KR20230041708A - Eye implants containing glucocorticoids - Google Patents

Abstract

In certain embodiments, the present invention relates to a sustained release biodegradable intracanalicular implant containing a glucocorticoid dispersed within a hydrogel for the treatment of dry eye disease.

Description

Eye implants containing glucocorticoids

CROSS REFERENCES TO RELATED APPLICATIONS

The present invention is disclosed in U.S. Provisional Application Serial No. 63/052,646, filed on July 16, 2020, U.S. Provisional Application Serial No. 63/124,176, filed on December 11, 2020, and filed on April 29, 2021. Priority is claimed to U.S. Provisional Application Serial No. 63/181,720, all of which are hereby incorporated by reference.

technical field

The present invention relates to the treatment of dry eye disease (DED), and in certain embodiments to the acute treatment of DED or intermittent flares of DED. According to certain embodiments of the present invention, DED is treated by administering a biodegradable implant into the upper and/or lower canaliculi of the eye, wherein the implant provides sustained release of a glucocorticoid such as dexamethasone.

Dry eye disease (DED), also known as keratoconjunctivitis sicca (KCS) (simply referred to as "dry eye syndrome"), is one of the most frequent eye diseases. Currently, hundreds of patients visiting eye clinics report symptoms of dry eye, which is an increasingly public health concern and one of the most common conditions seen by ophthalmologists. Prevalence increases significantly in older age and in women.

DED is a multifactorial disorder of the tear and ocular surface characterized by symptoms of dryness, irritation, burning, stinging, roughness, foreign body sensation, tears and ocular fatigue. Although the etiology of DED is not fully understood, it is recognized that inflammation plays an important role in the development and spread of this debilitating condition. Factors that adversely affect tear film stability and osmotic pressure can initiate inflammatory cascades that cause ocular surface damage and activate innate and acquired immune responses. This immunoinflammatory response leads to further ocular surface damage and the development of a self-sustaining inflammatory cycle. For example, inflammation of the ocular surface reduces tear production, further exacerbating the mentioned condition. In humans, dry eye has been found to be associated with the presence of conjunctival T cells and elevated levels of inflammatory cytokines in tears compared to controls, supporting the inflammation that contributes to the disorder.

DED is considered a chronic condition that greatly affects the patient's daily life, with intermittent flare-ups involving rapid onset of symptoms and exacerbation of symptoms. Several pharmacological therapies for DED have been studied, starting with over-the-counter lubricants and artificial tear substitutes (delivered as eye drops) and progressing to topical anti-inflammatory therapy using a punctal or intracanalicular plug for tear retention and lacrimal duct occlusion. Include a step-by-step approach. The plug is often composed of collagen, acrylic polymer or silicone. Although plugs have been shown to be effective in patients with DED, plugs are sometimes lost (i.e., have poor retention) and may migrate into the nasolacrimal canal, which may contribute to inflammation or other pathological conditions (Fezza, et al. Study Raises Concern Over Plug). , Review of Ophthalmology, 2011).

DED currently has topical glucocorticoids such as fluorometholone (FML), loteprednol etabonate (Alrex ^® and Lotemax ^® ), and prednisolone acetate (PRED MILD ^® ) as well as cyclosporine (Restasis ^® ) and lipitegrast (Xiidra ^® ), and all these active agents are delivered in the form of eye drops. EYSUVIS ^™ (Kala Pharmaceuticals) eye drops containing dexamethasone have recently been approved for the treatment of DED. A particular problem with currently available ophthalmic formulations, including cyclosporine and lipitegrast, is tolerability issues such as burning and stinging sensations that can last from several weeks to several months. In addition, a relatively slow onset of action is generally observed with eye drops. In addition, since most active ingredients are rapidly washed from the eye, eye drops may need to be administered multiple times a day because the eye surface is exposed to the active agent for a short period of time. For this reason, formulations often maximize concentration to compensate for this inefficiency, which can be associated with acutely high concentrations on the ocular surface which can lead to safety concerns. Additionally, burning, itching and stinging associated with preservatives such as anti-microbial preservatives included in eye drops may be observed. In addition, patients may need to administer eye drops multiple times per day, which can significantly affect daily life and result in poor patient compliance. The accuracy of eye drop delivery to the ocular surface may also be limited, as administering eye drops to the eye may be perceived as difficult. Thus, over- or under-dosing may occur.

Glucocorticoids have been used to treat dry eye disease. However, long-term use of glucocorticoids in eye drops can induce an increase in intraocular pressure (IOP) and cause cataracts.

In view of the deficiencies and problems experienced with currently available treatments, glucocorticoids are effectively delivered in appropriate doses while avoiding the need for daily glucocorticoid administration and over an extended period of time to treat DED, including intermittent flare-ups of DED of 1 week or longer. New treatment methods that are effective across the board will provide benefits to patients.

It is an object of certain embodiments of the present invention to provide an ocular implant comprising a glucocorticoid, such as dexamethasone, which is effective for the treatment of DED, in particular the acute treatment of DED, in patients with intermittent flare-ups, for example for a period of one week or more.

Another object of certain embodiments of the present invention is to provide an ocular implant comprising a glucocorticoid, such as dexamethasone, which provides sustained release of the glucocorticoid to the ocular surface via the lacrimal fluid.

Yet another object of certain embodiments of the present invention is to provide an ocular implant comprising a glucocorticoid, such as dexamethasone, that provides sustained release of the glucocorticoid to the ocular surface via the lacrimal fluid, wherein the sustained release period is consistent release of the glucocorticoid per day. include the period

Another object of certain embodiments of the present invention is to provide an ocular implant comprising a glucocorticoid, such as dexamethasone, that provides treatment of DED for a period of one week or longer with only a single administration.

Another object of certain embodiments of the present invention is to provide an ocular implant comprising a glucocorticoid such as dexamethasone that increases tear retention in the eye.

Another object of certain embodiments of the present invention is an anti-inflammatory therapy and increased tear retention that provide additive or synergistic, beneficial effects, all of which are rapidly onset and that persist for an extended period of time after administration, such as over a period of one week or more, with only a single administration. It is to provide an ocular implant comprising a glucocorticoid such as dexamethasone that provides sustained delivery of the glucocorticoid such as dexamethasone for both.

Another object of certain embodiments of the present invention is to provide an ocular implant comprising a glucocorticoid such as dexamethasone that is sufficiently biodegradable to avoid the need to remove the drug-depleted implant.

Another object of certain embodiments of the present invention is to provide an ocular insert comprising a glucocorticoid such as dexamethasone that has a prolonged therapeutic effect of tear retention after a period of glucocorticoid release through the tear film to the ocular surface.

Another object of certain embodiments of the present invention is to provide an ocular implant comprising a glucocorticoid, such as dexamethasone, which is biocompatible and low or non-immunogenic due to certain embodiments of the implant that are free of animal- or human-derived components. is to provide

Another object of certain embodiments of the present invention is to provide an ocular implant comprising a glucocorticoid such as dexamethasone that is free of anti-microbial preservatives.

Another object of certain embodiments of the present invention is to provide an ocular implant comprising a glucocorticoid such as, for example, dexamethasone, which is dimensionally stable when in a dry state after administration to the eye, but changes dimensions when hydrated.

Another object of certain embodiments of the present invention is to provide an ocular implant comprising a glucocorticoid, such as dexamethasone, which is administered in a dry state and hydrated when inserted into, for example, the canaliculus.

Another object of certain embodiments of the present invention is that they are easy to administer in a dry state but are firmly anchored in the canaliculus to avoid potential loss of the implant during treatment to provide improved retention, especially when compared to commonly applied plugs such as collagen or silicone plugs. To provide an ocular implant comprising a glucocorticoid such as dexamethasone.

Another object of certain embodiments of the present invention is to provide an ocular implant comprising a glucocorticoid such as dexamethasone, wherein the implant is stable and has a defined shape and surface before and after implantation (i.e., inside the canaliculus).

Another object of certain embodiments of the present invention is to provide an ocular implant comprising a glucocorticoid such as dexamethasone that is easy to handle and does not spill or break particularly easily.

Another object of certain embodiments of the present invention is to provide an ocular implant containing a glucocorticoid such as dexamethasone that avoids the risk of over and underdosage by allowing administration of precise doses (within a wide dosage range).

Another object of certain embodiments of the present invention is to provide an ocular implant comprising a glucocorticoid such as dexamethasone that does not cause a glucocorticoid peak or substantial peak that can potentially lead to side effects such as elevated intraocular pressure, glaucoma and cataract. .

Another object of certain embodiments of the present invention is a gluco, such as dexamethasone, for the treatment of dry eye disease, such as the acute treatment of DED, which lowers the incidence of side effects such as burning, stinging, or itching compared to generally known dry eye therapies. An ocular implant comprising a corticoid is provided.

Another object of certain embodiments of the present invention is to provide an ocular implant comprising a glucocorticoid such as dexamethasone that provides a hands-free alternative to patients compared to conventional DED treatment.

Another object of certain embodiments of the present invention is to provide an ocular implant comprising a glucocorticoid, such as dexamethasone, which is not overused, for example because it is administered by a physician.

Another object of certain embodiments of the present invention is to provide an ocular implant comprising a glucocorticoid such as dexamethasone that is generally maintained in the area of the eye to which it is administered, such as the lower and/or upper (vertical) canaliculus.

Another object of certain embodiments of the present invention is to provide an ocular implant comprising a glucocorticoid such as dexamethasone that is safe and well tolerated.

Another object of certain embodiments of the present invention is to provide an ocular implant comprising a glucocorticoid such as dexamethasone with increased patient compliance compared to currently available DED treatments.

Another object of certain embodiments of the present invention is to provide an ocular implant comprising a glucocorticoid such as dexamethasone that can be visualized by non-invasive methods in a quick and simple manner.

Another object of certain embodiments of the present invention is to administer a therapeutically effective amount of a glucocorticosteroid, such as dexamethasone, over an extended period of time, such as up to about 7 days, up to about 14 days, or up to about 21 days, or up to about 25 days after administration. It is to provide an ocular implant comprising a glucocorticoid such as dexamethasone that provides sustained release of the corticoid.

Another object of certain embodiments of the present invention is to administer an amount or essentially a constant amount of dexamethasone over an extended period of time, such as a period of up to about 7 days, or up to about 14 days, or up to about 21 days, or up to about 25 days after administration. An ocular implant comprising a glucocorticoid such as dexamethasone that releases a glucocorticoid such as

Another object of certain embodiments of the invention is to administer a therapeutically effective amount of dexamethasone over an extended period of time, such as up to about 7 days, or up to about 14 days, or up to about 21 days, or up to about 25 days after administration. It is to provide an ocular implant comprising a glucocorticoid such as dexamethasone that provides sustained release of the glucocorticoid thereby avoiding the need for frequent administration of the glucocorticoid required several times a day, for example when using eye drops.

Another object of certain embodiments of the present invention is the administration of a therapeutically effective amount of a glucocorticosteroid, such as dexamethasone, over an extended period of time after administration, such as for a period of up to about 7 days, up to about 14 days, or up to about 21 days, or up to about 25 days. An ocular insert comprising a glucocorticoid, such as dexamethasone, provides sustained release of the corticoid, wherein the amount of the glucocorticoid in the tear film is maintained consistently at a therapeutically effective level sufficient for anti-inflammatory therapy of the ocular surface.

Another object of certain embodiments of the present invention is the administration of a therapeutically effective amount of a glucocorticosteroid, such as dexamethasone, over an extended period of time after administration, such as for a period of up to about 7 days, up to about 14 days, or up to about 21 days, or up to about 25 days. To provide an ocular insert comprising a glucocorticoid such as dexamethasone that provides sustained release of the corticoid, wherein essentially no toxic concentrations of the glucocorticoid are observed in the ocular surface and/or tear film.

Another object of certain embodiments of the present invention is the administration of a therapeutically effective amount of a glucocorticosteroid, such as dexamethasone, over an extended period of time after administration, such as for a period of up to about 7 days, up to about 14 days, or up to about 21 days, or up to about 25 days. To provide an ocular implant comprising a glucocorticoid, such as dexamethasone, that provides sustained release of the corticoid, wherein the glucocorticoid is not or substantially not reabsorbed systemically, thereby minimizing or avoiding systemic toxicity.

Another object of certain embodiments of the present invention is to provide a method for treating DED in a patient in need thereof, in particular a method for acute treatment (of intermittent flares) of DED.

Another object of certain embodiments of the present invention is to provide a method of making an ocular implant comprising a glucocorticoid such as dexamethasone.

One or more of these objects and others of the present invention are solved by one or more embodiments of the present invention as disclosed and claimed herein.

In certain embodiments, the present invention provides a simple, hands-free (e.g., doctor-administered) implant that combines the benefits of anti-inflammatory glucocorticoid therapy and the tear-sparing effect of lacrimal duct occlusion in one single therapy. It enables effective short-term treatment of the signs and symptoms of DED through topical glucocorticoids such as dexamethasone. In certain embodiments, an insert of the present invention is administered only once at the beginning of a treatment period (eg, to treat intermittent flares of DED), and thus does not require repeated administration by the patient, thereby avoiding over- or under-dosing as well as over- or under-dosing. Potential abuse/misuse can be avoided. In certain embodiments, the dosage of the glucocorticoid, such as dexamethasone, and the duration of release of the active agent are adjusted to match the short treatment period of about 2 or about 3 weeks required, for example, to treat intermittent flare-ups of DED. Exposure to unnecessarily high doses of glucocorticoids, as well as unnecessarily prolonged exposure to glucocorticoids, is reduced to avoid prolonged and/or high dose use or dose peaks, and potential side effects of glucocorticoids that may be associated with patient abuse or misuse, as much as possible. avoid a lot Additionally, in certain embodiments, the inserts of the present invention do not require antimicrobial preservatives, thus further reducing the potential for allergic reactions or adverse effects that may be associated with preservatives often used in topical ocular formulations. The implants of the present invention may also increase patient compliance due to increased comfort and may increase the effectiveness of DED treatment, including intermittent flare-ups of DED.

Individual aspects of the invention are disclosed herein and claimed in the independent claims, while the dependent claims claim specific embodiments and variations of these aspects of the invention. Details of various aspects of the invention are provided in the detailed description below.

1 schematic diagram of exemplary insert packaging. The insert was placed in a foam carrier and sealed with a foil pouch.
2 Schematic illustrative representation of placement of the implant through the inferior punctum of the eye into the lower vertical canaliculus ( A ). Visualization of the implant is possible, for example, by illumination with blue light ( B ). In one embodiment, the fluorescein within the endoductal implant illuminates when excited with blue light allowing the presence of the implant to be confirmed in a non-invasive manner.
Fig. 3 Schematic illustrative representation of the change in dimensions of the insert upon contact with the lacrimal fluid after insertion of the dry insert into the canaliculus hydrated by the lacrimal fluid.
Fig. 4 over time In vitro dexamethasone release from an intraductal implant according to an embodiment of the invention comprising 0.2 mg and 0.3 mg of dexamethasone (in PBS at 37° C. pH 7.4).
5 Pharmacokinetic profile of dexamethasone release from a 0.22 mg dexamethasone insert into the lacrimal fluid of a beagle dog to illustrate release from the insert according to an embodiment of the present invention. Inserts were placed bilaterally in the punctum of 7 beagles (i.e., 14 total eyes) on day 0. Tear samples were collected from beagle eyes using 10 mm Schirmer tear test strips on days 1, 2, 4, 7, 10, 14, 17, 21, 28, 35, 37, and 40 after insertion of the implant into the canaliculus. did The level of dexamethasone in tear fluid was measured by LC-MS/MS. Dexamethasone is presented as mean values with corresponding standard deviation error bars. Number of samples measured: on day 1 n was 6 eyes; On day 2, n was 8 eyes; On days 14 and 21, n were 7 eyes; At day 28, n was 6 eyes; At day 35 n was 2 eyes. A single implant delivered dexamethasone to the ocular surface for approximately 14 days, and levels of dexamethasone in the tear fluid were maintained through day 7, tapering from day 7 to day 14, and completely released by day 17.
Figure 6 Dexamethasone release from a 0.37 mg dexamethasone insert to illustrate release from an insert according to an embodiment of the present invention at different study time points. Dexamethasone is released over time primarily in the lacrimal fluid at the insertion site close to the punctal opening. The dark shading of the insert reflects the presence of dexamethasone and the transparent portion reflects the dexamethasone-depleted insert region. Dexamethasone is released essentially completely from the 0.37 mg implant after 28 days.
FIG. 7 Phase 2 Clinical Study Overview After a 14-day wash-out period, patients (3 groups, n=50 per group) received 0.2 mg dexamethasone insert, 0.3 mg dexamethasone insert, or a hydrogel vehicle, i.e., dexamethasone. The implant without the implant was administered. The primary efficacy endpoint is week 2.

Justice

As used herein, the term "insert" refers to an active agent, specifically a glucocorticoid such as dexamethasone, which is administered to the body of a human or animal, such as the canal of the eye (one or both eyes, as well as the lower and/or upper canaliculi). Refers to an object in which the implant is maintained for a period of time while releasing an active agent into the surrounding environment. The insert may have any shape predetermined prior to insertion, and this general shape may be retained to some extent upon placement of the insert in a desired location, although the dimensions (eg, length and/or diameter) of the insert are herein disclosed. may change due to hydration after administration as further disclosed in That is, what is administered to the canal of the eye is not a solution or suspension, but a pre-shaped and coherent object. Thus, the implant is fully formed according to the methods disclosed herein, eg, prior to administration. Over time, in certain embodiments, the inserted insert may biodegrade (as disclosed herein) and change its shape (e.g., expand in diameter and decrease in length) until completely dissolved/resorbed. has exist). As used herein, the term "insert" refers to hydration or rehydration when the implant contains water, for example when the implant is administered to the eye or otherwise immersed in an aqueous environment (such as in vitro), followed by hydration (also referred to as "in vitro" herein). It is used to refer to both inserts in a wet (also referred to as "wet") state, as well as inserts in a dry (dried/dehydrated) state. Thus, in certain embodiments, an insert in the context of the present invention may contain less than about 1% water by weight in the dry/dried state. The moisture content of the insert in the dry/dried state can be measured, for example, via the Karl Fischer coulometric method. Whenever a dimension (i.e., length, diameter or volume) of an insert in a hydrated state is reported herein, such dimension is measured after immersing the insert in phosphate buffered saline at a pH value of 7.4 at 37°C for 24 hours. Whenever dimensions of an insert in a dry state are reported herein, these dimensions are measured after the insert is completely dry (thus, in certain embodiments, contains less than about 1% water by weight). In certain embodiments, the insert is maintained in an inert atmosphere glove box containing less than 20 ppm of both oxygen and moisture for at least about 7 days.

In certain embodiments of the present invention, the term "fiber" (used interchangeably herein with the term "rod") refers to an object having a generally elongated shape (i.e., in the present case, an insert according to certain embodiments of the present invention). ) is characterized. Specific dimensions of the inserts of the present invention are disclosed herein. The insert may have a cylindrical or essentially cylindrical shape, or may have a non-cylindrical shape. The cross-sectional area of the fiber or insert can be round or essentially round, but in certain embodiments it can also be oval or oblong, or in other embodiments it can have a different geometry, such as a cross, star shape or others as disclosed herein. .

As used herein, the term "eyeball" generally refers to the eye or any part or part of the eye (an "ocular implant" according to the present invention is in principle an implant that can be administered to any part or part of the eye. referred to). In certain embodiments, the present invention relates to intracanal administration of an eye implant, in which case an "ocular implant" is thus an "endocanal insert", and treatment of dry eye disease (DED), as further disclosed herein. .

As used herein, the term “biodegradable” refers to a material or object that is degraded in vivo, ie when placed in the human or animal body (eg, an endoductal implant according to the present invention). In the context of the present invention, as disclosed in detail herein, an implant comprising a hydrogel having particles of a glucocorticoid, such as dexamethasone, dispersed therein, once deposited within the eye, for example within the canaliculus, may, over time, is slowly biodegraded. Biodegradation occurs at least in part through ester hydrolysis in an aqueous environment provided by the lacrimal fluid. In certain embodiments, the endocanal insert of the present invention slowly softens and liquefies, and is eventually removed (treated/washed out) through the nasolacrimal canal.

A "hydrogel" is one or more hydrophilic natural or synthetic polymers (herein referred to herein) that swell in water and are capable of retaining an amount of water while retaining or substantially retaining their structure, for example due to chemical or physical crosslinking of individual polymer chains. As disclosed) is a three-dimensional network of. Due to their high water content, hydrogels are soft and flexible, very similar to natural tissue. As used herein, the term "hydrogel", as disclosed herein, refers to a hydrogel that is hydrated when it contains water (e.g., after the hydrogel is formed in an aqueous solution, or when inserted into the eye or otherwise immersed in an aqueous environment). hydrogels in a hydrated state (also synonymously referred to herein as “wet state”) after being rehydrated, and in a dry (dried/dehydrated) state when dried to a low moisture content, e.g., 1% by weight or less. It is used to refer to all hydrogels in In the present invention, when an active ingredient is contained (eg, dispersed) in a hydrogel, the hydrogel is also referred to as a “matrix”.

As used herein, "polymer network" describes a structure formed of polymer chains (of the same or different molecular structure or of the same or different average molecular weight) that are cross-linked to each other. Types of polymers suitable for the purposes of the present invention are disclosed herein. Polymer networks can also be formed with the aid of crosslinking agents as disclosed herein.

The term “amorphous” refers to a polymer or polymer network or other chemical substance or entity that does not exhibit a crystalline structure in X-ray or electron scattering experiments.

The term "semi-crystalline" refers to a polymer or polymer network or other chemical substance or entity that has some crystalline properties, i.e., exhibits some crystalline properties in X-ray or electron scattering experiments.

The term “crystalline” refers to a polymer or polymer network or other chemical or entity having crystalline properties as evidenced by X-ray or electron scattering experiments. As used herein, the term "precursor" or "polymer precursor" or specifically "PEG precursor" refers to molecules or compounds that react with each other and connect via crosslinks to form a polymer network and thus a hydrogel matrix. Other materials such as active agents, visualizers or buffers may be present in the hydrogel, but are not referred to as "precursors".

The molecular weight of the polymer precursors used for the purposes of this invention and as disclosed herein can be determined by analytical methods known in the art. The molecular weight of polyethylene glycol can be determined by gel electrophoresis, e.g. SDS-PAGE (sodium dodecyl sulfate-polyacrylamide electrophoresis), gel permeation chromatography (GPC) including GPC with dynamic light scattering (DLS), liquid chromatography (LC), as well as mass spectrometry methods such as matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) spectroscopy or electrospray ionization (ESI) mass spectroscopy; It can be determined by any method known to. The molecular weight of polymers comprising polyethylene glycol precursors as disclosed herein is the average molecular weight (based on the molecular weight distribution of the polymer) and thus can be varied at various average values including weight average molecular weight (Mw) and number average molecular weight (Mn). can be indicated by Any of these average values may generally be used in the context of the present invention. In the context of the present invention, the average molecular weight of a polyethylene glycol unit or other precursor or unit as disclosed herein is the number average molecular weight (Mn), denoted by the unit "Dalton".

The portion of the precursor molecule still present in the final polymer network is also referred to herein as a "unit". Thus, a "unit" is a building block or component of a polymer network forming a hydrogel. For example, polymer networks suitable for use in the present invention may contain the same or different polyethylene glycol units as further disclosed herein.

As used herein, the term “crosslinking agent” or “crosslinker” refers to any molecule suitable for linking precursors through crosslinking to form a polymer network and thus a hydrogel matrix. refers to In certain embodiments, the crosslinking agent may be a low molecular weight compound or may be a polymeric compound as disclosed herein.

The term "sustained release" generally refers to making an active agent such as a glucocorticoid according to the present invention, specifically including but not limited to dexamethasone, available over an extended period of time after administration, such as one week or more for purposes of this invention. is defined for the purposes of the present invention to refer to pharmaceutical dosage forms or products (in which case these products are inserts) formulated for Compared to glucocorticoid solutions (i.e., glucocorticoid-containing eye drops), the frequency of dosing may be reduced. Another term that may be used interchangeably with "sustained release" herein is "extended release" or "controlled release". Thus "sustained release" generally characterizes the release of an API, in particular a glucocorticoid, such as dexamethasone, contained in an insert according to the present invention. The term "sustained release" per se is not associated with or limited to a specific rate of release (in vitro or in vivo), but in certain embodiments of the present invention the insert is a specific average rate of release (in vitro or in vivo) disclosed herein or It can be characterized by a specific release profile. Since the inserts of the present invention (explicitly referred to herein as "sustained release" inserts or simply "inserts") provide sustained release of the API, the inserts of the present invention may therefore also be referred to as "depots". .

