Sustained release silica hydrogel composites for treatment of ophthalmic conditions and methods of use thereof

Abstract

The present disclosure relates to a sustained release silica hydrogel composite comprising an anti-complement agent and methods of using the composite to treat ophthalmic conditions. The anticomplement agent may be an anti-C5 agent comprising a C5 specific aptamer.

Description

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 357,631, filed on June 30, 2022, which is incorporated herein by reference in its entirety for all purposes. References to Electronic Sequence Listings

[0002] The contents of the electronic sequence listing (OPHT_038_01WO_SeqList_ST26.xml; size: 1,232,057 bytes; creation date: June 27, 2023) are hereby incorporated by reference in their entirety. Technical Field

[0003] The present disclosure relates to a sustained release silica hydrogel composite comprising an anti-complementary agent and methods of using the composite to treat ophthalmic conditions. Background Art

[0004] Age-Related Macular Degeneration (“AMD”) is a disease characterized by progressive degenerative abnormalities in the macula (the area in the central part of the retina). AMD is a complex, gradually progressive eye disorder that can cause distortion and / or blind spots (scotomas), changes in dark adaptation (diagnostic of the health of rods), changes in color interpretation (diagnostic of the health of cones), decreased visual acuity, or irreversible blindness.

[0005] AMD is typically a disease of the elderly and is the leading cause of blindness in individuals >50 years of age in developed countries. In the United States, it is estimated that approximately 6% of individuals aged 65-74 years and 20% of individuals aged 75 years and older have AMD. Due to increasing life expectancy in both developed and developing countries, the elderly population is expected to grow at the fastest rate in the coming decades. In the absence of adequate prevention or treatment, the number of cases of AMD with vision loss is expected to grow in tandem with the aging population.

[0006] Non-exudative AMD is the non-neovascular ("dry") form of the disease ("dry AMD"). Dry AMD accounts for approximately 90% of all AMD cases. Dry AMD is characterized by macular degeneration and, as it continues to progress over many years, may eventually lead to central retinal atrophy associated with central vision loss. Dry AMD is an important cause of moderate and severe central vision loss and in most patients it is bilateral. In dry AMD, the retinal pigment epithelium (RPE) in the macula thins, along with other age-related changes in adjacent retinal tissue layers.

[0007] Once neovascularization occurs in non-exudative AMD, the disease is referred to as exudative AMD, the neovascular ("wet") form of the disease ("wet AMD"), which is still present and may progress in the patient. Wet AMD may cause sudden, often severe, loss of central vision.

[0008] Recent advances in imaging technology, particularly optical coherence tomography ("OCT"), and more specifically spectral domain optical coherence tomography ("SD-OCT"), have enabled the reproducible and reliable measurement of morphological changes in the eyes of subjects exhibiting AMD disease states and monitoring disease progression over time. Such disease states include incomplete retinal pigment epithelium ("RPE") and outer retinal atrophy ("iRORA"), risk factors for progression to iRORA, complete RPE and outer retinal atrophy ("cRORA"), neonatal geographic atrophy ("nGA"), and / or geographic atrophy ("GA"). See, e.g., Guymer et al., “Incomplete Retinal Pigment Epithelial and Outer Retinal Atrophy in Age-Related Macular Degeneration: Classification of Atrophy Meeting Report 4,” Ophthalmology 2020;127:394-409; and Wu et al., “Optical Coherence Tomography-Defined Changes Preceding the Development of Drusen-Associated Atrophy in Age-Related Macular Degeneration,” Ophthalmology 2014;121:2415-2422.

[0009] Administration of drugs to treat ophthalmic conditions, such as those described above, has been achieved via intravitreal administration, sometimes requiring monthly administration. There is a need for sustained-release ophthalmic dosage forms including anti-complement agents that can be administered at longer intervals, which can result in greater patient comfort, satisfaction, and / or compliance. Such compositions must also meet and exhibit characteristics sufficient for administration via the ophthalmic route. Summary of the invention

[0010] Provided herein is a sustained-release silica hydrogel composite material, the composite material comprising: a silica content in the range of 5-35% and an anti-C5 agent in the range of 1-40%, wherein the anti-C5 agent comprises a C5-specific aptamer, wherein the aptamer comprises a nucleotide sequence of fCmGfCfCGfCmGmGfUfCfUfCmAmGmGfCGfCfUmGmAmGfUfCfUmGmAmGfUfUfUAfCfCfUmGfCmG-3T (SEQ ID NO: 1), wherein fC and fU=2' fluoro nucleotides, mG and mA=2'-OMe nucleotides, all other nucleotides are 2'-OH, and 3T represents inverted deoxythymidine.

[0011] In some embodiments, the composite material comprises a silica content in the range of 5-35% and an anti-C5 agent in the range of 5-40%. In some embodiments, the composite material comprises a silica content in the range of 5-30% and an anti-C5 agent in the range of 1-5%, 5-10%, 10-15%, 15-20%, 20-25% or 25-30%. In some embodiments, the composite material comprises a silica content in the range of 25-30% and an anti-C5 agent in the range of 5-10%. In some embodiments, the composite material comprises a silica content of about 27.4% and an anti-C5 agent of about 8%.

[0012] In some embodiments, the composite material comprises silica microparticles dispersed in a silica sol hydrogel.

[0013] In some embodiments, the ratio of the silica dissolution rate to the anti-C5 agent dissolution rate of the composite material is 2:1, 1:1 or 1:2.

[0014] In some embodiments of the composite materials provided herein, the anti-C5 agent is pegylated. In some embodiments of the composite materials provided herein, the anti-C5 agent is non-pegylated.

[0015] Provided herein is a syringe comprising the sustained-release silica hydrogel composite material disclosed herein.

[0016] Provided herein is a method for improving, treating, or reducing the severity of a symptom of an ophthalmic condition in a subject in need thereof, the method comprising administering to the subject a sustained release silica hydrogel composite disclosed herein.

[0017] Provided herein is a method for preventing or delaying progression of an ophthalmic condition in a subject in need thereof, the method comprising administering to the subject a sustained release silica hydrogel composite disclosed herein.

[0018] Provided herein is a method for treating or reducing the severity of an ophthalmic condition in a subject in need thereof, the method comprising administering to the subject a sustained release silica hydrogel composite disclosed herein.

[0019] In some embodiments of the methods provided herein, the ophthalmic condition is incomplete retinal pigment epithelium (RPE) and outer retinal atrophy, complete RPE and outer retinal atrophy, neonatal geographic atrophy, geographic atrophy, or wet age-related macular degeneration.

[0020] In some embodiments of the methods provided herein, the sustained release silica hydrogel composite is administered to the subject by subconjunctival, retrobulbar, intracameral, sub-Tenon's fascia, subretinal, suprachoroidal or intravitreal injection. In some embodiments of the methods provided herein, the sustained release silica hydrogel composite is administered to the subject by intravitreal injection. In some embodiments of the methods provided herein, the sustained release silica hydrogel composite is administered to the subject by suprachoroidal injection.

[0021] In some embodiments of the methods provided herein, the sustained release silica hydrogel composite is administered to the subject at a dose of about 0.3 mg / eye to about 5 mg / eye. In some embodiments of the methods provided herein, the sustained release silica hydrogel composite is administered to the subject at a dose of about 2 mg / eye.

[0022] In some embodiments of the methods provided herein, the sustained-release silica hydrogel composite is administered to the subject at a frequency of at least about three months between doses. In some embodiments of the methods provided herein, the sustained-release silica hydrogel composite is administered to the subject at a frequency of about four months, about five months, or about six months between doses.

[0023] Provided herein is a formulation comprising a population of microparticles comprising: a silica content in the range of 10-70% and an anti-C5 agent in the range of 5-50%, wherein the anti-C5 agent comprises a C5-specific aptamer, wherein the aptamer comprises a nucleotide sequence of fCmGfCfCGfCmGmGfUfCfUfCmAmGmGfCGfCfUmGmAmGfUfCfUmGmAmGfUfUfUAfCfCfUmGfCmG-3T (SEQ ID NO: 1), wherein fC and fU=2' fluoro nucleotides, mG and mA=2'-OMe nucleotides, all other nucleotides are 2'-OH, and 3T represents inverted deoxythymidine.

[0024] In some embodiments, the microparticles contain a silica content in the range of 60-75% and an anti-C5 agent in the range of 2.5-5.0%, 5-10%, 10-15%, 15-20%, 20-25%, or 25-30%. In some embodiments, the microparticles contain a silica content in the range of 60-72% and an anti-C5 agent in the range of 2.5-25%. In some embodiments, the microparticles contain a silica content in the range of 64-68% and an anti-C5 agent in the range of 15-19%.

[0025] In some embodiments of the formulations provided herein, the anti-C5 agent is pegylated. In some embodiments of the formulations provided herein, the anti-C5 agent is non-pegylated. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1A Particle size distribution of an exemplary microparticle formulation is shown.

[0027] Figure 1B The D10, D50 and D90 values ​​for formulations #01-#03 are shown.

