containing a nucleophilic group. The polymer precursor is a 4-10 arm polyethylene glycol precursor or an 8 arm In certain embodiments, the precursor is polyethylene glycol.

[0121] In certain embodiments, the PEG precursors used in conjunction with the hydrogels of the present invention include: The electrophilic end group for this is an N-hydroxysuccinimidyl (NHS) ester. , including succinimidyl malonate groups, succinimidyl maleate groups, succin "SAZ" referring to the succinimidyl fumarate group, "SAZ" referring to the succinimidyl azelate end group, and "Succinimidyl azelate" referring to the succinimidyl fumarate end group. "SAP" refers to succinimidyl adipate end groups, and "SAP" refers to succinimidyl glutarate end groups. NHS dimers such as "SG" referring to the succinimidyl succinate end group, and "SS" referring to the succinimidyl succinate end group. These include, but are not limited to, carboxylic acid esters.

[0122] In certain embodiments, the multi-arm polymer precursor is an 8-arm-15K-SG polymer. polyethylene glycol or 8-arm-15K-SAZ polyethylene glycol are selected.

[0123] In certain embodiments, the electrophilic groups are succinimidyl glutarate (SG) groups and succinimidyl glutarate (SG) groups. cinimidyl azelate (SAZ) groups.

[0124] In certain embodiments of the present invention, the polymer network comprises an electrophilic group-containing multi-arm polymer. The polymer precursor is formed by reacting with a crosslinker containing a nucleophilic group, and the electrophilic group is Succinimidyl glutarate (SG) and succinimidyl azelate (SAZ) groups and the multi-arm polymer precursor is selected from the group consisting of 8-arm-15K-SG polyethylene. polyethylene glycol or 8-arm-15K-SAZ polyethylene glycol and the nucleophilic group-containing crosslinker is trilysine, or 8-arm-15K-SA Z polyethylene glycol; and the nucleophilic group-containing crosslinker is trilysine, or -The network has the following formula: [ka] wherein m is 2 or 6. Contains ethylene glycol.

[0125] Thus, in certain embodiments, the PEG precursor can be represented by the formula NHS Dicarboxylate-terminated multi-arm PEG precursor: [ka] In the formula, n is determined by the molecular weight of each PEG arm, and m is an integer from 0 to 10. Specifically, x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, and x is the number of arms. is a number (so it can be, for example, 2, 4, 8, etc., see above) When m is 1, each arm is terminated with a succinimidyl succinate (SS) end group. When m is 2, each arm is terminated with a succinimidyl glutarate (SG) group. , when m is 3, each arm terminates in a succinimidyl adipate (SAP) group; and when m is 6, each arm terminates in a succinimidyl azelate (SAZ) group. With these specific electrophilic end groups, the multi-arm PEG unit can be, for example, 4a It may be omitted in the form of 20kPEG-SAP, which has a succinimidyl adipate terminal group and In the above formula, R represents the desired number of arms. For the 4-arm PEG unit and precursor, R can be a pentaerythritol structure, whereas 8-arm PEG units and In the case of the precursor, R can be a hexaglycerol structure.

[0126] In certain embodiments, the multi-arm polymer precursor has a molecular weight of from about 10,000 to about 20,000. In more specific embodiments, the polymer has a weight average molecular weight in the range of 100 to 150 Daltons. The thiame polymer precursor has a weight average molecular weight of 15,000±10% Daltons.

[0127] The molecular weight of polyethylene glycol and polyethylene glycol derivatives was determined using SDS-PA Gel electrophoresis, such as GE (sodium dodecyl sulfate-polyacrylamide gel electrophoresis) Gel permeation chromatography (GPC), GPC with dynamic light scattering (DLS), and Similarly, matrix-assisted laser desorption / ionization time-of-flight (MALDI-TOF) spectroscopy As disclosed herein, The molecular weight of the polyethylene glycol precursor was determined by SDS-PAGE, GPC, and MALDI. The determination can be performed by any method known to those skilled in the art, including time of flight (TOF), in particular by The molecular weight (e.g., as determined by MALDI-TOF) and polydispersity (e.g., Determined by GPC using PEG standards (determined by GPC). High accuracy. If this is required, MALDI-TOF can be used.

[0128] In certain embodiments, for example, an activated ester group-containing PEG unit of an amine group-containing crosslinker may be used. The reaction of a nucleophilic group-containing crosslinker with an electrophilic group-containing PEG unit, such as the reaction with , resulting in multiple PEG units being crosslinked by a crosslinker via amide groups.

[0129] Succinimidyl azelate (SAZ), succinimidyl adipate (SAP) or succinimidyl glutaric acid (SG)-terminated PEG units (see above). In the case of PEG with NHS-ester end groups, such as , a plurality of P's are crosslinked by a crosslinker via a hydrolyzable linker having the formula Bring on the EG unit: [ka] In the formula, m is an integer from 0 to 10, specifically 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10. For SAZ end groups, m is 6. For SAP end groups, m is 3, for SG end groups m is 2, and for SS end groups m is 1.

[0130] In certain embodiments, the nucleophilic group-containing crosslinker is an amine.

[0131] In another embodiment, the nucleophilic group-containing crosslinker is a molecule containing two or more primary aliphatic amine groups. It is a small molecule amine with an amount of less than 1,000 Da.

[0132] In certain embodiments, the nucleophilic group-containing crosslinker is a dilysine, trilysine, tetralysine, Ethylenediamine, 1,3-diaminopropane, 1,3-diaminopropane, diethylene a small molecule amine selected from the group consisting of triamine, and trimethylhexamethylenediamine; It's Min.

[0133] In one embodiment, the nucleophilic group-containing crosslinker is trilysine. The nucleophilic group-containing cross-linking agent is trilysine acetate.

[0134] In another embodiment, trilysine is selected from the group consisting of fluorescein, rhodamine, coumarin, and cyano. The antibody is labeled with a visualization agent selected from the group consisting of fluorophores such as thiazolinone. The nucleophilic group-containing crosslinker is fluorescein-conjugated trilysine. Oleoscein-conjugated trilysine is prepared by cleaving trilysine acetate with N-hydroxysuccinimide (NH More specifically, it can be obtained by reacting with tri(S)-fluorescein. The lysines are labeled by partial conjugation with a visualization agent.

[0135] In certain embodiments, the implant does not contain a visualization agent, e.g., trilysine is a visualization agent. Not labeled with the dye.

[0136] As part of one embodiment, provided herein is a compound comprising travoprost and a polymerase A sustained-release biodegradable intracameral hydrogel implant containing a vitreous network.

[0137] As part of further embodiments, the polymer nematics of the disclosed hydrogel implants The network (e.g., as in the first embodiment) is composed of a plurality of polyethylene glycols (P Includes EG) units.

[0138] As part of further embodiments, the disclosed implants may include a plurality of polyethylene terephthalates. The ethylene glycol (PEG) units are crosslinked to form a complex having at least two arms. forming a polymer network containing a number of multi-arm PEG units, The remaining features of the runt are as described herein, for example, as in the first or second embodiment. Alternatively, as part of a third embodiment, the polymer of the disclosed implant may be - the network comprises a plurality of multi-arm PEG units having 2 to 10 arms, The remaining features of the implant are as described herein, for example, in the embodiments above. In another alternative, the polymer network of the disclosed implants may comprise 4 to 8 The remaining features of the implant include a plurality of multi-armed PEG units having arms. , for example, as described herein above. In another alternative, The polymer network of the implant contains multiple four-arm PEG units, The remaining features of the component are as described herein, for example, above. The polymer network of the disclosed implant is composed of multiple 8-arm PEG units. The remaining features of the implant are described above.

[0139] As part of further embodiments, the polymer networks of the disclosed implants The compound is a PEG copolymer having a number average molecular weight (Mn) ranging from about 5 KDa to about 50 KDa. The remaining features of the implant are as described herein. The polymer network of the implant has a mean molecular weight ranging from about 5KDa to about 40KDa. The remaining characteristics of the implant are as follows: In another alternative, the polymer network of the disclosed implants The polymer comprises multiple PEG units having number-average molecular weights (Mn) ranging from about 5 KDa to about 30 KDa. The remaining features of the implant are as described herein. The polymer network of the disclosed implants has a molecular weight of about 10 KDa to about 50 KDa. The implant comprises a plurality of PEG units having a number average molecular weight (Mn) in the range of Other features are described herein. In another alternative, the disclosed implant The polymer network has a number average molecular weight (Mn) ranging from about 10 KDa to about 40 KDa. The remaining features of the implant are as described herein. In another alternative, the polymer network of the disclosed implants has a molecular weight of about 1 Multiple PEG units with number average molecular weights (Mn) ranging from 0 KDa to approximately 30 KDa The remaining features of the implant are as described herein. The polymer network of the implants is in the range of approximately 10KDa to approximately 20KDa. and a plurality of PEG units having a number average molecular weight (Mn) of 0.01 to 0.01, and the remaining characteristics of the implant In another alternative, the polymers of the disclosed implants The mer network has a number average molecular weight (Mn) ranging from about 30 KDa to about 50 KDa. The remaining characteristics of the implant include multiple PEG units as described herein. In another alternative, the polymer network of the disclosed implants may have a molecular weight of about 35 KD a plurality of PEG units having a number average molecular weight (Mn) ranging from about 40 to about 45 KDa; The remaining features of the implant are described herein. The polymer network of the implant has a number average molecular weight ranging from about 15 KDa to about 30 KDa. The remaining characteristics of the implant are as defined in the present invention. In another alternative, the polymer network of the disclosed implants The network is made up of multiple polymers having a number average molecular weight (Mn) in the range of about 15 KDa to about 25 KDa. The remaining characteristics of the implant include the PEG unit as described herein. Alternatively, the polymer network of the disclosed implants has a viscosity of at least about 5 KD. the remainder of the implant comprises a plurality of PEG units having a number average molecular weight (Mn) of a The features are described herein. In another alternative, the disclosed implants The polymer network comprises a plurality of polymers having a number average molecular weight (Mn) of at least about 10 KDa. The remaining features of the implant, including the EG unit, are as described herein. In one embodiment, the polymer network of the disclosed implant has a viscosity of at least about 15 KD. the remainder of the implant comprises a plurality of PEG units having a number average molecular weight (Mn) of a The features are described herein. In another alternative, the disclosed implants The polymer network comprises a plurality of polymers having a number average molecular weight (Mn) of at least about 20 KDa. The remaining features of the implant, including the EG unit, are as described herein. In one embodiment, the polymer network of the disclosed implant has a viscosity of at least about 30 KD. the remainder of the implant comprises a plurality of PEG units having a number average molecular weight (Mn) of a The features are described herein. In another alternative, the disclosed implants The polymer network comprises a plurality of polymers having a number average molecular weight (Mn) of at least about 40 KDa. The remaining features of the implant, including the EG unit, are as described herein. By way of example, the polymer network of the disclosed implant has a number average molecular weight of about 10 KDa. The remaining characteristics of the implant are as defined in the present invention. In another alternative, the polymer network of the disclosed implants The network comprises a plurality of PEG units having a number average molecular weight (Mn) of about 15 KDa. The remaining features of the implant are described herein. The polymer network of the implant has a number average molecular weight (Mn) of approximately 20 KDa. The remaining characteristics of the implant are as described herein. In another alternative, the polymer network of the disclosed implants has a viscosity of about 40 KD. the remainder of the implant comprises a plurality of PEG units having a number average molecular weight (Mn) of a The features are described herein.

[0140] In a further embodiment, the polymer network of the disclosed implant is hydrolyzed. The disclosed implants comprise a plurality of PEG units cross-linked by a degradable linker. The remaining features of the implant are described herein. Alternatively, the disclosed implant The polymer network has the following formula: [ka] wherein m is an integer of 1 to 9. and the remaining characteristics of the implant are described herein. In the alternative, the polymer network of the disclosed implant has the following formula: [ka] wherein m is an integer of 2 to 6. and the remaining characteristics of the implant are described herein. In the alternative, the polymer network of the disclosed implant has the following formula: [ka] (where n represents an ethylene oxide repeat unit, and the wavy lines represent the polymer network. The implant contains multiple PEG units with repeating units (representing the repeating units) Other features are described herein. In another alternative, the disclosed implant The polymer network of 8 contains multiple PEG units having the formula shown above. The remaining features of the implant, along with the PEG scaffolding of the arms, are as described herein.

[0141] In further embodiments, the polymer network of the disclosed hydrogel implants The compound is composed of multiple polyethylene glycol (PEG) units containing groups susceptible to nucleophilic attack. The polymer is formed by reacting the hydroxy group with one or more nucleophilic groups to form a polymer network. The remaining characteristics of the hydrogel are described herein. Examples of suitable groups include activated esters (e.g., thioesters, succinimidyl esters, benzyl esters, esters of acrylic acid, etc.) Examples of suitable nucleophilic groups include, but are not limited to, amines and thiols. I can't.

[0142] In further embodiments, the polymer network of the disclosed hydrogel implants Each of the nucleophiles has a molecular weight as described above in the fourth embodiment, and One or more polyethylene glycol (PEG) units containing groups susceptible to sexual attack formed by reacting with the nucleophilic groups of the The remaining characteristics of the gel are as described herein, for example, in the first to sixth embodiments. Alternatively, as part of the seventh embodiment, the disclosed hydrogel implant Each of the polymer networks may be any of the polymer networks described above in the fourth embodiment. Polyethylene glycols ( Reacting PEG) units with one or more nucleophilic groups to form a polymer network The remaining characteristics of the hydrogel are, for example, those of the first to sixth embodiments. As described herein, in another alternative, as part of the seventh embodiment, The polymer network of the hydrogel implant shown is 4a20K PEG S AZ, 4a20K PEG SAP, 4a20K PEG SG, 4a20K PEG SS, 8a20K PEG SAZ, 8a20K PEG SAP, 8a20K PEG Polyethylene glycol (PE) selected from SG, 8a20K PEG SS G) units, and the remaining characteristics of the hydrogel are determined by, for example, As in the first to sixth embodiments, they are described herein.

[0143] In further embodiments, the polymer network of the disclosed hydrogel implants The compound is composed of multiple polyethylene glycol (PEG) units containing groups susceptible to nucleophilic attack. The polymer is formed by reacting the amine group with one or more amine groups to form a polymer network. The remaining characteristics of the hydrogel are as described herein. The polymer network of the hydrogel implant contains multiple groups that are susceptible to nucleophilic attack. Polyethylene glycol (PEG) units of one or more PEG or lysine-based amino acids The hydrogel is formed by reacting the hydroxyl groups with the hydroxyl groups to form a polymer network. The remaining features are described herein. In another alternative, the disclosed hydrogel The polymer network of the implant is composed of multiple polyesters containing groups susceptible to nucleophilic attack. ethylene glycol (PEG) units: 4a20K PEG NH2, 8a20K PE G NH2, and one or more PEG or lysine bases selected from trilysine or a salt thereof The remaining characteristics of the hydrogel are as described herein. It is written.

[0144] As part of further embodiments, the polymer networks of the disclosed implants is amorphous (e.g., under aqueous conditions such as in vivo), and the remaining characteristics of the implant are As described herein.

[0145] Alternatively, as part of further embodiments, the polymeric nanoparticles of the disclosed implants may be The network is semi-crystalline (e.g., in the absence of water), and the remaining characteristics of the composition are as described herein. It is stated in the book.

[0146] As part of further embodiments, the travoprost of the disclosed implants is a poly The remaining characteristics of the implant are as described herein. It is listed.

[0147] Diversity of prostaglandin antagonist (e.g., travoprost) particles In one aspect, the present invention provides a multi-prostaglandin antagonist formed from a blend of particles. The present invention relates to agonist (e.g., travoprost) particles, the particles comprising: Prostaglandin antagonists (e.g., travoprost), a raw material consisting of a polylactide as defined in the above embodiment, having acid end groups; a degradable polymer; Optionally, in admixture with other pharmaceutically acceptable ingredients, e.g. It consists of.

[0148] In certain embodiments, the blend of particles is comprised of three types of particles, wherein the three types of particles are The products are distinguished from one another by including polylactide components having different intrinsic viscosities.

[0149] More specifically, each of the three polylactides has a viscosity of less than about 0.05 to about 0.5 dl / g. for example, in the range of about 0.35 to about 0.45 dL / g; in the range of less than about 0.6 to about 0.8 dL / g, for example, in the range of less than about 0.6 to about 0.8 dL / g; and Intrinsic viscosity specifications in the range of about 1.7 dl / g, for example, in the range of about 0.8 to about 1.0 dl / g Has.

[0150] In another embodiment, the blend of particles is comprised of two types of particles, wherein the two types of particles The products are distinguished from one another by containing polylactide components with different intrinsic viscosities. More specifically, each of the two polylactides has a viscosity of about 0.05 to about 0.5 dl / g or less. range, for example, from about 0.35 to about 0.45 dl / g; and from about 0.5 to about 1.7 dl / g, for example, in the range of about 0.6 to about 0.8 dl / g.

[0151] In certain embodiments, the travoprost particles have a molecular weight of 1 to 10 as determined by sieving. diameters ranging from 0 μm, 20-75 μm, 20-106 μm, or 20-55 μm , or 1-100 μm, 20-75 μm, 20-106 μm, as determined by laser diffraction μm, or have an average diameter in the range of 20 to 55 μm.

[0152] In a specific aspect, the present invention provides a method for treating prostaglandin-related disorders, comprising administering to a subject a prostaglandin-related disorder, e.g., a prostaglandin antagonist, Particles according to the first to fourth specific embodiments of the "(e.g., travoprost) particles," such as particles Based on the total amount of the prostaglandin antagonist, about 15 to about 25% by weight of the prostaglandin antagonist and about 15 to about 200 mg of travoprost (e.g., travoprost) particles according to a first specific embodiment of the present invention. 25% by weight of the section "Prostaglandin antagonist (e.g., travoprost) ) particles" and about 5 to about 15% of the section "Prostagram Particles according to a third aspect of the "Language antagonist (e.g., travoprost) particles" and and about 40 to about 60% by weight of a prostaglandin antagonist (e.g., A multi-prostasic compound formed from a blend of particles according to the fourth aspect of the "Laboprost" particle. prostasidin antagonist (e.g., travoprost) particles or About 15% by weight to about 2% by weight of the total amount of staglandin antagonist (e.g., travoprost) 5% by weight is a prostaglandin antagonist (e.g., travoprost) The compound is present in the form of particles according to a first specific embodiment of the present invention, and a prostaglandin antagonist is About 15% to about 25% by weight of the total amount of agonist (e.g., travoprost) is A second specific example of "prostaglandin antagonist (e.g., travoprost) particles" In one embodiment, the compound is present in the form of particles, and the compound is a prostaglandin antagonist (e.g., About 5% by weight to about 15% by weight of the total amount of Laboprost) is Particles according to a third specific embodiment of "antagonist (e.g., travoprost) microparticles" and the total amount of prostaglandin antagonists (e.g., travoprost) About 40% by weight to about 60% by weight of the amount is a prostaglandin antagonist (e.g., For example, the compound is present in the form of particles according to the fourth specific embodiment of "travoprost (for example) particles."

[0153] In another specific embodiment, the present invention provides the compounds described in the section "Prostaglandin Antagonists ( Particles according to the first to third specific embodiments of the "travoprost (e.g., travoprost) particles," such as particles Based on the total weight of the product, about 20 to about 35% by weight of the section "Prostaglandin Antagonists" and about 30 particles according to a first specific embodiment of the "antiseptic (e.g., travoprost) particles." ~ Approximately 50% by weight of the section "prostaglandin antagonist (e.g., travoprostaglandin) and about 25 to about 45% of the section "Particles" according to the second specific embodiment of the present invention. A third specific embodiment of prostaglandin antagonist (e.g., travoprost) particles Various prostaglandin antagonists (e.g., For example, travoprost) particles, or prostaglandin antagonists ( For example, about 20% by weight to about 35% by weight of the total amount of travoprost is According to a first specific embodiment of the "grandilagin antagonist (e.g., travoprost) particles" and prostaglandin antagonists (e.g., travoprosulfone). Approximately 30% to 50% by weight of the total amount of the prostaglandin antagonist The compound (e.g., travoprost) is present in the form of particles according to a second specific embodiment of the present invention. and about 25 times the total amount of a prostaglandin antagonist (e.g., travoprost). Approximately 45% by weight of the compound is a prostaglandin antagonist (e.g., traboviral). The compound is present in the form of particles according to a third specific embodiment of the present invention.

[0154] In a further specific aspect, the present invention provides the compounds described in the section "Prostaglandin Antagonists." Particles according to the first and second specific embodiments of "travoprost (e.g., travoprost) particles," e.g. , about 35 to about 55 wt. % of the section "Prostaglandin Amino Acids" based on the total amount of particles. and a particle according to a first specific embodiment of the "anti-agonist (e.g., travoprost) particle" and about 35 to approximately 55% by weight of the section "prostaglandin antagonist (e.g., trabo A multi-prototype formed from a blend of particles according to a second specific embodiment of the "prototype" particles. directed to staglandin antagonist (e.g., travoprost) particles, or About 35% by weight of the total amount of prostaglandin antagonist (e.g., travoprost) Approximately 55% by weight is described in the section "Prostaglandin antagonists (e.g., travoprostaglandins) The prostaglandin A is present in the form of particles according to the first specific embodiment of the "particles" About 35% by weight to about 55% by weight of the total amount of the antagonist (e.g., travoprost) is The second component of the "prostaglandin antagonist (e.g., travoprost) particle" The material is present in the form of particles according to the physical embodiment.

[0155] According to one embodiment, the present invention provides particles of embodiments (a) to (d) disclosed herein, e.g. For example, about 15 to about 25% by weight of the embodiments disclosed herein ( a) particles and about 15 to about 25 wt. % of particles of embodiment (b) disclosed herein; and about 5 to about 15% of the particles of embodiment (c) disclosed herein and about 40 to about 60 weight percent A variety of particles formed from a blend of particles of embodiment (d) disclosed herein in a volume percent or about 15% by weight to about 25% by weight of the total amount of travoprost % is in the form of particles of embodiment (a) disclosed herein, and about travoprost 15% by weight to about 25% by weight of the total amount of the particles of embodiment (b) disclosed herein and about 5% to about 15% by weight of the total amount of travoprost is present in the composition disclosed herein. and the travoprost is present in the form of particles of embodiment (c) in which the travoprost is present in an amount of about 40% by weight to about 100% by weight of the total amount of the travoprost. 60% by weight is present in the form of particles of embodiment (d) disclosed herein.

[0156] According to one embodiment, the present invention provides particles according to embodiments (a) to (c) disclosed herein, e.g. For example, about 20 to about 35% by weight of the embodiments disclosed herein ( a) particles and about 30 to about 50 wt. % of particles of embodiment (b) disclosed herein; and about 25 to about 45 weight percent of the particles of embodiment (c) disclosed herein. or about 2% of the total amount of travoprost. 0% to about 35% by weight is in the form of particles of embodiment (a) disclosed herein; and about 30% by weight to about 50% by weight of the total amount of travoprost is in the form disclosed herein. and the amount of travoprost is about 25% by weight to about 45% by weight of the total amount of travoprost. % is present in the form of particles according to embodiment (c) disclosed herein.

[0157] According to one embodiment, the present invention provides a method for producing particles of embodiments (a) and (b), e.g., particles based on the total amount of particles. about 35 to about 55% by weight of the particles of embodiment (a) and about 35 to about 55% by weight of the particles of embodiment (b) or a blend of travoprost particles formed from a mixture of travoprost particles; about 35% to about 55% by weight of the total amount of prost is present in the form of particles of embodiment (a); and Approximately 35% to 55% by weight of the total amount of travoprost is present in the form of particles (b).

