Ophthalmic compositions

Abstract

The hydrogel silica composition comprises: a) silica microparticles containing an active pharmaceutical ingredient and having a maximum diameter in the range of 0.5 to 40 μm; and b) a silica sol containing solid nanoparticles of <50 nm, wherein i) the silica sol has a solids content of <1% by weight; ii) the hydrogel silica composition comprises up to 30% by weight of the composition of the silica microparticles; and iii) the hydrogel silica composition is for topical ocular administration.

Description

[Technical Field]

[0001] The present invention relates to sustained or controlled release ophthalmic compositions for topical delivery. More specifically, disclosed herein are sustained or controlled release ophthalmic compositions comprising an active pharmaceutical ingredient in a hydrogel silica composition, which are particularly viable for administration as topical eye drops and suitable for once-daily administration of the active pharmaceutical ingredient. [Background technology]

[0002] Topical ophthalmic drug delivery systems for treating ocular inflammation are typically available in dosage forms such as solutions, suspensions, gels, and ointments. While these have proven suitable for delivering the necessary active ingredients to the eye, there are several drawbacks associated with these conventional dosage forms, the most common of which is the need for multiple daily administration. Conventional gel and ointment dosage forms are also known to affect vision or acuity, while solution dosage forms are too easily washed off the surface of the eye. Furthermore, suspension products can be gritty and cause corneal damage if not properly formulated. The pH of ophthalmic solution dosage forms is typically adjusted to keep the active ingredients contained therein in solution, but this pH is often inherently acidic, leading to corneal irritation and redness. Furthermore, preparing storage-stable ophthalmic formulations is challenging due to strict regulatory requirements. These issues create barriers to optimal delivery and patient compliance with one or more conventional ophthalmic dosage forms.

[0003] The drugs or active ingredients typically used for the treatment of ocular inflammation, such as those resulting from the disease state of the conjunctiva, cornea and front of the eye, such as anterior uveitis, iritis, cyclitis, allergic conjunctivitis and vernal conjunctivitis, herpes zoster keratitis, superficial punctate keratitis and nonspecific superficial keratitis; corneal damage after chemical, radiation or thermal burns or foreign body invasion; postoperative use to reduce inflammatory reaction; graft reaction, etc. include corticosteroids such as dexamethasone and their pharmaceutically acceptable salts, prostaglandins such as bimatoprost, latanoprost, etc. Most of these products are marketed as immediate release dosage forms that require several doses per day, and can be formulated as solution or suspension. Maxidex®, a 0.1% w / v suspension containing dexamethasone, is indicated for the treatment of steroid-responsive inflammatory conditions of the conjunctiva, cornea, and anterior segment of the eye, such as anterior uveitis, iritis, cyclitis, allergic and vernal conjunctivitis, herpes zoster keratitis, superficial punctate keratitis, and nonspecific superficial keratitis. It is also indicated for the treatment of corneal injury following chemical, radiation, or thermal burns, or foreign body intrusion, and for postoperative use to reduce inflammatory responses and inhibit graft reactions. The frequency of instillation of these drops and the duration of treatment vary depending on the severity of the underlying disease and response to treatment. Severe inflammation requires 1 to 2 drops of Maxidex® instilled into the eye every 30 to 60 minutes until a satisfactory response occurs. Once a favorable response is observed, the dosage of Maxidex® is reduced to 1 drop every 4 hours. Obviously, this can be problematic in that multiple doses may be required throughout the day, and apart from the sheer inconvenience of multiple injections, patients may forget to inject the drops.

[0004] Attempts have been made to develop sustained- or controlled-release dosage forms of dexamethasone for delivering dexamethasone to the ocular surface, such as resorbable PEG-hydrogels in the form of intraluminal inserts (approved by the U.S. FDA as DEXTENZA®). However, these require surgical implantation of the insert and cannot be self-administered locally or at home by patients. Thus, sustained- or controlled-release ophthalmic compositions that remain stable over long periods of storage are difficult to formulate due to various complexities involved, such as providing the desired therapeutic efficacy with once-daily administration without affecting safety, achieving the ideal pH and viscosity of a composition that remains on the ocular surface for an extended period of time without being washed away and yet does not irritate the eye, and achieving a composition that does not affect vision upon administration. Therefore, there is a need for a stable topical ophthalmic dosage form that overcomes these issues and can be administered once-daily.

[0005] PCT Publication WO 2014207304, entitled "Silica Hydrogel Composite," discloses a composition comprising an active ingredient encapsulated in silica particles and suspended in a silica sol, the composition being in the form of an injectable, flowable, or extrudable composition. While the composition provides sustained release of the active ingredient without a significant burst, the publication does not disclose any ophthalmic compositions suitable for administration as eye drops in the subconjunctival sac. The publication's disclosure relates to parenteral or surgically implanted products. Nothing herein teaches, suggests, or motivates the formulation of ophthalmic compositions.

[0006] PCT Publication WO 2017068245, entitled "Hydrogel Composite Depot Formulation," relies on WO 2014207304 for the composition of its depot formulation and focuses on controlled release of active ingredients from implants compared to traditional depot and microsphere formulations for parenteral administration. The compositions described herein are suitable for weekly to annual administration. However, the present disclosure does not teach the formulation of stable ophthalmic compositions that can be delivered topically. There are many differences between ophthalmic products and other parenteral products, including the lipophilic nature of the corneal tissue, which creates a less compatible environment for hydrophilic active pharmaceutical ingredients and excipients; faster clearance times from the eye reduce the retention time of active pharmaceutical ingredients in the eye, thereby resulting in low bioavailability; and the specific viscosity, tonicity, and pH requirements for ophthalmic compositions significantly limit the options available for physiochemically stabilizing active pharmaceutical ingredients in such compositions. Due to these differences, the teachings of making such parenteral compositions obviously cannot be applied to making stable topical ophthalmic compositions. Topical ophthalmic administration requires several other parameters to be met in order to successfully administer to the eye and achieve sustained or controlled release of the active ingredient contained therein. Ocular implants administered by injection, such as those described in the aforementioned PCT publications, are very different from ophthalmic compositions administered topically as drops that can provide sustained release of the drug contained therein. The latter is neither obvious nor derivable from the former. As far as this technology is concerned, both WO2014207304 and WO2017068245 are incorporated herein by reference.

[0007] A February 2019 publication by Nawrat et al. (available at https: / / www.pharmaceutical-technology.com / analysis / delsitech-leveraging-silicas-properties-to-improve-drug-delivery / ) discusses leveraging the properties of silica to improve drug delivery. It discloses a technology that allows for the controlled release of embedded active pharmaceutical ingredients and can heat-stabilize the product for years. It discusses that silica matrix technology may allow vaccines to be stored at room temperature or 4°C, allowing life-saving drugs to remain effective for much longer. The publication does not discuss sustained-release topical ophthalmic compositions and in no way teaches the use of the technology to obtain topical eye drops.

[0008] The prior art is also replete with examples of ophthalmic compositions containing anti-inflammatory agents such as dexamethasone, attempting to sustain or control the release of the drug to reduce the number of daily administrations. EP 1904108 discloses the use of a composition containing the penetration enhancer methylsulfonylmethane for the treatment of disorders, diseases, and other adverse medical conditions, including adverse eye conditions often associated with aging. EP 3265096 relates to compositions and methods useful for treating and / or preventing eye conditions, including dexamethasone as an active ingredient. WO 2019126176 relates to novel mixed transition metal oxides and their use as catalysts or catalyst precursors, such as hydrocarbon conversion catalysts or catalyst precursors, or specifically hydrotreating catalysts or catalyst precursors, together with active ingredients such as dexamethasone. None of these disclosures provide a composition suitable for once-daily administration to the eye in the form of eye drops that can be conveniently administered into the subconjunctival sac.