Within the specific meaning of the present invention, the term "sustained release" also refers to a constant or substantially constant (i.e., above a certain level) period of release over a day when a period of constant or substantially constant release is followed by a period of tapered glucocorticoid release. ) period of glucocorticoid release. However, in certain cases, the overall sustained release provided by the insert of the present invention (as defined above) may mean that the rate of release is not necessarily constant or essentially constant over the entire period of glucocorticoid release, although it may also mean that the rate of release is not necessarily constant or essentially constant, as just described. (i.e., a constant or essentially constant initial period, i.e., a sustained release followed by a tapered release period). Within the meaning of the present invention, the term "tapered" or "tapering" refers to a decrease in the release of a glucocorticoid such as dexamethasone over time until the glucocorticoid is completely released.

As used herein, the term "visualizer" can be contained within an implant of the present invention and readily visualized in a non-invasive manner when the implant is placed in the canal of the eye by illuminating the eye portion with a suitable light source, such as blue light. offers the possibility of Visualizers can be fluorophores such as fluorescein, rhodamine, coumarin, and cyanine, or other suitable agents as disclosed herein. In certain embodiments, the visualization agent is fluorescein or comprises a fluorescein moiety.

As used herein, the term “ocular surface” includes the conjunctiva and cornea, with elements such as the lacrimal apparatus including the lacrimal duct, as well as the canaliculus and associated eyelid structures. The ocular surface within the meaning of the present invention also includes the aqueous humor.

As used herein, the term “lacrimal fluid” or “tear” or “tear film” refers to the liquid secreted by the lacrimal glands that lubricates the eye. Tears are composed of water, electrolytes, proteins, lipids, and mucus.

As used herein, the terms "bilaterally" or "bilaterally" (in the context of administration of an implant of the present invention) refers to administration of an implant to both eyes of a patient. Thus, “unilaterally” or “unilaterally” means administration of the implant in only one eye. The implants may be inserted independently into the superior and/or inferior canaliculi of either eye or one eye.

As used herein, the terms "administration" or "administering" and the like in the context of an implant of the present invention refers to the process of inserting an implant through an opening in a punctum into the canal of the eye. Thus, "administering an implant" or similar terms refers to inserting an implant into a canal. The terms "insertion" or "inserting" or "inserted" and the like in the context of implants of the present invention refer to the process of inserting the implant through the opening of the punctum into the canal of the eye, and thus the terms "administration" or "insertion" are used herein. Used interchangeably with "to administer" or "to be administered". In contrast, the terms "administration" or "administering" or "administered" and the like in the context of topical ophthalmic pharmacological products such as eye drops (which are not the subject of this invention) refer to the topical application of such products to the eye.

As used herein, the term "insert stacking" or "stacking" refers to the first insert while still being retained in the canaliculus (because the first insert has not yet been fully biodegraded or removed through the nasolacrimal canal). Refers to inserting a further insert on top of the first insert. In certain embodiments, the additional insert is released after complete or essentially complete release of the glucocorticoid contained in the first insert, or at least about 70%, or at least about 80%, or at least about 90% of the glucocorticoid contained in the first insert. is released and then placed on top of the first insert. For example, implant stacking enables long-term glucocorticoid treatment.

As used herein, the term "plug" refers to a device capable of providing closure, substantial occlusion, or partial closure ("lacrimal duct occlusion") of the tear duct(s) to minimize or prevent the drainage of tears. Thus, the plug helps keep the eye moist by increasing tear retention. A plug may be classified as a “punctum plug” or “intracubital plug”. Intracanalicular plugs are also referred to in the literature as "canalicular plugs". Both types of plugs are inserted through the upper and/or lower punctum of the eye. The punctal plug is located in the punctal opening and is easily visible, so it can be removed without great difficulty. However, punctal plugs can have low retention rates and are more susceptible to contamination with microorganisms due to their exposed localization that can cause infection. In contrast, intracanalicular plugs are essentially invisible and offer better retention compared to punctal plugs because they are placed inside a vertical or horizontal canaliculus. However, currently available endoductal plugs may not be easy to remove and the loose fit may increase the risk of migration. Commercially available plugs are often made of collagen, acrylic polymers or silicone.

As used herein, a “canaliculus” (plural “canaliculi”) or alternatively “tear duct” refers to each eyelid that drains lacrimal fluid (lacrimal fluid) from the lacrimal punctum to the nasolacrimal duct. refers to a small channel of (see also Fig. 2A ). The canaliculus thus forms part of the lacrimal duct, which drains tear fluid from the ocular surface into the nasal duct. The canalicules in the upper eyelid are called "upper canaliculi" or "upper canaliculi", and those in the lower eyelid are called "lower canaliculi" or "lower canaliculi". Each canaliculus includes a vertical region called "vertical canaliculus" along the lacrimal duct punctum and a horizontal region termed "horizontal canaliculus" along the vertical canaliculus, where the horizontal canaliculus merges into the nasolacrimal canal.

The term "punctum" (plural "puncta") refers to the punctum of the lacrimal duct, the opening at the edge of the eyelid and denotes the canal opening. After tears are produced, some of the liquid evaporates between blinks and some is expelled through the lacrimal duct. Since both the upper and lower eyelids represent lacrimal punctures, the punctures are also referred to as "upper punctures" or "upper punctures" and "lower punctures" or "lower punctures", respectively (see also FIG. 2A ).

The term "endocanal insert" refers to an insert that can be administered through the superior and/or inferior punctum into the upper and/or lower canaliculi of the eye, in particular into the upper and/or lower vertical canal of the eye. Due to the intracanalinal localization of the implant, the implant blocks tear drainage through lacrimal duct obstruction, as also observed with the intracanal plug. The intracanalicular implant of the present invention may be inserted bilaterally or unilaterally into the lower and/or upper vertical canal of the eye. According to certain embodiments of the present invention, the endoductal implant is a sustained release biodegradable implant.

The terms "API", "active (pharmaceutical) ingredient", "active (pharmaceutical) agent", "active (pharmaceutical) ingredient", "(active) therapeutic agent", "active agent", and "drug" are used herein Articles, used interchangeably, that provide pharmacological activity or are otherwise intended to have a direct effect on diagnosis, cure, mitigation, treatment, or prevention, or to have a direct effect on restoring, correcting, or modifying the physiological function of a patient. Refers to substances used in pharmaceutical products (FPPs), and substances used in the manufacture of such finished pharmaceutical products.

The API used according to the present invention is a glucocorticoid such as dexamethasone. Glucocorticoids are a class of corticosteroids, a class of steroid hormones. The name “glucocorticoid” is a hybrid word ( gluco se (glucose) + cort ex (cortex) + ster oid (steroid)) and consists of its role in the regulation of glucose metabolism, its synthesis in the adrenal cortex and its steroid structure. A less common synonym is glucocorticosteroid. Glucocorticoids regulate gene expression through a glucocorticoid receptor-mediated pathway present in most cells in the body and suppress inflammatory cytokine (TNF alpha, IL-1a, and IL-6) and chemokine production through a non-receptor pathway and inhibits the synthesis of matrix metalloproteinases (Rosenbaum et al., 1980; Nature 286(5773): 611-613). Glucocorticoids such as dexamethasone inhibit inflammation by inhibiting edema, fibrin deposition, capillary deposition and phagocyte migration of the inflammatory response (Chrousos 1995, NEJM 332(20): 1351-1362; Abelson et al. 2002, Review of Ophthalmology: 110-114; Sherif and Pleyer 2002, Ophthalmologica 216(5): 305-315]). As in other tissues, glucocorticoids do not appear to have a specific mechanism of action in ocular tissues, but exert broad anti-inflammatory activity (Leopold 1985, ML Sears and A. Tarkkanen, ed. New York, Raven Press: 83-133; Kaiya 1990, J Cataract Refract Surg 16 (3): 320-324]). In general, most uses of glucocorticoids are limited to relatively short durations (about 2-3 weeks) due to concerns about potential side effects associated with long-term use. Cortisol (or its synthetic form, also called hydrocortisone) is the most important human glucocorticoid. In addition, various synthetic glucocorticoids with various potencies have been produced for therapeutic use. Examples of synthetic glucocorticoids are prednisone, prednisolone, prednisolone acetate, methylprednisolone, dexamethasone, dexamethasone acetate, betamethasone, betamethasone sodium phosphate, budesonide, flunisolide, fluticasone propionate, triamcinolone, triamcinolone acetonide, triamcinolone hexacetonide , triamcinolone diacetate, fluocinolone acetonide, fludrocortisone acetate, loteprednol, loteprednol etabonate, difluprednate, etafluorometholone, oxyfluorometholone, oxyfluorometholone aldosterone, rimexolone , beclomethasone and beclomethasone dipropionate. Any of these synthetic glucocorticoids are suitable for use in the present invention. In certain embodiments of the invention, the glucocorticoid is beclomethasone dipropionate, betamethasone sodium phosphate, budesonide, flunisolide, fluticasone propionate, triamcinolone acetonide, triamcinolone hexacetonide, triamcinolone diacetate, low solubility glucos, including but not limited to dexamethasone, dexamethasone acetate, prednisolone acetate, loteprednol etabonate, difluprednate, fluorometholone, fluocinolone acetonide and mometasone furooate corticoid (i.e., having a solubility in water of less than about 100 μg/mL). Dexamethasone is also sometimes referred to as "dexamethasone alcohol".

Generally, glucocorticoid potency is reported as relative potency in terms of cortisol potency. Determination of equivalent glucocorticoid doses is well established in the art. Equivalent oral doses and relative oral glucocorticoid potencies are illustratively presented in Table 1 for selected glucocorticoids (see, eg, Buttgereit et al. 2002, Ann Rheum Dis 61:718-722, incorporated herein by reference). reference).

Table 1 Established equivalent oral doses and relative oral glucocorticoid potencies of exemplarily selected glucocorticoids.

As used herein, the term "equivalent dose" refers to the administration of another glucocorticoid, such as another glucocorticoid, when delivered via the same route of administration (eg, oral, intravenous, topical, or via an intraductal insert of the present application). Refers to a dose of an active agent, such as a glucocorticoid, that is equivalent in terms of biological activity to the dose of the active agent. Examples of equivalent oral doses of glucocorticoids are presented in Table 1 . For example, oral administration of 20 mg hydrocortisone is expected to have similar biological effects compared to oral administration of 0.8 mg dexamethasone.

In certain embodiments, the glucocorticoid used in accordance with the present invention is dexamethasone. Dexamethasone is a long-acting anti-inflammatory 9-fluoroglucocorticoid (also called a glucocorticoid agonist) with a molecular weight of 392.47 g/mol. The molecular formula of dexamethasone is C ₂₂ H ₂₉ FO ₅ , and its IUPAC name is 9-fluoro-11 β ,17,21-trihydroxy-16 α -methyl-pregna-1,4-diene-3,20-dione (CAS number 50-02-2). The chemical structure of dexamethasone is reproduced as follows:

Dexamethasone is a white to almost white, odorless crystalline powder with low solubility in water (approximately 89 mg/L at 25° C.). Its partition coefficient (n-octane/water) is 1.83 (logP; see DrugBank entry “Dexamethasone”).

In certain embodiments, for any glucocorticoid used in the present invention, including dexamethasone, a particle size of less than about 100 μm, or less than about 75 μm, or less than about 50 μm (e.g., expressed as a d90 value) bar) may be used. In certain embodiments of the present invention, dexamethasone can be used in the form of micronized particles and are about 100 μm or less, or about 75 μm or less, or about 50 μm or less, or about 20 μm or less, or about 10 μm or less, or may have a d90 particle size of about 5 μm or less. In these and other embodiments, the micronized dexamethasone may have a d98 particle size of about 100 μm or less, or about 75 μm or less, or about 50 μm or less, or about 20 μm or less, or about 10 μm or less, or about 5 μm or less. there is. In certain embodiments of the invention, the micronized dexamethasone has a d90 particle size of less than about 5 μm and a d98 particle size of less than about 10 μm. A "d90" value means that at least 90% by volume of all particles in the measured bulk material (with a specified particle size distribution) have a particle size less than the indicated value. For example, a d90 particle size of less than about 50 μm means that at least 90% by volume of the particles of the measured bulk material have a particle size less than about 50 μm. The definition applies to other "d" values, such as the "d98" value. Particle size distribution can be measured by methods known in the art including sieving, laser diffraction, or dynamic light scattering. In embodiments where another glucocorticoid other than dexamethasone is used in the present invention, a similar particle size as disclosed for dexamethasone may be applied.

For the purposes of certain embodiments of the present invention, to increase content uniformity in the final product (thus avoiding too high or too low drug content due to individual particles) and/or during manufacture of the insert (e.g. as disclosed herein) greater than about 120 μm, in addition to meeting certain particle size specifications (e.g., d90 and/or d98 values as disclosed herein), to reduce potential agglomeration of individual API particles during casting of the same hydrogel; or It may be useful to determine whether individual particles larger than a certain size, such as greater than about 100 μm, or greater than about 90 μm, are present, absent, or essentially present in the API starting material. This can be achieved, for example, by sieving. In certain embodiments, the dexamethasone used to make an insert according to the present invention has a d90 particle size of less than about 5 μm, and a d98 particle size of less than about 10 μm, with all or essentially all individual particles having a particle size of about 90 μm. has a size less than

For purposes of this invention, any active agent polymorph or all possible forms of active agent (including dexamethasone) including any pharmaceutically acceptable salts, anhydrides, hydrates, other solvates or derivatives of active agents may be used. Even if an active agent is not referred to by a designation such as, for example, "dexamethasone" in the description or claims, this also means that any such pharmaceutically acceptable polymorph, salt, anhydride, solvate (including hydrate) or derivative of the active agent refers to In particular, the term "dexamethasone" refers to dexamethasone and pharmaceutically acceptable salts thereof, all of which may be used for the purposes of the present invention. As used herein, the term “polymorph” refers to any crystalline form of an active agent such as dexamethasone. Frequently, active agents that are solid at room temperature exist in a variety of different crystalline forms, or polymorphs, with one polymorph being the most thermodynamically stable at a given temperature and pressure.

Any and all dexamethasone polymorphs (anhydrous form or solvate) can be used to prepare inserts according to embodiments of the present invention. With respect to dexamethasone, suitable solid forms including, but not limited to, amorphous forms and polymorphs of dexamethasone are described, for example, in Oliveira et al., Cryst. Growth Des. 2018, 18, 1748-1757 and Aljarah et al., Indian Journal of Forensic Medicine & Toxicology, January-March 2019, Vol. 13, no. 1, 372-377 or in the references cited in any of them.

In addition to dexamethasone (alcohol) per se, solid forms of dexamethasone suitable for use in the present invention include, for example, dexamethasone sodium phosphate, dexamethasone acetate, dexamethasone benzoate, dexamethasone 21-(adamantane-1-carboxylate), dexamethasone iso nicotinate, dexamethasone valerate, dexamethasone tebutate, dexamethasone 21-sulfobenzoate, dexamethasone sodium-metasulfobenzoate, dexamethasone palmitate, dexamethasone cyfesylate, dexamethasone carboxamide, dexamethasone propionate and any of these including (but not limited to) mixtures.

As used herein, the term “therapeutically effective” refers to the amount of a drug or active agent (ie, glucocorticoid) required to produce a desired therapeutic response or outcome after administration. For example, in the context of the present invention, one desirable treatment outcome would be a reduction in symptoms associated with DED. As used herein, the abbreviation “DED” means “dry eye disease” or “dry eye syndrome”.

As used herein, the terms "dry eye disease", "DED", or "dry eye" are used interchangeably and have equivalent meaning. DED is also referred to in the literature as “keratoconjunctivitis sicca (KCS)”. DED refers to a multifactorial disorder of the tear and ocular surface characterized by symptoms such as dryness, irritation, burning, stinging, roughness, foreign body sensation, tearing, and ocular fatigue. Although the etiology of DED is not fully understood, inflammation is recognized to play a key role in the development and spread of this debilitating condition. Factors that adversely affect tear film stability and osmotic pressure can trigger ocular surface damage and initiate an inflammatory cascade that activates innate and acquired immune responses. This immunoinflammatory response leads to further ocular surface damage and the development of a self-sustaining inflammatory cycle. DED is considered a chronic condition that significantly affects the patient's daily life, with intermittent flare-ups involving rapid onset or exacerbation of symptoms.

As used herein, the term "intermittent flare-up" refers to a condition in which rapid onset of DED symptoms or worsening of DED symptoms occurs. Between the intermittent flare-ups of DED of relatively short duration, few or only mild symptoms may be experienced. In certain embodiments, the present invention specifically relates to acute (e.g., intermittent flare-ups of DED over a period of up to about 2 weeks or about 2 weeks, or up to about 3 weeks or about 3 weeks, or up to about 4 weeks or about 4 weeks). short-term) treatment.

As used herein, the term "acute treatment" or "acute treating" or similar phrases refers to short-term treatment or short-term treatment of DED, such as intermittent flares of DED. In certain embodiments of the present invention, the duration of acute treatment with a glucocorticoid contained in an insert according to the present invention is at least about 1 week, such as about 2 or about 3 weeks.

As used herein, the term “patient” includes both human and animal patients. Inserts according to the present invention are generally suitable for human or veterinary applications. A patient enrolled in and treated in a clinical study may also be referred to as a “subject”. Generally, a "subject" is an individual (human or animal) to whom an implant according to the present invention is administered, such as during a clinical study. A “patient” is a subject in need of treatment due to a particular physiological or pathological condition.

As used herein, the term "average" refers to the central or typical value of a set of data (points) (ie, the average value of a data set) calculated by dividing the sum of the data (points) in the set by their number.

As used herein, the term "about" in reference to a measured quantity means a normal change in the measured quantity as would be expected by one skilled in the art in making the measurement and exercising a level of care commensurate with the purpose of the measurement and the precision of the measuring equipment. refers to

As used herein, the term "at least about" with respect to a measured quantity means as would be expected by one skilled in the art in making the measurement and exercising a level of care commensurate with the purpose of the measurement and the precision of the measuring equipment and any higher amount. refers to the normal change in a measured quantity.

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

The term "and/or" used herein in a phrase such as "A and/or B" is intended to include both "A and B" and "A or B".

As used herein, open terms such as "comprises", "comprising", "includes", "including" and the like refer to "comprising" and are intended to refer to an open list or enumeration of elements, method steps, etc. is intended, and therefore is not limited to, recited elements, method steps, etc., but is intended to include additional non-recited elements, method steps, etc.

The term “maximum” when used herein with a particular value or number is meant to include each value or number. For example, the term "up to 25 days" means "up to 25 days".

The abbreviation "PBS" as used herein means phosphate buffered saline.

The abbreviation "PEG" as used herein means polyethylene glycol.

All references disclosed herein are incorporated by reference in their entirety for all purposes (in case of conflict, the present specification will prevail).

details

I. insertion

The present invention relates generally to a sustained release biodegradable ocular implant comprising a hydrogel and a glucocorticoid, wherein the glucocorticoid particles are dispersed within the hydrogel. In certain embodiments, the insert is for administration into the canal of the eye, i.e., an intracanal insert.

In one aspect, the present invention relates to a sustained release biodegradable ocular (eg intracanal) implant comprising a hydrogel and a glucocorticoid, wherein the glucocorticoid particles are dispersed within the hydrogel, and wherein the insert has a pH of about 2.75 in the dry state. have a length of less than mm.

In another aspect, the present invention relates to a sustained release biodegradable ocular (eg intracanal) implant comprising a hydrogel generally and up to about 375 μg of dexamethasone or an equivalent dose of another glucocorticoid.

In another aspect, the present invention generally relates to a sustained release biodegradable ocular (eg intracanal) implant comprising a hydrogel and a glucocorticoid, wherein the insert is about 2.75 mm or less in the dry state (such as prior to administration). have a length

In another aspect, the invention relates generally to a sustained release biodegradable ocular (eg intracanal) implant comprising a hydrogel and a glucocorticoid, wherein the insert contains a therapeutically effective amount of glucocorticoid for a period of up to about 25 days after administration. Provides release of corticoids.

In all these respects, a particular glucocorticoid for use in the present invention is dexamethasone.

In all of these aspects, in certain embodiments of the present invention the ocular implant may be an intracanal implant, i.e., the implant is intended for insertion/administration into the canal of one or both eye(s).

Each of the above-mentioned features in the three aspects of the present invention may be present individually in the sustained-release biodegradable insert of the present invention, any two of these features may be present in combination, or all three of these features may be present in combination can exist

Accordingly, in one specific embodiment, the present invention relates to a sustained release biodegradable intracanalicular implant comprising dexamethasone as a glucocorticoid and a hydrogel, wherein the implant comprises about 375 μg or less of dexamethasone and about 2.75 mm or less of dexamethasone. , and provides release of a therapeutically effective amount of dexamethasone for a period of up to about 25 days after administration.

Specific embodiments and features of the inserts of the present invention are disclosed below.

Active Ingredients:

In certain embodiments, the present invention generally relates to sustained release biodegradable ocular (eg intracanal) implants comprising a hydrogel and a glucocorticoid. One particular glucocorticoid for use in all aspects of the present invention is dexamethasone. Details of dexamethasone, its chemical structure and its properties, such as solubility, are disclosed in the Definitions section.

In one embodiment, the present invention relates to a sustained release biodegradable endoductal implant comprising a hydrogel and up to about 375 μg of dexamethasone or an equivalent dose of another glucocorticoid.

In yet another embodiment, the present invention relates to a sustained release biodegradable endoductal implant comprising a hydrogel and up to about 350 μg of dexamethasone or an equivalent dose of another glucocorticoid.

In certain embodiments of the present invention, the glucocorticoid contained in the sustained-release biodegradable ocular (eg intracanal) insert is dexamethasone, and in a dose range of about 100 μg to about 350 μg, or about 150 μg to about 320 μg of the insert exists in Any amount of dexamethasone within this dosage range can be used, such as about 100 μg, about 150 μg, about 200 μg, about 250 μg, about 300 μg, about 320 μg, about 350 μg, etc., all values also +25% and Include a variance of -20% or a variance of ± 10%. In certain specific embodiments, the dose of dexamethasone contained in the insert of the present invention is as follows:

- in the range of about 160 μg to about 250 μg, or in the range of about 180 μg to about 220 μg, or in very specific embodiments about 200 μg (i.e., deviations of +25% and -20% of 200 μg, or ±10% including deviations from), or

- in the range of about 240 μg to about 375 μg, in the range of about 270 μg to about 330 μg, or in very specific embodiments about 300 μg (i.e., deviations of +25% and -20% of 300 μg, or ±10% of with deviation).

In an alternative embodiment, the dose of glucocorticoid such as dexamethasone in the insert of the present invention is from about 50 μg to about 500 μg, such as about 50 μg, about 100 μg, about 150 μg, about 200 μg, about 250 μg, about 300 μg. μg, about 350 μg, about 400 μg, about 450 μg, or about 500 μg of dexamethasone or an equivalent dose of another glucocorticoid. In exceptional cases, these doses may exceed 500 μg.

When a glucocorticoid other than dexamethasone is used in the sustained release biodegradable intraductal implant according to the present invention, a dose of that other glucocorticoid is contained in the insert equivalent to any of the doses and ranges disclosed above for dexamethasone. Suitable conversion factors between glucocorticoids are known in the art and can be applied (see “Definitions” section above).

The disclosed amounts of glucocorticoids such as dexamethasone, including the stated variations, refer to both the amount of active ingredient used as a starting ingredient when preparing the insert as well as the final content of active ingredient in the insert.

In certain embodiments, the sustained-release biodegradable intraductal implant of the present invention is about 2.75 mm or less in length (as described herein below) and/or releases a therapeutically effective amount of a glucocorticoid for up to about 25 days after administration. (as disclosed herein below), the dose of dexamethasone (or an equivalent dose of another glucocorticoid) contained in the insert may also exceed 375 μg, and may also exceed about 400 μg, such as about 400 μg to about 600 μg, or about 500 μg of dexamethasone. However, doses of up to about 375 μg within the ranges disclosed herein are particularly suitable for the present invention.

In certain embodiments, a glucocorticoid, such as dexamethasone, may be incorporated into an insert of the present invention such that the glucocorticoid particles are dispersed or distributed within a hydrogel composed of a polymer network. In certain embodiments, the particles are homogeneously dispersed within the hydrogel. The hydrogel can prevent the drug particles from agglomeration and can provide a matrix for the particles that release the drug in a sustained manner upon contact with the lacrimal fluid.

In certain embodiments of the invention, glucocorticoid particles, such as dexamethasone particles, may be microencapsulated. The term "microcapsule" is sometimes defined as approximately spherical particles having various sizes, for example from about 50 nm to about 2 mm. A microcapsule has at least one individual domain (or core) of an active agent encapsulated in an enclosing or partially enclosing material, sometimes referred to as a shell. A suitable agent for microencapsulating glucocorticoids such as dexamethasone for the purposes of the present invention is poly(lactic-co-glycolic acid).