[0158] In another aspect, the present invention provides a blend of particles: Travoprost and a biodegradable polymer consisting of polylactide having acid end groups; Optionally, from a blend of particles consisting of a mixture with other pharmaceutically acceptable residual manufacturing ingredients. The present invention relates to various travoprost particles formed from the above.

[0159] Biodegradable intracameral sustained release prostaglandin antagonists (e.g., travoprost) Implants According to one aspect, the present invention provides a method for manufacturing a semiconductor device comprising: The preceding section and / or the section above entitled "Prostaglandin Antagonists" Various prostaglandins, such as those defined in the "Prostaglandin Particles" (e.g., travoprost) antagonist (travoprost) particles and Various prostaglandin antagonists (e.g., travoprost) particles are dispersed within the polymer, as defined in the section "Biodegradable Hydrogels" above. and a biodegradable hydrogel. The present invention relates to a sustained-release biodegradable intracameral implant of a drug (e.g., travoprost).

[0160] According to another aspect, the present invention provides a method for manufacturing a method of manufacturing a semiconductor device comprising: Biodegradable hydrogels, as defined above in the section "Biodegradable Hydrogels" and the section above "Prostaglandin antagonists (e.g., travoprost) Prostaglandin antagonist (travoprost) particles as defined in , Prostaglandin antagonists mixed with polylactide (e.g., travopros) prostaglandin antagonist (travoprost) particles in the form of Prostaglandin antagonists (e.g., trabeculopeptides) dispersed within the hydrogel prostaglandin antagonists (e.g., prostaglandin antagonists) containing, for example, consisting of, particles The present invention relates to a sustained-release biodegradable intracameral implant for the treatment of rheumatoid arthritis (e.g., travoprost), wherein the hydrogel is The gel is an 8-arm polymer, each with a mass average molecular weight of 15,000±10% Daltons. 15K-SG or 8-arm-15K-SAZ polyethylene glycol with tri-lysine acetate The polymer network formed by reacting the polymer with a salt.

[0161] According to another aspect, the present invention provides a method for manufacturing a method of manufacturing a semiconductor device comprising: The hydrogel is a polymer network containing one or more units of polyalkylene glycol. and a biodegradable hydrogel containing travoprost particles. Travoprost particles in the form of travoprost mixed with a biodegradable polymer; The present invention relates to an intracameral implant comprising travoprost particles dispersed within a hydrogel. Let's say.

[0162] According to another aspect, the present invention provides a method for manufacturing a method of manufacturing a semiconductor device comprising: The hydrogel is a polymer network containing one or more units of polyalkylene glycol. a biodegradable hydrogel comprising travoprost particles; Travoprost particles in the form of travoprost mixed with a biodegradable polymer; A travoprost sustained-release composition comprising travoprost particles dispersed within a hydrogel. Targeting biodegradable intracameral implants, In this case, the implant will be approximately 1.00mm to 2.50mm long and 0. Has a diameter of 30 mm or less.

[0163] According to another aspect, the present invention provides a method for manufacturing a method of manufacturing a semiconductor device comprising: (i) a polymer network comprising one or more units of polyalkylene glycol; ii) a biodegradable hydrogel comprising sustained-release travoprost particles; Sustained-release travoprost particles comprising travoprost and at least one biodegradable polymer With my child, an intracameral implant comprising sustained-release travoprost particles dispersed within a hydrogel; The target is.

[0164] In certain embodiments, the implant has a length in its dry state of about 1 mm to about 2.5 mm, Its diameter in dry state is 0.3 mm or less, and its weight in dry state is about 20 μg to about 110 μg It has a total weight.

[0165] In certain embodiments, the implant is prepared in phosphate buffered saline at a pH of 7.4 at 37°C. After hydration in a test tube with water for 24 hours, it has a diameter of less than 0.5 mm.

[0166] In certain embodiments, the implant is prepared in phosphate buffered saline at a pH of 7.4 at 37°C. After 24 hours of hydration in a test tube with water, the diameter ranges from about 0.3 mm to about 0.49 mm. do.

[0167] In certain embodiments, the implant is adapted to be an intracameral implant.

[0168] In certain embodiments, the hydrogel dissolves within 2 to 4 months when implanted in the eye. .

[0169] In certain embodiments, the hydrogel dissolves within 6 to 8 months when implanted in the eye. .

[0170] Without wishing to be bound by theory, the hydrogel implant is inserted into the anterior chamber of the eye. small enough to sink into the iridocorneal angle (e.g., below Schwalbe's line) when After that, it swells sufficiently by absorbing aqueous humor, and is thereby fixed to the iridocorneal angle. , and therefore is not expected to move during the entire period in which it is placed there. The implants become increasingly soft, allowing them to adapt better to anatomical conditions. This allows any further movement to be prevented before the hydrogel completely degrades. The immobilization and soft tissue-like texture are gentle on the endothelium and the entire implant. It provides substantial safety and therefore allows repeated administration. Because of this potential, such implants are suitable for a wide range of anatomical conditions, including narrow iridocorneal angles. It is believed to be suitable for the condition.

[0171] The following embodiments relate to each of the aspects described in the previous paragraph.

[0172] In one embodiment, prostaglandin antagonist (e.g., travoprost) particles The present invention relates to a method for preparing a biodegradable polymeric material comprising two types of particles: a first type of biodegradable polymer consisting of polylactide as defined above; Forms of prostaglandin antagonists (e.g., travoprost) mixed with a riboflavin and a second polylactide as defined above. Prostaglandin antagonists (e.g., travoprostaglandins) mixed with biodegradable polymers and optionally, including, for example, consisting of, a blend with a second type of particle in the form of a granular material. Optionally, the intracameral implant does not contain additional polylactide.

[0173] In another embodiment, prostaglandin antagonist (e.g., travoprost) particles The child may be a mixture of various types of particles, for example, a first polylactide as defined above. particles in the form of a prostaglandin antagonist (e.g., travoprost) mixed with and a prostaglandin mixed with a second polylactide as defined above. a blend of particles in the form of an antagonist (e.g., travoprost), optionally in the anterior chamber; The intra-implant does not contain any additional polylactide.

[0174] In certain embodiments, the travoprost particles as described herein comprise at least is also a blend of two types of travoprost particles, the blend comprising: (1) Travoprost and an acid end group and about 0.05 to about 0.5 dl / g or less, for example, One or more polylactides having an intrinsic viscosity specification in the range of about 0.35 to 0.45 dl / g. A first type of travoprost particles made of a mixture of a biodegradable polymer and a At this time, the first type of particles account for about 40% by weight to about 50% by weight based on the total mass of the first type of particles. A first type of formulation containing travoprost in an amount of, for example, about 43% to about 45% by weight. with travoprost particles; Travoprost and an acid end group and about 0.5 to about 0.80 dl / g or less, for example, about 0. One or more polylactides having an intrinsic viscosity specification ranging from 6 to less than about 0.80 dl / g A second type of travoprost particles made of a mixture with a biodegradable polymer comprising In this case, the second type of particles is about 40% by weight to about 50% by weight based on the total mass of the second type of particles. %, for example, about 45% to about 47% by weight of travoprost. Laboprost particles and a blend of particles made of In this case, for example, the blend may contain about 35% to about 55% by weight of the total amount of the blend. a first type of particle and about 35% to about 55% by weight of a second type of particle, or For example, about 35% to about 55% by weight of the total amount of travoprost in the implant is The total amount of travoprost in the implant is approximately 35 times that of the original amount of travoprost. % to about 55% by weight are present in the form of a second type of particles; Optionally, the polymer network may comprise a multi-arm polymer precursor containing an electrophilic group and a nucleophilic group. The electrophilic group is formed by reacting the crosslinker with succinimidyl glutarate. The multi-arm polymer precursor is an 8-arm-15K-SG polyethylene. the nucleophilic group-containing crosslinker is trilysine; (2) Travoprost and an acid end group and about 0.05 to about 0.5 dl / g or less, for example, one or more polylactides having an intrinsic viscosity specification in the range of about 0.35 to about 0.45 dl / g; A first type of particle made of a mixture of a biodegradable polymer and a tide, wherein the first The first type of particles is present in an amount of about 40% to about 50% by weight, based on the total mass of the first type of particles, e.g. a first type of particles containing about 43% to about 45% by weight of travoprost; Travoprost and an acid end group and about 0.5 to about 0.80 dl / g or less, for example, about 0. One or more polylactides having an intrinsic viscosity specification ranging from 6 to less than about 0.80 dl / g A second type of travoprost particles made of a mixture with a biodegradable polymer comprising In this case, the second type of particles is about 40% by weight to about 50% by weight based on the total mass of the second type of particles. %, for example, about 45% to about 47% by weight of travoprost. Boprost particles; Travoprost and an acid end group and about 0.8 to about 1.7 dl / g, for example, about 0.8 to about A raw material consisting of one or more polylactides having an intrinsic viscosity specification in the range of 1.0 dl / g. a third type of travoprost particles made in a mixture with a degradable polymer, wherein the third type The particles of the third type are about 40% by weight to about 50% by weight, for example, based on the total mass of the particles of the third type. A third type of travoprost granule containing about 41% to about 43% by weight of travoprost. Blending particles made with children, In this case, for example, the blend may contain about 20% to about 35% by weight of the first component based on the total weight of the blend. one type of particles, about 30% by weight to about 50% by weight of a second type of particles, and about 25% by weight to about 45% by weight of a third type of particles; or For example, about 20% by weight to about 35% by weight of the total amount of travoprost in the implant is The total amount of travoprost in the implant is approximately 30 times that of the original amount of travoprost. % to about 50% by weight of the implant is in the form of a second type of particle; and about 25% to about 45% by weight of the total amount of voprost is present in the form of a third type of particles; Optionally, the polymer network may comprise a multi-arm polymer precursor containing an electrophilic group and a nucleophilic group. The electrophilic group is formed by reacting the crosslinker with succinimidyl glutarate. The multi-arm polymer precursor is an 8-arm-15K-SG polyethylene. the nucleophilic group-containing crosslinker is trilysine; (3) Travoprost and an acid end group and about 0.05 to about 0.5 dl / g or less, for example, one or more polylactides having an intrinsic viscosity specification in the range of about 0.35 to about 0.45 dl / g; A first type of particle made of a mixture of a biodegradable polymer and a tide, wherein the first The first type of particles is present in an amount of about 40% to about 50% by weight, based on the total mass of the first type of particles, e.g. a first type of particles containing about 43% to about 45% by weight of travoprost; Travoprost and an acid end group and about 0.5 to about 0.80 dl / g or less, for example, about 0. One or more polylactides having an intrinsic viscosity specification ranging from 6 to less than about 0.80 dl / g A second type of particle made of a mixture with a biodegradable polymer comprising: The particles are about 40% by weight to about 50% by weight, for example, about a second type of particles containing 45% to about 47% by weight of travoprost; Travoprost and an acid end group and about 0.8 to about 1.7 dl / g, for example, about 0.8 to about A raw material consisting of one or more polylactides having an intrinsic viscosity specification in the range of 1.0 dl / g. a third type of particles made of a degradable polymer, wherein the third type of particles are About 40% by weight to about 50% by weight, for example, about 41% by weight to about 43% by weight, based on the total mass of the particles. a third type of particles containing travoprost in an amount of 0.05 wt. %; Travoprost and an ester end group and about 0.05 to about 1.7 dl / g, for example, about 0 One or more polylactides having an intrinsic viscosity specification ranging from 0.55 to about 0.75 dl / g and a fourth type of particle made of a biodegradable polymer comprising: a fourth type of particle containing about 40% to about 50% by weight of the first type of particle; In this case, for example, the blend may contain about 15% to about 25% by weight of the total amount of the blend. the first type of particles, about 15% to about 25% by weight of the second type of particles, and about 5% to about 1 Contains 5% by weight of a third type of particles and about 40% to about 60% by weight of a fourth type of particles. or For example, about 15% by weight to about 25% by weight of the total amount of travoprost in the implant is The total amount of travoprost in the implant is approximately 15 times that of the original amount of travoprost. % to about 25% by weight are present in the form of a second type of particles, About 5% by weight to about 15% by weight of the total amount of the resin is present in the form of a third type of particles, and Approximately 40% to 60% by weight of the total amount of travoprost in the plant is the fourth type of particles. exists in the form of a child, Optionally, the polymer network may comprise a multi-arm polymer precursor containing an electrophilic group and a nucleophilic group. The electrophilic group is formed by reacting the crosslinker with succinimidyl azelate. The multi-arm polymer precursor is an 8-arm-15K-SAZ polyester. the nucleophilic group-containing crosslinker is trilysine; is selected from.

[0175] In a further embodiment, the intracameral implant is administered under sink conditions at a pH of 7.2 to 7.4. % amount released per 70 days from day 1 to day 84 when measured at 37℃ in BS Based on this, the average prostaglandin concentration ranges from about 65% to about 85%, with a mean absolute deviation of at most 5%. In vitro release of proglandin antagonists (e.g., travoprost) .

[0176] In certain embodiments, the implant is prepared in 50 mL of 1× HCl at 37° C. with a pH of 7.2-7.4. Simulated physiological conditions in PBS, 0.5% castor oil, and 0.01% sodium fluoride buffer. Travoprosthesis of intracameral implants measured in vitro at day 1 under basin conditions The burst is less than 15% based on the total weight of the sample.

[0177] In a further embodiment, the implant provides a dose of 250 to 550 ng / week with a standard deviation of 450 to 550 ng / week. The average dose of prostaglandin antagonists (e.g., 100 mg / week) ranges from about 800 to about 1100 ng / week. For example, travoprost) release in vitro, where the average is under sink conditions, When measured at 37°C in PBS with a pH of 7.2-7.4, the burst was observed on the first day after administration. Weekly prostaglandin antagonists (e.g., travoprost) between days 7 and 98 ) based on release values; or measured under sink conditions in PBS pH 7.2-7.4 at 37°C. If specified, measurements should be taken at time intervals between days 7 and 98 after administration, excluding the burst on day 1. and weekly release of prostaglandin antagonists (e.g., travoprost) is approximately 10 The range is 0 to approximately 2300 ng.

[0178] In another embodiment, prostaglandin antagonist (e.g., travoprost) particles The child is a prostaglandin mixed with a first polylactide as defined above. Particles in the form of an antagonist (e.g., travoprost) and a medicament as defined above. a prostaglandin antagonist (e.g., Traboquinone) mixed with a suitable second polylactide; and a third polylactide as defined above. and particles in the form of a prostaglandin antagonist (e.g., travoprost). , a blend of various types of particles, each of which has an acid end group. and optionally the intracameral implant does not comprise an additional polylactide.

[0179] In one embodiment, prostaglandin antagonist (e.g., travoprost) particles The present invention relates to a method for preparing biodegradable polymer particles comprising three types of particles: first, a biodegradable polymer consisting of polylactide as defined above; Forms of prostaglandin antagonists (e.g., travoprost) mixed with a riboflavin and a second polylactide as defined above. Prostaglandin antagonists (e.g., travoprostaglandins) mixed with biodegradable polymers a second type of particles in the form of a polylactate (polylactate), and a third type of particles in the form of a polylactate (polylactate), as defined above. a prostaglandin compound mixed with a biodegradable polymer as defined above, comprising a Blend with a third type of particle in the form of a steroid antagonist (e.g., travoprost). and optionally the intracameral implant further comprises a polylactide. Does not include.

[0180] In a further embodiment, the intracameral implant is administered under sink conditions at a pH of 7.2 to 7.4. % amount released per 70 days from day 1 to day 98 when measured at 37℃ in BS Based on the average absolute deviation of 5% at most, the average prostaglandin concentration ranges from about 60% to about 80%. In vitro release of proglandin antagonists (e.g., travoprost) .

[0181] In certain embodiments, the implants provide a dose with a standard deviation in the range of 450 to 550 ng / week. The average prostaglandin antagonist (e.g., For example, travoprost) release in vitro, where the average is under sink conditions, p When measured in PBS at 37°C from H7.2 to H7.4, the burst was observed on the first day after administration. Weekly prostaglandin antagonists (e.g., travoprost) between days 7 and 98 Based on release values; or measured under sink conditions in PBS pH 7.2-7.4 at 37°C When measured at time intervals between days 7 and 98, excluding the burst on day 1 after administration, Weekly release of prostaglandin antagonists (e.g., travoprost) is approximately 100 ~ about 2300ng.

[0182] In certain embodiments, a prostaglandin antagonist (e.g., travoprost) The particles are comprised of a prostaglandin compound mixed with a first polylactide as defined above. and a compound in the form of a steroid antagonist (e.g., travoprost) as defined above. A prostaglandin antagonist (e.g., thiamin-3-one) mixed with a second polylactide such as and a third polylactide as defined above. particles in the form of a prostaglandin antagonist (e.g., travoprost) and a prostaglandin antagonist mixed with a fourth polylactide as defined above; The blending of various types of particles, including particles in the form of steroids (e.g., travoprost), and optionally the intracameral implant comprises a further polylactate. Does not contain chido.

[0183] In a further embodiment, a prostaglandin antagonist (e.g., travoprost) ) particles are composed of four types of particles: a first polylactide biomaterial as defined above; A prostaglandin antagonist (e.g., travoprost) mixed with a degradable polymer a first type of particle in the form of a polylactide; and a second type of particle in the form of a polylactide, as defined above. A prostaglandin antagonist (e.g., trastuzumab) mixed with a biodegradable polymer comprising a second type of particle in the form of poly(voprost) and a third type of particle as defined above. Prostaglandin antagonists (e.g., hydroxybenzoates) mixed with lactide-based biodegradable polymers a third type of particle in the form of a steroid (e.g., travoprost) and a third type of particle in the form of a steroid (e.g., travoprost) as defined above; Prostaglandin antagonists blended with a fourth polylactide-based biodegradable polymer. and a fourth type of particle in the form of a steroid (e.g., travoprost). or consisting thereof, and optionally the intracameral implant further comprises a polylactide. do not have.

[0184] In certain embodiments, the intracameral implant is placed in PB at a pH of 7.2 to 7.4 under sink conditions. % amount released per 14 days from day 1 to day 112 when measured at 37°C in S Based on the average absolute deviation of 3% at most, the average prostaglandin ranges from about 5% to about 15%. It has in vitro release by releasing a lanin antagonist (e.g., travoprost).

[0185] In a further embodiment, the total weight of the travoprost sustained-release biodegradable intracameral implant is The content of the biodegradable polymer is about 10% by weight to about 35% by weight, or about 23% by weight to about About 27% by weight, or about 12 to about 17% by weight, or about 30 to about 35% by weight, or about 2 5% by weight, or about 15% by weight, or about 34% by weight.

[0186] In another embodiment, the biodegradable fraction of the total weight of one sustained-release biodegradable intracameral implant is The content of the soluble polymer is about 30% by weight to about 70% by weight, or about 32% by weight to about 37% by weight. , or about 45 to about 55% by weight, or about 60 to about 70% by weight, or about 49.3% by weight , or about 37.5% by weight, or about 50.1% by weight, or about 66.8% by weight.

[0187] According to a further embodiment, the total weight of one sustained-release biodegradable intracameral implant is The content of the nucleophilic group-containing crosslinking agent is about 1 to about 5% by weight, or 1 to about 3% by weight, or 2 to about 5% by weight. about 4% by weight, or 4 to about 5% by weight, or about 3.2% by weight, or about 2.3% by weight, or or about 4.3% by weight.

[0188] In certain embodiments, the visible to the total weight of one sustained-release biodegradable intracameral implant The content of the stabilizer is about 0.1 to about 0.5 wt %, or 0.2 wt %, or 0.3 wt %. do.

[0189] In further embodiments, the implant contains from about 2 μg to about 30 μg, or from about 21 μg to about 30 μg, or about 11 μg to about 20 μg, or about 2 μg to about 10 μg of travopros In a specific embodiment, the implant contains about 5 μg of travoprost. In another specific embodiment, the implant contains about 15 μg of travopro In an alternative specific embodiment, the implant contains about 26 μg of Contains a dose of Lavoprost.

[0190] In certain embodiments, 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.

[0191] In certain embodiments, the implant contains less than 25 μg of travoprost, or Less than 0 μg or less than 10 μg.

[0192] In certain embodiments, the total mass of the implant in its dry state is less than 103 μg; is less than 80 μg, or less than 50 μg.

[0193] In certain embodiments, the implant contains a dose of about 5 μg of travoprost, The thiamin polymer precursor is an 8-arm-15K-SG polyethylene glycol, which is nucleophilic The functional group-containing crosslinking agent is trilysine.

[0194] In certain embodiments, the implant contains a dose of about 15 μg of travoprost. The multi-arm polymer precursor is 8-arm-15K-SG polyethylene glycol, The nucleophilic group-containing crosslinker is trilysine.

[0195] In certain embodiments, the implant contains a dose of about 15 μg of travoprost. The multi-arm polymer precursor is 8-arm-15K-SAZ polyethylene glycol, The nucleophilic group-containing crosslinker is trilysine.

[0196] In certain embodiments, the implant contains a dose of about 26 μg of travoprost. The multi-arm polymer precursor is 8-arm-15K-SAZ polyethylene glycol, The nucleophilic group-containing crosslinker is trilysine.

[0197] In certain embodiments, the implant is stored in phosphate buffered saline at a pH of 7.4 at 37°C. After 24 hours of hydration in a test tube, the diameter is less than 0.50 mm. The volume of PBS used for the sum is 5 ml added to the sample tube. Specifically, the implants are equilibrated at 37°C before adding 30 ml of PBS. After 24 hours of hydration in a test tube in phosphate buffered saline at pH 7.4 at 7°C, approximately 0.3 m The diameter ranges from 0.40 to 0.49 mm or from about 0.40 to about 0.49 mm.

[0198] In certain embodiments, the implant is stored in phosphate buffered saline at pH 7.4 at 37°C. The diameter of the implant after 24 hours of in vitro hydration was compared with that of the dry implant. The ratio of the diameter of the PBS to the volume of the PBS used for such hydration is less than 2.5. is the 5 ml added to the sample tube. The sample tube is specifically 3 ml before adding 5 ml of PBS. Equilibrate at 7°C.

[0199] In certain embodiments, the implant is in the form of a fiber. Length of less than 2.5 mm or approximately 1.0 mm to approximately 2.5 mm and 0.3 mm or less in dry state Or in the form of fibers having a diameter of 0.14 mm to about 0.29 mm. Plants were hydrated in test tubes in phosphate buffered saline at pH 7.4 at 37°C for 24 hours. In the equilibrium state after the treatment, the fibers are in the form of fibers with a diameter of 0.6 mm or less and a length of 3.0 mm or less. be.

[0200] In certain embodiments, the implant has a dry size of about 1.00 mm to about 2.50 mm. and a diameter of 0.30 mm or less.

[0201] In certain embodiments, the implant has a dry thickness of about 1.5 mm to about 2.5 mm. m, or about 1.8 mm to about 2.2 mm in length and 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 A diameter of about 0.19 mm to about 0.23 mm, or about 0.15 mm to about 0.19 mm. It is a fiber.

[0202] In certain embodiments, the implant, in its dry form, has a mass 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 a further embodiment, the implant has a total weight of about 20 μg in its dry form. The total weight of the medicament is from about 30 μg to about 105 μg.

[0203] In certain embodiments, the implant contains less than 25 μg of travoprost, or Less than 0 μg or less than 10 μg.

[0204] According to certain embodiments, the implants provide a dose ranging from 150 to 250 ng / week with a standard deviation. The mean prostaglandin antagonist (PAG) dose ranged from about 500 to about 900 ng / week. For example, travoprost) has an in vitro release due to travoprost release, and is measured under sink conditions in PBS pH 7.2-7.4 at 37°C, and 1 day after administration. Weekly prostaglandin antagonists ( ) between days 7 and 119, excluding the eye burst. e.g., travoprost) based on travoprost release values; or under sink conditions, pH 7. When measured in 2-7.4% PBS at 37°C, the 7-7.4% PBS concentration was observed, excluding the burst observed on the first day after administration. Weekly prostaglandin antagonists (e.g., For example, travoprost) The release of travoprost is in the range of about 100 to about 1500 ng.

