Ophthalmic composition

Abstract

A hydrogel silica composition comprising: a) silica microparticles comprising an active pharmaceutical ingredient and having a maximum diameter of from about 0.5 [mu] m to about 40 [mu] m, and b) comprising lt; a silica sol of solid nanoparticles with a particle size of 50 nm; wherein i) the silica sol has, by weight, lt; a solids content of 1%, ii) the hydrogel silica composition comprises at most 30% by weight of the silica microparticles of the composition, and iii) the hydrogel silica composition is for topical application.

Description

[0001] Field

[0002] The present invention relates to sustained release or controlled release ophthalmic compositions for topical delivery. More specifically, there are disclosed herein sustained release or controlled release ophthalmic compositions comprising an active pharmaceutical ingredient in a hydrogel silica composition, which are particularly suitable for administration as topical eye drops and are suitable for once-daily administration of the active pharmaceutical ingredient.

[0003] Background

[0004] Topical ocular drug delivery systems for the treatment of ocular inflammation are generally available in dosage forms such as solutions, suspensions, gels, and ointments. Although these dosage forms have been considered suitable for delivering the desired active components to the eye to date, these conventional dosage forms have several drawbacks, the most common of which is the need for multiple administrations per day. It is also known that conventional gel and ointment dosage forms can affect vision or its acuity, while solution dosage forms are too easily washed off the eye surface. In addition, if formulated improperly, suspension products can be gritty and thus cause damage to the cornea. The pH of eye drop dosage forms is usually adjusted to keep the active components contained therein in solution, but usually this pH is acidic, which can cause corneal irritation and redness. In addition, due to strict regulatory requirements, the preparation of storage-stable ophthalmic preparations is also a challenge. These problems are associated with one or more conventional ophthalmic dosage forms, thus creating obstacles in terms of optimal delivery and patient compliance.

[0005] Drugs or active components typically used to treat ocular inflammation include corticosteroids such as dexamethasone and its pharmaceutically acceptable salts; prostaglandins such as bimatoprost, latanoprost, etc., said ocular inflammation such as those caused by disease 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; corneal damage caused by chemical, radiation, or thermal burns or foreign body penetration; corneal damage caused after chemical, radiation, or thermal burns or foreign body penetration; for postoperative use to reduce the inflammatory response; graft reactions, etc. Most of these products are available on the market in immediate release dosage forms, which require several administrations per day and can be formulated as solutions or suspensions. It is a 0.1% w / v suspension containing dexamethasone, and its indications are for the treatment of steroid-responsive inflammation 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 non-specific superficial keratitis. It is also applicable to the treatment of corneal injuries caused by chemical, radiation or thermal burns or foreign body penetration, as well as for postoperative use to reduce the inflammatory response and inhibit graft reaction. The frequency of instilling these drops and the duration of treatment depend on the severity of the underlying condition and the response to treatment. Severe inflammation requires instilling 1 - 2 drops into the eye every 30 to 60 minutes until a satisfactory response is achieved. When a good response is observed, the dose is reduced to 1 drop every 4 hours. Obviously, this requires multiple doses throughout the day, and this can be a problem in that, in addition to the inconvenience of multiple instillations, the patient may forget to instill the said drops.

[0006] Attempts have been made to develop sustained-release or controlled-release dosage forms of dexamethasone, such as absorbable PEG-hydrogels in the form of intracanalicular inserts, in order to deliver dexamethasone to the eye surface (approved by the US FDA as ). However, this requires surgical implantation of the insert and cannot be topically administered by the patient himself or at home. Therefore, due to various complexities involved, it is not easy to formulate a sustained-release or controlled-release ophthalmic composition that remains stable for a long time during storage, said various complexities such as providing the desired therapeutic effect by once-daily administration without affecting safety, the composition having an ideal pH and viscosity to stay on the eye surface for a long time, not being washed away, and not irritating the eye, and the composition not affecting vision after administration. Therefore, there is a need for a stable topical ophthalmic dosage form that can overcome these problems and can be administered once a day.

[0007] PCT Publication No. WO2014207304 with the invention name "Silica Hydrogel Composite" discloses a composition that contains an active component encapsulated in silica particles and suspended in a silica sol, and this composition is in the form of an injectable, flowable or extrudable composition. This composition provides a sustained release of the active component without significant burst release, but this publication does not disclose any ophthalmic composition suitable for administration in the subconjunctival sac as eye drops. The disclosure of this publication relates to parenteral or surgically implanted products. There is nothing in the specification that teaches, implies or suggests the formulation of an ophthalmic composition.

[0008] The PCT publication number WO2017068245 with the invention title "Hydrogel composite depot formulation" relies on the depot formulation composition of WO2014207304 and focuses on the controlled release of the active ingredient in the implant (compared with conventional depot and microsphere formulations for parenteral administration). The compositions described herein are suitable for administration once a week to once a year. However, nothing in the specification teaches the formulation of a stable ophthalmic composition that can be delivered locally. There are many differences between ophthalmic products and other parenteral products. For example, the lipophilicity of corneal tissue results in a low-affinity environment for hydrophilic active pharmaceutical ingredients and excipients. The faster clearance time from the eye shortens the retention time of the active pharmaceutical ingredient in the eye, resulting in low bioavailability. Also, the specific viscosity, tonicity, and pH requirements of ophthalmic compositions significantly limit the available options for physically and chemically stabilizing the active pharmaceutical ingredient in such compositions. Due to these differences, the teachings for preparing such parenteral compositions are clearly not applicable to preparing stable topical ophthalmic compositions. Topical ophthalmic administration requires meeting several other parameters to be successfully administered to the eye and to achieve sustained or controlled release of the active ingredient contained therein. Ophthalmic implants administered by injection, such as those described in the above PCT publications, are very different from topical ophthalmic compositions in the form of drops that provide sustained release of the drug contained therein. The latter is neither obvious nor derivable from the former. Technically, both WO2014207304 and WO2017068245 are incorporated herein by reference.

[0009] The February 2019 publication by Nawrat et al. (obtained from https: / / www.pharmaceutical - technology.com / analysis / delsitech - leveraging - silicas - properties - to - improve - drug - delivery / ) discusses the use of the properties of silica to improve drug delivery. The publication discloses techniques that can enable controlled release of the encapsulated active pharmaceutical ingredient and can make the product thermally stable for many years. The publication discusses silica matrix techniques that can store vaccines at room temperature or 4°C, extending the shelf life of life - saving drugs. The publication does not discuss sustained - release topical ophthalmic compositions nor teach the application of this technology in obtaining topical eye drops in any way.

[0010] The prior art is also replete with examples of ophthalmic compositions of anti-inflammatory drugs such as dexamethasone, in which attempts have been made at sustained or controlled release of the drug in order to provide less frequent administration per day. EP1904108 generally discloses the use of compositions having the penetration enhancer dimethyl sulfone in the treatment of disorders, diseases and other adverse medical conditions, including adverse ophthalmic conditions commonly associated with aging. EP3265096 relates to compositions and methods useful for treating and / or preventing ophthalmic conditions, including dexamethasone as an active ingredient. WO2019126176 relates to novel mixed transition metal oxides and their use as catalysts or catalyst precursors, such as hydrocarbon conversion catalysts or catalyst precursors, or particularly hydrotreating catalysts or catalyst precursors, and active ingredients, such as dexamethasone. None of these disclosures provide a composition in the form of eye drops suitable for once-daily administration to the eye, which can be conveniently administered in the subconjunctival sac.

[0011] Accordingly, there is a need for an easy-to-administer, stable topical ophthalmic composition, such as eye drops, which can provide a desired therapeutic effect in the treatment of inflammatory eye diseases while being administered once a day.

[0012] Overview

[0013] One object of the present disclosure is to provide a hydrogel silica composition for topical ocular administration, which comprises an active pharmaceutical ingredient.

