Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0048—Eye, e.g. artificial tears
  • A61K9/0051—Ocular inserts, ocular implants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
  • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
  • A61P27/04—Artificial tears; Irrigation solutions

Definitions

• the present invention claims priority to U.S. Provisional Application Serial No. 63/052,646 filed July 16, 2020, to U.S. Provisional Application Serial No. 63/124,176 filed December 11, 2020, and to U.S. Provisional Application Serial No. 63/181,720 filed April 29, 2021, which are all hereby incorporated by reference herein.
• TECHNICAL FIELD [0002] The present invention relates to the treatment of dry eye disease (DED), and in certain embodiments to the acute treatment of DED or of episodic flares of DED.
• DED is treated by administering a biodegradable insert into the superior and/or inferior canaliculus of the eye, wherein the insert provides sustained release of a glucocorticoid such as dexamethasone.
• a biodegradable insert such as keratoconjunctivitis sicca (KCS) (and also simply referred to as “dry eye”) is among the most frequently encountered ocular morbidities.
• KCS keratoconjunctivitis sicca
• DED is a multifactorial disorder of the tears and ocular surface characterized by symptoms of dryness, irritation, burning, stinging, grittiness, foreign body sensation, tearing, and ocular fatigue.
• inflammation has a prominent role in the development and propagation of this debilitating condition.
• Factors that adversely affect tear film stability and osmolarity can induce ocular surface damage and initiate an inflammatory cascade that activates innate and adaptive immune responses. These immunoinflammatory responses lead to further ocular surface damage and the development of a self- perpetuating inflammatory cycle. For instance, inflammation of the ocular surface results in a reduction of tear production, which further deteriorates the mentioned conditions.
• DED In humans, dry eye was found to be associated with the presence of conjunctival T-cells and elevated levels of inflammatory cytokines in the tears compared with controls, supportive of inflammation as a driving source of the disorder.
• DED is thought to be a chronic state, with episodic flares encompassing rapid onset of symptoms or symptom worsening, highly affecting daily life of patients.
• pharmacological therapies for DED have been explored and include a step-wise approach starting with over the counter lubricants and artificial tear replacements (delivered as eye drops), progressing to topical anti-inflammatory therapy and lacrimal occlusion using punctal or intracanalicular plugs for tear retention. Plugs often consist of collagen, acrylic polymers or silicon.
• plugs have been shown to be effective in patients with DED, plugs are sometimes lost (i.e., show poor retention) and may even migrate into the nasolacrimal duct, where they may be the cause of inflammation or other pathological conditions (cf. Fezza, et al. Study Raises Concern Over Plug, Review of Ophthalmology, 2011).
• DED is currently short-term treated with topical glucocorticoids such as fluorometholone (FML), loteprednol etabonate (Alrex ® and Lotemax ® ), and prednisolone acetate (PRED MILD ® ), as well as with cyclosporine (Restasis ® ) and lifitegrast (Xiidra ® ), all of these actives delivered in the form of ophthalmic drops.
• FML fluorometholone
• Alrex ® and Lotemax ® loteprednol etabonate
• PRED MILD ® prednisolone acetate
• Restasis ® cyclosporine
• Xiidra ® lifitegrast
• a specific issue with currently available eye drop formulations comprising cyclosporine and lifitegrast are tolerability issues such as burning and stinging, which can last from many weeks to even months. Furthermore, a relatively slow onset of action is generally observed using ophthalmic drops. In addition, ophthalmic drops may have to be administered several times per day as a large portion of the active ingredient is washed out quickly out of the eye and therefore exposure of the eye surface to the active agent may be short. For this reason, formulations often maximize concentration to compensate for this inefficiency, which may be associated with acute high concentrations on the ocular surface that may result in safety issues.
• Glucocorticoids have been used to treat dry eye disease. However, glucocorticoids in ophthalmic drops when used long-term may lead to elevated intraocular pressure (IOP) and may induce cataract.
• IOP intraocular pressure
• Another object of certain embodiments of the present invention is to provide an ocular insert comprising a glucocorticoid such as dexamethasone that provides for sustained release of the glucocorticoid to the ocular surface through the tear fluid.
• Another object of certain embodiments of the present invention is to provide an ocular insert comprising a glucocorticoid such as dexamethasone that provides for sustained release of the glucocorticoid to the ocular surface through the tear fluid, wherein the period of sustained release comprises a period of constant glucocorticoid release per day.
• Another object of certain embodiments of the present invention is to provide an ocular insert comprising a glucocorticoid such as dexamethasone that provides for a treatment of DED for a period of one or more weeks, with only a single administration.
• Another object of certain embodiments of the present invention is to provide an ocular insert comprising a glucocorticoid such as dexamethasone that increases tear retention in the eye.
• Another object of certain embodiments of the present invention is to provide an ocular insert comprising a glucocorticoid such as dexamethasone that provides for sustained delivery of a glucocorticoid such as dexamethasone for both anti-inflammatory therapy and increased tear retention resulting in an additive or synergistic, beneficial effect that has both a rapid onset and that is maintained for an extended period of time after administration, such as a period of one or more weeks, with only a single administration.
• a glucocorticoid such as dexamethasone
• Another object of certain embodiments of the present invention is to provide an ocular insert comprising a glucocorticoid such as dexamethasone that is sufficiently biodegradable, thereby avoiding the need for removal of the drug-depleted insert.
• Another object of certain embodiments of the present invention is to provide an ocular insert comprising a glucocorticoid such as dexamethasone that, after the period of glucocorticoid release to the ocular surface through the tear film, has a prolonged therapeutic effect of tear retention.
• Another object of certain embodiments of the present invention is to provide an ocular insert comprising a glucocorticoid such as dexamethasone that is biocompatible and low or non-immunogenic due to certain embodiments of the insert being free of animal- or human-derived components.
• Another object of certain embodiments of the present invention is to provide an ocular insert 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 insert comprising a glucocorticoid such as dexamethasone that is dimensionally stable when in a dry state but changes its dimensions upon hydration, e.g. after administration to the eye.
• Another object of certain embodiments of the present invention is to provide an ocular insert comprising a glucocorticoid such as dexamethasone that is administered in a dry state and hydrates when inserted e.g. into the canaliculus.
• Another object of certain embodiments of the present invention is to provide an ocular insert comprising a glucocorticoid such as dexamethasone that in its dry state is easy to administer but that is firmly secured in the canaliculus, avoiding potential insert loss during the treatment period, thereby providing improved retention, especially when compared to commonly applied plugs such as collagen or silicone plugs.
• Another object of certain embodiments of the present invention is to provide an ocular insert comprising a glucocorticoid such as dexamethasone, wherein the insert is stable and has a defined shape and surface area both prior to as well as after insertion (i.e., inside the canaliculus).
• Another object of certain embodiments of the present invention is to provide an ocular insert comprising a glucocorticoid such as dexamethasone that is easy to handle, in particular that does not spill or fragment easily.
• Another object of certain embodiments of the present invention is to provide an ocular insert comprising a glucocorticoid such as dexamethasone that enables administration of an exact dose (within a broad dose range), thereby avoiding the risk of over- and under-dosing.
• Another object of certain embodiments of the present invention is to provide an ocular insert comprising a glucocorticoid such as dexamethasone that does not cause glucocorticoid peaks or substantial peaks that could potentially result in adverse effects such as elevated intraocular pressure, glaucoma and cataract.
• Another object of certain embodiments of the present invention is to provide an ocular insert comprising a glucocorticoid such as dexamethasone for the treatment of dry eye disease such as the acute treatment of DED that provides a lower incidence of side effects, such as burning, stinging or itching, as compared to commonly known dry eye therapies.
• Another object of certain embodiments of the present invention is to provide an ocular insert comprising a glucocorticoid such as dexamethasone that provides a hands-free alternative for the patient compared to conventional DED treatments.
• Another object of certain embodiments of the present invention is to provide an ocular insert comprising a glucocorticoid such as dexamethasone that is not subject to abuse, e.g. because it is administered by a physician.
• Another object of certain embodiments of the present invention is to provide an ocular insert comprising a glucocorticoid such as dexamethasone that generally stays in the area of the eye to which it was administered, such as in the inferior and/or superior (vertical) canaliculus.
• Another object of certain embodiments of the present invention is to provide an ocular insert 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 insert comprising a glucocorticoid such as dexamethasone that has increased patient compliance as compared to currently available DED treatments.
• Another object of certain embodiments of the present invention is to provide an ocular insert comprising a glucocorticoid such as dexamethasone that can be visualized in a fast and simple manner and by a non-invasive method.
• Another object of certain embodiments of the present invention is to provide an ocular insert comprising a glucocorticoid such as dexamethasone that provides for sustained release of a therapeutically effective amount of the glucocorticoid such as dexamethasone over an extended period of time, such as over 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 after administration.
• Another object of certain embodiments of the present invention is to provide an ocular insert comprising a glucocorticoid such as dexamethasone that releases a constant or essentially constant amount of the glucocorticoid such as dexamethasone over an extended period of time, such as 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 after administration.
• a glucocorticoid such as dexamethasone
• an extended period of time such as 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 after administration.
• Another object of certain embodiments of the present invention is to provide an ocular insert comprising a glucocorticoid such as dexamethasone that provides for sustained release of a therapeutically effective amount of the glucocorticoid such as dexamethasone over an extended period of time after administration, such as over 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, thereby avoiding the need for frequent glucocorticoid administrations, which are required e.g. several times a day when using ophthalmic drops.
• a glucocorticoid such as dexamethasone
• Another object of certain embodiments of the present invention is to provide an ocular insert comprising a glucocorticoid such as dexamethasone that provides for sustained release of a therapeutically effective amount of the glucocorticoid 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, wherein the glucocorticoid amount in the tear film is consistently maintained at a therapeutically effective level sufficient for anti-inflammatory therapy of the ocular surface.
• a glucocorticoid such as dexamethasone
• Another object of certain embodiments of the present invention is to provide an ocular insert comprising a glucocorticoid such as dexamethasone that provides for sustained release of a therapeutically effective amount of the glucocorticoid 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, wherein essentially no toxic concentrations of the glucocorticoid are observed on the ocular surface and/or in the tear film.
• a glucocorticoid such as dexamethasone
• Another object of certain embodiments of the present invention is to provide an ocular insert comprising a glucocorticoid such as dexamethasone that provides for sustained release of a therapeutically effective amount of the glucocorticoid 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, wherein the glucocorticoid is not resorbed systemically or not substantially resorbed systemically thereby minimizing or avoiding systemic toxicity.
• a glucocorticoid such as dexamethasone
• Another object of certain embodiments of the present invention is to provide a method of treating DED, in particular of acute treatment (of episodic flares) of DED, in a patient in need thereof.
• Another object of certain embodiments of the present invention is to provide a method of manufacturing an ocular insert comprising a glucocorticoid such as dexamethasone.
• the present invention enables the effective short-term treatment of signs and symptoms of DED through topical glucocorticoids such as dexamethasone by means of a simple, hands-free (e.g., physician-administered) insert that combines the benefits of an anti-inflammatory glucocorticoid therapy with the effect of tear conservation by means of punctal occlusion into one single therapy.
• a simple, hands-free insert e.g., physician-administered
• the insert of the invention in certain embodiments is administered only once at the beginning of the treatment period (e.g., to treat episodic flares of DED), and no repeated administration by the patient is thus necessary, over- or underdosing can be avoided, as well as potential abuse/misuse.
• the dose of glucocorticoid such as dexamethasone and the duration of release of the active is adjusted to conform to a short treatment period, e.g., of about 2 or about 3 weeks as required for the treatment of episodic flares of DED. Exposure to unnecessarily high doses of glucocorticoid as well as unnecessarily long exposure to glucocorticoid are reduced, thereby avoiding as much as possible potential adverse side effects of glucocorticoids that may be associated with long-term and/or high dose use or dose peaks, and patient abuse or misuse.
• the inserts of the present invention do not require antimicrobial perservatives and thereby further reduce the potential of e.g. allergic reactions or adverse effects that can be associated with preservatives often used in topically applied ocular formulations.
• the inserts of the present invention may also increase patient compliance due to increased convenience, and increase the effectiveness of the treatment of DED, including episodic flares of DED.
• FIG. 1 Schematic exemplary representation of insert placement into the inferior vertical canaliculus through the lower punctum of the eye (A). Visualization of the insert is possible e.g. by illumination with blue light (B). The fluorescein in the intracanalicular insert in one embodiment illuminates when excited with blue light enabling confirmation of insert presence in a non-invasive manner.
• Figure 3 Schematic exemplary representation of insert dimensional change upon contact with tear fluid after insertion of the dry insert into the canaliculus where it is hydrated by the tear fluid.
• Figure 4 In vitro dexamethasone release from intracanalicular inserts according to embodiments of the invention comprising 0.2 mg and 0.3 mg dexamethasone over time (in PBS at a pH of 7.4 at 37 °C).
• Figure 5 Pharmacokinetic profile of dexamethasone release into tear fluid of beagle dogs from a 0.22 mg dexamethasone insert to illustrate release from an insert according to an embodiment of the invention. Inserts were placed bilaterally into the punctum of 7 beagles (i.e., a total of 14 eyes) on day 0.
• Tear fluid samples were collected from beagle eyes with 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 insert into the canaliculus.
• Dexamethasone levels in tear fluid were measured by LC-MS/MS. Dexamethasone is presented as average values together with corresponding standard deviation error bars. Number of samples measured: For day 1, n was 6 eyes; for day 2, n was 8 eyes; for days 14 and 21, n was 7 eyes; for day 28, n was 6 eyes; for day 35, n was 2 eyes.
• a single insert delivered dexamethasone to the ocular surface for approximately 14 days, with a sustained level of dexamethasone in the tear fluid maintained through day 7, followed by a tapering from day 7 to day 14 with complete release 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 invention at different study time-points. Dexamethasone is released over time into the tear fluid primarily from the insert site proximal to the punctum opening. The darker shading of the insert reflects the presence of dexamethasone, and the clearing reflects the zone of the insert depleted of dexamethasone.
• Dexamethasone is essentially completely released from the 0.37 mg insert after 28 days.
• insert refers to an object that contains an active agent, specifically a glucocorticoid such as dexamethasone and that is administered into the human or animal body, such as to the canaliculus of the eye (one eye or both eyes, as well as inferior and/or superior canaliculus), where it remains for a certain period of time while it releases the active agent into the surrounding environment.
• An insert can have any predetermined shape before being inserted, which general shape may be maintained to a certain degree upon placing the insert into the desired location, although dimensions of the insert (e.g. length and/or diameter) may change after administration due to hydration as further disclosed herein.
• the insert in certain embodiments is biodegraded (as disclosed herein), and may thereby change its shape (e.g. may expand in diameter and decrease in length) until it has been completely dissolved/resorbed.
• the term “insert” is used to refer both to an insert in a hydrated (also referred to herein as “wet”) state when it contains water, e.g.
• an insert in its dry/dried state in the context of the present invention may contain no more than about 1% by weight water.
• the water content of an insert in its dry/dried state may be measured e.g. by means of a Karl Fischer coulometric method.
• the insert i.e., length, diameter, or volume
• these dimensions are measured after the insert has been immersed in phosphate-buffered saline at a pH value of 7.4 at 37 °C for 24 hours.
• these dimensions are measured after the insert has been fully dried (and thus, in certain embodiments, contains no more than about 1 % by weight water).
• the insert is kept in an inert atmosphere glove box containing below 20 ppm of both oxygen and moisture for at least about 7 days.
• the term “fiber” characterizes an object (i.e., in the present case an insert according to certain embodiments of the present invention) that in general has an elongated shape.
• 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 the insert may be either round or essentially round, but may in certain embodiments also be oval or oblong, or may in other embodiments have different geometries, such as cross-shaped, star-shaped or other as disclosed herein.
• ocular refers to the eye in general, or any part or portion of the eye (as an “ocular insert” according to the invention refers to an insert that can in principle be administered to any part or portion of the eye).
• the present invention in certain embodiments is directed to intracanalicular administration of an ocular insert (in this case the “ocular insert” is thus an “intracanalicular insert”), and to the treatment of dry eye disease (DED), as further disclosed herein.
• DED dry eye disease
• biodegradable refers to a material or object (such as the intracanalicular insert according to the present invention) which becomes degraded in vivo, i.e., when placed in the human or animal body.
• the insert comprising the hydrogel within which particles of a glucocorticoid, such as particles of dexamethasone, are dispersed, slowly biodegrades over time once deposited within the eye, e.g., within the canaliculus.
• biodegradation takes place at least in part via ester hydrolysis in the aqueous environment provided by the tear fluid.
• the intracanalicular inserts of the present invention slowly soften and liquefy, and are eventually cleared (disposed/washed out) through the nasolacrimal duct.
• a “hydrogel” is a three-dimensional network of one or more hydrophilic natural or synthetic polymers (as disclosed herein) that can swell in water and hold an amount of water while maintaining or substantially maintaining its structure, e.g., due to chemical or physical cross-linking of individual polymer chains. Due to their high water content, hydrogels are soft and flexible, which makes them very similar to natural tissue.
• the term “hydrogel” is used to refer both to a hydrogel in the hydrated state (also referred to herein synonymously as the “wet state”) when it contains water (e.g.
• the hydrogel after the hydrogel has been formed in an aqueous solution, or after the hydrogel has been hydrated or re-hydrated once inserted into the eye or otherwise immersed into an aqueous environment) and to a hydrogel in its/a dry (dried/dehydrated) state when it has been dried to a low water content of e.g. not more than 1% by weight as disclosed herein.
• the hydrogel may also be referred to as a “matrix”.
• polymer network as used herein describes a structure formed of polymer chains (of the same or different molecular structure and of the same or different average molecular weight) that are cross-linked with each other. Types of polymers suitable for the purposes of the present invention are disclosed herein. The polymer network may be formed with the aid of a crosslinking agent as also disclosed herein.
• amorphous refers to a polymer or polymer network or other chemical substance or entity which does not exhibit crystalline structures in X-ray or electron scattering experiments.
• micro-crystalline refers to a polymer or polymer network or other chemical substance or entity which possesses some crystalline character, i.e., exhibits some crystalline properties in X-ray or electron scattering experiments.
• crystalline refers to a polymer or polymer network or other chemical substance or entity which has crystalline character as evidenced by X-ray or electron scattering experiments.