[0205] According to another aspect, the present invention provides a method for manufacturing a method of manufacturing a semiconductor device comprising: Various transposon methods according to any one of the embodiments (a) to (d) disclosed herein Lost particles and an intracameral implant comprising a biodegradable hydrogel; In this case, various travoprost particles are dispersed within the hydrogel.

[0206] According to another aspect, the present invention provides a method for manufacturing a method of manufacturing a semiconductor device comprising: Biodegradable hydrogels and travoprost particles, Travoprost particles, which are in the form of travoprost mixed with polylactide; Intended for intracameral implants containing travoprost particles dispersed within a hydrogel The hydrogels each have a mass average molecular weight of 15,000±10% Daltons. 8-arm-15K-SG or 8-arm-15K-SAZ polyethylene glycol The polymer network formed by reacting the polymer with trilysine acetate is or a polymer network having the formula: [ka] wherein m is 2 or 6. Contains polyethylene glycol.

[0207] Biodegradable intracameral sustained release prostaglandin antagonists (e.g., travoprost) Method for manufacturing an implant In a further aspect, the present invention provides a prostaglandin antagonist (e.g., travoprostaglandin). The present invention is directed to a method for producing a sustained release biodegradable intracameral implant of (a) A prostaglandin antagonist (e.g., trastuzumab) mixed with a biodegradable polymer. preparing travoprost particles in the form of travoprost; (b) Hydrogel precursor and prostaglandin antagonist (e.g., travoprost) ) particles; (c) crosslinking the precursor mixture using a crosslinker to form a polymer network; - obtaining a hydrogel mixture comprising a network; (d) drying the hydrogel mixture to provide the implant.

[0208] See the preceding section "Prostaglandin Antagonists (e.g., Travoprost)" particles," "biodegradable hydrogels," "various prostaglandin antagonists (e.g. "Prostaglandin antagonists (e.g., travoprost) particles" and "prostaglandin antagonists (e.g., travoprost) particles" The types of ingredients and the content of ingredients described in "Slow-release biodegradable intracameral implant" The amounts and weight ratios of the weight ratios also apply correspondingly to the manufacturing method of the present invention.

[0209] In another aspect, the present invention provides the compounds described in the section "Prostaglandin Antagonists (e.g., "Method for producing sustained release biodegradable implants of Laboprost" The present invention relates to sustained-release biodegradable intracameral implants available therefor.

[0210] In another aspect, the present invention is directed to a method of making an intracameral implant, the method comprising: (a) Travoprost particles in the form of travoprost mixed with a biodegradable polymer preparing (b) preparing a precursor mixture containing a hydrogel precursor and travoprost particles; and, (c) crosslinking the precursor mixture using a crosslinker to form a polymer network; - obtaining a hydrogel mixture comprising a network; (d) drying the hydrogel mixture to provide the implant.

[0211] In another aspect, the invention is directed to an intracameral implant obtainable by the method of the preceding paragraph. do.

[0212] Syringe for intracameral injection According to one aspect, the present invention provides a prostaglandin antagonist as defined above. Intracameral injection containing a sustained-release biodegradable intracameral implant of a steroid (e.g., travoprost) This applies to syringes that are needed.

[0213] According to one aspect, the present invention provides an anterior chamber comprising an implant as disclosed herein. This applies to syringes for internal injection.

[0214] A particular embodiment of the syringe is shown in Example 4.

[0215] Methods of treating intraocular pressure in a human subject One aspect of the invention is to administer to a human subject with ocular hypertension or glaucoma, such as open-angle glaucoma, A single prostaglandin E1000 dose as defined in the above section for each eye requiring treatment Biodegradable intracameral implant for sustained release of a lanin antagonist (e.g., travoprost) The present invention relates to a method for treating intraocular pressure for a period of about 2 to about 12 months or about 3 to about 9 months by administering the and the method comprises, for each said eye: Step 1: providing treatment for a period ranging from about 2 to about 12 months or from about 3 to about 9 months; a biodegradable hydrogel as defined in the above section and a prostaglandin antagonist (travoprost) particle as defined above; Prostaglandin antagonists (e.g., trabeculopeptides) mixed with biodegradable polymers prostaglandin antagonist (travoprost) particles in the form of travoprost; A prostaglandin antagonist (travoprost) dispersed within the hydrogel particles and one prostaglandin as defined in the section above. and a biodegradable intracameral implant for sustained release of a vasoconstrictor (e.g., travoprost). Things and; Step 2: Inserting one sustained-release biodegradable intracameral implant of Step 1 into the anterior segment of the eye. and positioning it within the iridocorneal angle of said eye.

[0216] One aspect of the invention is to administer to a human subject with ocular hypertension or glaucoma, such as open-angle glaucoma, A single prostaglandin E1000 dose as defined in the above section for each eye requiring treatment Biodegradable intracameral implant for sustained release of a lanin antagonist (e.g., travoprost) and a method for treating intraocular pressure for a period ranging from about 2 to about 12 months or from about 3 to about 9 months. and for each said eye, the method comprises administering one sustained-release biodegradable intracameral implant to said eye. and inserting the implant into the anterior segment of the eye to position it within the iridocorneal angle of the eye, Runt is as defined in the section above, a biodegradable hydrogel as defined in the above section and a prostaglandin antagonist (travoprost) particle as defined above; Prostaglandin antagonists (e.g., trabeculopeptides) mixed with biodegradable polymers prostaglandin antagonist (travoprost) particles in the form of travoprost; A prostaglandin antagonist (travoprost) dispersed within the hydrogel particles, providing treatment for a period ranging from about 2 to about 12 months or from about 3 to about 9 months.

[0217] Another aspect of the present invention is a method for treating ocular hypertension and / or glaucoma in a human subject in need of treatment. A single travoprost sustained-release biodegradable intracameral implant for each affected eye provides approximately 1-3% For use in a method of treating intraocular pressure for a period of about 24 months, for example, in the range of about 3 to about 9 months. a travoprost sustained-release biodegradable intracameral implant as described herein, Target.

[0218] Another aspect of the present invention is a method for treating ocular hypertension and / or glaucoma in a human subject in need of treatment. A single intracameral implant according to any one of claims 1 to 20 is used for each eye to be treated. The present invention relates to a method for treating intraocular pressure for a period ranging from about 1 to about 24 months, for example, from about 3 to about 9 months. do.

[0219] According to certain embodiments of the invention, the implant is dry prior to insertion and is inserted into the eye. In certain embodiments, hydration occurs in less than 2 minutes.

[0220] In certain embodiments of the invention, the treatment period is about 6 to about 9 months, and the prostaglandin A biodegradable intracameral implant with sustained release of an antagonist (e.g., travoprost) is used for approximately 6 In another embodiment, the treatment period is from about 4 to about 7 months, and A sustained-release biodegradable intracameral implant for prostaglandin antagonists (e.g., travoprost) The implant provides treatment for about 4 to about 7 months. In an alternative embodiment, the treatment period is about 3 months. ~6 months, and prostaglandin antagonists (e.g., travoprost) are gradually The release biodegradable intracameral implant provides about 3 to about 6 months of treatment. In this case, the treatment period is about 3 to 4 months, and prostaglandin antagonists (e.g., The sustained-release biodegradable intracameral implant of travoprost provides approximately 3 to 4 months of treatment. In further embodiments, the treatment period is from about 7 to about 8 months, or from about 7 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 Approximately 9 months and prostaglandin antagonists (e.g., travoprost) The sustained-release biodegradable intracameral implant lasts for approximately 7 to 8 months, or approximately 7 to 9 months, respectively. , or about 4 months, or about 5 months, or about 6 months, or about 7 months, or about 8 months , or approximately nine months of treatment.

[0221] In certain embodiments, Intracameral implants were measured under sink conditions in PBS with a pH of 7.2-7.4 at 37°C. When the dose was measured, the mean absolute deviation was calculated based on the % amount released per 70-day period from Day 1 to Day 84. Tests with mean travoprost release ranging from approximately 65% ​​to approximately 85%, with a difference of at most 5% Intraluminal release, the treatment period is about 3 to about 6 months, or about 3 to 4 months. or Intracameral implants were measured under sink conditions in PBS with a pH of 7.2-7.4 at 37°C. When the dose was measured, the mean absolute deviation was calculated based on the % amount released per 70-day period from Day 1 to Day 98. Tests with mean travoprost release ranging from approximately 60% to approximately 80%, with a difference of at most 5% Intraluminal release, wherein the treatment period is about 3 to about 7 months, or about 4 to 7 months. or Intracameral implants were measured under sink conditions in PBS with a pH of 7.2-7.4 at 37°C. When administered, the average absolute values ​​were calculated based on the % amount released per 14-day period from Day 1 to Day 112. Tests with mean travoprost release ranging from approximately 5% to approximately 15% with a deviation of at most 3% Intraluminal release, wherein the treatment period is about 6 to about 9 months, or about 6 to about 12 months. is.

[0222] In certain embodiments of the invention, the treatment period is from about 3 to about 7 months, or from about 4 to 7 months. months, or about 3 to about 6 months, or about 3 to 4 months, and travoprost Sustained-release biodegradable intracameral implants last for about 3 to about 7 months, or about 4 to 7 months, or about 3 ~Provides treatment for approximately 6 months or 3-4 months, during which the polymer network By reacting an electrophilic group-containing multi-arm polymer precursor with an electrophilic group-containing crosslinker, The electrophilic group is a succinimidyl glutarate (SG) group, and the multi- The polymer precursor is an 8-arm 15K-SG polyethylene glycol; The crosslinking agent is trilysine, and the hydrogel dissolves within 2 to 4 months.

[0223] In certain embodiments, the treatment period is about 6 to about 9 months or about 6 to about 12 months. Voprost sustained-release biodegradable intracameral implant for approximately 6-9 months or approximately 6-12 months wherein the polymer network comprises an electrophilic group-containing multi-arm polymer It is formed by reacting a precursor with an electrophilic group-containing crosslinker, and the electrophilic group is a succinyl group. The multi-arm polymer precursor is an 8-arm-1 5K-SAZ polyethylene glycol; the nucleophilic group-containing crosslinker is trilysine; The hydrogel dissolves within 6 to 8 months.

[0224] In certain embodiments, the treatment is continued for about 2 to about 12 months, with the duration of the treatment ranging from about 3 to about 12 months. After a period ranging from about 9 months, the procedure continues by repeating steps 1 and 2. Specifically, treatment involves repeating steps 1 and 2 until no further treatment is required. More specifically, treatment is provided once a year for approximately 12 months. Prostaglandin antagonists (e.g., steroids) are used to provide 6-9 months of treatment twice a year. with sustained-release biodegradable intracameral implants of travoprost (e.g., travoprost) and three or more times a year Prostaglandin antagonists (e.g., trabeculectomy) provide 3-4 months of treatment four times a year. Once a year at approximately equal intervals with a sustained-release biodegradable intracameral implant of benzodiazepine (Prost) , including repeating steps 1 and 2 twice a year, three times a year, or four times a year.

[0225] In another embodiment, the first treatment period is 3 to 4 months and includes prostaglandin antagonists. Biodegradable intracameral implants with sustained release of steroids (e.g., travoprost) last for 3 to 4 months. Prostaglandin antagonists are used to treat 6 to 9 months of treatment. Six to nine months of treatment with sustained-release biodegradable intracameral implants (e.g., travoprost) Continue.

[0226] In certain embodiments, a travoprost sustained-release biodegradable intracameral implant or hydrogel is used. The gel dissolves / completely biodegrades within 5-7 months or within 3-5 months.

[0227] In certain embodiments, the treatment period ranges from 6 to 9 months or 6 to 12 months, and Prost sustained-release biodegradable intracameral implants or hydrogels dissolve within 5 to 7 months. In certain embodiments, the treatment period ranges from 3 to 6 months, and Voprost sustained-release biodegradable intracameral implants or hydrogels dissolve within 3 to 5 months completely biodegradable.

[0228] In certain embodiments, "glaucoma" encompasses open-angle and closed-angle forms of glaucoma. The subtypes of open-angle glaucoma disclosed herein include normal tension glaucoma, congenital glaucoma, Glaucoma, secondary glaucoma, pigmentary glaucoma, pseudoexfoliative glaucoma, traumatic glaucoma, neovascular glaucoma , iridocorneal endothelial syndrome (ICE), and / or uveitis glaucoma.

[0229] In certain embodiments, the treatment of the present invention is effective in treating mild, moderate, or severe open-angle glaucoma. It is the opposite.

[0230] In certain embodiments, in the treatment of the present invention, intraocular pressure is controlled by a method as described herein. or about 1 to about 12 months, or about 2 to about 12 months, or about 3 to about 9 months, for example, about 6 During a treatment period of, for example, about 6 to about 9 months, or during repeated administration A decrease of at least 4 mmHg or at least 5 mmHg from baseline IOP during follow-up treatment According to certain embodiments, intraocular pressure is reduced by up to 7-11 mmHg. In the treatment of the invention, intraocular pressure is controlled as described herein, or within about 1 to about 12 months. months or about 2 to about 12 months or about 3 to about 9 months, for example, about 6 to about 12 months or For example, during a treatment period of approximately 6 to 9 months or during continuous treatment with repeated administration, at least 20%, or at least 25%, or at least about 30%, or or about 20% to about 35%, or about 20% to about 30%. are applicable to each treatment period: 2 weeks, 6 weeks, 12 weeks, 4 months, 6 months, 9 months, and Measurements were taken at 8:00 AM, 10:00 AM and 4:00 PM at each relevant time point. Alternatively, treatment may be performed without inferiority to a different intraocular pressure medication, such as travoprost eye drops. The non-inferiority margin was 1.5 mmHg for each treatment period at each time point. be.

[0231] In certain embodiments, treatment prevents vision loss, such as peripheral vision loss.

[0232] In certain embodiments, the treatment prevents loss of optic nerve fibers.

[0233] In certain embodiments, the treatment prevents retinal ganglion cell death

[0234] In certain embodiments, the treatment prevents damage to the optic nerve.

[0235] In certain embodiments, the treatment of the present invention reduces intraocular pressure for at least 5 days or at least 10 days after administration. was also significantly reduced by day 3 or at least by day 2.

[0236] In certain embodiments, treatments of the present invention reduce intraocular pressure to levels comparable to topical travoprost therapy. It is a decline.

[0237] In certain embodiments, the change in endothelial cell number is measured over the course of treatment and / or throughout the entire treatment. It does not occur in the affected eye.

[0238] In certain embodiments, the change in corneal thickness is measured over the course of treatment and / or throughout the treatment. It does not occur in the affected eye.

[0239] In certain embodiments, the septum is measured as monitored, for example, by gonioscopy and slit lamp examination. In this case, the implant is virtually immobile.

[0240] In certain embodiments, the implant is invisible to the naked eye.

[0241] In certain embodiments, the treatment period is about 3 to about 6 months or about 3 to 4 months, and The sustained-release biodegradable intracameral implant provides treatment for approximately 3 to 6 months or 3 to 4 months. The travoprost particles are Travoprost and an acid end group and about 0.05 to about 0.5 dl / g or less, for example, about 0. From one or more polylactides having an intrinsic viscosity specification in the range of 35 to 0.45 dl / g A first type of travoprost particles made of a mixture with a biodegradable polymer comprising: the first type of particles are about 40 wt % to about 50 wt % based on the total mass of the first type of particles; For example, a first type of travoprost containing about 43% to about 45% by weight of travoprost. Prost particles and; Travoprost and an acid end group and about 0.5 to about 0.80 dl / g or less, for example, about 0. One or more polylactides having an intrinsic viscosity specification ranging from 6 to less than about 0.80 dl / g A second type of travoprost particles made of a mixture with a biodegradable polymer comprising In this case, the second type of particles is about 40% by weight to about 50% by weight based on the total mass of the second type of particles. %, for example, about 45% to about 47% by weight of travoprost. It is a blend of particles made from Laboprost particles, In this case, the blend contains about 35% to about 55% by weight of the first type of particles based on the total amount of particles. and about 35% to about 55% by weight of a second type of particles, or About 35% by weight to about 55% by weight of the total amount of travoprost in the composition is in the form of the first type of particles. and about 35% to about 55% by weight of the total amount of travoprost in the implant is present in the form of a second type of particle.

[0242] In certain embodiments, the treatment period is about 4 to about 7 months, and the travoprost sustained-release biologics The degradable intracameral implant provides approximately 4 to 7 months of treatment, and the travoprost particles Travoprost and an acid end group and about 0.05 to about 0.5 dl / g or less, for example, about 0. One or more polylactides having intrinsic viscosity specifications ranging from 35 to about 0.45 dl / g. A first type of particle made of a mixture with a biodegradable polymer, wherein the first type of particle The particles may comprise about 40% to about 50% by weight, for example, about a first type of particles containing 43% to about 45% by weight of travoprost; Travoprost and an acid end group and about 0.5 to about 0.80 dl / g or less, for example, about 0. One or more polylactides having an intrinsic viscosity specification ranging from 6 to less than about 0.80 dl / g A second type of particle made of a mixture with a biodegradable polymer comprising: The particles are about 40% by weight to about 50% by weight, for example, about a second type of particles containing 45% to about 47% by weight or more of travoprost; Travoprost and an acid end group and about 0.8 to about 1.7 dl / g, for example, about 0.8 to about A raw material consisting of one or more polylactides having an intrinsic viscosity specification in the range of 1.0 dl / g. a third type of particles made in a mixture with a degradable polymer, wherein the third type of particles are About 40% by weight to about 50% by weight, for example, about 41% by weight to about 50% by weight, based on the total mass of the type of particles. and a third type of particle containing about 43% by weight of travoprost. and In this case, the blend contains about 20% to about 35% by weight of the first type of particles based on the total amount of particles. and about 30% to about 50% by weight of the second type of particles and about 25% to about 45% by weight of the or about 2% of the total amount of travoprost in the implant. 0% to about 35% by weight of the first type of particles are present in the form of particles of the first type, and About 30% by weight to about 50% by weight of the total amount of travoprost is present in the form of the second type of particles. and about 25% to about 45% by weight of the total amount of travoprost in the implant is a third It exists in the form of several types of particles.

[0243] In certain embodiments, the treatment period is from about 6 to about 12 months or from about 6 to about 9 months. The boprost sustained-release biodegradable intracameral implant provides a healing period of approximately 6 to 12 months or approximately 6 to 9 months. and providing a treatment, wherein the travoprost particles Travoprost and an acid end group and about 0.05 to about 0.5 dl / g or less, for example, about 0. One or more polylactides having intrinsic viscosity specifications ranging from 35 to about 0.45 dl / g. A first type of particle made of a mixture with a biodegradable polymer, wherein the first type of particle The particles may be present in an amount of about 40% to about 50% by weight, for example, about 40% to about 50% by weight, based on the total mass of the first type of particles. a first type of particles containing 3% to about 45% by weight of travoprost; Travoprost and an acid end group and about 0.5 to about 0.80 dl / g or less, for example, about 0. One or more polylactides having an intrinsic viscosity specification ranging from 6 to less than about 0.80 dl / g A second type of particle made of a mixture with a biodegradable polymer comprising: The particles are about 40% by weight to about 50% by weight, for example, about a second type of particles containing 45% to about 47% by weight of travoprost; Travoprost and an acid end group and about 0.8 to about 1.7 dl / g, for example, about 0.8 to about A raw material consisting of one or more polylactides having an intrinsic viscosity specification in the range of 1.0 dl / g. a third type of particles made of a degradable polymer, wherein the third type of particles are About 40% by weight to about 50% by weight, for example, about 41% by weight to about 43% by weight, based on the total mass of the particles. a third type of particles containing travoprost in an amount of 0.05 wt. %; Travoprost and an ester end group and about 0.05 to about 1.7 dl / g, for example, about 0 One or more polylactides having an intrinsic viscosity specification ranging from 0.55 to about 0.75 dl / g and a fourth type of particle made of a biodegradable polymer comprising: About 40% by weight to about 50% by weight, for example, about 41% by weight, based on the total mass of the fourth type of particles. The particle blend was made of a fourth type of particle containing 43% to about 43% by weight of travoprost. and In this case, the blend contains about 15% to about 25% by weight of the first type of particles based on the total amount of particles. and about 15% to about 25% by weight of a second type of particles and about 5% to about 15% by weight of a third type of particles and about 40% to about 60% by weight of a fourth type of particles; or Approximately 15% to 25% by weight of the total amount of travoprost in the implant is the first type. and about 15% by weight of the total amount of travoprost in the implant. About 25% by weight is present in the form of second type particles, and the trabo-particles in the implant About 5% to about 15% by weight of the total amount of the resin is present in the form of a third type of particles, and Approximately 40% to 60% by weight of the total amount of travoprost in the plant is the fourth type of particles. It exists in the form of a child.

[0244] In certain embodiments, the treatment period is about 3 to about 6 months or about 3 to 4 months, and the implant The implants contained a dose of approximately 5 μg of travoprost, with a standard deviation of 100-200 μg. Mean travoprost release ranges from approximately 300 to approximately 500 ng / week, with a range of 0.00 ng / week. The mean travoprost release was measured under sink conditions at pH 7. When measured at 37°C in PBS containing 0.2 to 7.4 mg / mL of HCl, the 7-day burst was observed. Based on weekly travoprost release values ​​for up to 84 days; or under sink conditions, pH 7 When measured at 37°C in PBS containing 0.2 to 7.4 mg / mL of HCl, the 7-day burst was observed. Weekly travoprost release ranged from approximately 10 to approximately 700 nM when measured at time intervals between days 1 and 84. The range is g.

[0245] In certain embodiments, the treatment period is about 3 to about 7 months or about 4 to 7 months, and the implant The implants contained a dose of approximately 15 μg of travoprost, with a standard deviation of 450-450 μg. Average travoprost range of approximately 800 to approximately 1100 ng / week, with a range of 550 ng / week In vitro release was observed under sink conditions with a pH of 7.2-7.4. When measured at 37°C by BS, the mean values ​​were 7 to 98 days after administration, excluding the burst on the first day. Based on weekly travoprost release values; or P under sink conditions, pH 7.2-7.4 When measured at 37°C by BS, the mean values ​​were 7 to 98 days after administration, excluding the burst on the first day. When measured at time intervals, the weekly release of travoprost ranged from approximately 100 to approximately 2300 ng. be.

[0246] In certain embodiments, the treatment period is about 6 to about 9 months or about 6 to 12 months, and The plat contains a dose of travoprost of approximately 15 μg, and the implants have a standard deviation of 150 μg. Average travoprost range of approximately 500 to approximately 900 ng / week, with a range of ~250 ng / week In vitro release was observed under sink conditions with a pH of 7.2-7.4. When measured at 37°C by BS, the mean values ​​were 7 to 119 days after administration, excluding the burst on the first day. Based on weekly travoprost release values ​​of 100 mg / kg / day; or under sink conditions, pH 7.2-7.4 When measured in PBS at 37°C, the 7-119 day period after administration was significantly higher than the 1 day burst period. When measured at time intervals between doses, the weekly release of travoprost ranged from about 100 to about 1500 ng. It is an enclosure.

[0247] In certain embodiments, the treatment period is from about 6 to about 9 months or from about 6 to about 12 months. The implants contained a dose of approximately 26 μg of travoprost with a standard deviation of 10 The mean trabeculopeptides ranged from about 1000 to about 1500 ng / week, with a range of 0 to 400 ng / week. In vitro release by lost release was observed under sink conditions, with an average pH of 7.2-7. When measured in PBS at 37°C, the antibody response was 7 to 119 days after administration, excluding the burst on day 1. Based on weekly travoprost release values ​​between eyes; or under sink conditions, pH 7.2-7. When measured in 0.4 PBS at 37°C, the range was 7-119 h after administration, excluding the burst on the first day. Weekly travoprost release ranges from approximately 100 to approximately 2000 mg when measured at time intervals between days. The range is.