[0028] Figure 2A and Figure 2B In vitro dissolution data for Formulations #04-#06 are shown.

[0029] Figure 3A and Figure 3B In vitro dissolution data for formulations #07-#09 are shown. These experiments analyzed the effect of API (active pharmaceutical ingredient) loading.

[0030] Figure 4A and Figure 4B In vitro dissolution data are shown for formulations #02-replicate, #10 and #11. These experiments analyzed the effect of batch size.

[0031] Figure 5A The pH measurements for the microparticle and hydrogel formulations in Tables 1 and 2 are shown.

[0032] Figure 5B The D10, D50 and D90 values ​​of the microparticle formulations in Table 1 are shown.

[0033] Figure 5C The particle size distribution of the microparticle formulations in Table 1 is shown.

[0034] Fig. 6A SEM (scanning electron microscope) images of the microparticle formulations in Table 1 are shown at the first image magnification.

[0035] Figure 6B SEM images of the microparticle formulations in Table 1 at a second image magnification are shown.

[0036] Figure 7 The in vitro release of API and silica matrix degradation from microparticles #01-#03 in Table 3 are shown.

[0037] Fig. 8A The silica matrix degradation of the microparticles and hydrogel formulations in Tables 1 and 2 is shown.

[0038] Figure 8B The API release from the microparticle and hydrogel formulations in Tables 1 and 2 is shown.

[0039] Figure 8C A graph depicting the relationship between silica matrix degradation and API dissolution is shown.

[0040] Fig. 9 A graph depicting exposure of Dutch Band rabbit eye tissues to PK formulations is shown. Solid lines from top to bottom are: vitreous SR depot (1 mg); retinal SR depot (1 mg); RPE / choroidal SR depot (1 mg). "IVT" = intravitreal. "SR" = sustained release.

[0041] Figures 10A-10D Data from PK formulation stability analysis at 2-8°C after 8 weeks (8W) are shown. Fig. 10A Shows silica degradation. Fig. 10B Displays the release of the API. Fig. 10C The total silica content (wt %) in the hydrogel reservoir is shown. Fig. 10D The total API content (wt %) in the hydrogel reservoir is shown.

[0042] Figures 11A-11D Data from PK formulation stability analysis at room temperature (RT) after 8 weeks (8W) are shown. Fig.11A Shows silica degradation. Fig. 11B Displays the release of the API. Fig. 11C The total silica content (wt %) in the hydrogel reservoir is shown. Fig.11D The total API content (wt %) in the hydrogel reservoir is shown.

[0043] Figures 12A-12D Aging analysis data is shown for Formulation #11. "1W" = 1 week.

[0044] Fig.13A and Fig. 13B Rheological evaluation data of the composite reservoirs are shown.

[0045] Figure 14A-Figure 14C Experimental data analyzing the dissolution profiles and particle size distribution of various formulations are shown.

[0046] Figure 15A-Figure 15CExperimental data analyzing the dissolution profiles and particle size distribution of various formulations are shown.

[0047] Figure 16A-16C Experimental data analyzing the dissolution profiles and particle size distribution of various formulations are shown.

[0048] Figure 17A-Figure 17C Experimental data analyzing the dissolution profiles and particle size distribution of various formulations are shown.

[0049] Figure 18A-18B The silica ( Fig.18A ) and API ( Fig.18B ) Experimental data of dissolution curve. DETAILED DESCRIPTION

[0050] One aspect of the present disclosure relates to sustained-release silica hydrogel composites comprising an anti-complement agent (e.g., an anti-C5 agent or an anti-C3 agent) and methods of using the composites to treat ophthalmic conditions. The sustained-release silica hydrogel composites provided herein have favorable API delivery characteristics and stability properties, and less accumulation of residual matrix in the eye over time. These composites provide the unexpected advantage of a direct correlation between silica and API dissolution. Therefore, the matrix that controls drug release does not remain in the eye for a long time after the API is dissolved. In addition, the composites provided herein have the beneficial property of shear-thinning of composite reservoir formulations, which enables administration using narrow-bore or narrow-gauge needles that are conducive to intravitreal drug delivery. Anticomplement agents

[0051] Provided herein are sustained release silica hydrogel composites comprising an anti-complement agent. The term "anti-complement agent" refers to an agent that partially or completely reduces or inhibits the activity or production of a complement protein or variant thereof.

[0052] In some embodiments, the anti-complement agent is an anti-C5 agent. The term "anti-C5 agent" refers to an agent that partially or completely reduces or inhibits the activity or production of the C5 complement protein or its variants. The anti-C5 agent can reduce or inhibit the conversion of the C5 complement protein into its component polypeptides C5a and C5b. The anti-C5 agent can also reduce or inhibit the activity or production of C5a and / or C5b.

[0053] In some embodiments, the anti-C5 agent is an anti-C5 aptamer. Aptamers are nucleic acid molecules that have specific binding affinity for a molecule through interactions other than classical Watson-Crick base pairing. Aptamers, such as peptides produced by phage display or monoclonal antibodies ("mAbs"), are able to specifically bind to a selected target and modulate the activity of the target, for example, by binding to the aptamer, the ability of its target to function can be blocked. Aptamers can be non-PEGylated or PEGylated. In some embodiments, aptamers can include one or more 2' sugar modifications, such as 2'-O-alkyl (e.g., 2'-O-methyl or 2'-O-methoxyethyl) or 2'-fluoro modifications.

[0054] In some embodiments, an anti-C5 agent comprises a C5-specific aptamer, wherein the aptamer comprises a nucleotide sequence of fCmGfCfCGfCmGmGfUfCfUfCmAmGmGfCGfCfUmGmAmGfUfCfUmGmAmGfUfUfUAfCfCfUmGfCmG-3T (SEQ ID NO: 1), wherein fC and fU=2' fluoro nucleotides, mG and mA=2'-OMe nucleotides, all other nucleotides are 2'-OH, and 3T represents inverted deoxythymidine.

[0055] In addition, exemplary C5-specific aptamers may also include aptamers disclosed in PCT Publication No. WO 2007 / 103549, which is incorporated herein by reference in its entirety. For example, exemplary C5-specific aptamers can include aptamers ARC185 (SEQ ID NO: 25), ARC186 (SEQ ID NO: 26), ARC188 (SEQ ID NO: 27), ARC189 (SEQ ID NO: 28), ARC243 (SEQ ID NO: 29), ARC244 (SEQ ID NO: 30), ARC250 (SEQ ID NO: 31), ARC296 (SEQ ID NO: 32), ARC297 (SEQ ID NO: 33), ARC330 (SEQ ID NO: 34), ARC331 (SEQ ID NO: 35), ARC332 (SEQ ID NO: 36), ARC333 (SEQ ID NO: 37), ARC334 (SEQ ID NO: 38), ARC411 (SEQ ID NO: 39), ARC412 (SEQ ID NO: 40), ARC413 (SEQ ID NO: 41), ARC414 (SEQ ID NO: 42). 42), ARC415 (SEQ ID NO: 43), ARC416 (SEQ ID NO: 44), ARC417 (SEQ ID NO: 45), ARC418 (SEQ ID NO: 46), ARC419 (SEQ ID NO: 47), ARC420 (SEQ ID NO: 48), ARC421 (SEQ ID NO: 49), ARC422 (SEQ ID NO: 50), ARC423 (SEQ ID NO: 51), ARC424 (SEQ ID NO: 52), ARC425 (SEQ ID NO: 53), ARC426 (SEQ ID NO: 54), ARC427 (SEQ ID NO: 55), ARC428 (SEQ ID NO: 56), ARC429 (SEQ ID NO: 57), ARC430 (SEQ ID NO: 58), ARC431 (SEQ ID NO: 59), ARC432 (SEQ ID NO: 60), ARC433 (SEQ ID NO: 61), ARC434 (SEQ ID NO: 62), ARC435 (SEQ ID NO: 63), ARC436 (SEQ ID NO: 64), ARC437 (SEQ ID NO: 65), ARC438 (SEQ ID NO:66), ARC439 (SEQ ID NO: 67), ARC440 (SEQ ID NO: 68), ARC457 (SEQ ID NO: 69), ARC458 (SEQ ID NO: 70), ARC459 (SEQ ID NO: 71), ARC473 (SEQ ID NO: 72), ARC522 (SEQ ID NO: 73), ARC523 (SEQ ID NO: 74), ARC524 (SEQ ID NO: 75), ARC525 (SEQ ID NO: 76), ARC532 (SEQ ID NO: 77), ARC543 (SEQ ID NO: 78), ARC544 (SEQ ID NO: 79), ARC550 (SEQ ID NO: 80), ARC551 (SEQID NO: 81), ARC552 (SEQ ID NO: 82), ARC553 (SEQ ID NO: 83), ARC554 (SEQ ID NO: 84), ARC657 (SEQ ID NO: 85), ARC658 (SEQ ID NO: 86), ARC672 (SEQ ID NO: 87), ARC706 (SEQ ID NO: 88), ARC913 (SEQ ID NO: 89), ARC874 (SEQ ID NO: 90), ARC954 (SEQ ID NO: 91), ARC1537 (SEQ ID NO: 92), ARC1730 (SEQ ID NO: 93), or a pharmaceutically acceptable salt thereof.