[0014] The first aspect relates to a hydrogel silica composition, which comprises:

[0015] a) silica microparticles comprising an active pharmaceutical ingredient and having a maximum diameter of from about 0.5 μm to about 40 μm, and

[0016] b) a silica sol comprising solid nanoparticles of <50 nm;

[0017] wherein

[0018] i) the silica sol has a solids content of <1% by weight,

[0019] ii) the hydrogel silica composition comprises up to 30% by weight of the silica microparticles based on the weight of the composition, and

[0020] iii) the hydrogel silica composition is for topical administration.

[0021] In one embodiment, the hydrogel silica composition is a sustained-release or controlled-release composition, preferably the composition is a sustained-release composition.

[0022] In a 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.

[0023] In another aspect, the present disclosure provides a silica hydrogel composition for treating an eye disorder or eye disease. Preferably, the silica hydrogel composition is for topical ocular administration. More preferably, the hydrogel silica composition is topically administered once daily.

[0024] 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 non-specific superficial keratitis, or postoperative ocular inflammation or inflammatory response. In a more preferred embodiment, the ocular inflammation is postoperative ocular inflammation or inflammatory response.

[0025] In another embodiment, the eye disorder or eye disease is a corneal injury caused by chemical, radiation or thermal burns or foreign body penetration.

[0026] Another aspect relates to a method of treating an eye disorder or eye disease in a patient in need thereof, the method comprising topically administering the hydrogel silica composition to the patient. In one embodiment, the eye disease or eye disorder is ocular inflammation, which is selected from anterior uveitis, iritis, cyclitis, allergic or vernal conjunctivitis, herpes zoster keratitis, superficial punctate keratitis or non-specific superficial keratitis or postoperative ocular inflammation or inflammatory response, preferably, the ocular inflammation is postoperative ocular inflammation or inflammatory response. In a preferred embodiment, the hydrogel silica composition comprises dexamethasone or a pharmaceutically acceptable salt thereof as an active ingredient.

[0027] Yet another aspect relates to the use of the silica hydrogel composition in the treatment of an eye disorder or eye disease.

[0028] Another object of the present disclosure is to provide a method for preparing a hydrogel silica composition comprising an active pharmaceutical ingredient.

[0029] Another aspect relates to a method for preparing a hydrogel silica composition, wherein silica microparticles comprising an active pharmaceutical ingredient and having a maximum diameter of about 0.5 μm to about 40 μm are mixed with a silica sol such that

[0030] i) the silica sol has a solids content of ≤ 1% by weight; and

[0031] ii) The hydrogel silica composition comprises up to 30% by weight of the silica microparticles in the composition.

[0032] In a preferred embodiment, the method involves preparing a hydrogel silica composition comprising:

[0033] a) Silica microparticles comprising about ≤ 15 wt-%, preferably 10 wt-%, more preferably ≤ 7.5 wt-% of dexamethasone or a pharmaceutically acceptable salt thereof, wherein the silica microparticles have an average diameter D10 of 0.9 to 10 μm and / or an average diameter D50 of 0.5 to 15 μm and / or an average diameter D90 of 5 to 40 μm, preferably 5 to 20 μm; and

[0034] b) A silica sol comprising solid nanoparticles < 50 nm, wherein the silica sol has a solid content of < 1% by weight; and

[0035] wherein the hydrogel silica composition comprises up to 30% by weight of the silica microparticles in the composition.

[0036] In a preferred embodiment of the method, the silica microparticles are obtained by spray-drying an active pharmaceutical ingredient together with silica.

[0037] Another object of the present disclosure is to provide a hydrogel silica composition obtained by the above method.

[0038] Preferred aspects relate to providing a hydrogel silica composition obtainable by mixing the following components:

[0039] a) Silica microparticles comprising an active pharmaceutical ingredient and having a maximum diameter of about 0.5 μm to about 40 μm; and

[0040] b) A silica sol comprising solid nanoparticles < 50 nm;

[0041] wherein

[0042] i) the silica sol has a solid content of < 1% by weight; and

[0043] ii) the hydrogel silica composition comprises up to 30% by weight of the silica microparticles in the composition.

[0044] Without wishing to be bound by any theory, it is presumed that the hydrogel silica composition of the present application achieves sustained release of the active pharmaceutical ingredient by encapsulating the active pharmaceutical ingredient into silica microparticles and then mixing the microparticles with a silica sol to form a semi-solid hydrogel silica composition. The release of the active pharmaceutical ingredient mainly depends on the dissolution rate of the silica microparticles in the extraocular fluid.

[0045] The hydrogel silica composition provided herein is completely biodegradable and biodissolvable in body tissues, such as ocular fluid. Biodegradation is based on surface erosion by body fluid (i.e., ocular fluid), and biodegradation occurs within 24 hours. The release of the drug from the hydrogel silica composition is strictly controlled by matrix erosion and does not depend on the solubility of the drug or active pharmaceutical ingredient contained in the silica microparticles. The hydrogel silica composition provided herein is also designed to control or eliminate the initial burst release.

[0046] In one embodiment, the hydrogel silica composition comprises an active pharmaceutical ingredient selected from: anti-inflammatory drugs, particularly one or more anti-inflammatory drugs commonly used to treat ocular inflammation, such as corticosteroids, e.g., prednisolone, or dexamethasone, fluocinolone, fluorometholone, medrysone, rimexolone, and pharmaceutically acceptable salts thereof; non-steroidal anti-inflammatory compounds, such as ketorolac, flurbiprofen, bromfenac, diclofenac, nepafenac, and pharmaceutically acceptable salts thereof; immunosuppressive agents, such as cyclosporin or voculosporin, antibiotics, such as ofloxacin, lymphocyte function-associated antigen-1 (LFA-1) antagonists, such as lifitegrast; recombinant-human nerve growth factor, such as cenegermin; or other biologics for ophthalmic diseases or disorders. In a preferred embodiment, the active pharmaceutical ingredient is selected from lifitegrast, nepafenac, ofloxacin, cyclosporin, cenegermin, or dexamethasone. In a more preferred embodiment, the active pharmaceutical ingredient is dexamethasone or a medicinal salt thereof. Preferably, the ophthalmic composition is topically administered once daily into the subconjunctival sac.

[0047] In a most preferred embodiment, a hydrogel silica composition is provided, wherein the composition comprises:

[0048] a) silica microparticles comprising about ≤15 wt-%, preferably 10 wt-%, more preferably ≤7.5 wt-% of dexamethasone or a pharmaceutically acceptable salt thereof, wherein the silica microparticles have an average diameter D10 of 0.9 to 10 μm and / or an average diameter D50 of 0.5 to 15 μm and / or an average diameter D90 of 5 to 40 μm, preferably 5 to 20 μm; and

[0049] b) a silica sol containing solid nanoparticles of <50 nm, wherein the silica sol has a solid content of <1% by weight; and

[0050] wherein the hydrogel silica composition contains up to 30% by weight of the silica microparticles based on the weight of the composition.

[0051] Detailed Description

[0052] The hydrogel silica composition provided herein is suitable for topical ocular administration, wherein the rheological properties of the composition are desirable for providing once-daily administration and sustained release of the active pharmaceutical ingredient contained therein. In addition, the content of the silica microparticles containing the active pharmaceutical ingredient in the hydrogel silica composition may be unexpectedly low, while the composition remains stable during storage over an extended time period and is suitable for ophthalmic use, preferably suitable for once-daily administration.

[0053] In the context of the present disclosure, a hydrogel should be understood as a homogeneous mixture of at least one solid phase and one liquid phase, i.e., a colloidal dispersion, wherein the solid phase, such as silica (per se and / or partially or fully hydrolyzed), is the continuous phase, and the liquid (such as water, ethanol, and residues of silica precursors) is homogeneously dispersed in the structure. The hydrogel silica composition provided herein has a storage modulus (G', reflecting the elastic behavior of the composition upon deformation) and a loss modulus (G", reflecting the fluidity of the composition upon deformation), such that the composition exhibits sol-gel characteristics. When shear is applied, the composition flows, for example, when a drop is applied to the eye, and then when it remains in the eye, it turns into a gel and increases contact with the eye surface. Thus, a hydrogel should be understood as a gel wherein the liquid phase is water or water-based, which contains more than 50 weight-% (wt-%) of water, calculated based on the total weight of the hydrogel. The liquid phase may also contain other liquids, such as ethanol. Thus, the terms hydrogel and composition may be used interchangeably.