[0248] In certain embodiments, the implant is placed in the eye, for example, by gonioscopy and slit lamp examination. can be monitored.

[0249] In one specific aspect, the present invention relates to a method for treating glaucoma, such as ocular hypertension or open-angle glaucoma. In human subjects, a single prostaglandin antagonist is administered to each eye requiring such treatment. A sustained-release biodegradable intracameral implant of steroids (e.g., travoprost) provides approximately 2- The present invention relates to a method for treating intraocular pressure for a period of about 12 months or about 6 to about 9 months, the method comprising the steps of: For each eye, Step 1: When the implant is dry, it is about 1.0 mm to about 2.5 mm in length and 0.3 mm or less. In the form of fibers having a diameter of A biodegradable hydrogel as defined above and a prostaglandin as defined above. taglandin antagonist (travoprost) particles; Prostaglandin antagonist (e.g., travoprost) particles are available in four types: Intrinsic viscosity 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 a biodegradable polymer comprising a first polylactide having a viscosity grade and an acid end group. The first one is in the form of a combined prostaglandin antagonist (e.g., travoprost). and one type of particle; about 0.5 to less than about 0.8 dl / g, for example, about 0.6 to about 0.8 dl a second polylactide having an intrinsic viscosity specification in the range of less than 1 / g and having acid end groups; prostaglandin antagonists (e.g., trabeculopeptides) mixed with biodegradable polymers and a second type of particles in the form of (lost); about 0.8 to about 1.7 dl / g, e.g., 0. A third polymer having an intrinsic viscosity specification in the range of 8 to about 1.0 dl / g and having acid end groups. Prostaglandin antagonists (e.g., and a third type of particles in the form of about 0.05 to about 1.7 dL / g (e.g., travoprost). For example, the intrinsic viscosity specification is in the range of about 0.55 to 0.75 dl / g, and the ester powder Prostaglandins blended with biodegradable polymers based on quaternary polylactides with terminal groups. and a fourth type of particle in the form of a steroid antagonist (e.g., travoprost). prostaglandin antagonists (e.g., hydroxybenzoates) mixed with biodegradable polymers containing For example, prostaglandin antagonists in the form of travoprost g) particles, The hydrogel has an 8-arm -15K- with a mass average molecular weight of 15,000 ± 10% Daltons. Formed by reacting SAZ polyethylene glycol with trilysine acetate A prostaglandin antagonist dispersed within a hydrogel comprising a polymer network. 21-30 μg of prostaglandin antagonist containing travoprost particles One prostaglandin antagonist (travoprost) containing providing a boprost) sustained-release biodegradable intracameral implant; Step 2: Inserting one sustained-release biodegradable intracameral implant of Step 1 into the anterior segment of the eye. and positioning it within the iridocorneal angle of said eye.

[0250] In one specific aspect, the present invention relates to a method for treating glaucoma, such as ocular hypertension or open-angle glaucoma. In human subjects, a single prostaglandin antagonist is administered to each eye requiring such treatment. A sustained-release biodegradable intracameral implant of steroids (e.g., travoprost) provides approximately 2- The present invention relates to a method for treating intraocular pressure for a period of about 12 months or about 6 to about 9 months, the method comprising the steps of: 21–30 μg of a prostaglandin antagonist (e.g., travopros) per eye The implant containing the compound is as defined above, and the implant is dried. Fibers with a length of about 1.0 mm to about 2.5 mm and a diameter of 0.3 mm or less in the original state and a biodegradable hydrogel as defined above and a protease inhibitor as defined above staglandin antagonist (travoprost) particles; Prostaglandin antagonist (e.g., travoprost) particles are available in four types , about 0.05 to less than 5 dl / g, for example, in the range of about 0.35 to about 0.45 dl / g a biodegradable polymer comprising a first polylactide having a viscosity specification and having acid end groups; In the form of a mixed prostaglandin antagonist (e.g., travoprost) and a first type of particle; and a concentration of about 0.5 to about 0.8 dl / g, for example, about 0.6 to about 0.8 dl / g. a second polylactide having an intrinsic viscosity specification in the range of less than 1 / 4 l / g and having acid end groups; a prostaglandin antagonist (e.g., trabostatin) mixed with a biodegradable polymer comprising and a second type of particles in the form of a granular material (e.g., granular material); a third polymer having an intrinsic viscosity specification in the range of 0.8 to about 1.0 dl / g and having acid end groups; Prostaglandin antagonists (e.g., hydroxybenzoates) mixed with lactide-based biodegradable polymers and a third type of particles in the form of about 0.05 to about 1.7 dl / g, for example, in the range of about 0.55 to 0.75 dl / g, and Prostaglandins blended with biodegradable polymers consisting of a quaternary polylactide with terminal groups and a fourth type of particle in the form of a vasodilator antagonist (e.g., travoprost). A prostaglandin antagonist ( For example, prostaglandin antagonists in the form of travoprost (travoprost) (sto) particles and The hydrogel is an 8-arm 15K with a mass average molecular weight of 15,000 ± 10% Daltons. -SAZ polyethylene glycol is formed by reacting with trilysine acetate. The polymer network contains a prostaglandin antagonist dispersed within a hydrogel. and travoprost particles.

[0251] In another specific aspect, the present invention provides a method for treating glaucoma, such as ocular hypertension or open-angle glaucoma. In human subjects, a single prostaglandin antagonist was administered to each eye requiring such treatment. Approximately 2-4 days after delivery by a biodegradable intracameral implant that releases a gonist (e.g., travoprost) The present invention relates to a method for treating intraocular pressure for a period of about 12 months or about 6 to about 9 months, the method comprising the steps of: For each eye, Step 1: When the implant is dry, it is about 1.0 mm to about 2.5 mm in length and 0.3 mm or less. In the form of fibers having a diameter of a biodegradable hydrogel as defined above and a protease inhibitor as defined above staglandin antagonist (travoprost) particles; Prostaglandin antagonist (e.g., travoprost) particles are available in four types , about 0.05 to less than about 0.5 dl / g, for example, in the range of about 0.35 to about 0.45 dl / g and a biodegradable polymer comprising a first polylactide having an intrinsic viscosity specification of Forms of prostaglandin antagonists (e.g., travoprost) mixed with mers and a first type of particles having a dl / g of less than about 0.5 to about 0.8 dl / g, for example, about 0.6 to about 0 a second polylactate having an intrinsic viscosity specification in the range of less than 0.8 dl / g and having acid end groups; a prostaglandin antagonist (e.g., and a second type of particles in the form of travoprost; about 0.8 to about 1.7 dl / g, e.g., For example, a third copolymer having an intrinsic viscosity specification in the range of 0.8 to about 1.0 dl / g and having an acid end group. Prostaglandin antagonists blended with biodegradable polymers consisting of polylactide and a third type of particles in the form of a steroid (e.g., travoprost); A fourth polylactide having an intrinsic viscosity specification in the range of dl / g and having ester end groups. A prostaglandin antagonist (e.g., thiamin) mixed with a biodegradable polymer comprising a biodegradable polymer blend containing a fourth type of particle in the form of labioprost in the form of a prostaglandin antagonist (e.g., travoprost) mixed with A prostaglandin antagonist (travoprost) particle, The hydrogel has an 8-arm -15K- with a mass average molecular weight of 15,000 ± 10% Daltons. Formed by reacting SAZ polyethylene glycol with trilysine acetate A prostaglandin antagonist dispersed within a hydrogel comprising a polymer network. 11 to 20 μg of prostaglandin antagonist containing travoprost particles one prostaglandin as defined above, containing travoprost and providing an antagonist (travoprost) sustained-release biodegradable intracameral implant. , Step 2: Inserting one sustained-release biodegradable intracameral implant of Step 1 into the anterior segment of the eye. and positioning it within the iridocorneal angle of said eye.

[0252] In another specific aspect, the present invention provides a method for treating glaucoma, such as ocular hypertension or open-angle glaucoma. In human subjects, a single prostaglandin antagonist was administered to each eye requiring such treatment. Approximately 2-4 days after delivery by a biodegradable intracameral implant that releases a gonist (e.g., travoprost) The present invention relates to a method for treating intraocular pressure for a period of about 12 months or about 6 to about 9 months, the method comprising the steps of: One sustained-release biodegradable intracameral implant per eye is inserted into the anterior segment of said eye, and placing the implant within the iridocorneal angle of said eye, the implant being as defined above. and 11-20 μg of a prostaglandin antagonist (e.g., travoprosulfone). The implant contains a length of about 1.0 mm to about 2.5 mm in its dry state and a thickness of 0.01 mm. in the form of fibers having a diameter of 0.3 mm or less, a biodegradable hydrogel as defined above and a protease inhibitor as defined above staglandin antagonist (travoprost) particles; Prostaglandin antagonist (e.g., travoprost) particles are available in four types , about 0.05 to less than about 0.5 dl / g, for example, in the range of about 0.35 to about 0.45 dl / g and a biodegradable polymer comprising a first polylactide having an intrinsic viscosity specification of Forms of prostaglandin antagonists (e.g., travoprost) mixed with mers and a first type of particles having a dl / g of less than about 0.5 to about 0.8 dl / g, for example, about 0.6 to about 0 a second polylactate having an intrinsic viscosity specification in the range of less than 0.8 dl / g and having acid end groups; a prostaglandin antagonist (e.g., and a second type of particles in the form of travoprost; about 0.8 to about 1.7 dl / g, e.g., For example, a third copolymer having an intrinsic viscosity specification in the range of 0.8 to about 1.0 dl / g and having an acid end group. Prostaglandin antagonists blended with biodegradable polymers consisting of polylactide and a third type of particles in the form of a steroid (e.g., travoprost); A fourth polylactide having an intrinsic viscosity specification in the range of dl / g and having ester end groups. A prostaglandin antagonist (e.g., thiamin) mixed with a biodegradable polymer comprising a biodegradable polymer blend containing a fourth type of particle in the form of labioprost in the form of a prostaglandin antagonist (e.g., travoprost) mixed with A prostaglandin antagonist (travoprost) particle, The hydrogel is an 8-arm 15K with a mass average molecular weight of 15,000 ± 10% Daltons. -SAZ polyethylene glycol is formed by reacting with trilysine acetate. The polymer network contains a prostaglandin antagonist dispersed within a hydrogel. and travoprost particles.

[0253] In another specific aspect, the present invention provides a method for treating glaucoma, such as ocular hypertension or open-angle glaucoma. In human subjects, a single prostaglandin antagonist was administered to each eye requiring such treatment. Approximately 3-6 months after injection by a sustained-release biodegradable intracameral implant of an agonist (e.g., travoprost) The present invention relates to a method for treating intraocular pressure for a period of about six months or about three to about four months, the method comprising administering to the eye For each Step 1: The implant is approximately 1.0 mm to 2.5 mm long and 0.3 m long in its dry state. in the form of fibers having a diameter of less than 1 mm, a biodegradable hydrogel as defined above and a protease inhibitor as defined above staglandin antagonist (travoprost) particles; Prostaglandin antagonist (e.g., travoprost) particles are available in three types , about 0.05 to less than about 0.5 dl / g, for example, in the range of about 0.35 to about 0.45 dl / g and a biodegradable polymer comprising a first polylactide having an intrinsic viscosity specification of Forms of prostaglandin antagonists (e.g., travoprost) mixed with mers and a first type of particles having a densitometric value of about 0.5 to about 1.7 dl / g, for example, about 0.6 to about 0.8 a second polylactide having an intrinsic viscosity specification in the range of less than 200 dl / g and having acid end groups; A prostaglandin antagonist (e.g., trastuzumab) mixed with a biodegradable polymer comprising and a second type of particles in the form of benzoyl benzoate (boprost); about 0.8 to about 1.7 dl / g, e.g., a third polymer having an intrinsic viscosity specification in the range of 0.8 to about 1.0 dl / g and having acid end groups; Prostaglandin antagonists ( For example, a biodegradable composition containing a blend of a third type of particles in the form of a hydroxybenzoate (e.g., travoprost) A prostaglandin antagonist (e.g., travoprost) mixed with a degradable polymer and prostaglandin antagonist (travoprost) particles in the form of The hydrogel is an 8-arm 15K with a mass average molecular weight of 15,000 ± 10% Daltons. -SG polyethylene glycol is formed by reacting with trilysine acetate A prostaglandin antagonist dispersed within a hydrogel comprising a polymer network. 11 to 20 μg of prostaglandin antagonist containing travoprost particles One prostaglandin, as defined above, containing a prostaglandin (e.g., travoprost) A biodegradable intracameral implant for sustained release of a thiazolinone antagonist (e.g., travoprost) is provided. To provide and Step 2: Inserting one sustained-release biodegradable intracameral implant of Step 1 into the anterior segment of the eye. and positioning it within the iridocorneal angle of said eye.

[0254] In another specific aspect, the present invention provides a method for treating glaucoma, such as ocular hypertension or open-angle glaucoma. In human subjects, a single prostaglandin antagonist was administered to each eye requiring such treatment. Approximately 3-6 months after injection by a sustained-release biodegradable intracameral implant of an agonist (e.g., travoprost) The present invention relates to a method for treating intraocular pressure for a period of about six months or about three to about four months, the method comprising administering to the eye and inserting one sustained-release biodegradable intracameral implant into the anterior segment of said eye for each eye. and placing the implant within the iridocorneal angle of the eye, the implant being as defined above. and 11-20 μg of a prostaglandin antagonist (e.g., travoprost ) and in its dry state, the implant is approximately 1.0mm to 2.5mm long and 0. in the form of fibers having a diameter of 3 mm or less, a biodegradable hydrogel as defined above and a protease inhibitor as defined above staglandin antagonist (travoprost) particles; Prostaglandin antagonist (e.g., travoprost) particles are available in three types , about 0.05 to less than about 0.5 dl / g, for example, in the range of about 0.35 to about 0.45 dl / g and a biodegradable polymer comprising a first polylactide having an intrinsic viscosity specification of Forms of prostaglandin antagonists (e.g., travoprost) mixed with mers and a first type of particles having a densitometric value of about 0.5 to about 1.7 dl / g, for example, about 0.6 to about 0.8 a second polylactide having an intrinsic viscosity specification in the range of less than 200 dl / g and having acid end groups; A prostaglandin antagonist (e.g., trastuzumab) mixed with a biodegradable polymer comprising and a second type of particles in the form of benzoyl benzoate (boprost); about 0.8 to about 1.7 dl / g, e.g., a third polymer having an intrinsic viscosity specification in the range of 0.8 to about 1.0 dl / g and having acid end groups; Prostaglandin antagonists ( For example, a biodegradable composition containing a blend of a third type of particles in the form of a hydroxybenzoate (e.g., travoprost) A prostaglandin antagonist (e.g., travoprost) mixed with a degradable polymer and prostaglandin antagonist (travoprost) particles in the form of The hydrogel is an 8-arm 15K with a mass average molecular weight of 15,000 ± 10% Daltons. -SG polyethylene glycol is formed by reacting with trilysine acetate A prostaglandin antagonist dispersed within a hydrogel comprising a polymer network. It contains travoprost particles.

[0255] In a further specific aspect, the present invention provides a method for treating glaucoma, such as ocular hypertension or open-angle glaucoma. In a human subject with a single prostaglandin A administration to each eye requiring such treatment, Approximately 100% of patients with thromboembolism are treated with an intracameral biodegradable implant that releases an agonist (e.g., travoprost) sustained release. The present invention relates to a method for treating intraocular pressure for a period of 3 to about 6 months or about 3 to about 4 months, the method comprising the steps of: For each note, Step 1: The implant is approximately 1.0 mm to 2.5 mm long and 0.3 m long in its dry state. in the form of fibers having a diameter of less than 1 mm, A biodegradable hydrogel as defined above and a prostaglandin as defined above. taglandin antagonist (travoprost) particles; The prostaglandin antagonist (e.g., travoprost) particles are divided into two types of particles: About 0.05 to less than about 0.5 dL / g, for example, in the range of about 0.35 to about 0.45 dL / g A biodegradable polymer comprising a first polylactide having an intrinsic viscosity specification and having acid end groups. in the form of a prostaglandin antagonist (e.g., travoprost) mixed with and a first type of particle; about 0.5 to about 1.7 dl / g, for example, about 0.6 to about 0.8 dl / g. a second polylactide having an intrinsic viscosity specification in the range of 1 / 100 liters / g and having acid end groups; Prostaglandin antagonists (e.g., travoprostaglandins) mixed with biodegradable polymers A blend of a second type of particles in the form of a biodegradable polymer and a prostaglandin antagonists (e.g., travoprost) staglandin antagonist (travoprost) particles; The hydrogel has an 8-arm -15K- with a mass average molecular weight of 15,000 ± 10% Daltons. Polyethylene glycol formed by reacting SG with trilysine acetate Prostaglandin antagonists dispersed within hydrogels containing polymer networks 2 to 10 μg of a prostaglandin antagonist containing travoprost particles (e.g., travoprost) and providing a sustained-release biodegradable intracameral implant for a vasodilator antagonist (e.g., travoprost). And, Step 2: Inserting one sustained-release biodegradable intracameral implant of Step 1 into the anterior segment of the eye. and positioning it within the iridocorneal angle of said eye.

[0256] In a further specific aspect, the present invention provides a method for treating glaucoma, such as ocular hypertension or open-angle glaucoma. In a human subject with a single prostaglandin A administration to each eye requiring such treatment, Approximately 100% of patients with thromboembolism are treated with an intracameral biodegradable implant that releases an agonist (e.g., travoprost) sustained release. The present invention relates to a method for treating intraocular pressure for a period of 3 to about 6 months or about 3 to about 4 months, the method comprising the steps of: One sustained-release biodegradable intracameral implant per eye is inserted into the anterior segment of the eye, within the iridocorneal angle of said eye, the implant being as defined above. and 2-10 μg of a prostaglandin antagonist (e.g., travoprosulfone). The implant contains a length of about 1.0 mm to about 2.5 mm in its dry state and a thickness of 0.01 mm. in the form of fibers having a diameter of 0.3 mm or less, A biodegradable hydrogel as defined above and a prostaglandin as defined above. taglandin antagonist (travoprost) particles; The prostaglandin antagonist (e.g., travoprost) particles are divided into two types of particles: About 0.05 to less than about 0.5 dL / g, for example, in the range of about 0.35 to about 0.45 dL / g A biodegradable polymer comprising a first polylactide having an intrinsic viscosity specification and having acid end groups. in the form of a prostaglandin antagonist (e.g., travoprost) mixed with and a first type of particle; about 0.5 to about 1.7 dl / g, for example, about 0.6 to about 0.8 dl / g. a second polylactide having an intrinsic viscosity specification in the range of 1 / 100 liters / g and having acid end groups; Prostaglandin antagonists (e.g., travoprostaglandins) mixed with biodegradable polymers A blend of a second type of particles in the form of a biodegradable polymer and a prostaglandin antagonists (e.g., travoprost) staglandin antagonist (travoprost) particles; The hydrogel has an 8-arm -15K- with a mass average molecular weight of 15,000 ± 10% Daltons. Polyethylene glycol formed by reacting SG with trilysine acetate Prostaglandin antagonists dispersed within hydrogels containing polymer networks It contains travoprost particles.

[0257] In a further specific aspect, the present invention provides a method for treating glaucoma, such as ocular hypertension or open-angle glaucoma. In affected human subjects, a single prostaglandin B12 dose is administered to each eye requiring such treatment. antagonist (e.g., travoprost) sustained-release biodegradable intracameral implant The present invention relates to a method for treating intraocular pressure over a period of about 2 to about 12 months or about 6 to about 9 months, for each said eye, Step 1: The implant is approximately 1.0 mm to 2.5 mm long and 0.3 mm thick in its dry state. a biodegradable hydrogel as defined above in the form of fibers having a diameter of and a prostaglandin antagonist as defined above dispersed therein. The intracameral implant contains travoprost particles and is maintained at pH 7.2 under sink conditions. When measured in PBS at 37°C, the amount released over 14 days from days 1 to 112 was The average percentage range is about 5% to about 15%, with a mean absolute deviation of at most 3% based on the percentage of In vitro release of prostaglandin antagonists (e.g., travoprost) or prostaglandin antagonist (e.g., travoprost) release is 5% ~15% and the hydrogel dissolves within 6-8 months or within 5-7 months / Completely biodegradable, 21-30 μg of prostaglandin antagonist (e.g., Trabo one prostaglandin antagonist as defined above containing providing a sustained-release biodegradable intracameral implant for methicillin (e.g., travoprost); Step 2: Inserting one sustained-release biodegradable intracameral implant of Step 1 into the anterior segment of the eye. and positioning it within the iridocorneal angle of said eye.

[0258] In a more specific aspect, the present invention provides a method for treating glaucoma, such as ocular hypertension or open-angle glaucoma. In a human subject with a single prostaglandin A administration to each eye requiring such treatment, by a sustained-release biodegradable intracameral implant of an antagonist (e.g., travoprost) The present invention relates to a method for treating intraocular pressure over a period of about 2 to about 12 months or about 6 to about 9 months, inserting one sustained-release biodegradable intracameral implant per eye into the anterior segment of said eye; and placing it within the iridocorneal angle of said eye, the implant being as defined above. As previously reported, 21-30 μg of prostaglandin antagonists (e.g., Travo The implant contains 1.0mm to 2.5mm in length in its dry state. and in the form of fibers having a diameter of 0.3 mm or less, and a degradable hydrogel and a prostaglandin as defined above dispersed therein. The intracameral implant contains particles of a vasodilator antagonist (travoprost) and is Below, 14 days from days 1 to 112 when measured at 37°C in PBS with a pH of 7.2 to 7.4 Approximately 5% to 15% with a mean absolute deviation of at most 3% based on the % amount released per with mean prostaglandin antagonist (e.g., travoprost) release in the range of have in vitro release or prostaglandin antagonists (e.g., travopros The release rate ranges from about 5% to about 15%, and the hydrogel dissolves within 6 to 8 months. .

[0259] In another specific aspect, the present invention provides a method for treating glaucoma, such as ocular hypertension or open-angle glaucoma. In human subjects, a single prostaglandin antagonist was administered to each eye requiring such treatment. Approximately 3-6 months after injection by a sustained-release biodegradable intracameral implant of an agonist (e.g., travoprost) The present invention relates to a method for treating intraocular pressure for a period of about six months or about three to about four months, the method comprising administering to the eye For each Step 1: The implant is approximately 1.0 mm to 2.5 mm long and 0.3 mm thick in its dry state. in the form of fibers having a diameter of A biodegradable hydrogel as defined above and a polymeric material as defined above dispersed therein. and a prostaglandin antagonist (travoprost) particle, such as that described above, Intracameral implants were measured under sink conditions in PBS pH 7.2–7.4 at 37°C. In this case, the mean absolute deviation based on the % amount released per 70 days from days 1 to 84 was large. The average prostaglandin antagonist (e.g., α-glucan) concentration ranges from about 65% to about 85%, with the average prostaglandin antagonist concentration being 5%. In vitro release by prostaglandin antagonists (e.g., travoprost) The agonist (e.g., travoprost) release ranged from 65% to 85%, and the hydrogel Dissolves / completely biodegrades within 2-4 months or within 3-5 months, 11-20 μg a prostaglandin antagonist (e.g., travoprost) as defined above; One prostaglandin antagonist (e.g., travoprost) sustained-release Providing a biodegradable intracameral implant; Step 2: Inserting one sustained-release biodegradable intracameral implant of Step 1 into the anterior segment of the eye. and positioning it within the iridocorneal angle of said eye.