[0056] In some embodiments, the anti-C5 agent is an aptamer having a sequence of SEQ ID NO: 94, 95, or 96.

[0057] In some embodiments, ARC186 (SEQ ID NO: 26) can comprise 21 pyrimidine residues of ARC186 with 2'-fluoro modifications. Most of the purines (14 residues) have 2'-OMe modifications, except for three 2'-OH purine residues.

[0058] In some embodiments, the anti-C5 aptamer may also contain different mixtures of 2'-fluoro and 2'-H modifications. In some embodiments, the anti-C5 aptamer is ARC330. ARC330 (SEQ ID NO: 34) contains seven 2'-H modifications, 14 pyrimidine residues with 2'-fluoro modifications, 14 purine residues with 2'-OMe modifications, and three 2'-OH purine residues.

[0059] In some embodiments, the aptamer can be pegylated, for example, conjugated to a polyethylene glycol moiety (PEG) through a linker. The PEG moiety can have a molecular weight greater than about 10 kDa, for example, a molecular weight of about 20 kDa, or about 30 kDa, or about 40 kDa, or about 50 kDa, or about 60 kDa. In some embodiments, the PEG moiety is conjugated to the 5' end of the aptamer through a linker. In some embodiments, the PEG moiety conjugated to the 5' end is a PEG moiety with a molecular weight of about 40 kDa. In some embodiments, the about 40 kDa PEG moiety is a branched PEG moiety. The branched about 40 kDa PEG moiety can be, for example, 1,3-bis(mPEG-[about 20 kDa])-propyl-2-(4'-butyramide), or 2,3-bis(mPEG-[about 20 kDa])-propyl-1-carbamoyl. In some embodiments, the aptamer can be non-pegylated.

[0060] Unless otherwise indicated or the context clearly demonstrates otherwise, the term "about" means above or within 10% of the reported value (unless the number exceeds 100% or is below 0% of the possible value). When used in conjunction with a series of values, the term "about" applies to the endpoints of the range or each value listed in the series unless otherwise indicated. As used in this application, the terms "about" and "approximately" are used as equivalents.

[0061] In some embodiments, the aptamer is a compound having the structure ARC187 Or a pharmaceutically acceptable salt thereof, wherein aptamer=fCmGfCfCGfCmGmGfUfCfUfCmAmGmGfCGfCfUmGmAmGfUfCfUmGmAmGfUfUfUAfCfCfUmGfCmG-3T (SEQ ID NO: 1), wherein fC and fU=2'-fluoro nucleotides, mG and mA=2'-OMe nucleotides, all other nucleotides are 2'-OH, and wherein 3T represents inverted deoxythymidine. In some embodiments, each 20kDa mPEG of the above structure has a molecular weight of about 20kDa.

[0062] In some embodiments, the aptamer is the compound ARC1905 having the following structure: Or a pharmaceutically acceptable salt thereof, wherein aptamer=fCmGfCfCGfCmGmGfUfCfUfCmAmGmGfCGfCfUmGmAmGfUfCfUmGmAmGfUfUfUAfCfCfUmGfCmG-3T (SEQ ID NO: 1), wherein fC and fU=2'-fluoro nucleotides, mG and mA=2'-OMe nucleotides, all other nucleotides are 2'-OH, and wherein 3T represents inverted deoxythymidine. In some embodiments, each 20kDa mPEG of the above structure has a molecular weight of about 20kDa. As shown in the figure, the above structure has a hexylamino linker.

[0063] In some embodiments, the anti-C5 agent comprises an active ingredient called avacincaptad pegol (ACP). Avacincaptad pegol comprises the aptamer ARC1905.

[0064] In some embodiments, the anti-complement agent is an anti-C3 agent. The term "anti-C3 agent" refers to an agent that partially or completely reduces or inhibits the activity or production of the C3 complement protein or its variants. Anti-C3 agents can reduce or inhibit the conversion of the C3 complement protein into its component polypeptides C3a and C3b. Anti-C5 agents can also reduce or inhibit the activity or production of C3a and / or C3b.

[0065] In some embodiments, the anti-C3 agent is an anti-C3 aptamer. In some embodiments, the anti-C3 agent comprises an active ingredient called pegcetacoplan.

[0066] Examples of pharmaceutically acceptable salts include, but are not limited to, sulfates, citrates, acetates, oxalates, chlorides, bromides, iodides, nitrates, bisulfates, phosphates, acid phosphates, isonicotinates, lactates, salicylates, acid citrates, tartrates, oleates, tannates, pantothenates, bitartrates, ascorbates, succinates, maleates, gentisinates, fumarates, gluconates, glucuronates, saccharates, formates, benzoates, glutamates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, camphorsulfonates, pamoates, phenylacetates, trifluoroacetates, acrylates, chlorobenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, Formate, methylbenzoate, o-acetoxybenzoate, naphthalene-2-benzoate, isobutyrate, phenylbutyrate, α-hydroxybutyrate, butyne-1,4-dicarboxylate, hexyne-1,4-dicarboxylate, decanoate, octanoate, cinnamate, glycolate, heptanoate, hippurate, malate, hydroxymaleate, malonate, mandelate, methanesulfonate, nicotinate, phthalate, terephthalate, propiolate, propionate, phenylpropionate, sebacate, suberate, p-bromobenzenesulfonate, chlorobenzenesulfonate, ethylsulfonate, 2-hydroxyethylsulfonate, methanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, naphthalene-1,5-sulfonate, xylenesulfonate and tartrate. The term "pharmaceutically acceptable salt" includes, but is not limited to, hydrates of compounds provided herein, and may also refer to salts of antagonists having acidic functional groups (such as, but not limited to, carboxylic acid functional groups or hydrogen phosphate functional groups) and bases provided herein. Suitable bases include, but are not limited to, hydroxides of alkali metals such as sodium, potassium and lithium; hydroxides of alkaline earth metals such as calcium and magnesium; hydroxides of other metals such as aluminum and zinc; ammonia and organic amines such as unsubstituted or hydroxy-substituted mono-, di- or tri-alkylamines, dicyclohexylamine; tributylamine; pyridine; N-methyl, N-ethylamine; diethylamine; triethylamine; mono-, di- or tri-(2-OH-lower alkylamines), such as mono-, di- or tri-(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine or tris-(hydroxymethyl)methylamine; N,N-di-lower alkyl-N-(hydroxy-lower alkyl)-amines, such as N,N-dimethyl-N-(2-hydroxyethyl)amine or tris-(2-hydroxyethyl)amine; N-methyl-D-glucamine; and amino acids such as arginine, lysine, and the like.

[0067] An anti-complement agent (e.g., an anti-C5 agent or an anti-C3 agent) can be administered as a component of a composition that also includes a pharmaceutically acceptable carrier or vehicle, such as a pharmaceutical composition. For example, an anti-C5 agent can be mixed with a suitable carrier substance and is generally present in an amount of 1-95% by weight of the total weight of the composition. In some embodiments, an anti-complement agent (e.g., an anti-C5 agent or an anti-C3 agent) is present in an amount of 1-90%, 1-85%, 1-80%, 1-75%, 1-70%, 5-95%, 10-95%, 15-95%, 20-95%, 5-90%, 10-85%, 15-80%, or 20-75% by weight of the total weight of the composition. The composition can be provided in a dosage form suitable for injection, particularly suitable for direct injection into the eye (e.g., intravitreal injection). The composition can be in the form of, for example, a suspension, an emulsion, or a solution. The composition can include silicon dioxide.

[0068] Injectable preparations include sterile aqueous or non-aqueous solutions, suspensions, emulsions or gels. In some embodiments, the injectable preparation is a sol. In some embodiments, the injectable preparation is a hydrogel. Various aqueous carriers can be used, such as water, buffered water, saline, etc. Such preparations can also contain excipients, such as preservatives, wetting agents, buffers, emulsifiers, dispersants and suspending agents.