• precursor“ or “polymer precursor” or specifically “PEG precursor” herein refers to those molecules or compounds that are reacted with each other and that are thus connected via crosslinks to form a polymer network and thus the hydrogel matrix.
• polystyrene resin While other materials might be present in the hydrogel, such as active agents, visualization agents or buffers, they are not referred to as “precursors”. [0060]
• the molecular weight of a polymer precursor as used for the purposes of the present invention and as disclosed herein may be determined by analytical methods known in the art.
• the molecular weight of polyethylene glycol can for example be determined by any method known in the art, including gel electrophoresis such as SDS- PAGE (sodium dodecyl sulphate–polyacrylamide gel electrophoresis), gel permeation chromatography (GPC), including GPC with dynamic light scattering (DLS), liquid chromatography (LC), as well as mass spectrometry such as matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) spectrometry or electrospray ionization (ESI) mass spectrometry.
• gel electrophoresis such as SDS- PAGE (sodium dodecyl sulphate–polyacrylamide gel electrophoresis), gel permeation chromatography (GPC), including GPC with dynamic light scattering (DLS), liquid chromatography (LC), as well as mass spectrometry such as matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF)
• the molecular weight of a polymer is an average molecular weight (based on the polymer’s molecular weight distribution), and may therefore be indicated by means of various average values, including the weight average molecular weight (Mw) and the number average molecular weight (Mn). Any of such average values may generally be used in the context of the present invention.
• the average molecular weight of the polyethylene glycol units or other precursors or units as disclosed herein is the number average molecular weight (Mn) and is indicated in the unit “Daltons”.
• the “units” are thus the building blocks or constituents of a polymer network forming the hydrogel.
• a polymer network suitable for use in the present invention may contain identical or different polyethylene glycol units as further disclosed herein.
• crosslinking agent or “crosslinker” refers to any molecule that is suitable for connecting precursors via crosslinks to form the polymer network and thus the hydrogel matrix.
• crosslinking agents may be low-molecular weight compounds or may be polymeric compounds as disclosed herein.
• sustained release is generally defined for the purposes of the present invention to refer to pharmaceutical dosage forms or products (in the case of the present invention these products are inserts) which are formulated to make an active, 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 or more weeks, thereby allowing a reduction in dosing frequency compared to an immediate release dosage form, e.g. a solution of a glucocorticoid that is topically applied onto the eye (i.e. glucocorticoid-comprising eye drops).
• an active such as a glucocorticoid according to the present invention, specifically including but not limited to dexamethasone
• sustained release thus generally characterizes the release of an API, specifically, the glucocorticoid, such as dexamethasone, that is contained in an insert according to the present invention.
• the term “sustained release” per se is not associated with or limited to a particular rate of (in vitro or in vivo) release, although in certain embodiments of the invention an insert may be characterized by a certain average rate of (in vitro or in vivo) release or a certain release profile as disclosed herein.
• sustained release As an insert of the present invention (whether explicitly referred to herein as a “sustained release” insert or simply as an “insert”) provides for sustained release of the API, an insert of the present invention may therefore also be referred to as a “depot”.
• sustained release also comprises a period of constant or substantially constant (i.e, above a certain level) glucocorticoid release per day when this period of constant or substantially constant release is followed by a period of tapered glucocorticoid release.
• an overall sustained release provided by an insert of the present invention may mean that the release rate is not necessarily constant or essentially constant throughout the entire period of glucocorticoid release, but may change over time as just described (i.e., with an initial period of constant or essentially constant, i.e., sustained release, followed by a period of tapered release).
• the term “tapered” or “tapering” refers to a decreasing release of glucocorticoid such as dexamethasone over time until the glucocorticoid is completely released.
• the term “visualization agent” as used herein refers to a molecule or composition that may be contained within an insert of the present invention and that provides the possibility of easily visualizing the insert in a non- invasive manner when it is located in the canaliculus of the eye, e.g. by illuminating the corresponding eye parts with a suitable light source, such as blue light.
• the visualization agent may be a fluorophore such as fluorescein, rhodamine, coumarin, and cyanine, or other suitable agents as disclosed herein.
• the visualization agent is fluorescein or includes a fluorescein moiety.
• the term “ocular surface” comprises the conjunctiva and the cornea, together with elements such as the lacrimal apparatus, including the lacrimal punctum, as well as the lacrimal canaliculus and associated eyelid structures. Within the meaning of this invention, the ocular surface encompasses also the aqueous humor.
• the terms “tear fluid” or “tears” or “tear film” refer to the liquid secreted by the lacrimal glands, which lubricates the eyes. Tears are made up of water, electrolytes, proteins, lipids, and mucins.
• the term “bilaterally” or “bilateral” refers (in the context of administration of the inserts of the present invention) to an administration of the inserts into both eyes of a patient. “Unilaterally” or “unilateral” thus refers to an administration of the insert into one eye only. The inserts may be independently inserted into the superior and/or the inferior canaliculus of both eyes or of one eye.
• the terms “administration” or “administering” or “administered” etc. in the context of the inserts of the present invention refer to the process of insertion of the inserts through the opening of the punctum into the canaliculus of the eye.
• administering an insert refers to the insertion of the insert into the canaliculus.
• insertion or “inserting” or “inserted” etc. in the context of the inserts of the present invention equally refer to the process of insertion of the inserts through the opening of the punctum into the canaliculus of the eye and are thus herein used interchangeably with the terms “administration” or “administering” or “administered”.
• administration or “administering” or “administered” etc. in the context of topical ophthalmic pharmacological products such as eye drops (which are not the subject of the present invention) refer to topical application of these products onto the eye.
• the term “insert stacking” or “stacking” refers to the insertion of a further insert on top of a first insert while the first insert is still retained in the canaliculus (because it has not yet sufficiently biodegraded and/or has not yet cleared through the nasolacrimal duct).
• the further insert is placed on top of the first insert after the glucocorticoid contained in the first insert is completely or essentially completely released, or after at least about 70% or at least about 80% or at least about 90% of the glucocorticoid contained in the first insert has been released. Insert stacking enables, for instance, prolonged glucocorticoid treatment.
• plug refers to a device capable of providing an occlusion, substantial occlusion or partial occlusion of the tear duct(s) (“lacrimal occlusion”) thereby minimizing or preventing draining of tears.
• a plug thus increases tear retention, which helps to keep the eyes moist.
• Plugs can be classified into “punctal plugs” and “intracanalicular plugs”.
• Intracanalicular plugs are also referred to as “canalicular plugs” in literature. Both plug classes are inserted through the upper and/or lower punctum of the eye. Punctal plugs rest at the punctal opening making them easily visible and, hence, removable without much difficulty.
• punctal plugs may show poor retention rates and can be more easily contaminated with microbes due to their exposed localization which may result in infection.
• intracanalicular plugs are essentially not visible and provide a better retention rate compared to punctal plugs as they are placed inside either the vertical or the horizontal canaliculus.
• currently available intracanalicular plugs may not be easy to remove and/or may provide an increased risk of migration due to loose fit.
• Commercially available plugs are often made of collagen, acrylic polymers, or silicone.
• Canaliculi therefore form part of the lacrimal apparatus that drains lacrimal fluid from the ocular surface to the nasal cavity.
• the canaliculus in the upper eyelid is referred to as “superior canaliculus” or “upper canaliculus”, whereas the canaliculus in the lower eyelid is referred to as “inferior canaliculus” or “lower canaliculus”.
• Each canaliculus comprises a vertical region, referred to as “vertical canaliculus” following the lacrimal punctum and a horizontal region, referred to as “horizontal canaliculus” following the vertical canaliculus, wherein the horizontal canaliculus merges into the nasolacrimal duct.
• the term “punctum” refers to the lacrimal punctum, an opening on the margins of the eyelids, representing the entrance to the canaliculus. After tears are produced, some fluid evaporates between blinks, and some is drained through the lacrimal punctum.
• the puncta are therefore referred to as “upper punctum” or “superior punctum” and “lower punctum” or “inferior punctum”, respectively (see also Figure 2A).
• the term “intracanalicular insert” refers to an insert that can be administered through the upper and/or lower punctum into the superior and/or inferior canaliculus of the eye, in particular into the superior and/or inferior vertical canaliculus of the eye. Due to the intracanalicular localization of the insert, the insert blocks tear drainage through lacrimal occlusion such as also observed for intracanalicular plugs.
• the intracanalicular inserts of the present invention may be inserted bilaterally or unilaterally into the inferior and/or superior vertical canaliculi of the eyes.
• the intracanalicular insert is a sustained release biodegradable insert.
• the terms “API”, “active (pharmaceutical) ingredient”, “active (pharmaceutical) agent”, “active (pharmaceutical) principle”, “(active) therapeutic agent”, “active”, and “drug” are used interchangeably herein and refer to the substance used in a finished pharmaceutical product (FPP) as well as the substance used in the preparation of such a finished pharmaceutical product, intended to furnish pharmacological activity or to otherwise have direct effect in the diagnosis, cure, mitigation, treatment or prevention of a disease, or to have direct effect in restoring, correcting or modifying physiological functions in a patient.
• the API used according to the present invention is a glucocorticoid such as dexamethasone.
• Glucocorticoids are a class of corticosteroids, which are a class of steroid hormones.
• the name "glucocorticoid” is a portmanteau (glucose + cortex + steroid) and is composed from its role in regulation of glucose metabolism, synthesis in the adrenal cortex, and its steroidal structure.
• a less common synonym is glucocorticosteroid.
• Glucocorticoids act through glucocorticoid receptor-mediated pathways present in most cells in the body to regulate gene expression, and through non-receptor pathways to inhibit inflammatory cytokine (TNF alpha, IL-1a, and IL-6) and chemokine production and decrease the synthesis of matrix metalloproteinases (Rosenbaum et al., 1980; Nature 286(5773): 611-613).
• Glucocorticoids such as dexamethasone, suppress inflammation by inhibiting edema, fibrin deposition, capillary deposition, and phagocytic migration of the inflammatory response (Chrousos 1995, NEJM 332(20): 1351- 1362; Abelson et al.
• glucocorticoids do not appear to have a specific mechanism of action in ocular tissues but exert a broad spectrum of anti-inflammatory activity (Leopold 1985, M.L. 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 a relatively short duration (about 2 to 3 weeks), due to concerns regarding potential side effects associated with prolonged use.
• Cortisol (or the synthetic form, referred to as hydrocortisone) is the most important human glucocorticoid.
• 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, fluorometholone, mometasone
• the glucocorticoid is a low solubility glucocorticoid (i.e., having a solubility in water of less than about 100 ⁇ g/mL), including (but not limited to) beclomethasone dipropionate, betamethasone sodium phosphate, budesonide, flunisolide, fluticasone propionate, triamcinolone acetonide, triamcinolone hexacetonide, triamcinolone diacetate, dexamethasone, dexamethasone acetate, prednisolone acetate, loteprednol etabonate, difluprednate, fluorometholone, fluocinolone acetonide, and mometasone furoate.
• beclomethasone dipropionate betamethasone sodium phosphate, budesonide, flunisolide, fluticasone propionate
• glucocorticoid potencies are reported as relative potencies in view of cortisol potency. Determination of equivalent glucocorticoid doses is well established in the art. Equivalent oral doses and relative oral glucocorticoid potencies are presented in Table 1 for exemplarily selected glucocorticoids (see for instance, Buttgereit et al. 2002, Ann Rheum Dis 61:718-722, which is incorporated herein by reference). Table 1 Established equivalent oral doses and relative oral glucocorticoid potencies (with reference to cortisol) of exemplarily selected glucocorticoids.
• the term “equivalent dose” refers to a dose of an active such as a glucocorticoid that is equivalent in terms of biological activity to a dose of another active such as another glucocorticoid when delivered via the same administration route (e.g. oral, intravenous, topical, or via the intracanalicular inserts of the present application).
• Examples for equivalent oral doses of glucocorticoids are presented in Table 1. For instance, upon oral administration of 20 mg hydrocortisone, similar biological effects are to be expected when compared to oral administration of 0.8 mg dexamethasone.
• the glucocorticoid used according to the present invention is dexamethasone.
• Dexamethasone is a long-acting anti-inflammatory 9-fluoro glucocorticoid (also termed 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- Fluor-11 ⁇ ,17,21-trihydroxy-16 ⁇ -methyl-pregna-1,4-dien-3,20-dion (CAS No. 50-02-2).
• the chemical structure of dexamethasone is reproduced below: [0080] Dexamethasone is a white to practically white, odorless crystalline powder with poor solubility in water (approx. 89 mg/L at 25 °C).
• n-octanol/water Its partition coefficient (n-octanol/water) is 1.83 (logP; cf. DrugBank entry “dexamethasone”).
• particle sizes e.g. as expressed by the d90 value of about 100 ⁇ m or below, or of about 75 ⁇ m or below, or of about 50 ⁇ m or below may be used.
• dexamethasone may be used in the form of micronized particles and may have a d90 particle size of equal to or less than about 100 ⁇ m, or of equal to or less than about 75 ⁇ m, or of equal to or less than about 50 ⁇ m, or of equal to or less than about 20 ⁇ m, or of equal to or less than about 10 ⁇ m, or of equal to or less than about 5 ⁇ m.
• the d98 particle size of the micronized dexamethasone may be equal to or less than about 100 ⁇ m, or equal to or less than about 75 ⁇ m, or equal to or less than about 50 ⁇ m, or equal to or less than about 20 ⁇ m, or equal to or less than about 10 ⁇ m, or equal to or less than about 5 ⁇ m.
• the micronized dexamethasone has a d90 particle size of equal to or less than about 5 ⁇ m and a d98 particle size of less than about 10 ⁇ m.
• the “d90” value means that at least 90 volume-% of all particles within the measured bulk material (which has a certain particle size distribution) has a particle size below the indicated value.
• a d90 particle size of less than about 50 ⁇ m means that at least 90 volume-% of the particles in the measured bulk material have a particle size below about 50 ⁇ m.
• other “d” values such as the “d98” value.
• the particle size distribution can be measured by methods known in the art, including sieving, laser diffraction or dynamic light scattering. In embodiments in which another glucocorticoid than dexamethasone is used in the present invention similar particle sizes may apply as disclosed for dexamethasone.
• the dexamethasone used for manufacturing the inserts according to the present invention has a d90 particle size of equal to or less than about 5 ⁇ m, and a d98 particle size of less than about 10 ⁇ m, with all or essentially all discrete particles having a size of less than about 90 ⁇ m.
• active agents including dexamethasone
• active agent polymorphs or any pharmaceutically acceptable salts, anhydrates, hydrates, other solvates or derivatives of active agents can be used.
• an active agent is referred to by name, e.g., “dexamethasone”, even if not explicitly stated, it also refers to any such pharmaceutically acceptable polymorphs, salts, anhydrates, solvates (including hydrates) or derivatives of the active agent.
• the term “dexamethasone” refers to dexamethasone and pharmaceutically acceptable salts thereof, which may all be used for the purposes of the present invention.
• polymorph refers to any crystalline form of an active agent such as dexamethasone.
• dexamethasone polymorphs can be used for preparing inserts according to the embodiments of the present invention.
• suitable solid forms including amorphous forms and polymorphs of dexamethasone are for example disclosed in Oliveira et al., Cryst. Growth Des.
• dexamethasone alcohol
• suitable solid forms of dexamethasone for use in the present invention include for example (without being limited to these) dexamethasone sodium phosphate, dexamethasone acetate, dexamethasone benzoate, dexamethasone 21-(adamantane-1-carboxylate), dexamethasone isonicotinate, dexamethasone valerate, dexamethasone tebutate, dexamethasone 21-sulfobenzoate, dexamethasone sodium- metasulfobenzoate, dexamethasone palmitate, dexamethasone cipecilate, dexamethasone carboxamide,
• the term “therapeutically effective” refers to the amount of drug or active agent (i.e. glucocorticoid) required to produce a desired therapeutic response or result after administration.
• drug or active agent i.e. glucocorticoid
• one desired therapeutic result would be the reduction of symptoms associated with DED.
• DED refers to “dry eye disease” or “dry eye”.
• dry eye disease As used herein, the terms “dry eye disease”, “DED”, or “dry eye” are used interchangeably and bear equivalent meanings. DED is also referred to as “keratoconjunctivitis sicca (KCS)” in literature.
• DED refers to a multifactorial disorder of the tears and the ocular surface characterized by symptoms of dryness, irritation, burning, stinging, grittiness, foreign body sensation, tearing, and ocular fatigue.
• inflammation has a prominent role in the development and propagation of this debilitating condition.
• Factors that adversely affect tear film stability and osmolarity can induce ocular surface damage and initiate an inflammatory cascade that activates innate and adaptive immune responses. These immunoinflammatory responses lead to further ocular surface damage and the development of a self-perpetuating inflammatory cycle.
• DED is thought to be a chronic state, with episodic flares encompassing rapid onset of symptoms or symptom worsening, highly affecting daily life of patients.
• episodic flares refers to a condition, wherein rapid onset of DED symptoms or DED symptom worsening occurs. In between the relatively short-term episodic flares of DED, symptoms may mostly not be experienced or only mildly experienced.
• the present invention specifically relates to the acute (short-term) treatment of episodic flares of DED such as, for example, 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.
• the terms “acute treatment” or “acute treating” or similar phrases refer to a short-term treatment or short-term treating of DED, such as of episodic flares of DED.
• the acute treatment period with a glucocorticoid contained in an insert according to the present invention is about one week or more weeks such as about 2 or about 3 weeks.
• the term “patient” herein includes both human and animal patients.
• the inserts according to the present invention are generally suitable for human or veterinary medicinal applications.
• the patients enrolled and treated in a clinical study may also be referred to as “subjects”.
• a “subject” is a (human or animal) individual to which an insert 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.
• the term “average” as used herein refers to a central or typical value in a set of data(points), which is calculated by dividing the sum of the data(points) in the set by their number (i.e., the mean value of a set of data).
• the term “about” in connection with a measured quantity refers to the normal variations in that measured quantity, as expected by one of ordinary skill in the art in making the measurement and exercising a level of care commensurate with the objective of measurement and the precision of the measuring equipment.
• the term “at least about” in connection with a measured quantity refers to the normal variations in the measured quantity, as expected by one of ordinary skill in the art in making the measurement and exercising a level of care commensurate with the objective of measurement and precisions of the measuring equipment and any quantities higher than that.
• the singular forms "a,” “an”, and “the” include plural references unless the context clearly indicates otherwise.