[0260] In another specific aspect, the present invention provides a method for treating glaucoma, such as ocular hypertension or open-angle glaucoma. In a human subject, a single prostaglandin antagonist is administered to each eye requiring such treatment. Approximately 3 months after the initial release of a progesterone agonist (e.g., travoprost) by a biodegradable intracameral implant and a method for treating intraocular pressure for a period of about 1 to about 6 months or about 3 to about 4 months, the method comprising: One sustained-release biodegradable intracameral implant per eye is inserted into the anterior segment of said eye, and placing the insert within the iridocorneal angle of said eye, the insert being as defined above. and 11-20 μg of a prostaglandin antagonist (e.g., travoprost ) and in its dry state, the implant is approximately 1.0mm to 2.5mm long and 0. in the form of fibers having a diameter of 3 mm or less and made of biodegradable hydrogels as defined above. a prostaglandin antagonist as defined above dispersed therein; The intracameral implant contains travoprost particles and is maintained under sink conditions at pH 7. When measured at 37°C in PBS 7.2-7.4, the release rate was approximately 70 days from days 1 to 84. Based on the % amount dispensed, the average absolute deviation is at most 5% and ranges from about 65% to about 85%. In vitro mean prostaglandin antagonist (e.g., travoprost) release or prostaglandin antagonist (e.g., travoprost) releasing The hydrogel is in the range of 65% to 85% and the hydrogel is Dissolves in water / fully biodegrades.

[0261] In another specific aspect, the present invention provides a method for treating glaucoma, such as ocular hypertension or open-angle glaucoma. In human subjects, a single prostaglandin antagonist was administered to each eye requiring such treatment. Approximately 3-6 months after injection by a sustained-release biodegradable intracameral implant of an agonist (e.g., travoprost) The present invention relates to a method for treating intraocular pressure for a period of about six months or about three to about four months, the method comprising administering to the eye For each Step 1: The implant is approximately 1.0 mm to 2.5 mm long and 0.3 mm thick in its dry state. in the form of fibers having a diameter of A biodegradable hydrogel as defined above and a polymeric material as defined above dispersed therein. and a prostaglandin antagonist (travoprost) particle, such as that described above, Intracameral implants were measured under sink conditions in PBS pH 7.2–7.4 at 37°C. In this case, the mean absolute deviation based on the % amount released per 70 days from days 1 to 98 was large. The average prostaglandin antagonist (e.g., α-glucan) concentration ranges from about 60% to about 80%, with the average prostaglandin antagonist concentration being 5%. In vitro release by prostaglandin antagonists (e.g., travoprost) The agonist (e.g., travoprost) release ranged from 60% to 80%, and the hydrogel 2-10 μg of prostaglandin antagonist (e.g., thiamin) that dissolves within 2-4 months one prostaglandin antagonist as defined above, containing raboprost and providing a biodegradable intracameral implant for sustained release of an agonist (e.g., travoprost). , Step 2: Inserting one sustained-release biodegradable intracameral implant of Step 1 into the anterior segment of the eye. and positioning it within the iridocorneal angle of said eye.

[0262] In another specific aspect, the present invention provides a method for treating glaucoma, such as ocular hypertension or open-angle glaucoma. In human subjects, a single prostaglandin antagonist was administered to each eye requiring such treatment. Approximately 3 months after the initial release of a biodegradable intracameral implant containing a gonadotropin (e.g., travoprost) and a method for treating intraocular pressure for a period of about 1 to about 6 months or about 3 to about 4 months, the method comprising: One sustained-release biodegradable intracameral implant per eye is inserted into the anterior segment of said eye, and placing the implant within the iridocorneal angle of said eye, the implant being as defined above. and 2 to 10 μg of a prostaglandin antagonist (e.g., travoprost) ) and in its dry state, the implant is approximately 1.0mm to 2.5mm long and 0. in the form of fibers having a diameter of 3 mm or less and made of biodegradable hydrogels as defined above. a prostaglandin antagonist as defined above dispersed therein; The intracameral implant contains travoprost particles and is maintained under sink conditions at pH 7. When measured at 37°C in PBS 7.2-7.4, the release rate was approximately 70 days from days 1 to 98. Based on the % amount dispensed, the average absolute deviation is at most 5% and ranges from about 60% to about 80%. In vitro mean prostaglandin antagonist (e.g., travoprost) release or prostaglandin antagonist (e.g., travoprost) releasing The viscosity ranges from 60% to 80%, and the hydrogel dissolves within 2 to 4 months.

[0263] The implants of the present invention may be provided by the physician performing the procedure. In this state, the implant is in a syringe-like device packaged in a sterile package and delivered to a medical professional. The patient should unpack the implant immediately prior to the procedure and follow the implantation / insertion instructions described herein. The method provides an implant.

[0264] The disclosed implants are useful for reducing intraocular pressure. Provided herein is a method for administering a hydrogel implant as described herein. A method for reducing intraocular pressure in a subject in need thereof, comprising: Also disclosed is the use of the disclosed implants to The invention relates to the use of the disclosed implant in the manufacture of a drug for reducing intraocular pressure. The use of.

[0265] Also provided are methods for administering the hydrogel implants described herein. Disclosed is a method of treating intraocular pressure in a subject in need thereof, comprising: Also disclosed is the use of the disclosed implants to treat intraocular pressure in a subject. Provided in the patent application is the disclosed impact in the manufacture of a medicament for treating intraocular pressure. The use of runt.

[0266] Also provided are methods for administering the hydrogel implants described herein. and (iii) administering to a subject in need thereof a therapeutically effective amount of glaucoma, the therapeutically effective amount being 200 mg / kg body weight. Also disclosed are methods for treating glaucoma (open-angle glaucoma) in a subject. The use of implants that are currently being offered is also being considered for the treatment of glaucoma (open-angle glaucoma). and the use of the disclosed implants in the manufacture of a medicament for treating internal derangements.

[0267] In some further embodiments, travoprost is administered for a period ranging from about 1 month to about 1 year. and delivered to the eye continuously for a period of time, with the remaining characteristics of the implant being as described herein. Alternatively, as part of a further embodiment, travoprost is administered for about 1 month to about 11 months. The drug is delivered to the eye continuously for a period ranging from 1 month to 2 months, while maintaining the remaining characteristics of the implant. As another alternative, as part of this embodiment, Lost is delivered to the eye continuously for a period ranging from about 1 month to about 10 months, The remaining features of the implant are described herein. As part of this regimen, travoprost is continuously administered over a period ranging from approximately 1 month to approximately 9 months. The remaining characteristics of the implant are as described herein. Alternatively, as part of this embodiment, travoprost is administered for a period ranging from about 1 month to about 8 months. The remaining characteristics of the implant are as described herein. In another alternative, as part of this embodiment, travoprost is administered in an amount of about 2 The drug is delivered to the eye continuously for a period ranging from 1 month to approximately 8 months, during which the implant The remaining features are described herein. In another alternative, as part of this embodiment Travoprost is delivered to the eye continuously for a period ranging from about 3 months to about 7 months. , with the remaining features of the implant being as described herein. As part of this embodiment, travoprost is administered for a period ranging from about 4 months to about 6 months. and delivered to the eye continuously, with the remaining characteristics of the implant being as described herein. In another alternative, as part of this embodiment, travoprost is administered for a period of about one month. The remaining characteristics of the implant are as described herein. In another alternative, as part of this embodiment, travoprost is administered for about 2 months. The remaining characteristics of the implant are as described herein. In another alternative, as part of this embodiment, travoprost is administered in an amount of about 3 The remaining characteristics of the implant are maintained as described herein. In another alternative, travoprost may be used as part of this embodiment. is delivered to the eye continuously for a period of approximately four months, during which time the remaining characteristics of the implant As another alternative, as part of this embodiment, The rosto is delivered to the eye continuously for a period of approximately 5 months, during which time the remainder of the implant The features are described herein. In another alternative, as part of this embodiment, Laboprost is delivered to the eye continuously for a period of approximately six months, during which time the implant The remaining features of are described herein.

[0268] As some further embodiments, the sustained release of travoprost occurs in the aqueous humor, wherein The remaining features of the implant are described herein.

[0269] As part of further embodiments, the polymer nematics of the disclosed hydrogel implants The network is bound to fluorescein, whereby the remaining characteristics of the implant are as described herein. is described in.

[0270] As part of further embodiments, the disclosed implants are The implant is designed for implantation in accordance with the present invention, wherein the remaining features of the implant are as described herein. It is being done.

[0271] As part of further embodiments, the disclosed implants may be used to treat corneal aneurysms in the inferior iridocorneal angle. The implant is designed for implantation in accordance with the present invention, with the remaining features of the implant being as described herein. It is being done.

[0272] As part of further embodiments, the disclosed implants may be 5 pg, 15 pg or or 26 pg of travoprost, wherein the remaining characteristics of the implant are, e.g., As described herein, such as the first to fifteenth embodiments, or as disclosed herein. Contains 5 pg, 15 pg or 26 pg of travoprost as part of the implant ; multiple polyethylene glycol (PEG) units containing groups susceptible to nucleophilic attack 4a20K PEG NH2, 8a20K PEG NH2, and trilysine a polymer formed by reacting one or more PEG or lysine-based amine groups with the The remaining characteristics of the hydrogel, including the polymer network, are described herein.

[0273] As part of further embodiments, the disclosed implants contain a complete Following the release of the active ingredient, the active ingredient is completely degraded, at which point the remaining characteristics of the implant are as described herein. Alternatively, hydrogel implants may be used to release travoprost following its complete release. After about 12 months, after about 11 months, after about 10 months, after about 9 months, after about 8 months, after about 6 months, after about Completed after 5 months, approximately 4 months, 3 months, approximately 2 months, and approximately 1 month (i.e., approximately 30 days). completely disassembled, whereupon the remaining features of the implant remain as described herein. The hydrogel implant contains at least 90% of the travoprost (e.g., at least 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%) After release of the active ingredient, the implant is completely degraded and the remaining characteristics of the implant are as described herein.

[0274] In one embodiment, the present invention relates to a method for treating intraocular pressure disorders in a patient with a pulmonary artery disease, the method comprising administering to said patient a therapeutically effective amount of a pulmonary artery disease (ROI) treatment for a period of about 2 to about 12 months, or about 3 to about 9 months, for example, about 6 months. Approximately 5 to 7 mm below baseline intraocular pressure during the month-long treatment period or during continued treatment with repeated doses The methods disclosed herein are directed to a reduction in blood pressure by about 7 to about 9 mmHg. .

[0275] Methods of treating eye diseases in human subjects In one aspect, the present invention provides a single API-containing sustained-release ointment for each eye in need of such treatment. Biodegradable intracameral implants last for approximately 1 to 24 months, or approximately 2 to 12 months, or approximately The present invention relates to a method for treating an ocular disease in a human subject for a period ranging from 3 to about 9 months, the method comprising: Every memory Step 1: for a period ranging from about 1 to about 24 months, or from about 2 to about 12 months, or from about 3 to about 9 months provide treatment, a biodegradable hydrogel and API particles as defined above, A single API-containing sustained-release biodegradable pregelatinized formulation containing API particles dispersed within a hydrogel. Providing an intracameral implant; Step 2: Inserting one sustained-release biodegradable intracameral implant of Step 1 into the anterior segment of the eye. and positioning it within the iridocorneal angle of said eye.

[0276] In one aspect, the present invention provides a single API-containing sustained-release biologic for each eye in need of such treatment. Approximately 1 to 24 months, approximately 2 to 12 months, or approximately 3 months depending on the degradable intracameral implant The present invention relates to a method of treating an ocular disease in a human subject for a period of from about 9 months to about 10 months, the method comprising administering to each of said eyes a sustained-release biodegradable intracameral implant inserted into the anterior segment of the eye; and placing the implant within the iridocorneal angle of the eye, wherein the implant remains in place for about 1 to about 24 months or provides treatment for a period of about 2 to about 12 months or about 3 to about 9 months, a biodegradable hydrogel and API particles as defined above, A single API-containing sustained-release biodegradable pregelatinized formulation containing API particles dispersed within a hydrogel. It is an intracameral implant.

[0277] In another aspect, the present invention provides a single API-containing drug in a human subject in need of such treatment. The method involves treating eye diseases using implants within a period of 3 to 9 months.

[0278] In a further aspect, the present invention provides a method for administering a single API to a human subject in need of such treatment. It is intended to be used in a method for treating eye diseases within a period of 3 to 9 months using a containing implant. This applies to implants for this purpose.

[0279] In one embodiment, the one API is a prostaglandin antagonist. Specifically, the single API is composed of travoprost, bimatoprost, and latanoprost. is selected from the group consisting of:

[0280] Therapeutic agents include, for example, inflammatory or abnormal vascular conditions, retinal vein occlusion, geographic atrophy, These include medications to treat conditions that can result from retinitis pigmentosa, retinoblastoma, etc. For cancer, the drug may be, for example, an anti-cancer drug, an anti-VEGF drug, or a drug for use in cancer treatment. It may be a known drug.

[0281] The therapeutic agent may, for example, block VEGFR1, block VEGFR2, and block VEGFR3. Anti-VEGF, anti-PDGF, anti-angiogenesis, sunitinib, E7080, Takeda-6d, Tivozanib, regorafenib, sorafenib, pazopanib, axitinib, nintedanib , cediranib, vatalanib, motesanib, macrolides, sirolimus, everolimus, TKI, imatinib (GLEEVAC), gefitinib (IR ESSA), toceranib (PALLADIA), erlotinib (TARCEVA), rapamycin Tykerb (tykerb), nilotinib, bosutinib, neratinib, lapatinib, botaranib dasatinib, erlotinib, gefitinib, imatinib, lapatinib, lestaurine It may be nib, nilotinib, semaxanib, toceranib, or vandetanib. .

[0282] The therapeutic agent may comprise a macromolecule, e.g., an antibody or antibody fragment. The therapeutic macromolecule may be a VE GF inhibitors, such as ranibizumab, the active ingredient in the commercially available Lucentis™ The VEGF (vascular endothelial growth factor) inhibitor, when released into the vitreous humor of the eye, They can cause the regression of abnormal blood vessels and improve vision. Examples of VEGF inhibitors include: Lucentis™ (ranibizumab), Eylea™ (VEGF trap) , Avastin™ (bevacizumab), Macugen™ (pegaptanib) Platelet-derived growth factor (PDGF) inhibitors, such as anti-PDGF aptamers Fovista™, which is a steroid drug, may also be delivered.

[0283] The therapeutic agent may be a small molecule such as a steroid or corticosteroid and their analogs. For example, therapeutic corticosteroids may include trimacinarone, trimacinarone Acetonide, dexamethasone, dexamethasone acetate, fluocinolone, fluocinolone acetate may include one or more of the following: benzodiazepine, ... Alternatively, or in combination, the therapeutic small molecule may include a tyrosine kinase inhibitor. good.

[0284] Therapeutic agents may include anti-VEGF therapeutic agents. Anti-VEGF therapies and agents are used to treat certain cancers and and age-related macular degeneration. Examples of anti-VEGF therapeutic agents suitable for use in accordance with the present invention include bevacizumab (Avastin) and (TM) or a monoclonal antibody such as ranibizumab (Lucentis™) ), or antibody derivatives such as lapatinib (Tykerb™), sunitinib (Su tent™), sorafenib (Nexavar™), axitinib, or One or more small molecules that inhibit VEGF-stimulated tyrosine kinases, such as zopanib, The above are some examples.

[0285] Therapeutic agents include, for example, Sirolimus™ (rapamycin), Copaxone (trademark) (glatiramer acetate), Othera™ complement C5aR blocker, For dry AMD, one or more of the following treatments may be considered: ciliary neurotrophic factor, fenretinide, or rheumatoid arthritis. It may also contain a therapeutic agent suitable for treatment.

[0286] The therapeutic agents include REDD14NP (Quark), Sirolimus™ (rapamycin), EGFR), ATG003; EYELEA (VEGF trap) or complement inhibitor (POT-4 The composition may also include a therapeutic agent suitable for treating wet AMD, such as one or more of the following:

[0287] The therapeutic agents are BIBW 2992 (a small molecule targeting EGFR / Erb2), imatinib, and gefitinib (small molecule), ranibizumab (monoclonal antibody), pegap Tanib (small molecule), sorafenib (small molecule), dasatinib (small molecule), sunitinib (small molecule) child), erlotinib (small molecule), nilotinib (small molecule), lapatinib (small molecule), pancreatic Mumab (monoclonal antibody), vandetanib (small molecule) or E7080 (VEGFR 2 / VEGFR2-targeting small molecules commercially available from Esai, Co. Therapeutic agents may include antibody drugs, such as bevacizumab, trastuzumab, and the like. May include stuzumab, cetuximab, and panitumumab.

[0288] Therapeutic agents may include drugs from various classes, such as steroids, nonsteroidal anti-inflammatory drugs, and the like. Steroidal anti-inflammatory drugs (NSAIDS), anticancer drugs, antibiotics, anti-inflammatory drugs (e.g., dimethicone) lofenac), analgesics (e.g., bupivacaine), calcium channel blockers (e.g., nifedipine), antibiotics (e.g., ciprofloxacin), cell cycle inhibitors (e.g., simvastatin), proteins (e.g., insulin). For example, steroids, NSAIDs, antioxidants, antibiotics, analgesics, vascular endothelial growth factor (VEGF) This includes classes of drugs including inhibitors of inflammatory bowel disease (GF), chemotherapy agents, and antivirals. Examples of S are ibuprofen, meclofenamate sodium, mefanamic acid, salsa acetaminophen, sulindac, tolmetin sodium, ketoprofen, diflunisal, piroxicam Medicinal, naproxen, etodolac, flurbiprofen, fenoprofen calcium, These are endomethacin, ceroxib, ketorolac, and nepafenac. molecules, proteins, RNA fragments, proteins, glycosaminoglycans, carbohydrates, nucleic acids, Certain bioactive agents include enzymes, antibiotics, antitumor agents, local anesthetics, hormones, angiogenic agents, Anti-angiogenic agents, growth factors, antibodies, neurotransmitters, psychoactive drugs, anti-cancer drugs, chemotherapeutic drugs, biologics This includes drugs or other compounds that affect reproductive organs, genes, oligonucleotides, etc. The compounds may be, but are not limited to, inorganic and organic biologically active compounds.

[0289] Therapeutic agents may include proteins or other water-soluble biologics. Peptides include therapeutic proteins and peptides, antibodies, and peptides with molecular weights of 1000 to 10000. These include antibody fragments, single chain variable fragments (scFv), growth factors, angiogenic factors, and insulin. Other water-soluble biological agents include carbohydrates, polysaccharides, nucleic acids, antisense nucleic acids, RNA, DNA, small interfering RNA (siRNA), and aptamers.

[0290] Therapeutic agents may be used as part of a method of treating an indicated condition or to treat an indicated condition. For example, AZOPT (Brand Name) may be used as part of a method for making a composition for Linzolamide ophthalmic suspension is used to treat elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma. Betadine in povidone-iodine eye drops may be used for pre-treatment of the periocular area and for ophthalmic use. May be used for surface cleansing. BETOPTIC (betaxolol HCl) reduces intraocular pressure. It may also be used to reduce the risk of glaucoma, or for chronic open-angle glaucoma and / or ocular hypertension. LOXAN (ciprofloxacin HCl ophthalmic solution) is a ciprofloxacin-containing ophthalmic solution that can be used to treat ulcers caused by susceptible strains of microorganisms. It may also be used to treat infections caused by natamycin. may be used to treat fungal blepharitis, conjunctivitis, and keratitis. Fenac ophthalmic suspension may be used to treat pain and inflammation associated with cataract surgery. RAVATAN (travoprost ophthalmic solution) is a treatment for elevated intraocular pressure (OPE) – open-angle glaucoma or ocular hypertension FML FORTE (fluorometholone ophthalmic suspension) may be used to relieve eye irritation. For the treatment of corticosteroid-responsive inflammation of the bulbar and palpebral conjunctiva, cornea, and anterior segment of the eye May be used. LUMIGAN (bimatoprost ophthalmic solution) is used to treat elevated intraocular pressure (IOP) and open-angle glaucoma. May be used to relieve cataracts or ocular hypertension. PRED FORTE (Prednisone acetate) Ron) is used to treat steroid-responsive inflammation of the palpebral and bulbar conjunctiva, cornea, and anterior segment of the eye. PROPINE (dipivefrine hydrochloride) may be used to reduce intraocular pressure in chronic open-angle glaucoma. RESTASIS (cyclosporine ophthalmic emulsion) may be used to control to increase tear production in patients with ocular inflammation, for example, those associated with keratoconjunctivitis sicca. ALREX (loteprednol etabonate ophthalmic suspension) may be used seasonally. May also be used for the temporary relief of allergic conjunctivitis. Loteprednol ophthalmic suspension is used to treat the palpebral and bulbar conjunctiva, cornea, and anterior segment of the eye. It may also be used to treat asteroid-reactive inflammation. OPTIVA (injection) may be used to treat neovascular (wet) age-related macular degeneration. R (azelastine hydrochloride) is used to treat itchy eyes associated with allergic conjunctivitis. XALATAN (latanoprost ophthalmic solution) is used to treat, for example, open-angle glaucoma or high blood pressure. It may also be used to reduce elevated intraocular pressure in patients with ocular hypertension. solution) may be used to treat elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma. Tanoprost is a prostanoid-selective FP receptor agonist in the free acid form. Latanoprost reduces intraocular pressure in patients with glaucoma with few side effects. Noprost has relatively low solubility in aqueous solutions, but is suitable for the preparation of microspheres using solvent evaporation. It is readily soluble in organic solvents commonly used in manufacturing.

[0291] Further embodiments of therapeutic agents for delivery include those that specifically bind to target peptides in vivo. These include those that interfere with the interaction of the target peptide with its natural receptor or other ligands. For example, Avastin is an antibody that binds VEGF. IL-1 traps that utilize the ectodomain are also known; traps are used to trap IL-1 on the cell surface. An embodiment of the agent for delivery is a nucleic acid, e.g. For example, pegaptanib (MACUGEN) is a pegylated antibody. The advantage of the particle and hydrogel delivery process is that they release The goal is to protect the aptamer from the in vivo environment until it is released. In some embodiments, macromolecular drugs are used, i.e., drugs that are significantly larger than classical small molecule drugs. The terms i.e. oligonucleotides (aptamers, antisense, RNAi), ribozymes These include drugs such as immunizations, gene therapy nucleic acids, recombinant peptides and antibodies.

[0292] One embodiment includes extended release of medication for allergic conjunctivitis. Ketotifen, a steroid and mast cell stabilizer, is provided in particles to treat allergic conjunctivitis. They may be delivered to the eye as described herein in a therapeutically effective amount. Severe allergic conjunctivitis (SAC) and perennial allergic conjunctivitis (PAC) are allergic conjunctivitis. It is a membrane disorder. Symptoms include itching and pink to reddish eyes. The eye condition is mediated by mast cells. Traditionally, non-specific measures to improve symptoms include: Treatment includes cold compresses, irrigation with tear substitutes, and avoidance of allergens. Histamine mast cell stabilizers, dual mechanism antiallergens, or topical antihistamines Corticosteroids may be effective, but side effects mean that vernal ulcers more severe forms of allergic conjunctivitis such as keratoconjunctivitis (VKC) and atopic keratoconjunctivitis (AKC) It is reserved for the form of the disease.

