Method and use for delivering drugs to the posterior segment of the eye

Abstract

To provide: a method for delivering an agent to a posterior segment of an eye; and an eye drop and a method for treating an ocular disease in a subject in need of treatment.SOLUTION: The method for delivering an agent to a posterior segment of an eye comprises administering a pharmaceutical composition comprising the agent and mesoporous silica nanoparticles to the eye, where the agent is loaded by mesoporous silica nanoparticles.SELECTED DRAWING: None

Description

Technical Field

[0001] The present disclosure relates to a treatment method. More specifically, the present disclosure provides a method for delivering a drug to the posterior eye segment.

Background Art

[0002] The main causes of visual impairment and blindness are posterior eye segment-related diseases such as Leber's hereditary optic neuropathy (LHON), age-related macular degeneration (AMD), diabetic macular edema, glaucoma, and hereditary retinal degeneration. However, the static and dynamic barriers of the eye, such as the blood-eye barrier, prevent many therapeutic drugs from being transported into the eye, particularly the posterior eye segment. As a result, the drug concentration and duration are insufficient, which usually causes the failure of clinical trials for ophthalmic drug development.

[0003] Intravitreal drug delivery has become the gold standard for the treatment of many retinal diseases, including AMD, diabetic retinopathy, and retinal vein occlusion. However, each injection is associated with the risk of endophthalmitis, uveitis, vitreous hemorrhage, and other complications. Therefore, repeated intravitreal injections, which are unrealistic for the treatment of chronic eye diseases, need to reduce the dosing frequency, whether the active ingredient is a small molecule drug or a protein (antibody) drug.

[0004] The use of topical administration (eye drops) for the treatment of anterior eye segment diseases is a preferred and convenient treatment option for patients. However, since topical administration cannot deliver sufficient drugs to the retinal tissue, it is rarely used for the treatment of posterior eye segment diseases. The blood-eye barrier limits drug penetration and distribution, resulting in significantly low bioavailability (1-5%) and intraocular penetration rate (less than 0.001%) in eye tissues. Therefore, there is no topical preparation approved by the FDA as a therapeutic drug for posterior eye segment diseases.

Summary of the Invention

[0005] The present disclosure provides a method for delivering a drug to the posterior eye segment, which includes administering to the eye a pharmaceutical composition containing a drug and mesoporous silica nanoparticles (MSN).

[0006] In one embodiment of the present disclosure, the drug is preferably a small molecule drug or a biomolecule, and the small molecule drug is hydrophobic or hydrophilic. In another aspect, the biomolecule is preferably a polypeptide, an antibody, an antibody fragment, a fusion protein, a ligand, a biomolecule-binding protein, a functional fragment of a protein, an enzyme, or a nucleotide.

[0007] Examples of drugs include, but are not limited to, difluprednate, loteprednol, dexamethasone, dexamethasone sodium phosphate, fluorocinolone acetonide, fluorometholone, triamcinolone, triamcinolone acetonide, rimexolone, prednisolone, medrysone, verteporfin, bevacizumab, ranibizumab, pegaptanib, aflibercept, brolucizumab, falisimab, axitinib, idebenone, azathioprine, methotrexate, mycophenolate mofetil, cyclosporine, tacrolimus, sirolimus, cyclophosphamide, chlorambucil, infliximab, adalimumab, etanercept, and brimonidine.

[0008] In some embodiments of this disclosure, the drug is loaded into the pores of mesoporous silica nanoparticles.

[0009] In some embodiments of this disclosure, the drug is linked to or adsorbed onto mesoporous silica nanoparticles via chemical bonding. Examples of chemical bonding include, but are not limited to, covalent bonds, electrostatic interactions, hydrogen bonds, or van der Waals forces.

[0010] In some embodiments of this disclosure, the drug and mesoporous silica nanoparticles are conjugated via a functional group or linker.

[0011] In one embodiment of the present disclosure, the method includes administering a pharmaceutical composition by local administration or by intravitreous, subretinal, subconjunctival, periocular, posterior, anterior chamber, sub-Tenon's capsule, near the posterior sclera, or suprachoroidal injection.

[0012] In one embodiment of this disclosure, the pharmaceutical composition is in the form of eye drops.

[0013] In one embodiment of the present disclosure, the method is for delivering a drug via the cornea, corneal epithelium, Bowman's layer, interstitium, Descemet's membrane, corneal endothelium, conjunctiva, blood-aqueous barrier, blood-retinal barrier, retina, retinal blood vessels, or retinal pigment epithelium.

[0014] In one embodiment of this disclosure, the method is for delivering a drug to a layer of the retina of the eye.

[0015] In one embodiment of this disclosure, the method is for delivering a drug to the choroid of the eye.

[0016] In one embodiment of the present disclosure, the method is for delivering a drug to the sclera of the eye.

[0017] In one embodiment of the present disclosure, the average particle size of the mesoporous silica nanoparticles is 20nm-100nm, 20nm-80nm, 20nm-60nm, 20nm-50nm, 20nm-40nm, 20nm-30nm, 22nm-28nm, 24nm-26nm, 22nm-48nm, 24nm-46nm, 26nm-44nm, 28nm-42nm, 30nm-40nm, 32nm-38nm, or 34nm-38nm, and is measured by a transmission electron microscope (TEM).

[0018] In one embodiment of the present disclosure, the average particle size of mesoporous silica nanoparticles used in eye drops is 20nm-50nm, 20nm-40nm, 20nm-30nm, 22nm-28nm, 24nm-26nm, 22nm-48nm, 24nm-46nm, 26nm-44nm, 28nm-42nm, 30nm-40nm, 32nm-38nm, or 34nm-38nm, and is measured by a transmission electron microscope (TEM).

[0019] In one embodiment of this disclosure, the average hydrodynamic diameter of mesoporous silica nanoparticles is 20nm-100nm, 20nm-80nm, 20nm-60nm, 20nm-50nm, 20nm-40nm, 20nm-40nm, 20nm-30nm, 22nm-28nm, 24nm-26nm, 22nm-58nm, 24nm-56nm, 26nm-54nm, 28nm-52nm, 30nm-50nm, 32nm-50nm, 34nm-50nm, 36nm-50nm, 38nm-48nm, 40nm-46nm, 22nm-48nm, 24nm-46nm, 26nm-44nm, 28nm-42nm, 30nm-40nm, 32nm-38nm, or 34nm-38nm, and is measured by dynamic light scattering in phosphate-buffered saline (PBS).

[0020] In one embodiment of the present disclosure, the average hydrodynamic diameter of mesoporous silica nanoparticles used in eye drops is 20nm-60nm, 20nm-50nm, 20nm-40nm, 20nm-30nm, 22nm-28nm, 24nm-26nm, 22nm-58nm, 24nm-56nm, 26nm-54nm, 28nm-52nm, 30nm-50nm, 32nm-50nm, 34nm-50nm, 36nm-50nm, 38nm-48nm, 40nm-46nm, 22nm-48nm, 24nm-46nm, 26nm-44nm, 28nm-42nm, 30nm-40nm, 32nm-38nm, or 34nm-38nm, and is measured by dynamic light scattering in phosphate-buffered saline (PBS).

[0021] In one embodiment of the present disclosure, the mesoporous silica nanoparticles may or may not have metal atoms. In a further embodiment of the present disclosure, the mesoporous silica nanoparticles do not contain metal atoms.

[0022] The present disclosure provides an eye drop comprising a pharmaceutical composition, the pharmaceutical composition comprising a drug and mesoporous silica nanoparticles, the drug being carried by the mesoporous silica nanoparticles, the average particle size of the mesoporous silica nanoparticles being 20 nm to 50 nm measured by a transmission electron microscope, or the average hydrodynamic diameter of the mesoporous silica nanoparticles or the average hydrodynamic diameter of the mesoporous silica nanoparticles loaded with the drug being less than 60 nm measured in phosphate buffered saline (PBS) by dynamic light scattering.

[0023] The present disclosure also provides a method for treating an eye disease in a subject that requires such treatment, the method comprising a method for delivering a drug to the posterior eye.

[0024] In some embodiments of the present disclosure, the eye disease is a posterior eye-related disease.

[0025] In one embodiment of the present disclosure, the eye disease is associated with abnormal reactive oxygen species levels, abnormal apoptosis, mitochondrial dysfunction, inflammation, abnormal protein levels, or protein misfolding / aggregation / dysfunction or complete loss of function.

[0026] In one embodiment of the present disclosure, the treatment of the eye disease is by treating the eye tissue.

[0027] In one embodiment of the present disclosure, the eye tissue is the retina, choroid, sclera, macula, fovea, optic nerve, vitreous humor, iris, cornea, pupil, lens, zonular fibers, or ciliary muscle.

[0028] In one embodiment of the present disclosure, the treatment of the eye disease is by treating the eye cells.

[0029] In one embodiment of the present disclosure, the cells of the eye are Müller cells, photoreceptors, bipolar cells, ganglion cells, horizontal cells, or amacrine cells.

[0030] In one embodiment of this disclosure, the treatment of an eye disease is performed by treating nerve cells.

[0031] In one embodiment of the present disclosure, the nerve cell is a photoreceptor, bipolar cell, ganglion cell, horizontal cell, or amacrine cell.

[0032] In one embodiment of the present disclosure, the eye disease is age-related macular degeneration, Leber's hereditary optic neuropathy, glaucoma, or X-linked juvenile retina. separation Diabetic retinopathy (XLRS), diabetic macular edema, retinal vein occlusion, uveitis, and endophthalmitis, myopia foveoschisis These include myopic orbital edema, macular edema, enhanced blue cone syndrome, post-cataract surgery inflammation (Irvine-Gass syndrome), retinal detachment, cystic macular edema, retinal lacerations, and retinal damage.

[0033] In one embodiment of the present disclosure, the eye diseases associated with abnormal reactive oxygen species levels are selected from the group consisting of Leber's hereditary optic neuropathy, age-related macular degeneration, cataracts, diabetic retinopathy (DR), glaucoma, dry eye, uveitis, and retinitis pigmentosa.