• the term “up to 25 days” means “up to and including 25 days”.
• the abbreviation “PBS” when used herein means phosphate-buffered saline.
• PEG when used herein means polyethylene glycol.
• All references disclosed herein are hereby incorporated by reference in their entireties for all purposes (with the instant specification prevailing in case of conflict).
• the insert [0101] The present invention generally relates to a sustained release biodegradable ocular insert comprising a hydrogel and a glucocorticoid, wherein glucocorticoid particles are dispersed within the hydrogel.
• the insert is for administration into the canaliculus of the eye, i.e., is an intracanalicular insert.
• the present invention in one aspect relates to a sustained release biodegradable ocular (such as intracanalicular) insert comprising a hydrogel and a glucocorticoid, wherein glucocorticoid particles are dispersed within the hydrogel, and wherein the insert in its dry state has a length of less than about 2.75 mm.
• the present invention in another aspect generally relates to a sustained release biodegradable ocular (such as intracanalicular) insert comprising a hydrogel and equal to or less than about 375 ⁇ g dexamethasone or an equivalent dose of another glucocorticoid.
• the present invention in another aspect generally relates to a sustained release biodegradable ocular (such as intracanalicular) insert comprising a hydrogel and a glucocorticoid, wherein the insert in a dry state (such as prior to being administered) has a length of equal to or less than about 2.75 mm.
• the present invention in another aspect generally relates to a sustained release biodegradable ocular (such as intracanalicular) insert comprising a hydrogel and a glucocorticoid, wherein the insert provides for a release of a therapeutically effective amount of the glucocorticoid for a period of up to about 25 days after administration.
• a particular glucocorticoid for use in the present invention is dexamethasone.
• the ocular insert in certain embodiments of the invention may be an intracanalicular insert, i.e., the insert is for insertion/administration into the canaliculus of one or both eye(s).
• the present invention relates to a sustained release biodegradable intracanalicular insert comprising a hydrogel and dexamethasone as the glucocorticoid, wherein the insert comprises equal to or less than about 375 ⁇ g dexamethasone, has a length of equal to or less than about 2.75 mm and provides for a release of a therapeutically effective amount of dexamethasone for a period of up to about 25 days after administration.
• the present invention in certain embodiments generally relates to a sustained release biodegradable ocular (such as an intracanalicular) insert comprising a hydrogel and a glucocorticoid.
• a sustained release biodegradable ocular such as an intracanalicular
• glucocorticoid for use in all aspects of the present invention is dexamethasone. Details on dexamethasone, its chemical structure and its properties such as solubility are disclosed herein in the definitions section.
• the present invention relates to a sustained release biodegradable intracanalicular insert comprising a hydrogel and equal to or less than about 375 ⁇ g dexamethasone or an equivalent dose of another glucocorticoid.
• the present invention relates to a sustained release biodegradable intracanalicular insert comprising a hydrogel and equal to or less than about 350 ⁇ g dexamethasone or an equivalent dose of another glucocorticoid.
• the glucocorticoid contained in a sustained release biodegradable ocular (such as intracanalicular) insert is dexamethasone, and is present in the insert in a range of doses, from about 100 ⁇ g to about 350 ⁇ g, or from about 150 ⁇ g to about 320 ⁇ g.
• Any dexamethasone amount within these dose ranges may be used, such as about 100 ⁇ g, about 150 ⁇ g, about 200 ⁇ g, about 250 ⁇ g, about 300 ⁇ g, about 320 ⁇ g, about 350 ⁇ g etc., all values also including a variance of +25% and -20%, or a variance of ⁇ 10%.
• the doses of dexamethasone contained in an insert of the invention are: - In a range from about 160 ⁇ g to about 250 ⁇ g, or in a range from about 180 ⁇ g to about 220 ⁇ g, or in very particular embodiments about 200 ⁇ g (i.e., including a variance of +25% and -20%, or a variance of ⁇ 10% of 200 ⁇ g), or - In a range from about 240 ⁇ g to about 375 ⁇ g, or in a range from about 270 ⁇ g to about 330 ⁇ g, or in very particular embodiments about 300 ⁇ g (i.e., including a variance of +25% and -20%, or a variance of ⁇ 10% of 300 ⁇ g).
• the dose of the glucocorticoid such as dexamethasone in the insert of the invention may be from about 50 ⁇ g to about 500 ⁇ g, such as about 50 ⁇ g, about 100 ⁇ g, about 150 ⁇ g, about 200 ⁇ g, about 250 ⁇ g, about 300 ⁇ g, about 350 ⁇ g, about 400 ⁇ g, about 450 ⁇ g, or about 500 ⁇ g dexamethasone or an equivalent dose of another glucocorticoid. In exceptional cases, such dose may be above 500 ⁇ g.
• glucocorticoid other than dexamethasone is used in a sustained release biodegradable intracanalicular insert according to the invention, a dose of that other glucocorticoid is contained in the insert that is equivalent to any of the dose amounts and ranges disclosed above for dexamethasone. Suitable conversion factors between glucocorticoids are known in the art and may be applied (see the section “Definitions” above).
• the disclosed amounts of glucocorticoid, such as dexamethasone, including the mentioned variances refer to both the final content of the active principle in the insert, as well as to the amount of active principle used as a starting component when manufacturing the insert.
• the sustained release biodegradable intracanalicular insert of the present invention is defined by a length of equal to or less than about 2.75 mm (as disclosed herein below) and/or a release of a therapeutically effective amount of a glucocorticoid for a period of up to about 25 days after administration (as disclosed herein below)
• the dose of the dexamethasone (or equivalent dose of another glucocorticoid) contained in the insert may also exceed 375 ⁇ g, and may also be about 400 ⁇ g or higher, such as from about 400 ⁇ g to about 600 ⁇ g, or of about 500 ⁇ g dexamethasone.
• the glucocorticoid such as dexamethasone
• the insert of the invention such that particles of the glucocorticoid are dispersed or distributed in a hydrogel comprised of a polymer network.
• the particles are homogeneously dispersed in the hydrogel.
• the hydrogel may prevent the drug particles from agglomerating and may provide a matrix for the particles which releases the drug in a sustained manner upon contact with the tear fluid.
• the glucocorticoid particles may be microencapsulated.
• microcapsule is sometimes defined as a roughly spherical particle with a size varying between e.g. about 50 nm to about 2 mm. Microcapsules have at least one discrete domain (or core) of active agent encapsulated in a surrounding or partially surrounding material, sometimes also referred to as a shell.
• a suitable agent for microencapsulating the glucocorticoid, such as the dexamethasone, for the purposes of the present invention is poly(lactic-co-glycolic acid).
• the glucocorticoid particles may have a small particle size and may be micronized particles. In another embodiment, the glucocorticoid particles, such as the dexamethasone particles, may not be micronized. Micronization refers to the process of reducing the average diameter of particles of a solid material. Particles with reduced diameters may have inter alia higher dissolution rates, which increases the bioavailability of active pharmaceutical ingredients. In the composite materials field, particle size is known to affect the mechanical properties when combined with a matrix, with smaller particles providing superior reinforcement for a given mass fraction.
• a hydrogel matrix within which micronized glucocorticoid particles are dispersed may have improved mechanical properties (e.g. brittleness, strain to failure, etc.) compared to a similar mass fraction of larger glucocorticoid particles. Such properties are important in manufacturing, during administration, and during degradation of the insert. Micronization may also promote a more homogeneous distribution of the active ingredient in the chosen dosage form or matrix.
• particle sizes e.g.
• dexamethasone may be used in the form of micronized particles and may have a d90 particle size of equal to or less than about 100 ⁇ m, or of equal to or less than about 75 ⁇ m, or of equal to or less than about 50 ⁇ m, or of equal to or less than about 20 ⁇ m, or of equal to or less than about 10 ⁇ m, or of equal to or less than about 5 ⁇ m.
• the d98 particle size of the micronized dexamethasone may be equal to or less than about 100 ⁇ m, or equal to or less than about 75 ⁇ m, or equal to or less than about 50 ⁇ m, or equal to or less than about 20 ⁇ m, or equal to or less than about 10 ⁇ m, or equal to or less than about 5 ⁇ m.
• the micronized dexamethasone used in (or used for preparing) an insert of the present invention has a d90 particle size of equal to or less than about 5 ⁇ m and a d98 particle size of less than about 10 ⁇ m.
• glucocorticoid in particular the dexamethasone
• similar particle sizes may apply as disclosed for dexamethasone.
• starting material that are larger than a certain size, such as larger than about 120 ⁇ m, or larger than about 100 ⁇ m, or larger than about 90 ⁇ m
• the bulk glucocorticoid material meeting the (d90 and/or d98) particle size specification(s) as disclosed herein may be sieved prior to preparing the wet composition of the insert.
• the dexamethasone used for manufacturing the inserts according to the present invention has a d90 particle size of equal to or less than about 5 ⁇ m, and a d98 particle size of less than about 10 ⁇ m, with all or essentially all discrete particles having a size of less than about 90 ⁇ m.
• Micronized dexamethasone particles may be purchased per specification from the supplier (e.g. from Pfizer or Sanofi), or may be prepared according to any of the processes known in the art. For example, micronization processes may be used as e.g.
• the hydrogel may be formed from precursors having functional groups that form crosslinks to create a polymer network. These crosslinks between polymer strands or arms may be chemical (i.e., may be covalent bonds) and/or physical (such as ionic bonds, hydrophobic association, hydrogen bridges etc.) in nature.
• the polymer network may be prepared from precursors, either from one type of precursor or from two or more types of precursors that are allowed to react. Precursors are chosen in consideration of the properties that are desired for the resultant hydrogel. There are various suitable precursors for use in making the hydrogels. Generally, any pharmaceutically acceptable and crosslinkable polymers forming a hydrogel may be used for the purposes of the present invention. The hydrogel and thus the components incorporated into it, including the polymers used for making the polymer network, should be physiologically safe such that they do not elicit e.g. an immune response or substantial immune response or other adverse effects. Hydrogels may be formed from natural, synthetic, or biosynthetic polymers.
• Natural polymers may include glycosaminoglycans, polysaccharides (e.g. dextran), polyaminoacids and proteins or mixtures or combinations thereof, while this list is not intended to be limiting.
• Synthetic polymers may generally be any polymers that are synthetically produced from a variety of feedstocks by different types of polymerization, including free radical polymerization, anionic or cationic polymerization, chain-growth or addition polymerization, condensation polymerization, ring-opening polymerization etc. The polymerization may be initiated by certain initiators, by light and/or heat, and may be mediated by catalysts.
• Synthetic polymers may in certain embodiments be used to lower the potential of allergies in dosage forms that do not contain any ingredients from human or animal origin.
• one or more synthetic polymers of the group comprising one or more units of polyalkylene glycol, particularly including but not limited to polyethylene glycol (PEG), polyalkylene oxide such as polyethylene oxide, polypropylene oxide, polyvinyl alcohol, poly (vinylpyrrolidinone), polylactic acid, polylactic-co-glycolic acid, random or block copolymers or combinations/mixtures of any of these can be used, while this list is not intended to be limiting.
• PEG polyethylene glycol
• polyalkylene oxide such as polyethylene oxide, polypropylene oxide, polyvinyl alcohol, poly (vinylpyrrolidinone)
• polylactic acid polylactic-co-glycolic acid
• random or block copolymers or combinations/mixtures of any of these can be used, while this list is not intended to be limiting.
• the precursors may be covalently cross
• precursors with at least two reactive centers can serve as crosslinkers since each reactive group can participate in the formation of a different growing polymer chain.
• the precursors may have biologically inert and hydrophilic portions, e.g., a core.
• a core refers to a contiguous portion of a molecule joined to arms that extend from the core, where the arms carry a functional group, which is often at the terminus of the arm or branch.
• Multi-armed PEG precursors are examples of such precursors and are used in particular embodiments of the present invention as further disclosed herein.
• a hydrogel for use in the present invention can be made e.g.
• a multi-armed precursor may have hydrophilic arms, e.g., polyethylene glycol units, terminated with primary amines (nucleophile), or may have activated ester end groups (electrophile).
• the polymer network according to the present invention may contain identical or different polymer units crosslinked with each other.
• the precursors may be high-molecular weight components (such as polymers having functional groups as further disclosed herein) or low-molecular weight components (such as low-molecular amines, thiols, esters etc. as also further disclosed herein).
• activating groups include (but are not limited to) carbonyldiimidazole, sulfonyl chloride, aryl halides, sulfosuccinimidyl esters, N- hydroxysuccinimidyl (abbreviated as “NHS”) ester, succinimidyl ester, benzotriazolyl ester, thioester, epoxide, aldehyde, maleimides, imidoesters, acrylates and the like.
• activating groups include (but are not limited to) carbonyldiimidazole, sulfonyl chloride, aryl halides, sulfosuccinimidyl esters, N- hydroxysuccinimidyl (abbreviated as “NHS”) ester, succinimidyl ester, benzotriazolyl ester, thioester, epoxide, aldehyde, maleimides, imidoesters,
• the NHS esters are useful groups for crosslinking with nucleophilic polymers, e.g., primary amine-terminated or thiol-terminated polyethylene glycols or other nucleophilic group-containing agents, such as nucleophilic group-containing crosslinking agents.
• An NHS-amine crosslinking reaction may be carried out in aqueous solution and in the presence of buffers, e.g., 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 9.0-10.0).
• buffers e.g., 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 9.0-10.0).
• each precursor may comprise only nucleophilic or only electrophilic functional groups, so long as both nucleophilic and electrophilic precursors are used in the crosslinking reaction.
• the precursor polymer may have electrophilic functional groups such as N-hydroxysuccinimides.
• the functional polymer may have nucleophilic functional groups such as amines or thiols.
• a precursor for the polymer network forming the hydrogel in which the glucocorticoid is dispersed to form the insert according to the present invention has about 2 to about 16 nucleophilic functional groups each (termed functionality), and in another embodiment a precursor has about 2 to about 16 electrophilic functional groups each (termed functionality).
• Reactive precursors having a number of reactive (nucleophilic or electrophilic) groups as a multiple of 4, thus for example 4, 8 and 16 reactive groups, are particularly suitable for the present invention.
• PEG hydrogels [0135]
• the polymer network forming the hydrogel contains polyethylene glycol (“PEG”) units.
• PEGs are known in the art to form hydrogels when crosslinked, and these PEG hydrogels are suitable for pharmaceutical applications e.g. as matrix for drugs intended to be administered to any part of the human or animal body.
• the polymer network of the hydrogel inserts of the present invention may comprise one or more multi-arm PEG units having from 2 to 10 arms, or from 4 to 8 arms, or 4, 5, 6, 7 or 8 arms.
• the PEG units used in the hydrogel of the present invention have 4 arms.
• the PEG units used in the hydrogel of the present invention have 8 arms.
• PEG units having 4 arms and PEG units having 8 arms are used in the hydrogel of the present invention.
• one or more 4- armed PEGs is/are utilized. Any combination of multi-armed PEGs may be used. In specific embodiments, only 4-arm PEG units are used (which may be the same or different).
• the number of arms of the PEG(s) used contributes to controlling the flexibility or softness of the resulting hydrogel.
• hydrogels formed by crosslinking 4-arm PEGs are generally softer and more flexible than those formed from 8-arm PEGs of the same molecular weight.
• a more flexible hydrogel may be used, such as a 4-arm PEG, optionally in combination with another multi-arm PEG, such as an 8-arm PEG as disclosed above, or another (different) 4-arm PEG.
• polyethylene glycol units used as precursors have an average molecular weight (Mn) in the range from about 2,000 to about 100,000 Daltons, or in a range from about 10,000 to about 60,000 Daltons, or in a range from about 15,000 to about 50,000 Daltons.
• the polyethylene glycol units have an average molecular weight in a range from about 10,000 to about 40,000 Daltons, or in a range from about 15,000 to about 30,000 Daltons, or in a range from about 15,000 to about 25,000 Daltons.
• the polyethylene glycol units used for making the hydrogels according to the present invention have an average molecular weight (Mn) of about 20,000 Daltons.
• Polyethylene glycol precursors of different molecular weight may be combined with each other.
• a variance of ⁇ 10% is intended to be included, i.e., referring to a material having an average molecular weight of about 20,000 Daltons also refers to such a material having an average molecular weight of about 18,000 to about 22,000 Daltons.
• the abbreviation “k” in the context of the molecular weight refers to 1,000 Daltons, i.e., “20k” means 20,000 Daltons.
• the indicated average molecular weight refers to the PEG part of the precursor, before end groups are added (“20k” here means 20,000 Daltons, and “15k” means 15,000 Daltons – the same abbreviation is used herein for other average molecular weights of PEG precursors).
• the Mn of the PEG part of the precursor is determined by MALDI.
• the degree of substitution with end groups as disclosed herein may be determined by means of 1 H-NMR after end group functionalization.
• each of the arms may have an average arm length (or molecular weight) of the total molecular weight of the PEG divided by 4.
• a 4a20kPEG precursor which is a particularly suitably precursor for use in the present invention thus has 4 arms with an average molecular weight of about 5,000 Daltons each and a total molecular weight of 20,000 Daltons.
• An 8a20k PEG precursor which could also be used in combination with or alternatively to the 4a20kPEG precursor in the present invention, thus has 8 arms (“8a”) each having an average molecular weight of 2,500 Daltons and a total molecular weight of 20,000 Daltons. Longer arms may provide increased flexibility as compared to shorter arms.
• PEGs with longer arms may swell more as compared to PEGs with shorter arms.
• a PEG with a lower number of arms also may swell more and may be more flexible than a PEG with a higher number of arms.
• only one or more 4-arm PEG precursor(s) is/are utilized in the present invention.
• a combination of one or more 4- arm PEG precursor(s) and one or more 8-arm PEG precursor(s) is utilized in the present invention.
• longer PEG arms have higher melting temperatures when dry, which may provide more dimensional stability during storage.
• electrophilic end groups for use with PEG precursors for preparing the hydrogels of the present invention are N-hydroxysuccinimidyl (NHS) esters, including but not limited to NHS dicarboxylic acid esters such as the succinimidylmalonate group, succinimidylmaleate group, succinimidylfumarate group, “SAZ” referring to a succinimidylazelate end group, “SAP” referring to a succinimidyladipate end group, “SG” referring to a succinimidylglutarate end group, and “SS” referring to a succinimidylsuccinate end group.