In one embodiment, the glucocorticoid particles, such as dexamethasone particles, may have a small particle size and may be micronized particles. In another embodiment the glucocorticoid particles, such as dexamethasone particles, may not be micronized. Micronization refers to the process of reducing the average diameter of particles of a solid material. Particles with a reduced diameter may have a higher rate of dissolution which in particular increases the bioavailability of the active pharmaceutical ingredient. In the field of composite materials, particle size is known to affect mechanical properties when combined with a matrix, with smaller particles providing better reinforcement for a given mass fraction. Thus, a hydrogel matrix in which micronized glucocorticoid particles are dispersed may have improved mechanical properties (eg, brittleness, deformation to breakage, etc.) compared to a similar mass fraction of larger glucocorticoid particles. These properties are important during manufacture, administration, and disassembly of the implant. Micronization can also promote a more uniform distribution of the active ingredient in a selected dosage form or matrix. In certain embodiments, for any glucocorticoid used in the present invention, including dexamethasone, a particle size of about 100 μm or less, or about 75 μm or less, or about 50 μm or less (e.g., as defined herein and also expressed as d90 values measured as disclosed herein) can be used. In certain embodiments, dexamethasone can be used in the form of micronized particles, which are about 100 μm or less, or about 75 μm or less, or about 50 μm or less, or about 20 μm or less, or about 10 μm or less, or about 5 μm or less. It may have a d90 particle size of In these and other embodiments, the micronized dexamethasone may have a d98 particle size of about 100 μm or less, or about 75 μm or less, or about 50 μm or less, or about 20 μm or less, or about 10 μm or less, or about 5 μm or less. there is. In certain embodiments of the present invention, the micronized dexamethasone used in (or used in the manufacture of) the inserts of the present invention has a d90 particle size of less than about 5 μm and a d98 particle size of less than about 10 μm. In embodiments in the present invention where another glucocorticoid other than dexamethasone is used, a similar particle size as disclosed for dexamethasone may be applied.

In certain embodiments, to reduce the presence of individual particles in a glucocorticoid, particularly dexamethasone, starting materials of a certain size, such as greater than about 120 μm, or greater than about 100 μm, or greater than about 90 μm, disclosed herein Bulk glucocorticoid material that meets the (d90 and/or d98) particle size specification(s) as described above may be sieved prior to preparing the wet composition of the insert. In certain embodiments, the dexamethasone used to prepare an insert according to the present invention has a d90 particle size of about 5 μm or less, and a d98 particle size of about 10 μm or less, wherein all or essentially all individual particles are about 90 μm. has a size less than

Micronized dexamethasone particles can be purchased according to specifications from a supplier (eg Pfizer or Sanofi) or prepared according to any process known in the art. For example, the micronization process can be used as exemplarily disclosed for certain glucocorticoids, for example in EP 2043698 A2 or EP 2156823 A1 (incorporated herein by reference), or the process can be used for different active agents, for example WO 2016/183296 A1 (incorporated herein by reference), similar to the exemplary procedure as disclosed in Example 13.

Polymer Network:

In certain embodiments, hydrogels may be formed from precursors having functional groups that form crosslinks to create a polymer network. Such crosslinking between polymeric strands or arms may be chemical in nature (ie, may be covalent) and/or physical (eg, ionic bonding, hydrophobic associations, hydrogen bridges, etc.).

The polymer network can be made from precursors, from one type of precursor or from two or more types of precursors that are allowed to react. Precursors are selected in consideration of desired properties for the resulting hydrogel. There are a variety of precursors suitable for use in making hydrogels. In general, any pharmaceutically acceptable, crosslinkable polymer that forms a hydrogel may be used for purposes of the present invention. The hydrogel and the components contained therein, including the polymers used to make the polymer network, must be physiologically safe, for example not to elicit an immune response or a substantial immune response or other side effects. Hydrogels can be formed from natural, synthetic, or biosynthetic polymers.

Natural polymers may include glycosaminoglycans, polysaccharides (eg dextran), polyamino acids and proteins or mixtures or combinations thereof, but this list is not intended to be limiting.

A synthetic polymer can be any polymer that is produced synthetically from various feedstocks by various types of polymerization, including generally free radical polymerization, anionic or cationic polymerization, chain growth or addition polymerization, condensation polymerization, ring-opening polymerization, and the like. Polymerization can be initiated by specific initiators, light and/or heat, and can be mediated by catalysts. Synthetic polymers may be used in certain embodiments to reduce the allergenic potential in dosage forms that do not contain any ingredients of human or animal origin.

In general, for the purposes of the present invention, in particular polyethylene glycol (PEG), polyalkylene oxides such as polyethylene oxide, polypropylene oxide, polyvinyl alcohol, poly (vinylpyrrolidinone), polylactic acid, polylactic-co- Although one or more synthetic polymers of the group comprising one or more units of polyalkylene glycols, including but not limited to glycolic acid, random or block copolymers, or combinations/mixtures of any of these, may be used, although this list It is not intended to be limiting.

To form a covalently crosslinked polymer network, the precursors can be covalently crosslinked to one another. In certain embodiments, a precursor having at least two reaction centers (eg, in free radical polymerization) can act as a crosslinker because each reactive group can participate in the formation of a different growing polymer chain.

A precursor may have a biologically inert and hydrophilic part, such as a core. In the case of branched polymers, the core refers to the adjacent portion of the molecule connected to an arm extending from the core, where the arm often has functional groups at the end of the arm or branch. A multi-arm PEG precursor is an example of such a precursor and is used in certain embodiments of the present invention as further disclosed herein.

A hydrogel for use in the present invention may be, for example, one multi-arm precursor having a first (set) functional group(s) and another (eg, set) having a second (set) functional group(s). multi-arm) bulbs. For example, a multi-arm precursor may have a hydrophilic arm, eg, a polyethylene glycol unit terminated with a primary amine (nucleophile) or may have an activated ester end group (electrophile). The polymer networks according to the present invention may contain identical or different units crosslinked to one another. Precursors can be high molecular weight constituents (such as polymers having functional groups as further disclosed herein) or low molecular weight constituents (such as low molecular weight amines, thiols, esters, etc., as also further disclosed herein).

Certain functional groups can be made more reactive using activating groups. Such activating groups include carbonyldiimidazoles, sulfonyl chlorides, aryl halides, sulfosuccinimidyl esters, N-hydroxysuccinimidyl (abbreviated "NHS") esters, succinimidyl esters, benzothiazolyl esters, thioesters, epoxides, aldehydes, maleimides, imidoesters, acrylates, and the like. NHS esters are useful groups for crosslinking with nucleophilic polymers, such as primary amine-terminated or thiol-terminated polyethylene glycols or other nucleophilic group-containing agents, such as nucleophilic group-containing crosslinkers. The NHS-amine crosslinking reaction is performed in aqueous solution and in a buffer such as phosphate buffer (pH 5.0-7.5), triethanolamine buffer (pH 7.5-9.0), borate buffer (pH 9.0-12), or sodium bicarbonate buffer (pH 5.0-7.5). 9.0-10.0).

In certain embodiments, each precursor may include a nucleophilic or electrophilic functional group, so long as both nucleophilic and electrophilic precursors are used in the crosslinking reaction. Thus, for example, if the crosslinking agent has a nucleophilic functional group such as an amine, the precursor polymer may have an electrophilic functional group such as N-hydroxysuccinimide. Meanwhile, when the crosslinking agent has an electrophilic functional group such as sulfosuccinimide, the functional polymer may have a nucleophilic functional group such as an amine or a thiol. Thus, functional polymers such as proteins, poly (allyl amine), or amine-terminated difunctional or polyfunctional poly (ethylene glycol) may also be used to make the polymer networks of the present invention.

In one embodiment of the present invention, the precursors for the polymer networks forming the hydrogels in which the glucocorticoids are dispersed to form the inserts according to the present invention contain about 2 to about 16 nucleophilic functional groups (functionality). In another embodiment, the precursors each have from about 2 to about 16 electrophilic functional groups (referred to as functional groups). Reactive precursors having a multiplicity of reactive (nucleophilic or electrophilic) groups as multiples of 4, eg 4, 8 and 16 reactive groups, are particularly suitable for the present invention. However, any number of functional groups, such as including any of the 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 groups, are present. It is possible for the precursors used according to the invention to ensure that the functionality is sufficient to form a properly crosslinked network.

PEG hydrogel :

In certain embodiments of the present invention, the polymer network forming the hydrogel contains polyethylene glycol ("PEG") units. PEGs are known in the art to form hydrogels when cross-linked, and such PEG hydrogels are suitable for pharmaceutical applications, for example as matrices for drugs intended to be administered to any part of the human or animal body. .

The polymer network of the hydrogel insert of the present invention may comprise one or more multi-arm PEG units having 2 to 10 arms, or 4 to 8 arms, or 4, 5, 6, 7 or 8 arms. In certain embodiments, the PEG units used in the hydrogels of the present invention have four arms. In certain embodiments, the PEG units used in the hydrogels of the present invention have eight arms. In certain embodiments, PEG units with 4 arms and PEG units with 8 arms are used in the hydrogels of the present invention. In certain specific embodiments, one or more 4-armed PEGs are utilized. Any combination of multi-arm PEGs may be used. In certain embodiments, only a 4-arm PEG unit is used (which may be the same or different).

The number of arms of PEG(s) used serves to control the flexibility or softness of the resulting hydrogel. For example, hydrogels formed by crosslinking 4-arm PEG are generally softer and more flexible than those formed from 8-arm PEG of the same molecular weight. In particular, if it is desired to stretch the hydrogel before (or after) drying as described below in the section relating to fabrication of the insert, a more flexible hydrogel such as a 4-arm PEG may optionally be mixed with another multi-arm PEG, such as An 8-arm PEG as described above, or in combination with another (different) 4-arm PEG.

In certain embodiments of the present invention, the polyethylene glycol unit used as a precursor has an average molecular weight (Mn) in the range of about 2,000 to about 100,000 Daltons, or in the range of about 10,000 to about 60,000 Daltons, or in the range of about 15,000 to about 50,000 Daltons. In certain specific embodiments, the polyethylene glycol unit has an average molecular weight in the range of about 10,000 to about 40,000 Daltons, or in the range of about 15,000 to about 30,000 Daltons, or in the range of about 15,000 to about 25,000 Daltons. In certain embodiments, the polyethylene glycol units used to prepare hydrogels according to the present invention have an average molecular weight (Mn) of about 20,000 Daltons. Polyethylene glycol precursors of different molecular weights may be combined with each other. When referring herein to a PEG material having a particular average molecular weight (as defined herein), such as about 20,000 Daltons, a deviation of ± 10% is intended to be included, i.e. refers to materials having an average molecular weight of about 20,000 Also refers to those materials having an average molecular weight of from about 18,000 to about 22,000 daltons. As used herein, the abbreviation “k” in the context of molecular weight refers to 1,000 daltons, i.e. “20k” means 20,000 daltons.

Also, when referring to a PEG precursor having a specific average molecular weight, such as a 15 kPEG- or 20 kPEG-precursor, the average molecular weight indicated (i.e., Mn of 15,000 or 20,000, respectively) refers to the PEG portion of the precursor before end groups are added (where , "20k" means 20,000 daltons, "15k" means 15,000 daltons - the same abbreviation is used herein for other average molecular weights of PEG precursors). In certain embodiments, the Mn of the PEG portion of the precursor is determined by MALDI. The degree of substitution of end groups as disclosed herein can be determined by ¹ H-NMR after end group functionalization.

In a 4-arm ("4a") PEG, in certain embodiments each arm may have an average arm length (or molecular weight) of the total molecular weight of the PEG divided by 4. Thus, the 4a20kPEG precursor, a precursor particularly suitable for use in the present invention, has four arms each having an average molecular weight of about 5,000 daltons and a total molecular weight of 20,000 daltons. Thus, the 8a20k PEG precursor, which may be used in combination with or alternatively to the 4a20kPEG precursor in the present invention, has eight arms ("8a") each having an average molecular weight of 2,500 daltons and a total molecular weight of 20,000 daltons. A longer arm may provide more flexibility compared to a shorter arm. PEGs with longer arms are more inflated compared to PEGs with shorter arms. A PEG with a low number of arms may also be more swollen and more flexible than a PEG with a high number of arms. In certain specific embodiments, only one or more 4-armed PEG precursor(s) are used in the present invention. In certain other embodiments, a combination of one or more 4-arm PEG precursor(s) and one or more 8-arm PEG precursor(s) are utilized in the present invention. Also, longer PEG arms can provide higher dimensional stability during storage because they have a higher melting temperature when dry.

In certain embodiments, the electrophilic end groups for use with the PEG precursors for preparing the hydrogels of the present invention are NHS dicarboxylic acid esters, such as succinimidylmalonate groups, succinimidylmaleate groups, succinimidyl groups. “SAZ” refers to the fumarate group, succinimidyladipate end group, “SAP” refers to the succinimidyl adipate end group, “SG” refers to the succinimidylglutamate end group, and succinimide hydroxysuccinimidyl (NHS) esters, including but not limited to "SS", which refers to dilsuccinate end groups. Examples of activated esters other than NHS esters useful in the present invention are (but are not limited to) thioesters, benzotriazolyl esters, and esters of acrylic acid.

In certain embodiments, the nucleophilic end groups for use with the electrophilic group-containing PEG precursors for preparing the hydrogels of the present invention are amine (denoted “NH ₂ ”) end groups. Thiol (-SH) end groups or other nucleophilic end groups are also possible.

In certain embodiments of the present invention, a 4-arm PEG having an average molecular weight of about 20,000 Daltons and an electrophilic end group (such as SAZ, SAP, SG and SS end groups, particularly SG end groups) as disclosed herein is cross-linked. combined to form a polymer network and thus a hydrogel according to the present invention. Suitable PEG precursors are available from Jenkem Technology and several other suppliers.

, 식 중 m은 0 내지 10의 정수, 및 구체적으로 1, 2, 3, 4, 5, 6, 7, 8, 9, 또는 10이다. SAZ-말단기의 경우 m은 6일 것이고, SAP-말단기의 경우 m은 3일 것이고, SG-말단기의 경우 m은 2일 것이고, SS-말단기의 경우 m은 1일 것이다. 특정 구현예에서, m은 2이다. 중합체 네트워크 내의 모든 가교결합은 동일하거나 상이할 수 있다.The reaction of a nucleophilic group-containing crosslinking agent with an electrophilic group-containing PEG unit, such as, for example, the reaction of an amine group-containing crosslinking agent with an activated ester-group containing PEG unit, is crosslinked by a hydrolysable linker having the formula Produces a plurality of PEG units that are linked to:

, wherein m is an integer from 0 to 10, and specifically 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. For SAZ-terminals m shall equal 6, for SAP-terminals m shall equal 3, for SG-terminals m shall equal 2, and for SS-terminals m shall equal 1. In certain embodiments, m is 2. All crosslinks within the polymer network may be the same or different.

In certain embodiments, the polymer precursor used to form a hydrogel according to the present invention is 4a20kPEG-SAZ, 4a20kPEG-SAP, 4a20kPEG-SG, 4a20kPEG-SS, 8a20kPEG-SAZ, 8a20kPEG-SAP, 8a20kPEG-SG, 8a20kPEG- SS, or mixtures thereof, wherein the one or more PEG- or lysine-based-amine groups are selected from 4a20kPEG-NH ₂ , 8a20kPEG-NH ₂ , and trilysine, or trilysine salts or derivatives such as trilysine acetate. .

In certain embodiments, SG end groups are utilized in the present invention. This endgroup provides a higher number of carbons to the linker and therefore is more hydrophobic and therefore less prone to ester hydrolysis than the SG endgroup compared to the use of other endgroups, such as the SAZ endgroup, which allows hydrogels to function in aqueous environments such as lacrimal fluid. It can be given for a shorter period of time until biodegradation.

In certain embodiments, a 4-arm 20,000 dalton PEG precursor (as defined above) with SG end groups is crosslinked with a crosslinking agent having one or more reactive amine end groups. This PEG precursor is abbreviated herein as 4a20kPEG-SG. The schematic chemical structure of 4a20kPEG-SG is reproduced as follows:

In the above formula, n is determined by the molecular weight of each PEG-arm.

In certain particular embodiments, the crosslinking agent (also referred to herein as "crosslinking agent") used is a low molecular weight component containing a nucleophilic end group such as an amine or thiol end group. In certain embodiments, the nucleophilic group-containing crosslinking agent is a small molecule amine having a molecular weight of less than 1,000 Da. In certain embodiments, the nucleophilic-group containing crosslinker comprises 2, 3 or more primary aliphatic amine groups. Crosslinking agents suitable for use in the present invention include spermine, spermidine, lysine, dilysine, trilysine, tetralysine, polylysine, ethylenediamine, polyethyleneimine, 1,3-diaminopropane, 1,3-dia Minopropane, diethylenetriamine, triethylhexamethylenediamine, 1,1,1-tris(aminoethyl)ethane, pharmaceutically acceptable salts, hydrates or other solvates thereof and derivatives thereof such as conjugates (crosslinked as long as sufficient nucleophilic groups are present for binding) and any mixtures thereof. Particular crosslinkers for use in the present invention are lysine-based crosslinkers, such as trilysine or trilysine salts or derivatives. A particular nucleophilic crosslinker for use in the present invention is trilysine acetate. Other low molecular weight multi-arm amines may also be used. The chemical structure of trilysine is reproduced as follows:

In a very specific embodiment of the present invention, the 4a20kPEG-SG precursor is reacted with trilysine acetate to form a polymer network.

In certain embodiments, the nucleophilic group-containing crosslinking agent is bonded to or conjugated to a visualization agent. Fluorophores such as fluorescein, rhodamine, coumarin, and cyanine can be used as visualizers as disclosed herein. In certain embodiments of the present invention, fluorescein is used as a visualizing agent. The visualizing agent may be conjugated with the crosslinking agent, for example via a portion of a nucleophilic group of the crosslinking agent. Since a sufficient amount of a nucleophilic group is required for cross-linking, "conjugated" or "conjugation" generally includes partial conjugation, meaning that only a portion of the nucleophilic group is available for conjugation with a visualizer; For example, about 1% to about 20%, or about 5% to about 10%, or about 8% of the nucleophilic groups of the crosslinking agent may be conjugated with the visualizing agent. In certain embodiments, the crosslinking agent is trilysine acetate and is conjugated with fluorescein.

In another embodiment, the visualizing agent may also be conjugated to the polymer precursor, for example via a specific reactive (eg electrophilic) group of the polymer precursor. In certain embodiments, the crosslinking agent itself or the polymer precursor itself may contain, for example, a fluorophore or other visualization-capable group.

In the present invention, conjugation of the visualizer to the polymer precursor(s) or crosslinking agent as described below is intended to retain the visualizer in the hydrogel while the active agent is released into the lacrimal fluid, in a convenient and non-invasive manner. The presence of an intraductal implant can be confirmed.

In certain embodiments, the molar ratio of the nucleophilic and electrophilic end groups reacting with each other is about 1:1, i.e., one amine group per one electrophilic group, such as SG, is provided. In the case of 4a20kPEG-SG and trilysine (acetate), this results in a molar ratio of the two components of about 1:1 since trilysine has four primary amine groups that can react with the electrophilic SG ester groups. However, an excess of electrophilic (eg NHS such as SG) endgroup precursors or nucleophilic (eg amine) endgroup precursors may be used. In particular, precursors or crosslinkers containing the same excess nucleophilic, such as amine end groups, may be used. In certain embodiments, the molar ratio of electrophilic group-containing precursor to nucleophilic group-containing cross-linking agent, such as 4a20kPEG-SG to trilysine acetate, is from about 1:2 to about 2:1.

Finally, in an alternative embodiment the amine linking agent is also another PEG precursor having the same or different number of arms or the same or different arm length (average molecular weight) as 4a20kPEG-SG but with a terminal amine group, i.e. 4a20kPEG-NH ₂ can be

Additional Ingredients:

The insert of the present invention may contain other additional components than the active ingredient and the polymer units forming the polymer network as described above. Such additional components are, for example, salts derived from buffers used during the manufacture of hydrogels such as phosphates, borates, bicarbonates or other buffers such as triethanolamine. In certain embodiments of the present invention sodium phosphate buffers (specifically monobasic and dibasic sodium phosphate) are used.

In certain embodiments, the inserts of the present invention are free of anti-microbial preservatives or contain at least significant amounts of anti-microbial preservatives (benzalkonium chloride (BAK), chlorobutanol, sodium perborate and stabilized oxychloro complexes (SOC), but but not limited thereto).

In a further specific embodiment, the insert of the present invention does not contain any ingredients of animal or human origin, only synthetic ingredients.

In certain embodiments, the inserts of the present invention contain a visualizing agent. Visualizers used according to the present invention are all agents which can be conjugated to the components of the hydrogel or entrapped within the hydrogel and which are visible or which can be made visible, for example when exposed to light of a particular wavelength, or which are contrast agents. . Visualizers suitable for use in the present invention include, for example, fluorescein, rhodamine, coumarin, cyanine, europium chelate complex, boron dipyrromethene, benzoprazan, dansyl, bimine, acridine, triazapentalene , pyrendyl are (but are not limited to) derivatives of these. Such visualizers are commercially available, for example from TCI. In certain embodiments, the visualizing agent is a fluorophore such as fluorescein or comprises a fluorescein moiety. Visualization of the fluorescein-containing insert is possible by illumination with blue light and a yellow filter. The fluorescein of the intracanalicular implant can be illuminated when excited with blue light to confirm the presence of the implant. In certain embodiments, the visualizing agent is conjugated with one of the components forming the hydrogel. For example, a visualization agent such as fluorescein is conjugated with a crosslinking agent such as trilysine or a trilysine salt or derivative (eg trilysine acetate), or a PEG-component. For example, NHS-fluorescein can be conjugated with trilysine acetate prior to cross-linking reaction with the PEG precursor(s). Conjugation of the visualizer prevents elution or release of the visualizer. A method of conjugating a visualizer and a crosslinking agent is illustrated in Example 1 . Since a sufficient amount of nucleophilic groups (at least one molar equivalent) is required for crosslinking, partial conjugation of the crosslinker and the visualizer, for example as disclosed herein, can be performed.

The inserts of the present invention may contain surfactants in certain embodiments. The surfactant may be a non-ionic surfactant. Non-ionic surfactants can include poly(ethylene glycol) chains. Exemplary non-ionic surfactants are commercially available poly( ethylene glycol) sorbitan monolaurate, poly(ethylene glycol) esters commercially available as Cremophor (and especially Cremophor40 which is PEG-40-castor oil), and ethoxylated-4-tert-octylphenol commercially available as Tyloxapol /formaldehyde condensation polymers and others, such as Triton. Surfactants can help disperse the active ingredients and prevent particle aggregation, and can also reduce the adhesion of the hydrogel strands to the tubing during drying.

Formulation:

In certain embodiments, an insert according to the present invention may contain a glucocorticoid such as dexamethasone, a polymer network prepared from one or more polymer precursors as disclosed herein in the form of a hydrogel, and a visualizer remaining in the insert from the production process, salts, etc. ( eg phosphate salts used as buffers, etc.). In certain preferred embodiments, the glucocorticoid is dexamethasone. In certain embodiments, the insert is free of preservatives.

In some embodiments, an insert according to the present invention contains from about 30% to about 70% by weight of a glucocorticoid, such as dexamethasone, as described above, and from about 25% to about 60% by weight of a polymer unit in a dry state. do. In a further embodiment, an insert according to the present invention contains from about 30% to about 60% by weight of a glucocorticoid, such as dexamethasone, as described above in the dry state, and from about 30% to about 60% by weight of a polymer unit. do.

In certain embodiments, an insert according to the present invention comprises from about 40% to about 56% by weight of a glucocorticoid, such as dexamethasone, and from about 36% to about 55% by weight of a polyethylene glycol unit, such as a polyethylene glycol unit, in the dry state. Contains polymeric units.

In certain particular embodiments, an insert according to the present invention contains from about 40% to about 46% dexamethasone by weight and from about 45% to about 55% PEG units by weight in the dry state.

In certain other specific embodiments, an insert according to the present invention contains from about 50% to about 56% dexamethasone by weight and from about 36% to about 46% PEG units by weight in the dry state.

In certain embodiments, an insert according to the present invention may contain from about 0.1% to about 1% by weight of a visualizer, such as fluorescein or a molecule comprising a fluorescein moiety, in the dry state. Additionally, in certain embodiments, an insert according to the present invention may contain from about 0.5% to about 5% by weight of one or more buffer salt(s) (separately or together) in the dry state. In certain embodiments, the insert may contain, for example, from about 0.01% to about 2% or from about 0.05% to about 0.5% surfactant by weight in the dry state.