[0069] In some embodiments, excipients of a composition comprising an anti-complement agent (e.g., an anti-C5 agent or an anti-C3 agent) include, but are not limited to, buffers, nonionic surfactants, preservatives, tonicity agents, sugars, amino acids, and pH adjusters. Suitable buffers include, but are not limited to, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium acetate, sodium borate, and other buffers containing phosphates, acetates, borates, citrates, carbonates, and / or histidine. Suitable nonionic surfactants include, but are not limited to, polyoxyethylene sorbitol fatty acid esters, such as polysorbate 20 and polysorbate 80. Suitable preservatives include, but are not limited to, benzyl alcohol, ascorbic acid / salts / esters, butylated hydroxytoluene, sulfites, and thiosulfates. Suitable tonicity agents include, but are not limited to, sodium chloride, mannitol, and sorbitol. Suitable sugars include, but are not limited to, α, α-trehalose, glucose / dextrose, sucrose, mannitol, and sorbitol. Suitable amino acids include, but are not limited to, glycine and histidine. Suitable pH adjusters include, but are not limited to, hydrochloric acid, acetic acid, and sodium hydroxide. In some embodiments, the one or more pH adjusting agents are present in an amount effective to provide a pH of about 3 to about 8, about 6 to about 8, about 6.5 to about 8, about 4 to about 7, about 5 to about 6, about 6 to about 7, about 7 to about 8, or about 7 to about 7.5. In some embodiments, the one or more pH adjusting agents are present in an amount effective to provide a pH of about 6.0 to about 6.5, about 6.5 to about 7.0, about 7.0 to about 7.5, or about 7.5 to about 8.0. In some embodiments, the one or more pH adjusting agents are present in an amount effective to provide a pH of about 6.8 to about 7.8. In some embodiments, the composition does not include a preservative. In some embodiments, the composition does not include an antimicrobial agent. In some embodiments, the composition does not include a bacteriostatic agent. Silicon dioxide

[0070] Silicon dioxide (SiO2) is a versatile material that can be obtained naturally or prepared synthetically in a variety of forms. Silica can be prepared / modified into many different structures by fumigation or wet synthesis methods, which leads to different properties in terms of textural characteristics and (surface) chemistry. For example, silica can be prepared by sol-gel methods. Sol-gel derived SiO2 and other SiO2-based materials can generally be prepared from alkoxides, alkylalkoxides, aminoalkoxides or inorganic silicates, which are hydrolyzed to form a sol containing partially hydrolyzed silica species and / or fully hydrolyzed silicic acid. Subsequent condensation reactions of Si(OH)4-containing species lead to the formation of larger silica species with an increased number of siloxane bonds. These silica species oligomerize / polymerize to form small particles, turning the reaction solution into a sol.

[0071] Silica prepared by the sol-gel method can be processed into three-dimensional structures by casting (e.g., monolithic rods), spinning (fibers), impregnation / drainage / spinning (coatings), or preparing particles of different sizes. In some embodiments, the particles are prepared by spray drying, which produces particles or spheres that are mostly micron-sized, or by allowing the particles to increase in size and number in a sol under alkaline conditions, thereby producing a colloidal silica dispersion, i.e., submicron and nanometer-sized particles in solution. The liquid in the colloidal dispersion can be evaporated, and the colloidal particle powder formed is usually washed and dried several times. Sometimes particles are also prepared by grinding, for example, the whole material to the desired size. All conventional sol-gel processing methods involve a step in which the structure is dried and / or heat-treated to a certain extent, and the amount of solution / solvent (e.g., water and alcohol) is more or less reduced. In some embodiments, silica particles are prepared by spray drying or liquid phase synthesis, by chopping spun or drawn silica fibers, by molding or casting silica monoliths, and by pulverizing molded or cast silica monoliths when desired to obtain a specified particle size.

[0072] In some embodiments, the gel can be a homogeneous mixture of at least one solid phase and one liquid phase, i.e., a colloidal dispersion, in which the solid phase (e.g., silica itself and / or partially or completely hydrolyzed silica) is the continuous phase, and the liquid (e.g., water, ethanol, and residues of silica precursors) is uniformly dispersed in the structure. The gel is viscoelastic, and the elastic properties are dominant, as shown by rheological measurements under small-angle oscillatory shear, where the storage modulus (elastic component) G' is greater than the loss modulus (viscous component) G'' (G'> ×G''). The gel does not flow at rest, but flows under shear. In some embodiments, G'>2×G'', G'>3×G'', G'>4×G'', G'>5×G'', G'>6×G'', G'>7×G'', G'>8×G'', G'>9×G'', G'>10×G'', G'>25×G'', G'>50×G'', G'>75×G'', G'>100×G'', G'>250×G'', G'>500×G'', G'>750×G'', or G'>1000×G''.

[0073] In some embodiments, the sol can be a uniform mixture of at least one liquid phase and one solid phase, i.e., a colloidal dispersion, wherein the liquid phase (e.g., water, ethanol, and residues of a silica precursor) is a continuous phase, and the solid phase (e.g., colloidal particles of silica and / or partially or completely hydrolyzed silica and / or aggregates of said particles) is uniformly dispersed in the liquid phase, characterized in that the sol has transparent fluid properties and the liquid phase is dominant. Compositions comprising an anti-complementary agent and silicon dioxide

[0074] In some embodiments, an exemplary composition for treating an ophthalmic condition may be a microparticle composition comprising a silica content in the range of 30-90% (preferred embodiments are 30-40%, 40-50%, 30-65%, 50-60%, 60-70%, 70-80% or 80-90%), an anti-C5 agent content in the range of 1-60% (preferred embodiments are 1-10%, 10-20%, 20-30%, 20-55%, 30-40%, 40-50% or 50-60%), a silica content in the range of 1-40% precursor residues (preferred embodiments are 1-5%, 5-10%, 10-15%, 15-20%, 20-25%, 25-30%, 30-35%, 35-40%, 40-45% or 45-50%). In some embodiments, the microparticle composition comprises a silica content in the range of 64-68%, an anti-C5 agent content in the range of 15-19%, and a residue of a silica precursor in the range of 14-18%. In some embodiments, the microparticle composition comprises a silica content in the range of 30-65% and an anti-C5 agent content in the range of 20-55%. In some embodiments, the anti-C5 agent comprises a C5-specific aptamer, wherein the aptamer comprises a nucleotide sequence of fCmGfCfCGfCmGmGfUfCfUfCmAmGmGfCGfCfUmGmAmGfUfCfUmGmAmGfUfUfUAfCfCfUmGfCmG-3T (SEQ ID NO: 1), wherein fC and fU=2'fluoro nucleotides, mG and mA=2'-OMe nucleotides, all other nucleotides are 2'-OH, and 3T represents inverted deoxythymidine. In some embodiments, the residue comprises one or more products from a silica precursor. In certain embodiments, the silica precursor is tetraethyl ethyl orthosilicate (TEOS) and the hydrolysis product is ethanol.

[0075] In some embodiments, the sustained release silica hydrogel composite may include a silica content in the range of 10-50% (preferred embodiments are 10-30%, 20-50%, 20-25%, 25-30%, 30-35%, 35-40%, 40-45% or 45-50%), an anti-C5 agent content in the range of 1-30% or 1-50% (preferred embodiments are 1-5%, 5-10%, 5-30%, 10-15%, 15-20%, 20-25% or 25-30%), and a water and silica content precursor residue in the range of 40-80% (preferred embodiments are 40-50%, 50-60%, 55-70%, 60-70% or 70-80%). In some embodiments, the silica composite comprises a silica content in the range of 24-34%, an anti-C5 agent content in the range of 6-9%, and water and residues of a silica content precursor in the range of 61-69%. In some embodiments, the silica composite comprises a silica content in the range of 10-30%, an anti-C5 agent content in the range of 5-30%, and water and residues of a silica content precursor in the range of 55-70%. In some embodiments, the anti-C5 agent comprises a C5-specific aptamer, wherein the aptamer comprises a nucleotide sequence of fCmGfCfCGfCmGmGfUfCfUfCmAmGmGfCGfCfUmGmAmGfUfCfUmGmAmGfUfUfUAfCfCfUmGfCmG-3T (SEQ ID NO: 1), wherein fC and fU=2' fluoro nucleotides, mG and mA=2'-OMe nucleotides, all other nucleotides are 2'-OH, and 3T represents inverted deoxythymidine. In some embodiments, the residue comprises water and one or more products from a silica precursor. In some embodiments, the silica precursor is TEOS and the hydrolysis product is ethanol. In some embodiments, the silica hydrogel composite is a silica-based microparticle containing an anti-C5 agent, which is dispersed, suspended or contained in a silica-based hydrogel.

[0076] The present invention provides a sustained-release silica hydrogel composite material, the composite material comprising: a silica content in the range of 5-35% and an anti-C5 agent in the range of 1-40%, wherein the anti-C5 agent comprises a C5-specific aptamer, wherein the aptamer comprises a nucleotide sequence of fCmGfCfCGfCmGmGfUfCfUfCmAmGmGfCGfCfUmGmAmGfUfCfUmGmAmGfUfUfUAfCfCfUmGfCmG-3T (SEQ ID NO: 1), wherein fC and fU=2' fluoro nucleotides, mG and mA=2'-OMe nucleotides, all other nucleotides are 2'-OH, and 3T represents inverted deoxythymidine.

[0077] In some embodiments, the composite material comprises a silica content in the range of 5-35% and an anti-C5 agent in the range of 5-40%. In some embodiments, the composite material comprises a silica content in the range of 5-30% and an anti-C5 agent in the range of 1-5%, 5-10%, 10-15%, 15-20%, 20-25% or 25-30%. In some embodiments, the composite material comprises a silica content in the range of 25-30% and an anti-C5 agent in the range of 5-10%. In some embodiments, the composite material comprises a silica content of about 27.4% and an anti-C5 agent of about 8%.