[0034] In one embodiment of the present disclosure, ocular diseases associated with abnormal neovascularization are selected from the group consisting of age-related macular degeneration (AMD), diabetic retinopathy, retinal artery or vein occlusion, retinopathy of prematurity (ROP), neovascular glaucoma, and corneal neovascularization secondary to infectious or inflammatory processes.

[0035] In one embodiment of the present disclosure, the ocular diseases associated with abnormal apoptosis are selected from the group consisting of Leber's hereditary optic neuropathy, glaucoma, retinitis pigmentosa, cataract formation, retinoblastoma, retinal ischemia, and diabetic retinopathy.

[0036] In one embodiment of the present disclosure, ocular diseases associated with mitochondrial dysfunction are selected from the group consisting of Leber's hereditary optic neuropathy, age-related macular degeneration, diabetic retinopathy, glaucoma, Kearns-Sayre syndrome (KSS), and optic atrophy dominant (DOA).

[0037] In one embodiment of the present disclosure, the ocular diseases associated with inflammation are selected from the group consisting of uveitis, orbital inflammatory disease, scleritis, episcleritis, iritis, sarcoidosis, Fuchs heterochromia iridocyclitis, bullous pemphigoid, ocular toxoplasmosis and ocular graft-versus-host disease, and dry eye.

[0038] In one embodiment of the present disclosure, the eye disease is associated with abnormal protein levels or protein misfolding / aggregation / dysfunction or complete loss of function and is selected from the group consisting of cataract, age-related macular degeneration, retinitis pigmentosa (RP), X-linked juvenile retinopathy (XLRS), and Stargardt disease.

[0039] This disclosure is described in detail in the following sections. Other features, purposes, and advantages of this disclosure can be found in the detailed description and the claims. [Brief explanation of the drawing]

[0040] [Figure 1] TEM images of internally and externally modified MSNs of different sizes are shown.

[0041] [Figure 2] This shows the distribution of 30 nm MSN particles in the retina, choroid, and sclera layers one hour and one day after intravitreal injection.

[0042] [Figure 3] The particle distribution in the retina, choroid, and sclera layers 0.5, 1, 4, and 24 hours after administration of MSN eye drops is shown.

[0043] [Figure 4]The pharmacokinetics of AXT@MSN in rat eyes after ophthalmic administration are shown.

[0044] [Figure 5] This shows a comparison of AXT concentrations in the eye 1 hour and 4 hours after axitinib monotherapy (IVT) and axitinib@MSN administration.

[0045] [Figure 6] These are fundus images (fluorescein angiography) of mouse eyes treated with AXT alone (IVT) and AXT@MSN (eye drops). Detailed description of the invention

[0046] This disclosure may be more readily understood by referring to the following detailed descriptions of various embodiments of this disclosure, examples, and the accompanying chemical drawings and tables. Unless otherwise specifically indicated by the claims, this disclosure is not limited to any particular preparation method, carrier or formulation, or any particular way of formulating the compounds of this disclosure into products or compositions intended for topical, oral or parenteral administration, for such things can change, as is well known to those skilled in the art. It should also be understood that the terms used herein are for the purpose of describing only particular embodiments and are not intended to limit them.

[0047] "Optional" or "optionally" means that the event or situation described afterward may or may not occur, and the description includes examples where the event or situation occurs and examples where it does not. For example, the phrase "optionally includes a drug" means that the drug may or may not be present.

[0048] As used in the specification and appended claims, the singular forms "a," "an," and "the" include singular and / or plural references unless the context explicitly indicates otherwise. Therefore, unless the context requires otherwise, singular terms shall include plurals, and plural terms shall include singulars.

[0049] In this disclosure, unless otherwise specified, the prefix "nano" means a size of about 300 nm or less, as used herein. Unless otherwise specified, the prefix "meso" means a size of about 5 nm or less, as used herein, in contrast to the definition suggested by IUPAC.

[0050] In this disclosure, the term “silane,” as used herein, refers to a derivative of SiH4. Typically, at least one of the four hydrogen atoms is substituted with a substituent such as alkyl, alkoxyl, or amino, as described below. The term “alkoxysilane,” as used herein, refers to a silane having at least one alkoxyl substituent directly bonded to a silicon atom. The term “organoalkoxysilane,” as used herein, refers to a silane having at least one alkoxyl substituent and at least one hydrocarbyl substituent directly bonded to a silicon atom. The term “silicate source,” as used herein, refers to a substance that can be considered as a salt or ester form of orthosilicic acid, such as sodium orthosilicate, sodium metasilicate, tetraethyl orthosilicate (tetraethoxysilane, TEOS), tetramethyl orthosilicate, or tetrapropyl orthosilicate. The hydrocarbyl substituent may be further substituted or interrupted by a heteroatom.

[0051] In this disclosure, the term "hydrocarbyl," as used herein, refers to a monovalent radical derived from a hydrocarbon. The term "hydrocarbon," as used herein, refers to a molecule consisting only of carbon and hydrogen atoms. Examples of hydrocarbons include, but are not limited to, (cyclo)alkanes, (cyclo)alkenes, alkadienes, and aromatic compounds. If the hydrocarbyl is further substituted as described above, the substituents may be halogens, amino groups, hydroxyl groups, thiol groups, and the like. If the hydrocarbyl is interrupted by a heteroatom as described above, the heteroatom may be S, O, or N. In the present invention, the hydrocarbyl preferably contains 1 to 30 carbon atoms.

[0052] In the present invention, the term "alkyl" refers to a saturated, linear, or branched alkyl group preferably containing 1 to 30 carbon atoms, more preferably 1 to 20 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, 2-ethylbutyl, n-pentyl, isopentyl, 1-methylpentyl, 1,3-dimethylbutyl, n-hexyl, 1-methylhexyl, n-heptyl, isoheptyl, 1,1,3,3-tetramethylbutyl, 1-methylheptyl, 3-methylheptyl, n-octyl, 2-ethylhexyl, 1,1,3-trimethylhexyl, 1,1,3,3-tetramethylpentyl, nonyl, decyl, undecyl, 1-methylundecyl, dodecyl, 1,1,3,3,5,5-hexamethylhexyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, and octadecyl.

[0053] In this disclosure, the term "alkylene" refers to the divalent radical of the alkyl group described above. The term "short chain" means that the radical or repeating unit contains up to six carbon atoms, preferably up to four carbon atoms, in the main chain.

[0054] In the present invention, the terms "alkoxyl" or "alkoxy" as used herein mean a group having the formula "-O-alkyl", and the definition of "alkyl" in the formula has the meaning of "alkyl" as described above.

[0055] In the present invention, the term "cycloalkyl," as used herein, means a saturated or partially unsaturated cyclic carbon radical containing 3 to 10 cyclic carbon atoms, more preferably 3 to 8 cyclic carbon atoms, and optionally an alkyl substituent on the ring. Examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclopropenyl, cyclobutyl, cyclopentyl, cyclohexyl, and 2-cyclohexen-1-yl.

[0056] In this invention, the term "halogen" or "halo" means fluorine, chlorine, bromine, or iodine.

[0057] In the present invention, the term "amino" as used herein means the functional group of formula -NR1R2, where R1 and R2 each independently represent hydrogen or a hydrocarbyl group as defined above.

[0058] In this disclosure, the term "internal surface" refers to the surface of the "wall" that defines the pore, and the term "external surface" refers to the outermost layer, wall, or structure surface of the nanoparticle.

[0059] In this disclosure, the term “drug” means, as used herein, a substance that has a therapeutic effect on a living organism, particularly the eye. Drugs such as those disclosed herein may be small molecule drugs. Small molecule drugs, such as active pharmaceutical ingredients (APIs), may be hydrophobic or hydrophilic, and in other embodiments, they may be positively charged, negatively charged, or neutral. Particulate examples of drugs include axitinib, dexamethasone, and dexamethasone sodium phosphate. Drugs such as those disclosed herein may be biomolecules. Biomolecules include, but are not limited to, polypeptides, antibodies, antibody fragments, fusion proteins, ligands, biomolecule-binding proteins, functional protein fragments, enzymes, or nucleotides.

[0060] In some embodiments of this disclosure, the drug is an ophthalmic drug. Examples of drugs include, but are not limited to, steroids such as difluprednate, lotepanol, dexamethasone, dexamethasone sodium phosphate, fluorocinolone acetonide, fluorometholone, triamcinolone, triamcinolone acetonide, rimexolone, prednisolone, Medrizon (medrysone); vascular endothelial growth factor (VEGF) inhibitors, e.g., verteporfin, bevacizumab, ranibizumab, pegaptanib, aflibercept, brolucizumab, falisimab; VEGF receptor inhibitors, e.g., axitinib; LHON treatments, e.g., idebenone; immunosuppressants, e.g., azathioprine, methotrexate, mycophenolate mofetil, cyclosporine, tacrolimus, sirolimus, cyclophosphamide, chlorambucil; TNFα inhibitors, e.g., infliximab, adalimumab, etanercept; and others such as brimonidine. Examples of ophthalmic drugs include the following.

[0061] As used herein, the term “subject” refers to any animal, preferably a mammal, more preferably a human. Examples of subjects include humans, non-human primates, rodents, guinea pigs, rabbits, sheep, pigs, goats, cattle, horses, dogs, and cats.

[0062] The term "effective dose" means an amount of the active ingredient provided herein that is sufficient to provide the desired modulation of the desired function. As noted below, the exact amount required will vary from subject to subject, depending on the disease state, physical condition, age, sex, species and weight of the subject, the specific identity and formulation of the composition, etc. The dosing plan may be adjusted to induce the optimal therapeutic response. For example, several divided doses may be administered daily, or the dose may be proportionally reduced, as indicated by the urgency of the treatment situation. Therefore, it is not possible to specify an exact "effective dose." However, an appropriate effective dose can be determined by those skilled in the art using only routine experiments.