• NHS N-hydroxysuccinimidyl
• nucleophilic end groups for use with electrophilic group-containing PEG precursors for preparing the hydrogels of the present invention are amine (denoted as “NH 2 ”) end groups.
• Thiol (-SH) end groups or other nucleophilic end groups are also possible.
• 4-arm PEGs with an average molecular weight of about 20,000 Daltons and electrophilic end groups as disclosed above are crosslinked for forming the polymer network and thus the hydrogel according to the present invention.
• Suitable PEG precursors are available from a number of suppliers, such as Jenkem Technology and others.
• nucleophilic group-containing crosslinkers and electrophilic group-containing PEG units such as reaction of amine group-containing crosslinkers with activated ester-group containing PEG units, result in a plurality of PEG units being crosslinked by a hydrolyzable linker having the formula: wherein m is an integer from 0 to 10, and specifically is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
• m is an integer from 0 to 10, and specifically is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
• m would be 6, for a SAP-end group, m would be 3, for a SG-end group, m would be 2 and for an SS-end group, m would be 1.
• m is 2. All crosslinks within the polymer network may be the same, or may be different.
• the polymer precursors used for forming the hydrogel according to the present invention may be selected from 4a20kPEG-SAZ, 4a20kPEG-SAP, 4a20kPEG-SG, 4a20kPEG-SS, 8a20kPEG-SAZ, 8a20kPEG-SAP, 8a20kPEG-SG, 8a20kPEG-SS, or mixtures thereof, with one or more PEG- or lysine based-amine groups selected from 4a20kPEG-NH 2 , 8a20kPEG-NH 2 , and trilysine, or a trilysine salt or derivative, such as trilysine acetate.
• the SG end group is utilized in the present invention. This end group may provide for a shorter time until the hydrogel is biodegraded in an aqueous environment such as in the tear fluid, when compared to the use of other end groups, such as the SAZ end group, which provides for a higher number of carbon atoms in the linker and may thus be more hydrophobic and therefore less prone to ester hydrolysis than the SG end group.
• a 4-arm 20,000 Dalton PEG precursor having a SG end group (as defined above), is crosslinked with a crosslinking agent having one or more reactive amine end groups. This PEG precursor is abbreviated herein as 4a20kPEG-SG.
• n is determined by the molecular weight of the respective PEG-arm.
• the crosslinking agent (herein also referred to as “crosslinker”) used is a low-molecular weight component containing nucleophilic end groups, such as amine or thiol end groups.
• the nucleophilic group-containing crosslinking agent is a small molecule amine with a molecular weight below 1,000 Da.
• the nucleophilic-group containing crosslinking agent comprises two, three or more primary aliphatic amine groups.
• Suitable crosslinking agents for use in the present invention are (without being limited to) spermine, spermidine, lysine, dilysine, trilysine, tetralysine, polylysine, ethylenediamine, polyethylenimine, 1,3-diaminopropane, 1,3-diaminopropane, diethylenetriamine, trimethylhexamethylenediamine, 1,1,1-tris(aminoethyl)ethane, their pharmaceutically acceptable salts, hydrates or other solvates and their derivatives such as conjugates (as long as sufficient nucleophilic groups for crosslinking remain present), and any mixtures thereof.
• a particular crosslinking agent for use in the present invention is a lysine-based crosslinking agent, such as trilysine or a trilysine salt or derivative.
• a particular nucleophilic crosslinking agent for use in the present invention is trilysine acetate. Other low-molecular weight multi-arm amines may be used as well. The chemical structure of trilysine is reproduced below: [0149] In very particular embodiments of the present invention, a 4a20kPEG-SG precursor is reacted with trilysine acetate, to form the polymer network. [0150] In certain embodiments, the nucleophilic group-containing crosslinking agent is bound to or conjugated with a visualization agent.
• Fluorophores such as fluorescein, rhodamine, coumarin, and cyanine can be used as visualization agents as disclosed herein.
• fluorescein is used as the visualization agent.
• the visualization agent may be conjugated with the crosslinking agent e.g. through some of the nucleophilic groups of the crosslinking agent.
• conjugation in general includes partial conjugation, meaning that only a part of the nucleophilic groups may be used for conjugation with the visualization agent, such as 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 a visualization agent.
• the crosslinking agent is trilysine acetate and is conjugated with fluorescein.
• the visualization agent may also be conjugated with the polymer precursor, e.g. through certain reactive (such as electrophilic) groups of the polymer precursors.
• the crosslinking agent itself or the polymer precursor itself may contain an e.g. fluorophoric or other visualization- enabling group.
• conjugation of the visualization agent to either the polymer precursor(s) or to the crosslinking agent as disclosed below is intended to keep the visualization agent in the hydrogel while the active agent is released into the tear fluid, thus allowing confirmation of insert presence within the canaliculus by a convenient, non-invasive method.
• the molar ratio of the nucleophilic and the electrophilic end groups reacting with each other is about 1:1, i.e., one amine group is provided per one electrophilic, such as SG, group.
• the molar ratio of the electrophilic group containing precursor to the nucleophilic group-containing crosslinking agent is from about 1:2 to about 2:1.
• the amine linking agent can also be another PEG precursor with the same or a different number of arms and the same or a different arm length (average molecular weight) as the 4a20kPEG-SG, but having terminal amine groups, i.e., 4a20kPEG-NH 2 .
• Additional ingredients [0155]
• the insert of the present invention may contain, in addition to the polymer units forming the polymer network as disclosed above and the active principle, other additional ingredients.
• Such additional ingredients are for example salts originating from buffers used during the preparation of the hydrogel, such as phosphates, borates, bicarbonates, or other buffer agents such as triethanolamine.
• buffers used during the preparation of the hydrogel such as phosphates, borates, bicarbonates, or other buffer agents such as triethanolamine.
• sodium phosphate buffers specifically, mono- and dibasic sodium phosphate
• the insert of the present invention is free of anti-microbial preservatives or at least does not contain a substantial amount of anti-microbial preservatives (including, but not limited to benzalkonium chloride (BAK), chlorobutanol, sodium perborate, and stabilized oxychloro complex (SOC)).
• BAK benzalkonium chloride
• SOC stabilized oxychloro complex
• the insert of the present invention does not contain any ingredients of animals or human origin but only contains synthetic ingredients.
• the inserts of the present invention contain a visualization agent.
• Visualization agents to be used according to the present invention are all agents that can be conjugated with the components of the hydrogel or can be entrapped within the hydrogel, and that are visible, or may be made visible when exposed e.g. to light of a certain wavelength, or that are constrast agents.
• Suitable visualization agents for use in the present invention are (but are not limited to) e.g.
• fluoresceins fluoresceins, rhodamines, coumarins, cyanines, europium chelate complexes, boron dipyromethenes, benzofrazans, dansyls, bimanes, acridines, triazapentalenes, pyrenes and derivatives thereof.
• visualization agents are commercially available e.g. from TCI.
• the visualization 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 in the intracanalicular insert illuminates when excited with blue light enabling confirmation of insert presence.
• the visualization agent is conjugated with one of the components forming the hydrogel.
• the visualization agent such as fluorescein
• the crosslinking agent such as the trilysine or trilysine salt or derivate (e.g. the trilysine acetate), or with the PEG-component.
• NHS-fluorescein may be conjugated with trilysine acetate prior to the crosslinking reaction with the PEG precursor(s). Conjugation of the visualization agent prevents the visualization agent from being eluted or released out of the insert.
• a method of conjugating a visualization agent with the crosslinking agent is illustrated in Example 1.
• the insert of the present invention may in certain embodiments contain a surfactant.
• the surfactant may be a non-ionic surfactant.
• the non-ionic surfactant may comprise a poly(ethylene glycol) chain.
• non-ionic surfactants are poly(ethylene glycol) sorbitan monolaurate commercially available as Tween® (and in particular Tween®20, a PEG-20-sorbitan monolaurate, or Tween®80, a PEG-80-sorbitan monolaurate), poly(ethylene glycol) ester of castor oil commercially available as Cremophor (and in particular Cremophor40, which is PEG-40-castor oil), and an ethoxylated 4-tert-octylphenol/formaldehyde condensation polymer which is commercially available as Tyloxapol and others such as Triton.
• inserts according to the present invention comprise a glucocorticoid, such as dexamethasone, a polymer network made from one or more polymer precursors as disclosed herein in the form of a hydrogel, and optional additional components such as visualization agents, salts etc. remaining in the insert from the production process (such as phosphate salts used as buffers etc.).
• the glucocorticoid is dexamethasone.
• the insert is preservative-free.
• the inserts according to the present invention in a dry state contain from about 30% to about 70% by weight glucocorticoid, such as dexamethasone, and from about 25% to about 60% by weight polymer units, such as those disclosed above. In further embodiments, the inserts according to the present invention in a dry state contain from about 30% to about 60% by weight glucocorticoid, such as dexamethasone, and from about 30% to about 60% by weight polymer units, such as those disclosed above.
• the inserts according to the present invention in a dry state contain from about 40% to about 56% by weight glucocorticoid, such as dexamethasone, and from about 36% to about 55% by weight polymer units, such as polyethylene glycol units as disclosed above.
• the inserts according to the present invention in a dry state contain from about 40% to about 46% by weight dexamethasone and from about 45% to about 55% by weight PEG units.
• the inserts according to the present invention in a dry state contain from about 50% to about 56% by weight dexamethasone and from about 36% to about 46% by weight PEG units.
• the inserts according to the present invention may contain in a dry state about 0.1% to about 1% by weight visualization agent, such as fluorescein or a molecule comprising a fluorescein moiety. Also in certain embodiments, the inserts according to the present invention may contain in a dry state about 0.5% to about 5% by weight of one or more buffer salt(s) (separately or taken together). In certain embodiments, the insert in a dry state may contain, e.g., from about 0.01% to about 2% by weight or from about 0.05% to about 0.5% by weight of a surfactant.
• an insert according to the present invention may be made from about 200 ⁇ g dexamethasone (i.e., containing a target dose of about 200 ⁇ g dexamethasone within a variance of +25% and -20%, or within a variance of ⁇ 10 %, as disclosed herein), and about 200 ⁇ g to about 250 ⁇ g PEG-units, such as 4a20kPEG- SG, about 5 ⁇ g to about 7 ⁇ g trilysine acetate, about 1 ⁇ g to about 3 ⁇ g visualization agent, such as fluorescein, and about 2.5 ⁇ g to about 20 ⁇ g buffer salt, such as sodium phosphate (mono- and/or dibasic).
• dexamethasone i.e., containing a target dose of about 200 ⁇ g dexamethasone within a variance of +25% and -20%, or within a variance of ⁇ 10 %, as disclosed herein
• an insert according to the present invention may be made from about 300 ⁇ g dexamethasone (i.e., containing a target dose of about 300 ⁇ g dexamethasone within a variance of +25% and - 20%, or within a variance of ⁇ 10 %, as disclosed herein), and about 200 ⁇ g to about 250 ⁇ g PEG-units, such as 4a20kPEG-SG, about 5 ⁇ g to about 7 ⁇ g trilysine acetate, about 1 ⁇ g to about 3 ⁇ g visualization agent, such as fluorescein and about 2.5 ⁇ g to about 20 ⁇ g buffer salt, such as sodium phosphate (mono- and/or dibasic).
• the balance of the insert in its dry state may be salts remaining from the buffer used during manufacture of the inserts as disclosed herein, or may be other ingredients used during manufacturing of the insert (such as surfactants if used).
• such salts are phosphate, borate or (bi) carbonate salts.
• a buffer salt is sodium phosphate (mono- and/or dibasic).
• the amounts of the glucocorticoid and the polymer(s) may be varied, and other amounts of the glucocorticoid and the polymer hydrogel than those disclosed herein may also be used to prepare inserts according to the invention.
• the maximum amount (in weight%) of drug within the formulation is about two times the amount of the polymer (e.g., PEG) units, but may be higher in certain cases, as long as the mixture comprising e.g., the precursors, visualization agent, buffers and drug (in the state before the hydrogel has gelled completely) can be uniformly cast into a desired mold or thin-diameter tubing and/or the hydrogel is still sufficiently stretchable as disclosed herein, and/or sufficiently increases in diameter upon hydration as also disclosed herein.
• the polymer e.g., PEG
• solid contents of about 20% to about 50% (w/v) are utilized for forming the hydrogel of the inserts according to the present invention.
• the water content of the hydrogel in a dry (dehydrated/dried) state may be low, such as not more than about 1% by weight of water (determined e.g. as disclosed herein). The water content may in certain embodiments also be lower than that, possibly no more than about 0.25% by weight or even no more than about 0.1% by weight.
• the dried insert may have different geometries, depending on the method of manufacture, such as the inner diameter or shape of a mold or tubing into which the mixture comprising the hydrogel precursors including the glucocorticoid is cast prior to complete gelling.
• the insert according to the present invention is also referred as a “fiber” (which term is used interchangeably herein with the term “rod”), wherein the fiber in general has a length that exceeds its diameter.
• the insert (or the fiber) may have different geometries, with specific dimensions as disclosed herein.
• the insert is cylindrical or has an essentially cylindrical shape.
• the insert in the context of the shape of the insert, this always includes “essentially cylindrical”.
• the insert has a round or an essentially round cross-section.
• the insert is non-cylindrical.
• the insert according to the present invention is optionally elongated in its dry state, wherein the length of the insert is greater than the width of the insert, wherein the width is the largest cross sectional dimension that is substantially perpendicular to the length. In a cylindrical or essentially cylindrical insert, the width is also referred to as the diameter.
• the outer insert shape or its cross-section may also be used in the present invention.
• an oval (or elliptical) diameter fiber may be used instead of a round diameter fiber (i.e., in the case of a cylindrical insert).
• Other cross-sectional geometries such as oval or oblong, rectangular, triangular, star-shaped, cross-shaped etc. may generally be used.
• the exact cross-sectional shape is not decisive, as tissue will form around the insert.
• 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 aids in keeping the insert in place in the canaliculus and prevents the insert from twisting and turning within the canaliculus, and also aids in maintaining a close contact with surrounding tissue. In certain embodiments, this ratio may be less than about 2, or less than about 1.75.
• the polymer network, such as the PEG network, of the hydrogel insert according to certain embodiments of the present invention may be semi-crystalline in the dry state at or below room temperature, and amorphous in the wet state.
• the dry insert may be dimensionally stable at or below room temperature, which may be advantageous for administering the insert into the canaliculus, and also for quality control.
• the tear fluid which can be simulated in vitro e.g. by immersing the insert into PBS, pH 7.4 at 37 °C after 24 hours, which is considered equilibrium
• the dimensions of the insert according to the invention may change.
• the diameter of the insert may increase, while its length may decrease or in certain embodiments may stay the same or essentially the same.
• this dimensional change is that, while the insert in its dry state is sufficiently thin to be administered and placed into the canaliculus through the punctum (which itself is smaller in diameter than the canaliculus) upon hydration and thereby through expansion of its diameter it fits closely into the canaliculus and thus acts as a canalicular plug.
• the insert therefore provides for lacrimal occlusion and thereby tear conservation in addition to releasing the active principle in a controlled manner to the tear fluid over a certain period of time as disclosed herein.
• this dimensional change is enabled at least in part by the “shape memory” effect introduced into the insert by means of stretching the hydrogel strand in the longitudinal direction during its manufacture as also disclosed herein.
• this stretching may be performed in the wet state, i.e., before drying.
• the stretching of the hydrogel strands may be performed in the dry state (i.e., after drying the hydrogel strands). It is noted that if no stretching is performed at all the insert may merely swell due to the uptake of water, but the dimensional change of an increase in diameter and a decrease in length disclosed herein may not be achieved, or may not be achieved to a large extent.
• the hydrogel strand may e.g. be dry or wet stretched in order to provide for expansion of the diameter upon rehydration.
• a degree of molecular orientation may be imparted by stretching the material then allowing it to solidify, locking in the molecular orientation. The molecular orientation provides one mechanism for anisotropic swelling upon contacting the insert with a hydrating medium such as tear fluid.
• the insert of certain embodiments of the present invention Upon hydration, the insert of certain embodiments of the present invention will swell only in the radial dimension, while the length will either decrease or be maintained or essentially maintained.
• anisotropic swelling means swelling preferentially in one direction as opposed to another, as in a cylinder that swells predominantly in diameter, but does not appreciably expand (or does even contract) in the longitudinal dimension.
• the degree of dimensional change upon hydration may depend inter alia on the stretch factor. Merely as an example to illustrate the effect of stretching, stretching at e.g. a stretch factor of about 1.3 (e.g. by means of wet stretching) may have a less pronounced effect or may not change the length and/or the diameter during hydration to a large extent.
• stretching at e.g. a stretch factor of about 1.8 may result in a shorter length and/or an increased diameter during hydration.
• Stretching at e.g. a stretch factor of about 3 or 4 could result in a much shorter length and a much larger diameter upon hydration.
• Other factors besides stretching can also affect swelling behavior.
• those with a lower number of arms contribute to providing a higher flexibility in the hydrogel than those with a higher number of arms (such as 8-armed PEG precursors).
• a hydrogel contains more of the less flexible components (e.g. a higher amount of PEG precursors containing a larger number of arms, such as the 8-armed PEG units)
• the hydrogel may be firmer and less easy to stretch without fracturing.
• a hydrogel containing more flexible components such as PEG precursors containing a lower number of arms, such as 4-armed PEG units
• the behavior and properties of the insert once it has been administered and is rehydrated can be tailored by means of varying structural features as well as by modifying the processing of the insert after it has been initially formed.
• the dried insert dimensions inter alia may depend on the amount of glucocorticoid incorporated as well as the ratio of glucocorticoid to polymer units and can additionally be controlled by the diameter and shape of the mold or tubing in which the hydrogel is allowed to gel.
• the diameter of the dried insert may be further controlled by (wet or dry) stretching of the hydrogel strands once formed as disclosed herein.
• the dried hydrogel strands (after stretching) are cut into segments of the desired length to form the insert; the length can thus be chosen as desired.
• inserts with specific dimensions relate to the length and the diameter of cylindrical or essentially cylindrical inserts. However, all values and ranges for cylindrical inserts may also be used correspondingly for non- cylindrical inserts. In case several measurements of the length or diameter of one insert are conducted, or several datapoints are collected during the measurement, the average (i.e., mean) value is reported as defined herein.