[0054] A sol should be understood as a homogeneous mixture of at least one liquid phase and one solid phase, i.e., a colloidal dispersion, wherein the liquid phase, such as water, ethanol, and possible residues of silica precursors, is the continuous phase, and the solid phase, such as colloidal particles of silica and / or partially or fully hydrolyzed silica and / or aggregates of said particles, is homogeneously dispersed in the liquid phase. The sol has a distinct fluidity, and the liquid phase is dominant. A suspension may also be referred to as a sol, especially if the solid particles are colloidal and have a diameter of less than 1 μm. However, in the context of the present disclosure, the term sol refers to a colloidal dispersion wherein the solid nanoparticles are ≤50 nm, and the term suspension refers to a dispersion wherein the solid particles are >50 nm.

[0055] The term sol-gel transition refers to the process by which a sol becomes a gel under different conditions. The most typical example of sol-gel transition in the present disclosure is that when silica and other corresponding materials (synthesized from liquid-phase precursors, usually alkoxides and inorganic precursors, such as the silicate solution formed after hydrolysis and the first condensation of particles) are present in the sol system, once the particles aggregate and / or increase in size, the sol will turn into a gel. This can occur spontaneously (usually in acidic sols) or through induced changes, such as pH change or addition of salts (usually in basic sols). Sol-gel-derived silica can also be prepared by processing to obtain different morphologies, for example, by simultaneous gelling, aging, drying, and spray drying to obtain microparticles.

[0056] Shear thinning refers to an effect in which the viscosity of a fluid, which is a measure of the resistance to fluid flow, decreases as the shear stress yield increases. In the context of the present disclosure, shear thinning is a rheological property of the hydrogel silica composition. Whenever the shear stress or shear rate of this composition changes, the composition will gradually move towards its new equilibrium state. At lower shear rates, the shear-thinning composition is more viscous than a Newtonian fluid, while at higher shear rates it is less viscous.

[0057] In the context of the present disclosure, not flowing at rest refers to a typical property of a gel or a composition containing a gel, where the elastic property (represented by G', elastic / storage modulus) exceeds the viscous property (represented by G", viscous / loss modulus). In a preferred embodiment, the silica hydrogel composition disclosed herein has a storage (elastic) modulus G' that is higher than the loss (viscous) modulus G". They can be measured using a rheometer (e.g., using a cone-plate or plate-plate geometry rheometer) under small-angle oscillatory shear, within the linear viscoelastic region, i.e., the oscillatory shear is very small and actually corresponds to the properties of a gel (such as a hydrogel or a hydrogel composition) at rest.

[0058] 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 higher than the loss (viscous) modulus G".

[0059] Silica microparticles in the context of the present disclosure refer to silica particles preferably prepared by spray drying. When measured by laser diffraction methods, such as using a Sympatec HELOS 2370 laser diffractometer (see Example 5 below), the maximum diameter of the silica microparticles of the compositions provided herein is ≤ about 40 μm, preferably ≤ about 20 μm, and more preferably ≤ about 10 μm. The silica microparticles have a maximum diameter of from about 0.5 μm to about 40 μm. According to one embodiment, the silica microparticles can have a maximum diameter of from 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 can have a maximum diameter of from 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 can have an average diameter D50 of from 0.5 to 15 μm and / or an average diameter D90 of from 5 to 40 μm, preferably 5 to 20 μm. In a preferred embodiment, the silica microparticles can have an average diameter D10 of from 0.9 to 10 μm and / or an average diameter D50 of from 0.5 to 15 μm and / or an average diameter D90 of from 5 to 40 μm, preferably 5 to 20 μm. It has surprisingly been found that these particle size values provide optimal rheological properties for topical ocular administration and sustained release of the active pharmaceutical ingredient, enabling, for example, once-daily administration.

[0060] In the context of the present disclosure, silica preferably refers to amorphous silica, such as hydrated amorphous silica, fully or partially hydrolyzed amorphous silicon, or the water-soluble form of silica, such as silicic acid.

[0061] The R-value mentioned in the present application, especially in the examples, is defined by the molar ratio of water to alkoxide of the composition. The 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 ratio of water to alkoxide after adding additional liquid during some stages of the preparation, the additional liquid being, for example, water or other liquids, such as ethanol, or an ethanol-water mixture, the volume of which is the same as the volume of water required for the water to alkoxide ratio providing Y. For example, in the R-value R6-50, 6 is the initial molar ratio used, and 50 corresponds to the total molar water alkoxide ratio after adding additional liquid during some stages of the preparation, the volume of the additional liquid being the same as the volume of water required for the water to alkoxide ratio providing 50.

[0062] In the context of the present disclosure, the term active pharmaceutical ingredient (API) refers to any substance or mixture of substances intended for use in the manufacture of a pharmaceutical (medicinal) product and which becomes the active ingredient of the pharmaceutical product when used in the production of the pharmaceutical product. APIs that can be used in the silica hydrogel compositions of the present disclosure include: pharmaceuticals used as anti-inflammatory agents, particularly those commonly used to treat ocular inflammation, such as corticosteroids, for example prednisolone, dexamethasone, fluocinolone acetonide, fluorometholone, medrysone, rimexolone or pharmaceutically acceptable salts thereof; non-steroidal anti-inflammatory compounds, such as ketorolac, flurbiprofen, bromfenac, diclofenac, nepafenac or pharmaceutically acceptable salts thereof; 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 cenegermin; or other biologics for ophthalmic diseases or disorders. Preferably, the active pharmaceutical ingredient is selected from lifitegrast, nepafenac, ofloxacin, cyclosporine, cenegermin or dexamethasone. In a most preferred embodiment, the active pharmaceutical ingredient is dexamethasone or a medicinal salt thereof. In a preferred embodiment, the present disclosure provides a topical ophthalmic composition of dexamethasone in a silica hydrogel composition, wherein the composition is suitable for once-daily administration. Preferably, the composition is stable when stored at 2 - 8 °C for a long time period, such as at least one month, at least two months or preferably at least three months.

[0063] In the context of the present disclosure, a silica composition refers to a hydrogel composition that contains a specific weight percentage (wt-%) of silica microparticles which, in combination with a silica sol, results in a material that does not flow in a static state. Thus, a silica hydrogel composition can be obtained by mixing a specific weight percentage (wt-%) of silica microparticles with a silica sol, resulting in the desired hydrogel composition that does not flow in a static state. The weight percentage is calculated based on the total weight of the composition, as described below.

[0064] According to a preferred embodiment, the silica hydrogel composition is non-flowing after administration to the eye.

[0065] In the context of the present disclosure, the solids content refers to the proportion of non-volatile material contained in a suspension left after evaporation of the volatile solvent. More specifically, it can refer to the solids content of the silica sol used to obtain the hydrogel compositions provided herein, or the solids content of the silica hydrogel composition.

[0066] The hydrogel composition comprises silica microparticles in a specific weight percentage (wt-%), where the wt-% is calculated based on the amounts of silica particles and silica sol used to obtain the hydrogel composition. Thus, for example, if 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 based on the original weight of the silica particles compared to the final weight of the silica hydrogel composition (i.e., the weight of the silica particles + the weight of the liquid used to prepare the suspension of silica particles + the weight of the silica sol).

[0067] The silica hydrogel compositions provided herein are illustrated by comparing their main features with different materials, such as comparing with the properties of the individual components in the composition, such as gels and microparticles, and with other prior art gel and hydrogel systems. Gels are commonly used as drug delivery systems in this regard because they are soft and they can generally be injected into the target tissue or used topically in the form of a sol or macromolecular solution before turning into a gel. However, gels typically have a loose structure, which may lead to rapid release of the API contained therein. In contrast, microparticles can be easily combined with water and other liquids to form an administrable topical suspension, but the microparticles are prone to outflow from the eye through tears. The present disclosure provides an ophthalmic composition comprising individual components, wherein the release of the API is maintained or controlled by the silica hydrogel. The API release rate is significantly reduced compared to conventional topical products, such as typical eye drops without sustained release characteristics. The preferred type of ophthalmic composition is a composite of different silica morphologies, which, compared to individual silica morphologies, together provide unique sustained release characteristics in the overall structure, i.e., provide a synergistic effect, thereby providing a matrix designed for the sustained release of the drug or API contained therein. One of the advantageous features of the compositions provided herein is that the combined compositions are easy to handle and it is easy to mix the individual components into a homogeneous and easily administrable topical ophthalmic composition.