[0293] Moxifloxacin is the active ingredient in VIGAMOX, used to treat bacterial eye infections or VKC and AKC are fluoroquinolones approved for prophylaxis. Eosinophils, conjunctival fibroblasts, epithelial cells, mast cells, and / or TH2 lymphocytes contribute to the biosynthesis of the conjunctiva. VKC and AKC are chronic allergic diseases that worsen the inflammatory and histological findings of allergic It can be treated with drugs used to combat inflammatory conjunctivitis. and, as described herein, gels, hydrogels, organogels, xerogels, and biomaterials. These are agents that aid in the penetration of drugs into target tissues. The permeation agent may be selected as needed for the tissue, for example, a permeation agent for the skin, a permeation agent for the eardrum, There are penetration agents for the eye and penetration agents for the eye.

[0294] The drug may be a treatment for an ocular fundus disease, for example, the ocular fundus disease is age-related macular degeneration (AMD). D), cystoid macular edema (CME), diabetic macular edema (DME), posterior uveitis, and If you have diabetic retinopathy or glaucoma.

[0295] The agent may, for example, block VEGFR1, block VEGFR2, and block VEGFR3. anti-VEGF, anti-PDGF, anti-PDGF-R that blocks PDGFRβ, anti-angiogenic agents, Sunitinib, E7080, Takeda-6d, tivozanib, regorafenib, sorafenib, Pazopanib, axitinib, nintedanib, cediranib, vatalanib, motesanib, mazopanib Chloride, sirolimus, everolimus, tyrosine kinase inhibitors (TKIs), imatinib , gefitinib, toceranib, erlotinib, lapatinib, nilotinib, bosutinib, nephropathy Medications including latinib, lapatinib, and vatalanib, low-solubility prostaglandins for glaucoma Drugs containing analogues, nepafenac, macrolides, rapamycin, sirolimus, and tacrolimus or blocking the mTOR receptor in AMD (also known as choroidal neovascularization (CNV)). mTOR refers to mammalian target of rapamycin. Examples of drugs include moxifloxacin, dexamethasone, travoprost, steroids, The agent may be a fluoroquinolone, a prostaglandin analogue, or a prostamide.

[0296] Ocular diseases include hyphema, ocular hypertension, and glaucoma, conditions treated with anterior chamber depots. Certain ocular conditions include: many medications, e.g., NSAIDs, administered via intracameral injection; DS, steroids, antiglaucoma drugs, antivirals, antibiotics, mydriatics, and antifungals are used in the treatment of ophthalmopathy. Suitable for delivery to

[0297] Some of the pathologies are ocular diseases. The term ocular diseases is used by experts in these fields. are recognized by the National Institute of Neurology and commonly affect the vasculature and integrity of the retina, macula, or choroid. It refers to eye diseases in the posterior segment of the eye that affect the eyes and lead to impaired vision, loss of vision, or blindness. The condition may be due to age, trauma, surgical intervention, and genetic factors. The diseases include age-related macular degeneration (AMD), cystoid macular edema (CME), and diabetic macular edema (DME). ME), posterior uveitis, and diabetic retinopathy. Some fundus diseases include macular degeneration. This is due to unwanted angiogenesis or vascular proliferation, such as diabetic retinopathy. Drug treatment options for these and other eye conditions are available through drug delivery from implants. It may be provided as follows. [Example]

[0298] The following examples illustrate certain aspects and implementations of the invention as claimed. However, the following description is by way of example only and is not intended to be limiting of the invention. It should be understood by those skilled in the art that this should not be construed as limiting in any way.

[0299] Example 1: Preparation of Travoprost Implant Formulations 1a, 1b, 2 and 3, respectively, for use in the Phase 1 clinical trial shown in Example 3. and travoprost implant or "OTX-TIC implant" having the chemical composition and weight of 3. Laboprost Implants (see Tables 1 and 2a) were prepared. The types of ingredients used in the manufacture of each of the above items and the mass and content of the ingredients are as follows: Reference is generally made to Table 1, which shows the chemical composition and content. The masses and contents in Table 1 are based on the following formulations: The details may be repeated in the description of the corresponding manufacturing processes in paragraphs 1a, 1b, 2 and 3. , and would not be converted into initial mass. [Table 1-1] [Table 1-2]

[0300] Preparation of biodegradable travoprost particles Prepare travoprost implants according to either formulation 1a, 1b, 2 or 3. Travoprost particles, in which travoprost is mixed with polylactide (PLA), are prepared. First, polylactide and travoprosin were prepared by oil-in-water emulsion solvent evaporation / extraction technique. The compound was dissolved in dichloromethane (DCM) to form the dispersed phase (DP) described in the process. Single-phase solutions containing polymers of different molecular weights were prepared (see Table 2a). , 9A, and 5.5E PLA, where the numbers correlate to the PLA molecular weight. Specifies the target intrinsic viscosity (IV) of the polymer in chloroform, and the letter suffix indicates the acid (A). Or specify the terminal group of ester (E). Measured in 0.5% w / v chloroform at 30°C. When the specification is made, 4A PLA has an intrinsic viscosity specification of 0.35 to 0.45 dl / g; PLA has an intrinsic viscosity specification of 0.60 to 0.80 dl / g or less, and 9A PLA is 0.8 The intrinsic viscosity specification is 0 to 1.0 dl / g. Details of the measurement of the intrinsic viscosity of polylactide are as follows: The results are shown in Table 2b below. When measured in 0.1% w / v chloroform at 25°C, the .5E PLA has an intrinsic viscosity specification of 0.55-0.75 dl / g. DP is PVA Approximately 1% (w / w) of polyvinyl alcohol, known as the continuous phase (CP), acts as an emulsifier. The aqueous solution of ethanol (PVA) was injected via a syringe pump. This occurred just before passing through an in-line homogenizer to disperse the nascent particles. The addition of the dispersed phase to the continuous aqueous phase during this incorporation step hardens to form the primary emulsion. The droplets were allowed time to disperse before the CP flow. The quenching catalyst (CP) was stirred in a jacketed reactor maintained at a controlled temperature. The emulsion was stirred overnight in a quenching medium to extract and evaporate the DCM. The resulting particles were washed and then mixed properly using a vibrating sieve mixer. These microparticles (4 microparticles loaded with travoprost) were then sieved into appropriate size fractions. A PLA, 7A PLA, 9A PLA, or 5.5E PLA) with glass vias The resulting solution was collected in a tube and freeze-dried for the production of OTX-TIC (travoprost) implants. Dry microparticles were obtained. Travoprost-loaded microparticles were measured by sieving. The average diameter of the microparticles measured by laser diffraction is 35 μm. do. [Table 2] [Table 3]

[0301] Preparation of travoprost implant General Procedure Lyophilized microparticles (4A, 7A, 9A, and 5.5E, according to the formulations shown in Table 1) Mix and measure into syringes in the prescribed proportions (see Table 2a above) and add water for injection (WFI ) for 15 μg and 26 μg. 10%) and 5.5E (50%) PLA microparticle blends, formulations 1a and 1b OTX- TIC implant, 4A (25%), 7A (40%), 9A (35%) for 15 μg ) PLA microparticle blend, formulation 2 OTX-TIC implant, and 5 μg Blend of 4A (47%) and 7A (53%) PLA microparticles, formulation 3 OTX-TIC The multi-arm PEG precursor solution was injected into a syringe into sodium phosphate monohydrate. Trilysine acetate or Trilysine acetate / NHS were dissolved separately in ethanol or WFI. - The fluorescein buffer was transferred into the syringes. All syringes were placed under vacuum. The syringes of polymer and PEG precursor were first mixed and then combined with TLA or TLA / FL buffer. Together, these initiated the hydrogel formation. The resulting suspension was poured into a small ID tube. Table 3 highlights the differences between the formulations. [Table 4]

[0302] Trilysine acetate / NHS fluorescein (TLA / FL) at 15 μg and 26 μg doses Solutions and Syringes; Preparation of Formulations 1a and 1b The amount of trilysine acetate (TLA) was determined to be 0.001% by weight, and the amount of trilysine acetate (TLA) was determined to be 0.001% by weight. The calculation was based on a 1:1 molar ratio of amine to reactive PEG end groups forming a network. It was calculated.

[0303] The TLA solution was prepared in sodium hydrogen phosphate buffer. Adjust the pH of the solution to 8.40 ± 0.05 by adding TLA and NHS-fluorescein. After preparation, NHS-fluorescein was added to the TLA solution. Add the solution to the vial. Cap the vial and vortex to dissolve the NHS-fluorescein. The TLA / FL solution was left in the foil-covered vial and allowed to react at room temperature for 1–24 hours. I made him respond.

[0304] At the end of the reaction time, measure the pH of the solution and add a predefined volume of TLA / FL solution. The solution was pipetted into four separate syringes. The syringes were placed upright in a beaker to degas the solution. The sample was transferred to a vacuum chamber for further analysis.

[0305] Trilysine acetate (TLA) solution and syringes for 15 μg doses; Formulation 2 and 5 μg doses; Preparation of Agent 3 The amount of trilysine acetate (TLA) was determined to be 0.001% by weight, and the amount of trilysine acetate (TLA) was determined to be 0.001% by weight. The calculation was based on a 1:1 molar ratio of amine to reactive PEG end groups forming a network. The TLA solution was prepared in sodium hydrogen phosphate buffer. At the end of the mixing, the solution Measure the pH of the solution and pipette predefined amounts of TLA solution into four separate syringes. The syringe was placed upright in a beaker and the solution was transferred to a vacuum chamber to degas it.

[0306] Preparation of microparticle syringe For the 15 μg and 26 μg doses (formulations 1a and 1b), each microparticle syringe Predefined ratios of 4A PLA, 7A PLA, 9A PLA, and 5.5E PLA (See "General Procedure" above). For a dose of 15 μg of Formulation 2, Each microparticle syringe contains a predefined ratio of 4A PLA, 7A PLA, and 9A PLA. A PLA microparticles were added (see "General Procedure" above). Regarding the amount, each microparticle syringe contains a predefined ratio of 4 A of PLA and 7 A of P. After weighing the microparticles, the total WFI was added to each of the four syringes to suspend the microparticles. The syringes were then placed directly into the beaker. The mixture was allowed to stand and the suspension was transferred to a vacuum chamber for degassing.

[0307] Preparation of PEG syringe Predefined amounts of 8a15K PEG were weighed and transferred into four different syringes. For the 5 μg and 26 μg doses (formulations 1a and 1b), monosodium phosphate solution Pipette into each syringe and dissolve 8a15K PEG-SAZ. For 2 and 5 μg formulations 3, pipette WFI into each syringe and add 8a15K The PEG-SG was dissolved. The PEG solution was used within 60 minutes of preparation. The flask was then placed upright on a rack and transferred to a vacuum chamber to degas the solution.

[0308] casting For each trial, connect the microparticle syringe and the PEG syringe with a female-to-female Luer connector. Using slow, even pressure, pump the contents of each syringe back and forth (1 The contents of the syringes were mixed together for a total of 25-50 passes (each pass). The TLA / FL (15 μg and 26 μg doses of Formulation 1a) was then drawn into a single syringe. and 1b) or TLA (15 μg dose of formulation 2 and 5 μg dose of formulation 3). When the contents of the syringes were first mixed, the time for the suspension to gel was measured. A calibrated stopwatch was started to determine the pressure. The contents of each syringe were passed back and forth (one pass each) a total of 25 to 50 times to Microparticle / TLA / FL (Formulation 1 at 15 μg and 26 μg doses) or PEG / microparticle / T A suspension of LA (15 μg dose of Formulation 2 and 5 μg dose of Formulation 3) was created. The fluid was drawn into one syringe and stimulated to remove excess air.

[0309] While the suspension is still liquid, connect the syringe to the tubing and inject the suspension into the tubing. When the tube is full, attach the cap to the bottom end and remove it from the syringe. , and cap the casting end. Add the remaining 11 tubes of gel until they harden. Filled in the same way.

[0310] After capping all the tubes in each syringe set, add a small amount of the remaining suspension to the syringe. The gel formation was monitored by placing it on a glass plate until the suspension started to form strands ( (i.e., remain attached to the pipette tip for a complete tapping cycle) This was done for each syringe set (a total of four trials or series). Repeat for the ring set.

[0311] Drying Place the tube in a drying fixture that holds the hydrogel strands taut during drying. Each drying fixture may hold up to six strands at a time. The cells were placed horizontally in an incubator set at 33°C with nitrogen flow (10 L / min). The hydrogel strands remained in the incubator for 48 to 72 hours to dry. Ta.

[0312] Cutting and implant inspection Remove the dried strands from the tube and remove any strands that were damaged during the removal process. The strands were cut into implants approximately 2.0 mm long. During the cutting process, each syringe run was recorded with the batch number, part number, , and into a sterile, clear vial designated with the associated trial number and labeled "Untested." If the drug implant vial was not inspected immediately, The container was sealed under a blanket of dry nitrogen and refrigerated.

[0313] Final Chemical Composition and Weight of Travoprost Implants of Formulations 1a, 1b, 2, and 3 are shown in Table 1. Physical properties of travoprost implants of formulations 1a, 1b, 2, and 3 is shown in Table 4. [Table 5]

[0314] Each individual OTX-TIC drug is delivered by rotating the drug implant 360° and visually Visually assess the cylindrical shape using a system or microscope to ensure there are no gaps or foreign particles. Implants that passed the visual inspection were then distributed by dose and strength. The dimensions were inspected to the required specifications (see Table 5). [Table 6]

[0315] OTX-TIC ink that did not meet the visual, length, or diameter requirements of the treatment process The plant placed them in separate vials clearly labeled "failed inspection."

[0316] OTX-TIC implants are suitable for visual and dimensional inspection and are stored in a glove box. The contents were sealed under a blanket of dry nitrogen and refrigerated.

[0317] Filling of OTX-TIC (Travoprost) implants OTX-TIC implants that meet all process specifications are prepared for packing. A single OTX-TIC implant was placed into a syringe (27G, 5 μg and 15 μg). dose formulation) or 26G (26µg dose) 1 / 2” ultra-thin wall sterile needle) assembly and sealed in a peelable foil-LDPE laminate pouch.

[0318] Example 2: Characterization Example 2a: In vitro release measurements In vitro release of travoprost from OTX-TIC was measured using a 60 ml polypropylene tube in a water bath. 50 ml of 1x PBS, 0.5% castor oil, 0.01% sodium fluoride in a plastic bottle Ten OTX-TIC implants were placed in a cereal buffer solution (pH 7.2-7.4, 37°C). Sampling is performed under simulated physiological sink conditions using UV detection at 220 nm. Subsequent sample analysis on a C18 reversed-phase column using ultra-high performance liquid chromatography with At a predetermined time for

[0319] The in vitro release results of travoprost from the OTX-TIC test at 37°C are shown in Figure 1a. As shown in Table 3, the release time of travoprost was Depends on particulate blend.

[0320] In vitro release (in terms of percentage) of implants composed of formulations 1a, 1b, 2, and 3 The data points corresponding to Figure 1a for the 7-day period (represented by In vitro release values ​​(in nanograms) are shown in Table 7 below. [Table 7]

[0321] The emission was measured under the same conditions as above, except that it was measured at 40°C. The in vitro release of travoprost from formulations 1a, 1b, 2 and 3 is shown in Figure 1b. [Table 8] Example 2b: Implant Integrity / Softness

[0322] The integrity of the implant is determined by the implant's relationship to the tissues of the anterior chamber of the eye (particularly the iridocorneal angle). The implant integrity can be considered as a qualitative parameter of the softness of the implant. The results were determined based on the criteria shown in the box. The corresponding results for a, 1b, 2, and 3 are shown in Figure 1c. [Table 9]

[0323] Example 2c: Moisture content of dried implants In this example, a method for determining the water content of an intracameral implant of the present invention in a dry state was used. The protocol is described. 1.0 Purpose Travoprost intracanalicular insert using the Karl Fischer coulometric method To explain the procedure used to determine the moisture content of (OTX-TP). 2.0 Scope This procedure is applicable to OTX-TP Travoprost intracanalicular inserts requiring water content determination. It is used. Note: This test method was validated according to TP-1332 / TR-1297 Method Validation. Optimized water content measurement of travoprost intracanalicular depots Protocols / Reports 3.0 References Document Number Title SOP-10050 balance SOP-10053 Glove Box SOP-10080 Karl Fischer Coulometer from Metrohm (874 (Oven sample included) Processors using Tiamo software TP-1332 Travoprost Intracanalicular Depot Protocol for Optimized Water Content Measurement Verification of the method A method for optimized water content measurement of TP-1297 travoprost intracanalicular depot reports verification 4.0 Reagents, Materials, and Equipment Hydranal water standard - KF oven 140~160℃ 4.1.1 Reference Standard. The exact water percentage is specified on the Certificate of Analysis for each lot. reagent 4.2.1 Hydranal Coulomat AG Oven Anolyte material 4.3.1 Molecular sieve, 0.3 nm (VWR P / N: EM-MX1583D-1 or similar etc.) 4.3.2 Magnetic Stir Bar 4.3.3 Crimper 4.3.4 KarlFisc 20mm Vials with Crimp Caps and Septa her vial Device 4.4.1 Analytical balance 4.4.2 Portable glovebox with regulated nitrogen gas supply 4.4.3 Flow meter, in-line between regulated nitrogen supply and glovebox. 4.4.4 Oven samples, processors (autosamplers) and Dosino bottles Karl Fischer coulometric titrator with stopcock dispenser 4.4.5 Karl Fischer Coulometry with Tiamo Software -Titration device 5.0 Equipment Setup Configure the portable glove box according to SOP-10053 glove box. Place the flow meter vertically and securely in the Rotate the flowmeter valve to fully open. Open the valve with a regulated nitrogen supply and adjust as needed. Adjust the regulator accordingly to achieve a nitrogen flow of at least about 2-3 psi. is "full flow" nitrogen. Purge the glove box at full flow for at least 30 minutes. do. Instrument setup and analysis procedure using Tiamo software for 874 oven samples See Karl Fischer Coulometer with Processor SOP-10080 do 6.0 Preparation of Blanks Benchtop blank preparation - performed in triplicate (n=3) - System suitability blank 6.1.1 Equilibrate the empty vial at benchtop conditions for at least 30 minutes. 6.1.2 Crimp seal the empty vials prior to standard preparation. 6.1.3 Place the vial in the autosampler. 6.1.4 Analyze the blank for moisture content according to Section 9.0. Preparation of glove box blanks - run in triplicate (n=3) - sample blanks 6.2.1 Equilibrate the empty vial under full flow nitrogen for at least 30 minutes. 6.2.2 Crimp seal the empty vial prior to sample preparation. 6.2.3 Place the vial in the autosampler. 6.2.4 Analyze the blank for moisture content according to Section 9.0. 7.0 Preparation of Standards Preparation of water standards - performed in triplicate (n=3) 7.1.1 Equilibrate the empty vial at benchtop conditions for at least 30 minutes. 7.1.2 SOP-10050 Balance Analysis of Hydranal Water Standards Weigh 50.0±5.0 mg directly into a vial equilibrated at benchtop conditions for at least 30 minutes. Enter. 7.1.3 Apply the exact weight and moisture content of the standard (from the CoA) in the Tiamo software Record it in the appropriate line. 7.1.4 Crimp seal the vial and place it in the autosampler. 7.1.5 Analyze moisture content criteria in accordance with Section 9.0. Preparation of hierarchical classification criteria 7.2.2 Equilibrate the empty vial at benchtop conditions for at least 30 minutes. 7.2.2 50% of Hydranal Water Standards by Analytical Balance in accordance with SOP-10050 Weigh out 0.0 ± 5.0 mg directly into a vial that has been equilibrated at benchtop conditions for at least 30 minutes. . 7.2.3 Apply the exact weight and moisture content of the standard (from the CoA) in the Tiamo software Record it in the appropriate line. 7.2.4 Crimp seal the vial and place it in the autosampler. 7.2.5 Analyze moisture content criteria in accordance with Section 9.0. 8.0 Sample Preparation Preparation of OTX-TP intratubular insert samples - performed in triplicate (n=3) 8.1.1 Equilibrate the sample vial and cap under full flow nitrogen for at least 30 minutes. do. 8.1.3 Place the cap loosely onto the vial and remove from the glove box. 8.1.3 Obtain the weight of the empty vial and cap for each sample and measure the weight throughout the sample preparation period. Ensure the vial and cap match. Record the exact weight. 8.1.4 Replace the vial and cap in the glove box. Re-equilibrate under full flow nitrogen for a minimum of 5 minutes. 8.1.5 Immediately before sample preparation, adjust the flow meter dial until it reaches 4 ± 1 L / min. This can be done by first rotating the dial clockwise until the flow rate drops below 4 L / min, then This is achieved by rotating the valve counterclockwise to return to 4 L / min. Read the flow rate. 8.1.6 For each sample, remove the cap and insert 30 OTX-TP tubes. Place all the samples in one vial. 8.1.7 Crimp the sealing cap onto the vial. 8.1.8 Remove the sealed vial from the glove box and check that it contains the insert. Obtain the weight of the vial containing the solution. Record the exact weight. 8.1.9 Calculation of sample weight: Sample weight (mg) = Weight of vial with insert (mg ) - Weight of empty vial (mg) 8.1.10 Exact weight of sample in Tiamo software under appropriate sample line Record the following. 8.1.11 Place the sample in the automatic sampler. 8.1.12 Analyze the sample for moisture content in accordance with Section 9.0. 8.1.13 Samples are stable for 4 hours after preparation under ambient conditions of the instrument. 9.0 Analytical Procedures Procedure Reference 9.1.1 Typical Karl Fischer blanks obtained using this procedure See Figure 1d for plot. 9.1.2 Typical Karl Fischer profiles of water standards obtained using this procedure See Figure 1e for lots. 9.1.3 Typical Karl Fischer spectroscopy of OTX-TP samples obtained using this procedure See Figure 1f for the cher plot. 9.2 Karl Fischer Titrator with Oven Sample Processor System Ensure that the following parameters are set: [Table 10] Common variables 9.3.1 The Tiamo software allows you to specify appropriate blanks for the reference and sample injections. Two common variables are required to ensure that the temperature values ​​are applied: The established standards were corrected for ambient moisture by preparing blanks under ambient conditions. Samples prepared in a glove box under nitrogen are analyzed under glove box conditions. The ranking is adjusted to correct for glove box moisture. 9.3.1.1 Common Variable #1 - System Suitability Blank: This common variable is the This common variable value is characterized as the average blank value of the "system suitable blank" injections. The water content values ​​for the injections are used to determine the "System Suitability Criteria" and "Strategy Classification Criteria." 9.3.1.2 Common Variable #2 - Sample Blank: This common variable is the three "sample blanks" The average blank value of the injections is characterized. This common variable value determines the water content value of the sample injections. It is used for. Note: See the table below for a summary of common variables used. [Table 11] Karl Fischer analysis 9.4.1 Load one of the previously injected blank vials into the autosampler at position 1; Load one in the "condition" position. These are for preparing (equilibrating) the system. If a pre-filled blank vial is not available, use a freshly crimped empty vial. At the start of each trial, use the "KF system preparation" method in Tiamo. Perform system preparation. Note: For freshly crimped empty vials 9.4.2 Use Tiamo's "System Suitability Blank" method to determine each system suitability. A single injection of a single blank vial (n=3) was performed. 9.4.3 Use Tiamo's "KF benchtop standard" method to measure the water standard vials (n=3 ) is injected once. 9.4.4 Sample each glove box using the Tiamo "sample blank" method. A blank vial (n=3) is injected once. 9.4.5 Use the Tiamo "KF Glove Box Sample" method to measure the temperature of each glove box. Inject a single sample vial of the mix. 9.4.6 As a system check, Ti should be measured after every 15 samples and at the end of the analysis. Injecting hierarchical division standard vials using amo's "KF benchtop standard" method 9.5 Example Injection Sequence [Table 12] System Suitability Criteria 9.6.1 Percent relative standard deviation (%RSD) of water for three consecutive injections of the water standard ) The RSD for % water must be 2.0% or less. 9.6.2 The Tiamo software calculates the ratio of the water content of the reference injection to the water content of the CoA. The yield will be calculated. 9.6.2.1 The total average moisture recovery rate specified in the third standard is between 95.0 and 105 It must be within 0.0%. 9.6.3 The strata for the total average moisture content of the three system suitability criteria are as follows: Calculate the water recovery on a minute basis.

number

[0324] Example 3: Phase 1 clinical trial OTX-T in subjects with primary open-angle glaucoma (OAG) or ocular hypertension (OHT) To evaluate the safety, tolerability, and efficacy of IC (travoprost) intracameral implant A prospective, multicenter, open-label phase 1 study was conducted to evaluate the efficacy and safety of cerebrospinal fluid therapy.