In certain embodiments, an insert according to the present invention comprises about 200 μg of dexamethasone (i.e., within a deviation of +25% and -20%, or within a deviation of ±10% of about 200 μg of dexamethasone, as disclosed herein). containing the target dose), and from about 200 μg to about 250 μg of a PEG-unit such as 4a20kPEG-SG, from about 5 μg to about 7 μg of trilysine acetate, from about 1 μg to about 3 μg of fluorescein. and a buffering salt such as about 2.5 μg to about 20 μg of sodium phosphate (monobasic and/or dibasic).

In another specific embodiment, an insert according to the present invention contains about 300 μg of dexamethasone (i.e., within a deviation of +25% and -20%, or within a deviation of ±10%, as disclosed herein, of about 300 μg of dexamethasone). dexamethasone), and about 200 μg to about 250 μg of a PEG-unit such as 4a20kPEG-SG, about 5 μg to about 7 μg of trilysine acetate, about 1 μg to about 3 μg of fluorescein and a buffering salt such as about 2.5 μg to about 20 μg of sodium phosphate (monobasic and/or dibasic).

In certain embodiments, the remaining amount in the dry state of the insert (i.e., the remaining portion of the formulation if glucocorticoids such as dexamethasone, and trilysine-crosslinked PEG hydrogels, and optional visualizers such as fluorescein are already considered). ) may be a salt remaining from a buffer used during manufacture of the insert as disclosed herein, or may be another ingredient used during manufacture of the insert (such as a surfactant, if used). In certain embodiments, such salts are phosphate, borate or (bi) carbonate salts. In one embodiment the buffering salt is sodium phosphate (monobasic and/or dibasic).

The amount of glucocorticoid and polymer(s) may vary, and other amounts of glucocorticoid and polymer hydrogels than those disclosed herein may also be used to make inserts according to the present invention.

In certain embodiments, the maximum amount (wt%) of drug in the formulation is about twice the amount of polymer (e.g., PEG) units, but in certain cases, mixtures comprising, for example, precursors, visualizers, buffers and drugs (before the hydrogel is fully gelled) can be uniformly cast into desired molds or tubing of thin diameter, and/or the hydrogel is still sufficiently stretchable as disclosed herein, and/or also upon hydration as disclosed herein. It can be higher as long as the diameter increases sufficiently.

In certain embodiments, a solids content of about 20% to about 50% (w/v) (where "solids" means the combined weight of the polymer precursor(s), optional visualizer, salt, and drug in solution) is It is used to form the hydrogel of the insert according to the invention.

In certain embodiments, the water content of the hydrogel in the dry (dehydrated/dried) state can be as low as about 1% by weight or less water (eg, determined as disclosed herein). In certain embodiments the moisture content may also be lower, possibly less than about 0.25% by weight or even less than about 0.1% by weight.

Dimensions of the insert and dimensional change upon hydration:

The dried insert may have a different geometry depending on the method of manufacture, such as the inner diameter or shape of the tubing or mold into which the mixture containing the hydrogel precursor containing glucocorticoid is cast prior to complete gelation. Inserts according to the present invention are also referred to as “fibres” (this term is used interchangeably with the term “rod”), wherein the fibers generally have a length exceeding their diameter. The inserts (or fibers) may have different geometries with specific dimensions as disclosed herein.

In one embodiment, the insert has a cylindrical or essentially cylindrical shape. Whenever the specification or claims refer to “cylindrical” with respect to the shape of an insert, it always includes “essentially cylindrical”. In this case, the insert has a round or essentially round cross section. In another embodiment of the invention, the insert is non-cylindrical. An insert according to the present invention is optionally stretched in a dry state, wherein the length of the insert is greater than the width of the insert, the width being the largest cross-sectional dimension substantially perpendicular to the length. In cylindrical or essentially cylindrical inserts the width is also referred to as the diameter.

Various geometries of external insert shapes or cross-sections thereof may also be used in the present invention. For example, ovoid (or oval) diameter fibers may be used instead of round diameter fibers (ie, for cylindrical inserts). Other cross-sectional geometries such as oval or rectangular, rectangular, triangular, star-shaped, cross-shaped, etc. can generally be used. As long as the insert expands in diameter to the hydrated diameter upon hydration in the canaliculus as disclosed herein, the exact cross-sectional shape is not critical as tissue is formed around the insert. In certain embodiments, the ratio of the length of the insert to the diameter of the insert in the hydrated state is at least about 1, or at least about 1.1, or at least about 1.2, which helps to hold the insert in place within the canal, and allows the insert to move within the canal. It prevents twisting and turning, and also helps maintain close contact with the surrounding tissue. In certain embodiments, this ratio may be less than about 2 or less than about 1.75.

Polymer networks, such as the PEG networks of hydrogel inserts according to certain embodiments of the present invention, can be semi-crystalline in the dry state below room temperature and amorphous in the wet state. Even in a stretched form, the dry insert may be dimensionally stable at room temperature or below, which may be advantageous for canalicular dosing and quality control of the insert.

Upon hydration of the canalicular insert by tear fluid (which can be simulated in vitro, for example, by immersing the insert in PBS at pH 7.4 at 37° C. after 24 hours, which is considered equilibrium), the insert according to the present invention The dimensions of can be changed. In general, the diameter of an insert may increase, while the length of an insert may decrease, or in certain embodiments may be the same or essentially the same. The advantage of this dimensional change is that the insert is sufficiently thin in the dry state that upon hydration it can be administered and placed into the canaliculus through the punctum (which itself is smaller in diameter than the canaliculus) and thus adheres to the canaliculus through its expansion in diameter to act as a canaliculus plug. do Thus, the insert provides lacrimal duct closure to provide tear retention in addition to release of the active ingredient in the lacrimal fluid in a controlled manner over a specified period of time as disclosed herein.

In certain embodiments, these dimensional changes are also made possible, at least in part, by a “shape memory” effect introduced into the insert by stretching the hydrogel strands lengthwise during manufacture, as disclosed herein. In certain embodiments, such stretching may be performed in a wet state, i.e. prior to drying. However, in certain other embodiments, stretching of the hydrogel strands (once cast and cured) may be performed in the dry state (ie, after drying the hydrogel strands). Note that if no stretching is performed, the insert may simply swell due to absorption of water, but the dimensional changes of increasing diameter and decreasing length described herein may or may not be significantly achieved. This may result in sub-optimal fixation of the insert in the canaliculus, potentially leading to removal of the insert through the nasolacrimal duct or puncta (potentially even before the full dose of active ingredient has been released). If this is not desired, the hydrogel strands should be drawn dry or wet to provide expansion in diameter upon rehydration, for example.

In the hydrogels of the present invention, some degree of molecular orientation can be imparted by stretching the material and then allowing it to solidify and locking the molecular orientation. Molecular orientation provides one mechanism for anisotropic swelling when the implant is in contact with a hydrating medium such as lacrimal fluid. Upon hydration, the inserts of certain embodiments of the present invention will swell only in the radial dimension, and the length will decrease or remain or remain essentially the same. The term “anisotropic swelling” means swelling preferentially in one direction as opposed to the other, such as in a cylinder that swells primarily in diameter but does not swell appreciably (or even shrinks) in the longitudinal dimension.

The degree of dimensional change upon hydration may depend inter alia on the elongation factor. As an example to illustrate the effect of stretching, for example, stretching with a stretching factor of about 1.3 (eg by wet stretching) may have a less pronounced effect or may not significantly change length and/or diameter during hydration. there is. In contrast, stretching with a stretch factor of about 1.8 (eg, by wet stretching) can result in shorter lengths and/or increased diameters during hydration. For example, stretching with a draw factor of about 3 or 4 (eg, by dry stretching) can produce much shorter lengths and much larger diameters when hydrated. One skilled in the art will understand that factors other than stretching may also affect swelling behavior.

Among other factors that influence the ability to stretch the hydrogel and induce dimensional changes of the insert upon hydration is the composition of the polymer network. When using a PEG precursor, a low number of arms (eg a 4-arm PEG precursor) contributes to higher flexibility in the hydrogel than a higher number of arms (eg an 8-arm PEG precursor). If the hydrogel contains more of the less flexible component (e.g., a higher amount of PEG precursor containing a greater number of arms, such as an 8-armed PEG unit), the hydrogel is more rigid and unbreakable and can be stretched. It may not be easy to become. On the other hand, hydrogels containing more flexible components (eg PEG precursors containing fewer arms, such as a 4-armed PEG unit) may be more stretchable and softer, but may swell more upon hydration. Thus, once the implant is administered and rehydrated, the behavior and properties of the implant can be tuned by various structural features as well as by modifying the processing of the implant after it is initially formed.

The dried insert dimensions may depend inter alia on the amount of incorporated glucocorticoid as well as the ratio of glucocorticoid to polymer units, and may further be controlled by the diameter and shape of the mold or tubing into which the hydrogel is gelled. The diameter of the dried insert can be further controlled by (wet or dry) stretching of the hydrogel strands once formed as described herein. The dried hydrogel strands (after stretching) are cut into segments of desired length to form inserts; So, you can choose the length as you like.

In the following, examples of inserts having specific dimensions are disclosed. The dimensional ranges or values disclosed in certain embodiments herein relate to the length and diameter of cylindrical or essentially cylindrical inserts. However, all values and ranges for cylindrical inserts can also be used correspondingly for non-cylindrical inserts. When multiple measurements of the length or diameter of one insert are made or multiple datapoints are collected during a measurement, the average (i.e., median) value is reported as defined herein. The length and diameter of an insert according to the present invention can be measured, for example by means of a microscope or (optionally automated) camera system, as described in Example 1 . Other suitable methods of measuring insert dimensions may also be used.

In one embodiment, the present invention relates to a sustained release biodegradable endoductal implant comprising a hydrogel and a glucocorticoid, wherein the insert has a length of about 2.75 mm or less in the dry state. In certain embodiments, the glucocorticoid is dexamethasone.

In certain embodiments of the invention, the insert has a length of about 2.5 mm or less, or less than about 2.3 mm, or has a length of about 2.25 mm. In certain embodiments of the present invention, the insert has a length in the dry state greater than about 1 mm, or greater than about 1.5 mm, or greater than about 2 mm. In certain particular embodiments, the insert has a length of less than about 2.5 mm and greater than about 1.5 mm in the dry state.

In an alternative embodiment, the insert is about 0.5 mm to about 3 mm (e.g., about 0.5 mm to about 2.5 mm, about 1 mm to about 2.5 mm, about 1.25 mm to about 2.5 mm, about 1.5 mm to about 2.25 mm). mm, about 0.5 mm, about 0.75 mm, about 1 mm, about 1.25 mm, about 1.5 mm, about 1.75 mm, about 2.0 mm, about 2.25 mm, about 2.5 mm, about 2.75 mm, or about 3 mm) can have

In certain embodiments of the invention, the insert has a diameter in the dry state of less than about 1 mm, or less than about 0.8 mm, or less than about 0.75 mm, or less than about 0.6 mm, or from about 0.40 mm to about 0.58 mm, or about 0.45 mm. mm, or about 0.5 mm in diameter.

In certain embodiments of the present invention, the insert has a length in the dry state ranging from about 2.14 mm to about 2.36 mm and a diameter ranging from about 0.41 mm to about 0.55 mm.

In certain embodiments, an insert according to the present invention is cylindrical or essentially cylindrical, and upon hydration (either in vivo in the canal or in vitro after 24 hours in phosphate buffered saline at 37° C. and pH 7.2) the diameter of the insert increases and the insert length decreases. In particular, the diameter of the insert may be increased by a factor of about 1.5 to about 4, or about 2 to about 3.5, or about 3. That is, the ratio of the diameter of the insert in the hydrated state to the diameter of the insert in the dry state may be in the range of about 1.5 to about 4, in the range of about 2 to about 3.5, or about 3.

In certain embodiments, the length of an insert according to the present invention is reduced after hydration to about 0.9 times its length in the dry state, or to about 0.75 times its length in the dry state, or to about two-thirds its length in the dry state. do. That is, the ratio of the length of the insert in the hydrated state to the length of the insert in the dry state may be less than about 0.9, or less than about 0.75, or less than about 2/3, and may be at least about 0.25, or at least about 0.4.

Accordingly, in certain embodiments an insert according to the present invention has a diameter in the range of about 1 to about 2 mm in a hydrated state and a length less than the length of the insert in a dry state. In certain embodiments, in a hydrated state, for example when the insert is placed in the canaliculus, the ratio of length to diameter of the insert is suitably greater than 1, i.e., the length of the insert is greater than the diameter. This helps keep the implant in place in the canalula without twisting or rotating. This not only helps to close the canaliculus/punctum and keep the lacrimal fluid inside the eye, but also ensures contact between the insertion surface and the lacrimal fluid to release glucocorticoids such as dexamethasone.

In certain embodiments, an insert according to the present invention has a diameter in the hydrated state ranging from about 1.35 mm to about 1.80 mm and a length ranging from about 1.65 mm to about 2.0 mm. Specifically, an insert according to the present invention may have a diameter in a hydrated state ranging from about 1.40 mm to about 1.60 mm and a length ranging from about 1.70 mm to about 2.0 mm, such as a diameter of about 1.5 mm and a length of about 1.8 mm. .

In certain embodiments, dimensional change can be achieved by wet stretching the hydrogel strands with a draw factor ranging from about 1.5 to about 3, or from about 2.2 to about 2.8, or from about 2.5 to about 2.6. In another embodiment, this dimensional change can be achieved by dry stretching.

In certain embodiments, stretching creates shape memory, which means that when administered to the canal, upon hydration, the insert comes into contact with lacrimal fluid, particularly when it reaches (approximate) equilibrium dimensions determined by its original plastic dimensions and construction parameters. This means that the length decreases and the diameter widens. While the narrow dry dimensions facilitate administration of the insert through the punctum into the canaliculus, the widened diameter and shortened length after administration release the active agent primarily on its proximal surface (the surface of the insert in contact with the lacrimal fluid and facing the punctum opening). It creates a shorter but wider implant that fits closely to and closes the canaliculus.

In certain embodiments, when the sustained release biodegradable intraductal insert of the present invention is defined by a dexamethasone content of about 375 μg or less or an equivalent dose of another glucocorticoid (as described hereinabove) and/or after administration When releasing a therapeutically effective amount of a glucocorticoid for a period of up to about 25 days (as disclosed herein below), the length in the dry state of the insert may also exceed 2.75 mm, e.g., the dry state of the insert The length at may be about 3 mm or more. However, as disclosed herein, lengths of about 2.75 mm or less are particularly suitable for the present invention.

In one particular embodiment, the insert of the present invention contains about 200 μg of dexamethasone (with a deviation of +25%/-20% or ± 10% as disclosed herein), has (essentially) a cylindrical shape, and , in the dry state, in a diameter ranging from about 0.41 mm to about 0.49 mm, such as about 0.47 mm, or about 0.45 mm, and having a length ranging from about 2.14 mm to about 2.36 mm, such as about 2.25 mm. Such inserts may have a range of about 1.69 mm to about 1.87 mm upon hydration in vivo or in vitro in the canaliculus, wherein the in vitro hydration is measured in phosphate buffered saline at pH 7.4 at 37° C. after 24 hours, which is considered equilibrium. The length decreases to a length shorter than the length in the dry state, such as a length of about 1.79 mm or about 1.8 mm, and a diameter ranging from about 1.35 mm to about 1.80 mm, such as a diameter of about 1.5 mm or about 1.54 mm; diameter may increase.

In another specific embodiment, the insert of the present invention contains about 300 μg of dexamethasone (with a deviation of +25%/-20% or ± 10% as disclosed herein), has (essentially) a cylindrical shape, and , with a diameter in the dry state ranging from about 0.44 mm to about 0.55 mm, such as about 0.5 mm or about 0.51 mm, and a length ranging from about 2.14 mm to about 2.36 mm, such as about 2.25 mm. Such inserts may have a diameter ranging from about 1.64 mm to about 2.0 mm upon in vivo or in vitro hydration in the canaliculus, wherein the in vitro hydration is measured in phosphate buffered saline at pH 7.4 at 37° C. after 24 hours, which is considered equilibrium. decreasing in length to a length shorter than the length in the hydrated state, such as a length of about 1.8 mm or about 1.85 mm, and a diameter ranging from about 1.35 mm to about 1.80 mm, such as about 1.5 mm or about 1.47 mm; diameter may increase.

In certain embodiments, an insert of the present invention has a total weight in the range of about 100 to about 1000 μg, such as in the range of about 200 to about 800 μg, or in the range of about 300 to about 700 μg. In certain embodiments, an insert of the present invention contains dexamethasone in an amount in the range of about 400 to about 600 μg, such as about 400 to about 500 μg (particularly, about 200 μg, including variations as disclosed herein). ), or from about 500 to about 600 μg (particularly when the insert contains dexamethasone in an amount of about 300 μg, including variations as disclosed herein).

Active release and biodegradation of inserts:

In one embodiment, the present invention relates to a sustained release biodegradable ocular (eg intracanal) implant comprising a hydrogel and a glucocorticoid, wherein the insert is administered (i.e., after being inserted into the canaliculus) for up to about 25 days. Provides the release of a therapeutically effective amount of glucocorticoid for a period of time. In certain embodiments, the glucocorticoid is dexamethasone.

Without wishing to be bound by theory, the release of glucocorticoids into the lacrimal fluid is determined by the solubility of the glucocorticoids in the aqueous environment. One particular glucocorticoid for use according to the present invention is dexamethasone. The solubility of dexamethasone was determined to be very low in aqueous media (less than 100 μg/mL) such as tear fluid. When administered to the canaliculus, dexamethasone is released from the implant primarily at its surface proximate to the lacrimal fluid and thus to the surface of the eye (ie, at the implant surface facing the punctum opening).

In certain embodiments, the active agent dissolves slowly and diffuses from the hydrogel into the lacrimal fluid. It usually occurs in a unidirectional manner, starting at the interface of the implant and the lacrimal fluid on the proximal surface of the implant. The "drug front" generally runs in the opposite direction, away from the proximal surface, until eventually the entire implant is depleted of active agent. This is illustrated in FIG. 6 .

In certain embodiments, an insert according to the present invention is administered for a period of at least about 6 hours, such as at least about 12 hours, such as at least about 1 day, after administration, which is longer than known immediate release ophthalmic dosage forms, or Provides release of a glucocorticoid (therapeutically effective amount) such as dexamethasone over a period of at least about 7 days.

In certain embodiments, an insert according to the present invention can be administered for up to about 1 month, or up to about 25 days, or up to about 21 days (ie, about 3 weeks), or up to about 14 days (ie, about 2 weeks) after administration. Provides release of glucocorticoids such as dexamethasone (therapeutically effective amounts) over a period of time.

In certain embodiments, after administration, the level of active agent released from the insert per day (with limitation of release based on the solubility of the active agent) over a specified period of time, such as about 7 days, or about 11 days, or about 14 days in the case of dexamethasone. to) continue, be constant, or remain essentially constant. The amount of active agent released per day is then decreased over another period of time, such as an additional period of about 7 days (or longer in certain embodiments) in the case of dexamethasone, until all or substantially all of the active agent has been released (also " (also referred to as "tapering"), the "empty" hydrogel remains in the canal until completely disintegrated and/or removed (treated/washed out) through the nasolacrimal canal.

In certain embodiments, the inserts of the present invention release a sustained, constant, or essentially constant period of time, e.g., up to about 7 days, or up to about 11 days, or up to about 14 days or longer after administration. provides an average release of about 5 to about 50 μg, such as about 10 to about 35 μg, specifically about 15 μg to about 25 μg, such as about 20 μg, per day in the lacrimal fluid.

In certain embodiments, from an insert containing a target dose of about 200 μg (including deviations as disclosed herein) of dexamethasone, about 15 μg to about 25 μg, such as about 20 μg, dexamethasone is administered for a period of up to 7 days after administration. is released into the lacrimal fluid on average per day for an additional period of up to about 7 days or more, then smaller amounts of dexamethasone are released until all of the dexamethasone contained in the implant has been released. An insert containing a target dose of dexamethasone of about 200 μg overall (including deviations as disclosed herein) can provide a therapeutically effective amount for, for example, up to about 7 days post-administration, up to about 14 days post-administration, or more. Release of dexamethasone into the lacrimal fluid may be provided.

In another specific embodiment, from an insert containing a target dose of dexamethasone of about 300 μg (including deviations as disclosed herein), about 15 μg to about 25 μg, such as about 20 μg of dexamethasone, dexamethasone is administered at a maximum of about An average release per day for a period of 11 days or up to about 14 days is followed by lower amounts of dexamethasone being released for an additional period of up to about 7 days until all of the dexamethasone contained in the insert has been released. Overall, an insert containing a target dose of dexamethasone of about 300 μg (including deviations as disclosed herein) can provide release of a therapeutically effective amount of dexamethasone for a period of up to about 21 days or more after administration. .

In a further embodiment, when the sustained release biodegradable intraductal insert of the present invention is defined by a dose of dexamethasone of about 375 μg or less or an equivalent dose of another glucocorticoid contained in the insert (as described herein above) and / or when defined as a length of about 2.75 mm or less (as disclosed hereinbelow), the insert may be used after administration, for example, more than 25 days after administration, such as up to about 1 month or even more, such as up to about 2 days after administration months or for a period of up to about 3 months. However, release of a therapeutically effective amount of dexamethasone (or other glucocorticoid) for a period of up to about 25 days after administration, specifically up to about 14 days (i.e., about 2 weeks) or up to about 21 days (i.e., about 3 weeks) This is particularly suitable for the present invention.

When the drug is released primarily from the proximal surface of the insert, this area of the hydrogel insert is free of drug particles and may therefore be referred to as the “clearance zone”. In certain embodiments, an “interstitial zone” upon hydration is therefore a region of the insert that has a lower concentration of active agent than the active agent in other regions of the hydrated hydrogel. As the interstitial area increases, a concentration gradient may be created within the insert causing a tapering of the drug release rate.

Simultaneously with the drug diffusing out of the hydrogel (and also after the entire amount of drug has diffused out of the hydrogel) the hydrogel can be slowly degraded, for example by ester hydrolysis in the aqueous environment of the lacrimal fluid. Distortion and corrosion of the hydrogel start to occur in the advanced degradation stage. When this happens, the hydrogel becomes softer and more liquid (thus distorting its shape) until it finally dissolves and is completely reabsorbed. However, as the hydrogel becomes softer and thinner and distorts its shape, at a certain point the hydrogel no longer stays at the intended location in the canal where it was administered and proceeds deeper into the canal and is eventually removed through the nasolacrimal canal (processing/wash-out )do.

In one embodiment, the persistence of a hydrogel in an aqueous environment, such as the human eye (including the canaliculus), depends in particular on the structure of the linker that crosslinks the polymeric units, such as PEG units, in the hydrogel. In certain embodiments, the hydrogel biodegrades within a period of about 1 month, or about 2 months, or about 3 months, or up to about 4 months after administration. However, because the hydrogel gradually softens and distorts during degradation processes in an aqueous environment, such as intracanal lacrimal fluid, the insert can be removed (washed out/treated) through the nasolacrimal canal before it is fully biodegraded.

In embodiments of the present invention, the hydrogel and thus the insert remain in the canal for a period of up to about 1 month, or up to about 2 months, or up to about 3 months, or up to about 4 months after administration.

In certain embodiments of the invention, where the glucocorticoid is dexamethasone, the entire amount of dexamethasone can be released prior to complete disintegration of the hydrogel, after which the inserts can be released for up to about 1 month combined after administration, or up to about 2 months after administration, or It may remain in the canal for a period of up to about 3 months, or up to about 4 months after administration. In certain other embodiments, the hydrogel is fully biodegradable when the glucocorticoid, such as dexamethasone, has not yet been completely released into the insert. In other embodiments, the insert can be completely degraded after release of at least about 90%, or at least about 92%, or at least about 95%, or at least about 97% of the glucocorticoid.

In certain embodiments, in vitro release testing can be used to compare different inserts (eg, different product batches, different compositions, and different dosage strengths, etc.) to each other, for example, for quality control or other qualitative evaluation purposes. there is. In vitro-release of glucocorticoids from the implants of the present invention can be determined by a variety of methods, such as under non-sink simulated physiological conditions in PBS (phosphate buffered saline, pH 7.4) at 37° C. A similar volume of PBS is replaced daily.

about 200 μg Certain implants containing a dose of dexamethasone:

In one specific embodiment, the present invention provides a sustained-release biodegradable endoductal implant containing dexamethasone in an amount ranging from about 160 μg to about 250 μg, or about 180 μg to about 220 μg, or in particular in an amount of about 200 μg. , wherein dexamethasone is dispersed in a hydrogel. The insert has a cylindrical or essentially cylindrical shape with a diameter in the dry state ranging from about 0.41 mm to about 0.49 mm and a length ranging from about 2.14 mm to about 2.36 mm. In a hydrated state (in vivo hydration or in vitro hydration in canaliculi, where in vitro hydration is measured in phosphate buffered saline at pH 7.4 at 37° C. after 24 hours, which is considered equilibrium), the insert is about 1.35 mm to about 1.80 mm and a length to diameter ratio of greater than 1, in particular from about 1.69 mm to about 1.87 mm.