[0068] Typical components of the ophthalmic compositions provided herein are silica-based microparticles and a sol comprising silica nanoparticles. After combining and topically applying these components to the eye, an overall 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 and a liquid uniformly dispersed in the solid phase, where the elastic / storage modulus of the material is higher than the viscous / loss modulus, indicating that the composition does not flow at rest. Typically, the compositions provided herein are gels both before and after application to the eye.

[0069] One of the important properties of these ophthalmic compositions is that they are easy to administer as eye drops and can be provided as single-dosing units (SDUs), as exemplified in the examples. In a typical single-dose unit of an eye drop, a drop is administered from the unit and then the unit is discarded. The ophthalmic compositions are administrable and flowable because they have shear-thinning properties. The sol-gel properties of the ophthalmic compositions ensure that the composition thins and flows easily when administered from the SDU, but forms a gel after instillation or administration to the eye. This gelation prevents the composition from being washed away by the eye fluid and helps to provide a sustained release of the drug, thereby ensuring once-daily administration.

[0070] The hydrogel silica composition comprises silica microparticles in an amount not exceeding 30 wt-% of the total combined formulation, said silica microparticles being combined with a sol typically having a low silica content (i.e., silica with a solids content of less than 1 wt-%).

[0071] The silica microparticles can comprise up to 30 wt-%, preferably 0.1 to 30 wt-%, more preferably 0.5 to 20 wt-%, even more preferably 1.5 to 15 wt-%, and most preferably 3 - 7.5 wt-% of an active pharmaceutical ingredient such as dexamethasone or a pharmaceutically acceptable salt thereof. The silica microparticles typically comprise ≤15 wt-%, preferably ≤7.5 wt-% of an API such as dexamethasone or a pharmaceutically acceptable salt thereof.

[0072] The silica microparticles can have an average diameter D10 of 0.9 to 10 μm and / or an average diameter D50 of 0.5 to 15 μm and / or an average diameter D90 of 5 to 40 μm, preferably 5 to 20 μm. D10 represents a diameter value where 10% of the microparticles have a diameter less than D10; D50 represents a diameter value where 50% of the microparticles have a diameter less than D50; and D90 represents a diameter value where 90% of the microparticles have a diameter less than D90. Preferably, the silica microparticles have a size not exceeding 20 μm, more preferably not exceeding 10 μm.

[0073] In a preferred embodiment, the present disclosure provides a hydrogel silica composition comprising:

[0074] a) silica microparticles comprising about ≤15 wt-%, preferably 10 wt-%, more preferably ≤7.5 wt-% of dexamethasone or a pharmaceutically acceptable salt thereof, wherein the silica microparticles have an average diameter D10 of 0.9 to 10 μm and / or an average diameter D50 of 0.5 to 15 μm and / or an average diameter D90 of 5 to 40 μm, preferably 5 to 20 μm; and

[0075] b) a silica sol containing solid nanoparticles with a size less than 50 nm, wherein the silica sol has a solid content of less than 1% by weight, and

[0076] wherein the hydrogel silica composition contains up to 30% by weight of the silica microparticles in the composition.

[0077] The silica microparticles for preparing the hydrogel silica composition of the present disclosure are microparticles, preferably the microparticles have a maximum diameter of about 0.5 μm to about 40 μm, more preferably about 0.9 to about 30 μm, even more preferably about 0.9 μm to about 20 μm, and most preferably about 0.9 μm - about 10 μm. The silica microparticles for preparing the silica hydrogel composition may contain up to 30 wt-%, preferably ≤15 wt-%, more preferably ≤7.5 wt% of an active pharmaceutical ingredient, such as dexamethasone or a pharmaceutically acceptable salt thereof.

[0078] According to a preferred embodiment, the active pharmaceutical ingredient is dexamethasone or a pharmaceutically acceptable salt thereof.

[0079] In a preferred embodiment, the silica sol has a solid content of ≤1 wt-%, and the solid nanoparticles have a size less than 50 nm.

[0080] The hydrogel silica composition provided herein is for topical ocular administration. Typically, the use of the hydrogel silica composition is for eye drop formulations. According to one embodiment, the ophthalmic formulation contains or consists of the hydrogel silica composition provided herein.

[0081] According to one embodiment, the hydrogel silica composition is used for treating eye disorders or eye diseases by topical administration.

[0082] According to another embodiment, the hydrogel silica composition is used for treating ocular inflammation, preferably the ocular inflammation is selected from anterior uveitis, iritis, cyclitis, allergic or vernal conjunctivitis, herpes zoster keratitis, superficial punctate keratitis or non-specific superficial keratitis.

[0083] According to one embodiment, the hydrogel silica composition is used for treating corneal injuries caused by chemical, radiation or thermal burns or foreign body penetration, or for treating postoperative inflammatory reactions.

[0084] The hydrogel silica compositions disclosed herein are preferably stable after long-term storage at 2-8 °C or 25 °C / 60% relative humidity (RH). Preferably, the composition remains stable after a storage period of at least 1 month, more preferably at least 2 months, and even more preferably at least 3 months at 2-8 °C. The storage stability of ophthalmic compositions is particularly challenging and is determined by various parameters such as appearance change compared to the initial value, analytical % of the active pharmaceutical ingredient, pH, related substance analysis, particle size distribution, etc. The storage stability of some representative hydrogel silica compositions was demonstrated in the examples.

[0085] In a particularly preferred embodiment, the silica microparticles are obtained by spray-drying the silica microparticles together with an API, preferably dexamethasone or a pharmaceutically acceptable salt thereof.

[0086] Preferably, the hydrogel silica composition is obtained by mixing the silica microparticles with silica sol.

[0087] Accordingly, the present invention provides a formulation for topical ocular administration, which is a silica microparticle-silica hydrogel composition, wherein the total silica content is surprisingly low, while remaining stable for at least 3 months when stored at 2-8 °C, and is suitable for once-daily administration. These hydrogel silica compositions provide a sustained release of the API contained therein, while being easy to administer topically, and surprisingly, it is 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.

[0088] Drawings

[0089] Figure 1 Example of the in vitro cumulative dissolution rate of silica in microparticle formulations (R3-100) with 4 different dexamethasone loadings under sink conditions.

[0090] Figure 2 Example of the in vitro cumulative release rate of dexamethasone in microparticle formulations (R3-100) with 4 different dexamethasone loadings under sink conditions.

[0091] Figure 3 Example of the storage modulus of 3 different formulations (Formulation #04D-0.3, #06D-0.25, #06D-0.3) at room temperature (about 25 °C).

[0092] Figure 4 Example of the storage and loss moduli of Formulation #06-0.25.

[0093] Figure 5 Example of the dynamic viscosity with thixotropic behavior of #06D-0.3.

[0094] Figure 6 Mean dexamethasone concentrations in tears of example formulations #04D-0.3, #06D-0.25, #06D-0.3 and #06D-0.35.

[0095] Figure 7A Example single-dose formulations #09D-0.3 and #12D-0.3 and Mean dexamethasone concentrations in tears of the ophthalmic drop product.

[0096] Figure 7B Example formulations #09D-0.3 administered as a single dose and multi-dose Mean dexamethasone concentrations in tears after the ophthalmic drop product.

[0097] Figure 8 : Cumulative in vitro sink dissolution of dexamethasone in silica hydrogel microparticle formulation #09 after storage at 2 - 8 °C for 3 months.