[0063] The terms “to treat” or “to cure” as used herein mean to reverse, alleviate, suppress or improve the progression of a disorder, disease or condition to which such terms apply, or to one or more symptoms of such disorder, disease or condition.

[0064] The terms “carrier” or “excipient,” as used herein, refer to any substance that is not a therapeutic agent in itself but is used as a carrier and / or diluent and / or adjuvant or vehicle for the delivery of a therapeutic agent to a subject, or to improve its handling or storage properties, or to enable or facilitate the formation of dose units of a composition into individual articles of dose units of the composition (e.g., liquid solutions, suspensions, emulsions, granules, ampoules, injections, implants, inserts, infusions, kits, ointments, lotions, liniments, creams, gels, sprays, drops, aerosols, or combinations thereof for topical administration). Suitable carriers or excipients are well known to those skilled in the art who manufacture pharmaceutical formulations or food products. Carriers or excipients may include, but are not limited to, buffers, diluents, disintegrants, binders, adhesives, wetting agents, polymers, lubricants, lubricants, tumblers, substances added to mask or counteract unpleasant tastes or odors, flavoring agents, dyes, fragrances, and substances added to improve the appearance of a composition. Acceptable carriers or excipients include citrate buffer, phosphate buffer, acetate buffer, bicarbonate buffer, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric acid and sulfate, magnesium carbonate, talc, gelatin, acacia gum, sodium alginate, pectin, dextrin, mannitol, sorbitol, lactose, sucrose, starch, gelatin, cellulose substances (such as cellulose esters and alkyl cellulose esters of alkanates), low-melting-point waxes, cocoa butter, amino acids, urea, alcohol, ascorbic acid, phospholipids, proteins (e.g., serum albumin), ethylenediaminetetraacetic acid (EDTA), dimethyl sulfoxide (DMSO), sodium chloride or other salts, liposomes, mannitol, sorbitol, glycerol or powders, polymers (polyvinylpyrrolidone, polyvinyl alcohol and polyethylene glycol), and other pharmaceutically acceptable materials. The carrier should not disrupt the pharmacological activity of the therapeutic agent and should be non-toxic when administered in a dose sufficient to deliver a therapeutic amount of the drug.

[0065] This disclosure provides a method for delivering a drug to the posterior segment of the eye, comprising administering a pharmaceutical composition containing a drug and mesoporous silica nanoparticles to the eye.

[0066] This disclosure provides an eye drop comprising a pharmaceutical composition comprising a drug loaded within the pores of mesoporous silica nanoparticles and mesoporous silica nanoparticles; The average particle size of mesoporous silica nanoparticles is less than 50 nm, preferably 20 nm to 50 nm, as measured by a transmission electron microscope, or The average hydrodynamic diameter of mesoporous silica nanoparticles, or the average hydrodynamic diameter of drug-loaded mesoporous silica nanoparticles, is less than 60 nm, as measured by dynamic light scattering in phosphate-buffered saline (PBS).

[0067] This disclosure also provides a method for treating an ocular disease in a subject requiring such treatment, the method comprising a method for delivering a drug to the posterior segment of the eye.

[0068] MSNs can exert desired pharmacological effects, such as delivering drugs to the posterior segment of the eye, by undergoing specific surface modifications. Various MSNs can be used in this disclosure for drug loading. In some embodiments, MSNs are modified with various surface functional groups to improve their biocompatibility and design for different purposes. For example, (i) MSNs having organic molecules, oligomers, or polymers, and optionally (ii) MSNs having pore-internal surface modifications with positively charged molecules, uncharged molecules, oligomers, or polymers, and terminal hydrocarbyl moieties, positively charged molecules, or uncharged molecules.

[0069] The organic molecule, oligomer, or polymer (i) is not particularly limited, but examples include short-chain poly(alkylene glycol) (PAG), such as poly(ethylene glycol) (PEG), poly(propylene glycol) (PPG), and PEG-PPG copolymer. Furthermore, (organic) modifiers can be introduced to modify the properties of MSN (e.g., surface properties), and are not limited to these, but include, for example, propyltriethoxysilane, butyltrimethoxysilane, octyltrimethoxysilane, diphenyldiethoxysilane, n-octyltriethoxysilane, mercaptopropyltrimethoxysilane, chloromethyltrimethoxysilane, isobutyltriethoxysilane, ethyltrimethoxystyrenesilane, methyltriethoxysilane, phenyltriethoxysilane (PTEOS), phenyltrimethoxysilane (PTMOS), methyltrimethoxysilane (MTMOS), ethyltriacetoxysilane (ETAS), N-(trimethoxysilylpropyl)ethylenediaminetriacetic acid (EDTAS), (3-trihydroxysilyl)propylmethylphosphonate (THPMP), methyltriacetoxysilane (MTAS), (3-mercatopropyl)trimethoxysilane (MPTMS), zwitterionic silanes, and the like.

[0070] The positively charged molecule, oligomer, or polymer (ii) is not particularly limited, but includes, for example, polyethyleneimine (PEI); alkoxylsilane-terminated (poly)alkylene (poly)amines, such as N-[3-(trimethoxysilyl)propyl]-N,N,N-trimethylammonium chloride (TA), N-[3-(trimethoxysilyl)propyl]ethylenediamine (EDPTMS), N 1 Examples include (3-trimethoxysilylpropyl)diethylenetriamine; organo-alkoxysilanes, such as 3-aminopropyltrimethoxysilane (APTMS) and 3-aminopropyltriethoxysilane. Examples of load molecules include, but are not limited to, organo-alkoxysilanes negatively charged under pH 7 conditions.

[0071] When performing surface modifications that are thought to reduce nonspecific binding to non-targets, it is necessary to use positively charged molecules, negatively charged molecules, oligomers, or polymers (ii) that are shorter in length than the organic molecule, oligomer, or polymer (i).

[0072] Examples of terminal hydrocarbyl moieties include, but are not limited to, terminal aromatic moieties, terminal (cyclic) aliphatic moieties, or combinations thereof. The term "terminal" means that the hydrocarbyl moiety is directly bonded to a silicon atom of the silica nanoparticle. In some embodiments, the terminal aromatic moiety is substituted with a lower alkyl or halogen. In further embodiments, the terminal aromatic moiety is derived from trimethoxyphenylsilane (TMPS). In some embodiments, the terminal (cyclo)aliphatic moiety includes a (cyclo)alkyl, (cyclo)alkenyl, or a combination thereof, which can optionally be substituted with a lower alkyl or halogen. In one embodiment, the terminal aliphatic moiety is derived from long-chain alkylsilanes having 4 to 18 carbon atoms, including but not limited to butyltrimethoxysilane, butyltriethoxysilane, hexyltrimethoxysilane, hexyltriethoxysilane, octyltrimethoxysilane, octyltriethoxysilane, isooctyltrimethoxysilane, isooctyltriethoxysilane, doxytrimethoxysilane, doxytriethoxysilane, doxyltrimethoxysilane, doxyltriethoxysilane, dodecyltrimethoxysilane, dodecyltriethoxysilane, tetradecyltrimethoxysilane, tetradecyltriethoxysilane, hexadecyltrimethoxysilane, hexadecyltriethoxysilane, octadecyltrimethoxysilane, and octadecyltriethoxysilane. Preferably, trimethoxyC 6~8 It is an alkylsilane.

[0073] In one embodiment, pore surface modification can be achieved by using a silane without terminal hydrocarbyl moieties and a silane having at least one terminal hydrocarbyl moiety, where the terminal hydrocarbyl moieties originate from the silane having at least one terminal hydrocarbyl moiety. In one embodiment, the amount of terminal hydrocarbyl moieties per particle, expressed as the molar ratio of the silane without terminal hydrocarbyl moieties to the silane having at least one terminal hydrocarbyl moiety, is at least 50:1, or at least 40:1, at least 35:1, at least 30:1, at least 25:1, at least 20:1, at least 15:1, or any numerical range consisting of the above endpoints, e.g., 15:1 to 50:1, 20:1 to 40:1, etc. In one embodiment, calculations and / or measurements can be performed to obtain the number of silanes having at least one terminal hydrocarbyl moiety per particle.

[0074] In one embodiment, pore surface modification can be achieved by using positively charged silane, where the amount of positively charged silane per particle, expressed as the molar ratio of TEOS to positively charged silane, is at least 20:1, at least 15:1, at least 10:1, at least 5:1, or at least 3:1, or within any numerical range consisting of the above endpoints, e.g., 3:1 to 20:1, 5:1 to 10:1, 6:1 to 8:1, etc.

[0075] In one embodiment, pore surface modification can be achieved by using negatively charged silane, the amount of negatively charged silane per particle being at least 40:1 or at least 35:1, at least 1:30, at least 1:25, at least 1:20, at least 1:15, at least 1:10:1 or at least 5:1 in terms of the molar ratio of TEOS to negatively charged silane, or any numerical range consisting of the above endpoints, e.g., 5:1 to 40:1, 5:1 to 20:1, 7:1 to 15:1, 7:1 to 10:1, etc.

[0076] In one embodiment, the mesoporous silica nanoparticles of the present disclosure have average particle sizes of 100 nm or less, 90 nm or less, 80 nm or less, 70 nm or less, 60 nm or less, 50 nm or less, 40 nm or less, 30 nm or less, and 20 nm or less, as measured by TEM. In particular, the average particle size of the mesoporous silica nanoparticles, as measured by TEM, is 20 nm to 100 nm, 20 nm to 80 nm, 20 nm to 60 nm, 20 nm to 50 nm, 20 nm to 40 nm, 20 nm to 30 nm, 22 nm to 28 nm, 24 nm to 26 nm, 22 nm to 48 nm, 24 nm to 46 nm, 26 nm to 44 nm, 28 nm to 42 nm, 30 nm to 40 nm, 32 nm to 38 nm, or 34 nm to 38 nm.