[0009] Therefore, there is a need for easily administrable, stable topical ophthalmic compositions, such as eye drops, that can provide the desired therapeutic effect in the treatment of inflammatory eye conditions while being administered once daily. [Prior art documents] [Patent documents]

[0010] [Patent Document 1] International Publication No. 2014207304 [Patent Document 2] International Publication No. 2017068245 [Patent Document 3] European Patent No. 1904108 [Patent Document 4] European Patent No. 3265096 [Patent Document 5] International Publication No. 2019126176 [Non-patent literature]

[0011] [Non-Patent Document 1] Nawrat et al(https: / / www.pharmaceutical-technology.com / analysis / delsitech-leveraging-silicas-properties-to-improve-drug-delivery / ) Summary of the Invention [Problem to be solved by the invention]

[0012] An object of the present disclosure is to provide hydrogel silica compositions containing active pharmaceutical ingredients for topical ocular administration. [Means for solving the problem]

[0013] A first aspect is a hydrogel silica composition comprising: a) silica microparticles comprising an active pharmaceutical ingredient and having a maximum diameter in the range of about 0.5 μm to about 40 μm; b) a silica sol containing solid nanoparticles of <50 nm, i) the silica sol has a solids content of <1 wt. %; ii) the hydrogel silica composition comprises up to 30% by weight of the silica microparticles; iii) The hydrogel silica composition is for topical administration.

[0014] In one embodiment, the hydrogel silica composition is a sustained or controlled release composition, preferably the composition is a sustained release composition.

[0015] In one preferred embodiment, the hydrogel silica composition is provided in the form of a topical eye drop. In another preferred embodiment, the hydrogel silica composition is provided in a single-dose container.

[0016] In another aspect, the present disclosure provides a silica hydrogel composition for use in treating an ocular disorder or disease. Preferably, the silica hydrogel composition is for topical ocular administration. More preferably, the hydrogel silica composition is administered topically once daily.

[0017] In one embodiment, the eye disorder or eye disease is ocular inflammation. In a preferred embodiment, the ocular inflammation is selected from anterior uveitis, iritis, cyclitis, allergic or vernal conjunctivitis, herpes zoster keratitis, superficial punctate keratitis or nonspecific superficial keratitis, or postoperative ocular inflammation or inflammatory reaction. In a more preferred embodiment, the ocular inflammation is postoperative ocular inflammation or inflammatory reaction.

[0018] In another embodiment, the eye disorder or disease is corneal damage following chemical, radiation or thermal burns, or foreign body invasion.

[0019] Another aspect relates to a method for treating an ocular disorder or disease in a patient in need thereof, comprising topically administering to the patient the hydrogel silica composition. In one embodiment, the ocular disorder or disease is an ocular inflammation or inflammatory reaction selected from anterior uveitis, iritis, cyclitis, allergic or vernal conjunctivitis, herpes zoster keratitis, superficial punctate keratitis or nonspecific superficial keratitis, preferably a post-operative ocular inflammation or inflammatory reaction. In a preferred embodiment, the hydrogel silica composition comprises dexamethasone or a pharmaceutically acceptable salt thereof as an active ingredient.

[0020] Yet another aspect relates to the use of said silica hydrogel composition for the treatment of an ocular disorder or disease.

[0021] Another object of the present disclosure is to provide a method for preparing a hydrogel silica composition containing an active pharmaceutical ingredient.

[0022] A further aspect is a method for preparing a hydrogel silica composition, comprising mixing silica microparticles comprising an active pharmaceutical ingredient and having a maximum diameter in the range of about 0.5 μm to about 40 μm with a silica sol, i) the silica sol has a solids content of ≦1 wt. %; ii) The hydrogel silica composition comprises up to 30% by weight of the composition of said silica microparticles.

[0023] In a preferred embodiment, the method comprises: a) silica microparticles containing about ≦15 wt. %, preferably 10 wt. %, more preferably ≦7.5 wt. % dexamethasone or a pharmaceutically acceptable salt thereof, the silica microparticles having a mean diameter D10 in the range of 0.9 to 10 μm and / or a mean diameter D50 in the range of 0.5 to 15 μm and / or a mean diameter D90 in the range of 5 to 40 μm, preferably 5 to 20 μm; b) a silica sol containing solid nanoparticles of <50 nm, the silica sol having a solids content of <1 wt. %, The present invention relates to preparing a hydrogel silica composition, wherein the hydrogel silica composition comprises up to 30% by weight of the composition of said silica microparticles.

[0024] In a preferred embodiment of the method, the silica microparticles are obtained by a process of spray drying silica together with an active pharmaceutical ingredient.

[0025] Yet another object of the present disclosure is to provide a hydrogel silica composition obtainable by the above method.

[0026] A preferred embodiment is a) silica microparticles comprising an active pharmaceutical ingredient and having a maximum diameter in the range of about 0.5 μm to about 40 μm; b) a silica sol containing solid nanoparticles of <50 nm, i) the silica sol has a solids content of <1 wt. %; ii) providing a hydrogel silica composition, wherein the hydrogel silica composition comprises up to 30% by weight of the silica microparticles.

[0027] Without wishing to be bound by any theory, it is hypothesized that in the hydrogel silica composition of the present invention, sustained release of the active pharmaceutical ingredient is achieved by embedding the active pharmaceutical ingredient in silica microparticles, which are then mixed with silica sol to form a semi-solid hydrogel silica composition. The release of the active pharmaceutical ingredient is primarily dependent on the dissolution rate of the silica microparticles in extraocular fluid.

[0028] The hydrogel silica compositions provided herein are completely biodegradable and biosoluble in body tissues, such as ocular fluid. Biodegradation is based on surface erosion by body fluids, i.e., ocular fluid, and occurs within 24 hours. Drug release from the hydrogel silica compositions is strictly controlled by matrix erosion and is not dependent on the solubility of the drug or active pharmaceutical ingredient contained in the silica microparticles. The hydrogel silica compositions provided herein are also designed to control or eliminate initial burst.

[0029] In one embodiment, the hydrogel silica composition contains an active pharmaceutical ingredient selected from one or more anti-inflammatory agents conventionally used to treat ocular inflammation, such as corticosteroids, e.g., prednisolone, dexamethasone, fluocinolone, fluorometholone, medrysone, rimexolone, and their pharmaceutically acceptable salts; nonsteroidal anti-inflammatory compounds, such as ketorolac, flurbiprofen, bromfenac, diclofenac, nepafenac, and their pharmaceutically acceptable salts; immunosuppressants, such as cyclosporine or voclosporin; antibiotics, such as ofloxacin; lymphocyte function-associated antigen 1 (LFA-1) antagonists, such as lifitegrast; recombinant human nerve growth factor, such as senegermine; or other biological drugs used in ocular diseases or disorders. In a preferred embodiment, the active pharmaceutical ingredient is selected from lifitegrast, nepafenac, ofloxacin, cyclosporine, senegermine, or dexamethasone. In a more preferred embodiment, the active pharmaceutical ingredient is dexamethasone or a pharmaceutical salt thereof. Preferably, the ophthalmic composition is administered topically to the subconjunctival sac once daily.

[0030] In a most preferred embodiment, there is provided a hydrogel silica composition comprising: a) silica microparticles containing about ≦15 wt. %, preferably 10 wt. %, more preferably ≦7.5 wt. % dexamethasone or a pharmaceutically acceptable salt thereof, the silica microparticles having a mean diameter D10 in the range of 0.9 to 10 μm and / or a mean diameter D50 in the range of 0.5 to 15 μm and / or a mean diameter D90 in the range of 5 to 40 μm, preferably 5 to 20 μm; b) a silica sol containing solid nanoparticles of <50 nm, the silica sol having a solids content of <1 wt. %, A hydrogel silica composition is provided, wherein the hydrogel silica composition comprises up to 30% by weight of the composition of said silica microparticles. DETAILED DESCRIPTION OF THE INVENTION

[0031] The hydrogel silica composition provided herein is suitable for topical ocular administration, and the rheological properties of the composition are ideal for providing once-daily administration and sustained release of the active pharmaceutical ingredient contained therein.In addition, the content of silica microparticles containing active pharmaceutical ingredients can be surprisingly low in the hydrogel silica composition, yet the composition remains stable even during long-term storage, making it suitable for ophthalmic use, preferably for once-daily administration.