In this insert, the hydrogel comprises a polymer network comprising crosslinked multi-arm polyethylene glycol units, in particular 4a20kPEG units, wherein the crosslinks between the PEG units comprise groups represented by the formula:

In the formula, m is 2. To prepare this insert, the 4a20kPEG-SG units can be cross-linked with a cross-linking agent such as trilysine acetate. In this embodiment, the insert may also contain a polymer network and a visualizer, such as fluorescein conjugated with trilysine acetate.

Also in this embodiment, the insert is comprised of about 40% to about 46% dexamethasone and about 45% to about 55% polyethylene glycol units by weight in the dry state. The insert may also contain up to about 1% water by weight in the dry state.

The dexamethasone particles in the insert may have a d90 particle size of less than about 5 μm and/or a d98 particle size of less than about 10 μm, as determined by laser diffraction.

The insert provides release of a therapeutically effective amount of dexamethasone over a period of up to about 7 days or more, such as up to about 14 days, up to about 21 days, or up to about 25 days, or up to about 1 month after administration. In certain embodiments, the insert provides release of a therapeutically effective amount of dexamethasone over a period of up to about 14 days after administration (ie, for about 2 weeks or up to about 2 weeks).

The implant may be used for treatment of DED, including acute treatment of DED or intermittent flares of DED.

about 300 μg Certain implants containing a dose of dexamethasone:

In another specific embodiment, the present invention provides a sustained-release biodegradable endoductal implant containing dexamethasone in an amount ranging from about 240 μg to about 375 μg, or in an amount ranging from about 270 μg to about 330 μg, or in particular in an amount of about 300 μg. , wherein dexamethasone is dispersed within a hydrogel. The insert has a cylindrical or essentially cylindrical shape with a diameter in the dry state ranging from about 0.44 mm to about 0.55 mm and a length ranging from about 2.14 mm to about 2.36 mm. In a hydrated state (either in vivo hydration or in vitro hydration in canaliculi, where in vitro hydration is measured in phosphate buffered saline at pH 7.4 at 37° C. after 24 hours, which is considered equilibrium), the insert is between about 1.35 mm and It has a diameter in the range of about 1.80 mm and a length to diameter ratio greater than 1, in particular a length in the range of about 1.64 mm to about 2.0 mm.

In this insert, the hydrogel comprises a polymer network comprising crosslinked multi-arm polyethylene glycol units, in particular 4a20kPEG units, wherein the crosslinks between the PEG units comprise groups represented by the formula:

In the formula, m is 2. To prepare this insert, the 4a20kPEG-SG units can be cross-linked with a cross-linking agent such as trilysine acetate. In this embodiment, the insert may also contain a polymer network and a visualizer, such as fluorescein conjugated with trilysine acetate.

Also in this embodiment, the insert is comprised of about 50% to about 56% dexamethasone and about 36% to about 46% polyethylene glycol units by weight in the dry state. The insert may also contain up to about 1% water by weight in the dry state.

The dexamethasone particles in the insert may have a d90 particle size of less than about 5 μm and/or a d98 particle size of less than about 10 μm, as determined by laser diffraction.

The insert provides release of a therapeutically effective amount of dexamethasone over a period of up to about 14 days or more, such as up to about 21 days, or up to about 25 days, or up to about 1 month after administration. In certain embodiments, the insert provides release of a therapeutically effective amount of dexamethasone over a period of up to about 21 days (ie, for about 3 weeks or up to about 3 weeks) after administration.

The implant may be used for treatment of DED, including acute treatment of DED or intermittent flares of DED.

II. Manufacture of inserts

In certain embodiments, the present invention also relates to a method of making a sustained release biodegradable endoductal implant as disclosed herein comprising a hydrogel and a glucocorticoid such as dexamethasone.

In certain embodiments, a manufacturing method according to the present invention comprises forming a hydrogel comprising a polymer network (e.g., comprising PEG units) and glucocorticoid particles dispersed within the hydrogel, shaping or casting the hydrogel and drying the hydrogel. In one embodiment, glucocorticoids such as dexamethasone can be used in micronized form as disclosed herein to make inserts. In another embodiment, glucocorticoids such as dexamethasone can be used in non-micronized form to make inserts.

Suitable precursors for forming the hydrogels of certain embodiments of the present invention are as described above in the section on the insert itself. In certain specific embodiments, the hydrogel is made of a polymer network comprising crosslinked polyethylene glycol units as disclosed herein. In certain embodiments, the polyethylene glycol (PEG) unit is multi-armed, such as a 4-arm, and the PEG unit has a range of from about 2,000 to about 100,000 daltons, or from about 10,000 to about 60,000 daltons, or from about 15,000 to about 50,000 daltons, or from about It has an average molecular weight of 20,000 Daltons. Suitable PEG precursors having reactive groups such as electrophilic groups as disclosed herein are cross-linked to form polymer networks. Crosslinking can be effected by a crosslinking agent, which is a low molecular weight compound or another polymer compound comprising another PEG precursor having a reactive group, such as a nucleophilic group, as also disclosed herein. In certain embodiments, a PEG precursor having an electrophilic end group is reacted with a crosslinking agent (a low molecular weight compound, or another PEG precursor) having a nucleophilic end group to form a polymer network.

In certain embodiments, the method of making an insert of the present invention comprises an electrophilic group-containing multi-arm polyethylene glycol such as 4a20kPEG-SG and a nucleophilic group-containing crosslinking agent such as trilysine acetate in a buffered solution in the presence of dexamethasone particles. mixing and reacting, and gelling the mixture. In certain embodiments, the molar ratio of the electrophilic groups of the PEG precursor to the nucleophilic groups of the crosslinking agent is about 1:1, but may range from about 2:1 to about 1:2.

In certain embodiments, a visualization agent as disclosed herein is included in a mixture that forms a hydrogel such that the implant can be visualized upon administration into the canal. For example, the visualizer can be a fluorophore, such as fluorescein or a molecule comprising a fluorescein moiety, or another visualizer as described above. In certain embodiments, the visualizing agent may be firmly bonded to one or more components of the polymer network and remain on the insert at all times until the insert is biodegradable.

Visualizers can be conjugated with, for example, polymers such as PEG, precursors, or (polymeric or low molecular weight) crosslinkers. In certain embodiments, the visualizer is fluorescein and is conjugated to a trilysine acetate crosslinker prior to reacting the crosslinker with the PEG precursor as illustrated in Example 1 . For example, in the case of fluorescein, NHS-fluorescein (N-hydroxysuccinimidyl-fluorescein) can be reacted with trilysine acetate, monitoring the complete formation of the trilysine-fluorescein conjugate. (eg by RP-HPLC with UV-detection). This conjugate can then be further used to crosslink polymer precursor(s) such as 4a20kPEG-SG.

In certain specific embodiments, during manufacture of the insert of the present invention, a mixture/suspension in (optionally buffered) water of dexamethasone and a glucocorticoid and PEG precursor(s) such as 4a20kPEG-SG is prepared. This glucocorticoid/PEG precursor mixture can then be combined with a (optionally buffered) solution containing a crosslinking agent and a visualizer conjugated thereto, such as a lysine acetate/fluorescein conjugate. The resulting combined mixture contains a glucocorticoid, polymer precursor(s), a crosslinking agent, a visualizing agent, and (optionally) a buffering agent. This is exemplarily illustrated in Example 1 .

In certain embodiments, once the electrophilic group-containing polymer precursor, the nucleophilic group-containing cross-linking agent, a glucocorticoid such as dexamethasone, optionally a visualizing agent (optionally conjugated to, for example, a cross-linking agent), and optionally a buffer Once a mixture of is prepared (i.e., after these components are combined), the resulting mixture is cast into a suitable mold or tubing prior to complete gelation, for example to provide the desired final shape of the strand and ultimately the hydrogel. The mixture is then gelled. The resulting hydrogel is then dried.

When the final shape of the insert is cylindrical or essentially cylindrical, hydrogel strands are prepared by casting a hydrogel precursor mixture comprising glucocorticoid particles into fine diameter tubing, such as polyurethane (PU) tubing. Depending on the desired final cross-sectional shape of the hydrogel strand, and thus the final insert, its initial diameter (which may still be reduced by stretching), and also the ability of the reaction mixture to uniformly fill the tubing and to be removed from the tubing after drying, Different geometries and diameters of tubing may be used. Thus, the interior of the tubing may have a circular geometry or a non-circular geometry such as an elliptical (or other) geometry.

In certain embodiments, after the hydrogel strands have been formed and left within the tubing to complete the curing and gelation process, the hydrogel strands can be longitudinally stretched in a wet or dry state as disclosed herein. Stretching can result in a dimensional change of the insert upon hydration, eg, after placement in the canaliculus. In certain embodiments, the hydrogel strands are stretched prior to (complete) drying by a draw factor ranging from about 1 to about 3, or from about 1.5 to about 3, or from about 2.2 to about 2.8, or from about 2.5 to about 2.6. In certain embodiments, stretching may be performed while the hydrogel strand is still in the tubing. Alternatively, the hydrogel strands can be removed from the tubing prior to stretching. When dry stretching is performed in certain embodiments of the present invention, the hydrogel strand is first dried and then drawn (either while still inside the tubing or after being removed from the tubing). When wet stretching is performed in certain embodiments of the present invention, the hydrogel is stretched in a wet state (ie, before drying completely) and then left to dry under tension. Optionally, heat may be applied during stretching.

After stretching and drying, the hydrogel strands can be removed from the tubing and cut into segments of the desired length as disclosed herein to create final inserts (if cut within the tubing, the cut segments are removed from the tubing after cutting ). A particularly preferred length for purposes of the present invention is a length of about 2.75 mm or less, or a length of about 2.5 mm or less, such as a length ranging from about 2.0 mm to about 2.5 mm, or about 2.14 mm to about 2.36 mm, for example about 2.25 mm can be the length of

After cutting, the insert may be packaged in moisture-tight packaging, such as a sealed foil pouch. The insert can be secured to a mount or support to keep it in place and prevent damage to the insert, and also allows for easy removal of the insert from its packaging and gripping/holding of the insert for administration to the patient. For example, an insert of the present invention can be secured to an opening in a foam carrier, with a portion of the insert protruding for easy removal and gripping (as shown in FIG. 1 ). The insert can be inserted into the patient's canal immediately after being removed from the foam carrier by means of forceps.

A specific implementation of the manufacturing process according to the present invention is disclosed in detail in Example 1 .

III. therapy

In one aspect, the present invention relates to a method of treating dry eye disease (DED) in a patient in need thereof, comprising administering a sustained release biodegradable ocular (eg intracanal) implant as disclosed herein. includes

In another aspect, the present invention relates to a method of treating intermittent flares of DED in a patient in need thereof, the method comprising a sustained-release biodegradable ocular comprising a hydrogel and a hydrogel comprising a glucocorticoid (such as In) administering the implant to the patient, wherein the glucocorticoid particles are dispersed within the hydrogel.

A patient to be treated according to the present invention may be a human or animal subject in need of DED therapy, including acute DED therapy. In certain embodiments, the patient may be a subject in need of acute treatment of intermittent flares of DED.

In certain alternative embodiments, the treatment of DED can be a long-term (longer-term) treatment of DED.

In one embodiment, the present invention also relates to a sustained release biodegradable ocular (eg intracanal) implant as disclosed herein for use in treating DED in a patient in need thereof.

In one embodiment, the invention also relates to the use of a sustained release biodegradable ocular (eg intracanal) implant as disclosed herein for the manufacture of a medicament for treating DED in a patient in need thereof.

In certain embodiments, the treatment of DED is an acute, short-term treatment of DED (also referred to herein as treatment of intermittent flares of DED). The duration of acute treatment of intermittent flares of DED according to the present invention may be relatively short compared to continuous long-term (i.e., chronic) treatment of DED, and in certain embodiments up to about 1 month or about 1 month, or up to about 25 days or about 25 days, or up to 21 days or about 21 days (i.e. up to about 3 weeks or about 3 weeks), or up to about 14 days or about 14 days (i.e. up to about 2 weeks or about 2 weeks), or up to about 7 days or about 7 days (ie up to about 1 week or about 1 week). Long-term (chronic) treatment of DED can last about 1 month or more, such as several months or even more.

In certain embodiments, the sustained release biodegradable endoductal implant administered to a patient comprises dexamethasone.

In certain embodiments, the sustained release biodegradable endoductal implant administered to a patient comprises about 375 μg or less, or about 350 μg or less of dexamethasone or an equivalent dose of another glucocorticoid. An equivalent dose of another glucocorticoid can be determined as disclosed herein. In an embodiment of the present invention, a glucocorticoid such as dexamethasone is present in the insert as particles dispersed within a hydrogel formed of a polymer network as described herein.

In certain embodiments, the sustained release biodegradable endoductal implant administered to a patient comprises in the range of about 100 μg to about 350 μg of dexamethasone, or about 150 μg to about 320 μg of dexamethasone, or an equivalent dose of another glucocorticoid. do.

In certain embodiments, the sustained release biodegradable endoductal implant administered to a patient comprises about 160 μg to about 250 μg dexamethasone, or about 180 μg to about 220 μg dexamethasone, or about 200 μg dexamethasone.

In certain other embodiments, the sustained release biodegradable endoductal implant administered to a patient comprises about 240 μg to about 375 μg dexamethasone, or about 270 μg to about 330 μg dexamethasone, or about 300 μg dexamethasone.

The insert may contain additional components as disclosed herein.

Administration of the insert according to the present invention is performed through opening of the punctum into the lower and/or upper canaliculi.

In certain embodiments, upon administration to the canalicle and subsequent hydration in vivo, the sustained release biodegradable intracanalicular implant administered to the patient may increase in diameter and decrease in length as disclosed herein.

In certain embodiments, the sustained release biodegradable endoductal implant administered to a patient has a length in the dry state of about 2.75 mm or less, or about 2.5 mm or less. In certain embodiments, the sustained release biodegradable endoductal implant administered to a patient has a diameter in the dry state of less than about 1 mm, or less than about 0.75 mm. In the dry state, an insert having this diameter can be easily administered through the punctum of the eye. In certain of these embodiments, the glucocorticoid is dexamethasone.

In certain particular embodiments, the sustained-release biodegradable endoductal implant administered to a patient has a diameter in the dry state ranging from about 0.41 mm to about 0.55 mm and a length ranging from about 2.14 mm to about 2.36 mm. In certain embodiments, the sustained release biodegradable endoductal implant administered to a patient has a diameter of about 0.5 mm and a length of about 2.25 mm in the dry state. In certain embodiments, the glucocorticoid within the insert is dexamethasone and is present in the insert in an amount of about 200 μg or about 300 μg (including variations as disclosed herein).

In certain other specific embodiments, the sustained-release biodegradable endoductal implant administered to a patient has a diameter in the hydrated state ranging from about 1.35 mm to about 1.80 mm, and a length to diameter ratio greater than 1. In certain embodiments, the sustained release biodegradable endoductal implant administered to a patient has a diameter in the range of about 1.40 mm to about 1.60 mm, such as about 1.5 mm, and a length in the range of about 1.70 mm to about 2.0 mm when in a hydrated state. have In certain embodiments, the glucocorticoid within the insert is dexamethasone and is present in the insert in an amount of about 200 μg or about 300 μg (including variations as disclosed herein).

In certain embodiments, the method provides release of a glucocorticoid, such as dexamethasone, for an extended period of time of about 6 hours or more ("prolonged" as opposed to known immediate release ophthalmic dosage forms), such as a period of about 12 hours or more after administration. do. In certain embodiments, the extended period of time is one week or more after administration.

In certain embodiments, the method provides treatment with a glucocorticoid such as dexamethasone for a period of up to about 7 days, or up to about 14 days, or up to about 21 days, or up to about 25 days, or up to about 1 month after administration. Provides (acute, short-term) treatment ("short-term" as defined herein as opposed to long-term treatment of DED) of intermittent flare-ups of DED.

In certain embodiments of the methods of the present invention, the sustained release biodegradable intraductal implant administered to the patient contains about 200 μg of dexamethasone (including variations as disclosed herein) and is administered with dexamethasone for a period of up to about 14 days after administration. , such that the duration of treatment provided by the release of dexamethasone from the implant is up to about 14 days after administration. In certain embodiments, this treatment period may also be longer than about 14 days after administration.

In certain embodiments of the methods of the present invention, the sustained-release biodegradable intraductal implant administered to a patient contains about 300 μg of dexamethasone (including variations as disclosed herein) and is administered with dexamethasone for a period of up to about 21 days after administration. is released, such that the duration of treatment provided by the release of dexamethasone from the implant is up to about 21 days after administration. In certain embodiments, this treatment period can be longer than about 21 days after administration.

In certain embodiments of the methods of the present invention, the sustained-release biodegradable endoductal implant is administered to the patient for up to about 7 days, or up to about 14 days, or up to about 21 days, or up to about 25 days after administration, or It releases an average of about 15 to about 25 μg of dexamethasone per day for an extended period of time, such as up to about 1 month.

In certain of these embodiments, the sustained release biodegradable intracanalicular implant administered to a patient contains about 200 μg of dexamethasone and averages about 15 μg to about 25 μg per day for a period of up to about 7 days after administration. Releases dexamethasone. The implant may then still release dexamethasone, but at a lower rate, also referred to herein as “tapered release” (ie, may release less dexamethasone per day).

In certain other embodiments, the sustained release biodegradable endoductal implant administered to a patient contains about 300 μg of dexamethasone and averages about 15 μg to about 25 μg per day for a period of up to about 11, or up to about 14 days after administration. It releases μg of dexamethasone. Again, then, the implant may still release dexamethasone, but at a lower rate, also referred to herein as “tapered release” (i.e., may release less dexamethasone per day). .

In one embodiment of the method of the present invention, the sustained-release biodegradable intracanalicular implant administered to a patient in a method of treating DED, including intermittent flares of DED according to the present invention, comprises a hydrogel and dexamethasone particles dispersed within the hydrogel. wherein the insert contains from about 160 μg to about 250 μg or from about 180 μg to about 220 μg or about 200 μg of dexamethasone, is cylindrical or essentially cylindrical, and has a diameter in the dry state ranging from about 0.41 mm to about 0.49 mm. and a length ranging from about 2.14 mm to about 2.36 mm, having a diameter in the hydrated state of from about 1.35 mm to about 1.80 mm and a ratio of length to diameter greater than 1, up to 14 days, or up to about 21 days after administration release dexamethasone over a period of In this embodiment, the hydrogel comprises a polymer network, wherein the polymer network comprises 4a20kPEG units and is formed by reacting trilysine or trilysine with a 4a20kPEG-SG precursor as a crosslinking agent. In this embodiment, the insert further comprises a visualizing agent such as fluorescein. Also in this embodiment, the insert is comprised of about 40% to about 46% dexamethasone and about 45% to about 55% polyethylene glycol units by weight in the dry state. The insert may also contain up to about 1% water by weight in the dry state. The duration of treatment with this implant can be up to about 14 days or about 14 days (ie about 2 weeks).

In another embodiment of the method of the present invention, the sustained-release biodegradable intraductal insert administered to a patient in the method of treating DED including intermittent flare-ups of DED according to the present invention comprises a hydrogel and dexamethasone particles dispersed within the hydrogel. wherein the insert contains from about 240 μg to about 375 μg or from about 270 μg to about 330 μg or about 300 μg of dexamethasone, is cylindrical or essentially cylindrical, and in the dry state ranges from about 0.44 mm to about 0.55 mm. a diameter and a length ranging from about 2.14 mm to about 2.36 mm, and having a diameter in the hydrated state ranging from about 1.35 mm to about 1.80 mm and a length to diameter ratio greater than 1, up to about 21 days after administration, or up to about 21 days after administration It releases dexamethasone for a period of about 25 days, or up to about 1 month. In this embodiment, the hydrogel comprises a polymer network, wherein the polymer network comprises 4a20kPEG units and is formed by reacting a 4a20kPEG-SG precursor with trilysine acetate or a derivative as a crosslinking agent. In this embodiment, the insert further comprises a visualizing agent such as fluorescein. Also in this embodiment, the insert is comprised of about 50% to about 56% dexamethasone and about 36% to about 46% polyethylene glycol units by weight in the dry state. Additionally, the insert may contain less than about 1% water by weight in the dry state. The duration of treatment with this implant can be up to about 21 days or about 21 days (ie about 3 weeks).

In another embodiment of the methods of the present invention, the sustained release biodegradable intraductal implant administered to the patient is administered in a dose of up to about 375 μg of dexamethasone (as described hereinbelow) or an equivalent dose contained in the insert of another When defined as another glucocorticoid, and/or about 2.75 mm or less in length (as disclosed hereinbelow), the insert may be used for at least about 25 days after administration, such as up to about 1 month or even longer than treatment It is capable of releasing a scientifically effective amount of glucocorticoid.

To achieve an extended delivery time, such as a period of up to about 7 days, or up to about 14 days, or up to about 21 days, or up to about 25 days, or up to about 1 month, or in certain embodiments, a longer period after administration. Patient compliance is increased compared to the use of eye drops that must be administered daily or even multiple times a day, since only one single implant (or in certain exceptional embodiments, several implants at the same time) needs to be administered to the patient for the same purpose.

In certain embodiments, the insert is administered unilaterally or bilaterally through the lower punctum to the lower canaliculus. In another embodiment, the insert is administered unilaterally or bilaterally through the upper punctum to the upper canaliculus. In certain embodiments, the insert is administered both through the lower punctum to the lower canaliculus and through the superior punctum to the upper canaliculus. The specific dosage per eye can be independent of each other.

In certain embodiments, the insert is administered to the lower vertical canaliculus and/or upper vertical canaliculus.

In certain embodiments, the sustained-release biodegradable endoductal implant includes a visualization agent, such as fluorescein, that allows rapid, non-invasive visualization of the implant when placed inside the canaliculus. If the visualizer is fluorescein, the insert can be visualized using a blue light source and a yellow filter.

In certain embodiments, a glucocorticoid such as dexamethasone is delivered through the tear film to the ocular surface as the glucocorticoid dissolves in the tear film when released from the insert. Glucocorticoids are mainly released at the proximal end of the implant at the interface between the hydrogel and the lacrimal fluid (as shown by way of example in FIG. 6 ). The rate of sustained glucocorticoid release is controlled by the hydrogel matrix and the solubility of glucocorticoids in the lacrimal fluid. In certain embodiments, the glucocorticoid is dexamethasone, which has low solubility in aqueous media as disclosed herein.

In certain embodiments, the insert remains in the canaliculus after complete depletion of the glucocorticoid, such as dexamethasone, from the insert until the hydrogel is biodegraded and/or processed (washed out/removed) through the nasolacrimal duct. Because the hydrogel matrix of the insert is formulated to biodegrade, for example, through ester hydrolysis in the aqueous environment of the canalicular lacrimal fluid, the insert softens and liquefies over time and is removed through the nasolacrimal canal without the need for removal. Thus, unpleasant removal can be avoided. However, if the implant has to be removed, for example because of a potential allergic reaction or other circumstances requiring removal of the implant, such as an unpleasant foreign body sensation felt by the patient, or because treatment has to be terminated for other reasons, the implant must be removed for example. It can be manually ejected from the canal.

In certain embodiments, the insert remains in the canal for up to about 1 month, or up to about 2 months, or up to about 3 months, or up to about 4 months after administration.

In certain embodiments, systemic concentrations of glucocorticoids such as dexamethasone following administration of an insert of the present invention are very low, eg, less than quantifiable amounts. This can significantly reduce the risk of drug-to-drug interactions or systemic toxicity, which can be beneficial, for example, to elderly patients who frequently suffer from eye disease and take other medications in addition.

In certain embodiments, the sustained-release biodegradable endoductal implant of the present invention is administered to a patient for the treatment of the signs and symptoms of dry eye disease (DED), particularly for the acute treatment of DED, for example in intermittent flares. In certain embodiments, the insert of the present invention combines the benefits derived from lacrimal duct occlusion with the anti-inflammatory effect of glucocorticoid release, such as dexamethasone release. These combined effects may provide improved treatment of DED.

In certain embodiments, treatment of DED with the sustained-release biodegradable endoductal implant of the present invention may be combined with or subsequent to another treatment of DED. In certain embodiments, treatment of DED with the sustained-release biodegradable endoductal implant is combined with or subsequent to chronic treatment of DED, eg, with cyclosporine, lipitegrast, or tacrolimus. In certain other embodiments, treatment of DED with the sustained-release biodegradable endoprosthesis is combined with or subsequent to treatment with eye drops such as artificial tears.