[0098] Figure 9 : Cumulative in vitro sink dissolution of silica hydrogel microparticle formulation of ofloxacin. Examples

[0099] Example 1

[0100] Preparation of silica hydrogel composites from silica microparticles containing encapsulated dexamethasone or and silica sol (SS)

[0101] TEOS (tetraethyl orthosilicate, also known as tetraethoxysilane, purchased from Sigma-Aldrich) was used as the precursor of silica to prepare sol-gel derived silica microparticles (MP). Several batches of microparticles encapsulating dexamethasone with different formulations were prepared using the same general method. The initial ratio of water to TEOS (molar ratio) was changed from 3:1 to 5:1, denoted as R3 to R5. The initial pH of each sample was adjusted to pH 2 using 0.1 M HCl. Under continuous mixing, hydrolysis was carried out at room temperature (i.e., at about 21 °C to about 23 °C) for 25 minutes. The 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 about 3 to about 4 using 0.1 M NaOH. The percentage of dexamethasone loading in the final microparticles varied between about 2% and about 15% w / w (calculated based on the theoretical amount of silica). After hydrolysis, the sol was diluted by adding ethanol (including dissolved dexamethasone) so that the ratio of water to TEOS was equal to 100, denoted as R100 (i.e., the same volume of ethanol was used as water to obtain R100 from the initial ratio of 3 - 5). For example, the formulation "R3-100 MP" describes a spray-dried silica microparticle formulation where the initial R of the silica sol was 3 and R was 100 after dilution with ethanol, meaning the same volume of ethanol was added as water to obtain R100. Immediately after pH adjustment, each sol was spray-dried into microparticles using a Büchi B-290 spray dryer (spray-dryer parameters: inlet temperature: 100 °C; outlet temperature: 68–74 °C; suction device: 35m 3 / h; feed flow rate: 5.6 ml / min; atomizing air flow rate: 670 - 700 l / h). Encapsulated dexamethasone silica microparticles (MP) were thus obtained.

[0102] TEOS was used as the precursor to prepare silica sol (SS) that was to be mixed with the spray-dried dexamethasone-encapsulating silica microparticles (MP). An R of 400 was prepared (equivalent to about 0.9% w / w of silica in the silica sol). The initial pH of each sample was adjusted to pH 2 using 0.1 M HCl. Under continuous mixing, hydrolysis was carried out at room temperature (i.e., about 2 °C to about 23 °C) for 25 minutes. Then the pH was raised to about 5.8 to about 6.2 by adding 0.1 M NaOH under continuous stirring. Immediately after pH adjustment, the silica sol was mixed with the spray-dried microparticles.

[0103] Silica microparticles (MP) encapsulating dexamethasone were added to colloidal silica (SS), with the amount varying between 0.1 g and about 0.5 g of silica microparticles (MP) per 1 ml of colloidal silica (SS). The resulting silica microparticle - colloidal silica suspension was transferred to a syringe (1 ml BD luer lock). The silica microparticle - colloidal silica suspension in the syringe was kept in a rotating carousel mixer at room temperature, and they became immobile gels (silica hydrogel complexes) within 1 - 3 days. After gel formation, the resulting silica hydrogel complex was transferred by injection (through a 20G needle) to a single - dose unit (SDU, 0.6 ml, Lameplast). The single - dose units were stored in aluminum foil in a refrigerator at 2 - 8°C.

[0104] Example 2

[0105] In - vitro dissolution measurements of the silica dissolution rate and dexamethasone release rate under sink conditions

[0106] Five microparticle formulations (R3 - 100 with different dexamethasone loading percentages at pH 4.0 and formulation #09 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) placed in an oscillating water bath (60 strokes / min). Three replicate samples were collected at each time point for measurement. The measured dissolution rates of silica and release rates of dexamethasone are shown respectively as Figure 1 and 2 as shown. Figure 8 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.

[0107] Table 1 In - vitro measurements of microparticle formulations under sink conditions

[0108] Particle formulation Particle Diluent Dexamethasone loading* pH Formulation #01 R3-100 Ethanol 2％ 4.0 Formulation #03 R3-100 Ethanol 5％ 4.0 Formulation #04 R3-100 Ethanol 10％ 4.0 Formulation #06 R3-100 Ethanol 15％ 4.0 Formulation #09 R3-200 Ethanol 7.5％ 4.0

[0109] * Loading - based on the theoretical mass % (w / w) of silica in the microparticles

[0110] Example 3

[0111] Rheological characterization of the hydrogel complex containing colloidal silica (SS) and silica microparticles (MP) encapsulating dexamethasone

[0112] Rheological measurements were carried out using a rheometer (AR 2000Ex, equipped with a plastic plate measuring head with a diameter of 60 mm, TA Instruments, Germany) to measure the storage (elastic) and loss (viscous) moduli (using the oscillatory mode), as well as the dynamic viscosity and thixotropic behavior (using the rotational mode) of different compositions. The hydrogel composite was directly loaded from the single-dose unit (SDU) onto the measuring plate of the rheometer to simulate the properties of the hydrogel composite under actual operating conditions.

[0113] At a strain of 0.001 - 0.01 and an angular frequency of 1 Hz, at room temperature (about 25 °C), the storage moduli G' of three different formulations (Formulation #04D - 0.3, #06D - 0.25, #06D - 0.3) (see Figure 3 ) were relatively low, about 100 - 4000 Pa. Depending on the formulation, during the loading process, they were flowable (viscous but still very easy to flow), or were hydrogels that were directly easy to extrude. In addition, the loss moduli G'' of #04D - 0.3, #06D - 0.25, and #06D - 0.3 were low. In all the studied formulations, the storage modulus in the linear viscoelastic region (strain about 0.001 - 0.01 and angular frequency of 1 Hz) was greater than the loss modulus, indicating that the structure did not flow after loading. The storage modulus (about 100 - 150 Pa) and loss modulus (about 10 - 20 Pa) of #06 - 0.25 are as shown in Figure 4 . The storage modulus and loss modulus of #04D - 0.3 were about 400 to 460 Pa and about 15 to 30 Pa, respectively. At a strain of 0.001 - 0.01 and an angular frequency of 1 Hz, the storage modulus and loss modulus of #06D - 0.3 were about 3700 - 4000 Pa and 210 - 270 Pa, respectively. The low modulus values of the hydrogel composite indicate that it is a loose hydrogel that is easy to inject. This was verified by rotational measurements of the dynamic viscosity, indicating significant shear-thinning behavior. The dynamic viscosity with thixotropic behavior (time-dependent change in viscosity caused by shear stress) of #06D - 0.3, which has the strongest hydrogel structure (highest storage modulus), is as shown in Figure 5 , and significant shear-thinning behavior was observed. In addition, some thixotropic behavior was observed, that is, when returning from the maximum of 100 1 / s to a lower shear rate, at the same shear rate, the dynamic viscosity was slightly lower. The corresponding measured values of #04D - 0.3 and #06D - 0.25 also showed significant shear-thinning, but no or only very little thixotropic behavior. For #06D - 0.25, the dynamic viscosity was about 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, the dynamic viscosity was about 6.2 Pas at 1.1 1 / s and 0.06 Pas at 100 1 / s.

[0114] Generally, the lower the particle concentration in the depot, the weaker the depot gel becomes, and especially below 30%, phase separation may sometimes occur under high shear stress. However, surprisingly, in the formulations of the present invention, all the depots are non-flowing gel structures not only at rest but also after administration (for weak gels, this does not necessarily occur under higher shear stress). The above results indicate that the storage (elastic) modulus G' is unexpectedly higher than the loss (viscous) modulus G". This means that the administration of the eye drops (with relatively low shear stress) keeps the gel structure intact, and the formulation enters the eye in the form of a gel without immediate leakage. This enables controlled release over a specific time period, thereby improving efficacy.

[0115] Example 4

[0116] PK Study of a Single Dose of Silica Hydrogel Complex and In Vivo Release of Dexamethasone in Rabbits

[0117] Three specific pathogen-free (SPF) female New Zealand White (NZW) rabbits (Origin: Kaninfarm, Sweden) were used for the PK study. This study was conducted after approval by the National Laboratory Animal Board of Finland (Care and Use Committee). The quarantine / acclimation period was 5 days before the first experiment. The animal room temperature was 21°C ± 3°C, the relative humidity was at least 55 ± 15%, and the lighting was artificial lighting (12 h light and 12 h dark). The animals were housed in the Scanbur 8 system, one animal per cage. No randomization was performed.