[0032] In the context of this disclosure, a hydrogel should be understood to be a homogeneous mixture of at least one solid phase and one liquid phase, i.e., a colloidal dispersion, in which the solid phase(s), e.g., silica (itself and / or partially or fully hydrolyzed silica), is the continuous phase, and the liquid(s) (e.g., water, ethanol, and residues of the silica precursor) are uniformly dispersed throughout the structure. The hydrogel silica compositions provided herein have an elastic modulus (G', reflecting the elastic behavior of the composition upon deformation) and a viscous modulus (G"), reflecting the flow of the composition during deformation, such that the composition exhibits sol-gel properties. Upon application of shear, the composition flows, such as when drops are administered to the eye, and then gels upon placement in the eye, increasing contact with the ocular surface. Thus, a hydrogel should be understood to be a gel in which the liquid phase is water or aqueous and contains more than 50% by weight (wt%) of water, calculated from the total weight of the hydrogel. The liquid phase can further include other liquids, e.g., ethanol. Thus, the terms hydrogel and composition are used interchangeably.

[0033] A sol is understood to be a homogeneous mixture of at least one liquid phase and one solid phase, i.e., a colloidal dispersion, in which the liquid phase(s), e.g., water, ethanol, and possible residues of silica precursors, are the continuous phase, and the solid phase(s), e.g., colloidal silica particles and / or partially or completely hydrolyzed silica and / or aggregates of said particles, are uniformly dispersed in said liquid phase. A sol has distinct flow characteristics, and the liquid phase predominates. A suspension may also be called a sol, especially if the solid particles are colloidal and have a diameter of less than 1 μm. However, in the context of this disclosure, the term sol refers to a colloidal dispersion in which the solid nanoparticles are ≦50 nm, and the term suspension refers to a dispersion in which the solid particles are >50 nm.

[0034] The term sol-gel transition refers to the process by which a sol changes into a gel under various conditions. The most typical example of sol-gel transition in this disclosure is that silica and other corresponding materials (synthesized from liquid-phase precursors, typically alkoxides and inorganic precursors, such as silicate solutions formed after hydrolysis and first condensed particles) are sols when present in a system, but as the particles aggregate and / or grow in size, the sol changes into a gel. This can occur spontaneously (typically in acidic sols) or by induced changes such as pH change or salt addition (typically in alkaline sols). Sol-gel-derived silica can also be prepared by processing to obtain different morphologies, for example, by simultaneous gelation, aging, and drying, and by spray drying to obtain fine particles.

[0035] Shear thinning refers to the effect whereby the viscosity of a fluid, a measure of the fluid's resistance to flow, decreases with increasing shear stress rate. In the context of this disclosure, shear thinning is a rheological property of hydrogel silica compositions. Whenever the shear stress or shear rate of such a composition is changed, the composition gradually moves toward its new equilibrium state. At lower shear rates, shear thinning compositions are more viscous than Newtonian fluids, and at higher shear rates, they are less viscous.

[0036] Non-flowable at rest in the context of the present disclosure refers to the typical property of a gel or gel-containing composition in which the elastic properties (elastic / storage modulus, denoted G') dominate over the viscous properties (viscous / loss modulus, denoted G"). In preferred embodiments, the silica hydrogel compositions disclosed herein have a storage (elastic) modulus G' that is higher than the loss (viscous) modulus G". These can be measured using a rheometer, for example, using a cone-plate or plate-plate geometry in the linear viscoelastic region under small angle oscillatory shear, i.e., the oscillatory shear is so small that it actually corresponds to the properties of a gel, e.g., a hydrogel or hydrogel composition, at rest.

[0037] Thus, in a preferred embodiment, the present disclosure provides a hydrogel silica composition comprising an active pharmaceutical ingredient, preferably dexamethasone or a pharmaceutically acceptable salt thereof, wherein the storage (elastic) modulus G' of the composition is greater than the loss (viscous) modulus G".

[0038] In the context of the present disclosure, silica microparticles refer to silica particles, preferably prepared by spray drying. The silica microparticles of the compositions provided herein have a maximum diameter of ≦40 μm, preferably ≦20 μm, and more preferably ≦10 μm, as measured by laser diffraction, for example, using a Sympatec HELOS 2370 laser diffraction instrument (see Example 5 below). The silica microparticles have a maximum diameter in the range of about 0.5 μm to about 40 μm. According to one embodiment, the silica microparticles may have a maximum diameter in the range of about 1 to about 40 μm, preferably 1 to 30 μm, more preferably 1 to 20 μm, and even more preferably 1 to 10 μm. According to another embodiment, the silica microparticles may have a maximum diameter in the range of about 0.9 to about 40 μm, preferably 0.9 to 30 μm, more preferably 0.9 to 20 μm, and even more preferably 0.9 to 10 μm. In yet another embodiment, the silica microparticles may have an average diameter D50 in the range of 0.5 to 15 μm and / or an average diameter D90 in the range of 5 to 40 μm, preferably 5 to 20 μm. In a preferred embodiment, the silica microparticles may have an average diameter D10 in the range of 0.9 to 10 μm and / or an average diameter D50 in the range of 0.5 to 15 μm and / or an average diameter D90 in the range of 5 to 40 μm, preferably 5 to 20 μm. Surprisingly, these microparticle size diameter values ​​have been found to provide optimal rheological properties for topical ocular administration and sustained release of the active pharmaceutical ingredient, allowing, for example, once-daily administration.

[0039] Silica preferably refers in the context of this disclosure to amorphous silica, such as amorphous silica containing water, fully or partially hydrolyzed amorphous silica, or a water-dissolved form of silica, such as silicic acid.

[0040] The R value referred to in this application, especially in the examples, is defined by the molar ratio of water to alkoxide of the composition.Silica composition can also be represented by two R values, such as RX-Y, where X represents the initial molar ratio used, and Y represents the total molar water to alkoxide ratio after adding water or other liquids such as ethanol or additional liquids such as ethanol-water mixtures in some preparation steps, in a volume corresponding to the volume of water required to provide a water to alkoxide ratio of Y.For example, in the R value R6-50, 6 is the initial molar ratio used, and 50 corresponds to the total molar water to alkoxide ratio after adding additional liquids in some preparation steps, in the same volume corresponding to the volume of water required to achieve a water to alkoxide ratio of 50.

[0041] In the context of this disclosure, the term active pharmaceutical ingredient (API) refers to any substance or mixture of substances intended for use in the manufacture of a drug (pharmaceutical) product, which, when used in the production of the drug product, becomes the active pharmaceutical ingredient of the drug product. APIs that can be used in the hydrogel silica compositions of the present disclosure include drugs useful as anti-inflammatory agents, particularly corticosteroids such as prednisolone, dexamethasone, fluocinolone, fluorometholone, medrysone, rimexolone, or their pharmaceutically acceptable salts; nonsteroidal anti-inflammatory compounds such as ketorolac, flurbiprofen, bromfenac, diclofenac, nepafenac, or their pharmaceutically acceptable salts; immunosuppressants such as cyclosporine or voclosporin; antibiotics such as ofloxacin; lymphocyte function-associated antigen 1 (LFA-1) antagonists such as lifitegrast; recombinant human nerve growth factor such as cenegermine; or other biological drugs used in ocular diseases or disorders. Preferably, the active pharmaceutical ingredient is selected from lifitegrast, nepafenac, ofloxacin, cyclosporine, senegelamine, or dexamethasone. In a most preferred embodiment, the active pharmaceutical ingredient is dexamethasone or a pharmaceutical salt thereof. In a preferred embodiment, the present disclosure provides a topical ophthalmic composition of dexamethasone in a hydrogel silica composition, wherein the composition is suitable for once-daily administration. Preferably, the composition is stable upon storage at 2-8°C for an extended period of time, such as at least 1 month, at least 2 months, or preferably at least 3 months.