[0078] In some embodiments, the ratio of the dissolution rate of silica to the dissolution rate of the anti-C5 agent of the sustained-release silica hydrogel composite is 2: 1, 1: 1 or 1: 2. In some embodiments, the ratio of the dissolution rate of silica to the dissolution rate of the anti-C5 agent of the sustained-release silica hydrogel composite is 1:1.

[0079] In some embodiments, an exemplary composition can be a particulate composition comprising a silica content in the range of 5-70% or 40-90% (preferred embodiments are 40-50%, 50-60%, 60-70%, 70-80% or 80-90%), an anti-C3 agent content in the range of 1-60% (preferred embodiments are 1-10%, 1-40%, 10-20%, 20-30%, 30-40%, 40-50% or 50-60%), and a silica content precursor residue in the range of 1-40% (preferred embodiments are 1-5%, 5-10%, 10-15%, 15-20%, 20-25%, 25-30%, 30-35%, 35-40%, 40-45% or 45-50%).

[0080] Provided herein is a formulation comprising a population of microparticles comprising: a silica content in the range of 10-70% and an anti-C5 agent in the range of 5-50%, wherein the anti-C5 agent comprises a C5-specific aptamer, wherein the aptamer comprises a nucleotide sequence of fCmGfCfCGfCmGmGfUfCfUfCmAmGmGfCGfCfUmGmAmGfUfCfUmGmAmGfUfUfUAfCfCfUmGfCmG-3T (SEQ ID NO: 1), wherein fC and fU=2' fluoro nucleotides, mG and mA=2'-OMe nucleotides, all other nucleotides are 2'-OH, and 3T represents inverted deoxythymidine.

[0081] In some embodiments, the microparticles contain a silica content in the range of 60-75% and an anti-C5 agent in the range of 2.5-5.0%, 5-10%, 10-15%, 15-20%, 20-25%, or 25-30%. In some embodiments, the microparticles contain a silica content in the range of 60-72% and an anti-C5 agent in the range of 2.5-25%. In some embodiments, the microparticles contain a silica content in the range of 64-68% and an anti-C5 agent in the range of 15-19%.

[0082] In some embodiments, the sustained release silica hydrogel composite material comprises silica microparticles dispersed in a silica sol hydrogel. In some embodiments, the sustained release silica hydrogel composite material is a reservoir preparation, which is microparticles suspended in a silica sol hydrogel. In some embodiments, the reservoir preparation provided herein exhibits shear thinning. The reservoir preparation can be filled into a container closure system, such as a dosing syringe. A syringe is provided herein, which comprises a sustained release silica hydrogel composite material disclosed herein. Early AMD

[0083] Provided herein is a method for improving, treating or reducing the severity of an ophthalmic condition symptom in a subject in need, the method comprising administering to the subject a sustained release silica hydrogel composite material provided herein. Also provided herein is a method for preventing or delaying the progression of an ophthalmic condition in a subject in need, the method comprising administering to the subject a sustained release silica hydrogel composite material provided herein. Also provided herein is a method for treating or reducing the severity of an ophthalmic condition in a subject in need, the method comprising administering to the subject a sustained release silica hydrogel composite material provided herein. In some embodiments, the ophthalmic condition is iRORA, cRORA, nGA, GA and / or wet AMD.

[0084] In some embodiments, the present disclosure relates to methods and compositions useful for subjects with incomplete retinal pigment epithelium (RPE) and outer retinal atrophy ("iRORA"). iRORA is an ophthalmic disease, disorder, and / or condition characterized by the following three features, which are vertically aligned and determined by OCT: (1) areas of excessive signal transmission to the choroid, (2) corresponding areas of attenuation or disruption of the RPE, and (3) evidence or signs of overlying photoreceptor degeneration. Evidence or signs of overlying photoreceptor degeneration include depression of the inner nuclear layer ("INL") and outer plexiform layer ("OPL"), the presence of a hyporeflective wedge in the Henle fiber layer ("HFL"), thinning of the outer nuclear layer ("ONL"), disruption of the external limiting membrane ("ELM"), and disintegration of the elliptical zone ("EZ"). iRORA should not be used to refer to RPE tears.

[0085] In some embodiments, the present disclosure relates to methods and compositions useful for subjects with risk factors for progression to iRORA. Subjects showing risk factors for progression to iRORA show some but not all signs of iRORA as described above. In addition, subjects showing high-risk macular sclerosis and risk factors for progression to iRORA may also show high reflective lesions, heterogeneous internal reflectivity of macular sclerosis, and / or subretinal macular sclerosis-like deposits. Determining whether a subject has risk factors for progression to iRORA can also be accomplished by multimodal imaging, including but not limited to OCT. Subjects with risk factors for progression to iRORA may progress to iRORA, cRORA, nGA, GA, and / or wet AMD.

[0086] Risk factors are known in the art and include, for example, hypertension, obesity, atherosclerosis, focal deposits of acellular debris between the retinal pigment epithelium (RPE), family history of AMD (including genetic risk), smoking, high body mass index, high fat diet, low intake of antioxidants and zinc, previous cataract surgery, history of cardiovascular disease, elevated plasma fibrinogen, and / or diabetes (see, e.g., García-Layana et al., Clinical Interventions in Aging 2017: 121579-1587, the contents of which are incorporated herein by reference in their entirety).

[0087] In some embodiments, the present disclosure relates to methods and compositions useful for subjects with cRORA. cRORA is an ophthalmic disease, disorder and / or condition that meets the requirements of iRORA, and further requires changes in the RPE area, excessive transmission of at least 250 μm in diameter on OCTB scan, and evidence of photoreceptor loss. iRORA may progress to cRORA, nGA, GA and / or wet AMD.

[0088] In some embodiments, the present disclosure relates to methods and compositions useful for subjects with nGA. nGA is an ophthalmic disease, disorder, and / or condition characterized by: (i) depression of the inner nuclear layer (INL) and outer plexiform layer (OPL), and (ii) a low-reflective wedge within the OPL (including within the layer of Henle fibers). nGA may also be associated with RPE disturbances and increased excessive signal transmission to the choroid. In addition, common features of OPL and INL depression may include disruption of the inner segment ellipsoid ("ISe"), disruption of the ELM, and traces of increased signal transmission beneath Bruch's membrane. In addition, common features of the low-reflective wedge include eddy-like depression of the OPL and INL, regression of macular sclerosis, and traces of increased signal transmission beneath the RPE. The onset of nGA may also be accompanied by or preceded by regression of partial or complete macular sclerosis, resulting in characteristic changes of progressive atrophy of the overlying retinal layers. nGA may also be associated with and / or occur simultaneously with the iRORA disease state. Subjects presenting with nGA may have previously presented with risk factors for progression to iRORA and may subsequently present with cRORA and / or GA.

[0089] In some embodiments, the present disclosure includes methods of administering to a subject with high risk macular sclerosis. High risk macular sclerosis refers to macular sclerosis associated with high risk AMD and / or high risk disease progression from early AMD to late AMD. High risk macular sclerosis may have any of the following characteristics. For example, high risk macular sclerosis may be characterized by at least one macular sclerosis with a diameter of at least 250 μm observed on fundus biomicroscopy or color fundus photography and / or a total volume of macular sclerosis of at least 0.03 mm 3 , as measured by SD-OCT within a circle with a diameter of 3 mm centered on the macula. In some embodiments, the high risk macular sclerosis is at least 300 μm in diameter and is present within a circle with a diameter of 500 μm centered on the macula.

[0090] Additionally, high-risk macular sclerosis may have other morphological features. Additionally, high-risk macular sclerosis may have the following features: maximum lesion height and diameter, lesion internal reflectivity, presence and extent of hyperreflective lesions in the overlying retina, and choroidal thickness beneath the macula and below the macular sclerosis. Additionally, high-risk macular sclerosis may demonstrate hyperreflective lesions overlying the macular sclerosis, heterogeneous internal reflectivity of the macular sclerosis, or choroidal thickness less than 135 μm below the macular sclerosis baseline. Additionally, high-risk macular sclerosis may be soft, large, inconspicuous, and / or confluent.

[0091] In some embodiments, the subject exhibits hyperpigmentation or hypopigmentation. In some embodiments, increased pigmentation is another way to indicate disease progression. In some embodiments, hypopigmentation is associated with a specific disease state.