• the length and diameter of an insert according to the invention may be measured e.g. by means of microscopy, or by means of an (optionally automated) camera system, e.g. as disclosed in Example 1. Other suitable methods of measuring insert dimensions may also be used.
• the present invention relates to a sustained release biodegradable intracanalicular insert comprising a hydrogel and a glucocorticoid, wherein the insert in a dry state has a length of equal to or less than about 2.75 mm.
• the glucocorticoid is dexamethasone.
• the insert in a dry state has a length of equal to or less than about 2.5 mm, or less than about 2.3 mm, or has a length of about 2.25 mm.
• the insert in a dry state has a length of greater than about 1 mm, or greater than about 1.5 mm, or greater than about 2 mm.
• the insert in its dry state has a length of less than about 2.5 mm and greater than about 1.5 mm.
• the insert may have a length of 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, 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).
• the insert in a dry state has a diameter 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 a diameter from about 0.40 mm to about 0.58 mm, or of about 0.45 mm, or of about 0.5 mm.
• the insert in a dry state has a length in the range of about 2.14 mm to about 2.36 mm and a diameter in the range of about 0.41 mm to about 0.55 mm.
• an insert according to the invention is cylindrical or essentially cylindrical and upon hydration (in vivo in the canaliculus, or in vitro after 24 hours in phosphate-buffered saline at a pH of 7.2 at 37 °C) the diameter of the insert is increased and the length of the insert is decreased.
• the diameter of the insert may be increased by a factor in the range of about 1.5 to about 4, or of about 2 to about 3.5, or of about 3.
• 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, or of about 2 to about 3.5, or of about 3.
• the length of an insert according to the invention is decreased 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 of its length in the dry state.
• the ratio of the length of the insert in the hydrated state to the length of the insert in the dry state may be about 0.9 or less, or about 0.75 or less, or about two-thirds or less, and may be at least about 0.25, or at least about 0.4.
• an insert according to the present invention in its hydrated state has a diameter in the range of about 1 to about 2 mm, and a length that is shorter than the length of the insert in its dry state.
• the ratio of length to diameter of the insert is suitably greater than 1, i.e., the length of the insert is longer than its diameter. This aids in keeping the insert in place in the canaliculus without any twisting or turning. This aids in occluding the canaliculus/the punctum and keeping the tear fluid within the eye, as well as ensuring contact between the surface of the insert and the tear fluid for releasing the glucocorticoid such as dexamethasone.
• an insert according to the present invention in the hydrated state has a diameter in the range of about 1.35 mm to about 1.80 mm and a length in the range of about 1.65 mm to about 2.0 mm.
• an insert according to the present invention in the hydrated state may have a diameter in the range of about 1.40 mm to about 1.60 mm and a length in the range of 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.
• the dimensional change may be achieved by wet stretching the hydrogel strand at a stretch factor in the range of about 1.5 to about 3, or of about 2.2 to about 2.8, or of about 2.5 to about 2.6.
• such dimensional change may be achieved by dry stretching.
• the stretching thus creates a shape memory, meaning that the insert upon hydration when administered into the canaliculus and once it comes into contact with the tear fluid, will shrink in length and widen in diameter until it approaches (more or less) its equilibrium dimensions, which are determined inter alia by the original molded dimensions and compositional variables. While the narrow dry dimensions facilitate administration of the insert through the punctum into the canaliculus, the widened diameter and shortened length after administration yield a shorter but wider insert that fits closely into and occludes the canaliculus while releasing active agent primarily at its proximal surface (the surface of the insert that is in contact with the tear fluid and that is directed toward the punctum opening).
• the sustained release biodegradable intracanalicular insert of the present invention is defined by a content of dexamethasone of equal to or less than about 375 ⁇ g or an equivalent dose of another glucocorticoid (as disclosed herein above) and/or a release of a therapeutically effective amount of a glucocorticoid for a period of up to about 25 days after administration (as disclosed herein below), the length of the insert in a dry state may also exceed 2.75 mm, e.g. the length of the insert in a dry state may be equal to or above about 3 mm. However, a length of equal to or less than about 2.75 mm as disclosed herein is particularly suitable for the present invention.
• an insert of the present invention contains about 200 ⁇ g dexamethasone (including the variances of +25%/-20% or ⁇ 10% as disclosed herein), has an (essentially) cylindrical shape, and has in the dry state a diameter in the range of about 0.41 mm to about 0.49 mm, such as about 0.47 mm, or about 0.45 mm, and a length in the range of about 2.14 mm to about 2.36 mm, such as about 2.25 mm.
• Such an insert may decrease in length and increase in diameter upon hydration in vivo in the canaliculus or in vitro (wherein hydration in vitro is measured in phosphate-buffered saline at a pH of 7.4 at 37 °C after 24 hours, which is considered equilibrium) to a length that is shorter than its length in the dry state, such as to a length in the range of about 1.69 mm to about a 1.87 mm, such as about 1.79 mm or about 1.8 mm, and to a diameter in the range of about 1.35 mm to about 1.80 mm, such as about 1.5 mm or about 1.54 mm.
• an insert of the present invention contains about 300 ⁇ g dexamethasone (including the variances of +25%/-20% or ⁇ 10% as disclosed herein), has an (essentially) cylindrical shape, and has a diameter in the range of about 0.44 mm to about 0.55 mm, such as about 0.5 mm or about 0.51 mm, and a length in the range of about 2.14 mm to about 2.36 mm, such as about 2.25 mm, in its dry state.
• Such an insert may decrease in length and increase in diameter upon hydration in vivo in the canaliculus or in vitro (wherein hydration in vitro is measured in phosphate-buffered saline at a pH of 7.4 at 37 °C after 24 hours, which is considered equilibrium) to a length that is shorter than its length in the dry state, such as to a length in the range of about 1.64 mm to about 2.0 mm, such as about 1.8 mm or about 1.85 mm, and to a diameter in the range of about 1.35 mm to about 1.80 mm, such as about 1.5 mm or about 1.47 mm.
• an insert of the present invention has a total weight in the range of about 100 to about 1000 ⁇ g, such as in the range of about 200 to about 800 ⁇ g, or in the range of about 300 to about 700 ⁇ g.
• an insert of the present invention has a total weight in the range of about 400 to about 600 ⁇ g, such as from about 400 to about 500 ⁇ g (in particular, if the insert contains dexamethasone in an amount of about 200 ⁇ g including the variances as disclosed herein), or from about 500 to about 600 ⁇ g (in particular, if the insert contains dexamethasone in an amount of about 300 ⁇ g including the variances as disclosed herein).
• the present invention relates to a sustained release biodegradable ocular (such as intracanalicular) insert comprising a hydrogel and a glucocorticoid, wherein the insert provides for a release of a therapeutically effective amount of the glucocorticoid for a period of up to about 25 days after administration (i.e., after having been inserted into the canaliculus).
• the glucocorticoid is dexamethasone.
• release of the glucocorticoid into the tear fluid is determined by the glucocorticoid’s solubility in an aqueous environment.
• One particular glucocorticoid for use according to the present invention is dexamethasone.
• the solubility of dexamethasone has been determined to be very low in an aqueous medium (less than 100 ⁇ g/mL), such as the tear fluid.
• the dexamethasone is released from the insert primarily at its surface proximal to the tear fluid and thus proximal to the eye surface (i.e., at the insert surface facing the punctum opening).
• the active agent gradually gets dissolved and diffuses out of the hydrogel into the tear fluid. This happens primarily in a unidirectional manner, starting at the interface of the insert and the tear fluid at the proximal surface of the insert.
• the “drug front” generally progresses in the opposite direction, i.e., away from the proximal surface until eventually the entire insert is depleted of active agent. This is illustrated in Figure 6.
• the insert according to the present invention provides for the release of a (therapeutically effective amount of) glucocorticoid, such as dexamethasone, for a period of about 6 hours or longer, such as for a period of about 12 hours or longer, such as for a period of at least about 1 day, or for a period of at least about 7 days, after administration, which is longer than known immediate release ophthalmic dosage forms.
• a (therapeutically effective amount of) glucocorticoid such as dexamethasone
• the insert according to the present invention provides for the release of a (therapeutically effective amount of) glucocorticoid, such as dexamethasone, for a period of up to about 1 months, or up to about 25 days, or up to about 21 days (i.e., about 3 weeks), or up to about 14 days (i.e., about 2 weeks) after administration.
• a (therapeutically effective amount of) glucocorticoid such as dexamethasone
• the levels of active agent released from the insert per day remain sustained, constant or essentially constant over a certain period of time (due to the limitation of release based on the active agent’s solubility), such as for about 7 days, or for about 11 days, or for about 14 days in the case of dexamethasone.
• the amount of active agent released per day may decrease for another period of time (also referred to as “tapering”), such as for a period of about 7 additional days (or longer in certain embodiments) in the case of dexamethasone until all or substantially all of the active agent has been released and the “empty” hydrogel remains in the canaliculus until it is fully degraded and/or until it is cleared (disposed/washed out) through the nasolacrimal duct.
• an insert of the invention provides for an average release of about 5 to about 50 ⁇ g, such as about 10 to about 35 ⁇ g, specifically about 15 ⁇ g to about 25 ⁇ g, such as about 20 ⁇ g, dexamethasone per day into tear fluid during the period in which the release is sustained, constant or essentially constant, for example during a period of up to about 7 days, or up to about 11 days, or up to about 14 days after administration, or longer.
• dexamethasone from an insert containing a target dose of about 200 ⁇ g (including variances as disclosed herein) dexamethasone, about 15 ⁇ g to about 25 ⁇ g, such as about 20 ⁇ g, dexamethasone are released on average per day into tear fluid for a period of up to 7 days after administration, followed by a period of up to about 7 additional days or longer during which lower amounts of dexamethasone are released until all of the dexamethasone contained in the insert has been released.
• an insert containing a target dose of about 200 ⁇ g may provide for release of a therapeutically effective amount of dexamethasone into tear fluid for a period of, e.g., up to about 7 days after administration, up to about 14 days after administration, or longer.
• dexamethasone from an insert containing a target dose of about 300 ⁇ g (including variances as disclosed herein) dexamethasone, about 15 ⁇ g to about 25 ⁇ g, such as about 20 ⁇ g, dexamethasone are released on average per day for a period of up to about 11 days, or up to about 14 days after administration, followed by a period of up to about 7 additional days or longer during which lower amounts of dexamethasone are released until all of the dexamethasone contained in the insert has been released.
• an insert containing a target dose of about 300 ⁇ g (including variances as disclosed herein) dexamethasone may provide for release of a therapeutically effective amount of dexamethasone for a period of up to about 21 days after administration, or longer.
• the sustained release biodegradable intracanalicular insert of the present invention is defined by a dose of equal to or less than about 375 ⁇ g dexamethasone (as disclosed herein above) or an equivalent dose of another glucocorticoid contained in the insert, and/or by a length of equal to or less than about 2.75 mm (as disclosed herein above), the insert may provide for a release of a therapeutically effective amount of a glucocorticoid, e.g., for a period of longer than 25 days after administration, such as up to about 1 month, or even longer, such as up to about 2 months, or up to about 3 months after administration.
• a release of a therapeutically effective amount of dexamethasone (or other glucocorticoid) for a period of up to about 25 days, specifically for up to about 14 days (i.e., about 2 weeks) or up to about 21 days (i.e., about 3 weeks) after administration is particularly suitable for the present invention.
• this region of the hydrogel insert becomes devoid of drug particles and may therefore also be called the “clearance zone”.
• the “clearance zone” is thus a region of the insert that has a concentration of active agent that is less than the active agent in another region of the hydrated hydrogel.
• the hydrogel may be slowly degraded e.g. by means of ester hydrolysis in the aqueous environment of the tear fluid.
• ester hydrolysis e.g., ester hydrolysis in the aqueous environment of the tear fluid.
• distortion and erosion of the hydrogel begins to occur. As this happens, the hydrogel becomes softer and more liquid (and thus its shape becomes distorted) until the hydrogel finally dissolves and is resorbed completely.
• the hydrogel becomes softer and thinner and its shape becomes distorted, at a certain point it may no longer remain at its intended site in the canaliculus to which it had been administered, but it may progress deeper into the canaliculus and eventually may be cleared (disposed/washed out) through the nasolacrimal duct.
• the persistence of the hydrogel within an aqueous environment such as in the human eye (including the canaliculus) depends inter alia on the structure of the linker that crosslinks the polymer units, such as the PEG units, in the hydrogel.
• the hydrogel is biodegraded within a period of about 1 month, or about 2 months, or about 3 months, or up to about 4 months, after administration.
• the insert may be cleared (washed out/disposed) through the nasolacrimal duct before it is completely biodegraded.
• the hydrogel and thus the insert remains in the canaliculus 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.
• the entire amount of dexamethasone may be released prior to the complete degradation of the hydrogel, and the insert may persist in the canaliculus thereafter, for a period of altogether up to about 1 month after administration, or up to about 2 months after administration, or up to about 3 months, or up to about 4 months, after administration.
• the hydrogel may be fully biodegraded when the glucocorticoid, such as dexamethasone, has not yet been completely released from the insert.
• the insert may be fully degraded following at least about 90%, or at least about 92%, or at least about 95%, or at least about 97% release of the glucocorticoid.
• in vitro release tests may be used to compare different inserts (e.g. of different production batches, of different composition, and of different dosage strength etc.) with each other, for example for the purpose of quality control or other qualitative assessments.
• the in vitro-release of a glucocorticoid from the inserts of the invention can be determined by various methods, such as under non-sink simulated physiological conditions in PBS (phosphate-buffered saline, pH 7.4) at 37 °C, with daily replacement of PBS in a volume comparable to the tear fluid in the human eye.
• PBS phosphate-buffered saline, pH 7.4
• the present invention relates to a sustained release biodegradable intracanalicular insert containing dexamethasone in an amount in the range from about 160 ⁇ g to about 250 ⁇ g, or from about 180 ⁇ g to about 220 ⁇ g, or particularly in an amount of about 200 ⁇ g, wherein the dexamethasone is dispersed in a hydrogel.
• This insert in the dry state has a cylindrical or an essentially cylindrical shape with a diameter in the range of about 0.41 mm to about 0.49 mm and a length in the range of about 2.14 mm to about 2.36 mm.
• the hydrogel comprises a polymer network comprising crosslinked multi-arm polyethylene glycol units, particularly 4a20kPEG units, wherein the crosslinks between the PEG units include a group represented by the following formula wherein m is 2.
• 4a20kPEG-SG units may be crosslinked by means of a crosslinking agent, such as trilysine acetate.
• the insert may also contain a visualization agent, such as fluorescein, which is conjugated with the polymer network, such as with the trilysine acetate.
• fluorescein conjugated with the polymer network, such as with the trilysine acetate.
• the insert in a dry state is made up from about 40% to about 46% by weight dexamethasone and from about 45% to about 55% by weight polyethylene glycol units.
• the insert furthermore in its dry state may contain no more than about 1% by weight water.
• the dexamethasone particles in this insert may have a d90 particle size of equal to or less than about 5 ⁇ m and/or a d98 particle size of less than about 10 ⁇ m as determined by laser diffraction.
• This insert provides for a 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 specific embodiments, this insert provides for a release of a therapeutically effective amount of dexamethasone over a period of up to about 14 days after administration (i.e., for about 2 weeks or up to about 2 weeks).
• This insert may be used in the treatment of DED, including the acute treatment of DED or of episodic flares of DED.
• Specific insert containing a dose of about 300 ⁇ g dexamethasone [0221]
• the present invention relates to a sustained release biodegradable intracanalicular insert containing dexamethasone in an amount in the range from about 240 ⁇ g to about 375 ⁇ g, or from about 270 ⁇ g to about 330 ⁇ g, or particularly in an amount of about 300 ⁇ g, wherein the dexamethasone is dispersed in a hydrogel.
• This insert in the dry state has a cylindrical or an essentially cylindrical shape with 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.
• this insert In the hydrated state (hydration in vivo in the canaliculus or in vitro, wherein hydration in vitro is measured in phosphate-buffered saline at a pH of 7.4 at 37 °C after 24 hours, which is considered equilibrium) this insert has a diameter in the range of about 1.35 mm to about 1.80 mm and a ratio of length to diameter of greater than 1, and may particularly have a length in the range of about 1.64 mm to about 2.0 mm.
• the hydrogel comprises a polymer network comprising crosslinked multi-arm polyethylene glycol units, particularly 4a20kPEG units, wherein the crosslinks between the PEG units include a group represented by the following formula wherein m is 2.
• 4a20kPEG-SG units may be crosslinked by means of a crosslinking agent, such as trilysine acetate.
• the insert may also contain a visualization agent, such as fluorescein, which is conjugated with the polymer network, such as with the trilysine acetate.
• the insert in a dry state is made up from about 50% to about 56% by weight dexamethasone and from about 36% to about 46% by weight polyethylene glycol units.
• the insert furthermore in its dry state may contain no more than about 1% by weight water.
• the dexamethasone particles in this insert may have a d90 particle size of equal to or less than about 5 ⁇ m and/or a d98 particle size of less than about 10 ⁇ m as determined by laser diffraction.
• This insert provides for a 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 specific embodiments, this insert provides for a release of a therapeutically effective amount of dexamethasone over a period of up to about 21 days after administration (i.e., for about 3 weeks or up to about 3 weeks). [0226] This insert may be used in the treatment of DED, including the acute treatment of DED or of episodic flares of DED. II.
• the present invention also relates to a method of manufacturing a sustained release biodegradable intracanalicular insert as disclosed herein, comprising a hydrogel and a glucocorticoid, such as dexamethasone.
• the method of manufacturing according to the present invention comprises the steps of forming a hydrogel comprising a polymer network (e.g., comprising PEG units) and glucocorticoid particles dispersed in the hydrogel, shaping or casting the hydrogel and drying the hydrogel.
• the glucocorticoid such as dexamethasone, may be used in micronized form as disclosed herein for preparing the insert.
• the glucocorticoid such as dexamethasone
• the hydrogel is made of a polymer network comprising crosslinked polyethylene glycol units as disclosed herein.
• the polyethylene glycol (PEG) units in particular embodiments are multi-arm, such as 4-arm, PEG units having an average molecular weight 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 of about 20,000 Daltons.
• Suitable PEG precursors having reactive groups such as electrophilic groups as disclosed herein are crosslinked to form the polymer network.