[0042] In the context of this disclosure, a silica composition refers to a hydrogel composition comprising a specific weight percent (wt%) of silica microparticles, combined with a silica sol, to obtain a non-flowable material at rest. Thus, a silica hydrogel composition can be obtained by mixing a specific weight percent (wt%) of silica microparticles with a silica sol to obtain a desired non-flowable hydrogel composition at rest. The weight percentage is calculated from the total weight of the composition, as described below.

[0043] According to one preferred embodiment, the hydrogel silica composition is non-flowing upon administration to the eye.

[0044] In the context of the present disclosure, the solid content refers to the proportion of non-volatile material contained in the suspension remaining after the volatile solvent has evaporated. More specifically, it can refer to the solid content of the silica sol used to obtain the hydrogel composition provided herein or the solid content of the silica hydrogel composition.

[0045] The hydrogel composition contains a specific weight percent (wt%) of silica microparticles, and wt% is calculated from the amount of silica particles and silica sol used to obtain the hydrogel composition. Thus, for example, when 100 g of silica microparticles are mixed with 900 g of silica sol, the wt% of silica particles in the hydrogel composition is 10 wt%. If the silica hydrogel composition is obtained by first preparing a suspension of silica particles, the percentage is calculated from the original weight of the silica particles compared to the final weight of the silica hydrogel composition (i.e., the weight of silica particles + the weight of the liquid used to make the suspension of silica particles + the weight of silica sol).

[0046] The silica hydrogel compositions provided herein demonstrate their key characteristics by comparing them with the properties of their individual components, such as gels and microparticles, as well as with other prior art gel and hydrogel systems. Such gels are often used as drug delivery systems due to their softness, typically injected into target tissues or applied topically in the form of a sol or polymer solution before gel formation. However, gels typically have a loose structure, resulting in immediate release of the API contained therein. While the microparticles can then be easily combined with water and other liquids to form administrable topical suspensions, they can easily be washed out of the eye via tears. The present disclosure provides ophthalmic compositions containing separate components in which the release of the API is sustained or controlled by the silica hydrogel. The API release rate is significantly reduced compared to conventional topical products, such as typical eye drops, that lack sustained-release properties. A preferred type of ophthalmic composition is a composite of different silica forms, which, combined in a unified structure, provide unique sustained-release properties compared to the individual silica forms, i.e., a synergistic effect, thereby providing a matrix for the engineered sustained release of the drug or API contained therein. One of the advantageous features of the compositions provided herein is the ease with which the combined composition can be handled and the ease with which the separate components can be mixed into a homogeneous, easily administrable topical ophthalmic composition.

[0047] A typical component of the ophthalmic composition provided herein is a sol containing silica-based microparticles and silica nanoparticles. After the components are combined and topically applied to the eye, a monolithic structure is formed that can be defined as a hydrogel. The gel is a silica-based hydrogel. In the compositions provided herein, a typical gel consists of a continuous solid phase with a liquid uniformly dispersed within the solid phase, and the elastic / storage modulus of the material is higher than the viscous / loss modulus, indicating that the composition is non-flowable at rest. The compositions provided herein are typically gels both before and after administration to the eye.

[0048] One important feature of these ophthalmic compositions is that they can be easily administered as eye drops and provided as single-dose units (SDUs), as shown in the examples. A typical single-dose eye drop unit involves administering drops from the unit, which is then discarded. The ophthalmic compositions possess shear-thinning properties, making them both administrable and flowable. The sol-gel properties of the ophthalmic compositions ensure that the compositions are thin and flow easily when administered from the SDU, but form a gel upon instillation or administration to the eye. This gelation prevents the compositions from being washed away by ocular fluids and helps provide sustained release of the drug, thereby ensuring once-daily administration.

[0049] Hydrogel silica compositions contain silica microparticles in an amount of 30% or less by weight of the total combined formulation, together with a sol having a low silica content, i.e., solids content, typically less than 1% by weight of silica.

[0050] The silica microparticles may contain up to 30% by weight of an active pharmaceutical ingredient, such as dexamethasone or a pharmaceutically acceptable salt thereof, preferably in the range of 0.1-30% by weight, more preferably 0.5-20% by weight, even more preferably 1.5-15% by weight, and most preferably 3-7.5% by weight. Silica microparticles typically contain ≦15% by weight, preferably ≦7.5% by weight, of the API, e.g., dexamethasone or a pharmaceutically acceptable salt thereof.

[0051] The silica microparticles may have an average diameter D10 in the range of 0.9 to 10 μm and / or an average diameter D50 in the range of 0.5 to 15 μm and / or an average diameter D90 in the range of 5 to 40 μm, preferably 5 to 20 μm. D10 indicates the diameter value at which 10% of the microparticles have a diameter smaller than D10, D50 indicates the diameter value at which 50% of the microparticles have a diameter smaller than D50, and D90 indicates the diameter value at which 90% of the microparticles have a diameter smaller than D90. Preferably, the silica microparticles are 20 μm or less in size, more preferably 10 μm or less.

[0052] In a preferred embodiment, the present disclosure provides a hydrogel silica composition comprising: a) silica microparticles containing about ≦15 wt. %, preferably 10 wt. %, more preferably ≦7.5 wt. % dexamethasone or a pharmaceutically acceptable salt thereof, the silica microparticles having a mean diameter D10 in the range of 0.9 to 10 μm and / or a mean diameter D50 in the range of 0.5 to 15 μm and / or a mean diameter D90 in the range of 5 to 40 μm, preferably 5 to 20 μm; b) a silica sol containing solid nanoparticles of <50 nm, the silica sol having a solids content of <1 wt. %, The hydrogel silica composition comprises up to 30% by weight of the silica microparticles.

[0053] The silica microparticles used to prepare the hydrogel silica composition of the present disclosure are preferably microparticles having a maximum diameter ranging from about 0.5 μm to about 40 μm, more preferably from about 0.9 μm to about 30 μm, even more preferably from about 0.9 μm to about 20 μm, and most preferably from about 0.9 μm to about 10 μm. The silica microparticles used to prepare the silica hydrogel composition may contain up to 30 wt. % of an active pharmaceutical ingredient, such as dexamethasone or a pharmaceutically acceptable salt thereof, preferably ≦15 wt. %, more preferably ≦7.5 wt. %.

[0054] According to one preferred embodiment, the active pharmaceutical ingredient is dexamethasone or a pharmaceutically acceptable salt thereof.

[0055] In a preferred embodiment, the silica sol has a solids content of ≦1% by weight and the solid nanoparticles are less than 50 nm in size.

[0056] The hydrogel silica compositions provided herein are intended for topical ocular administration. Typically, the hydrogel silica compositions are used in eye drop formulations. According to one embodiment, the ophthalmic formulation comprises or consists of the hydrogel silica compositions provided herein.

[0057] According to one embodiment, the hydrogel silica composition is for use in treating an ocular disorder or disease by topical administration.

[0058] According to another embodiment, the hydrogel silica composition is for use in the treatment of ocular inflammation, preferably selected from anterior uveitis, iritis, cyclitis, allergic or vernal conjunctivitis, herpes zoster keratitis, superficial punctate keratitis or nonspecific superficial keratitis.

[0059] According to one embodiment, the hydrogel silica composition is for use in the treatment of corneal damage following chemical, radiation or thermal burns, or foreign body intrusion, or for use in the treatment of post-operative inflammatory reactions.

[0060] The hydrogel silica compositions disclosed herein are preferably stable upon storage at 2-8°C or 25°C / 60% relative humidity (RH) for extended periods of time. Preferably, the compositions are stable for at least 1 month, more preferably at least 2 months, and even more preferably, the compositions are stable for at least 3 months upon storage at 2-8°C. Storage stability of ophthalmic compositions is particularly challenging and is determined based on multiple parameters, such as changes in appearance compared to initial values, assay % of active pharmaceutical ingredient, pH, related substances analysis, particle size distribution, etc. The storage stability of some representative hydrogel silica compositions is demonstrated in the Examples.