[0325] Test Purpose The primary study objective was to evaluate the efficacy and safety of OTX-TIC (Trabopro) in subjects with primary OAG or OHT. To evaluate the safety, tolerability, and efficacy of a single dose of the intracameral implant (ROST). It was.

[0326] Test evaluation details Safety Assessment Details The investigator graded the ease of the injection procedure. Safety assessment items included the injection of the implant. Assessments were conducted immediately after admission (within 1 hour) and continued throughout the study. Safety assessment Adverse event reporting (adverse events are evaluated to determine whether they are related to the procedure) Ta) Subject ocular comfort assessment Investigator's overall tolerability score BCVA Slit-lamp biomicroscopy Gonioscopy Fundus examination Endothelial cell count using a specular microscope Corneal thickness measurement ·Anterior segment (AS)-OCT Automatic vision OCT Optic Nerve NFL Posterior segment OCT was included.

[0327] Efficacy evaluation details Efficacy evaluation details Daily IOP (8:00 AM, 10:00 AM, 4:00 PM) at baseline, day 14 (visit 5), 42nd day (visit 7), 85th day (visit 8), 4th month (visit 9), 6th month (visit 11) was checked. In addition, intraocular pressure was checked at 8:00 AM on the day of injection, days 3, 7, and 28, and at month 5 (visit 10). Checked.

[0328] Exploratory Evaluation Details Whether there is enough space in the iridocorneal angle for the implant to be safely inserted To determine the iridocorneal angle, investigators used keratoscopy to determine the size of the iridocorneal angle. Determination of angles using AS-OCT read by a masked reading center The comparison of the two served as exploratory endpoints.

[0329] Test Design This was a multicenter, open-label, phase 1 clinical trial. 19 subjects were treated in one study. Cohort 1 (15 μg, formulation 1a as described in Example 1) consisted of 5 subjects Each received a single implant in one eye. Cohort 2 (26 μg, formulation 1b as described in Example 1) consisted of 4 subjects Each received a single implant in one eye. Cohort 3 (15 μg, Formulation 2 as described in Example 1) consisted of 5 subjects Each received a single implant in one eye. Cohort 4 (5 μg, formulation 3 as described in Example 1) consisted of 5 subjects , each received a single implant in one eye.

[0330] Subjects were intended to be followed for approximately 7 months (OTX-TIC implant injection followed by a one-month washout and six-month follow-up), but some lasted longer.

[0331] If bioactivity was observed or the implant was present at the 6-month visit, The patient was monitored until IOP was within 10% of the baseline measurement or the patient was clinically stable. Patients were observed monthly until the investigator felt that the condition was improving.

[0332] Selecting a target Study population Subjects enrolled in this study had stable primary OAG or OHT in the study eye and local Current IOP lowering, if applicable, administered or unadministered medications Medications were stopped at the beginning of the screening visit (Visit 1). Prior to randomization on Day 1, Eligible subjects completed a 4-6 week washout period. No additional IOP-lowering therapy was recommended for the subject over the past 8 weeks and no further IOP-lowering therapy was recommended by the investigator If the patient did not show evidence of functionally significant central visual field loss in either eye based on the evaluation, or significant progressive visual field loss in either eye within the last year based on investigator assessment Subjects were considered stable if they recorded a loss of activity. Following a washout period, eligible subjects Elephants were required to have a baseline IOP as described in the inclusion criteria below. If both eyes were eligible (i.e., all inclusion criteria were met and none of the exclusion criteria were met), If neither of these conditions was met, the eye with the highest baseline IOP after the washout period was the test eye. Both eyes were eligible, and after the washout period both eyes had the same baseline IOP. If so, the right eye was selected as the study eye.

[0333] Selection Criteria An individual of either gender: 1. 18 years of age or older at the time of screening 2. Patients had a diagnosis of OHT or primary OAG in the study eye. 3. Had currently controlled IOP (assessed by the investigator) 4. Mean baseline variability after a 4-6 week washout period of current treatment (if required) in the study eye. Sline IOP: 5. 24 mmHg at Time 0 (T0) of Baseline Visit 2 (Day 0) after the washout period or more and 36 mmHg or less, and 6. (T0+2 hours) was 22mmHg or more 7. Open enough to insert the implant without contacting the corneal endothelium. Visible anterior chamber angle (determined by keratoscopy), i.e., grade 3 (20° to 35°, Shaffer- Grade 4 (35°-45°, ciliary body visible) or Grade 5 (scleral spur visible) The test eye had an approach angle of 20° or more according to the Etienne classification. 8.Compliant with all testing requirements 9. If you have provided written, signed informed consent, They were eligible to participate in the study.

[0334] Exclusion criteria An individual: 1. Angle-closure glaucoma, narrow-angle glaucoma, pseudoexfoliation syndrome, pseudoexfoliation glaucoma, pigment dispersion or pigmentary Glaucoma, glaucoma diagnosed before age 15, inflammatory, neovascular or other secondary glaucoma were tested. It caught my eye 2.Have a history of intracameral implants in the anterior chamber of the study eye 3. Discontinue contact lens use prior to corneal thickness measurement (3 days) and throughout the study. I didn't want 4. Prostaglandins (i.e., travoprost), fluorescein, or test drugs had a known or suspected allergy and / or hypersensitivity to any ingredient of the product 5. Corneal or other ocular or adnexal abnormalities with reliable applanation tonometry in either eye was hindering the decision 6. Central corneal thickness of either eye was less than 480 μm or more than 620 μm (or The interocular difference was more than 70 μm. 7. A cup-to-disc ratio (level to disc diameter) of >0.8 in the study eye as assessed by the investigator or vertical measurement) 8. Had functionally significant central visual field loss in the study eye as assessed by the investigator or significant progressive visual field loss documented within the last year 9. Active blepharitis or ocular disease (i.e., moderate or severe) in either eye within the past 3 months Mild or severe blepharitis, meibomianitis, dry eye disease, eye infections (viral or fungal) had scleritis, uveitis, or corneal edema 10. Endothelial cell count: 1,800 cells / mm 2 and / or other internal Skin abnormalities were present (based on specular microscopy and central reading center) (Confirmed by this) 11. Endothelial cell count: 1,800 cells / mm 2 and / or other Endothelial abnormalities were present (based on specular microscopy, central reading center) (Confirmed by 12. History of significant ocular trauma in the study eye within the past 6 months 13. History of peripheral iridotomy / iridectomy 180° below the iris of the study eye 14. In the opinion of the investigator, bleeding events that may occur during implant insertion in subjects at high risk had a history of substance use disorder 15. Ophthalmic surgical procedure (e.g., glaucoma laser, minimally invasive glaucoma) in the study eye within the past 6 months have had eye surgery, refractive surgery, or will require eye surgery during the study period. Subjects enrolled or scheduled to receive treatment during the study with an implant were excluded. 16. History of corneal transplantation in the test eye 17. Had proliferative diabetic retinopathy or had a history of macular edema in either eye Ta 18. Uncontrolled systemic or debilitating disease (e.g., cardiovascular, hypertension, uncontrolled diabetes) had a history of urinary tract infection (urinary tract disease, or cystic fibrosis) 19. Have participated in a clinical trial involving an investigational drug in the US or outside the US within the past 30 days 20. Was or is an employee of a facility directly involved in the administration, administration, or support of a study He was a direct family member of the facility. 21. Pregnant or breastfeeding at the time of enrollment without using adequate contraception during the study period, or if there was a possibility of childbirth, They were not eligible to participate in the study.

[0335] Test data collection The study times and event schedule are presented in Table 8. [Table 13] [Table 14-1] [Table 14-2] [Table 14-3]

[0336] Test Observations and Procedures Subject screening and informed consent Prior to enrollment in the study, subjects were evaluated to determine potential eligibility. The nurse and study staff determined the subjects' willingness and ability to complete follow-up requirements. If you wish to participate, you will be required to provide written informed consent before undergoing any study-specific tests. After completion of screening and baseline assessments, subjects received all eligible The investigator and study staff will make the decision as to whether the criteria are met. If subjects met the eligibility criteria and agreed to participate, they were enrolled.

[0337] Once a subject signs the informed consent, the subject is considered enrolled in the study. Once a subject is eligible for and randomized to the study, the subject will be assigned to the treatment Subjects had to be followed regardless of whether they received the drug.

[0338] If the OTX-TIC implant injection was unsuccessful, the eCRF should state injection failure. If so, record the reason as an infusion failure rather than an AE; and the subject is medically fit. was tracked as far as possible.

[0339] Screening ineligible Enrolled, i.e., signed the informed consent document but did not complete the screening Ineligible at the baseline visit but not during evaluation or before treatment with OTX-TIC Subjects determined to be ineligible for screening will be considered screened, removed from the study, and will not be required to undergo additional No study follow-up visit was required. Reason(s) for screening ineligibility were eCR Recorded in F.

[0340] Subjects who did not meet the eligibility criteria experienced an AE during screening or the baseline visit. If experienced, subjects were followed until the AE resolved or stabilized.

[0341] Subject withdrawal All subjects treated in the study will undergo follow-up surveillance as described in this protocol. They were asked to adhere to the schedule.

[0342] Subjects may participate in the study at any time without risk, prejudice, and without compromising clinical care by the investigator. The investigator may discontinue the clinical trial for any reason, regardless of whether the patient is a patient with an intercurrent illness, AE, or prognosis. Subjects may be withdrawn from the study in the event of protocol violations and / or administrative reasons. had the right to do so.

[0343] For subjects who withdraw consent after treatment, whenever possible, the reason(s) for withdrawal will be communicated at the end of the study. This was documented in the completed eCRF. Subjects were required to have an intracameral implant (IVI) prior to withdrawal from the study. Returning for removal of the stencil (if present) was encouraged but not required.

[0344] If withdrawal from the study was the result of an AE or death, an AE form was also completed. If a subject withdraws from the study as a result, the investigator will continue to monitor the patient until the AE resolves or stabilizes. Physicians will make every attempt to track the subject.

[0345] Any attempt to contact non-compliant or untraceable subjects will be made and such attempts was documented in the subject's study record.

[0346] Withdrew from the study after receiving an OTX-TIC (travoprost) intracameral implant The subject was not replaced.

[0347] Product malfunction All malfunctions of the OTX-TIC (travoprost) intracameral implant injector are considered appropriate. documented in the appropriate eCRF and reported to Ocular Therapeutix within 24 hours Ocular Therapeutix reported that its intracameral implants were The incidence of malfunctions will be included in the final analysis. Deaf.

[0348] Treatment points Once a subject is determined to be eligible for the study and has completed all screening tests, including the washout period, Once the screening assessment was completed, the investigator confirmed eligibility prior to treatment.

[0349] In this study, four possible cohorts were included: 15 μg (as described in Example 1) 26 μg (formulation 1b as described in Example 1), 15 μg (formulation 1b as described in Example 1), 5 μg (formulation 2 as described in Example 1), and 5 μg (formulation 3 as described in Example 1) Nineteen subjects (approximately five subjects per cohort) were treated with one of the three agents (agent 3).

[0350] Subjects may have only one eye treated with OTX-TIC as part of this study. Well; that eye was designated as the study eye SE. If both eyes were eligible for study enrollment, S E was selected based on the eye with the highest IOP after the washout period described in the protocol. If the IOP in both eyes was the same after the washout period, the right eye was selected as the SE. .

[0351] The Data Safety Monitoring Committee (DSMC) conducted a data safety monitoring study of Cohort 1 before enrolling subjects in Cohort 2. Safety data was reviewed.

[0352] Cohort 1 is fully enrolled and all OTX-TIC data for each subject in Cohort 1 are Safety and tolerability data (minimum follow-up data of 2 weeks) were obtained for any subject in the cohort. Dose escalation for Cohort 2 was based on the recommendation of the DSMC. , as determined by the medical monitor (MM) or the sponsor.

[0353] Cohort 4 was a lower dose, and the implants were administered at doses higher than those examined in cohorts 1, 2, and 3. Because these studies were of short duration, cohorts 3 and 4 were initiated in parallel.

[0354] If one dose-limiting toxicity (DLT) was identified in any dose arm of Cohort 2, enrollment would continue. However, if another DLT is identified, the previous (even lower) cohort 1 ) dose was declared as the MTD. However, there was no MTD.

[0355] The contralateral eye, designated the non-study eye (NSE), was treated with Travatan Z as needed. NSE treatment remained consistent throughout the study. Ocular evaluations were All were performed in both eyes at all visits.

[0356] Concomitant medications Concomitant ophthalmic and systemic medications, prescription or over-the-counter, for up to 3 years prior to the screening visit Medication use, along with the reason the medication was taken, will be recorded from the screening visit through the end of the study. All medications administered had to be recorded in the subject's medical record and corresponding eCRF. AIDs, or steroids, except for IOP measurement and insertion procedures (i.e., Betadine or Herbal or vitamin supplements used in ophthalmic evaluations, including topical anesthetics, and dilation Use of ointments and other standard care drops was not recorded.

[0357] The following restrictions were applied in relation to drugs and treatments: Topical or systemic intraocular pressure-lowering medications will not be used during the study, except for study treatment. Screening of subjects currently taking prostaglandin analogues for OAG / OHT The washout period for medication between the screening and baseline visits (Visit 2, Day 0) is approximately 4–10 days. It was six weeks. NOTE: Subject's current ocular hypertensive medications may present potential risks to the subject due to elevated IOP during the washout period. To minimize risk, you can replace it with one that requires a shorter rinse period. (For example, if you are currently taking prostaglandins that require a 4-6 week washout period, Subjects receiving the drug instead received a carbonic anhydrase inhibitor for 3 weeks, then received a 2-week steroid dose at Visit 2 (Day 0). Allow washout of the carbonic anhydrase inhibitor for 1 week before inclusion in the study. Systemic beta-blockers were permitted, but were not included from 8 weeks before screening until the final study visit. Initiation or change of systemic beta-blocker-containing medication regimens was excluded. Short-term inhaled (using a mouthpiece), local injection, intranasal, and topical steroid use was permitted and, if used, should have been recorded on the eCRF. Chronic criteria administered by any route and not on a stable dose for 8 weeks prior to screening Drugs or substances used in. Non-diagnostic topical eye drops (other than study treatment) were not permitted from the baseline visit through the study period. Note: The use of artificial tears or eye lubricants should be avoided, but may be used if necessary. , intermittent use may be permitted. Contact lenses should be worn at any time during the study after the screening visit. In addition, contact lens wear should be discontinued for at least 3 days before corneal thickness measurement. There was a need.

[0358] Salvage therapy IOP was not adequately controlled as determined by the investigator at any time during the study If necessary, IOP-lowering eye drops may be used as rescue therapy at the investigator's discretion to ensure the subject's safety. IOP-lowering medications were recorded on the appropriate eCRF.

[0359] Test evaluation Screening assessment: up to 4-6 weeks prior to the baseline visit At the screening visit, the subject's eligibility to participate in the study was confirmed by all of the following criteria: The subjects were judged by checking the inclusion and exclusion criteria of each of the or failed one of the exclusion criteria, the subject was screen-ineligible; No further evaluation was performed.

[0360] Details of these evaluation procedures are found below, and both eyes were evaluated at each visit. :AS-OCT, OCT optic nerve NFL, posterior segment OCT, evaluation of endothelial cell count is a reading habit The test was conducted in accordance with the test manual of the center.

[0361] The following procedures and assessments should be completed within a maximum of 4-6 weeks prior to Baseline Visit 2 (Day 0). Pupil dilation was to occur after the final IOP measurement of the day was completed.

[0362] Screening Visit (Visit 1, up to 4-6 weeks) Obtain written informed consent Demographic information, including age, gender, race, and ethnicity Medical and ophthalmological history, including interventions Inclusion and Exclusion Criteria Previous and concomitant medications and procedures Vital signs (blood pressure and heart rate) BCVA Slit lamp biomicroscopy (including external ophthalmology examination) Measurement of IOP by applanation (Goldmann) tonometry Gonioscopy Dilated fundus examination ·Field of view Corneal thickness measurement (contact lens wear must be discontinued 3 days prior to the measurement) ·Posterior segment OCT OCT Optic Nerve NFL Endothelial cell count (specular microscope confirmed by a central reading center) Urine pregnancy test: For women of childbearing potential, subjects will be screened for pregnancy at the discretion of the investigator for the duration of the study. Must be using a reliable method of birth control and have a negative urine pregnancy test . At the end of screening, potentially eligible subjects for Visit 1 will be required to discontinue IOP-lowering medication. I was instructed to start rinsing.

[0363] NOTE: Prior to enrollment, patients had stable primary OAG or O2 who had not previously taken IOP-lowering medication. For HT subjects, the screening and baseline visits were combined into one visit. It may be possible.

[0364] Screening failures due to reasons expected to be temporary will be reported to the sponsor. There will be contact with the patient and there may be one re-screening visit. Rescreened subjects will be given a new subject number and all screening The tracking procedure had to be repeated (including signing a new informed consent document) .

[0365] For eligible subjects, all information must be recorded on the subject's eCRF. For subjects who did not meet the criteria, the minimum information to be recorded on the eCRF is: The information included the screening date, subject number, and reason for screening ineligibility.

[0366] Baseline visits (Visit 2, Day 0, Day -4) The following assessments were performed in both eyes: IOP measurements taken on day 0 were baseline IOP It was a measurement.

[0367] 8:00 AM (T0) Confirmation of inclusion and exclusion criteria Concomitant medications Adverse event evaluation BCVA Slit-lamp biomicroscopy, including external ophthalmic examination IOP Fundus examination ·Anterior segment OCT

[0368] 10:00 AM (T0+2 hours) and 4:00 PM (T0+8 hours) Measurement of IOP by applanation (Goldmann) tonometry

[0369] NOTE: All IOP measurements must be performed within ±60 min of the required time and should be taken at each lapse The IOP was measured by two masked readers at the observation visit. was measured using the method.

[0370] Day of intracameral injection, visit 3 (day 1) Assessments performed before the procedure The following procedures and assessments were performed prior to treatment. -Review of concomitant medications and procedures Adverse events (before injection) Vital signs (heart rate and blood pressure) Subject's eye comfort score Investigator's overall tolerability score BCVA Slit-lamp biomicroscopy, including external ophthalmic examination IOP by applanation (Goldmann) tonometry only at 8 AM. IOP measurement is not necessary. The test had to be performed within ±60 minutes of the scheduled time.

[0371] Treatment with OTX-TIC intracameral implant After all assessments were completed, subjects were assigned to the study treatment (OTX-TIC Imp The investigator and clinical trial staff will be informed in accordance with the procedures recommended in the clinical trial manual. The investigator recorded the ease of the injection procedure.

[0372] If both eyes were eligible (i.e., all inclusion criteria were met and all exclusion criteria were met), If none of the above conditions are met, the test eye should be selected as described above. The contralateral eye, designated as the non-study eye (NSE), was treated with Travatan as needed. Treatment of NSE should remain consistent for the duration of the study. There was.

[0373] Approximately 1 hour after the infusion, before leaving the clinic, the investigator and study staff will He was responsible for that. The investigator confirmed the proper placement of the OTX-TIC (travoprost) intracameral implant. confirmed. Whenever possible, the investigator will document the presence of an intracameral implant by slit-lamp photography. was documented Adverse events (after injection) Subject ocular comfort assessment Investigator's overall tolerability assessment

[0374] Exit instructions Subject experiences excessive pain, excessive discomfort, bloodshot eyes, changes in vision, or loss of vision If this occurred, participants were instructed to refrain from rubbing their eyes and to contact the investigator.

[0375] Standard ocular post-injection treatment includes topical administration up to four times daily for one week at the investigator's discretion. These included broad-spectrum antibiotic eye drops and topical steroids.

[0376] Follow-up evaluation: Visit 4 (Day 3, Day -1) The following will be administered to both eyes of each subject by the investigator and study staff at 8:00 AM only: It was held. Concomitant medications and procedures Adverse events Subject ocular comfort assessment Investigator's overall tolerability score BCVA Slit-lamp biomicroscopy, including external ophthalmic examination Product visualization and explanation (by slit lamp) IOP measurement

[0377] Visit 4.1 (7th day, ±1 day) The following will be administered to both eyes of each subject by the investigator and study staff at 8:00 AM only: It was held. Concomitant medications and procedures Adverse events Subject's eye comfort Investigator's overall tolerability score BCVA Slit-lamp biomicroscopy, including external ophthalmic examination Product visualization and explanation (by slit lamp) IOP measurement

[0378] Visit 5 (Day 14, ±1 day) The following was performed in both eyes:

[0379] 8:00 AM (T0) Concomitant medications Adverse events Subject's eye comfort Investigator's overall tolerability score BCVA Slit-lamp biomicroscopy, including external ophthalmic examination Product visualization and explanation (by slit lamp) IOP measurement

[0380] 10:00 AM (T0+2 hours) and 4:00 PM (T0+8 hours) IOP measurement

[0381] Visit 6 (Day 28, ±2 days) The following will be administered to both eyes of each subject by the investigator and study staff at 8:00 AM only: It was held. Concomitant medications and procedures Adverse events Subject's eye comfort Investigator's overall tolerability score BCVA Slit-lamp biomicroscopy, including external ophthalmic examination Product visualization and explanation (by slit lamp) IOP measurement

[0382] Visit 7 (Day 42, ±2 days) The following was performed in both eyes:

[0383] 8:00 AM (T0) Concomitant medications Adverse events Subject's eye comfort Investigator's overall tolerability score BCVA Slit-lamp biomicroscopy, including external ophthalmic examination Product visualization and explanation (by slit lamp) IOP measurement Corneal thickness measurement

[0384] 10:00 AM (T0+2 hours) and 4:00 PM (T0+8 hours) IOP measurement

[0385] Visit 8 (85th day, ±2 days) The following was performed in both eyes at 8:00 AM (T0) during the study visit: Concomitant medications Adverse events Subject's eye comfort Investigator's overall tolerability score BCVA Slit-lamp biomicroscopy, including external ophthalmic examination Product visualization and explanation (by slit lamp) IOP measurement Gonioscopy Fundus examination Corneal thickness measurement ·Anterior segment OCT ·Posterior segment OCT OCT Optic Nerve NFL Endothelial cell count (specular microscope confirmed by a central reading center)

[0386] 10:00 AM (T0+2 hours) and 4:00 PM (T0+8 hours) IOP measurement

[0387] Visit 8 (85th day, ±2 days) The following was performed in both eyes at 8:00 AM (T0) during the study visit: Concomitant medications Adverse events Subject's eye comfort Investigator's overall tolerability score BCVA Slit-lamp biomicroscopy, including external ophthalmic examination Product visualization and explanation (by slit lamp) IOP measurement Gonioscopy Fundus examination Corneal thickness measurement ·Anterior segment OCT ·Posterior segment OCT OCT Optic Nerve NFL Endothelial cell count (specular microscope confirmed by a central reading center)

[0388] 10:00 AM (T0+2 hours) and 4:00 PM (T0+8 hours) IOP measurement

[0389] Visit 9 (4th month, ±3 days) The following was performed in both eyes:

[0390] 8:00 AM (T0) Concomitant medications Adverse events Subject's eye comfort Investigator's overall tolerability score BCVA Slit-lamp biomicroscopy, including external ophthalmic examination Product visualization and explanation (by slit lamp) IOP measurement

[0391] 10:00 AM (T0+2 hours) and 4:00 PM (T0+8 hours) IOP measurement

[0392] Visit 10 (5th month, ±3 days) The following will be administered to both eyes of each subject by the investigator and study staff at 8:00 AM only: It was held. Concomitant medications and procedures Adverse events Subject's eye comfort Investigator's overall tolerability score BCVA Slit-lamp biomicroscopy, including external ophthalmic examination Product visualization and explanation (by slit lamp) IOP measurement

[0393] Final Study Visit 11 (Month 6, ±3 days) The following was performed in both eyes:

[0394] 8:00 AM (T0) Concomitant medications Adverse events Vital signs (heart rate and blood pressure) Subject's eye comfort Investigator's overall tolerability score BCVA Slit-lamp biomicroscopy, including external ophthalmic examination Product visualization and explanation (by slit lamp) IOP measurement Gonioscopy Dilated fundus examination ·Field of view Corneal thickness measurement ·Anterior segment OCT ·Posterior segment OCT OCT Optic Nerve NFL Endothelial cell count (specular microscope confirmed by a central reading center) · Urine pregnancy test (if applicable)

[0395] 10:00 AM (T0+2 hours) and 4:00 PM (T0+8 hours) IOP measurement

[0396] If bioactivity was observed or the implant was present at the 6-month visit, The patient was monitored until IOP was within 10% of the baseline measurement or the patient was clinically stable. Patients were observed monthly until the investigator felt that the patient was still healthy. The same assessment schedule as that outlined at the 7-month visit was to be followed (see below). If residual microspheres are observed at 12 months, the subject will be Follow-up was discretionary. The final study visit should follow the evaluation at Visit 11.