• Crosslinking may be performed by means of a crosslinking agent that is either a low molecular compound or another polymeric compound, including another PEG precursor, having reactive groups such as nucleophilic groups as also disclosed herein.
• a PEG precursor with electrophilic end groups is reacted with a crosslinking agent (a low-molecular compound, or another PEG precursor) with nucleophilic end groups to form the polymer network.
• the method of manufacturing the insert of the present invention comprises mixing and reacting an electrophilic group-containing multi-arm polyethylene glycol, such as 4a20kPEG-SG, with a nucleophilic group-containing crosslinking agent, such as trilysine acetate, in a buffered solution in the presence of dexamethasone particles, and allowing the mixture to gel.
• an electrophilic group-containing multi-arm polyethylene glycol such as 4a20kPEG-SG
• a nucleophilic group-containing crosslinking agent such as trilysine acetate
• the molar ratio of the electrophilic groups in the PEG precursor to the nucleophilic groups in the crosslinking agent is about 1:1, but may also be in a range from about 2:1 to about 1:2.
• a visualization agent as disclosed herein is included in the mixture forming the hydrogel so that the insert can be visualized once it has been administered into the canaliculus.
• the visualization agent may be a fluorophore, such as fluorescein or a molecule comprising a fluorescein moiety, or another visualization agent as disclosed above.
• the visualization agent may be firmly conjugated with one or more components of the polymer network so that it remains in the insert at all times until the insert is biodegraded.
• the visualization agent may for example be conjugated with either the polymer, such as the PEG, precursor, or the (polymeric or low molecular weight) crosslinking agent.
• the visualization agent is fluorescein and is conjugated to the trilysine acetate crosslinking agent prior to reacting the crosslinking agent with the PEG precursor, as illustrated in Example 1.
• NHS-fluorescein N- hydroxysuccinimidyl-fluorescein
• This conjugate may then be used further to crosslink the polymeric precursor(s), such as the 4a20kPEG-SG.
• a (optionally buffered) mixture/suspension of the glucocorticoid and the PEG precursor(s), such as the dexamethasone and the 4a20kPEG-SG, in water is prepared.
• This glucocorticoid/PEG precursor mixture is then combined with a (optionally buffered) solution containing the crosslinking agent and the visualization agent conjugated thereto, such as the lysine acetate/fluorescein conjugate.
• the resulting combined mixture thus contains the glucocorticoid, the polymer precursor(s), the crosslinking agent, the visualization agent and (optionally) buffer. This is illustrated exemplarily in Example 1.
• the resulting mixture is cast into a suitable mold or tubing prior to complete gelling in order to provide e.g. a hydrogel strand, and ultimately the desired final shape of the hydrogel.
• the mixture is then allowed to gel.
• the resulting hydrogel is then dried.
• a hydrogel strand is prepared by casting the hydrogel precursor mixture comprising the glucocorticoid particles into a fine diameter tubing, such as a polyurethane (PU) tubing.
• PU polyurethane
• Different geometries and diameters of the tubing may be used, depending on the desired final cross-sectional geometry of the hydrogel strand and thus the final insert, its initial diameter (which may still be decreased by means of stretching), and depending also on the ability of the reactive mixture to uniformly fill the tubing and to be removed from the tubing after drying.
• the inside of the tubing may have a round geometry or a non-round geometry, such as an oval (or other) geometry.
• the hydrogel strand may be longitudinally stretched in the wet or dry state as disclosed herein.
• the stretching may result in a dimensional change of the insert upon hydration, e.g. after it has been placed into the canaliculus.
• the hydrogel strand is stretched prior to (complete) drying by a stretching factor in a range of about 1 to about 3, or of about 1.5 to about 3, or of about 2.2 to about 2.8, or of about 2.5 to about 2.6.
• the stretching may be performed when the hydrogel strand is still in the tubing.
• the hydrogel strand may be removed from the tubing prior to being stretched.
• the hydrogel strand is first dried and then stretched (when still inside of the tubing, or after having been removed from the tubing).
• wet stretching is performed in certain embodiments of the invention, the hydrogel is stretched in a wet state (i.e., before it has dried completely) and then left to dry under tension.
• heat may be applied upon stretching.
• the hydrogel strand may be removed from the tubing and cut into segments of a desired length, such as disclosed herein, to produce the final insert (if cut within the tubing, the cut segments are removed from the tubing after cutting).
• a particularly desired length for the purposes of the present invention is for example a length of equal to or less than about 2.75 mm, or equal to or less than about 2.5 mm, such as a length in the range of about 2.0 mm to about 2.5 mm, or of about 2.14 mm to about 2.36 mm, for example a length of about 2.25 mm.
• the inserts may then be packaged into a packaging that keeps out moisture, such as a sealed foil pouch.
• the inserts may be fixated to a mount or support to keep them in place and to avoid damage to the insert, and also to facilitate removing the insert from the packaging and gripping/holding the insert for administration to a patient.
• an insert of the present invention may be fixated into the opening of a foam carrier, with a portion of the insert protruding for easy removal and gripping (as illustrated in Figure 1).
• the insert may be removed from the foam carrier by means of forceps and then immediately inserted into the canaliculus of a patient.
• a particular embodiment of a manufacturing process according to the invention is disclosed in detail in Example 1.
• III. Therapy relates to a method of treating dry eye disease (DED) in a patient in need thereof, the method comprising administering to the patient a sustained release biodegradable ocular (such as intracanalicular) insert as disclosed herein.
• DED dry eye disease
• the present invention also relates to a method of treating episodic flares of DED in a patient in need thereof, the method comprising administering to the patient a sustained release biodegradable ocular (such as intracanalicular) insert comprising a hydrogel and a glucocorticoid, wherein glucocorticoid particles are dispersed within the hydrogel.
• a sustained release biodegradable ocular (such as intracanalicular) insert comprising a hydrogel and a glucocorticoid, wherein glucocorticoid particles are dispersed within the hydrogel.
• the patient to be treated in accordance with the invention may be a human or animal subject in need of DED therapy, including acute DED therapy.
• the patient may be a subject in need of acute treatment of an episodic flare of DED.
• the treatment of DED may be a long (or longer) term treatment of DED.
• the present invention also relates to a sustained release biodegradable ocular (such as intracanalicular) insert as disclosed herein for use in treating DED in a patient in need thereof.
• the present invention also relates to the use of a sustained release biodegradable ocular (such as intracanalicular) insert as disclosed herein for the manufacture of a medicament for treating DED in a patient in need thereof.
• the treatment of DED is an acute, short-term treatment of DED (also herein referred to as a treatment of episodic flares of DED).
• the period for acute treatment of episodic flares of DED according to the present invention may be relatively short as compared to a continuous longer-term (i.e., chronic) treatment of DED, and may in certain embodiments be up to about 1 month or about 1 month, or up to about 25 days or about 25 days, or up to about 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 (i.e., up to about 1 week or about 1 week).
• a longer-term (chronic) treatment of DED may last longer than about 1 month, such as several months or even longer.
• the sustained release biodegradable intracanalicular insert administered to the patient comprises dexamethasone.
• the sustained release biodegradable intracanalicular insert administered to the patient comprises equal to or less than about 375 ⁇ g, or equal to or less than about 350 ⁇ g dexamethasone or an equivalent dose of another glucocorticoid.
• the equivalent dose of another glucocorticoid can be determined as disclosed herein.
• the glucocorticoid such as dexamethasone, is present in the insert as particles dispersed in a hydrogel formed of a polymer network as disclosed herein.
• the sustained release biodegradable intracanalicular insert administered to the patient comprises a dose in the range of about 100 ⁇ g to about 350 ⁇ g dexamethasone, or in the range of about 150 ⁇ g to about 320 ⁇ g dexamethasone, or an equivalent dose of another glucocorticoid.
• the sustained release biodegradable intracanalicular insert administered to the patient comprises from about 160 ⁇ g to about 250 ⁇ g dexamethasone, or from about 180 ⁇ g to about 220 ⁇ g dexamethasone, or about 200 ⁇ g dexamethasone.
• the sustained release biodegradable intracanalicular insert administered to the patient comprises from about 240 ⁇ g to about 375 ⁇ g dexamethasone, or from about 270 ⁇ g to about 330 ⁇ g dexamethasone, or about 300 ⁇ g dexamethasone.
• the insert may contain additional ingredients as disclosed herein.
• Administration of the insert according to the invention is performed through the opening of the punctum into the inferior and/or superior canaliculus.
• the sustained release biodegradable intracanalicular insert administered to the patient increases in diameter and may decrease in length as disclosed herein.
• the sustained release biodegradable intracanalicular insert administered to the patient has a length of equal to or less than about 2.75 mm, or equal to or less than about 2.5 mm in a dry state. In certain embodiments, the sustained release biodegradable intracanalicular insert administered to the patient has a diameter of less than about 1 mm, or a diameter of less than about 0.75 mm in the dry state. An insert that has such a diameter in the dry state may be administered easily through the punctum of the eye. In particular ones of these embodiments, the glucocorticoid is dexamethasone.
• the sustained release biodegradable intracanalicular insert administered to the patient in a dry state has a diameter in the range of about 0.41 mm to about 0.55 mm and a length in the range of about 2.14 mm to about 2.36 mm. In certain embodiments, the sustained release biodegradable intracanalicular insert administered to the patient has a diameter of about 0.5 mm and a length of about 2.25 mm in a dry state.
• the glucocorticoid in this insert is dexamethasone and is present in the insert in an amount of about 200 ⁇ g or about 300 ⁇ g (including the variances as disclosed herein) [0257]
• the sustained release biodegradable intracanalicular insert administered to the patient has a diameter in the range of about 1.35 mm to about 1.80 mm and a ratio of length to diameter of greater than 1 when it is in the hydrated state.
• the sustained release biodegradable intracanalicular insert administered to the 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 it is in the hydrated state.
• the glucocorticoid in this insert is dexamethasone and is present in the insert in an amount of about 200 ⁇ g or about 300 ⁇ g (including the variances as disclosed herein).
• the method provides for the release of a glucocorticoid, such as dexamethasone, for an extended period of time (“extended” as opposed to known immediate release ophthalmic dosage forms) of about 6 hours or longer, such as for a period of about 12 hours or longer after administration.
• the extended period of time is one or more weeks after administration.
• the method provides for (acute, short-term) treatment of episodic flares of DED (“short” as opposed to a long-term treatment of DED as defined herein), providing a treatment with 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.
• glucocorticoid such as dexamethasone
• the sustained release biodegradable intracanalicular insert administered to the patient contains about 200 ⁇ g dexamethasone (including the variances as disclosed herein) and releases dexamethasone for a period of up to about 14 days after administration, such that the period of treatment provided by the dexamethasone release from the insert is up to about 14 days after administration. In certain embodiments, this treatment period may also be longer than about 14 days after administration.
• the sustained release biodegradable intracanalicular insert administered to the patient contains about 300 ⁇ g dexamethasone (including the variances as disclosed herein) and releases dexamethasone for a period of up to about 21 days after administration, such that the period of treatment provided by the dexamethasone release from the insert is up to about 21 days after administration. In certain embodiments, this treatment period may also be longer than about 21 days after administration.
• the sustained release biodegradable intracanalicular insert administered to the patient releases on average from about 15 to about 25 ⁇ g dexamethasone per day for an extended period of time, such for as 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.
• the sustained release biodegradable intracanalicular insert administered to the patient contains about 200 ⁇ g dexamethasone and releases on average from about 15 ⁇ g to about 25 ⁇ g dexamethasone per day for a period of up to about 7 days after administration.
• the insert may still release dexamethasone, but may release dexamethasone at a lower rate (i.e., may release a lower amount of dexamethasone per day), also referred to herein as “tapered release”.
• the sustained release biodegradable intracanalicular insert administered to the patient contains about 300 ⁇ g dexamethasone and releases on average from about 15 ⁇ g to about 25 ⁇ g dexamethasone per day for a period of up to about 11, or up to about 14 days after administration.
• the insert may still release dexamethasone, but may release dexamethasone at a lower rate (i.e., may release a lower amount of dexamethasone per day), also referred to herein as “tapered release”.
• the sustained release biodegradable intracanalicular insert administered to the patient in the method of treatment of DED, including episodic flares of DED comprises a hydrogel and dexamethasone particles dispersed within the hydrogel, wherein the insert contains from about 160 ⁇ g to about 250 ⁇ g or from about 180 ⁇ g to about 220 ⁇ g or about 200 ⁇ g dexamethasone, is cylindrical or essentially cylindrical and has in a dry state a diameter in the range of about 0.41 mm to about 0.49 mm and a length in the range of about 2.14 mm to about 2.36 mm, and in a hydrated state a diameter from about 1.35 mm to about 1.80 mm and a ratio of length to diameter of greater than 1, and releases dexamethasone for a period of up to about 14 days, or up to about 21 days after administration.
• the hydrogel comprises a polymer network, wherein the polymer network comprises 4a20kPEG units and is formed by reacting 4a20kPEG-SG precursor with trilysine or a trilysine acetate as crosslinking agent.
• the insert further comprises a visualization agent such as fluorescein.
• the insert in a dry state is made up from about 40% to about 46% by weight dexamethasone and from about 45% to about 55% by weight polyethylene glycol units.
• the insert furthermore in its dry state may contain no more than about 1% by weight water.
• the treatment period with this insert may be up to or about 14 days (i.e., about 2 weeks).
• the sustained release biodegradable intracanalicular insert administered to the patient in the method of treatment of DED, including episodic flares of DED comprises a hydrogel and dexamethasone particles dispersed within the hydrogel, wherein the insert contains from about 240 ⁇ g to about 375 ⁇ g or from about 270 ⁇ g to about 330 ⁇ g or about 300 ⁇ g dexamethasone, is cylindrical or essentially cylindrical and has in a dry state 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, and in a hydrated state a diameter in the range of about 1.35 mm to about 1.80 mm and a ratio of length to diameter of greater than 1, and releases dexamethasone for a period of up to about 21 days, or up to about 25 days, or up to about 1 month, after administration.
• the hydrogel comprises a polymer network, wherein the polymer network comprises 4a20kPEG units and is formed by reacting 4a20kPEG-SG precursor with trilysine acetate or derivative as crosslinking agent.
• the insert further comprises a visualization agent such as fluorescein.
• the insert in a dry state is made up from about 50% to about 56% by weight dexamethasone and from about 36% to about 46% by weight polyethylene glycol units.
• the insert furthermore in its dry state may contain no more than about 1% by weight water.
• the treatment period with this insert may be up to or about 21 days (i.e., about 3 weeks).
• the sustained release biodegradable intracanalicular insert administered to the patient is defined by a dose of equal to or less than about 375 ⁇ g dexamethasone (as disclosed herein above) or an equivalent dose of another glucocorticoid contained in the insert, and/or by a length of equal to or less than about 2.75 mm (as disclosed herein below), the insert may release a therapeutically effective amount of a glucocorticoid for a period of longer than about 25 days after administration, such as up to about 1 month, or even longer, after administration.
• the insert is administered unilaterally or is administered bilaterally through the lower punctum to the inferior canaliculus. In other embodiments, the insert is administered unilaterally or is administered bilaterally through the upper punctum to the superior canaliculus.
• the insert is administered both through the lower punctum to the inferior canaliculus and through the upper punctum to the superior canaliculus.
• the particular administration per eye can be independent of the other.
• the insert is administered to the inferior vertical canaliculus and/or the superior vertical canaliculus.
• the sustained release biodegradable intracanalicular insert comprises a visualization agent such as fluorescein to enable quick and noninvasive visualization of the insert when placed inside the canaliculus.
• the visualization agent is fluorescein
• the insert may be visualized by illuminating with a blue light source and using a yellow filter.
• the glucocorticoid such as dexamethasone is delivered from the insert to the ocular surface through the tear film as the glucocorticoid dissolves in the tear film when released from the insert.
• the glucocorticoid is released primarily from the proximal end of the insert at the interface between the hydrogel and the tear fluid (as exemplarily shown in Figure 6).
• the sustained glucocorticoid release rate is controlled by glucocorticoid solubility in the hydrogel matrix and the tear fluid.
• the glucocorticoid is dexamethasone, which has a low solubility in aqueous medium as disclosed herein.
• the insert remains in the canaliculus after complete depletion of the glucocorticoid such as dexamethasone from the insert until the hydrogel has biodegraded and/or is disposed (washed out/cleared) through the nasolacrimal duct.
• the hydrogel matrix of the insert is formulated to biodegrade e.g. via ester hydrolysis in the aqueous environment of the tear fluid in the canaliculus, the insert softens and liquefies over time and is cleared through the nasolacrimal duct without the need for removal. Unpleasant removal may thus be avoided.
• an insert should be removed e.g.
• the insert may be expelled from the canaliculus e.g. manually.
• the insert remains in the canaliculus 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.
• the systemic concentration of glucocorticoid such as dexamethasone after administration of the insert of the present invention is very low, such as below quantifiable amounts. This significantly reduces the risk of drug-to-drug interactions or systemic toxicity, which can be beneficial e.g.
• the sustained release biodegradable intracanalicular inserts of the present invention are administered to a patient for the treatment of signs and symptoms of dry eye disease (DED), in particular for the acute treatment of DED, for instance, upon episodic flares.
• the inserts of the present invention combine the effect of inflammation suppression due to glucocorticoid release such as dexamethasone release with benefits derived from lacrimal occlusion. These combined effects may provide for an improved treatment of DED.
• the treatment of DED by means of the sustained release biodegradable intracanalicular insert of the present invention can be combined with or followed up by another treatment of DED.
• the treatment of DED by means of the sustained release biodegradable intracanalicular insert is combined with or followed up by chronic treatment of DED, for instance by chronic treatment with cyclosporine, lifitegrast or tacrolimus.
• the treatment of DED by means of the sustained release biodegradable intracanalicular insert is combined with or followed up by treatment with ophthalmic drops, such as artificial tears.
• a patient treated with an insert of the present invention may be any person in need of treatment.
• the patient may be male or female.
• the patient is female.
• the patient is over 50 years of age, or over 60 years of age, or over 70 years of age, or over 80 years of age.
• the patient may have had laser surgery of the eye, such as photorefractive keratectomy (PRK) or Laser-in-situ-Keratomileusis (LASIK) or any particular varieties thereof.
• PRK photorefractive keratectomy
• LASIK Laser-in-situ-Keratomileusis
• the patient treated with an insert of the present invention is on artificial tears and/or other palliative treatments and experiences episodic DED flares.