[0061] In a highly preferred embodiment, the silica microparticles are obtained by a process of spray drying silica microparticles together with the API, preferably dexamethasone or a pharmaceutically acceptable salt thereof.

[0062] The hydrogel silica composition is preferably obtained by mixing silica fine particles with a silica sol.

[0063] Thus, the present disclosure provides topical ophthalmic formulations that are silica microparticle-silica hydrogel compositions that have surprisingly low total silica content, yet are stable for at least three months when stored at 2-8°C and suitable for once-daily administration. These hydrogel silica compositions surprisingly provide sustained release of the API contained therein while being easy to administer topically as a once-daily eye drop composition. According to a preferred embodiment, the hydrogel silica composition can be administered once daily to a patient in need thereof. [Brief explanation of the drawings]

[0064] [Figure 1] FIG. 1 shows the cumulative silica dissolution rate in vitro under sink conditions for a microparticle formulation (R3-100) with four different dexamethasone loadings. [Figure 2] FIG. 1 shows the cumulative in vitro dexamethasone release rate under sink conditions for a microparticle formulation (R3-100) with four different dexamethasone loadings. [Figure 3] FIG. 1 shows the storage modulus of three different formulations (formulations #04D-0.3, #06D-0.25, #06D-0.3) at room temperature (approximately 25° C.). [Figure 4] FIG. 1 shows storage and loss moduli for formulation #06-0.25. [Figure 5] FIG. 1 shows the dynamic viscosity of #06D-0.3 with thixotropic behavior. [Figure 6] FIG. 1 shows the mean dexamethasone concentrations in tears for formulations #04D-0.3, #06D-0.25, #06D-0.3, and #06D-0.35. [Figure 7A] FIG. 1 shows the mean dexamethasone concentrations in tears for formulations #09D-0.3 and #12D-0.3 and Maxidex® eye drop product at a single dose. [Figure 7B] FIG. 1 shows the mean dexamethasone concentrations in tears after a single dose of formulation #09D-0.3 and multiple doses of Maxidex® eye drop product. [Figure 8] FIG. 1 shows the cumulative in vitro sink dissolution of dexamethasone silica hydrogel microparticle formulation #09 after 3 months of storage at 2-8° C. [Figure 9] FIG. 1 shows the cumulative in vitro sink dissolution of silica hydrogel microparticle formulations of ofloxacin.

[0065] [Example] [Example 1] Preparation of silica hydrogel composites from dexamethasone-encapsulated silica microparticles (MP) and silica sol (SS) Sol-gel-derived silica microparticles (MPs) were prepared using TEOS (tetraethyl orthosilicate, also known as tetraethoxysilane, available from Sigma-Aldrich) as the silica precursor. Several batches of dexamethasone-encapsulated microparticles with different formulations were prepared using the same general procedure. The initial molar ratio of water to TEOS varied from 3:1 to 5:1 and are designated R3 to R5. The initial pH in all samples was adjusted to pH 2 using 0.1 M HCl. Hydrolysis was allowed to occur for 25 minutes at room temperature (i.e., approximately 21 to 23 °C) under continuous mixing. A solution of dexamethasone in ethanol was cooled to 0 °C and added to the sol, which was also cooled to 0 °C. The pH of the mixture of silica sol and dexamethasone in ethanol was adjusted to approximately 3 to 4 using 0.1 M NaOH. The percent loading of dexamethasone in the final microparticles varied between about 2% and about 15% w / w (calculated with respect to the theoretical silica amount). After hydrolysis, the sol was diluted by adding ethanol (containing dissolved dexamethasone) so that the water to TEOS ratio was equal to 100, as indicated by R100 (i.e., the same volume of ethanol was used as water to obtain R100 from an initial ratio of 3 to 5). For example, formulation "R3-100MP" describes a spray-dried silica microparticle formulation in which the initial R of the silica sol is 3, and after dilution with ethanol, R is 100, meaning that an equal volume of ethanol was added to obtain R100. A Buchi B-290 spray dryer (spray-dryer parameters: inlet temperature: 100°C, outlet temperature: 68-74°C, aspirator: 35 m) was used. 3 Immediately after adjusting the pH using a 5000 sachetidine sol (pH 7.0), a feed flow rate of 5.6 ml / min, and an atomization airflow of 670-700 l / h), all sols were spray-dried into microparticles. In this way, dexamethasone-encapsulated silica microparticles (MPs) were obtained.

[0066] Silica sol (SS) for blending with spray-dried silica microparticles (MP) encapsulating dexamethasone was prepared using TEOS as a precursor. An R of 400 (corresponding to approximately 0.9% w / w of silica in the silica sol) was prepared. The initial pH of all samples was adjusted to pH 2 using 0.1 M HCl. Hydrolysis was allowed to occur for 25 minutes at room temperature (i.e., approximately 2 °C to approximately 23 °C) with continuous mixing. The pH was then increased from approximately 5.8 to approximately 6.2 by adding 0.1 M NaOH with continuous stirring. After pH adjustment, the silica sol was immediately blended with the spray-dried microparticles.

[0067] Dexamethasone-encapsulated silica microparticles (MP) were added to silica sol (SS) in amounts varying from 0.1 g to approximately 0.5 g per 1 ml of SS. The resulting silica microparticle-silica sol suspension was transferred into a syringe (1 ml BD Luer-Lock). The silica microparticle-silica sol suspension in the syringe was kept at room temperature in a rotating carousel mixer, and became a non-flowable gel (silica hydrogel complex) within 1 to 3 days. After gel formation, the formed silica hydrogel complex was transferred by injection (through a 20G needle) into single-dose units (SDU, 0.6 ml, Lameplast). The single-dose units were stored in aluminum foil in a refrigerator at 2 to 8 °C.

[0068] [Example 2] In vitro dissolution measurements under sink conditions for silica dissolution rate and dexamethasone release rate Five microparticle formulations (R3-100 and formulation #09 at pH 4.0 with different dexamethasone loading percentages as shown in Table 1) were selected for in vitro measurements under sink conditions. The dissolution rate of the silica matrix and the release of dexamethasone were tested by incubating the silica microparticles in a dissolution medium containing 50 mM TRIS buffer (pH 7.4 at 37°C) in a shaking water bath (60 strokes / min). Three replicate samples were collected at each time point for measurement. The measured dissolution rate of silica and the release rate of dexamethasone are shown in Figures 1 and 2, respectively. Figures 8A and 8B provide the dissolution rate of silica and the release rate of dexamethasone for formulation #09. This is a suitable model for the ocular use of the ophthalmic compositions provided herein. [Table 1] [Example 3] Rheological characterization of hydrogel composites containing silica sol (SS) and dexamethasone-encapsulated silica microparticles (MP) Rheological measurements were performed using a rheometer (AR 2000Ex, 60 mm diameter plastic plate measuring head, TA instruments, Germany) to measure the storage (elastic) and loss (viscous) moduli (oscillatory mode), as well as the dynamic viscosity and thixotropic behavior (rotational mode) for different compositions. To simulate the properties of the hydrogel composites under real operating conditions, the hydrogel composites were injected directly from single dosage units (SDUs) onto the measuring plate of the rheometer.