[0077] In one embodiment of the present disclosure, the average particle size of mesoporous silica nanoparticles used in eye drops is 20nm-50nm, 20nm-40nm, 20nm-30nm, 22nm-28nm, 24nm-26nm, 22nm-48nm, 24nm-46nm, 26nm-44nm, 28nm-42nm, 30nm-40nm, 32nm-38nm, or 34nm-38nm, and is measured by a transmission electron microscope (TEM).

[0078] In one embodiment, the mesoporous silica nanoparticles of the present disclosure have pore sizes of 50 nm or less, 45 nm or less, 40 nm or less, 35 nm or less, 30 nm or less, 25 nm or less, 20 nm or less, 15 nm or less, 10 nm or less, 5 nm or less, or 3 nm or less, or any numerical range consisting of the above endpoints such as 1 nm to 3 nm, 3 nm to 50 nm, 5 nm to 35 nm, 10 nm to 45 nm.

[0079] In one embodiment, the mesoporous silica nanoparticles of the present disclosure have average hydrodynamic diameters of 100 nm or less, 90 nm or less, 80 nm or less, 70 nm or less, 60 nm or less, 50 nm or less, 40 nm or less, and 30 nm or less, as measured in phosphate-buffered saline by dynamic light scattering. In particular, the average hydrodynamic diameters of mesoporous silica nanoparticles are 20nm-100nm, 20nm-80nm, 20nm-60nm, 20nm-50nm, 20nm-40nm, 20nm-30nm, 22-28nm, 24nm-26nm, 22nm-58nm, 24nm-56nm, 26nm-54nm, 28nm-52nm, 32nm-50nm, 32-50nm, 34-50nm, 36nm-50nm, 38nm-48nm, 40nm-46nm, 22nm-48nm, 24nm-46nm, 24nm-46nm, 26nm-44nm, 28nm-42nm, 30nm-40nm, 32nm-38nm, or 34nm-38nm, and are measured by dynamic light scattering in PBS.

[0080] In one embodiment of the present disclosure, the average hydrodynamic diameter of mesoporous silica nanoparticles used in eye drops is 20nm-60nm, 20nm-50nm, 20nm-40nm, 20nm-30nm, 22nm-28nm, 24nm-26nm, 22nm-58nm, 24nm-56nm, 26nm-54nm, 28nm-52nm, 30nm-50nm, 32nm-50nm, 34nm-50nm, 36nm-50nm, 38nm-48nm, 40nm-46nm, 22nm-48nm, 24nm-46nm, 26nm-44nm, 28nm-42nm, 30nm-40nm, 32nm-38nm, or 34nm-38nm, and is measured by dynamic light scattering in phosphate-buffered saline (PBS).

[0081] In certain embodiments, the zeta potential of the MSN (under pH 7.4 conditions) may be in the range of -30 to +30 mV, -25 to +25 mV, -20 to +20 mV, -15 to +15 mV, or -10 to +10 mV, or a reasonable numerical range within the endpoints described herein, for example, -30 to -10, -15 to +20 mV, -10 to +25 mV, -15 to +10 mV, +10 to +30 mV, etc. In one embodiment, the mesoporous silica nanoparticles are 1000 m 2 / g or less, 750m 2 / g or less, or 500m 2 It has a BET surface area of ​​less than or equal to / g.

[0082] In some embodiments of this disclosure, the mesoporous silica nanoparticles have at least one of the following characteristics: (a) (i) Surface modification with organic molecules, oligomers or polymers and (ii) positively charged molecules, oligomers or polymers, wherein the molar ratio of (i) and (ii) is in the range of 60:1 to 2:1; (b) Pore ​​internal surface modification by terminal hydrocarbyl moieties; (c) The average particle size measured by TEM is 60 nm or less; and (d) The average hydrodynamic diameter measured by dynamic light scattering using PBS must be 60 nm or less.

[0083] In one embodiment, the MSN has features (a) and (b); preferably features (a), (b) and (c); preferably features (a), (b) and (d); more preferably features (a), (b), (c) and (d).

[0084] MSN loading with drugs exhibiting barrier penetration ability demonstrates the advantage of being a high-potential drug delivery system for treating ocular diseases. All examples, components, reaction conditions, or parameters illustrated in the examples are for illustrative purposes only and are not intended to limit materials or preparation methods by the exemplary embodiments described herein.

[0085] In some embodiments of this disclosure, the drug is loaded into the pores of mesoporous silica nanoparticles.

[0086] In some embodiments of this disclosure, the drug is linked to or adsorbed onto mesoporous silica nanoparticles via chemical bonding. Examples of chemical bonding include, but are not limited to, covalent bonds, electrostatic interactions, hydrogen bonds, or van der Waals forces.

[0087] In some embodiments of this disclosure, the drug and mesoporous silica nanoparticles are conjugated via a functional group or linker.

[0088] MSN has a distinct structure that can be modified with a wide range of organic functional groups and a high density of surface silanol groups. MSN of various sizes was prepared using an ammonia-based catalytic method. Particle size was controlled by adjusting the ammonia concentration, the amount and concentration of the silane source, the reaction temperature, etc.

[0089] In one embodiment, MSN can be produced by (a) providing an alkaline solution containing a surfactant at a concentration sufficient to form micelles; (b) introducing a silane source into the solution; (c) (i) introducing organic molecules, oligomers, or polymers, and optionally (ii) positively charged molecules, negatively charged molecules, oligomers, or polymers into the solution; (d) performing hydrothermal treatment on the solution; (e) recovering the product; (f) removing residual surfactant from the product; and optionally (g) purifying or washing the product.

[0090] Typically, 0.2–0.4 g of surfactant was dissolved in 150–250 mL of alkaline aqueous solution (e.g., ammonium hydroxide solution (0.1–0.25 M)) in a sealed beaker at the desired temperature (45–65°C). After stirring for 10–30 minutes, 150–450 μL of silane (TEOS) and optionally 15–110 μL of internally surface-modified silane (for pore internal surface modification) were added to the solution continuously or simultaneously in 0.8–1.6 mL of solvent (e.g., alcohol such as ethanol) while stirring, preferably vigorously. After stirring for 0.5–1.5 hours, 100–300 μL of silane (TEOS) in 0.6–1.3 mL of solvent (e.g., alcohol such as ethanol) was added separately. After 2-4 hours of reaction, 700-1200 μL of PEG-silane (silane having a PEG moiety, e.g., (2-[methoxy(polyethyleneoxy)propyl]-trimethoxysilane) and 10-600 μL of charged molecules, oligomers, or polymers (e.g., TA-silane, (N-[3-(trimethoxysilyl)propyl]-N,N,N-trimethylammonium chloride)) were reacted in 2.5-4 mL of solvent (e.g., alcohol such as ethanol). The mixture was stirred for 0.5-1.5 hours, and then aged at the desired temperature (e.g., 45-65°C) without stirring for at least 12 hours. The solution was then sealed and aged at 65-75°C for 18-60 hours, or at 65-75°C and 85-95°C for 2 hours. The product was placed in an oven for hydrothermal treatment for 0-28 hours. The as-synthesized product was washed and recovered by centrifugation or cross-flow apparatus. To remove surfactants from the pores of the MSN, the as-synthesized product was incubated in 40-60 mL of an acidic solvent (e.g., an alcohol such as ethanol) containing an acid (e.g., hydrochloric acid (37%)) at 55-65°C for 0.5-1.5 hours for extraction, with one or more incubations. The product was washed and recovered by centrifugation or cross-flow system and finally stored, preferably in ethanol of 85% or higher. Different hydrocarbyl moieties, positively charged molecules, and negatively charged molecules were used for the synthesis of different pore-internal surface-modified MSNs.For the synthesis of different externally surface-modified MSN-PEGs, different positively charged molecules, oligomers, or polymers, such as TA-silane, EDPTMS-silane, or other functionalized silanes, were used. MSNs have various surface charges by adjusting the ratio of PEG to the charged molecules present on the MSN-PEG (the surface charge can be negative, neutral, or positive).

[0091] In one embodiment, the silane source consists of tetraethoxysilane (TEOS), tetramethoxysilane (TMOS), sodium silicate, or a mixture thereof. Surface modifiers can be used to adjust the properties of the MSN. In one embodiment, the (organic) modifiers include, but are not limited to, propyltriethoxysilane, butyltrimethoxysilane, octyltrimethoxysilane, diphenyldiethoxysilane, n-octyltriethoxysilane, mercaptopropyltrimethoxysilane, chloromethyltrimethoxysilane, isobutyltriethoxysilane, ethyltrimethoxystyrenesilane, methyltriethoxysilane, phenyltriethoxysilane (PTEOS), phenyltrimethoxysilane (PTMOS), methyltrimethoxysilane (MTMOS), ethyltriacetoxysilane (ETAS), N-(trimethoxysilylpropyl)ethylenediaminetriacetic acid (EDTAS), (3-trihydroxysilyl)propylmethylphosphonate (THPMP), methyltriacetoxysilane (MTAS), (3-mercatopropyl)trimethoxysilane (MPTMS), zwitterionic silanes, and the like.