[0092] SD-OCT in particular provides a reliable and reproducible method to measure the morphology of macular sclerosis over time, as well as other features of AMD. In addition, SD-OCT algorithms can be used to quantify features of macular sclerosis. Such algorithms can be fully automated and reliably report changes in macular sclerosis burden, macular sclerosis volume and area, and morphology over time using cube and square root transformations, respectively. Advances in imaging technology using SD-OCT and color fundus imaging have made it possible to study and measure the morphology of macular sclerosis by providing a three-dimensional geometric assessment. SD-OCT imaging also allows for multimodal imaging, and other macular features that increase the risk of vision loss have been identified, including decreased internal reflectivity of macular sclerosis (identified as calcific macular sclerosis), intraretinal hyperreflective lesions, and subretinal macular sclerosis-like deposits. Instruments for SD-OCT are known in the art, such as the Cirrus HD-OCT. Administration and Dosage

[0093] The dosage of an anti-complement agent (e.g., an anti-C5 agent) for administration to the eye can be about 0.1 mg / eye to about 5 mg / eye, about 0.3 mg / eye to about 5 mg / eye, about 0.5 mg / eye to about 3 mg / eye, about 1 mg / eye to about 3 mg / eye, about 1 mg / eye to about 4 mg / eye, or about 2 mg / eye to about 4 mg / eye. In some embodiments, the dose of the anti-C5 agent for administration to the eye can be about 0.3 mg / eye, or about 0.5 mg / eye, or about 0.75 mg / eye, or about 1 mg / eye, or about 1.25 mg / eye, or about 1.50 mg / eye, or about 1.75 mg / eye, or about 2 mg / eye, or about 2.25 mg / eye, or about 2.50 mg / eye, or about 2.75 mg / eye, or about 3 mg / eye, or about 3.25 mg / eye, or about 3.50 mg / eye, or about 3.75 mg / eye, or about 4 mg / eye.

[0094] In some embodiments, the dose of an anti-complementary agent (e.g., an anti-C5 agent) for administration to the eye may be about 0.3 mg / eye to about 5 mg / eye. In some embodiments, the dose of an anti-complementary agent (e.g., an anti-C5 agent) for administration to the eye may be about 2 mg / eye.

[0095] The dosage of an anti-complement agent (eg, an anti-C5 agent) for administration to the eye can be about 100-200, about 200-400, about 400-600, about 600-800, or about 800-1000 μg of an oligonucleotide equivalent dose.

[0096] The silica composite material (e.g., microparticles and silica hydrogel) can provide a daily drug dose of about 0.1-100 μg, or about 0.1-0.5 μg, or about 0.5-1.0 μg, or about 1-5 μg, or about 5-10 μg, or about 10-20 μg, or about 20-30 μg, or about 30-40 μg, or about 40-50 μg, or about 50-60 μg, or about 60-70 μg, or about 70-80 μg, or about 80-90 μg, or about 90-100 μg.

[0097] The dosage of anti-complementary agents (e.g., anti-C5 agents) for administration to the eye may be 10-100 ng / day, 100-1000 ng / day, 1-10 μg / day, and 10-100 μg / day. In some embodiments, the dosage of anti-complementary agents (e.g., anti-C5 agents) for administration to the eye may range from 0.5 μg / day to 15 μg / day.

[0098] The silica composite material (e.g., microparticles and silica hydrogel) can be administered once every 8 weeks, once every 9 weeks, once every 10 weeks, once every 11 weeks, once every 12 weeks, once every 13 weeks, once every 14 weeks, once every 14 weeks, once every 15 weeks, once every 16 weeks, once every 17 weeks, once every 18 weeks, once every 19 weeks, once every 20 weeks, once every 21 weeks, once every 22 weeks, once every 23 weeks, once every 24 weeks, once every 25 weeks, once every 26 weeks, once every 6 months, once every 7 months, once every 8 months, once every 9 months, once every 10 months, once every 11 months, or once every 12 months. The dosage can be administered once every two months, once every three months, once every four months, once every five months, or once every six months.

[0099] In some embodiments, the silica composite material (e.g., microparticles and silica hydrogel) can be administered intraocularly or periocularly, for example, by subconjunctival, retrobulbar, intracameral, subTenon's fascia, subretinal, suprachoroidal, or intravitreal injection. In some embodiments, the silica composite material is administered by intravitreal injection. In some embodiments, the silica composite material is administered by suprachoroidal injection. The silica composite material can be in the form of a reservoir.

[0100] In some embodiments, a dosing regimen comprising a loading phase and a maintenance phase may be administered. In some embodiments, the silica composite material (e.g., microparticles and silica hydrogel) may be administered in a dosing regimen comprising a loading phase and a maintenance phase. In some embodiments, the loading phase may include administration of an anti-C5 agent, while the maintenance phase may include administration of a silica composite material (e.g., microparticles and silica hydrogel). In some embodiments, the anti-C5 agent is avacincaptad pegol. In some embodiments, the loading phase may include administration of avacincaptad pegol at a different dose, a different frequency, or a combination thereof as compared to avacincaptad pegol in the silica composite material during the maintenance phase. For example, the loading phase may include administering avacincaptad pegol at a dose of about 0.3 mg / eye, 0.5 mg / eye, or about 1 mg / eye, or about 2 mg / eye, or about 3 mg / eye, or about 4 mg / eye; the maintenance phase may include administering avacincaptad pegol in the silica composite at a dose equal to or greater than a percentage of the avacincaptad pegol dose in the loading phase, e.g., avacincaptad pegol in the loading phase. or about 10%, or about 20%, or about 25%, or about 30%, or about 33%, or about 40%, or about 50%, or about 60%, or about 67%, or about 70%, or about 75%, or about 80%, or about 90%, or about 100%, or about 125%, or about 150%, or about 175%, or about 200%, or about 225%, or about 250%, or about 275%, or about 300%, or about 325%, or about 350%, or about 375%, or about 400% of the pegol dose.Alternatively or additionally, the loading phase may include administering avacincaptad at a frequency of pegol, wherein the duration between doses is one week, two weeks, three weeks, four weeks, one month, five weeks, six weeks, seven weeks, eight weeks, two months, nine weeks, ten weeks, eleven weeks, twelve weeks, three months, four months, five months or six months; the maintenance phase may include administering avacincaptad pegol in a silica composite at a certain frequency, wherein the duration between doses is a percentage of the duration between doses in the loading phase or greater, for example, about 10%, or about 20%, or about 25%, or about 30%, or about 33%, or about 40%, or about 50%, or about 60%, or about 67%, or about 70%, or about 75%, or about 80%, or about 90%, or about 100%, or about 125%, or about 150%, or about 175%, or about 200%, or about 225%, or about 250%, or about 275%, or about 300%, or about 325%, or about 350%, or about 375%, or about 400% of the duration between doses in the loading phase. In some embodiments, the loading phase can last about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 2 months, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 12 months, about 15 months, about 18 months, about 21 months, or about 24 months; and the maintenance phase can begin simultaneously with the loading phase, at any time within the loading phase, or at the end of the loading phase.

[0101] In certain embodiments, avacincaptad pegol can be administered according to a dosing regimen comprising a loading phase comprising administering a dose of about 2 mg / eye once a month for up to one year, followed by a maintenance phase comprising a dose of about 0.1 mg / eye, or about 0.3 mg / eye, or about 0.5 mg / eye, or about 0.75 mg / eye, or about 1 mg / eye, or about 1.25 mg / eye, or about 1.50 mg / eye, or about 1.75 mg / eye, or about 2 mg / eye, or about 2.25 mg / eye, or about 2.50 mg / eye, or about 2.75 mg / eye, or about 3 mg / eye, or about 3.25 mg / eye, or about 3.50 mg / eye in the silica composite. , or about 3.75 mg / eye, or about 4 mg / eye, once every 8 weeks, once every 9 weeks, once every 10 weeks, once every 11 weeks, once every 12 weeks, once every 13 weeks, once every 14 weeks, once every 14 weeks, once every 15 weeks, once every 16 weeks, once every 17 weeks, once every 18 weeks, once every 19 weeks, once every 20 weeks, once every 21 weeks, once every 22 weeks, once every 23 weeks, once every 24 weeks, once every 25 weeks, or once every 26 weeks. In certain embodiments, avacincaptad pegol can be administered according to a dosing regimen comprising a loading phase comprising administering a dose of about 4 mg / eye once monthly for up to one year, followed by a maintenance phase comprising avacincaptad pegol in a silica composite. The dosage of pegol is about 0.3 mg / eye, or about 0.5 mg / eye, or about 0.75 mg / eye, or about 1 mg / eye, or about 1.25 mg / eye, or about 1.50 mg / eye, or about 1.75 mg / eye, or about 2 mg / eye, or about 2.25 mg / eye, or about 2.50 mg / eye, or about 2.75 mg / eye, or about 3 mg / eye, or about 3.25 mg / eye, or about 3.50 mg / eye, or about 3. 75 mg / eye, or about 4 mg / eye, once every 8 weeks, once every 9 weeks, once every 10 weeks, once every 11 weeks, once every 12 weeks, once every 13 weeks, once every 14 weeks, once every 14 weeks, once every 15 weeks, once every 16 weeks, once every 17 weeks, once every 18 weeks, once every 19 weeks, once every 20 weeks, once every 21 weeks, once every 22 weeks, once every 23 weeks, once every 24 weeks, once every 25 weeks or once every 26 weeks.In certain embodiments, avacincaptad pegol may be administered according to a dosing regimen comprising a loading phase comprising a dose of about 2 mg / eye administered once a month for about 6 months, followed by a maintenance phase comprising a dose of about 0.3 mg / eye, or about 0.5 mg / eye, or about 0.75 mg / eye, or about 1 mg / eye, or about 1.25 mg / eye, or about 1.50 mg / eye, or about 1.75 mg / eye, or about 2 mg / eye, or about 2.25 mg / eye, or about 2.50 mg / eye, or about 2.75 mg / eye, or about 3 mg / eye, or about 3.25 mg / eye, or about 3.50 mg / eye, or about 3. 75 mg / eye, or about 4 mg / eye, once every 8 weeks, once every 9 weeks, once every 10 weeks, once every 11 weeks, once every 12 weeks, once every 13 weeks, once every 14 weeks, once every 14 weeks, once every 15 weeks, once every 16 weeks, once every 17 weeks, once every 18 weeks, once every 19 weeks, once every 20 weeks, once every 21 weeks, once every 22 weeks, once every 23 weeks, once every 24 weeks, once every 25 weeks or once every 26 weeks.