In certain embodiments, the implant is a contact lens because the implant is located in the canaliculus and therefore not on the surface of the eye and requires only a single administration to provide release of the glucocorticoid for an extended period of time as disclosed herein. do not interfere or substantially interfere with the contact lens, and thus may be particularly suitable and convenient for patients wearing contact lenses.

A patient treated with an implant of the present invention can be any person in need of treatment. The patient may be male or female. In certain embodiments the patient is a female. In certain embodiments, the age of the patient is greater than 50 years, or greater than 60 years, or greater than 70 years, or greater than 80 years. In certain embodiments, the patient may have undergone laser surgery of the eye, such as photorefractive keratectomy (PRK) or Laser-in-situ-Keratomileusis (LASIK) or any particular type thereof.

In certain embodiments, a patient treated with an implant of the present invention is receiving artificial tears and/or other palliative treatment and experiences intermittent DED flare-ups.

In certain embodiments, the patient requires induction therapy while initiating treatment for DED. Pre-treatment with the sustained-release biodegradable endoductal implant according to the present invention prior to initiation of long-term therapy for DED can lead to a faster resolution of the signs and symptoms of DED, and can lead to faster resolution of the signs and symptoms of DED by active ingredients for the treatment of DED, such as cyclosporine. Reduction of side effects such as induced burning sensation or stinging may be induced. The pre-treatment period with an insert according to the present invention may last for example up to about 7 days, or up to about 14 days, or up to about 21 days, or in certain embodiments up to about 1 month before initiating long-term therapy. .

In certain embodiments, a patient treated with an implant of the present invention is undergoing chronic DED treatment, for example with cyclosporine or lipitegrast, and experiences intermittent flares of DED that can be treated with an implant according to the present invention.

In certain embodiments, patients treated with the implants of the present invention require DED treatment prior to cataract and refractive surgery to improve the outcome/satisfaction of such surgery.

In certain embodiments, patients treated with the implants of the present invention require short-term treatment of the signs and symptoms of DED following cataract or refractive surgery.

In certain embodiments, treatment of DED with an implant disclosed herein is combined with application of artificial tears and/or eye drops and/or nasal neurostimulation devices. The co-administered artificial tears and/or eye drops and/or nasal neurostimulation device may include an anti-infective component. In certain embodiments, the co-administered eye drops may include a glucocorticoid other than the glucocorticoid (eg dexamethasone) of the administered insert. In certain embodiments, the co-administered eye drops may contain the same glucocorticoid (such as dexamethasone) contained in the administered insert. Pharmacological products suitable for co-administration include Restasis ^® and Cequa ^® (eye drops containing cyclosporine), Xiidra ^® (eye drops containing the lymphocyte function-associated antigen 1 (LFA-1) antagonist lipitegrast), and TrueTear ^® (nasal nerve stimulation devices that temporarily increase tear production). In certain embodiments, which may be combined with any of the embodiments in this paragraph, the treatment of DED with the sustained-release biodegradable endoprosthesis can include eyelash line (BlephEx ^® ), eyelid heat pulse ( ^iLux® ), and eyelid warming. and combined with eyelid exfoliation in stimulation (LipiFlow ^® ).

In certain embodiments of the present invention, while the first sustained-release biodegradable endoductal insert is still retained in the canaliculus (this procedure is referred to as "insert stacking" or abbreviated "stacking"), the first insert contains a glucocorticoid while still releasing, or after complete depletion of the glucocorticoid, or after the first insert is partially depleted of the glucocorticoid by at least about 70%, or at least about 80%, or at least about 90%, and/or after the first insert A further sustained-release biodegradable endoprosthesis is administered into the canaliculus through the punctum of the eye while the insert releases a lower amount of glucocorticoid than the initial one after administration.

In certain embodiments, implant stacking enables long-term treatment with glucocorticoids such as dexamethasone. In certain embodiments, the insert stacking thus results in a therapeutically effective amount for a total period of up to about 14 days, or up to about 28 days, or up to about 42 days, or up to about 50 days, or up to about 2 months after administration of the first insert. of glucocorticoids.

IV. kit

In certain embodiments, the invention further relates to a kit comprising one or more insert(s) disclosed herein or made according to a method as disclosed herein.

In certain specific embodiments, the kit comprises one or more sustained release biodegradable intraductal implant(s), wherein each insert contains between about 160 μg and about 250 μg or between about 180 μg and about 220 μg or about 200 μg of dexamethasone. and has a diameter in the dry state ranging from about 0.41 mm to about 0.49 mm and a length ranging from about 2.14 mm to about 2.36 mm, and a diameter in the hydrated state ranging from about 1.35 mm to about 1.80 mm and a diameter greater than 1 length to ratio, wherein each insert provides release of dexamethasone for a period of up to about 14 days, or up to about 21 days after administration.

In certain other specific embodiments, the kit comprises one or more sustained-release biodegradable intraductal insert(s), wherein each insert contains between about 240 μg and about 375 μg or between about 270 μg and about 330 μg or about 300 μg. dexamethasone, having a diameter in the dry state ranging from about 0.44 mm to about 0.55 mm and a length ranging from about 2.14 mm to about 2.36 mm, and a diameter in the hydrated state ranging from about 1.35 mm to about 1.80 mm and a diameter greater than 1 , where each implant provides release of dexamethasone for a period of up to about 21 days, or up to about 1 month after administration.

In certain embodiments, the kit further includes instructions for using the one or more sustained-release biodegradable endoductal implant(s). Instructions for using the one or more sustained-release biodegradable endoductal implant(s) may be in the form of an operating manual for a physician administering the implant(s). The kit may further include a package insert containing product-related information.

In certain embodiments, the kit may further comprise one or more means for administration of one or more sustained-release biodegradable intraductal implant(s). The means for administration may be one or more suitable tweezers(s) or forceps, eg for single use or repeated use. For example, suitable forceps are blunt (without teeth). The means for administration may also be an injection device such as a syringe or applicator system.

In certain embodiments, the kit further comprises an ophthalmic dilator to dilate the punctum prior to administration of the one or more sustained-release biodegradable endoductal insert(s) to facilitate insertion of the insert(s) through the punctum into the canaliculus. can do. The dilator may also be combined/integrated with forceps or an applicator such that one end of the device is the dilator and the other end of the device is suitable for administering the implant. Alternatively, the kit may include a modified applicator with a tapered tip that can be used for both dilation and insertion.

In certain embodiments, one or more sustained-release biodegradable endoductal implant(s) are individually packaged for single administration. In certain embodiments, one or more sustained release biodegradable intraductal insert(s) are individually packaged for single administration by securing each insert to a foam carrier sealed in a foil pouch. The foam carrier may, for example, have a circular cutout or V-notch with an opening at the bottom of the V-notch to secure an insert (eg, see FIG. 1 ).

If two or more sustained-release biodegradable endoductal inserts are included in the kit, these inserts may be the same or different and may contain the same or different doses of a glucocorticoid such as dexamethasone.

In addition to the above disclosure, the following other embodiments are also disclosed herein:

First list of implementations:

One. A method of treating dry eye syndrome in a subject in need thereof, comprising administering to the subject a biodegradable ocular hydrogel composition comprising a therapeutically effective amount of a corticosteroid for a period of at least about 12 hours.

2. The method of embodiment 1, wherein the polymer network comprises a plurality of polyethylene glycol (PEG) units.

3. The method of embodiment 1 or 2, wherein the polymer network comprises a plurality of multi-arm PEG units having 2 to 10 arms.

4. The method of any one of embodiments 1-3, wherein the polymer network comprises a plurality of multi-arm PEG units having 4-10 arms.

5. The method of any one of embodiments 1-4, wherein the polymer network comprises a plurality of multi-arm PEG units having 4-8 arms.

6. The method of any one of embodiments 1-5, wherein the polymer network comprises a plurality of multi-arm PEG units having 8 arms.

7. The method of any one of embodiments 1-5, wherein the polymer network comprises a plurality of multi-arm PEG units having four arms.

8. The method of any one of embodiments 1-5, wherein the polymer network comprises a plurality of PEG units having the formula:

In the formula, n represents an ethylene oxide repeating unit, and the dotted line represents the repeating unit point of the polymer network.

9. The method according to any one of embodiments 1 to 8, wherein the polymer network is from 4a20k PEG-SAZ, 4a20kPEG-SAP, 4a20kPEG-SG, 4a20kPEG-SS, 8a20kPEG-SAZ, 8a20kPEG-SAP, 8a20kPEG-SG, 8a20kPEG-SS formed by reaction of a selected plurality of polyethylene glycol (PEG) units with one or more PEGs or lysine based-amine groups selected from 4a20kPEG-NH ₂ , 8a20kPEG-NH ₂ , and trilysine, or salts thereof.

10. The method according to any one of embodiments 1 to 9, wherein the polymer network is formed by reaction of 4a20kPEG-SG with trilysine or a salt thereof.

11. The method of any of embodiments 1-10, wherein the polymer network is amorphous under aqueous conditions.

12. The method of any one of embodiments 1-11, wherein the polymer network is semi-crystalline in the absence of water.

13. The method of any one of embodiments 1-12, wherein the corticosteroid is dexamethasone.

14. The method of any one of embodiments 1-12, wherein the corticosteroid is dexamethasone formulated for delivery at a dosage of about 0.2 mg to about 0.3 mg.

15. The method of any one of embodiments 1-14, wherein the hydrogel composition is an endoductal insert.

16. The method of any one of embodiments 1-15, wherein the hydrogel composition is an endoductal insert having a length of about 1.0 mm to about 3.0 mm.

17. The method of any one of embodiments 1-16, wherein the hydrogel composition is completely degraded after release of the corticosteroid.

18. The method of any one of embodiments 1-17, wherein intermittent flare-ups of dry eye disease are treated.

19. An intracanal implant for the treatment of dry eye syndrome, wherein the intraductal implant occludes a punctum and delivers a therapeutically effective amount of a steroid for up to 3 weeks.

20. The intracanalicular implant of embodiment 19, wherein the intraductal implant delivers a therapeutically effective amount of a steroid for up to 2 weeks.

21. The endoductal implant of embodiment 19 or 20, wherein the steroid is dexamethasone.

22. The intraductal insert of any one of embodiments 19-21, wherein the steroid is dexamethasone formulated for delivery at a dosage of about 0.2 mg to about 0.3 mg.

23. The method of any one of embodiments 19-22, wherein the endoductal insert has a length of about 1.0 mm to about 3.0 mm.

24. The endoductal insert of any one of embodiments 19-23, wherein the endoductal insert is biodegradable.

25. The endoductal insert of any one of embodiments 19-24, wherein the endoductal insert comprises a hydrogel comprising a polymer network having a plurality of polyethylene glycol (PEG) units.

26. The endoductal insert of embodiment 25, wherein the polymeric network comprises a plurality of multi-arm PEG units having 2 to 10 arms.

27. The endoductal insert of embodiment 25 or 26, wherein the polymeric network comprises a plurality of multi-arm PEG units having 4 to 10 arms.

28. The endoductal insert of any one of embodiments 25-27, wherein the polymeric network comprises a plurality of multi-arm PEG units having 4 to 8 arms.

29. The endoductal insert of any one of embodiments 25-28, wherein the polymer network comprises a plurality of multi-arm PEG units having 8 arms.

30. The endoductal insert of any one of embodiments 25-29, wherein the polymeric network comprises a plurality of multi-arm PEG units having four arms.

31. The intraductal insert of any one of embodiments 25-30, wherein the polymer network comprises a plurality of PEG units having the formula:

In the formula, n represents an ethylene oxide repeating unit, and the dotted line represents the repeating unit point of the polymer network.

32. The method according to any one of embodiments 25 to 31, wherein the polymer network is from 4a20k PEG-SAZ, 4a20kPEG-SAP, 4a20kPEG-SG, 4a20kPEG-SS, 8a20kPEG-SAZ, 8a20kPEG-SAP, 8a20kPEG-SG, 8a20kPEG-SS An intraductal insert formed by reaction of a selected plurality of polyethylene glycol (PEG) units with one or more PEG or lysine based-amine groups selected from 4a20kPEG-NH ₂ , 8a20kPEG-NH ₂ , and trilysine, or salts thereof.

33. The endoductal insert according to any one of embodiments 25 to 32, wherein the polymer network is formed by reaction of 4a20kPEG-SG with trilysine or a salt thereof.

34. The endoductal insert of any one of embodiments 25-33, wherein the polymer network is amorphous under aqueous conditions.

35. The endoductal insert of any one of embodiments 25-34, wherein the polymer network is semi-crystalline in the absence of water.

36. The endoductal implant of any one of embodiments 25-35, wherein the hydrogel completely degrades after release of the steroid.

Second list of implementations:

One. A sustained-release, biodegradable endoductal implant comprising a hydrogel and up to about 375 μg of dexamethasone or an equivalent dose of another glucocorticoid.

2. A sustained-release biodegradable endoductal implant comprising a hydrogel and a glucocorticoid, wherein the implant has an average length of about 2.75 mm or less in a dry state.

3. A sustained-release biodegradable intraductal implant comprising a hydrogel and a glucocorticoid, wherein the implant provides release of a therapeutically effective amount of a glucocorticoid for a period of up to about 25 days after administration. .

4. The method according to any one of embodiments 1 to 3 comprising dexamethasone as the glucocorticoid. Sustained-release biodegradable endoductal implant.

5. The sustained-release biodegradable endothelial implant of any one of embodiments 2, 3 or 4 comprising no more than about 375 μg of dexamethasone.

6. The sustained-release, biodegradable endoductal implant of any one of embodiments 1-5, comprising no more than about 350 μg of dexamethasone.

7. The sustained release biodegradable endothelial implant of embodiment 6 comprising about 100 μg to about 350 μg of dexamethasone, or about 150 μg to about 320 μg of dexamethasone.

8. The sustained-release, biodegradable endoductal implant of embodiment 5 comprising about 160 μg to about 250 μg of dexamethasone.

9. The sustained-release biodegradable endoductal implant of embodiment 8 comprising about 180 μg to about 220 μg of dexamethasone.

10. The sustained-release biodegradable endoductal implant of embodiment 9 comprising about 200 μg of dexamethasone.

11. The sustained-release biodegradable endoductal implant of embodiment 5 comprising about 240 μg to about 375 μg of dexamethasone.

12. The sustained release biodegradable endothelial implant of embodiment 11 comprising about 270 μg to about 330 μg of dexamethasone.

13. The sustained-release biodegradable endoductal implant of embodiment 12 comprising about 300 μg of dexamethasone.

14. The sustained-release biodegradable endoductal implant according to any one of embodiments 1 to 13, wherein the glucocorticoid particles are homogeneously dispersed within the hydrogel.

15. The sustained-release biodegradable endoductal implant according to embodiment 14, wherein the glucocorticoid particles are micronized particles.

16. The method of embodiment 15, wherein the glucocorticoid particles are micronized dexamethasone particles having a d90 particle size of less than about 100 μm, or less than about 75 μm, or less than about 50 μm, or less than about 20 μm, or less than about 10 μm , Sustained-release biodegradable endoductal implants.

17. The sustained-release biodegradable endoductal insert of any one of embodiments 1-16, wherein the insert is in a dry state prior to administration and is hydrated upon administration into the canalicle.

18. The method according to any one of embodiments 1 to 17, wherein the hydrogel is polyethylene glycol, polyethylene oxide, polypropylene oxide, polyvinyl alcohol, poly (vinylpyrrolidinone), polylactic acid, polylactic-co-glycolic acid, random or long-lasting, comprising a polymer network comprising one or more crosslinked polymer units of a block copolymer or a combination or mixture of any one of them, or one or more units of a polyamino acid, glycosaminoglycan, polysaccharide, or protein. Releaseable biodegradable endoductal implants.

19. The method of embodiment 18, wherein the polymer network comprises one or more crosslinked polyethylene glycol units having an average molecular weight ranging from about 2,000 to about 100,000 Daltons, or from about 10,000 to about 60,000 Daltons, or from about 15,000 to about 50,000 Daltons, Sustained-release biodegradable endoductal implant.

20. The sustained-release biodegradable endothelial implant of embodiment 19, wherein the polyethylene glycol unit has an average molecular weight of about 20,000 Daltons.

21. The sustained release biodegradable according to any one of embodiments 18 to 20, wherein the polymer network comprises one or more cross-linked 2- to 10-arm polyethylene glycol units, or one or more 4- to 8-arm polyethylene glycol units. Sexual canalicular implants.

22. The sustained release biodegradable endothelial implant of embodiment 21, wherein the polymer network comprises 4-armed polyethylene glycol units.

23. The sustained release biodegradable endotoxin according to any one of embodiments 18 to 22, wherein the polymer network is formed by reacting an electrophilic group-containing multi-arm-polymer precursor with a nucleophilic group-containing crosslinking agent.

24. The sustained-release biodegradable endotube according to embodiment 23, wherein the nucleophilic group is an amine group and the electrophilic group is an activated ester group.

25. The sustained-release biodegradable endodontoblast of embodiment 24, wherein the electrophilic group-containing multi-arm-polymer precursor is 4a20kPEG-SG and the crosslinker is trilysine acetate.

26. The sustained release biodegradable endothelial implant according to any one of embodiments 1 to 25, which contains a visualizing agent.

27. The sustained-release biodegradable endoductal implant of embodiment 26, wherein the visualizing agent is a fluorophore.

28. The sustained-release biodegradable endoductal implant according to embodiment 27, wherein the visualization agent is fluorescein.

29. The sustained release biodegradable material of any one of the foregoing embodiments, wherein the insert contains from about 40% to about 56% glucocorticoid and from about 36% to about 55% polymer units by weight in the dry state. Endoductal implants.

30. 29. The sustained release biodegradable endoductal implant of embodiment 29, wherein the insert contains from about 40% to about 46% dexamethasone and from about 45% to about 55% polyethylene glycol units by weight in the dry state.

31. 29. The sustained release biodegradable endoprosthesis of embodiment 29, wherein the insert contains from about 50% to about 56% dexamethasone and from about 36% to about 46% polyethylene glycol units by weight in the dry state.

32. The sustained-release biodegradable endoductal implant of any one of embodiments 26-31, wherein the insert contains from about 0.1% to about 1% by weight of a visualizer in the dry state.

33. The sustained-release biodegradable endodonteal implant of any one of embodiments 1-32, wherein the insert contains one or more phosphate, borate, and carbonate salt(s) in the dry state.

34. The sustained-release biodegradable endoductal implant of embodiment 33, wherein the insert contains from about 0.5% to about 5% by weight of one or more phosphate salt(s).

35. The sustained-release biodegradable endoductal implant of any one of the preceding embodiments, wherein the insert contains less than about 1% water by weight in a dry state.

36. The sustained-release biodegradable endoductal implant of any one of embodiments 1-35, wherein the insert is free or substantially free of an anti-microbial preservative.

37. The sustained-release biodegradable endothelial implant according to any one of the preceding embodiments, wherein the implant has an essentially cylindrical shape.

38. The sustained-release biodegradable endoductal insert of any one of embodiments 1 or 3-37, wherein the insert has an average length in the dry state of less than about 3 mm.

39. The sustained-release biodegradable endoductal implant of embodiment 38, wherein the implant has an average length of less than or equal to about 2.75 mm.

40. The sustained-release biodegradable endoductal insert of embodiment 2 or 39, wherein the insert has an average length in the dry state of less than or equal to about 2.5 mm.

41. The sustained-release biodegradable endoductal implant of any one of the foregoing embodiments, wherein the insert has an average diameter of less than about 1 mm, or an average diameter of less than about 0.75 mm in the dry state.

42. The sustained release biodegradable intraductal cavity of any one of embodiments 1-41, wherein the insert has an average length in the dry state ranging from about 2.14 mm to about 2.36 mm and an average diameter ranging from about 0.41 mm to about 0.55 mm. insertion.

43. The sustained-release biodegradable endoductal implant of embodiment 42, wherein the insert has an average length of about 2.25 mm and an average diameter of about 0.5 mm in the dry state.

44. The sustained-release biodegradable endotoxal implant of any one of the foregoing embodiments, wherein upon in vivo or in vitro hydration in the canaliculus, the average diameter of the implant increases and optionally the average length of the implant decreases.

45. The sustained release biodegradable endoductal insert according to embodiment 44, wherein in vitro hydration is measured in phosphate buffered saline at pH 7.4 at 37° C. after 24 hours.

46. 45. The sustained-release biodegradable endoductal implant of embodiment 44 or 45, wherein upon hydration the average diameter of the implant increases by a factor in the range of about 1.5 to about 4, or in the range of about 2 to about 3.5.

47. The sustained-release biodegradable endoductal implant of embodiment 46, wherein upon hydration the average diameter of the implant increases by a factor of about 3.

48. The sustained release form of any one of embodiments 44-47, wherein upon hydration the average length of the insert decreases to less than or equal to about 0.9 times the average length in the dry state, or less than or equal to about 0.75 times the average length in the dry state. Biodegradable endoductal implants.

49. The sustained release biodegradable endoductal implant of embodiment 48, wherein the average length of the implant upon hydration is reduced to about 2/3 of its average length in a dry state.

50. The method of any one of embodiments 1-49, wherein the insert has an average diameter ranging from about 1 mm to about 2 mm in a hydrated state and an average length less than the average length of the insert in a dry state. Sexual canalicular implants.

51. 50. The sustained release biodegradable endoductal insert of embodiment 50, wherein the insert has an average diameter in the hydrated state ranging from about 1.35 mm to about 1.80 mm and a length to diameter ratio of greater than 1.

52. 51. The sustained release biodegradable endoductal implant of embodiment 51, wherein the insert has an average diameter in the hydrated state ranging from about 1.40 mm to about 1.60 mm and an average length from about 1.70 mm to about 2.0 mm.

53. The sustained-release biodegradable endoductal implant of any one of the preceding embodiments, wherein the insert provides release of a therapeutically effective amount of glucocorticoid for a period of about 6 hours or longer after administration.

54. The sustained-release biodegradable endoductal implant of embodiment 53, wherein the insert provides release of a therapeutically effective amount of glucocorticoid for a period of at least about 12 hours after administration.

55. The method of any one of embodiments 1, 2, or 4-54, wherein the insert provides a therapeutically effective amount of a glucocorticoid for up to about 14 days, or up to about 21 days, or up to about 25 days, or up to about 1 month after administration. Sustained-release biodegradable endoductal implants that provide release.

56. The sustained release biodegradable tubule of embodiment 3 or 55, wherein the insert provides release of a therapeutically effective amount of glucocorticoid for a period of up to about 14 days, or up to about 21 days, or up to about 25 days after administration. my insert.

57. The sustained release biodegradable intracanalicular implant of any one of embodiments 1-56, wherein the insert contains about 200 μg of dexamethasone and provides release of dexamethasone for a period of up to about 14 days after administration.

58. The sustained release biodegradable intracanalicular implant of any one of embodiments 1-57, wherein the insert contains about 300 μg of dexamethasone and provides release of dexamethasone for a period of up to about 21 days after administration.

59. The method of any one of embodiments 1-58, wherein the insert produces an average release of from about 15 μg to about 25 μg of dexamethasone per day for a period of up to about 7 days, or up to about 14 days, or up to about 21 days after administration. Provided, a sustained-release biodegradable intraductal insert.

60. The method of any one of embodiments 1 to 57, wherein the insert contains about 200 μg of dexamethasone and provides an average release of about 15 μg to about 25 μg of dexamethasone per day for a period of up to about 7 days after administration. Sustained-release biodegradable endoductal implant.

61. The method of any one of embodiments 1-56 or 58, wherein the insert contains about 300 μg of dexamethasone and about 15 μg to about 25 μg of dexamethasone per day for a period of up to about 11 days, or up to about 14 days after administration. A sustained-release biodegradable intracanalicular implant that provides an average release of

62. The method of any one of the foregoing embodiments, wherein after complete depletion of glucocorticoids from the insert, the hydrogel biodegrades in the canaliculus and/or within about 1 month, or within about 2 months, or within about 3 months of administration, or a sustained-release, biodegradable endoductal implant that is removed through the nasolacrimal tract within about 4 months.

63. The sustained-release biodegradable endoductal implant of any one of embodiments 1-61, wherein the hydrogel is biodegraded prior to complete depletion of glucocorticoid from the implant.

64. A sustained release biodegradable intracanalicular implant comprising a hydrogel and dexamethasone particles dispersed within the hydrogel, wherein the insert contains about 160 μg to about 250 μg or about 180 μg to about 220 μg or about 200 μg of dexamethasone , having an average diameter in a dry state ranging from about 0.41 mm to about 0.49 mm and an average length ranging from about 2.14 mm to about 2.36 mm, and in a hydrated state having an average diameter ranging from about 1.35 mm to about 1.80 mm and a diameter greater than 1 wherein the insert provides release of dexamethasone for a period of up to about 14 days, or up to about 21 days after administration.