[0069] The storage modulus G' (see Figure 3) for the three different formulations (formulations #04D-0.3, #06D-0.25, and #06D-0.3) at room temperature (approximately 25 °C) was relatively low, approximately 100-4000 Pa at strains of 0.001-0.01 and an angular frequency of 1 Hz. Depending on the formulation, they were either flowable (viscous, but still easily flowing) or directly extrudable hydrogels during injection. Additionally, the loss modulus G" for #04D-0.3, #06D-0.25, and #06D-0.3 was low. In all formulations tested, the storage modulus was greater than the loss modulus in the linear viscoelastic region (at strains of approximately 0.001-0.01 and an angular frequency of 1 Hz), indicating a non-flowable structure after injection. The storage modulus (approximately 100-150 Pa) and loss modulus (approximately 10-20 Pa) for #06-0.25 are shown in Figure 4. The storage and loss moduli for #04D-0.3 were found to be approximately 400-460 Pa and approximately 15-30 Pa, respectively. The storage and loss moduli for #06D-0.3 were found to be approximately 400-460 Pa and approximately 15-30 Pa, respectively. The elastic modulus was found to be approximately 3700–4000 Pa and 210–270 Pa at strains of 0.001–0.01 and an angular frequency of 1 Hz, respectively. The low modulus values ​​for the hydrogel composites indicate loose hydrogels that are easily injectable. This is verified by rotational measurements of the dynamic viscosity, which shows clear shear-thinning behavior. The dynamic viscosity with thixotropic behavior (time-dependent change in viscosity with shear stress) for #06D-0.3, which has the strongest hydrogel structure (highest storage modulus), is shown in Figure 5, and clear shear-thinning behavior was observed. In addition, some thixotropic behavior was observed, i.e., up to 100 When returning to lower shear rates from 1 / s, the dynamic viscosity became slightly lower at the same shear rate. Corresponding measurements for #04D-0.3 and #06D-0.25 also showed clear shear thinning, but no or very little thixotropy. The dynamic viscosity for #06D-0.25 was approximately 1.5 Pas at a shear rate of 1.3 1 / s and 0.026 Pas at 100 1 / s, while for #04D-0.3 it was approximately 6.2 Pas at 1.1 1 / s and 0.06 Pas at 100 1 / s.

[0070] Generally, depot gels become weaker at lower microparticle concentrations in the depot, and phase separation can occur under high shear stress, especially at concentrations below 30%. Surprisingly, however, in this formulation, all depots maintained a non-flowable gel structure not only at rest but also after administration (which does not necessarily occur at higher shear stresses for weaker gels). The above results demonstrate that the storage (elastic) modulus G' is surprisingly higher than the loss (viscous) modulus G". This means that eye drop administration (at relatively low shear stress) keeps the gel structure intact, and the formulation enters the eye in gel form without immediately leaking out. This allows for controlled release over a period of time, thereby improving efficacy.

[0071] [Example 4] PK study of single-dose silica hydrogel composite and in vivo release of dexamethasone in rabbits Three specific pathogen-free (SPF) NZW female rabbits (origin: Lidköpings Kaninfarm, Sweden) were used for the PK study. The study was performed after obtaining approval from the Finnish National Laboratory Animal Care and Use Committee. The isolation / acclimation period was 5 days before the first experiment. The temperature in the animal room was 21°C ± 3°C, the relative humidity was at least 55 ± 15%, and the lighting was artificial (12 hours light and 12 hours dark). The animals were housed in a Scanbur No. 8 system, one animal per cage. No randomization was performed.

[0072] The gel does not leak readily, allowing for controlled release over a period of time, thereby improving efficacy.

[0073] Test items and medication In Experiment 1, hydrogel composites were prepared using silica microparticles from the R3-100 (pH 4.0) formulation with 10% w / w dexamethasone encapsulated (calculated relative to the theoretical silica content) and R400 silica sol (0.3 mg silica microparticles per ml of silica sol). In Experiments 2, 3, and 4, hydrogel composites were prepared using silica microparticles from the R3-100 (pH 4.0) formulation with 15% w / w dexamethasone encapsulated (calculated relative to the theoretical silica content) and R400 silica sol containing 0.25 mg, 0.30 mg, and 0.35 mg silica microparticles per ml of silica sol, respectively (see Table 2). [Table 2] One drop of each hydrogel complex, equivalent to approximately 16 mg / ml dexamethasone in Experiment 1, approximately 26 mg / ml dexamethasone in Experiment 2, approximately 28 mg / ml dexamethasone in Experiment 3, and approximately 32 mg / ml dexamethasone in Experiment 4, was placed into the conjunctival sac of both eyes of each rabbit after gently separating the lower eyelid from the eyeball. The eyelids were then gently held together for approximately 1 second to prevent loss of material. The rabbits were kept in restrainers for approximately 1–2 minutes after dosing, after which they were returned to their cages where they could move freely. Each rabbit was dosed four times, followed by a 1–2 week washout period (details in Table 3 below). [Table 3] sampling Tear fluid (2 μl) was collected from rabbit eyes at time points 0 (before dosing), 1 hour, 2 hours, 6 hours, 12 hours, 24 hours, and 48 hours after dosing. Tear fluid was collected using a 2 μl capillary tube (Microcaps®). Using a pipette (pressure technique), tear fluid was removed from the capillary tube into a plastic vial. Immediately after placing the sample in the vial, 48 μl of 30% acetonitrile solution was added, and the vial was sealed to mix the tear fluid with the acetonitrile. Samples were stored at 4-8°C until testing.

[0074] In vivo release rate of dexamethasone Dexamethasone in tear samples was analyzed by HPLC to establish its in vivo release profile. A 1260 Infinity II HPLC with an Agilent Technologies Model G7117C diode array detector was used. The column used was a Waters Xbridge C18 2.1 x 50 mm 2.5 μm column, with a column temperature of 40°C. Water / trifluoroacetic acid 1000 + 1 (v / v) was used as mobile phase A, and acetonitrile / trifluoroacetic acid 1000 + 0.9 (v / v) was used as mobile phase B. The gradient run is listed in Table 4 below. The flow rate was 0.5 ml / min, the wavelength was 254 nm, the injection volume was 20 μl, the run time was 6.5 min, and the retention time of dexamethasone was 2.9 min. Standards were prepared in 50 mM Tris, pH 7.4. The standards were stored at 4°C. [Table 4] Tables 5A-5D below show the dexamethasone concentrations in tears for all four formulations tested in vivo, representing parallel samples from both eyes of the three rabbits examined, as described above in Table 3. In Tables 5A-5D, all concentrations and hourly releases are given in μg / ml, with SD = standard deviation. [Table 5] [Table 6] [Table 7] [Table 8] Clinical observations The rabbits were monitored for 48 hours after dosing with each formulation: #04D-0.3, #06D-0.25, #06D-0.3, and #06D-0.35. Clinical observations made before sampling during each study are reported in Tables 6-9. [Table 9] [Table 10] [Table 11] [Table 12] No abnormal clinical signs were observed in these studies, thereby indicating that the ophthalmic composition does not cause side effects such as eye irritation and / or redness and may be safe for longer term use.

[0075] [Example 5] Silica particle size distribution Particle size distribution measurements were performed on seven samples of the dexamethasone-containing compositions using a Sympatec HELOS 2370 laser diffraction instrument. A particle-in-liquid (PIL) method was used, using ethanol as the solvent. The particle size distributions of the microparticle formulations are shown in Table 10 below. [Table 13] [Example 6] PK Study of the In Vivo Release of a Single Dose of Silica Hydrogel Composition and Dexamethasone in Rabbits and Comparison with Existing Maxidex® Eye Drop Product Specific pathogen-free (SPF) NZW rabbits (origin: Lidkopings Kaninfarm, Sweden) were used in the PK study. Two experiments (Experiments 1 and 2) with four rabbits each were used to conduct the PK study of the Maxidex® eye drop product, and two experiments (Experiments 3 and 4) with three rabbits each were used to conduct the PK study of the silica hydrogel composition. The study was approved by the Finnish National Laboratory Animal Care and Use Committee. The isolation / acclimation period was 8 days before the experiment. The temperature in the animal room was 21°C ± 3°C, the relative humidity was at least 55 ± 15%, and the lighting was artificial (12 hours light and 12 hours dark). The animals were housed in a Scanbur No. 8 system, one animal per cage. No randomization was performed.