• the patient requires induction therapy while initiating treatment of DED.
• Pre- treatment with the sustained release biodegradable intracanalicular inserts according to the present invention before initiating long-term therapy for DED can lead to a faster resolution of signs and symptoms of DED and to a reduction in side effects such as burning or stinging caused by active ingredients for DED treatment such as cyclosporine.
• the pre-treatment period with the insert according to the present invention may last, e.g., for up to about 7 days, or up to about 14 days, or up to about 21 days, or in specific embodiments up to about 1 month prior to initiating a longer- term therapy.
• the patient treated with an insert of the present invention is on chronic DED treatment with for instance cyclosporine or lifitegrast and experiences episodic flares of DED which may be treated with an insert according to the present invention.
• the patient treated with an insert of the present invention requires treatment of DED before cataract and refractive surgery to improve outcomes/satisfaction of such surgery.
• the patient treated with an insert of the present invention requires short-term treatment of signs and symptoms of DED after cataract or refractive surgery.
• the treatment of DED with the inserts disclosed herein are combined with the application of artificial tears and/or ophthalmic drops and/or nasal neurostimulatory devices.
• the co-administered artificial tears and/or ophthalmic drops and/or nasal neurostimulatory devices may comprise anti-infective ingredients.
• the co-administered ophthalmic drops may comprise other glucocorticoids than the glucocorticoid of the administered insert (such as dexamethasone).
• the co-administered ophthalmic drops may comprise the same glucocorticoid as the glucocorticoid contained in the administered insert (such as dexamethasone).
• Suitable pharmacological products for co-administration include Restasis ® and Cequa ® (ophthalmic drops comprising cyclosporine), Xiidra ® (ophthalmic drops comprising the lymphocyte function- associated antigen 1 (LFA-1) antagonist lifitegrast), and TrueTear ® (nasal neurostimulatory device to temporarily increase tear production).
• the treatment of DED by means of the sustained release biodegradable intracanalicular insert is combined with eyelid exfoliation at the lash line (BlephEx ® ), eyelid thermal pulsation (iLux ® ), and eyelid warming and stimulation (LipiFlow ® ).
• a further sustained release biodegradable intracanalicular insert is administered into the canaliculus through the ocular punctum while the first sustained release biodegradable intracanalicular insert is still retained in the canaliculus (which procedure is referred to as “insert stacking” or short “stacking”), either while the first insert still releases glucocorticoid, or after the first insert has been completely depleted of glucocorticoid, or after the first insert has been partially depleted of glucocorticoid by at least about 70%, or at least about 80%, or at least about 90% and/or the first insert releases a lower amount of glucocorticoid than initially after its administration.
• insert stacking enables prolonged treatment with a glucocorticoid such as dexamethasone. In certain embodiments, insert stacking thus provides for a release of a therapeutically effective amount of glucocorticoid 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.
• IV. Kit [0288] In certain embodiments, the present invention is further directed to a kit comprising one or more insert(s) as disclosed herein or manufactured in accordance with the methods as disclosed herein.
• the kit comprises one or more sustained release biodegradable intracanalicular insert(s), wherein each insert contains from about 160 ⁇ g to about 250 ⁇ g or from about 180 ⁇ g to about 220 ⁇ g or about 200 ⁇ g dexamethasone and has in a dry state a diameter in the range of about 0.41 mm to about 0.49 mm and a length in the range of about 2.14 mm to about 2.36 mm, and has in the hydrated state a diameter in the range of about 1.35 mm to about 1.80 mm and a ratio of length to diameter of greater than 1, and wherein each insert provides for a release of dexamethasone for a period of up to about 14 days, or up to about 21 days, after administration.
• each insert contains from about 160 ⁇ g to about 250 ⁇ g or from about 180 ⁇ g to about 220 ⁇ g or about 200 ⁇ g dexamethasone and has in a dry state a diameter in the range of about 0.41 mm to about 0.49 mm and a
• the kit comprises one or more sustained release biodegradable intracanalicular insert(s), wherein each insert contains from about 240 ⁇ g to about 375 ⁇ g or from about 270 ⁇ g to about 330 ⁇ g or about 300 ⁇ g dexamethasone and has in a dry state 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, and has in the hydrated state a diameter in the range of about 1.35 mm to about 1.80 mm and a ratio of length to diameter of greater than 1, and wherein each insert provides for a release of dexamethasone for a period of up to about 21 days, or up to about 1 month, after administration.
• each insert contains from about 240 ⁇ g to about 375 ⁇ g or from about 270 ⁇ g to about 330 ⁇ g or about 300 ⁇ g dexamethasone and has in a dry state a diameter in the range of about 0.44 mm to about 0.
• the kit further comprises instructions for using the one or more sustained release biodegradable intracanalicular insert(s).
• the instructions for using the one or more sustained release biodegradable intracanalicular insert(s) may be in the form of an operation manual for the physician who is administering the insert(s).
• the kit may further comprise a package insert with product-related information.
• the kit may further comprise one or more means for administration of the one or more sustained release biodegradable intracanalicular insert(s).
• the means for administration may be for example one or more suitable tweezer(s) or forceps, either for one time use or for repeated use. For instance, suitable forceps are blunt (non-toothed).
• the means for administration may also be an injection device such as a syringe or applicator system.
• the kit may further comprise an ophthalmic dilator to dilate the punctum prior to the administration of the one or more sustained release biodegradable intracanalicular insert(s) and thereby facilitate insertion of the insert(s) through the punctum into the canaliculus.
• a dilator may also be combined/integrated with forceps or an applicator, such that e.g. one end of the device is a dilator, and the other end of the device is suitable to administer the insert.
• the kit may also contain a modified applicator that e.g.
• the one or more sustained release biodegradable intracanalicular insert(s) are individually packaged for a single administration.
• the one or more sustained release biodegradable intracanalicular insert(s) are individually packaged for a single administration by fixating each insert in foam carrier, which is sealed in a foil pouch.
• the foam carrier may have e.g. a V-notch or a circular incision with an opening at the bottom of the V-notch to hold the insert (see, for instance, also Figure 1).
• kits may be identical or different, and may contain identical or different doses of the glucocorticoid such as dexamethasone.
• glucocorticoid such as dexamethasone.
• PEG polyethylene glycol
• n represents an ethylene oxide repeating unit and the dashed lines represent the points of repeating units of the polymer network.
• the polymer network is formed by reacting a plurality of polyethylene glycol (PEG) units selected from 4a20k PEG-SAZ, 4a20kPEG-SAP, 4a20kPEG- SG, 4a20kPEG-SS, 8a20kPEG-SAZ, 8a20kPEG-SAP, 8a20kPEG-SG, 8a20kPEG-SS with one or more PEG or lysine based-amine groups selected from 4a20kPEG-NH 2 , 8a20kPEG-NH 2 , and trilysine, or a salt thereof.
• PEG polyethylene glycol
• An intracanalicular insert for treating dry eye wherein the intracanalicular insert occludes the punctum and delivers a therapeutically effective amount of a steroid for up to 3 weeks. 20.
• the intracanalicular insert of any one of Embodiments 19 to 22, wherein the intracanalicular insert has a length of about 1.0 mm to about 3.0 mm. 24.
• PEG polyethylene glycol
• the intracanalicular insert of Embodiments 25, wherein the polymer network comprises a plurality of multi- arm PEG units having from 2 to 10 arms.
• n represents an ethylene oxide repeating unit and the dashed lines represent the points of repeating units of the polymer network.
• PEG polyethylene glycol
• a sustained release biodegradable intracanalicular insert comprising a hydrogel and equal to or less than about 375 ⁇ g dexamethasone or an equivalent dose of another glucocorticoid.
• a sustained release biodegradable intracanalicular insert comprising a hydrogel and a glucocorticoid, wherein the insert in a dry state has an average length of equal to or less than about 2.75 mm.
• a sustained release biodegradable intracanalicular insert comprising a hydrogel and a glucocorticoid, wherein the insert provides for a release of a therapeutically effective amount of the glucocorticoid for a period of up to about 25 days after administration. 4.
• the sustained release biodegradable intracanalicular insert of any of the preceding Embodiments comprising dexamethasone as the glucocorticoid. 5.
• the sustained release biodegradable intracanalicular insert of any of the preceding Embodiments comprising equal to or less than about 350 ⁇ g dexamethasone.
• the sustained release biodegradable intracanalicular insert of Embodiment 5 comprising from about 160 ⁇ g to about 250 ⁇ g dexamethasone.
• the sustained release biodegradable intracanalicular insert of Embodiment 8 comprising from about 180 ⁇ g to about 220 ⁇ g dexamethasone.
• the sustained release biodegradable intracanalicular insert of Embodiment 9, comprising about 200 ⁇ g dexamethasone.
• the sustained release biodegradable intracanalicular insert of Embodiment 5, comprising from about 240 ⁇ g to about 375 ⁇ g dexamethasone. 12.
• the sustained release biodegradable intracanalicular insert of Embodiment 11 comprising from about 270 ⁇ g to about 330 ⁇ g dexamethasone. 13.
• the sustained release biodegradable intracanalicular insert of any of the preceding Embodiments wherein the hydrogel comprises a polymer network comprising one or more crosslinked polymer units of polyethylene glycol, polyethylene oxide, polypropylene oxide, polyvinyl alcohol, poly (vinylpyrrolidinone), polylactic acid, polylactic-co-glycolic acid, random or block copolymers or combinations or mixtures of any of these, or one or more units of polyaminoacids, glycosaminoglycans, polysaccharides, or proteins. 19.
• the hydrogel comprises a polymer network comprising one or more crosslinked polymer units of polyethylene glycol, polyethylene oxide, polypropylene oxide, polyvinyl alcohol, poly (vinylpyrrolidinone), polylactic acid, polylactic-co-glycolic acid, random or block copolymers or combinations or mixtures of any of these, or one or more units of polyaminoacids, glycosaminoglycans, poly
• 26. The sustained release biodegradable intracanalicular insert of any of the preceding Embodiments, containing a visualization agent.
• 27. The sustained release biodegradable intracanalicular insert of Embodiment 26, wherein the visualization agent is a fluorophore.
• the sustained release biodegradable intracanalicular insert of any of the preceding Embodiments, wherein the insert in a dry state has an average length in the range of about 2.14 mm to about 2.36 mm and an average diameter in the range of about 0.41 mm to about 0.55 mm. 43.
• the sustained release biodegradable intracanalicular insert of Embodiment 42 wherein the insert in a dry state has an average length of about 2.25 mm and an average diameter of about 0.5 mm.
• the sustained release biodegradable intracanalicular insert of any of the preceding Embodiments wherein upon hydration in vivo in the canaliculus or in vitro the average diameter of the insert is increased and optionally its average length is decreased.
• 45. The sustained release biodegradable intracanalicular insert of Embodiment 44, wherein hydration in vitro is measured in phosphate-buffered saline at a pH of 7.4 at 37 °C after 24 hours. 46.
• the sustained release biodegradable intracanalicular insert of Embodiment 44 or 45 wherein upon hydration the average diameter of the insert is increased 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 intracanalicular insert of Embodiment 46 wherein upon hydration the average diameter of the insert is increased by a factor of about 3.
• the sustained release biodegradable intracanalicular insert of any of Embodiments 44 to 47 wherein upon hydration the average length of the insert is decreased to about 0.9 times its average length in the dry state or less, or to about 0.75 times its average length in the dry state or less. 49.
• the sustained release biodegradable intracanalicular insert of Embodiment 48 wherein upon hydration the average length of the insert is decreased to about two-thirds of its average length in the dry state.
• 50. The sustained release biodegradable intracanalicular insert of any of the preceding Embodiments, wherein the insert in a hydrated state has an average diameter in the range of about 1 mm to about 2 mm and an average length that is shorter than the average length of the insert in the dry state.
• the sustained release biodegradable intracanalicular insert of Embodiment 50 wherein the insert in a hydrated state has an average diameter in the range of about 1.35 mm to about 1.80 mm and a ratio of length to diameter of greater than 1. 52.
• the sustained release biodegradable intracanalicular insert of Embodiment 51 wherein the insert in a hydrated state has an average diameter in the range of about 1.40 mm to about 1.60 mm and an average length in the range of about 1.70 mm to about 2.0 mm.
• 53. The sustained release biodegradable intracanalicular insert of any of the preceding Embodiments, wherein the insert provides for a release of a therapeutically effective amount of glucocorticoid for a period of about 6 hours or longer after administration.
• 54 The sustained release biodegradable intracanalicular insert of Embodiment 53, wherein the insert provides for a release of a therapeutically effective amount of glucocorticoid for a period of about 12 hours or longer after administration. 55.
• the sustained release biodegradable intracanalicular insert of any of the preceding Embodiments wherein the insert provides for an average release from about 15 ⁇ g to about 25 ⁇ g dexamethasone per day during a period of up to about 7 days, or up to about 14 days, or up to about 21 days after administration.
• 60. The sustained release biodegradable intracanalicular insert of any of Embodiments 1 to 57, wherein the insert contains about 200 ⁇ g dexamethasone and provides for an average release from about 15 ⁇ g to about 25 ⁇ g dexamethasone per day during a period of up to about 7 days after administration. 61.
• a sustained release biodegradable intracanalicular insert comprising a hydrogel and dexamethasone particles dispersed within the hydrogel, wherein the insert contains from about 160 ⁇ g to about 250 ⁇ g or from about 180 ⁇ g to about 220 ⁇ g or about 200 ⁇ g dexamethasone and has in the dry state an average diameter in the range of about 0.41 mm to about 0.49 mm and an average length in the range of about 2.14 mm to about 2.36 mm, and has in the hydrated state an average diameter in the range of about 1.35 mm to about 1.80 mm and a ratio of length to diameter of greater than 1, and wherein the insert provides for a release of dexamethasone for a period of up to about 14 days, or up to about 21 days, after administration.
• a sustained release biodegradable intracanalicular insert comprising a hydrogel and dexamethasone particles dispersed within the hydrogel, wherein the insert contains from about 240 ⁇ g to about 375 ⁇ g or from about 270 ⁇ g to about 330 ⁇ g or about 300 ⁇ g dexamethasone and has in the dry state an average diameter in the range of about 0.44 mm to about 0.55 mm and an average length in the range of about 2.14 mm to about 2.36 mm, and has in the hydrated state an average diameter in the range of about 1.35 mm to about 1.80 mm and a ratio of length to diameter of greater than 1, and wherein the insert provides for a release of dexamethasone for a period of up to about 21 days, or up to about 1 month, after administration.
• the visualization agent is fluorescein.
• 71. The method of Embodiment 69 or 70, wherein the glucocorticoid particles are homogeneously dispersed within the hydrogel.
• Embodiment 71 or 72 wherein the glucocorticoid particles are micronized dexamethasone particles having a d90 particle size of less than about 100 ⁇ m, or of less than about 75 ⁇ m, or of less than about 50 ⁇ m, or of less than about 20 ⁇ m, or of less than about 10 ⁇ m and are homogeneously dispersed within the hydrogel.
• 74 The method of any of Embodiments 69 to 73, wherein equal to or less than about 375 ⁇ g, or equal to or less than about 350 ⁇ g, or from about 100 ⁇ g to about 350 ⁇ g, or from about 150 ⁇ g to about 320 ⁇ g dexamethasone are contained in the insert. 75.
• Embodiment 74 wherein from about 160 ⁇ g to about 250 ⁇ g dexamethasone, or from about 180 ⁇ g to about 220 ⁇ g dexamethasone, or about 200 ⁇ g dexamethasone are contained in the insert. 76. The method of Embodiment 74, wherein from about 240 ⁇ g to about 375 ⁇ g dexamethasone, or from about 270 ⁇ g to about 330 ⁇ g dexamethasone, or about 300 ⁇ g dexamethasone are contained in the insert. 77.
• the polymer network is formed from one or more crosslinked polymer units of polyethylene glycol, polyethylene oxide, polypropylene oxide, polyvinyl alcohol, poly (vinylpyrrolidinone), polylactic acid, polylactic-co-glycolic acid, random or block copolymers or combinations or mixtures of any of these, or one or more units of polyaminoacids, glycosaminoglycans, polysaccharides, or proteins.
• the polymer network is formed by crosslinking multi- arm polyethylene glycol units in a buffered solution.
• 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 allowing the mixture to gel.
• 80. The method of Embodiment 79, wherein the crosslinking agent contains amine groups.
• 81. The method of Embodiment 79 or 80, wherein the electrophilic group-containing multi-arm-polymer precursor is 4a20kPEG-SG and the crosslinking agent is trilysine acetate.
• 82 The method of any of Embodiments 69 to 81, comprising admixing a visualization agent.
• Embodiments 82 comprising conjugating the visualization agent with the polymer network.
• the method of Embodiment 83 comprising conjugating the visualization agent with the crosslinking agent prior to crosslinking the polymer precursor.
• the visualization agent is a fluorophore.
• the visualization agent is fluorescein.
• the method of any of Embodiments 79 to 88, wherein the method comprises the steps of filling the mixture into a mold or tubing prior to complete gelling of the hydrogel, allowing the mixture to gel, and drying the hydrogel.
• the method of Embodiment 90, wherein the inside of the tubing has a round geometry. 92.
• Embodiment 90 or 91 wherein the method further comprises stretching the hydrogel strand.
• 93 The method of Embodiment 92, wherein the stretching of the hydrogel strand is performed prior to drying the hydrogel strand.
• 94 The method of Embodiment 93, wherein the hydrogel strand is stretched by a stretch factor in the range of about 1.5 to about 3, or of about 2.2 to about 2.8, or of about 2.5 to about 2.6.
• Embodiment 95 wherein the dry hydrogel strand is cut into segments having an average length of equal to or less than about 2.5 mm.
• a method of treating dry eye disease in a patient in need thereof comprising administering to the patient a sustained release biodegradable intracanalicular insert according to any of Embodiments 1 to 68 or manufactured in accordance with the method of any of Embodiments 69 to 97. 99.
• the method of Embodiment 98, wherein the treatment is an acute treatment of dry eye disease. 100.
• Embodiment 98 or 99 wherein the treatment is an acute treatment of episodic flares of dry eye disease.
• 101 The method of any of Embodiments 98 to 100, wherein the insert is administered to the inferior and/or superior canaliculus.
• 102 The method of any of Embodiments 98 to 100, wherein the insert is administered to the vertical canaliculus.