[0118] The gel does not leak immediately. This enables controlled release over a specific time period, thereby improving efficacy.

[0119] Test Substances and Administration

[0120] In Experiment 1, a hydrogel complex was prepared using silica particles containing 10% w / w of encapsulated dexamethasone (calculated based on the theoretical silica amount) formulated with R3-100 (pH 4.0) and R400 silica sol (0.3 mg of silica particles in 1 ml of silica sol). In Experiments 2, 3, and 4, hydrogel complexes prepared using silica particles containing 15% w / w of encapsulated dexamethasone (calculated based on the theoretical silica amount) formulated with R3-100 (pH 4.0) and R400 silica sol were used, which contained 0.25 mg, 0.30, and 0.35 mg of silica particles in 1 ml of silica sol, respectively (see Table 2).

[0121] Table 2 Hydrogel composite formulations for in vivo experiments

[0122]

[0123] * Loading - Based on the theoretical mass percentage (w / w) of silica in the microparticles

[0124] After gently pulling the lower eyelid away from the eyeball, 1 drop of each hydrogel composite equivalent to 30 - 40 μl (corresponding 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 sacs of both eyes of each rabbit. Then the eyelids were gently closed together for about 1 second to prevent material loss. After administration, the rabbits were placed in a restraint device for about 1 - 2 minutes, after which the rabbits were returned to their own cages where they could move freely. Each rabbit was administered 4 times, and the wash-out period was 1 - 2 weeks (see Table 3 below for details).

[0125] Table 3

[0126]

[0127] Sampling

[0128] Tear fluid (2 μl) was collected from the eyes of the rabbits at time points 0 (before administration), 1 h, 2 h, 6 h, 12 h, 24 h, and 48 h after administration. A 2 μl capillary was used to collect the tear fluid. The tear fluid was transferred from the capillary to a plastic vial using a pipette (pressure technique). Immediately after placing the sample in the vial, 48 μl of 30% acetonitrile solution was added, and the vial was shaken to mix the tear fluid and acetonitrile. The samples were stored at 4 - 8 °C until testing.

[0129] In vivo release rate of dexamethasone

[0130] Analysis of dexamethasone in tear samples by HPLC measurement was performed to establish the in vivo release profile of dexamethasone. A 1260 Infinity II HPLC from Agilent Technologies equipped with a G7117C diode array detector was used. The column used was an Xbridge C18 2.1x50 mm 2.5μm from Waters, and the column temperature was 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 was performed as described 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 at pH 7.4. The standards were stored at 4°C.

[0131] Table 4 Gradient run for dexamethasone analysis

[0132] Time (hours) Mobile phase A (%) Mobile phase B (%) 0.00 80 20 2.00 30 70 2.20 1 99 3.20 1 99 3.70 80 20 6.50 80 20

[0133] The following Tables 5A - 5D describe the dexamethasone concentrations in tears for all 4 formulations in the in vivo study as described in Table 3 above, showing parallel samples in both eyes of the three rabbits tested. In Tables 5A - 5D, all concentrations and hourly release are given in μg / ml, SD = standard deviation.

[0134] Table 5A Dexamethasone concentration in tears for Test Article #04D - 0.3

[0135]

[0136] Table 5B Dexamethasone concentration in tears for Test Article #06D - 0.25

[0137]

[0138]

[0139] Table 5C Dexamethasone concentration in tears for Test Article #06D - 0.3

[0140]

[0141] Table 5D Dexamethasone concentration in tears for Test Article #06D - 0.35

[0142]

[0143] Clinical observations

[0144] Rabbits were monitored for 48 hours after administration of each formulation #04D-0.3, #06D-0.25, #06D-0.3, and #06D-0.35. Table 6-9 reports the clinical observations before sampling during each study period.

[0145] Table 6 Clinical observations conducted after administration of formulation #04D-0.3

[0146]

[0147]

[0148] Time point 0 represents the time immediately after administration.

[0149] Table 7 Clinical observations conducted after administration of formulation #06D-0.25

[0150]

[0151] Table 8 Clinical observations conducted after administration of formulation #06D-0.3

[0152]

[0153]

[0154] Table 9 Clinical observations conducted after administration of formulation #06D-0.35

[0155]

[0156] No abnormal clinical signs were observed in the study, indicating that the ophthalmic composition does not cause side effects such as irritation and / or eye redness and may be safe for use over a longer period.

[0157] Example 5

[0158] Particle size distribution of silica

[0159] The particle size distribution of 7 dexamethasone-containing composition samples was measured using a Sympatec HELOS2370 laser diffraction instrument. The Particles in Liquid (PIL) method was used, with ethylene glycol as the solvent. The particle size distribution of the microparticle formulation is shown in Table 10 below.

[0160] Table 10 Measured particle size distribution of the microparticle formulation

[0161]

[0162]

[0163] Example 6

[0164] PK study of a single-dose silica hydrogel composition in rabbits and in vivo release of dexamethasone and comparison with existing ophthalmic drop products

[0165] Specific pathogen-free (SPF) NZW rabbits (Origin: Kaninfarm, Sweden) were used for the PK study. Two experiments (Experiment 1 and 2) were conducted for the PK study of the ophthalmic drop product, with 4 rabbits used in each experiment, and two experiments (Experiment 3 and 4) were conducted for the PK study of the silica hydrogel composition, with 3 rabbits used in each experiment. This study has been approved by the Finnish National Committee for Laboratory Animals (Care and Use Committee). The quarantine / acclimation period was 8 days before the experiment. The animal room temperature was 21 °C ± 3 °C, the relative humidity was at least 55 ± 15%, and the lighting was artificial lighting (12 h light and 12 h dark). The animals were housed in the Scanbur 8 system, with 1 animal per cage. No randomization was performed.

[0166] Test articles and administration

[0167] In Experiment 3, a silica hydrogel composition prepared as follows was used: (i) silica microparticles of R3-200 formulation at pH 4.0 (diluted from R3 to 200 using ethanol as a diluent) containing 7.5% w / w of encapsulated dexamethasone (calculated based on the theoretical silica amount) were combined with (ii) R400 silica sol (0.3 g of silica microparticles in 1 ml of silica sol). In Experiment 3, a silica hydrogel composition prepared as follows was used: (i) a silica microparticle formulation R3-200 at pH 4.0 containing 7.5% w / w of encapsulated dexamethasone (calculated based on the theoretical silica amount) formulated with 50 volume-% of ethanol in water as a diluent and diluted from R3 to 200 was combined with (ii) R400 silica sol (0.3 g of silica microparticles in 1 ml of silica sol) (details are included in Table 11 below).

[0168] Table 11 Prepared silica hydrogel composition, API - dexamethasone * Loading - based on the theoretical mass % (w / w) of silica in the microparticles

[0169] In Experiment 1, a single dose of was administered in the form of 1 drop per eye. In Experiment 2, multiple doses of - 1 drop was administered per eye every 4 hours Lasted for 24 hours (i.e., 7 times in total).

[0170] After gently pulling the lower eyelid away from the eyeball, 1 drop of each hydrogel complex equivalent to 30 - 40 μl (corresponding to approximately 14 mg / ml dexamethasone in Experiment 3 and approximately 17 mg / ml in Experiment 4) was placed into the conjunctival sacs of both eyes of each animal. Then the eyelids were gently closed together for about 1 second to prevent material loss. After administration, the animals were placed in a restraint device for about 1 - 2 minutes, and thereafter the animals were returned to their own cages where they could move freely.

[0171] Sampling

[0172] Tear fluid (2 μl) was collected from the rabbit eyes at the time points shown in Table 13 below. A 2 μl capillary was used to collect the tear fluid. The tear fluid was transferred from the capillary to a plastic vial using a pipette (pressure technique). The samples were stored at -20 °C in dry ice until testing.