[0397] Follow-up visits 12 and 7 months (± 3 days) and 13 and 8 months (± 3 days) If necessary, the following will be administered by the investigator and study staff at 8:00 AM only for each subject: was performed on both eyes. Concomitant medications and procedures Adverse events Subject's eye comfort Investigator's overall tolerability score BCVA Slit-lamp biomicroscopy, including external ophthalmic examination Product visualization and explanation (by slit lamp) IOP measurement

[0398] Follow-up visit 14, 9 months (± 3 days) As needed, the following were performed during study visits: Concomitant medications Adverse events Subject's eye comfort Investigator's overall tolerability score BCVA Slit-lamp biomicroscopy, including external ophthalmic examination Product visualization and explanation (by slit lamp) IOP measurement Gonioscopy Fundus examination Corneal thickness measurement ·Anterior segment OCT ·Posterior segment OCT OCT Optic Nerve NFL Endothelial cell count (specular microscope confirmed by a central reading center)

[0399] 10:00 AM (T0+2 hours) and 4:00 PM (T0+8 hours) IOP measurement

[0400] Unscheduled visit Whenever the investigator determines that a subject needs to be seen outside the study visit window These visits may be scheduled as needed. and assessments were performed at the investigator's discretion based on the reason for the visit. For example, clinical If there was evidence of corneal edema, the evaluation had to include AS-OCT.

[0401] Unscheduled visits were recorded on an electronic case report form for "unscheduled" visits along with the reason for the visit. .

[0402] Adverse events Throughout the course of the study, all Every effort was made. If an AE occurred, the first concern was the safety and welfare of the subject. Any medical intervention observed by the investigator or study staff was warranted. Any AE reported by a subject, whether or not attributable to the study treatment, will be considered a valid Adverse events were recorded on the eCRF.

[0403] Documentation of AEs was based on symptoms observed by a physician or reported by the subject. or the nature of symptoms, date of onset, date of end, severity and relationship to the investigational drug, and actions taken (multiple Assessment of risk, severity, and outcome was needed.

[0404] NOTE: Subjects were monitored for the presence or absence of the following ocular symptoms: excessive tearing, foreign body sensation, stinging / burning, and itching. Affirmative responses to these standardized ocular complaints indicated that the complaint (1) Meets the criteria for a specific event described; (2) Exceeds normal limits. or (3) unless associated with clinical sequelae (e.g., adverse slit-lamp findings). These were to be reported as ocular complaints rather than AEs.

[0405] Definition of adverse events An AE is any adverse medical event in a subject administered a medicinal product or in a clinical investigation. This is an incident that does not necessarily have a causal relationship with the treatment.

[0406] Therefore, an AE is considered to be a medical condition, regardless of whether it is related to the medicinal (investigational) product. Any undesirable and unintended side effects temporarily associated with the use of a medicinal (investigational) product. It can be a sign (including clinically significant abnormal laboratory findings), symptom, or disease. Lack of efficacy of the study drug does not constitute an adverse event.

[0407] Definition of Serious Adverse Events (SAEs) SAEs are those at any dose: Fatal Life-threatening - The term "life-threatening" means that the subject was at risk of death at the time of the event. refers to an event; if it were more serious, it could have virtually caused death It doesn't refer to an elephant. Requires inpatient hospitalization or extension of current hospitalization. Hospitalization for elective surgery is not covered by the S Do not configure AE ·Causes permanent or serious disability / incapacity · Congenital or birth defects Any adverse medical event.

[0408] For example, a condition that is not immediately life-threatening or does not result in death or hospitalization, but May put at risk or require intervention to prevent one of the other outcomes listed above Whether other situations, such as potentially serious medical events, should be considered SAEs The decision required the exercise of medical and scientific judgment.

[0409] Examples of such events include allergic bronchospasm in the emergency room or at home, blood poisoning, Intensive care for fluids, neoplasms, or convulsions that do not result in hospitalization.

[0410] AEs rated as "severe" should not be confused with SAEs. The intensity (i.e., severity) of a particular event (such as mild, moderate, or severe myocardial infarction) however, the event itself is often a relatively minor medical This may be a symptom of a life-threatening event (e.g., a severe headache). is not the same as "serious" based on the criteria of related consequences or behaviors. The causal relationship serves as a guide for defining regulatory reporting obligations.

[0411] severity The severity of the AE was determined by the investigator or by the subject. The severity rating is defined as a qualitative assessment of the degree of intensity of an AE reported to the study drug. This should be done regardless of the relationship to the patient or the severity of the event and should be rated according to the following scale: Mild: The event is noticeable to the subject, but is easily tolerated and does not interfere with the subject's daily life. do not have. Moderate: The event is bothersome, may require additional treatment, and interferes with the subject's daily life. It may cause disruption. Severe: The event is intolerable, requires additional treatment or a change in treatment, and interferes with the subject's daily life. To interfere.

[0412] For AEs with varying intensities, the start and end dates of each intensity had to be recorded.

[0413] Intracameral implant or its relationship to the procedure For each (S)AE, the treating investigator must determine whether the event is related to the infusion procedure or It was necessary to determine whether the risk of HIV infection was related to the intracameral implant. The physician must determine, in his or her medical judgment, that the event was caused by the intracameral implant or the injection procedure. It was necessary to determine whether there was a reasonable possibility that it could have been caused .

[0414] The following should be used by investigators when assessing the causality of (S)AEs: Attribution of causality to the injection procedure or intracameral implant is specified in the CRF. was done.

[0415] No suspected relationship: This category is used after careful consideration to determine whether an unrelated cause (disease, environmental (S)AEs are applied to clear and undisputed (S)AEs due to factors such as the injection procedure; Reasonable probability that the injury may have been caused by a posterior or intracameral implant If the investigator determines that the AE is unlikely to be related to the study drug, was the appropriate category.

[0416] Suspected Relationship: Consider including an (S)AE in this category if: Standards had to be applied. 1) It has a reasonable temporal relationship to the injection procedure or the presence of an intracameral implant . 2) It is not affected by known characteristics of the subject's clinical condition, environmental or toxic factors, or other factors (e.g., For example, the disease under investigation, the concurrent disease(s) and concomitant medications, and the treatment modality administered to the subject. So I couldn't give a rational explanation. 3) It disappears or decreases after removal of the intracameral implant. 4) it follows known patterns of response to injection procedures or intracameral implants;

[0417] A suspected AE is one where there is a reasonable possibility that the investigational drug caused the AE. "Reasonable possibility" means that there is evidence suggesting a causal relationship between the study drug and the AE. Types of evidence suggesting a causal relationship between an investigational drug and an AE include rare events that are related to drug exposure. isolated events known to be strongly associated with drug exposure; Single or multiple occurrences of rare events in the exposed population (e.g., tendon rupture); Specific events (known consequences of the underlying disease or condition under investigation or events occurring during the study unrelated to drug therapy) Aggregate analysis of events (such as other events that commonly occur in a population) that occur simultaneously or over time These findings have been shown to occur more frequently in drug-treated groups than in control groups.

[0418] Predictable (S)AEs are predictable using these guidelines based on existing safety information about the investigational drug. The decision had to be made based on the Unexpected: AE or study protocol, investigator's brochure, or registration of travoprost Not listed in the formulation information for the formulation (Travatan®) or observed AEs not listed by specificity or severity. Predicted: The observed specificity or severity is based on the study protocol, investigator's brochure, or AEs listed in the formulation information for travoprost.

[0419] Investigator's Brochure, a class of drugs that occurs or is expected from the pharmacological properties of the drug Although mentioned as occurring with the specific drug under investigation, AEs not mentioned are to be considered expected.

[0420] The investigator should initially classify the AE as predictable, but the final classification should be determined by medical monitoring. It depends on the decision of the supplier.

[0421] Clarification diagnosis To the extent possible, events recorded and reported should be indicative of signs or symptoms of the event. This is a diagnosis of the event.

[0422] hospitalization Pre-existing conditions that did not worsen during the study (i.e., subjects had a history of any of the conditions listed in the informed consent document) Hospitalization for elective treatment of a condition (existing prior to signing the agreement) is not considered an SAE. Complications that occur during hospitalization are AEs. If a complication prolongs hospitalization or is associated with other SAE criteria, If any of the following conditions are met, the complication is an SAE.

[0423] pre-existing conditions, including glaucoma The expected day-to-day variation of the pre-existing condition(s) that does not worsen relative to the baseline is ( S) Not AE.

[0424] Glaucoma worsening or progression was determined as either "lack of efficacy" or "expected" per protocol. This is considered a "lack of pharmacological activity" and is already recorded as part of the efficacy evaluation. , there was no need to record it as an (S)AE.

[0425] medical or surgical procedures elective medical or surgical procedures or pre-existing conditions that did not worsen during the study (i.e. (i.e., conditions that exist before the subject signs the informed consent document) In the case of a previously planned medical or surgical procedure, the conditions leading up to the procedure are considered as (S)AEs. There is no need to report it.

[0426] death Death is not an SAE; the conditions that lead to death are an SAE.

[0427] Abnormal laboratory values Abnormal laboratory values ​​judged by the investigator to be clinically significant were recorded as (S)AEs. Clinically significant symptoms that were present at baseline and worsened significantly after the start of the study Any abnormal laboratory findings were also reported as (S)AEs. The clinical significance of the document must be reviewed, signed, dated, and determined within 24-48 hours of receipt. It was expected.

[0428] AE timing Regardless of severity or relationship to injection or intracameral implants All observations during the course of this study from the time the subject signed the informed consent document will be recorded. All AEs were recorded in the appropriate eCRF(s).

[0429] Procedures for reporting adverse events All "suspected" and "unexpected" AEs are reviewed by the IRB / IEC, local regulations, and administrative Report to Ocular Therapeutix and the IRB as required by applicable health authorities. Any unforeseen event was to be reported to Salus within 10 business days of the event being identified. Serious unexpected and suspicious adverse events were to be reported to the IRB. within 7 days for serious and life-threatening events, and within 15 days for all others. It was reported.

[0430] Serious or serious adverse events, whether or not attributable to the study treatment, Notify Ocular Therapeutix by fax or telephone within 24 hours. The investigators received all relevant medical information from colleagues who assisted in the treatment and follow-up of the subjects. Medical records, information, and medical decisions must be obtained and maintained in the subject's files; ar Therapeutix if an event is suspected to be related to the use of an investigational drug or Provide a complete medical history, including references to unsuspected events; It was necessary to provide information on AEs to the IRB / IEC within the scope of EC guidelines. A written report detailing the event, signed by the investigator, will be sent to the sponsor within 5 business days. All subjects experiencing an SAE were required to submit to the FDA for resolution or stabilization of the event. Patients were required to be followed until the outcome was reported on the CRF.

[0431] Type and duration of follow-up of adverse events AEs were followed until: Resolution of the event, i.e., return to baseline value or state or "normal." - AE may be determined to have resolved completely or with residual effects. The principal investigator may consider the condition to be chronic for events that were not completed (e.g., metastases). The event may be determined to be resolved or resolved with sequelae. Events were stable, i.e., there was no worsening as predicted by the investigator.

[0432] All AEs were documented on the CRF(s). For subjects who reached the 6th month, an unscheduled visit was then conducted to confirm the clinical trial status. AEs that are not deemed resolved or stable by the investigator may be observed.

[0433] Exam proctor Data Safety Monitoring Committee (DSMC) The DSMC is appointed by the sponsor to monitor the safety of clinical trial subjects during the course of a clinical trial. The DSMC is composed of a panel of independent glaucoma physician experts in the field of ophthalmology. In its role as a visionary, DSMC adheres to the standards listed in the next section, as well as supplementary criteria. The test mission statement, operating procedures, and proposed monitoring criteria, including any proposed test suspension rules. The DSMC established a declaration containing the following: The dose in these cohorts was lower than in Cohort 2, and the duration of treatment was shorter. This pre-screening was performed in cohorts 3 and 4 because it was shorter than that studied in cohorts 1 and 2. It does not have to be implemented.

[0434] Written minutes of all meetings must be prepared after each DSMC meeting and key document the study's conclusions (i.e., evaluation of study continuation versus study recommendation to discontinue the study) It was necessary to make it.

[0435] statistical analysis Statistical and analytical plans This study was not designed to demonstrate statistical significance, so statistical analysis was not completed. No. General information that briefly summarizes how the data are presented, i.e., descriptive statistics, etc. There is a statistical plan.

[0436] Sample size determination No formal sample size calculation has been performed for this Phase 1 trial. Product Safety A sample size of five subjects is considered sufficient to inform sex.

[0437] Analysis Dataset The safety population consisted of all subjects who received an OTX-TIC implant. Safety and efficacy analyses were performed on the safety population.

[0438] Demographic and baseline data Subject dispositions were presented, including the number of subjects screened, enrolled, and treated. The number of subjects who completed the study and reasons for discontinuation were summarized.

[0439] Demographic and baseline characteristics (including disease and medical history) were summarized.

[0440] Safety analysis Safety was assessed by adverse events, subject's ocular comfort assessment, and investigator's overall tolerability score. , and other eye-related outcomes.

[0441] Adverse events were classified by system organ class and preferred term using the Medical Dictionary of Clinical Terms (MedDRA). Adverse events related to the injection procedure and the intracameral implant were coded separately. In addition, serious adverse events were summarized.

[0442] A summary of other safety-related results was provided.

[0443] Efficacy analysis Efficacy was assessed by daily IOP at baseline, Day 14 (Visit 5), Day 42 (Visit 6), and Day 7 (Visit 8). At visit 7), 85 days (visit 8), 4 months (visit 9), and 6 months (visit 11), Measurements taken at 8:00 AM, 10:00 AM, and 4:00 PM were summarized. If necessary, IOP measurements were continued (see below). In addition, IOP was measured on days 3, 7, and 28 of injection. Intraocular pressure was summarized at 8:00 AM on day 1, and at month 5 (visit 10).

[0444] Exploratory analysis Angle size was assessed in two ways: by investigators using keratoscopy to measure angle size; In addition, AS-OCT images were read by a masked reading center. The angle sizes obtained by the method were summarized.

[0445] General information End of exam Ocular Therapeutix will, as appropriate, review the investigators and IRB / IEC and The right to discontinue the trial at any stage by giving appropriate written notice to other regulatory authorities Similarly, the investigator must notify the Ocular Therapist within 30 days of the intention to withdraw. You may withdraw from participation in the exam project provided you notify rapeutix in writing. However, Ocular Therapeutix and the investigators are not The study was obligated to complete follow-up of subjects treated at the clinical protocol. Therefore, they must be followed up, and information obtained during the follow-up of the subjects is reported on the CRF. There was a need.

[0446] All serious AEs will be evaluated and the sponsor will determine if they pose a potential unreasonable risk to the subject. If the study is deemed to be successful, the trial will be terminated and all regulatory authorities and participating investigator(s) will be notified. The termination must be effected within five business days of the sponsor's decision and within five business days of the trial's submission. occurred within 15 business days after the reliant first received notice of the effect.

[0447] Completed clinical trials may not be restarted without approval from loca...

Claims

1. Travoprost and A biodegradable polymer comprising polylactide having acid end groups and an intrinsic viscosity specification ranging from 0.05 dl / g to less than 0.5 dl / g when measured in 0.5% w / v chloroform at 30°C. Travoprost particles made of a mixture of the mixture contains 43% to 45% by weight of travoprost based on the total weight of the mixture; The travoprost particles have an average diameter in the range of 20 μm to 55 μm as determined by laser diffraction.

2. 2. The travoprost particles of claim 1, wherein the intrinsic viscosity specification is in the range of 0.35 dl / g to 0.45 dl / g.

3. The travoprost particles according to claim 1 or 2, wherein the particles are spherical particles.

4. Travoprost and A biodegradable polymer comprising polylactide having acid end groups and an intrinsic viscosity specification ranging from 0.5 dl / g to 0.80 dl / g or less when measured in 0.5% w / v chloroform at 30°C. Travoprost particles made of a mixture of the mixture contains 45% to 47% by weight of travoprost based on the total weight of the mixture; The travoprost particles have an average diameter in the range of 20 to 55 μm as determined by laser diffraction.

5. 5. The travoprost particles according to claim 4, wherein the intrinsic viscosity specification is in the range of 0.60 dl / g to 0.80 dl / g.

6. The travoprost particles according to claim 4 or 5, wherein the particles are spherical particles.

7. Travoprost and A biodegradable polymer comprising polylactide having acid end groups and an intrinsic viscosity specification ranging from 0.8 dl / g to 1.7 dl / g when measured in 0.5% w / v chloroform at 30°C. Travoprost particles made of a mixture of the mixture contains 41% to 43% by weight of travoprost based on the total weight of the mixture; The travoprost particles have an average diameter in the range of 20 to 55 μm as determined by laser diffraction.

8. 8. The travoprost particles of claim 7, wherein the intrinsic viscosity specification is in the range of 0.8 dl / g to 1.0 dl / g.

9. The travoprost particles according to claim 7 or 8, wherein the particles are spherical particles.

10. Travoprost and A biodegradable polymer comprising polylactide having ester end groups and an intrinsic viscosity specification ranging from 0.05 dl / g to 1.7 dl / g when measured in 0.1% w / v chloroform at 25°C. Travoprost particles made of a mixture of the mixture contains 41% to 43% by weight of travoprost based on the total weight of the mixture; The travoprost particles have an average diameter in the range of 20 to 55 μm as determined by laser diffraction.

11. 11. The travoprost particles of claim 10, wherein the intrinsic viscosity specification is in the range of 0.55 dl / g to 0.75 dl / g.

12. The travoprost particles according to claim 10 or 11, wherein the particles are spherical particles.

13. Various travoprost particles formed from a blend of at least two types of travoprost particles selected from the group consisting of first, second, third, and fourth types of travoprost particles, wherein the first type of travoprost particles are the travoprost particles described in any one of claims 1 to 3, the second type of travoprost particles are the travoprost particles described in any one of claims 4 to 6, the third type of travoprost particles are the travoprost particles described in any one of claims 7 to 9, and the fourth type of travoprost particles are the travoprost particles described in any one of claims 10 to 12.

14. 13. Various travoprost particles formed from a blend of first, second, third, and fourth types of travoprost particles, wherein the first type of travoprost particles are the travoprost particles of any one of claims 1 to 3, the second type of travoprost particles are the travoprost particles of any one of claims 4 to 6, the third type of travoprost particles are the travoprost particles of any one of claims 7 to 9, and the fourth type of travoprost particles are the travoprost particles of any one of claims 10 to 12.

15. The various travoprost particles according to claim 14, wherein, based on the total amount of particles, 15% to 25% by weight of the first type of particles, 15% to 25% by weight of the second type of particles, 5% to 15% by weight of the third type of particles, and 40% to 60% by weight of the fourth type of particles; or 15% to 25% by weight of the total amount of travoprost is present in the form of the first type of particles, 15% to 25% by weight of the total amount of travoprost is present in the form of the second type of particles, 5% to 15% by weight of the total amount of travoprost is present in the form of the third type of particles, and 40% to 60% by weight of the total amount of travoprost is present in the form of the fourth type of particles.

16. 10. Various travoprost particles formed from a blend of first, second, and third types of travoprost particles, wherein the first type of travoprost particles are the travoprost particles of any one of claims 1 to 3, the second type of travoprost particles are the travoprost particles of any one of claims 4 to 6, and the third type of travoprost particles are the travoprost particles of any one of claims 7 to 9.

17. The various travoprost particles according to claim 16, wherein, based on the total amount of particles, 20% to 35% by weight are the first type of particles, 30% to 50% by weight are the second type of particles, and 25% to 45% by weight are the third type of particles; or 20% to 35% by weight of the total amount of travoprost is present in the form of the first type of particles, 30% to 50% by weight of the total amount of travoprost is present in the form of the second type of particles, and 25% to 45% by weight of the total amount of travoprost is present in the form of the third type of particles.

18. Various travoprost particles formed from a blend of first and second types of travoprost particles, wherein the first type of travoprost particles are the travoprost particles described in any one of claims 1 to 3, and the second type of travoprost particles are the travoprost particles described in any one of claims 4 to 6.

19. The various travoprost particles of claim 18, wherein, based on the total amount of particles, 35% to 55% by weight are the first type of particles and 35% to 55% by weight are the second type of particles; or 35% to 55% by weight of the total amount of travoprost is present in the form of the first type of particles and 35% to 55% by weight of the total amount of travoprost is present in the form of the second type of particles.

20. Use of travoprost particles according to any one of claims 1 to 12 or the various travoprost particles according to any one of claims 13 to 19 in the manufacture of an intracameral implant, wherein the intracameral implant comprises a biodegradable hydrogel, the hydrogel comprising a polymer network comprising one or more units of polyalkylene glycol, and the travoprost particles or the various travoprost particles are dispersed within the hydrogel.

21. 1. A method for producing a sustained-release biodegradable intracameral implant of travoprost, said method comprising: a) preparing travoprost particles according to any one of claims 1 to 12 or various travoprost particles according to any one of claims 13 to 19; b) preparing a precursor mixture containing a hydrogel precursor and the travoprost particles or the various travoprost particles; c) crosslinking the precursor mixture using a crosslinker to form a polymer network to obtain a hydrogel mixture comprising the polymer network; and d) drying the hydrogel mixture to provide the intracameral implant.

22. 22. The use of claim 20 or the method of claim 21, wherein the polymer network is formed by reacting an electrophilic group-containing multi-arm polymer precursor with a nucleophilic group-containing crosslinker.

23. 23. The use or method of claim 22, wherein the electrophilic-group-containing multi-arm polymer precursor is a 4-10 arm polyethylene glycol precursor and the nucleophilic-group-containing crosslinker is an amine.

24. 24. The use or method of claim 22 or 23, wherein the electrophilic group is selected from the group consisting of succinimidyl glutarate (SG) and succinimidyl azelate (SAZ) groups, the multi-arm polymer precursor is selected from the group consisting of 8-arm-15K-SG polyethylene glycol or 8-arm-15K-SAZ polyethylene glycol, and the nucleophilic group-containing crosslinker is trilysine.

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