[0092] Examples of surfactants suitable for the production of MSN include, but are not limited to, cationic surfactants, anionic surfactants, and nonionic surfactants. The appropriate surfactant is selected based on reaction conditions such as pH value, ionic strength, temperature, reactants, and products. Examples of cationic surfactants include pH-dependent primary, secondary, or tertiary amines having long-chain hydrocarbyl groups, where the terminal amine group becomes positively charged when presented below a certain pH value; for example, primary and secondary amines become positively charged at pH < 10, e.g., octenidine dihydrochloride; and permanently charged quaternary ammonium salts, e.g., cetrimonium bromide (CTAB), cetylpyridinium chloride (CPC), benzalkonium chloride (BAC), benzethonium chloride (BZT), dimethyldioctadecylammonium chloride, and dioctadecyldimethylammonium bromide (DODAB). Examples of anionic surfactants include, but are not limited to, sulfates, sulfonates, phosphates, or esters; for example, ammonium lauryl sulfate, sodium lauryl sulfate (sodium dodecyl sulfate, SLS, or SDS), and related alkyl ether sulfates, sodium laureth sulfate (sodium lauryl ether sulfate or SLES), sodium myreth sulfate, docusate (sodium dioctyl sulfosuccinate), perfluorooctanesulfonic acid (PFOS), perfluorobutanesulfonic acid, alkyl allyl ether phosphates, and alkyl ether phosphates. Examples of nonionic surfactants include, but are not limited to, poly(oxyethylene) nonylphenyl ether, polyoxyethylene glycol sorbitan alkyl ester, polyethylene glycol alkyl ether, glucoside alkyl ether, polyethylene glycol octylphenyl ether, polyethylene glycol alkylphenyl ether, glycerol alkyl ester, polypropylene glycol alkyl ether, block copolymer, poloxamer, cocamide MEA, cocamide DEA, lauryl dimethylamine oxide, or polyethoxylated taloamine.

[0093] MSNs of different sizes can be prepared using an ammonia-based catalytic method. In one embodiment, the MSNs are prepared under highly diluted, low-surfactant conditions. In this disclosure, the MSNs preferably have an average diameter of less than 100 nm as measured by TEM. In this disclosure, the MSNs used in eye drops preferably have an average diameter of less than 50 nm as measured by TEM. Control of the MSN size can be achieved by adjusting the ammonia concentration, the amount and concentration of alkoxylsilane, the reaction temperature, etc. Although not theoretically bound, the size of the MSNs increases with increasing ammonia concentration and vice versa; the size of the MSNs may also increase with increasing amounts of alkoxylsilane. In various embodiments, 0.14 to 0.5 g of CTAB is used in 150 mL of ammonium hydroxide solution, with an ammonia concentration of 0.05 to 1.5 M, preferably 0.1 to 0.5 M, more preferably 0.1 to 0.25 M; the amount of alkoxysilane added to 150 mL of ammonium hydroxide solution is 1 mL to 5 mL, preferably 1 mL to 3 mL, more preferably 2 mL to 2.5 mL of ethanol TEOS (i.e., TEOS in ethanol, about 0.862 to 1.2 M); and the reaction temperature is in the range of 30°C to 60°C, preferably 40°C to 60°C, more preferably 50°C to 60°C. Any combination of these conditions may function as embodiments of the present disclosure.

[0094] At least one drug can be distributed, for example, within the space of the MSN, on the surface of the MSN, etc., and thus mounted on and / or within the MSN. The drug can be appropriately selected based on its size and the associated disorder / disease.

[0095] In one embodiment of the present disclosure, the mesoporous silica nanoparticles may or may not contain metal atoms. In a further embodiment of the present disclosure, the mesoporous silica nanoparticles are free of metal atoms.

[0096] In some embodiments of this disclosure, the pharmaceutical composition comprises a drug and optionally a pharmaceutically acceptable carrier or excipient.

[0097] In some embodiments of this disclosure, the pharmaceutical composition comprises an effective amount of the drug.

[0098] To overcome the blood-ocular barrier, properties of MSNs and exMSNs, such as nanoparticle size, surface charge, and composition, can be modulated to increase passage through the static and dynamic barriers of the eye, thereby improving the bioavailability of the eye. Mesoporous silica nanoparticles (MSNs) have been considered to have great potential as drug delivery systems due to their unique physical / chemical properties, including large pore volume, chemical / thermal stability, high loading capacity, modifiable surface properties, and excellent biocompatibility. Small-sized MSNs (<100 nm) with particle and pore surface modifications by specific functional groups and ratios are provided to encapsulate hydrophobic drugs in the pore space and allow the particles to exhibit excellent suspension in aqueous solutions. Furthermore, for drug delivery to the eye, MSNs can be modified by adjusting the nanoparticle size, surface charge, and bound ligands to enhance their permeability through the static and dynamic barriers of the eye, which limit most therapeutic drugs delivered to the posterior segment of the eye. Herein, drugs are evaluated as potential treatments for posterior segment-related eye diseases, and the route of administration can be in the form of intravitreal administration or eye drops. MSN offers an approach to overcome the challenges faced by intraocular drug delivery, particularly in clinical use for retinal diseases. There is a need to deliver therapeutic agents via an appropriate delivery system that can overcome the ocular barrier, enhance therapeutic efficacy, reduce administration frequency, and offer more route-of-administration options than intravitreous injection.

[0099] While eye drops are the most convenient and patient-friendly route of drug administration for eye diseases, eye drop delivery for posterior segment-related eye diseases (retinal diseases) is one of the most challenging areas. The static and dynamic barriers of the eye prevent most therapeutic agents from reaching the posterior segment, resulting in low ocular penetration and bioavailability. To date, only a limited number of drugs have been approved as treatments or drug candidates for posterior segment diseases, and none have been approved as eye drops for retinal diseases because most drug molecules cannot effectively enter the posterior segment. Prescribing eye drops is extremely difficult, but it is crucial for drug success. Different types of nanoparticles have been developed as eye drop formulations for the treatment of retinal diseases (e.g., polymer / cyclodextrin nanoparticles), with drug particle sizes ranging from several hundred nanometers to 1 micrometer, and as a result, instead of carrying drugs across the ocular barrier to the posterior segment, the nanoparticles release drugs that remain on the cornea for extended periods and penetrate the eye. In this invention, the smaller hydrodynamic size of drug-loaded MSNs can increase the penetration of the static and dynamic barriers of the eye, enabling the delivery of therapeutic agents to the posterior segment of the eye to treat posterior segment diseases. MSN nanoparticles can address unmet medical needs in eye drop formulations, including producing highly concentrated drug aqueous solutions, overcoming the ocular barrier to enhance bioavailability, and maintaining effective drug concentrations at the target site.

[0100] Drugs loaded, bound to, or adsorbed onto MSNs can provide sustained release, increase the drug's half-life, and reduce the frequency of administration. MSNs with specifically tuned properties can effectively penetrate the static and dynamic barriers of the eye, opening up the possibility of using MSN nanoparticles in the development of eye drops to deliver therapeutic agents to the posterior segment of the eye via eye drop administration. Drug-loaded MSN solutions can be potential nano-formulations for ocular drug delivery, with administration routes including topical (eye drops), intravitreous, subconjunctival, subretinal, peribulbar, near the posterior sclera, suprachoroidal, posterior, anterior chamber, sub-Tenon's capsule, and systemic injection.

[0101] The pharmaceutical compositions relating to this disclosure are preferably administered topically by any method known in the art. Appropriate routes, formulations, and administration schedules can be determined by those skilled in the art. In this disclosure, the pharmaceutical compositions can be formulated in a variety of ways according to the corresponding route of administration, such as liquid solutions, suspensions, emulsions, granules, ampoules, injections, implants, inserts, infusions, kits, ointments, lotions, liniments, creams, gels, sprays, drops, aerosols, or combinations thereof. They may be sterilized or mixed with pharmaceutically acceptable carriers or excipients as needed, many of which are known to those skilled in the art.

[0102] Ointments, creams, and gels can be formulated, for example, with aqueous or oily bases to which suitable thickeners and / or gelling agents and / or solvents are added. Thus, such bases may include, for example, water and / or oil, such as liquid paraffin or vegetable oil, such as peanut oil or castor oil, or solvents, such as polyethylene glycol. Thickeners and gelling agents that may be used depending on the properties of the base include soft paraffin, aluminum stearate, cetostearyl alcohol, polyethylene glycol, wool fat, beeswax, carboxypolymethylene and cellulose derivatives, and / or glyceryl monostearate and / or nonionic emulsifiers.

[0103] Lotions can be formulated with an aqueous or oily base and generally also contain one or more emulsifiers, stabilizers, dispersants, suspending agents, or thickeners.

[0104] The spray composition may be formulated, for example, as an aqueous solution or suspension, or as an aerosol delivered from a pressurized pack, such as a metered-dose inhaler, using a suitable liquefied propellant. An aerosol composition suitable for inhalation may be either a suspension or a solution. The aerosol composition may optionally contain additional formulation excipients well known in the art, such as a surfactant, e.g., oleic acid or lecithin, and a co-solvent, e.g., ethanol. Preferably, the pharmaceutical composition is in the form of eye drops.

[0105] Preferably, the method involves administering the pharmaceutical composition to the target eye via intravitreous, subretinal, subconjunctival, periocular, posterior, anterior chamber, sub-Tenon's capsule, near the posterior sclera, or suprachoroidal injection. More preferably, the method involves administering the pharmaceutical composition to the target eye via intravitreous or subretinal injection.

[0106] In one embodiment of this disclosure, the method is for delivering a drug to layers of the retina of the eye. The MSN modulates the distribution of particles / drugs in layers of the retina, including, but not limited to, the internal limiting membrane, nerve fiber layer, ganglion cell layer, medial reticular layer, medial nuclear layer, lateral reticular layer, lateral nuclear layer, external limiting membrane, photoreceptor layer, or retinal pigment epithelium.

[0107] In one embodiment of this disclosure, it is demonstrated that smaller MSNs can efficiently penetrate mouse retinal cells in vivo, and their distribution and retention time within the retina can be controlled by particle size and surface properties. Thus, MSNs can be designed to deliver drugs to disease lesions such as those in AMD and retinal degeneration where the lesions are located in the deep layers of the retina (PR, RPE), and those in LHON and X-linked juvenile retinopathy (XLRS) where the lesions are located in the middle and upper layers of the retina.