• 103 The method of any of Embodiments 98 to 102, wherein the insert is administered bilaterally.
• 104 The method of any of Embodiments 98 to 103, wherein the glucocorticoid is delivered to the ocular surface through the tear film. 105.
• Embodiment 105 wherein the insert contains from about 160 ⁇ g to about 250 ⁇ g dexamethasone, or from about 180 ⁇ g to about 220 ⁇ g dexamethasone, or about 200 ⁇ g dexamethasone.
• the insert contains from about 240 ⁇ g to about 375 ⁇ g dexamethasone, or from about 270 ⁇ g to about 330 ⁇ g dexamethasone, or about 300 ⁇ g dexamethasone.
• 111. The method of any of Embodiments 98 to 110, wherein the insert releases a therapeutically effective amount of dexamethasone for a period of about 6 hours or longer after administration. 112.
• Embodiment 111 wherein the insert releases a therapeutically effective amount of dexamethasone for a period of about 12 hours or longer after administration.
• 113 The method of any of Embodiments 98 to 112, wherein the insert releases a therapeutically effective amount of 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.
• 114. The method of Embodiment 113, wherein the insert contains about 200 ⁇ g dexamethasone and releases dexamethasone for a period of up to about 14 days after administration.
• 115 The method of Embodiment 111, wherein the insert releases a therapeutically effective amount of dexamethasone for a period of about 12 hours or longer after administration.
• Embodiment 113 wherein the insert contains about 300 ⁇ g dexamethasone and releases dexamethasone for a period of up to about 21 days after administration.
• 116 The method of any of Embodiments 98 to 115, wherein the insert releases on average about 15 ⁇ g to about 25 ⁇ g 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 ⁇ g dexamethasone and releases on average about 15 ⁇ g to about 25 ⁇ g dexamethasone per day for a period of up to about 7 days after administration.
• 118 the insert contains about 300 ⁇ g dexamethasone and releases dexamethasone for a period of up to about 21 days after administration.
• Embodiment 116 wherein the insert contains about 300 ⁇ g dexamethasone and releases on average about 15 ⁇ g to about 25 ⁇ g dexamethasone per day for a period of up to about 11 days, or up to about 14 days after administration.
• the insert contains about 300 ⁇ g dexamethasone and releases on average about 15 ⁇ g to about 25 ⁇ g 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 of Embodiments 98 to 118, wherein after complete depletion of the glucocorticoid from the insert the insert remains in the canaliculus until the hydrogel has biodegraded and/or is cleared through the nasolacrimal duct. 120.
• Embodiment 119 wherein the insert remains in the canaliculus 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.
• the method of any of Embodiments 98 to 120 comprising the administration of a further sustained release biodegradable intracanalicular insert according to any of claims 1 to 68 or manufactured in accordance with the method of any of claims 69 to 97 into the canaliculus while the first insert is still retained in the canaliculus (“insert stacking”).
• insert stacking 122.
• Embodiment 121 or 122 wherein the further insert is administered when the first insert has been completely depleted of glucocorticoid. 124.
• the other treatment of dry eye disease is a chronic treatment of dry eye disease. 127.
• a kit comprising one or more sustained release biodegradable intracanalicular insert(s) according to any of Embodiments 1 to 68 or manufactured in accordance with the method of any of Embodiments 69 to 97 and instructions for using the insert(s). 130.
• the kit according to Embodiment 129 further comprising one or more means for administration of the insert(s).
• 132 The kit according to any one of Embodiments 129 to 131, wherein the insert(s) is/are fixated in a foam carrier which is sealed in a foil pouch.
• Example 1 Preparation of dexamethasone inserts
• the dexamethasone inserts of some embodiments of the present application are essentially cylindrical having a certain length and diameter as specified herein, with dexamethasone homogeneously dispersed and entrapped within a PEG-based hydrogel matrix to provide sustained release of dexamethasone to the ocular surface through the tear fluid.
• dexamethasone has a low aqueous solubility.
• an autoclaved polyurethane tubing was cut into appropriate length pieces first. The formulation process involved preparing 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). The contents of these two syringes are then combined to form a mixture (a suspension), which is allowed to gel to form the hydrogel with dexamethasone dispersed therein.
• the first syringe contained a suspension of corresponding amounts of sieved, micronized dexamethasone (Pfizer) in water (Table 3).
• the dexamethasone had a particle size of d90 ⁇ 5 ⁇ m and d98 ⁇ 10 ⁇ m, and had been additionally sieved to remove particles that are 90 ⁇ m or larger.
• the second syringe contained 5,620 ⁇ 10 mg of a solution of 4a20k PEG-SG and sodium phosphate monobasic buffer solution that was prepared by mixing the corresponding amounts (Table 3) in a sterile container.
• the dexamethasone suspension syringe was then connected to the 4a20k PEG-SG syringe luer-to-luer and the contents of the syringes were mixed by passing back and forth between each syringe. The suspension was then transferred into one single syringe to form the dexamethasone/4a20k PEG-SG syringe.
• Table 3 Ingredients of the dexamethasone/4a20k PEG-SG syringe.
• the strands were stretched at a controlled rate to approximately 2.5-2.6 times the original tubing length.
• the stretched strands were stored vertically in nitrogen-flashed atmosphere for 60 to 72 hours at 32.0 ⁇ 2.0 °C to allow the strands to dry completely.
• the dried strands were removed from the polyurethane tubing and cut into approximately 2.25 mm segments. The surface of the cut inserts was inspected for particulate, cylindrical shape and any visible surface defects. Inserts that did not show any defects and provided the required shape were evaluated for dimensional length and diameter. Inserts that did not meet all requirements were rejected.
• the inserts were packaged separately into foam carrier (one insert per foam carrier) and sealed in an aluminum-low density polyethylene (LDPE) foil pouch that can be peeled open by the user (Figure 1).
• foam carrier one insert per foam carrier
• LDPE aluminum-low density polyethylene
• Figure 1 an insert was placed with forceps into the opening in a foam carrier with a portion of the insert protruding for easy removal.
• the foam carrier with insert was placed into the foil pouch.
• the unsealed foil pouches were transferred into a glovebox and kept there for 16-96 hours in an inert nitrogen environment to reduce residual moisture from the foam and pouch material (moisture content ⁇ 1.0%).
• the pouches were then sealed within the glovebox using a pouch sealer to create a complete, continuous seal on the pouch.
• the duration of dexamethasone release is estimated to last for 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).
• the hydrated dimensions were measured as disclosed herein after 24 hours in biorelevant media (phosphate buffered saline (PBS), pH 7.4 at 37 °C), which is considered equilibrium. Measurement of insert dimensions (both in the dry and in the wet state) were performed by a custom 3- camera Keyence Inspection System.
• Inserts are intended for administration through the upper and/or lower punctum of the eye into the superior and/or inferior vertical canaliculus of the eye using e.g. tweezers ( Figure 2A). The insert can be visualized by illuminating the fluorescent PEG with a blue light source and using a yellow filter ( Figure 2B).
• Stretching of the strands during the production process creates a shape memory, meaning that the insert upon hydration when administered into the canaliculus of the eye will rapidly shrink in length (e.g. to about 2/3 of the length in the dry state) and widen in diameter (e.g. to about 3x the diameter in the dry state) to approach its original wet casted dimension (Figure 3 and Table 5).
• the degree of shrinking in length and expanding in diameter upon hydration depends inter alia on the stretch factor. While the narrow dry dimensions facilitate administration of the insert through the punctum into the canaliculus, the shortened length after administration yields a shorter insert in the canaliculus of the eye minimizing potentially disturbing effects for the patient and provides for a good fit and thus a good retention in the vertical canaliculus.
• the insert As the insert’s diameter expands upon hydration, it thereby adapts to and closely fits within the individual canaliculus size of the patient. Thereby, unintended loss of the insert as sometimes experienced with commonly used plugs such as collagen or silicon plugs is greatly reduced.
• the micronized dexamethasone contained in the insert dissolves in tear fluid to provide a sustained topical delivery of therapeutically effective amounts of dexamethasone to the ocular surface.
• the release of a therapeutically effective amount of dexamethasone lasts, for instance, up to about 14 days in case of the 0.2 mg insert and up to about 21 days in case of the 0.3 mg insert.
• the dexamethasone-depleted insert remains in the canaliculus for a certain period of time, such as for about 1, about 2, about 3, or about 4 months after administration, and is slowly biodegraded and becomes smaller until it is cleared (disposed/washed out) through the nasolacrimal duct.
• a certain period of time such as for about 1, about 2, about 3, or about 4 months after administration
• patient compliance is increased as compared to the use of eye drops that have to be administered daily or even several times per day.
• Dexamethasone is released primarily from the proximal end of the insert at the interface between the hydrogel and the tear fluid (as shown exemplarily in Figure 6).
• the sustained drug release rate is controlled by drug solubility in the hydrogel matrix and the tear fluid.
• the hydrogel matrix of the insert is formulated to biodegrade e.g. via ester hydrolysis in the aqueous environment of the canaliculus. Thereby, over time, the insert softens, liquefies and is cleared (disposed/washed out) through the nasolacrimal duct without the need for removal (unless removal is desired in a particular circumstance). Unpleasant removal can thus be avoided.
• the inserts are applied for the treatment of signs and symptoms of dry eye disease (DED), in particular for the acute treatment of DED, for instance, upon episodic flares of DED.
• DED dry eye disease
• the dexamethasone inserts of the present application combine the effect of inflammation suppression due to dexamethasone release with benefits from lacrimal occlusion, wherein the combined effects provide an improved treatment of DED.
• Example 2 In vitro dexamethasone release [0309] The release rate of dexamethasone from the 0.2 mg and 0.3 mg inserts (Table 4 and 5) was determined by in vitro testing. In vitro release was examined under accelerated conditions as briefly described in the following: One insert was placed into a bottle and 100 mL of buffer solution were added (1x phosphate buffer saline, PBS at pH 7.4) in order to expose the entire insert surface to buffer solution.
• Dexamethasone concentration in plasma, aqueous humor and tear fluid samples were determined by high performance liquid chromatography combined with tandem mass spectrometry (LC-MS/MS) using a triple quadrupole mass spectrometer.
• LC-MS/MS tandem mass spectrometry
• For preparation of tear fluid samples deionized water was added to the tear fluid samples to obtain a volume of 50 ⁇ L for each tear sample. Then, 50 ⁇ L of internal standard solution (prednisolone-21 acetate) were added to each tear sample.
• 50 ⁇ L of each aqueous humor sample were mixed with 50 ⁇ L internal standard solution.
• the HPLC mobile phases were acetonitrile and HPLC-grade water with 0.1% formic acid (v/v).
• the column was kept at ambient temperature, the sample compartment was kept at 2-5°C.
• the analytes were eluted from the column at 0.8 mL/min using a gradient resulting from mixture of the mobile phases.
• Dexamethasone was ionized by negative ion electrospray. The MS system was operated at negative ion mode. Dexamethasone (391.0-361.1 m/z; retention time 1.23 ⁇ 0.5 min) and the internal standard (prednisolone-21 acetate, 401.2-321.0 m/z; 1.29 ⁇ 0.5 min) were fragmented in the MS.
• the total run time was 2.4 min.
• Dexamethasone concentration was determined from a calibration curve. Prior to analysis of the samples, the method was validated using dexamethasone-comprising beagle plasma and artificial tears. The method was shown to be reproducible, precise, linear, accurate and specific.
• the lower limit of quantification was determined to be 1.0 ng/mL, the lower limit of detection to be 0.08-0.06 ng/mL.
• Table 8 Dexamethasone concentrations in aqueous humor of beagle dogs delivered from different doses of dexamethasone inserts over time. [0317] Pharmacokinetic results in tear fluid and aqueous humor samples were comparable. The values demonstrate a sustained release of dexamethasone with approximately constant levels of dexamethasone in the tear fluid and aqueous humor for several days depending on the dose, followed by a reduction in released drug amounts (tapering) until ultimately complete release.
• the 0.22 mg dexamethasone insert provided approximately constant dexamethasone levels in the tear fluid through 7 days followed by tapering from day 7 on with complete release of dexamethasone from the insert after 17 days following administration, thus resulting in an overall sustained release time of 17 days (Figure 5).
• inserts were placed bilaterally into the punctum of 7 beagles (i.e., a total of 14 eyes) on day 0.
• Tear fluid samples were collected from beagle eyes with 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 insert into the canaliculus.
• Dexamethasone levels in tear fluid were measured by LC-MS/MS. Dexamethasone is presented as average values together with corresponding standard deviation error bars. The numbers of samples measured were as follows: For day 1, n was 6 eyes; for day 2, n was 8 eyes; for days 14 and 21, n was 7 eyes; for day 28, n was 6 eyes; for day 35, n was 2 eyes.
• a single insert delivered dexamethasone to the ocular surface for approximately 14 days, with a sustained level of dexamethasone in the tear fluid maintained through day 7, followed by a tapering from day 7 to day 14 with complete release by day 17.
• the 0.37 mg dexamethasone insert resulted in constant dexamethasone levels in the tear fluid through 21 days followed by tapering from day 21 through day 28 (Table 7). The tapering was also evident in the aqueous humor in the 0.37 mg dose at day 21 and the 0.46 mg dose at day 28 (Table 8).
• the aqueous humor and tear fluid dexamethasone concentrations resulting from the doses tested corresponded to the concentrations achieved by the application of MAXIDEX ® eye drops (0.1% dexamethasone suspension) 4 times per day, which contain approximately 50 ⁇ g of dexamethasone per drop.
• dexamethasone concentrations in the aqueous humor of beagle dogs at 7 and 14 days were comparable between all doses tested.
• dexamethasone concentrations in tear fluid of beagle dogs were also comparable between all doses tested at 7 days.
• Dexamethasone inserts were removed from the canaliculus by manual expression out of the punctum opening at selected time points for a defined number of animals. Remaining dexamethasone was extracted from the inserts and measured by LC-MS/MS as described above.
• the dexamethasone release rate per day prior to tapering and complete depletion from the insert was calculated by determining the amount of dexamethasone released from the insert divided by the study day the insert was removed (Table 9).
• the results demonstrate that the determined dexamethasone release rates per day are comparable between all doses tested. This is in line with the fact that the dexamethasone release rate from an insert according to the present invention is regulated by the drug’s solubility in the hydrogel matrix and the tear fluid.
• Dexamethasone is released from the insert primarily at the interface proximal to the tear fluid, i.e.
• the released drug levels thus remain largely constant until dexamethasone amounts in the insert are sufficiently reduced at the interface between the insert and the tear fluid, which leads to a gradual tapering effect as observed in the tear fluid and aqueous humor pharmacokinetic profiles.
• the average amount of dexamethasone released from the inserts according to the invention measured in these studies is essentially independent of the dexamethasone dose and is approximately 0.020 mg per day (or from about 0.015 mg to about 0.025 mg per day) prior to tapering and complete depletion.
• Table 9 Dexamethasone released per day from dexamethasone inserts comprising different doses prior to tapering and complete depletion (note that the two 0.85 mg inserts in the table were two different lots and measured in two different studies). [0320] The unidirectional drug release into the tear fluid is visually demonstrated exemplarily for the 0.37 mg dexamethasone insert in Figure 6. Although dexamethasone is released from the inserts prior to (complete) biodegradation of the insert (e.g. for the 0.37 mg dexamethasone insert the drug is completely released after approximately 28 days while the insert has not yet visually degraded to a large extent), extended presence of the drug depleted insert provides the additional longer-term benefit of lacrimal occlusion.
• Inserts comprising 0.2mg and 0.3 mg dexamethasone, respectively, are expected to provide an essentially constant concentration of dexamethasone to the ocular surface for a period of up to about 7 days (for the 0.2 mg insert) and up to about 11, or up to about 14 days (for the 0.3 mg insert), after administration.
• the dexamethasone concentrations will then decrease (taper) over approximately the next 7 days until the active is completely depleted from the 0.2 mg and 0.3 mg dexamethasone insert.
• a sustained release of therapeutically effective amounts from the inserts according to the present invention is therefore provided for a period of about 14 days and for a period of about 21 days, respectively.
• Safety and tolerability of inserts [0322] Potential ocular toxicity, irritation, and systemic exposure were evaluated for a 0.72 mg dexamethasone insert over a 35-day period after intracanalicular insertion in beagle dogs. Reversibility and delayed occurrence of any toxic effects were assessed after a 14-day recovery period.
• the first insert type comprised 100% 4-arm 20k PEG-SG hydrogel material (as described above in Example 1).
• the second insert type comprised a 50/50 blend of 4-arm 20k PEG-SG and 4-arm 20k PEG-SS hydrogel material. Both insert types were prepared according to the same method as described above in Example 1, except that for the second insert type the mentioned PEG precursor blend was used.
• Animals of the second group (n 16) received the control inserts (without dexamethasone), i.e. the first insert type with 100% 4-arm 20k PEG-SG in one eye and the second insert type with the 50/50 PEG blend in the other eye, so each animal received one insert type (without dexamethasone) in each eye.
• Evaluations included any observed toxic effects, gross necropsy, and histopathological findings.
• Ophthalmic examinations included slit lamp biomicroscopy, fluorescein staining, fundoscopy, and tonometry. The slit lamp examination was used to track potential alterations in the cornea, conjunctiva, iris, anterior chamber, and lens. The corneal surface was also assessed using fluorescein stain. The retina was examined for gross changes to the retina or optic nerve and noted as normal or abnormal. Daily clinical and food consumption observations were conducted. Body weight was measured weekly. [0326] In summary, the dexamethasone inserts were well tolerated.
• the subjects receive bilaterally either a 0.2 mg or a 0.3 mg dexamethasone insert, or an insert that does not comprise dexamethasone (hydrogel vehicle only, placebo control) into the inferior or superior vertical canaliculi through the lower or upper puncta of the eye (intracanalicular inserts).
• Screening visits occur at week 1, week 2, week 3, week 4, and week 8 after insertion to evaluate bulbar conjunctival hyperemia, eye dryness score (VAS scale), total corneal fluorescein staining, and adverse events (ocular and non-ocular).
• VAS scale eye dryness score
• adverse events ocular and non-ocular
• the primary efficacy end- point is at week 2 after insertion. Patients are followed for an extended period of time (for another 6 weeks; “safety follow-up”) after the primary efficacy end-point in order to, for instance, evaluate insert presence. Additional screening visits or an extended safety follow-up may be scheduled depending on the study course.

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