[0173] In - vivo release rate of dexamethasone

[0174] Prior to analysis, an aliquot of 2 μl of the tear fluid sample was mixed with 18 μl of an internal standard solution (10 ng / ml cortisol + prednisone, in phosphate - buffered saline solution with 25% methanol). Dexamethasone in the tear fluid samples was analyzed by UPLC. An Acquity UPLC from Waters equipped with an Xevo TQ - S triple quadrupole MS was used. The column used was a Kinetex Biphenyl 2.1x50 mm 2.7 μm from Phenomenex, and the column temperature was 40 °C. An aqueous solution of 0.025 volume - % acetic acid was used as mobile phase A, and acetonitrile was used as mobile phase B. The gradient run was as shown in Table 12. The flow rate was 0.5 ml / min, and the injection volume was 4 μl.

[0175] Table 12 Gradient run for dexamethasone analysis

[0176] Time (min) Mobile phase A (%) Mobile phase B (%) 0.00 90 10 0.50 90 10 1.50 50 50 2.00 2 98 2.50 2 98 3.50 90 10

[0177] Tables 13A - 13D show the dexamethasone concentrations in tear fluid of all the compositions of the in - vivo study, showing parallel samples in both eyes. In Tables 13A to 13D, all concentrations and releases per hour are given in μg / ml, SD = standard deviation.

[0178] The mean values of all the results are shown in Figure 7A and 7B .

[0179] Table 13A Dexamethasone concentration in tear fluid of Composition #09D - 0.3

[0180]

[0181]

[0182] Dexamethasone Concentration in Tears of Composition #12D-0.3 in Table 13B

[0183]

[0184] Table 13C Single Dose of Dexamethasone Concentration in Tears.

[0185]

[0186] Table 13D Multiple Doses of Dexamethasone Concentration in Tears.

[0187]

[0188]

[0189] Clinical Observation

[0190] After administration of the hydrogel compositions #09D-0.3 and #12D-0.3, rabbits were monitored for 48 hours. The clinical observation results before sampling during each study period are reported in Tables 14 and 15.

[0191] Clinical Observations Conducted after Administration of Formulation #09D-0.3 in Table 14

[0192]

[0193] Clinical Observations Conducted after Administration of Formulation #12D-0.3 in Table 15

[0194]

[0195]

[0196] No abnormal clinical signs were observed in this study. This indicates that the ophthalmic composition is safe to use and does not cause irritation or other side effects.

[0197] Example 7

[0198] The precision of the dosing unit was tested with two silica hydrogel compositions (#09D-0.3 and #12D-0.3). The test was carried out by dropping 1 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 over 3 days. The API content in the sample solution was determined by HPLC.

[0199] Table 16 Administration Precision of Single-Dose Unit System, Mass, and Concentration

[0200]

[0201] 1 Calculated Concentration of API in the Final Depot Formulation

[0202] 2 Average of Three Replicate Samples

[0203] 3 Measured API Concentration of the Sample, Average of Three Replicate Samples (Average = AVG, and Standard Deviation = SD)

[0204] Both formulations were administered very precisely from single-dose units, showing only a small deviation in the dexamethasone concentration per dose.

[0205] Example 8

[0206] Storage Stability Test of Dexamethasone Hydrogel Silica Eye Drop Composition

[0207] The storage stability of the drug substance and the drug product (composition) of the representative formulation #09 was studied. The silica-dexamethasone microparticles were mixed with R400 silica sol at a weight - volume ratio (w / v) of 0.3. Then the suspension was transferred to single-dose units (SDUs) through a 20G needle. After filling, the SDUs were gelled for 2 - 3 days. Before starting the stability study, the samples were packaged in aluminum bags and irradiated with gamma rays at an irradiation dose of 25.09 - 26.06 kGy.

[0208] One of the objectives of this study was to evaluate how the quality of the drug substance and the drug product changes over time under the influence of different storage conditions. The chemical and physical stability of the formulation was evaluated under the following two storage conditions: 2 - 8°C and 25°C ± 2°C / 60% ± 5% relative humidity (RH), over a three-month period (using a monthly test frequency). Different parameters were used to evaluate the stability of the microparticles and formulation #09. The reverse-phase HPLC (RP-HPLC) method and the parameters for analyzing dexamethasone and related substances are shown in Table 17 below. The storage stability study results are provided in Tables 18 - 21 and Figure 8 A - 8B.

[0209] Table 17: RP-HPLC Method for Dexamethasone and Related Substances

[0210]

[0211] Table 18. Dexamethasone Microparticle Stability Data (R3 - 200)

[0212]

[0213] Table 19. Related Substances Analysis during Storage Stability of Particles (R3-200)

[0214]

[0215] -: Not detected or area percentage less than 0.05%.

[0216] 1): Purity-% is calculated based on the relationship between the main peak area and the total value of the main peak area and the peak areas of related substances (peaks with an area percentage less than 0.05% are not included in the calculation).

[0217] 2): Co-eluting impurity peaks in the samples at 25 °C and 40 °C cannot be separated by the current method.

[0218] 3): Due to the change in the retention time of the API, the RRT varies slightly in different runs.

[0219] 4): Matrix interference in some samples.

[0220] Table 20. Storage Stability Data of Formulation #09

[0221]

[0222]

[0223] Table 21. Related Substances Analysis during Storage Stability of Formulation #09 -: Detected, but area percentage less than 0.05%.

[0224] 1): Purity-% is calculated based on the relationship between the main peak area and the total value of the main peak area and the peak areas of related substances (peaks with an area percentage less than 0.05% are not included in the calculation).

[0225] 2): Co-eluting impurity peaks in the samples cannot be separated by the current method.

[0226] 3): Due to the change in the retention time of the API, the RRT varies slightly in different runs.

[0227] Results: Under both storage conditions, the visible appearance, API content, silica content, unencapsulated API level, pH, and particle size distribution of the microparticles and formulation #09 remained unchanged for up to 3 months (Tables 17 and 19). Although a slight degradation of the API over time was observed at 25 °C / 60% RH, no significant degradation of the API was observed in the microparticles or formulation #09 stored at 2 - 8 °C for up to 3 months (Tables 18 and 20). The cumulative in vitro dissolution rate of the silica matrix in the depot formulation remained stable after storage at 2 - 8 °C and 25 °C / 60% RH for at least 2 months. Overall, it was surprisingly found that the formulations remained stable under the storage conditions despite having a low silica microparticle wt-%.

[0228] Example 9

[0229] Sustained-release silica hydrogel ophthalmic composition of ofloxacin

[0230] Two silica hydrogel compositions of ofloxacin were prepared as follows: (i) silica microparticles containing 5% w / w of encapsulated ofloxacin (calculated based on the theoretical amount of silica) of R3-200 formulation at pH 4.0 (diluted from R3 to 200 using 80% ethanol as a diluent) and (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)) were combined. Then the suspension was transferred to single-dose units (SDUs) through a 20G needle. After filling, the SDUs were gelled for 1 day.

[0231] Results: Figure 9 The release profiles of these ofloxacin microparticle formulations are shown. The retarding effect of the hydrogel component could be observed in both depot agents, and ofloxacin was released within 8 - 10 hours in both depot stock formulations.

[0232] It should be understood that the compositions and methods provided herein can be incorporated in the form of various embodiments, only a few of which are disclosed herein. It will be apparent to those skilled in the art that there are other embodiments, and the described embodiments are exemplary and should not be construed as restrictive.

[0233] 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 terms used in the specification disclosed herein are only for the purpose of describing particular embodiments and are not intended to be limiting.

[0234] Unless the context otherwise indicates, it is specifically intended that the various features of the present disclosure described herein can be used in any combination.

[0235] In addition, the present disclosure contemplates that in some embodiments of the present disclosure, any feature or combination of features described herein can be excluded or omitted.

[0236] All publications, patent applications, patents, and other references mentioned herein are hereby incorporated by reference in their entirety for all purposes.

[0237] As used herein, "a", "an", "the", or "said" can refer to one or more than one.

[0238] Also as used herein, "and / or" means and includes any and all possible combinations of one or more of the associated listed items, as well as no combinations when interpreted as an alternative ("or").