[0108] MSNs are particularly well-suited to all kinds of modifications to adjust their porous structure, particle size, surface properties, and degree of pegylation, resulting in nanoparticles that can penetrate deep into the posterior segment of the eye. MSNs provide a simple nano-formulation for intraocular drug delivery that can enhance solubility, deliver various drugs with diverse physicochemical properties across the ocular barrier, and enhance therapeutic effects. Drug-loaded nanoparticles exhibit high initial drug concentrations and good dispersion in aqueous solutions without aggregation, especially for drugs with poor water solubility, and the route of administration is ophthalmic instillation or intravitreal injection. MSNs are composed of amorphous silica, which is known to be biocompatible and biodegradable. Preliminary ocular toxicity studies in rats did not show significant acute irritation / corrosion or ocular toxicity to eye tissue.

[0109] In one embodiment of the present disclosure, the eye disease is associated with abnormal reactive oxygen species levels, abnormal apoptosis, mitochondrial dysfunction, inflammation, abnormal protein levels, or protein misfolding / aggregation / dysfunction or complete loss of function.

[0110] In one embodiment of this disclosure, the eye disease is Leber's hereditary optic neuropathy or X-linked juvenile retinopathy.

[0111] In one embodiment of the present disclosure, eye diseases associated with abnormal reactive oxygen species levels are selected from the group consisting of Leber's hereditary optic neuropathy, age-related macular degeneration (AMD), cataracts, diabetic retinopathy (DR), glaucoma, dry eye, uveitis, and retinitis pigmentosa.

[0112] In one embodiment of the present disclosure, ocular diseases associated with abnormal neovascularization are selected from the group consisting of age-related macular degeneration (AMD), diabetic retinopathy, retinal artery or vein occlusion, retinopathy of prematurity (ROP), neovascular glaucoma, and corneal neovascularization secondary to infectious or inflammatory processes.

[0113] In one embodiment of the present disclosure, the treatment of an eye disease is performed by reducing the level of reactive oxygen species.

[0114] Mitochondria are the primary site of reactive oxygen species (ROS) production for most eukaryotic cells. While not wishing to be limited by theory, the applicant believes that ROS are produced as natural byproducts of the normal metabolism of oxygen in oxidative phosphorylation (OXPHOS), which plays a crucial role in cellular signaling and homeostasis. ROS include peroxides, superoxide, hydroxyl radicals, and singlet oxygen. Their levels are also increased by environmental stresses (e.g., UV or heat exposure), pollutants, tobacco, smoke, drugs, xenobiotics, and radiation, which are collectively characterized as oxidative stress. Oxidative stress often leads to damage to proteins, lipids, and DNA, and in the case of LHON, it causes optic neuropathy due to RGC death.

[0115] In one embodiment of the present disclosure, ocular diseases associated with abnormal neovascularization are selected from the group consisting of age-related macular degeneration (AMD), diabetic retinopathy, retinal artery or vein occlusion, retinopathy of prematurity (ROP), neovascular glaucoma, and corneal neovascularization secondary to infectious or inflammatory processes.

[0116] Age-related macular degeneration (AMD) is a leading cause of irreversible blindness in adults over 50, sometimes resulting in blurred or lost central vision. The global prevalence of AMD is approximately 8.69% in adults aged 45-85, affecting about 11 million people in the United States and about 170 million worldwide. AMD is classified into two types: (I) Dry AMD (without choroidal neovascularization): Patients may have yellow deposits called drusen in the macula. A few small drusen may not cause changes in vision. However, as they grow larger and increase in number, vision may become dim or distorted. As the condition worsens, the photosensitive cells in the macula thin and eventually die. In the atrophic type, patients may have a blind spot in the center of their vision. With further deterioration, central vision may be lost. (II) Wet AMD (with CNV): Blood vessels grow from beneath the macula. These vessels leak blood and fluid into the retina. Visual acuity is distorted, causing straight lines to appear wavy. Patients may also experience blind spots or loss of central vision. These blood vessels and their bleeding eventually form scars, leading to permanent loss of central vision. There is no medical or surgical treatment for dry AMD. Wet AMD can be treated with VEGF inhibitors (ranibizumab, aflibercept, and brolucizumab) and laser coagulation therapy, but unfortunately, there is no cure. However, treatment can slow disease progression and prevent patients from experiencing severe vision loss.

[0117] Leber's hereditary optic neuropathy (LHON) is the most common hereditary mitochondrial disorder, typically affecting young men (male-to-female ratio of approximately 9:1). Patients diagnosed with LHON may initially be asymptomatic or experience mild central visual field blurring in one eye, but symptoms can progress from mild unilateral vision loss to severe bilateral vision loss. Once vision loss begins in one eye, the other eye is usually affected within weeks to months, and bilateral vision deteriorates over time, with significant loss of clarity and color vision.

[0118] The prevalence of LHON is approximately 1 in 50,000 people worldwide, with about 10,000 cases in the United States, and it can lead to legal blindness. There is no cure for LHON, and supportive care options are limited. The use of antioxidant supplements (idebenone [orphan drug], vitamins B12 and C, coenzyme Q10, brimonidine, and lutein) to help reduce neurotoxic stress caused by reactive oxygen species has shown minimal benefit but may be recommended, and gene therapy trials are currently underway.

[0119] In one embodiment of the present disclosure, the ocular diseases associated with abnormal apoptosis are selected from the group consisting of Leber's hereditary optic neuropathy, glaucoma, retinitis pigmentosa, cataract formation, retinoblastoma, retinal ischemia, and diabetic retinopathy.

[0120] In one embodiment of this disclosure, the treatment of an eye disease is achieved by reducing apoptosis.

[0121] In one embodiment of the present disclosure, ocular diseases associated with mitochondrial dysfunction are selected from the group consisting of Leber's hereditary optic neuropathy, age-related macular degeneration, diabetic retinopathy, glaucoma, Kearns-Sayre syndrome (KSS), and optic atrophy dominant (DOA).

[0122] In one embodiment of this disclosure, the treatment of an eye disease is achieved by treating mitochondrial dysfunction.

[0123] mtDNA point mutations are strictly maternally inherited. Genetically, over 90% of LHON cases are caused by three mtDNA point mutations: m.3460G>A, m.11778G>A, and m.14484T>C, all of which are located in different NADH dehydrogenase (ND) subunits of complex I in the mitochondrial respiratory chain. Of the three, the m.11778G>A mtDNA mutation in the MT-ND4 gene is the most common cause of LHON (60%). Unlike other mitochondrial diseases, whose phenotypes are often heteroplasmic, most LHON patients carry mtDNA pathogenic mutations in a homoplasmic manner (100% of the mtDNA molecule is mutated). Mitochondrial dysfunction resulting from impaired function of ND complex I led to retinal ganglion cell (RGC) death. While not wanting to be limited by theory, the applicant believes that the loss of RGCs in LHON is due to the release of cytochrome c into the cytosol and Fas-induced apoptosis. This may also be related to caspase-independent apoptosis driven by energetic failure. Mitochondrial dysfunction is associated with RGC apoptosis, ultimately leading to atrophy patterns.

[0124] In one embodiment of the present disclosure, the ocular diseases associated with inflammation are selected from the group consisting of uveitis, orbital inflammatory disease, scleritis, episcleritis, iritis, sarcoidosis, Fuchs heterochromia iridocyclitis, bullous pemphigoid, ocular toxoplasmosis and ocular graft-versus-host disease, and dry eye.

[0125] In one embodiment of the present disclosure, the eye disease is associated with abnormal protein levels or protein misfolding / aggregation / loss of function or complete loss and is selected from the group consisting of cataract, age-related macular degeneration, retinitis pigmentosa (RP), X-linked juvenile retinopathy (XLRS), and Stargardt disease.

[0126] In one embodiment of this disclosure, treatment of an eye disease is performed by treating the tissue of the eye.

[0127] In one embodiment of the present disclosure, the tissues of the eye include the retina, choroid, sclera, macula, fovea, optic nerve, vitreous fluid, iris, cornea, pupil, lens, zonular fibers, or ciliary muscle.

[0128] In one embodiment of this disclosure, the treatment of an eye disease is performed by treating the cells of the eye.

[0129] In one embodiment of the present disclosure, the cells of the eye are Müller cells, photoreceptors, bipolar cells, ganglion cells, horizontal cells, or amacrine cells.

[0130] In one embodiment of this disclosure, the treatment of an eye disease is performed by treating nerve cells.

[0131] In one embodiment of the present disclosure, the nerve cell is a retinal nerve cell photoreceptor, bipolar cell, ganglion cell, horizontal cell, or amacrine cell.

[0132] The following embodiments are provided to assist those skilled in the art in carrying out the present disclosure. [Examples]

[0133] Materials, methods, and test models

[0134] Transmission electron microscope (TEM)

[0135] The appearance of silica nanoparticles was directly examined and verified using a transmission electron microscope (TEM). TEM images were taken with a Hitachi H-7100 transmission electron microscope operating at an accelerating voltage of 100 kV. Samples dispersed in ethanol or water were dropped onto a carbon-coated copper grid and dried in air for TEM observation.

[0136] Dynamic light scattering (DLS) and zeta potential

[0137] The size of silica nanoparticles in different solution environments was measured using dynamic light scattering (DLS) on a Malvern Zetasizer Nano ZS (Malvern, UK). The particle size formed (solvated) in different solutions was analyzed: H2O and PBS buffer (pH 7.4) at room temperature. The surface charge (zeta potential) of silica nanoparticles in PBS (0.01x, pH 7.4) with a particle concentration of 0.1 mg / mL was measured using the Malvern Zetasizer Nano ZS.

[0138] elemental analysis

[0139] The mass percentages of carbon, nitrogen, oxygen, and hydrogen in silica nanoparticles were measured using an elemental analyzer (elementar Vario EL cube type for NCSH, German).

[0140] Example 1

[0141] Preparation of mesoporous silica nanoparticles having various internal and external surface modifications.