[0076] Test items and medication Experiment 3 used a silica hydrogel composition prepared by combining (i) silica microparticles having a formulation of R3-200 (using ethanol as a diluent for dilution of R3 to 200) at pH 4.0 with 7.5% w / w dexamethasone encapsulated (calculated relative to the theoretical silica content) and (ii) R400 silica sol (0.3 g of silica microparticles in 1 ml of silica sol). Experiment 4 used a silica hydrogel composition prepared by combining (i) silica microparticle formulation R3-200 (using 50% vol. aqueous ethanol as a diluent for dilution of R3 to 200) at pH 4.0 with 7.5% w / w dexamethasone encapsulated (calculated relative to the theoretical silica content) and (ii) R400 silica sol (0.3 g of silica microparticles in 1 ml of silica sol) (details included in Table 11 below). [Table 14] In Experiment 1, a single dose of Maxidex® was administered—one drop of Maxidex® in each eye at a time. In Experiment 2, multiple doses of Maxidex® were administered—one drop of Maxidex® in each eye every four hours for 24 hours (i.e., a total of seven doses).

[0077] One drop of each hydrogel complex, equivalent to 30-40 μl of approximately 14 mg / ml dexamethasone in Experiment 3 and approximately 17 mg / ml dexamethasone in Experiment 4, was placed in the conjunctival sac of both eyes of each animal after gently separating the lower eyelid from the eyeball. The eyelids were then gently held together for approximately 1 second to prevent loss of material. The animals were kept in a restrainer for approximately 1-2 minutes after administration, after which they were returned to their cages where they could move freely.

[0078] sampling Tear fluid (2 μl) was collected from the rabbit eyes at the time points shown in Table 13 below. Tear fluid was collected using 2 μl capillary tubes (Microcaps®). A pipette (pressure technique) was used to remove the tear fluid from the capillary tubes into plastic vials. Samples were stored on dry ice at −20° C. until testing.

[0079] In vivo release rate of dexamethasone Aliquots of 2 μl of tear samples were mixed with 18 μl of an internal standard solution (10 ng / ml cortisol + prednisone in 25% methanol in phosphate-buffered saline) and then analyzed. Analysis of dexamethasone in tear samples was performed by UPLC. A Waters Acquity UPLC with a Xevo TQ-S triple quadrupole MS was used. The column used was a Phenomenex Kinetex Biphenyl 2.1 × 50 mm, 2.7 μm column, and the column temperature was 40°C. A 0.025% (v / v) aqueous solution of acetic acid was used as mobile phase A, and acetonitrile was used as mobile phase B. The gradient run is listed in Table 12. The flow rate was 0.5 ml / min, and the injection volume was 4 μl. [Table 15] Tables 13A-13D show the dexamethasone concentrations in tears for all compositions tested in vivo, representing parallel samples from both eyes. In Tables 13A-13D, all concentrations and hourly releases are given in μg / ml, with SD = standard deviation.

[0080] The averages for all results are shown in Figures 7A and 7B. [Table 16] [Table 17] [Table 18] [Table 19] Clinical observations The rabbits were monitored for 48 hours after dosing with silica hydrogel compositions #09D-0.3 and #12D-0.3. Clinical observations made before sampling during each study are reported in Tables 14 and 15. [Table 20] [Table 21] No abnormal clinical signs were observed in the study, indicating that the ophthalmic composition is safe to use and does not cause irritation or other side effects.

[0081] [Example 7] Two silica hydrogel compositions (#09D-0.3 and #12D-0.3) were used to test the accuracy of the dosage units. Testing was performed by dropping a single drop from a single-dose unit (each single-dose unit was used only once) into a 160 ml container. The weight of the sample was recorded, and the sample was completely dissolved in 150 ml of 50 mM glycine buffer (pH 9.4 at 37°C) at 37°C for 3 days. The API content of the sample solution was measured by HPLC. [Table 22] Both formulations were administered very accurately from a single dose unit, which showed only minor deviations in dexamethasone concentration per dose.

[0082] [Example 8] Storage stability study of dexamethasone hydrogel silica eye drop compositions The storage stability of the drug substance and drug product (composition) for representative formulation #09 was tested. Silica-dexamethasone microparticles were mixed with R400 silica sol at a 0.3 weight-to-volume ratio (w / v). This suspension was then transferred into single-dose units (SDUs) through a 20G needle. After filling, the SDUs were allowed to gel for 2-3 days. Prior to initiating the stability test, samples were packaged in aluminum pouches and gamma-irradiated at doses ranging from 25.09 to 26.06 kGy.

[0083] One of the objectives of this study was to evaluate how the quality of the drug substance and drug product changes over time under various storage conditions. The chemical and physical stability of the formulations will be evaluated for three months (with monthly testing) at two storage conditions: 2-8°C and 25°C ± 2°C / 60% ± 5% relative humidity (RH). Microparticles and Formulation #09 were evaluated for stability against various parameters. The reverse-phase HPLC (RP-HPLC) method and parameters used for the analysis of dexamethasone and related substances are shown in Table 17 below. The results of the storage stability study are shown in Tables 18-21 and Figures 8A-8B. [Table 23] [Table 24] [Table 25] [Table 26] [Table 27] Results: The visual appearance, API content, silica content, level of unencapsulated API, pH, and particle size distribution of microparticles and Formulation #09 remained unchanged at both storage conditions for up to 3 months (Tables 17 and 19). No significant API degradation was observed in microparticles or Formulation #09 stored at 2-8°C for up to 3 months, but slight degradation was observed over time at 25°C / 60% RH conditions (Tables 18 and 20). The in vitro cumulative sink silica matrix dissolution rate in the sink of the depot formulation remains stable at 2-8°C and 25°C / 60% RH for up to at least 2 months of storage. Overall, it was surprisingly found that the formulation remained stable during storage conditions despite the low weight percent silica microparticles.

[0084] [Example 9] Sustained release silica hydrogel ophthalmic compositions of ofraxaxin - Patent Application 20070122999 Two silica hydrogel compositions of ofloxacin were prepared by combining (i) silica microparticles with a pH 4.0 formulation of R3-200 (using 80% ethanol as a diluent to dilute R3 to 200) encapsulating 5% w / w ofloxacin (calculated relative to the theoretical silica content) with (ii) R400 silica sol (0.3 g of silica microparticles in 1 ml of silica sol (ofloxacin #04D-0.3) and 0.4 g of silica microparticles in 1 ml of silica sol (ofloxacin #04D-0.4)). This suspension was then transferred into single-dose units (SDUs) through a 20G needle. After filling, the SDUs were allowed to gel for 1 day.

[0085] Results: The release profiles of ofloxacin from these microparticle formulations are shown in Figure 9. The retarding effect of the hydrogel component was observed in both depot formulations, with ofloxacin being released over 8-10 hours in both depot formulations.

[0086] It will be understood that the compositions and methods provided herein can be incorporated in the form of a variety of embodiments, only a few of which are disclosed herein. It will be apparent to those skilled in the art that other embodiments exist, and that the described embodiments are illustrative and should not be construed as limiting.

[0087] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. The terminology used in the description of the disclosure herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[0088] Unless the context indicates otherwise, it is specifically contemplated that the various features of the disclosure described herein can be used in any combination.

[0089] Furthermore, the present disclosure also contemplates that some embodiments of the present disclosure may exclude or omit any feature or combination of features described herein.

[0090] All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety for all purposes.

[0091] As used herein, "a," "an," or "the" can mean one or more.

[0092] Also, as used herein, "and / or" refers to and includes any and all possible combinations of one or more of the associated listed items, as well as the lack of combinations when interpreted in the alternative ("or").

[0093] Additionally, the term "about" as used herein when referring to a measurable value such as an amount, dose, time, temperature, pH, etc. of a compound or agent of the present disclosure is meant to encompass a ±20% variation of the specified amount.