65. A sustained release biodegradable intraductal implant comprising a hydrogel and dexamethasone particles dispersed within the hydrogel, wherein the insert contains between about 240 μg and about 375 μg or between about 270 μg and about 330 μg or about 300 μg of dexamethasone; , in the dry state, having an average diameter ranging from about 0.44 mm to about 0.55 mm and an average length ranging from about 2.14 mm to about 2.36 mm, and having an average diameter ranging from about 1.35 mm to about 1.80 mm and a length for diameters greater than 1 wherein the implant provides release of dexamethasone for a period of up to about 21 days, or up to about 1 month after administration.

66. The sustained-release biodegradable endothelial implant of embodiment 64 or 65, wherein the hydrogel comprises a polymer network comprising units of cross-linked multi-arm polyethylene glycol and a visualizer.

67. The sustained-release biodegradable endothelial implant of any one of embodiments 64-66, wherein the polymer network comprises 4a20kPEG-SG units crosslinked with trilysine acetate.

68. The sustained-release biodegradable endothelial implant according to any one of embodiments 64 to 67, wherein the visualizing agent is fluorescein.

69. A method for preparing a sustained-release biodegradable intracanalicular implant according to any one of embodiments 1 to 68, the method comprising forming a hydrogel comprising glucocorticoid particles dispersed in a polymer network and a hydrogel, the hydrogel A method comprising shaping, and drying the hydrogel.

70. The method of embodiment 69, wherein the glucocorticoid is dexamethasone.

71. The method of embodiment 69 or 70, wherein the glucocorticoid particles are homogeneously dispersed within the hydrogel.

72. The method of any one of embodiments 69-71, wherein the glucocorticoid particles are micronized particles.

73. The method of embodiment 71 or 72, wherein the glucocorticoid particles are micronized dexamethasone having a d90 particle size of less than about 100 μm, or less than about 75 μm, or less than about 50 μm, or less than about 20 μm, or less than about 10 μm particles and homogeneously dispersed within the hydrogel.

74. The method of any one of embodiments 69 to 73, wherein about 375 μg or less, or about 350 μg or less, or about 100 μg to about 350 μg, or about 150 μg to about 320 μg of dexamethasone is contained in the insert. .

75. The method of embodiment 74, wherein about 160 μg to about 250 μg of dexamethasone, or about 180 μg to about 220 μg of dexamethasone, or about 200 μg of dexamethasone is contained in the insert.

76. The method of embodiment 74, wherein about 240 μg to about 375 μg of dexamethasone, or about 270 μg to about 330 μg of dexamethasone, or about 300 μg of dexamethasone is contained in the insert.

77. The method according to any one of embodiments 69 to 76, wherein the polymer network is polyethylene glycol, polyethylene oxide, polypropylene oxide, polyvinyl alcohol, poly (vinylpyrrolidinone), polylactic acid, polylactic-co-glycolic acid, random or A method formed from one or more crosslinked polymeric units of a block copolymer or a combination or mixture of any of them, or one or more units of a polyamino acid, glycosaminoglycan, polysaccharide, or protein.

78. The method of any of embodiments 69-77, wherein the polymer network is formed by crosslinking multi-arm polyethylene glycol units in a buffered solution.

79. The method of embodiment 78, wherein the polymer network is formed by mixing and reacting an electrophilic group-containing multi-arm polyethylene glycol with a nucleophilic group-containing crosslinking agent in a buffered solution in the presence of dexamethasone, and gelling the mixture. method.

80. The method of Embodiment 79, wherein the crosslinker contains an amine group.

81. The method of embodiment 79 or 80, wherein the electrophilic group-containing multi-arm-polymer precursor is 4a20kPEG-SG and the crosslinker is trilysine acetate.

82. The method of any of embodiments 69-81 comprising mixing a visualizer.

83. The method of embodiment 82 comprising conjugating the visualizer with the polymer network.

84. The method of embodiment 83 comprising conjugating the visualization agent with the crosslinking agent prior to crosslinking the polymer precursor.

85. The method of any one of embodiments 82-84, wherein the visualizing agent is a fluorophore.

86. The method of embodiment 85, wherein the visualization agent is fluorescein.

87. The method of embodiment 86, wherein the fluorescein is conjugated to the trilysine acetate prior to the crosslinking reaction.

88. The method of any one of embodiments 81-87, wherein the molar ratio of 4a20kPEG-SG to trilysine acetate is from about 1:2 to about 2:1.

89. The method of any one of embodiments 79-88, wherein the method comprises filling a mold or tubing prior to complete gelation of the hydrogel, allowing the mixture to gel, and drying the hydrogel.

90. The method of embodiment 89, wherein the mixture is packed into fine diameter tubing to make a hydrogel strand.

91. The method of Embodiment 90, wherein the interior of the tubing has a circular geometry.

92. The method of embodiment 90 or 91, wherein the method further comprises stretching the hydrogel strands.

93. The method of embodiment 92, wherein stretching the hydrogel strands is performed prior to drying the hydrogel strands.

94. The method of embodiment 93, wherein the hydrogel strand is stretched by a draw factor in the range of about 1.5 to about 3, or in the range of about 2.2 to about 2.8, or in the range of about 2.5 to about 2.6.

95. The method of any one of embodiments 90-94, wherein the dry hydrogel strands are cut into segments having an average length of about 2.75 mm or less.

96. The method of embodiment 95, wherein the dry hydrogel strands are cut into segments having an average length of about 2.5 mm or less.

97. The method of embodiment 96, wherein the hydrogel strands are cut into segments with an average length of about 2.25 mm.

98. A method of treating dry eye disease in a patient in need thereof, the method comprising a sustained-release biodegradable intracanalicular implant prepared according to any one of embodiments 1 to 68 or prepared according to any one of embodiments 69 to 97. comprising administering to the patient.

99. The method of embodiment 98, wherein the treatment is an acute treatment of dry eye disease.

100. The method of embodiment 98 or 99, wherein the treatment is an acute treatment of intermittent flares of dry eye disease.

101. The method according to any one of embodiments 98 to 100, wherein the insert is administered to the lower canaliculus and/or upper canaliculus.

102. The method of any one of embodiments 98-100, wherein the insert is administered to the vertical canaliculus.

103. The method of any one of embodiments 98-102, wherein the insert is administered bilaterally.

104. The method of any one of embodiments 98-103, wherein the glucocorticoid is delivered to the ocular surface through the tear film.

105. The method of any one of embodiments 98-104, wherein the insert contains a dose of dexamethasone of about 375 μg or less or an equivalent dose of another glucocorticoid.

106. The method of embodiment 105, wherein the insert contains a dose of about 350 μg or less of dexamethasone or an equivalent dose of another glucocorticoid.

107. The method of any one of embodiments 98-106, wherein the insert contains dexamethasone.

108. The method of embodiment 107, which contains from about 100 μg to about 350 μg of dexamethasone.

109. The method of embodiment 105, wherein the insert contains about 160 μg to about 250 μg dexamethasone, or about 180 μg to about 220 μg dexamethasone, or about 200 μg dexamethasone.

110. The method of embodiment 105, wherein the insert contains about 240 μg to about 375 μg dexamethasone, or about 270 μg to about 330 μg dexamethasone, or about 300 μg dexamethasone.

111. The method of any one of embodiments 98-110, wherein the insert releases a therapeutically effective amount of dexamethasone for a period of at least about 6 hours after administration.

112. The method of embodiment 111, wherein the insert releases a therapeutically effective amount of dexamethasone for a period of at least about 12 hours after administration.

113. The method of any one of embodiments 98 to 112, wherein the insert is administered in a therapeutically effective amount for a period of up to about 7 days, or up to about 14 days, or up to about 21 days, or up to about 25 days, or up to about 1 month. A method of releasing dexamethasone.

114. The method of embodiment 113, wherein the insert contains about 200 μg of dexamethasone and releases dexamethasone for a period of up to about 14 days after administration.

115. The method of embodiment 113, wherein the insert contains about 300 μg of dexamethasone and releases dexamethasone for a period of up to about 21 days after administration.

116. The method of any one of embodiments 98-115, wherein the insert releases an average of about 15 μg to about 25 μg of dexamethasone per day for a period of up to about 14 days, or up to about 21 days after administration.

117. The method of embodiment 116, wherein the insert contains about 200 μg of dexamethasone and releases an average of about 15 μg to about 25 μg of dexamethasone per day for a period of up to about 7 days after administration.

118. The method of embodiment 116, wherein the insert contains about 300 μg of dexamethasone and contains an average of about 15 μg to about 25 μg of dexamethasone per day for a period of up to about 11 days, or up to about 14 days after administration. .

119. The method of any one of embodiments 98-118, wherein after complete depletion of glucocorticoid from the insert, the insert remains in the canal until the hydrogel is biodegraded and/or removed through the nasolacrimal duct.

120. The method of embodiment 119, wherein the insert remains in the canal for up to about 1 month, or up to about 2 months, or up to about 3 months, or up to about 4 months after administration.

121. The method according to any one of embodiments 98 to 120, wherein the first insert is still retained in the canaliculus (“insert stacking”) according to any one of claims 1 to 68 or claims 69 to 120. 98. A method comprising administering an additional sustained release biodegradable intracanalicular implant prepared according to the method of any one of claims 97.

122. The method of embodiment 121, wherein the further insert is the same as or different from the first insert.

123. The method of embodiment 121 or 122, wherein the first insert is administered when the first insert is completely depleted of glucocorticoid.

124. The method of embodiment 121 or 122, wherein the additional insert is inserted when the first insert is not completely depleted of glucocorticoid.

125. The method according to any one of embodiments 98 to 124, wherein the treatment of dry eye disease with the sustained release biodegradable endoprosthesis is combined with or subsequent to another treatment of dry eye disease.

126. The method of embodiment 125, wherein the other treatment for dry eye disease is a chronic treatment for dry eye disease.

127. According to any one of Embodiments 1 to 68 or according to the method of any one of Embodiments 69 to 97 for use in treating a dry eye disease in a patient in need of treatment according to the method of any one of Embodiments 98 to 126 Manufactured sustained-release biodegradable endoductal implant.

128. Any one of embodiments 1 to 68 or any one of embodiments 69 to 97 for the manufacture of a medicament for treating dry eye disease in a patient in need of treatment according to the method of any one of embodiments 98 to 126. Use of a sustained-release biodegradable endoductal implant prepared according to the method of

129. One or more sustained-release biodegradable endoductal implant(s) according to any one of embodiments 1-68 or prepared according to the method of any one of embodiments 69-97 and instructions for using the insert(s) Including, kit.

130. The kit of embodiment 129, further comprising one or more means for administration of the insert(s).

131. The kit of embodiment 129 or 130, wherein the insert(s) are individually packaged for single administration.

132. The kit of any of embodiments 129-131, wherein the insert(s) are secured to a foam carrier sealed in a foil pouch.

Example

The following examples are included to demonstrate certain aspects and embodiments of the invention as described in the claims. However, it should be understood by those skilled in the art that the following description is exemplary only and should not be taken as limiting the present invention in any way.

Example 1: Preparation of dexamethasone insert

The dexamethasone implants of some embodiments of the present invention are cylindrical in nature having a specific length and diameter as specified herein, wherein dexamethasone is homogeneously dispersed and entrapped within a PEG-based hydrogel to provide sustained release of dexamethasone to the ocular surface via the lacrimal fluid. to provide. The release of dexamethasone from the insert of the present invention is solubility-centric because dexamethasone has low water solubility.

For the manufacture of the inserts used in the examples, autoclaved polyurethane tubing was first cut into pieces of appropriate length. The formulation process includes making one syringe containing trilysine acetate and NHS fluorescein and another syringe containing dexamethasone and 4a20k PEG-SG (4-arm 20,000 Da PEG succinimidyl glutarate ester) do. Then, the contents of these two syringes are combined to form a mixture (suspension), which is gelled to form a hydrogel in which dexamethasone is dispersed. In the following, the production process for implants containing 0.2 mg or 0.3 mg dexamethasone is exemplarily described.

For the preparation of trilysine acetate/NHS fluorescein syringes, the corresponding amounts of buffer (dibasic sodium phosphate), water for injection, and trilysine acetate were mixed and the pH was adjusted to 8.4 ( Table 2 ). 16,045 ± 10 mg of the resulting solution was then mixed with a corresponding amount of NHS-fluorescein ( Table 2 ). A mixture of trilysine acetate and NHS-fluorescein was reacted at room temperature for 1 to 24 hours to form a trilysine-fluorescein conjugate. After the reaction time had elapsed (and the formation of trilysine-fluorescein conjugate was confirmed using RP-HPLC with UV detection), the solution was filtered and an aliquot of 4,200 ± 10 mg of the prepared solution was aliquoted into a syringe. .

Table 2 Components of trilysine acetate/NHS fluorescein syringes.

For the preparation of the dexamethasone/4a20k PEG-SG syringe, two separate syringes were first prepared and then combined to create the dexamethasone/4a20k PEG-SG syringe. The first syringe contained a suspension of the corresponding amount of sieved micronized dexamethasone (Pfizer) in water ( Table 3 ). Dexamethasone had a particle size of d90 < 5 μm and d98 < 10 μm, and was further sieved to remove particles larger than 90 μm. The second syringe contained 5,620 ± 10 mg of monobasic sodium phosphate buffer solution and 4a20k PEG-SG solution prepared by mixing corresponding amounts in a sterile container ( Table 3 ). The dexamethasone suspension syringe was then connected to a 4a20k PEG-SG syringe luer-to-luer, and the contents of the syringe were passed back and forth between each syringe to mix. The suspension was then transferred into one single syringe to form a dexamethasone/4a20k PEG-SG syringe.

Table 3 Components of the dexamethasone/4a20k PEG-SG syringe.

A trilysine acetate/NHS fluorescein syringe and a dexamethasone/4a20k PEG-SG syringe are connected luer-to-luer, and the contents of the syringes are mixed by passing back and forth between each syringe to obtain a mixture (suspension) of the hydrogel component and dexamethasone. After creation, the mixture was transferred into a single syringe. The suspension was cast through a polyurethane tube prepared prior to (complete) gelation of the hydrogel. A gel tap test was performed to confirm the gelation time. The cast strands were stored vertically for 3-6 hours to allow the hydrogel to harden. The strand was then stretched approximately 2.5-2.6 times the original tubing length at a controlled rate. The drawn strand was stored vertically in a nitrogen-flash atmosphere at 32.0±2.0° C. for 60 to 72 hours to allow the strand to dry completely.

After drying, the dried strands were removed from the polyurethane tubing and cut into approximately 2.25 mm segments. The surfaces of the cut inserts were inspected for particulates, cylindrical shapes, and visible surface defects. The inserts were evaluated for the dimensions length and diameter that showed no defects and provided the required shape. Inserts that did not meet all requirements were rejected.

After quality inspection, the inserts were individually packaged in foam carriers (one insert per foam carrier) and sealed in a user peelable aluminum-low density polyethylene (LDPE) foil pouch ( FIG. 1 ). To this end, the insert was placed using forceps into an opening in the foam carrier where a portion of the insert protruded for easy removal. The unsealed foil pouches were transferred to a glove box and stored in an inert nitrogen environment for 16-96 hours to reduce residual moisture in the foam and pouch materials (moisture content ≤ 1.0%). The pouch was then sealed within the glove box using a pouch sealer to create a complete and continuous seal to the pouch. After sealing the pouches, they were inspected and stored at 2-8° C. until sterilized. Inserts packaged for sterilization were gamma-irradiated (internal dose delivered 25.0-45.1 kGy). The packaged inserts were then stored at 2-8° C. protected from light prior to administration.

The percent composition, target dose per insert, and function of each component for both the 0.2 mg and 0.3 mg dexamethasone inserts are presented in Table 4 .

Table 4 Dexamethasone implant composition (0.2 mg and 0.3 mg doses). Percentages refer to weight percent (% w/w).

The properties of the 0.2 mg and 0.3 mg dexamethasone inserts are presented in Table 5 . The duration of dexamethasone release was estimated to last up to about 14 days for the 0.2 mg insert and up to about 21 days for the 0.3 mg insert (see also Example 3 below). Hydrated dimensions were measured as described herein after 24 hours in a biorelevant medium (Phosphate Buffered Saline (PBS), pH 7.4, at 37° C.) considered equilibrium. Measurements of implant dimensions (both dry and wet) were performed with a custom 3-camera Keyence Inspection System. Two cameras were used to measure the diameter with a tolerance of ± 0.002 mm (the average (=median) value of all data points acquired was recorded), and one camera was used to measure the length with a tolerance of ± 0.04 mm. (longest measured length among several data points recorded).

Table 5 Dexamethasone implant characteristics (0.2 mg and 0.3 mg doses). Mean dimension values represent the median of 22 implant measurements.

The insert is for administration into the upper and/or lower vertical canaliculi of the eye via the upper and/or lower punctum of the eye using, for example, forceps ( FIG. 2A ). The insert can be visualized by illuminating the fluorescent PEG with a blue light source and using a yellow filter ( Figure 2B ). The elongation of the strands during the creation process creates shape memory, i.e., when administered to the canaliculus of the eye, upon hydration, the insert rapidly loses length to approach its original wet casting dimensions (e.g., approximately approx. 2/3) in diameter (eg, about 3 times the diameter in the dry state) ( FIG. 3 and Table 5 ). In general, the degree of length contraction and diameter swelling upon hydration depends in particular on the elongation factor. The narrow dry dimensions facilitate administration of the implant through the punctum into the canal, while the shortened length after administration creates a shorter implant in the canal of the eye, potentially minimizing confounding effects on the patient and providing a good fit. Provides excellent retention for vertical canaliculi. Additionally, as the implant's diameter expands upon hydration, it adjusts and closely fits the patient's individual canalicular size. Thus, the unintentional loss of implantation sometimes experienced with commonly used plugs, such as collagen or silicone plugs, is greatly reduced.

After placement of the implant in the canaliculus, the micronized dexamethasone contained in the implant dissolves in the lacrimal fluid to provide sustained local delivery of a therapeutically effective amount of dexamethasone to the ocular surface. The release of a therapeutically effective amount of dexamethasone lasts, for example, up to about 14 days for a 0.2 mg insert and up to about 21 days for a 0.3 mg insert. After all dexamethasone has been released from the insert, the dexamethasone-depleted insert remains in the canaliculus for a period of time, such as about 1, about 2, about 3, or about 4 months after administration, and then removed via the nasolacrimal canal (treatment/washout) It slowly biodegrades and shrinks until it becomes small. Because only one administration is required with an extended delivery time of up to several weeks, patient compliance is increased compared to the use of eye drops that require daily or even multiple administration of eye drops per day. Dexamethasone is released primarily at the proximal end of the insert at the interface between the hydrogel and the lacrimal fluid (as exemplarily illustrated in FIG. 6 ). The sustained drug release rate is controlled by the hydrogel matrix and drug solubility in the lacrimal fluid. The hydrogel matrix of the insert is formulated to biodegrade, for example, via ester hydrolysis in the aqueous environment of the canal. Thus, over time, the implant softens, liquefies and is removed (treated/washed out) through the nasolacrimal canal without the need for removal (unless removal is required under certain circumstances). Thus, unpleasant removal can be avoided. The insert is indicated for the treatment of the signs and symptoms of dry eye disease (DED), in particular for the acute treatment of DED, for example during intermittent flares of DED. Thus, the dexamethasone implant of the present application combines the anti-inflammatory effect of dexamethasone release with the benefit of lacrimal duct occlusion, and the combined effect provides improved treatment of DED.

Example 2: in vitro Dexamethasone release

0.2 mg and 0.3 mg inserts ( Table 4 and The release rate of dexamethasone of 5 ) was determined by in vitro testing. In vitro release was tested under accelerated conditions as outlined in the following: one insert was placed in a bottle and the entire insert surface was exposed to the buffer solution in 100 mL of buffer solution (1x phosphate buffered saline, pH 7.4; PBS) was added. At that point, 1 mL of the supernatant was removed for HPLC analysis. 1 mL of fresh buffer solution was added to the bottle as a replacement. In vitro assays can be used for quality control, for example to determine batch-to-batch suitability of an insert.

Dexamethasone was completely released after 3 days with the 0.2 mg implant and 4 days with the 0.3 mg implant ( FIG. 4 ).

Example 3: preclinical Evaluation of dexamethasone implants in studies

The safety, tolerability and drug release of dexamethasone implants containing various doses of the active ingredient were evaluated in beagle dogs.

Determination of Dexamethasone by LC-MS/MS

Dexamethasone concentrations in plasma, aqueous humor and lacrimal fluid samples were determined by high-performance liquid chromatography combined with tandem mass spectrometry (LC-MS/MS) using a triple quadrupole mass spectrometer.

For the preparation of tear fluid samples, deionized water was added to the tear samples to obtain a volume of 50 μL for each tear sample. Then, 50 μL of an internal standard solution (prednisolone-21 acetate) was added to each tear sample. For preparation of aqueous humor samples, 50 μL of each aqueous humor sample was mixed with 50 μL of internal standard solution. Samples were centrifuged at 13,500 rpm for 5 minutes. For preparation of plasma samples, 50 μL Beagle plasma was mixed with 200 μL internal standard solution of acetonitrile with 0.1% formic acid (v/v). Plasma samples were vortexed and then centrifuged at 4,000 rpm for 15 minutes. Different sample supernatants were used for LC-MS/MS analysis.

The high-performance liquid chromatography (HPLC) system consists of a Shimadzu AD10vp pump and a CTC autosampler. The mass spectrometer (MS) was an ABI 3000 tandem mass spectrometer. The instrument was operated with Analyst 1.4.2 software. The HPLC mobile phase was acetonitrile with 0.1% formic acid (v/v) and HPLC-grade water. The column was maintained at room temperature and the sample compartment was maintained at 2-5 °C. The analyte was eluted from the column at 0.8 mL/min using a gradient generated from the mixture of mobile phases. Dexamethasone was ionized by negative ion electrospray. The MS system was operated in negative ion mode. Dexamethasone (391.0-361.1 m/z; retention time 1.23 ± 0.5 min) and internal standard (prednisolone-21 acetate, 401.2-321.0 m/z; 1.29 ± 0.5 min) were fragmented in MS. The total running time was 2.4 minutes. Dexamethasone concentration was determined from a calibration curve. Before analyzing the samples, the method was validated using dexamethasone-containing beagle plasma and artificial tears. This method was found to be reproducible, accurate, linear, accurate and specific. The lower limit of quantification was determined to be 1.0 ng/mL and the lower limit of detection was determined to be 0.08-0.06 ng/mL.

Release of drug from implant

To investigate the release of dexamethasone from implants according to the present invention containing different doses of dexamethasone, implants containing 0.22, 0.37, 0.46, 0.58, 0.65, 0.72, and 0.85 mg of dexamethasone, respectively, were administered intrathecally to healthy beagle dogs. (n=10-14 per dose). Tear samples were collected from the eyes of the beagles using 10 mm Schirmer tear test strips after the insert was inserted into the canaliculus. Dexamethasone levels in tear fluid were measured by LC-MS/MS. Inserts were prepared according to the same method as described in Example 1 above. The exact composition of the insert used in this example is given in Table 6 .

Table 6 Compositions of 0.22, 0.37, 0.46, 0.58, 0.65, 0.72, and 0.85 mg dexamethasone inserts by weight (% w/w).

Aqueous and/or lacrimal fluid samples were collected at the indicated time points and analyzed using LC-MS/MS as described above ( Tables 7 and 8 ; Figure 5 for the 0.22 mg insert).

TABLE 7 Concentrations of dexamethasone in tear fluid of beagle dogs delivered from different doses of dexamethasone implants over time (SD = standard deviation).

TABLE 8 Concentrations of dexamethasone in the aqueous humor of beagle dogs delivered from different doses of dexamethasone implants over time.