[0102] The amount of silica composite material (e.g., microparticles and silica hydrogel) administered to a subject can be in the range of about 10 to about 2000 μL, or about 25 to about 2000 μL. In some embodiments, the silica composite material can be administered intraocularly or periocularly, for example, by subconjunctival, retrobulbar, intracameral, subtenon, subretinal, suprachoroidal, or intravitreal injection. In some embodiments, the silica composite material can be administered by intravitreal injection. In some embodiments, the silica composite material can be administered by suprachoroidal injection.

[0103] In this specification, any concentration range, percentage range, ratio range or integer range should be understood to include the value of any integer within the range, and where appropriate, include fractions thereof (such as one tenth and one hundredth of an integer), unless otherwise specified. Numbered implementation plan

[0104] Notwithstanding the appended claims, the present disclosure sets forth the following numbered embodiments:

[0105] Embodiment 1. A sustained-release silica hydrogel composite material, the composite material comprising: a silica content in the range of 5-35% and an anti-C5 agent in the range of 1-40%, wherein the anti-C5 agent comprises a C5-specific aptamer, wherein the aptamer comprises a nucleotide sequence of fCmGfCfCGfCmGmGfUfCfUfCmAmGmGfCGfCfUmGmAmGfUfCfUmGmAmGfUfUfUAfCfCfUmGfCmG-3T (SEQ ID NO: 1), wherein fC and fU=2' fluoro nucleotides, mG and mA=2'-OMe nucleotides, all other nucleotides are 2'-OH, and 3T represents inverted deoxythymidine.

[0106] Embodiment 2. The sustained release silica hydrogel composite of embodiment 1, wherein the composite comprises a silica content in the range of 5-35% and an anti-C5 agent in the range of 5-40%.

[0107] Embodiment 3. The sustained release silica hydrogel composite of embodiment 1, wherein the composite comprises a silica content in the range of 5-30% and an anti-C5 agent in the range of 1-5%, 5-10%, 10-15%, 15-20%, 20-25% or 25-30%.

[0108] Embodiment 4. The sustained release silica hydrogel composite of embodiment 1, wherein the composite comprises a silica content in the range of 25-30% and an anti-C5 agent in the range of 5-10%.

[0109] Embodiment 5. The sustained release silica hydrogel composite of Embodiment 1, wherein the composite comprises about 27.4% silica content and about 8% anti-C5 agent.

[0110] Embodiment 6. The sustained release silica hydrogel composite material of any one of Embodiments 1-5, wherein the composite material comprises silica microparticles dispersed in a silica sol hydrogel.

[0111] Embodiment 7. The sustained-release silica hydrogel composite material according to any one of Embodiments 1 to 6, wherein the ratio of the silica dissolution rate to the anti-C5 agent dissolution rate of the composite material is 2:1, 1:1 or 1:2.

[0112] Embodiment 8. The sustained release silica hydrogel composite material of any one of Embodiments 1-7, wherein the anti-C5 agent is pegylated.

[0113] Embodiment 9. The sustained release silica hydrogel composite of any one of Embodiments 1-7, wherein the anti-C5 agent is non-PEGylated.

[0114] Embodiment 10. A syringe comprising the sustained-release silica hydrogel composite material according to any one of embodiments 1-9.

[0115] Embodiment 11. A method for improving, treating or reducing the severity of symptoms of an ophthalmic disorder in a subject in need thereof, the method comprising administering to the subject the sustained-release silica hydrogel composite material of any one of Embodiments 1-9.

[0116] Embodiment 12. A method for preventing or delaying progression of an ophthalmic condition in a subject in need thereof, the method comprising administering to the subject the sustained release silica hydrogel composite material of any one of Embodiments 1-9.

[0117] Embodiment 13. A method for treating or reducing the severity of an ophthalmic condition in a subject in need thereof, the method comprising administering to the subject the sustained release silica hydrogel composite of any one of Embodiments 1-9.

[0118] 14. The method according to any one of embodiments 11 to 13, wherein the ophthalmic condition is incomplete retinal pigment epithelium (RPE) and outer retinal atrophy, complete RPE and outer retinal atrophy, neonatal geographic atrophy, geographic atrophy or wet age-related macular degeneration.

[0119] Embodiment 15. The method of any one of Embodiments 11-14, wherein the sustained release silica hydrogel composite is administered to the subject by subconjunctival, retrobulbar, intracameral, subTenon's, subretinal, suprachoroidal, or intravitreal injection.

[0120] Embodiment 16. The method of any one of Embodiments 11-14, wherein the sustained release silica hydrogel composite is administered to the subject by intravitreal injection.

[0121] Embodiment 17. The method of any one of Embodiments 11-14, wherein the sustained release silica hydrogel composite is administered to the subject by suprachoroidal injection.

[0122] Embodiment 18. The method of any one of Embodiments 11-17, wherein the sustained release silica hydrogel composite is administered to the subject at a dose of about 0.3 mg / eye to about 5 mg / eye.

[0123] Embodiment 19. The method of any one of Embodiments 11-17, wherein the sustained release silica hydrogel composite is administered to the subject at a dose of about 2 mg / eye.

[0124] Embodiment 20. The method of any one of Embodiments 11-19, wherein the sustained release silica hydrogel composite is administered to the subject at a frequency such that the duration between doses is at least about three months.

[0125] Embodiment 21. The method of any one of Embodiments 11-19, wherein the sustained release silica hydrogel composite is administered to the subject at a frequency such that the duration between doses is about four months, about five months, or about six months.

[0126] Embodiment 22. A formulation comprising a population of microparticles, the microparticles comprising: a silica content in the range of 10-70% and an anti-C5 agent in the range of 5-50%, wherein the anti-C5 agent comprises a C5-specific aptamer, wherein the aptamer comprises a nucleotide sequence of fCmGfCfCGfCmGmGfUfCfUfCmAmGmGfCGfCfUmGmAmGfUfCfUmGmAmGfUfUfUAfCfCfUmGfCmG-3T (SEQ ID NO: 1), wherein fC and fU=2' fluoro nucleotides, mG and mA=2'-OMe nucleotides, all other nucleotides are 2'-OH, and 3T represents inverted deoxythymidine.

[0127] Embodiment 23. The formulation of embodiment 22, wherein the microparticles comprise a silicon dioxide content in the range of 60-75% and an anti-C5 agent in the range of 2.5-5.0%, 5-10%, 10-15%, 15-20%, 20-25% or 25-30%.

[0128] Embodiment 24. The formulation of embodiment 22, wherein the microparticles comprise a silicon dioxide content in the range of 60-72% and an anti-C5 agent in the range of 2.5-25%.

[0129] Embodiment 25. The formulation of embodiment 22, wherein the microparticles comprise a silicon dioxide content in the range of 64-68% and an anti-C5 agent in the range of 15-19%.

[0130] Embodiment 26. The formulation of any one of Embodiments 22-25, wherein the anti-C5 agent is pegylated.

[0131] Embodiment 27. The formulation of any one of Embodiments 22-25, wherein the anti-C5 agent is non-PEGylated.

[0132] The present disclosure will be further clarified by the following examples, which are intended to be merely illustrative of the present disclosure and are in no way limiting. Example 1A: Preparation of silica microparticles containing anti-C5 agents using a semi-batch reactor process

[0133] The silica microparticles were prepared using the following general procedure: preparation of anti-C5 agent (avacincaptad pegol) and NaOH solutions, preparation of silica sol by TEOS hydrolysis in a batch reactor, mixing of component solutions (avacincaptad pegol solution, NaOH solution, and silica sol) in a semi-batch reactor, and then spray drying.

[0134] To prepare the avacincaptad pegol-water solution, 538.2 mg of avacincaptad pegol was weighed and dissolved in 35.9 ml of milli-Q water to obtain a 15 mg / ml solution.