[0142] The external or pore surfaces of MSNs can be easily modified individually with various functional groups. MSNs of different sizes were prepared using an ammonia-based catalytic method under high dilution and low surfactant conditions. Particle size was controlled by adjusting the ammonia concentration, TEOS addition amount, and reaction temperature. Different hydrocarbyl moieties (such as octyltriethoxysilane (C8-silane)), positively charged molecules (such as TA-silane, EDPTMS-silane), and negatively charged molecules were used for the synthesis of different internal pore surface-modified MSNs. Different positively charged molecules, oligomers, or polymers, such as TA-silane, EDPTMS-silane, or other functional silanes, were used for the synthesis of different external surface-modified MSN-PEGs. Typically, 0.2-0.4 g of surfactant was dissolved in 150-250 mL of alkaline aqueous solution (e.g., ammonium hydroxide solution (0.1-0.25 M)) in a sealed beaker at the desired temperature (45-65°C). After stirring for 10 to 30 minutes, 150 to 450 μL of silane (TEOS) and 15 to 110 μL of internal surface-modified silane (for pore internal surface modification) in 0.8 to 1.6 mL of solvent (e.g., alcohol such as ethanol) were added to the solution continuously or simultaneously, preferably with vigorous stirring. After stirring for 0.5 to 1.5 hours, 100 to 300 μL of silane (TEOS) in 0.6 to 1.3 mL of solvent (e.g., alcohol such as ethanol) was added separately. Two to four hours after the reaction, 700 to 1200 μL of PEG-silane (silane having a PEG moiety, e.g., (2-[methoxy(polyethyleneoxy)propyl]-trimethoxysilane) and 10 to 600 μL of positively charged molecules, oligomers, or polymers (e.g., TA-silane, (N-[3-(trimethoxysilyl)propyl]-N,N,N-trimethylammonium chloride)) were reacted in 2.5 to 4 mL of solvent (e.g., alcohol such as ethanol). The mixture was stirred for 0.5 to 1.5 hours, and then aged at the desired temperature (e.g., 45 to 65°C) without stirring for at least 12 hours. The solution was then sealed and placed in an oven for hydrothermal treatment at 65 to 75°C for 18 to 60 hours, or at 65 to 75°C and 85 to 95°C for 20 to 28 hours. The as-synthesized product was washed and recovered by centrifugation or cross-flow apparatus.To remove surfactants from the pores of MSN, the as-synthesized product was incubated in 40-60 mL of an acidic solvent (e.g., an alcohol such as ethanol) containing an acid (e.g., hydrochloric acid (37%)) at 55-65°C for 0.5-1.5 hours for extraction, with one or more incubations. The product was washed, recovered by centrifugation or a cross-flow system, and finally stored, preferably in ethanol of 85% or higher. MSN has various surface charges by adjusting the ratio of PEG to charge molecules present on the MSN-PEG. For example, the surface charge of C8-MSN can be negative, neutral, or positive by modifying the different ratios of PEG to TA on the surface of C8-MSN.

[0143] Example 2

[0144] TEM and DLS measurements

[0145] The MSN synthesized in Example 1 was subjected to TEM and DLS measurements. All particles had small particle sizes and exhibited good dispersibility in PBS. The results are shown in Table 1 below.

[0146] [Table 1]

[0147] Example 3

[0148] Small molecule drugs loaded onto MSN

[0149] APIs (low molecular weight) are loaded into the pores of MSNs, and the APIs can be hydrophobic or hydrophilic drugs. Encapsulation of hydrophobic and hydrophilic drugs in MSNs is important for maintaining the surface properties and permeability of MSNs. It did not significantly affect the dispersibility and hydrodynamic size in the culture medium (the medium is biologically similar to or equivalent to phosphate-buffered saline (PBS)). The small hydrodynamic size of API-loaded MSNs (API@MSN) allows for better water dispersion to maintain API@MSN mobility during the permeation process. Furthermore, given the lack of bioavailability, as only a limited volume can be injected into the eye or instilled on the ocular surface, a high initial drug concentration is required to achieve an effective level in the posterior segment. MSNs can increase the water solubility of hydrophobic drugs by up to 1 million times, and drug-loaded nanoparticles showed good dispersion in aqueous solutions without aggregation. API@MSN eye drops improve the solubility of drugs, and especially in the case of hydrophobic compounds, the drug concentration in aqueous solution (0.1-2% (mg / mL)) becomes much higher, solving the problem of drugs that are difficult to prepare in aqueous solution at high drug concentrations.

[0150] Hydrophobic drug loading in MSN with modified internal pore surface

[0151] C8-MSN particles were dispersed in 50 mL of H2O. A hydrophobic drug stock solution (drug dissolved in an organic solution, e.g., DMSO) was slowly added dropwise to the particle solution with vigorous stirring. After the solution was completely mixed, the mixture was further diluted with 50 mL of H2O to reduce the DMSO ratio. To remove trace amounts of free drug aggregates, the mixture was filtered through a 0.22 μm filter. Next, the mixture was washed with 7-10 times the amount of H2O. Finally, the product was stored in H2O.

[0152] Hydrophilic drug loading in MSNs with modified internal pore surfaces

[0153] PC-MSN or NC-MSN particles were dispersed in water, buffer, or a mixture of buffer and organic solution. A hydrophilic drug stock solution (drug dissolved in water, buffer, or organic solution) was gradually added dropwise to the particle solution with vigorous stirring, and the mixture was stirred for 15–60 minutes. To remove trace amounts of free drug not supported on the MSN, the mixture was washed with 7–10 times the amount of buffer or H2O. Finally, the product was stored in buffer or H2O.

[0154] Axitinib (AXT) loading in pore-internal surface-modified MSN

[0155] NC-MSN particles were dispersed in 0.25 mL of 50% DMSO with 10 mM acetate buffer, and then 18.8 μL of AXT stock (25 mg / mL in DMSO) was added and thoroughly mixed. After washing, the AXT-loaded particles were stored in acetate buffer.

[0156] [Table 2]

[0157] Protein drugs (antibodies) bound to or adsorbed to MSNs

[0158] The external surface of MSNs can be modified with various functional groups to modulate the protein-MSN binding approach, protein-MSN interactions, and particle properties. Protein drugs can be bound to the surface of MSNs via functional groups or linkers, or adsorbed onto the surface of MSNs via interactions between the drug and the MSN (such as electrostatic interactions, hydrogen bonds, or van der Waals forces).

[0159] Antibody-MSN properties that may be relevant to intraocular particle distribution: particle size (TEM), hydrodynamic diameter (DLS), surface charge (positive, neutral, negative), surface modification by poly(ethylene glycol) moiety and optionally functional groups, length / molecular weight of functional groups or linkers, and the number of protein drugs conjugated or adsorbed onto the MSN.

[0160] Example 4

[0161] Particle size affects intraocular distribution and pharmacokinetics (Administration route: Intravitreal injection)

[0162] Fluorescently labeled MSNs of different particle sizes (TEM sizes: 20, 30, and 50 nm) were suspended in PBS and injected into mouse eyes by intravitreous injection. Mouse eyes were harvested 1 hour and 24 hours after injection, and frozen sections were analyzed by immunochemical analysis. Nuclei were stained with DAPI. Each layer of the retina was identified through the location of nuclei, including the vitreous humor, GCL, IPL, INL, OPL, ONL, PR, and RPE. The choroid and sclera surrounding the retina may also be located. (GCL - ganglion cell layer, IPL - inner plexiform layer, INL - inner nuclear layer, OPL - outer plexiform layer, ONL - outer nuclear layer, PR - photoreceptor, RPE - retinal pigment epithelium). The fluorescence signal of the MSNs was observed to evaluate the distribution of MSNs in the posterior segment. 1 hour after injection, 20 nm MSNs rapidly passed through the retina and remained in the RPE, choroid, and sclera. 30 nm MSNs were observed in all layers of the retina, choroid, and sclera, and 50 nm MSNs were observed in all layers of the retina, but not in the choroid and sclera. One day after injection, most of the signals from 20 nm MSNs were clear, and most of the 30 nm MSN particles distributed in the PR and RPE layers of the retina, choroid, and sclera were 50 nm MSN particles distributed in all layers of the retina, choroid, and sclera (Figure 2). The results revealed that MSNs exhibit effective retinal penetration, that their distribution can be modulated by particle size, that smaller-sized MSNs have higher penetration capacity, and that larger sizes can be retained in longer retinal layers, and therefore, the distribution and half-life of MSNs in the retina can be modulated through particle size. The effect of MSN particle size on penetration capacity has also been studied in a rat model, and the results were similar to those in the mouse study.

[0163] Particle size and charge affect intraocular distribution and kinetics (Route of administration: Ophthalmic solution).

[0164] Fluorescently labeled MSNs of different particle sizes (TEM sizes: 20 and 30 nm, respectively) or different surface charges (negative, neutral, and positive) were suspended in PBS and dropped onto the surface of mouse eyes via eye drops. At each time point after administration (0.5, 1, 4, and 24 hours), mouse eyes were collected and frozen sections were immunochemically analyzed. Nuclei were stained with DAPI. Each layer of the retina was identified via the location of the nuclei, and the fluorescence signal of MSNs was observed to assess the distribution of MSNs in the posterior segment of the eye. Clear signals of MSNs were observed in the PR and RPE layers of the retina, choroid, and sclera up to 4 hours after administration. Most MSN particles were removed from the eye 24 hours after administration, and only a small amount of MSNs were observed at the edges of the RPE layer (Figure 3). Furthermore, small-sized MSNs with different surface charges (negative, neutral, and positive, respectively) can still reach the retina, choroid, and sclera through eye drops, with MSNs having a neutral surface charge exhibiting longer retention times. The results revealed that MSNs can effectively reach the posterior segment of the eye via the periorbital pathway and be retained for several hours.