[0239] In addition, as used herein, the term "about" when referring to a measurable value such as the amount, dose, time, temperature, pH, etc. of a compound or substance of the present disclosure means including a variation of ±20% of the specified amount.

Claims

1. A hydrogel silica composition, comprising: a) silica microparticles comprising an active pharmaceutical ingredient and having a maximum diameter of from about 0.5 μm to about 40 μm, and b) a silica sol comprising solid nanoparticles <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 silica microparticles based on the weight of the composition; and iii) the hydrogel silica composition is for topical ocular administration.

2. The hydrogel silica composition of claim 1, wherein the active pharmaceutical ingredient is selected from anti-inflammatory drugs, corticosteroids, non-steroidal anti-inflammatory compounds, immunosuppressants, antibiotics, lymphocyte function-associated antigen-1 (LFA-1) antagonists or recombinant-human nerve growth factor.

3. The hydrogel silica composition of claim 2, wherein the corticosteroid is selected from prednisolone, dexamethasone, fluocinolone acetonide, fluorometholone, medrysone or rimexolone or a pharmaceutically acceptable salt thereof, preferably the corticosteroid is dexamethasone or a pharmaceutically acceptable salt thereof.

4. The hydrogel silica composition of claim 2, wherein the non-steroidal anti-inflammatory compound is selected from ketorolac, flurbiprofen, bromfenac, diclofenac, nepafenac or a pharmaceutically acceptable salt thereof, preferably the non-steroidal anti-inflammatory compound is nepafenac or a pharmaceutically acceptable salt thereof.

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

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

7. The hydrogel silica composition of claim 2, wherein the recombinant-human nerve growth factor is sinapine.

8. The hydrogel silica composition of any one of the preceding claims 1-7, wherein the silica microparticles have a maximum diameter of from about 1 - about 40 μm, preferably 1 - 30 μm, more preferably 1 - 20 μm.

9. The hydrogel silica composition of any one of the preceding claims 1-8, wherein the silica microparticles have a maximum diameter of from 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 of any one of the preceding claims 1-8, wherein the silica microparticles have an average diameter D10 of 0.9 to 10 μm and / or an average diameter D50 of 0.5 to 15 μm and / or an average diameter D90 of 5 to 40 μm, preferably 5 to 20 μm.

11. The hydrogel silica composition of any one of the preceding claims 1-10, wherein the silica microparticles comprise up to 30 wt-%, preferably 0.1-30 wt-%, more preferably 0.5 to 20 wt-%, even more preferably 1.5 to 15 wt-%, and most preferably 3-7.5 wt-% of the active pharmaceutical ingredient.

12. A hydrogel silica composition, comprising: a) Silica microparticles, which contain about ≤15 wt-%, preferably 10 wt-%, more preferably < 7.5 wt-% of dexamethasone or a pharmaceutically acceptable salt thereof, wherein the silica microparticles have an average diameter D10 of 0.9 to 10 μm and / or an average diameter D50 of 0.5 to 15 μm and / or an average diameter D90 of 5 to 40 μm, preferably 5 to 20 μm; and b) a silica sol comprising solid nanoparticles with a size < 50 nm, wherein the silica sol has a solid content of < 1% by weight, and wherein the hydrogel silica composition comprises up to 30% by weight of the silica microparticles based on the weight of the composition.

13. The hydrogel silica composition according to any one of the preceding claims 1 - 12, wherein the composition is non - flowing after being applied to the eye.

14. The hydrogel silica composition according to any one of the preceding claims 1 - 13, wherein the storage (elastic) modulus G' of the composition is higher than the loss (viscous) modulus G".

15. The hydrogel silica composition according to any one of the preceding claims 1 - 14, wherein the composition is a sustained - release composition.

16. The hydrogel silica composition according to any one of the preceding claims 1 - 15, wherein the composition remains stable after a storage period of at least 1 month, preferably at least 2 months, and most preferably at least 3 months at 2 - 8 °C.

17. The hydrogel silica composition according to any one of the preceding claims 1 - 16, wherein the composition is provided in the form of a topical eye drop.

18. The hydrogel silica composition according to any one of the preceding claims 1 - 16, wherein the composition is provided in a single - dose container.

19. The hydrogel silica composition according to any one of the preceding claims 1 - 18, which is used for treating eye disorders or eye diseases by topical administration.

20. The hydrogel silica composition for the said use according to claim 19, wherein the eye disorder or eye disease is a corneal injury caused by chemical, radiation or thermal burns or foreign body penetration.

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

22. The hydrogel silica composition for the said 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 non - specific superficial keratitis or postoperative ocular inflammation.

23. The hydrogel silica composition for the said use according to any one of the preceding claims 19–22, wherein the composition provides a sustained release of the active pharmaceutical ingredient contained therein.

24. The hydrogel silica composition for the said use according to any one of the preceding claims 19 - 23, wherein the active pharmaceutical ingredient is dexamethasone or a pharmaceutically acceptable salt thereof.

25. The hydrogel silica composition according to claim 12, which is used for treating postoperative ocular inflammation.

26. The hydrogel silica composition for the said use according to any one of the preceding claims 19 - 25, wherein the composition is topically administered once a day to a patient in need.

27. A method for preparing a hydrogel silica composition, which comprises mixing silica microparticles having a maximum diameter of about 0.5 μm to about 40 μm and containing an active pharmaceutical ingredient with a silica sol such that: i) the silica sol has a solid content of ≤ 1% by weight; and ii) The hydrogel silica composition comprises the silica microparticles in an amount of up to 30% by weight of the composition.

28. The method of claim 27, wherein the silica microparticles are obtained by spray drying the active pharmaceutical ingredient together with silica.

29. The method of claim 27 or 28, wherein the active pharmaceutical ingredient is selected from anti-inflammatory drugs, corticosteroids, non-steroidal anti-inflammatory compounds, immunosuppressants, antibiotics, lymphocyte function-associated antigen-1 (LFA-1) antagonists, or recombinant-human nerve growth factor.

30. The method of claim 29, wherein the corticosteroid is selected from prednisolone, dexamethasone, fluocinolone acetonide, fluorometholone, medrysone, or rimexolone, or a pharmaceutically acceptable salt thereof, preferably the corticosteroid is dexamethasone or a pharmaceutically acceptable salt thereof.

31. The method of claim 29, wherein the non-steroidal anti-inflammatory compound is selected from ketorolac, flurbiprofen, bromfenac, diclofenac, nepafenac, or a pharmaceutically acceptable salt thereof, preferably the non-steroidal anti-inflammatory compound is nepafenac or a pharmaceutically acceptable salt thereof.

32. The method of claim 29, wherein the immunosuppressant is cyclosporine or voclosporin, or a pharmaceutically acceptable salt thereof, preferably the immunosuppressant is cyclosporine or a pharmaceutically acceptable salt thereof.

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

34. The method of claim 29, wherein the recombinant-human nerve growth factor is sinapigmin.

35. A hydrogel silica composition obtainable by the method of any one of the preceding claims 27 - 34.

36. A method of treating an eye disorder or eye disease in a patient in need thereof, the method comprising topically administering to the patient the hydrogel silica composition of any one of the preceding claims 1 - 18.

37. A method of treating ocular inflammation, which comprises topically administering the hydrogel silica composition of claim 12.

38. The method of claim 37, wherein the ocular inflammation is selected from anterior uveitis, iritis, cyclitis, allergic or vernal conjunctivitis, herpes zoster keratitis, superficial punctate keratitis, or non-specific superficial keratitis, or postoperative ocular inflammation.

39. Use of the hydrogel silica composition of any one of the preceding claims 1 - 18 in the treatment of an eye disorder or eye disease.

40. Use of the hydrogel silica composition of claim 12 in the treatment of ocular inflammation.

41. The use of claim 40, wherein the ocular inflammation is selected from anterior uveitis, iritis, cyclitis, allergic or vernal conjunctivitis, herpes zoster keratitis, superficial punctate keratitis, or non-specific superficial keratitis, or postoperative ocular inflammation.

Images