The pharmacokinetic results of lacrimal fluid and aqueous humor samples were similar. Values demonstrated sustained release of dexamethasone with approximately constant levels of dexamethasone in the lacrimal and aqueous humor over several days depending on the dose, and eventually a decrease (tapering) in the amount of drug released until complete release. For example, a 0.22 mg dexamethasone insert provides constant dexamethasone levels in the lacrimal fluid for 7 days and then tapers from day 7 to complete release of dexamethasone from the insert after 17 days of dosing, so the overall sustained-release period is 17 days ( Fig . 5 ). To determine the intralacrimal pharmacokinetic profile of these 0.22 mg inserts as shown in Figure 5 , the inserts were placed bilaterally in the punctum of 7 beagles (i.e., 14 total eyes) on day 0. Tear samples were collected from beagle eyes using 10 mm Schirmer test strips at 1, 2, 4, 7, 10, 14, 17, 21, 28, 35, 37, and 40 days after insertion of the canalicular implant. . Dexamethasone levels in tear fluid were measured by LC-MS/MS. Dexamethasone is presented as mean values with corresponding standard deviation error bars. The number of samples measured was as follows: on day 1 n was 6 eyes; On day 2, n was 8 eyes; On days 14 and 21, n were 7 eyes; At day 28, n was 6 eyes; At day 35 n was 2 eyes. A single implant delivered dexamethasone to the ocular surface for approximately 14 days, and levels of dexamethasone in the tear fluid were maintained through day 7, tapering from day 7 to day 14, and completely released by day 17. The 0.37 mg dexamethasone insert produced constant dexamethasone levels in the lacrimal fluid for 21 days, then tapering from day 21 to day 28 ( Table 7 ). Tapering was also evident in the aqueous humor with the 0.37 mg dose on day 21 and the 0.46 mg dose on day 28 ( Table 8 ). Of note, aqueous humor and lacrimal dexamethasone concentrations from the doses tested are consistent with those achieved by application of MAXIDEX ^® eye drops (0.1% dexamethasone suspension) four times a day, which contain approximately 50 μg of dexamethasone per drop. has been

In summary, dexamethasone concentrations in the aqueous humor of beagle dogs on days 7 and 14 were similar between all doses tested. In addition, the concentration of dexamethasone in the tear fluid of beagle dogs was similar between all doses tested on the 7th day.

The dexamethasone insert was removed from the canaliculus by manual expression out of the punctal opening at selected time points for a defined number of animals. Remaining dexamethasone was extracted from the insert and measured by LC-MS/MS as described above. The rate of dexamethasone release and complete depletion from the implant on the day before tapering (as evidenced by a decrease in dexamethasone concentration in the lacrimal fluid and/or aqueous humor) was calculated by determining the amount of dexamethasone released from the implant divided by the study day on which the implant was removed. ( Table 9 ). The results show that the rate of release of dexamethasone determined per day was similar between all doses tested. This is consistent with the fact that the release rate of dexamethasone from the insert according to the present invention is controlled by the solubility of the drug in the hydrogel matrix and lacrimal fluid. Dexamethasone is mainly released from the insert at the interface proximal to the lacrimal fluid, i.e. from the insert facing the punctal opening (as exemplarily illustrated in FIG. 6 ). Thus, the released drug level remains almost constant at the interface between the insert and the lacrimal fluid until the amount of dexamethasone in the insert is sufficiently reduced, resulting in a gradual tapering effect observed in the lacrimal and aqueous humor pharmacokinetic profiles. The average amount of dexamethasone released from implants according to the invention determined in these studies is essentially independent of dexamethasone dose and is approximately 0.020 mg per day (or about 0.015 mg to about 0.025 mg per day) before tapering and complete exhaustion.

TABLE 9 Dexamethasone released per day from dexamethasone inserts containing different doses before tapering and complete depletion (note that the two 0.85 mg inserts in the table are 2 different lots and were measured in 2 different studies).

Unidirectional drug release into the lacrimal fluid was exemplarily demonstrated visually for the 0.37 mg dexamethasone implant in FIG. 6 . Although dexamethasone is released from the implant prior to (complete) biodegradation of the implant (e.g., for the 0.37 mg dexamethasone implant, the drug is completely released after approximately 28 days while the implant has not yet visually significantly degraded), but the drug is depleted. The extended presence of the implant provides additional long-term benefits of lacrimal duct occlusion. If longer term dexamethasone treatment is necessary or desired in a particular patient, a new implant may be placed over the old drug-depleted implant (also referred to as "insert stacking"). In any case, since the implant is biodegradable, there is no need to remove the implant, which greatly improves patient compliance.

Implants containing 0.2 mg and 0.3 mg dexamethasone, respectively, remain essentially on the ocular surface for a period of up to about 7 days (for the 0.2 mg implant) and up to about 11 days, or up to about 14 days (for the 0.3 mg implant) after administration. is expected to provide a constant concentration of dexamethasone. Dexamethasone concentrations decrease (taper) over approximately the next 7 days until the active ingredient is completely depleted from the 0.2 mg and 0.3 mg dexamethasone inserts. Thus, sustained release of a therapeutically effective amount from an insert according to the present invention is provided for a period of about 14 days and a period of about 21 days, respectively.

safety of implants and tolerability

Potential ocular toxicity, irritation and systemic exposure were evaluated for a 0.72 mg dexamethasone implant over a period of 35 days after intracanal insertion in beagle dogs. Reversibility and delayed onset of any toxic effects were assessed after a 14-day recovery period.

Two different types of inserts (and in both versions with and without dexamethasone, respectively) were evaluated. The first insert type consisted of 100% 4-arm 20k PEG-SG hydrogel material (as described in Example 1 above). The second insert type consisted of a 50/50 blend of 4-arm 20k PEG-SG and 4-arm 20k PEG-SS hydrogel materials. Both insert types were prepared according to the same method as described in Example 1 above, except that the PEG precursor blend mentioned for the second insert type was used. See Table 6 for the exact composition of the 0.72 mg insert (only 50% of the 4a20kPEG-SG in the 0.72 mg insert reported in Table 6 was replaced by 4a20kPEG-SS for inserts containing PEG blends).

This study consisted of two groups of beagle dogs. Animals in the first group (n=17) received implants with dexamethasone, i.e. type 1 implant with 100% 4-arm 20k PEG-SG and dexamethasone in one eye and 50/50 PEG blend and dexamethasone in the other eye. Each animal received one implant type (with dexamethasone) in each eye, resulting in a total exposure dose of 1.44 mg dexamethasone per animal. Animals in the second group (n=16) received control implants (no dexamethasone), i.e. implant type 1 with 100% 4-arm 20k PEG-SG in one eye and 50/50 PEG blend in the other eye. As they received the second implant type, each animal received one implant type (no dexamethasone) in each eye.

Evaluation included all observed toxic effects, gross necropsy and histopathological findings. Ophthalmic examination included slit lamp biomicroscopy, fluorescein staining, fundus examination, and tonometry. Slit-lamp examination was used to track potential changes in the cornea, conjunctiva, iris, anterior chamber, and lens. The corneal surface was also evaluated using fluorescein staining. The retina was examined for macroscopic changes to the retina or optic nerve and scored as normal or abnormal. Daily clinical and food consumption observations were performed. Body weight was measured weekly.

In summary, the dexamethasone implant was well tolerated. Systematically, no treatment-related effects were observed on body weight, food consumption, hematology, clinical chemistry, coagulation and urinalysis parameters. No effect was observed in intraocular pressure and posterior segment evaluation. Macroscopic and microscopic evaluations did not yield test article related results indicating direct test article toxicity. Results in puncta may be due to procedural complications or normal background effects.

Observations from ophthalmic examination showed mild to no irritation, as well as mild conjunctival congestion and discharge, and slow to absent pupillary light reflexes. Results were similar in all groups regardless of the type of implant (PEG composition) and whether or not dexamethasone was present in the implant. Congestion outcomes were mild and not considered adverse. The discharge was specifically considered to be related to the presence of punctal plugs and not to the material containing the test article. Slow or lack of pupillary light reflection observations, which were considered due to subjectivity of observation, were limited and not considered disadvantageous. No delayed onset of toxic effects was observed after a 14-day recovery period.

Plasma concentrations (determined as described above) were below the lower limit of quantification (1.0 ng/mL) for all animals over the study period, indicating clinically significant systemic exposure to dexamethasone even at a high total dose of 1.44 mg per animal. was confirmed absent (occurring in 2 implants, one implant per eye).

In addition, the presence of dexamethasone containing as well as the vehicle control insert was monitored over the study period of 35 days. For all groups, endoductal implants were still present in at least 84% of the animals after the treatment period. However, implants containing 100% 4-arm 20k PEG-SG had a higher overall incidence of implant presence (retention), with or without dexamethasone, when compared to 50/50 PEG blend inserts.

Example 4: Clinical trial (expected)

The 0.2 mg and 0.3 mg dexamethasone inserts (see Table 4 and Table 5 for composition and dimensions of the insert) were evaluated for potential acute short-term treatment of dry eye disease (DED) in humans. In a prospective, randomized, double-masked Phase 2 study, subjects with a diagnosis of DED in both eyes for at least 6 months were enrolled. In addition, the dry eye severity score on the Visual Analogue Scale (VAS) should be 30 points or more and the conjunctival congestion grade should be 2 points or more (Cornea and Contact Lens Research Unit, CCLRU scale).

The Phase 2 clinical study is summarized in FIG. 7 . Prior to insertion of the implant, the subject needs to discontinue any pre-treatment of the DED, e.g., application of eye drops, for 2 weeks to avoid any effects unrelated to the application of the 0.2 mg and 0.3 mg dexamethasone implant (" wash-out period"). Subjects (50 subjects in the 0.2 mg group and another 50 subjects in the 0.3 mg group and 50 additional subjects receiving only placebo vehicle without dexamethasone) received either the 0.2 mg or 0.3 mg dexamethasone insert or the insert without dexamethasone (hydrogel vehicle but placebo control) is received bilaterally through the lower or upper punctum of the eye into the lower or upper vertical canaliculus (endocanalicular implant). Screening visits were performed at 1, 2, 3, 4, and 8 weeks post implantation to assess conjunctival congestion, dry eye score (VAS scale), total corneal fluorescein staining, and adverse events (ocular or non-ocular). Evaluate. In addition, the presence of implants was assessed at all study visits. The primary efficacy endpoint is 2 weeks post implantation. For example, patients are followed for an extended period after the primary efficacy endpoint ("safety follow-up" for an additional 6 weeks) to assess the presence of the implant. Depending on the course of the study, additional screening visits or extended safety follow-up may be scheduled.

Claims (82)

A sustained release biodegradable ocular implant comprising a hydrogel and a glucocorticoid, wherein glucocorticoid particles are dispersed within the hydrogel, wherein the insert has a length in a dry state of less than about 2.75 mm. insertion. The sustained release biodegradable ocular implant of claim 1 , wherein the implant contains less than about 375 μg of dexamethasone or an equivalent dose of another glucocorticoid. 3. The sustained-release biodegradable ocular implant of claim 1 or 2, wherein the implant provides release of a therapeutically effective amount of glucocorticoid for a period of up to about 1 month after administration. 4. The sustained-release biodegradable ocular implant according to any one of claims 1 to 3, wherein the glucocorticoid is dexamethasone. The sustained-release biodegradable ocular implant according to any one of claims 1 to 4, wherein the implant is an intracanal implant. 6. The sustained release biodegradable ocular implant of any one of claims 1 to 5 comprising about 160 μg to about 250 μg of dexamethasone. 7. The sustained release biodegradable ocular implant of claim 6 comprising about 180 μg to about 220 μg of dexamethasone. 8. The sustained release biodegradable ocular implant of claim 7 comprising about 200 μg of dexamethasone. 6. The sustained release biodegradable ocular implant of any one of claims 1 to 5 comprising from about 240 μg to about 375 μg of dexamethasone. 10. The sustained release biodegradable ocular implant of claim 9 comprising about 270 μg to about 330 μg of dexamethasone. 11. The sustained release biodegradable ocular implant of claim 10 comprising about 300 μg of dexamethasone. 12. The sustained release biodegradable ocular implant according to any one of claims 1 to 11, wherein the implant is cylindrical or essentially cylindrical. 12. The sustained release biodegradable ocular implant according to any one of claims 1 to 11, wherein the insert is non-cylindrical. 13. The sustained release biodegradable ocular insert of any one of claims 1-12, wherein the insert is cylindrical or essentially cylindrical and has a length in the dry state of less than about 2.5 mm. 15. The sustained release biodegradable ocular implant of any one of claims 1-12 and 14, wherein the insert is cylindrical or essentially cylindrical and has a diameter in the dry state of less than about 0.75 mm. 16. The method of any one of claims 1-12, 14 or 15, wherein the insert is cylindrical or essentially cylindrical, and in the dry state has a length of about 2.14 mm to about 2.36 mm and a length of about 0.41 mm to about 0.41 mm. A sustained release biodegradable ocular implant having a diameter of about 0.55 mm. 17. The method according to any one of claims 1 to 12 or 14 to 16, wherein the insert is cylindrical or essentially cylindrical, and upon hydration (after 24 hours in phosphate buffered saline pH 7.2 at 37°C) ) Sustained release biodegradable ocular implant wherein the diameter of the implant increases and the length of the implant decreases. 18. The sustained release biodegradable ocular implant of claim 17, wherein the ratio of the diameter in the hydrated state of the insert to the diameter in the dry state of the insert ranges from about 1.5 to about 4. 19. The sustained release biodegradable ocular implant of claim 18, wherein the ratio of the diameter of the insert in the hydrated state to the diameter of the insert in the dry state ranges from about 2 to about 3.5. 20. The sustained-release biodegradable ocular implant of any of claims 17-19, wherein the ratio of the length of the insert in the hydrated state to the length in the dry state of the insert is less than about 0.9. 21. The sustained release biodegradable ocular implant of claim 20, wherein the ratio of the length of the insert in the hydrated state to the length of the insert in the dry state is less than about 0.75. 22. The method according to any one of claims 1 to 12 or 14 to 21, wherein the insert is cylindrical or essentially cylindrical, and in a hydrated state (24 hours in phosphate buffered saline pH 7.2 at 37 °C). post) a sustained release biodegradable ocular implant having a length to diameter ratio of greater than 1. 23. The method of any one of claims 1-12 or 14-22, wherein the insert is cylindrical or essentially cylindrical and has a diameter in the hydrated state ranging from about 1.35 mm to about 1.80 m and about 1.64 m. A sustained-release biodegradable ocular implant having a length ranging from mm to about 2.0 mm. 24. The sustained release biodegradable ocular implant of any one of claims 1 to 23, having a total weight in the range of about 100 to about 1000 μg. 25. The sustained release biodegradable ocular implant of claim 24 having a total weight in the range of about 400 to about 600 μg. 26. The sustained release biodegradable eye of any one of claims 1-25, wherein the insert provides for release of a therapeutically effective amount of glucocorticoid for a period of at least about 12 hours, such as for a period of at least about 1 day after administration. insertion. 27. The continuous use of any one of claims 1-26, wherein the insert provides release of a therapeutically effective amount of dexamethasone for a period of up to about 14 days, or up to about 21 days, or up to about 25 days after administration. Releasable biodegradable ocular implant. 28. The method of any one of claims 1-27, wherein the glucocorticoid is dexamethasone and the insert delivers dexamethasone into the lacrimal fluid at an average rate of about 5 μg to about 50 μg per day for a period of up to about 21 days after administration. Sustained release biodegradable ocular implant providing release. 29. The sustained release biodegradable ocular implant of claim 28, wherein the implant provides release of dexamethasone into the lacrimal fluid at an average rate of about 15 μg to about 25 μg per day for a period of up to about 21 days after administration. 30. The method of claim 29, wherein the insert contains about 200 μg of dexamethasone and provides release of dexamethasone at an average rate of about 15 μg to about 25 μg of dexamethasone per day for a period of up to about 7 days after administration. Releasable biodegradable ocular implant. 30. The method of claim 29, wherein the insert contains about 300 μg of dexamethasone and provides release of dexamethasone at an average rate of about 15 μg to about 25 μg of dexamethasone per day for a period of up to about 14 days after administration. Releasable biodegradable ocular implant. 32. The sustained release biodegradable eye of any one of claims 1 to 31, wherein the implant biodegrades within about 1 month, or within about 2 months, or within about 3 months, or within about 4 months after administration. insertion. 33. The sustained release biodegradable ocular implant of claim 32, wherein the implant biodegrades after complete or essentially complete depletion of glucocorticoid from the implant. 34. The method of any one of claims 1 to 33, wherein the hydrogel is polyalkylene glycol, polyethylene glycol (PEG), polyalkylene oxide, polyethylene oxide, polypropylene oxide, polyvinyl alcohol, poly (vinylpyrroly dinon), polylactic acid, polylactic-co-glycolic acid, random or block copolymers, or units of one or more of any combination or mixture thereof, or one or more of polyamino acids, glycosaminoglycans, polysaccharides, or proteins. Sustained-release biodegradable ocular implant comprising a polymer network comprising units. 35. The sustained release biodegradable ocular implant of claim 34, wherein the hydrogel comprises multi-arm PEG units that are the same or different and have a number average molecular weight of about 10,000 to about 60,000 Daltons. 36. The sustained release biodegradable ocular implant of claim 35, wherein the hydrogel comprises multi-arm PEG units that are the same or different and have a number average molecular weight of from about 10,000 to about 40,000 Daltons, or about 20,000 Daltons. The sustained-release biodegradable ocular implant according to claim 35 or 36, wherein the hydrogel includes cross-linked PEG units, and the cross-links between the PEG units include a group represented by the following formula:

In the formula, m is an integer from 0 to 10, such as 2. 38. The sustained release biodegradable according to any one of claims 35 to 37, wherein the PEG unit comprises a 4-arm and/or 8-arm PEG unit, such as a 4a20kPEG unit, having a number average molecular weight of about 20,000 Daltons. Sexual eye implants. 39. The method of any one of claims 34-38, wherein the insert contains from about 40% to about 56% glucocorticoid and from about 36% to about 55% polymer units (dry composition) by weight in the dry state. A sustained-release, biodegradable ocular implant containing 40. The sustained release biodegradable eye according to claim 39, wherein the insert contains, in a dry state, from about 40% to about 46% dexamethasone and from about 45% to about 55% PEG units (dry composition). insertion. 40. The sustained release biodegradable eye according to claim 39, wherein the insert contains, in a dry state, from about 50% to about 56% dexamethasone and from about 36% to about 46% PEG units (dry composition). insertion. The method of claim 1 , wherein the insert is an intracanalicular insert and comprises about 160 μg to about 250 μg or about 180 μg to about 220 μg or about 200 μg of dexamethasone, is cylindrical or essentially cylindrical, and in the dry state is about It has a diameter ranging from 0.41 mm to about 0.49 mm and a length ranging from about 2.14 mm to about 2.36 mm, and in a hydrated state (after 24 hours in phosphate buffered saline pH 7.2 at 37° C.) from about 1.35 mm to about 1.80 mm. having a diameter and a ratio of length to diameter greater than 1, wherein the hydrogel comprises crosslinked 4a20k PEG units, and the crosslinks between the PEG units comprise a group represented by the formula: Eye Implant:

In the formula, m is 2. 43. The sustained release biodegradable ocular implant of claim 42, wherein the implant provides release of dexamethasone for a period of up to about 14 days, or up to about 21 days after administration. 2. The method of claim 1, wherein the insert is an intracanalicular insert and comprises about 240 μg to about 375 μg or about 270 μg to about 330 μg or about 300 μg of dexamethasone, is cylindrical or essentially cylindrical, and in the dry state It has a diameter in the range of about 0.44 mm to about 0.55 mm and a length in the range of about 2.14 mm to about 2.36 mm, in a hydrated state (after 24 hours in phosphate buffered saline pH 7.2 at 37° C.) in the range of about 1.35 mm to about 1.80 mm has a diameter of and a ratio of length to diameter greater than 1, wherein the hydrogel comprises crosslinked 4a20k PEG units, and the crosslinks between the PEG units comprise a group represented by the formula: Sustained release biodegradation Sex Eye Implants:

In the formula, m is 2. 45. The sustained release biodegradable ocular implant of claim 44, wherein the implant provides release of dexamethasone for a period of up to about 21 days, or up to about 1 month after administration. 46. The method of any one of claims 1-45, wherein the glucocorticoid is dexamethasone and the dexamethasone particles have a d90 particle size of less than about 5 μm and/or a d98 particle size of less than about 10 μm as determined by laser diffraction wherein, optionally all or essentially all of the particles are smaller than about 90 μm. 47. The sustained-release biodegradable ocular implant of any one of claims 1-46, which contains a visualizing agent. 48. The sustained release biodegradable ocular implant according to any one of claims 1 to 47, wherein the visualizing agent is a fluorophore such as fluorescein. 49. The sustained release biodegradable ocular implant of any one of claims 1-48, wherein the insert is or is substantially free of an antimicrobial preservative. 50. A method of manufacturing a sustained-release biodegradable ocular implant according to any one of claims 1 to 49, said method comprising the steps of forming a hydrogel comprising glucocorticoid particles dispersed in a polymer network and a hydrogel; A method comprising shaping a hydrogel and drying the hydrogel. 51. The method of claim 50, wherein the polymer network is formed by mixing and reacting an electrophilic group-containing PEG precursor and a nucleophilic group-containing crosslinking agent in a buffered solution in the presence of glucocorticoid particles, and gelling the mixture to form a hydrogel. Formed by doing, the method. 52. The method of claim 51, wherein the crosslinker contains an imine group. 53. The method of claim 52, wherein the crosslinker is trilysine or trilysine acetate. 54. The method of any one of claims 51-53, wherein the electrophilic group of the PEG precursor is an activated ester group. 55. The method of claim 54, wherein the PEG precursor is 4a20kPEG-SG. 56. The method of any one of claims 50-55 comprising bonding the polymer network and a visualizer. 57. The method of claim 56 comprising conjugating the crosslinking agent and the visualizing agent prior to crosslinking the polymer precursor. 58. The method of claim 56 or 57, wherein the visualizing agent is fluorescein, a fluorescein derivative or another fluorophore. 59. The method of any one of claims 51 to 58, wherein forming the hydrogel by casting the mixture into a mold or tubing before completely gelling the hydrogel to form the hydrogel strands, and forming the hydrogel strands A method comprising drying. 60. The method of claim 59, further comprising the step of stretching (wet stretching or dry stretching) the hydrogel strands before or after drying the hydrogel. 60. The method of claim 59, further comprising stretching the hydrogel strands lengthwise (wet stretching) with a draw factor ranging from about 1 to about 3 prior to drying the hydrogel. 62. The method of claim 60 or 61, wherein the elongation factor ranges from about 2.2 to about 2.8. A method of treating dry eye disease (DED) in a patient in need thereof, said method according to any one of claims 1 to 49 or according to the method of any one of claims 50 to 62. Administering the prepared sustained-release biodegradable ocular implant to the patient. 64. The method of claim 63, wherein the treatment of DED is an acute treatment of DED. A method of treating intermittent flares of dry eye disease (DED) in a patient in need thereof, the method comprising administering to the patient a sustained-release biodegradable ocular implant comprising a hydrogel and a glucocorticoid; , wherein the glucocorticoid particles are dispersed within the hydrogel. 66. The method of any one of claims 63-65, wherein the treatment period is up to about 1 month. 67. The sustained release biodegradable ocular implant according to claims 65 or 66, wherein the implant is prepared according to any one of claims 1 to 49 or according to the method of any one of claims 50 to 62. in, how. 68. The method of any one of claims 63-67, wherein the insert is as defined in claim 42 and the treatment period is at most or about 14 days. 68. The method of any one of claims 63-67, wherein the insert is as defined in claim 44 and the treatment period is at most or about 21 days. 70. The method of any one of claims 63-69, wherein the implant is administered by insertion into the canal of the eye. 71. The method of claim 70, wherein the insert is administered to the lower and/or upper canaliculi. 72. The method of any one of claims 63-71, wherein the insert is administered unilaterally. 72. The method of any one of claims 63-71, wherein the insert is administered bilaterally. 74. The method of any one of claims 63-73, comprising administering additional sustained release biodegradable inserts into the canaliculus while the first insert is still retained in the canaliculus ("insert stacking"). How to. 75. The method of claim 74, wherein the additional insert is administered when the first insert is completely or essentially completely depleted of glucocorticoid. 76. The method of any one of claims 63-75, wherein the treatment of DED with the sustained-release biodegradable endoductal implant is combined with or subsequent to another treatment of DED. 77. The method of claim 76, wherein the another treatment is chronic treatment of DED. The sustained-release biodegradable ocular implant according to any one of claims 1 to 49, or any one of claims 50 to 62, for use in a method according to any one of claims 63 to 77. Sustained-release biodegradable ocular implant manufactured according to the method of claim 1. The sustained release ocular implant according to any one of claims 1 to 49, or claims 50 to 62, for the manufacture of a medicament for use in a method according to any one of claims 63 to 77. Use of a sustained release biodegradable ocular implant prepared according to any one of the methods of claim 1. Using one or more sustained-release biodegradable ocular implant(s) according to any one of claims 1 to 49 or prepared according to the method of any one of claims 50 to 62 and the implant(s) A kit comprising instructions to do so, wherein the insert(s) are individually packaged for single administration. 81. The kit of claim 80, wherein the insert(s) are secured to the foam carrier. 82. The kit of claim 80 or 81, further comprising one or more means for administration of the insert(s).

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