[0165] Example 5

[0166] Intraocular pharmacokinetics of axitinib @MSN after eye instillation

[0167] To evaluate the drug delivery efficiency of MSN eye drops, axitinib-loaded MSN (AXT@MSN) was suspended in PBS and instilled as one drop (10 μL / drop) into the surface of rat eyes. Eyes were collected at 0.5, 1, 4, 8, and 24 hours, and the aqueous humor, cornea, lens, vitreous humor, retina, and sclera were separated and analyzed. The tissues were weighed, homogenized with 80% ACN using a ZrO2 bead homogenizer, and a 50% MeOH / 50% ACN / 0.3% HF (v / v) solution was used for AXT extraction. The extract was centrifuged, the supernatant was collected, and dried under a gentle stream of nitrogen. The dried supernatant was redissolved in a solution (80% DMSO / 10% acetonitrile / 10% H2O), centrifuged, and the supernatant was collected. The supernatant was prepared in a solution (35.8% DMSO / 2.1% acetonitrile / 62.1% H2O) for quantitative analysis by LC-MS / MS. The results showed that AXT was predominantly distributed in the cornea and sclera, clearly detectable in the vitreous humor and retina 0.5 hours after administration, and AXT concentrations in different parts of the eye decreased over time. AXT@MSN can deliver AXT to the posterior segments of the eye (retina, choroid, and sclera), and AXT can be retained in the retina for up to 8 hours (Figure 4). Furthermore, a comparison of intraocular AXT concentrations between AXT alone (intravitreal injection (IVT) administration) and AXT@MSN (eye drops) was evaluated. AXT is poorly soluble in water and cannot be instilled alone. AXT was dissolved in an organic solvent and diluted with PBS to the maximum concentration that did not show aggregation in solution. AXT concentrations in different parts of the eye were detected 1 and 4 hours after administration. As a result, it was found that AXT concentrations in the posterior segment (retina, choroid, and sciatic nerve) treated with AXT@MSN via eye drops were higher than in the AXT-alone (IVT) treatment group (Figure 5). This means that MSN eye drops can deliver the drug to the posterior segment, offering a more route of administration option than intravitreous injection.

[0168] Efficacy of axitinib @MSN eye drops in a laser-induced mouse model of wet AMD syndrome

[0169] Example 6

[0170] The inhibitory effect of AXT@MSN on neovascularization was evaluated using a laser-induced mouse model of wet AMD syndrome. Treatment was initiated 3 days after laser induction. AXT alone or AXT-loaded MSN (AXT@MSN) was administered intraocularly once a week by suspension in PBS, or as eye drops twice daily for 5 days a week. Fundus images were obtained every 2-3 days by optical coherence tomography (OCT), and fluorescein angiography was used to detect leakage from neovascularization by injecting fluorescence (Figure 6). Choroidal neovascularization (CNV) is new blood vessels that grow from the choroid beneath the RPE layer of the retina and involve vascular leakage. The area of ​​dye leakage from CNV lesions can be used to assess the level of neovascularization. The area of ​​dye leakage from CNV lesions was significantly reduced in the AXT@MSN (eye drops) and AXT alone (intravitreal injection) groups compared to the control group, and the leakage area decreased over time. The results revealed that AXT in MSN nanoformulations can be delivered to the posterior segment of the eye via eye drops, achieving an effective dose to inhibit neovascularization. MSN loaded with the therapeutic agent can be used in the treatment of wet AMD via eye drops.

[0171] Example 7

[0172] MSN ocular toxicity

[0173] The ocular toxicity of MSN was evaluated in mice and rats. MSNs were injected into mouse eyes via intravitreous injection. Morphological changes in mice were observed (OCT and fundus imaging) 1 hour, 1 day, and 3 days after nanoparticle injection, and retinal structures were examined through frozen tissue sections at different time points. No acute eye irritation / corrosion or retinal damage was observed in eyes treated with MSN. The ocular toxicity of MSN eye drops was evaluated in rats. MSN was applied to the surface of rat eyes four times at 2-hour intervals. Eye irritation / corrosion was assessed using the Draize eye irritation test and the modified OECD 405 guidelines, and eyes were collected for histopathological examination 1 hour after the final dose. No acute eye irritation / corrosion was observed, and no significant changes were found in the eye tissue of eyes treated with MSN. The results demonstrate that MSN is biocompatible for application to the eye.

[0174] In summary, small-sized MSNs with specific pore internal and external surface modifications have the ability to carry a variety of active ingredients, deliver drugs across the ocular barrier, and provide an alternative route of administration to intravitreal injection. MSNs offer an attractive technology for expanding the formulation toolbox to ocular delivery and provide a method for delivering drugs to the posterior segment of the eye, particularly via eye drops.

[0175] While this disclosure is described in conjunction with the specific embodiments described above, many alternatives and modifications and variations thereof will be apparent to those skilled in the art. All such alternatives, modifications and variations are deemed to fall within the scope of this disclosure.

Claims

1. A pharmaceutical composition for use in a method of delivering a drug to the posterior segment of the eye, comprising a drug and mesoporous silica nanoparticles, wherein the drug is loaded onto mesoporous silica nanoparticles, the mean hydrodynamic diameter of the mesoporous silica nanoparticles measured in phosphate-buffered saline (PBS) by dynamic light scattering, or the mean hydrodynamic diameter of the drug-loaded mesoporous silica nanoparticles, is less than 60 nm, and the method comprises administering the pharmaceutical composition to the eye, wherein the posterior segment of the eye comprises the vitreous humor, ganglion cell layer (GCL), inner plexiform layer (IPL), inner nucleus layer (INL), outer plexiform layer (OPL), outer nucleus layer (ONL), layers of the retina, choroid surrounding the retina, or sclera surrounding the retina.

2. The pharmaceutical composition according to claim 1, wherein the layers of the retina include an internal limiting membrane, a nerve fiber layer, a ganglion cell layer, an internal plexiform layer, an internal nuclear layer, an external plexiform layer, an external nuclear layer, an external limiting membrane, a photoreceptor (PR) layer, or retinal pigment epithelium (RPE).

3. The pharmaceutical composition according to claim 1, wherein the drug is a small molecule drug or biomolecule selected from polypeptides, antibodies, antibody fragments, fusion proteins, ligands, biomolecule-binding proteins, functional protein fragments, enzymes, or nucleotides.

4. The pharmaceutical composition according to claim 1, wherein the drug is difluprednate, loteprednol, dexamethasone, dexamethasone sodium phosphate, fluorocinolone acetonide, fluorometholone, triamcinolone, triamcinolone acetonide, rimexolone, prednisolone, medrysone, verteporfin, bevacizumab, ranibizumab, pegaptanib, aflibercept, brolucizumab, falisimab, axitinib, idebenone, azathioprine, methotrexate, mycophenolate mofetil, cyclosporine, tacrolimus, sirolimus, cyclophosphamide, chlorambucil, infliximab, adalimumab, etanercept, or brimonidine.

5. The pharmaceutical composition according to claim 1, wherein the drug is loaded into the pores of the mesoporous silica nanoparticles.

6. The pharmaceutical composition according to claim 1, wherein the method includes administering the pharmaceutical composition by local administration, intravitreous, subretinal, subconjunctival, periocular, posterior, anterior chamber, sub-Tenon's capsule, near the posterior sclera, or suprachoroidal injection.

7. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is in the form of eye drops.

8. The pharmaceutical composition according to claim 1, for delivering the drug through the cornea, corneal epithelium, Bowman's layer, interstitium, Descemet's membrane, corneal endothelium, conjunctiva, blood-aqueous barrier, blood-retinal barrier, retina, retinal blood vessels, or retinal pigment epithelium, or for delivering the drug to the retina, choroid, or sclera layers of the eye.

9. The pharmaceutical composition according to claim 5, wherein the average particle size of mesoporous silica nanoparticles measured by a transmission electron microscope is less than 50 nm.

10. A pharmaceutical composition according to claim 1 for treating eye diseases.

11. The pharmaceutical composition according to claim 8, wherein the eye disease is a posterior segment-related disease.

12. The pharmaceutical composition according to claim 9 for treating the tissues of the retina, choroid, sclera, macula, fovea, optic nerve, vitreous humor, iris, cornea, pupil, lens, zonular fibers, or ciliary muscle.

13. The pharmaceutical composition according to claim 9 for treating Muller cells, photoreceptors, bipolar cells, ganglion cells, horizontal cells, or amacrine cells.

14. The aforementioned eye diseases include age-related macular degeneration (AMD), Leber's hereditary optic neuropathy, glaucoma, X-linked juvenile retinolysis (XLRS), diabetic retinopathy, diabetic macular edema, retinal artery or vein occlusion, uveitis, endophthalmitis, myopic foveal schizophrenia, macular edema, and enhanced blue cone syndrome. The pharmaceutical composition according to claim 9, which is a combination of: syndrome, inflammation after cataract surgery (Irvine-Gass syndrome), retinal detachment, cystic macular edema, retinal laceration, retinal injury, cataract, dry eye, retinitis pigmentosa, retinoblastoma, retinal ischemia, Kearns-Sayre syndrome (KSS), optic atrophy dominant (DOA), orbital inflammatory disease, scleritis, episcleritis, iritis, sarcoidosis, Fuchs heterochromia iridocyclitis, bullous pemphigoid, ocular toxoplasmosis, ocular graft-versus-host disease, Stargardt disease, retinopathy of prematurity (ROP), neovascular glaucoma, and corneal neovascularization due to infection or inflammatory disease.

15. The pharmaceutical composition according to claim 14, wherein the eye disease is wet-type AMD.

16. The pharmaceutical composition according to claim 1, wherein the mesoporous silica nanoparticles have their inner pore surfaces modified with positively charged or negatively charged molecules, and the drug is hydrophilic and / or positively or negatively charged.

17. The pharmaceutical composition according to claim 6, wherein the mesoporous silica nanoparticles have their inner pore surfaces modified with positively charged or negatively charged molecules, and the drug is hydrophilic and / or positively or negatively charged.

18. The pharmaceutical composition according to any one of claims 1 to 17, wherein the average hydrodynamic diameter of mesoporous silica nanoparticles measured in phosphate-buffered saline (PBS) by dynamic light scattering or the average hydrodynamic diameter of drug-loaded mesoporous silica nanoparticles is less than 50 nm.

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