Claims

1. A hydrogel silica composition, a) Silica microparticles containing an active pharmaceutical ingredient and having a maximum diameter in the range of approximately 0.5 μm to approximately 40 μm, b) A silica sol containing solid nanoparticles <50 nm, i) The silica sol has a solid content of <1% by weight, ii) The hydrogel silica composition comprises up to 30% by weight of the silica fine particles, iii) A hydrogel silica composition wherein the hydrogel silica composition is for topical ophthalmic administration.

2. The hydrogel silica composition according to claim 1, wherein the active pharmaceutical ingredient is selected from an anti-inflammatory agent, a corticosteroid, a nonsteroidal anti-inflammatory compound, an immunosuppressant, an antibiotic, a lymphocyte function-associated antigen 1 (LFA-1) antagonist, or a recombinant human nerve growth factor.

3. The hydrogel silica composition according to claim 2, wherein the corticosteroid is selected from prednisolone, dexamethasone, fluocinolone, fluorometholone, medrizone, or rimexolone, or pharmaceutically acceptable salts thereof, preferably the corticosteroid is dexamethasone or a pharmaceutically acceptable salt thereof.

4. The hydrogel silica composition according to claim 2, wherein the nonsteroidal anti-inflammatory compound is selected from ketrolac, flurbiprofen, bromfenac, diclofenac, nepafenac, or pharmaceutically acceptable salts thereof, and preferably the nonsteroidal anti-inflammatory compound is nepafenac or a pharmaceutically acceptable salt thereof.

5. The hydrogel silica composition according to claim 2, wherein the immunosuppressant is cyclosporine or voclosporine, or a pharmaceutically acceptable salt thereof, preferably the immunosuppressant is cyclosporine or a pharmaceutically acceptable salt thereof.

6. The hydrogel silica composition according to claim 2, wherein the antibiotic is ofloxacin or a pharmaceutically acceptable salt thereof.

7. The hydrogel silica composition according to claim 2, wherein the recombinant human nerve growth factor is senegelmin.

8. The hydrogel silica composition according to claim 1, wherein the silica fine particles have a maximum diameter in the range of about 1 to about 40 μm, preferably 1 to 30 μm, and more preferably 1 to 20 μm.

9. The hydrogel silica composition according to claim 1, wherein the silica fine particles have a maximum diameter in the range of about 0.9 to about 40 μm, preferably 0.9 to 30 μm, more preferably 0.9 to 20 μm, and even more preferably 0.9 to 10 μm.

10. The hydrogel silica composition according to claim 1, wherein the silica fine particles have an average diameter D10 in the range of 0.9 to 10 μm and / or an average diameter D50 in the range of 0.5 to 15 μm and / or an average diameter D90 in the range of 5 to 40 μm, preferably in the range of 5 to 20 μm.

11. The hydrogel silica composition according to claim 1, wherein the silica fine particles contain the active pharmaceutical ingredient in an amount of up to 30% by weight, preferably 0.1 to 30% by weight, more preferably 0.5 to 20% by weight, even more preferably 1.5 to 15% by weight, and most preferably 3 to 7.5% by weight.

12. A hydrogel silica composition, a) Silica fine particles containing approximately ≤15% by weight, preferably 10% by weight, more preferably ≤7.5% by weight of dexamethasone or a pharmaceutically acceptable salt thereof, wherein the silica fine particles have an average diameter D10 in the range of 0.9 to 10 μm and / or an average diameter D50 in the range of 0.5 to 15 μm and / or an average diameter D90 in the range of 5 to 40 μm, preferably 5 to 20 μm. b) A silica sol containing solid nanoparticles <50 nm and having a solid content of <1% by weight, comprising: A hydrogel silica composition comprising up to 30% by weight of the silica fine particles.

13. The hydrogel silica composition according to claim 1 or 12, wherein the composition is non-flowing when administered to the eye.

14. The hydrogel silica composition according to claim 1 or 12, wherein the storage modulus (elastic modulus) G' of the composition is higher than the loss modulus (viscous modulus) G''.

15. The hydrogel silica composition according to claim 1 or 12, wherein the composition is a sustained-release composition.

16. The hydrogel silica composition according to claim 1 or 12, wherein the composition remains stable for at least one month, preferably at least two months, and more preferably at least three months, when stored at 2 to 8°C.

17. The hydrogel silica composition according to claim 1 or 12, wherein the composition is provided in the form of a topical eye drop.

18. The hydrogel silica composition according to claim 1 or 12, wherein the composition is provided in a single-dose container.

19. A hydrogel silica composition according to claim 1 or 12 for use in the treatment of eye disorders or eye diseases by local administration.

20. The hydrogel silica composition for use according to claim 19, wherein the eye disorder or eye disease is a chemical, radiation or thermal burn, or corneal damage following foreign body intrusion.

21. The hydrogel silica composition for use according to claim 19, wherein the aforementioned eye disorder or eye disease is ocular inflammation.

22. The hydrogel silica composition for use according to claim 21, wherein the ocular inflammation is selected from anterior uveitis, iritis, cyclitis, allergic or vernal conjunctivitis, herpes zoster keratitis, superficial punctate keratitis or nonspecific superficial keratitis, or postoperative ocular inflammation.

23. The hydrogel silica composition for use according to claim 19, wherein the composition provides sustained release of the active pharmaceutical ingredient contained therein.

24. The hydrogel silica composition for use according to claim 19, wherein the active pharmaceutical ingredient is dexamethasone or a pharmaceutically acceptable salt thereof.

25. A hydrogel silica composition according to claim 12 for use in the treatment of postoperative ocular inflammation.

26. The hydrogel silica composition for use according to claim 19, wherein the composition is administered topically once daily to a patient in need thereof.

27. A method for preparing a hydrogel silica composition, wherein silica fine particles containing an active pharmaceutical ingredient and having a maximum diameter in the range of about 0.5 μm to about 40 μm are mixed with a silica sol, i) The silica sol has a solid content of ≤1% by weight, ii) A method wherein the hydrogel silica composition contains up to 30% by weight of the silica fine particles.

28. The method according to claim 27, wherein the silica fine particles are obtained by a process of spray-drying the silica together with the active pharmaceutical ingredient.

29. The method according to claim 27 or 28, wherein the active pharmaceutical ingredient is selected from an anti-inflammatory agent, a corticosteroid, a nonsteroidal anti-inflammatory compound, an immunosuppressant, an antibiotic, a lymphocyte function-associated antigen 1 (LFA-1) antagonist, or a recombinant human nerve growth factor.

30. The method according to claim 29, wherein the corticosteroid is selected from prednisolone, dexamethasone, fluocinolone, fluorometholone, medrizone, or rimexolone, or pharmaceutically acceptable salts thereof, preferably the corticosteroid is dexamethasone or a pharmaceutically acceptable salt thereof.

31. The method according to claim 29, wherein the nonsteroidal anti-inflammatory compound is selected from ketrolac, flurbiprofen, bromfenac, diclofenac, nepafenac, or pharmaceutically acceptable salts thereof, preferably the nonsteroidal anti-inflammatory compound is nepafenac or a pharmaceutically acceptable salt thereof.

32. The method according to claim 29, wherein the immunosuppressant is cyclosporine or voclosporine, or a pharmaceutically acceptable salt thereof, preferably the immunosuppressant is cyclosporine or a pharmaceutically acceptable salt thereof.

33. The method according to claim 29, wherein the antibiotic is ofloxacin or a pharmaceutically acceptable salt thereof.

34. The method according to claim 29, wherein the recombinant human nerve growth factor is senegermin.

35. A hydrogel silica composition obtained by the method of claim 27.

36. The hydrogel silica composition according to claim 1 or 12, for use in a method of treating eye disorders or eye diseases by topical administration in patients requiring treatment of eye disorders or eye diseases.

37. The hydrogel silica composition according to claim 12 for use in a method for treating ocular inflammation by topical administration.

38. The composition according to claim 37, wherein the ocular inflammation is selected from anterior uveitis, iritis, cyclitis, allergic or vernal conjunctivitis, herpes zoster keratitis, superficial punctate keratitis or nonspecific superficial keratitis, or postoperative ocular inflammation.

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