[0135] TEOS was hydrolyzed in a batch reactor. Silica microparticles with 15% (w / w) encapsulated avacincaptad pegol were prepared starting from the preparation of a silica sol. The sol was prepared by mixing the silica precursor tetraethylorthosilicate (TEOS, Sigma Aldrich) with milli-Q water (Merck Millipore) and 0.1 M hydrochloric acid (HCl, Merck Titripur). The molar ratio of water to TEOS (referred to as the R value) was 5. The pH of the final mixture was adjusted to 2 using a 0.1 M HCl stock solution. The hydrolysis reaction was allowed to proceed at room temperature (21-23°C) for 25 min with continuous stirring. The silica sol was diluted with Milli-Q H2O to an R value of 55-56 and the pH was adjusted to 3.0 ± 0.1 using a 0.1 M sodium hydroxide (NaOH, Merck Titripur) solution. Next, 33.58 ml of avacincaptad pegol-water solution was added to the silica sol and mixed. Finally, the pH of the silica sol containing avacincaptad pegol was adjusted to 6.0 ± 0.1 with 0.1 M NaOH solution. The R value of the silica sol containing soluble avacincaptad pegol was 100 with respect to the components other than 0.1 M NaOH.

[0136] The sol containing silica and ACP was pumped to a spray dryer (SD, Büchi B-290) with an outlet temperature between 52-66°C to provide spray-dried silica microparticles containing avacincaptad pegol. The ACP-silica microparticles were stored at 4-8°C until further processing.

[0137] The semi-batch process was used to prepare formulations with different API drug loads, first or 1R values, and batch sizes, as shown in Table 1. Table 1A. Feasible Formulations (Microparticles) #01-#11

[0138] Feasibility formulations (microparticles) #01-#11 (Tables 1A and 1B) were characterized by light scattering particle size distribution, scanning electron microscopy, and in vitro dissolution. The results showed that increasing API loading accelerated in vitro dissolution ( Figure 3A , Figure 3B ). The 1R value had no measurable effect on light scattering particle size distribution or in vitro dissolution. The semi-batch process allows for repeatable preparation and increased batch size in the laboratory. Table 1B. Characterization of Feasible Formulations (Microparticles) #01-#11

[0139] Figure 1A The particle size distribution of an exemplary microparticle formulation prepared by the semi-batch process described in Example 1A is shown. Specifically, the figure shows the particle size distribution of microparticles #01-#03 in Table 1.

[0140] Further with respect to Table 1, the target API loading is defined as the ratio of the theoretical API content (i.e., anti-C5 agent) to the theoretical silica content in the microparticles, i.e., API loading = m API / m SiO2 Furthermore, pH corresponds to the pH of the API-sol mixture at the start of spray drying. Furthermore, inlet / outlet temperatures correspond to the spray drying inlet and outlet air temperatures.

[0141] In this regard, Figure 1A As shown, the population of #01 is slightly separated from #02 and #03. In addition, all formulations show a shoulder on the right side of the distribution, which may indicate the presence of particle aggregates and / or agglomerates.

[0142] Figure 1BThe D10, D50 and D90 values ​​of formulations #01-#03 are shown. In this regard, the particle size distribution is suitable for injection through a narrow gauge needle. For example, the particle size values ​​of D10, D50 and D90 can be one of 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20% or 10% of the needle inner diameter or cavity size.

[0143] The particle size distributions of feasibility formulations #04-#06 are shown in Table 2. The microparticle formulations appear very similar. All formulations show a shoulder on the right side of the distribution, which may indicate the presence of particle agglomerates (microparticles that have fused together during the spray drying process). Figure 2A and Figure 2B In vitro dissolution data for feasibility formulations #04-#06 are shown. It was concluded from the formulation #04-#06 studies that the 1st R value had no effect on in vitro dissolution or spray dried particle size distribution. Table 2. D10, D50 and D90 values ​​of formulations #04-#06

[0144] Drug Loading Evaluation 2: A second study on the effect of drug loading was conducted to increase the particle size or fill the gap between the 20% and 40% loading studied in formulations #02 and #03. Drug loadings of 25%, 30%, and 35% were studied here. The data showed that the release rates of formulations #07-#09 were between the borderline formulations #02 and #03 with drug loadings of 20% and 40%, respectively. The results support the conclusion that increasing drug loading results in faster in vitro dissolution kinetics but does not affect the particle size distribution of the spray-dried material.

[0145] The particle size distributions of feasibility formulations #07-#11 are shown in Table 3. All formulations showed a shoulder on the right side of the distribution, which may indicate the presence of particle agglomerates. Figure 3A and Figure 3B shown. Table 3. D10, D50 and D90 values ​​of formulations #07-#11

[0146] Scale-up. The bench-scale process was scaled based on the input amount of silica source material (TEOS). In vitro dissolution data for feasibility formulations #02 (replicate), #10, and #11 are shown in Figure 2. Figure 4A and Figure 4B Laboratory scale-up work demonstrated that the silica input could be increased 5-fold without affecting the in vitro dissolution kinetics or particle size distribution of the spray-dried material. Example 1B: Preparation of Additional Exemplary Formulations Containing Anti-C5 Agents

[0147] As described in more detail in the Examples below, additional exemplary formulations provided in Table 4 were generated and tested. Formulation Aging Study 1 was prepared using an appropriately scaled semi-batch process as described in Example 1A. The remaining formulations labeled with a CSTR (continuous stirred reactor) designation were prepared according to Example 2 scaled to the listed batch sizes. Formulation #11 CSTR-3 (PK) is also referred to as "PK" or "PK formulation" in subsequent Examples.

[0148] Fig.18A and Fig.18B The dissolution rates of silica and API were comparable for formulations #11 CSTR-1, #11 CSTR-2, and #11 CSTR-3. These data suggest that the CSTR batches have comparable dissolution release profiles. Example 2: Preparation of silica microparticles containing anti-C5 agents using a continuous stirred reactor process

[0149] The silica microparticles were prepared using the following general procedure: preparation of anti-C5 agent (avacincaptad pegol) and NaOH solutions, preparation of silica sol by TEOS hydrolysis in a batch reactor, mixing of the component solutions (avacincaptad pegol solution, NaOH solution, and silica sol) in a continuous stirred tank reactor, and then spray drying.

[0150] To prepare the avacincaptad pegol-water solution, 3.92 g of avacincaptad pegol was weighed and dissolved in 261.3 ml of milli-Q water to obtain a 15 mg / ml solution.

[0151] To prepare the NaOH solution, mix 16.17 ml of 0.1 M NaOH solution and 269.21 ml of milli-Q water to achieve the desired dilution, where the pH of the solution should be 11.7.

[0152] TEOS was hydrolyzed in a batch reactor. Silica microparticles with 17.7% (w / w) encapsulated avacincaptad pegol were prepared starting from the preparation of a silica sol. The sol was prepared by mixing the silica precursor tetraethylorthosilicate (TEOS, Sigma Aldrich) with milli-Q water (Merck Millipore) and 0.1 molar hydrochloric acid (Merck Titripur). The molar ratio of water to TEOS (referred to as the R value) was 5. 0.1 M HCl was used to bring the pH of the final mixture to 2. The hydrolysis reaction was allowed to proceed at room temperature (21-23°C) for 25 minutes with continuous stirring.

[0153] The prepared solutions were combined in a continuous stirred tank reactor. The prepared solutions (silica sol, avacincaptad pegol-aqueous solution and NaOH-aqueous solution) were pumped by a peristaltic pump (inlet pump) and mixed in a continuous stirred tank reactor (CSTR) with a target volume flow ratio of 1:3.21:2.83, respectively. The target average residence time for the CSTR was 3-5 min. The concentration of silica should be between 16.7 and 30.1 mg / ml and the solution pH should be between 5.6-6.4. After mixing, the solution was pumped to a spray dryer (SD, Büchi B-290) by a second peristaltic pump (outlet pump). The interval time of the flow reactor step between the CSTR and the SD should be 1 min. The outlet temperature of the spray dryer should be between 52-66 °C.

[0154] The following spray drying parameters were used: Aspirator (air): 538.3 L / min; Atomizing air flow: 11.2 L / min; Nozzle type: Co-current two-fluid; Nozzle insert diameter: 0.7 mm; Nozzle cover diameter: 1.4 mm; Volume flow rate: 5.5-5.7 ml / min

[0155] The following shows the total content determination results of the microparticle preparation within 1 week of storage time: Table 5

[0156] Determination of the total content of the microparticles showed no material changes (e.g., no changes greater than the experimental variability / measurement precision) during the 1-week holding time. Example 3: Preparation of a silica hydrogel composite material containing an anti-C5 agent

[0157] The silica hydrogel composite containing the anti-C5 agent was prepared using the following general procedure. The avacincaptad pegol-silica microparticles in Example 2 were mixed with a diluted silica sol (prepared separately by TEOS hydrolysis) at a desired pH to obtain an avacincaptad pegol-silica-microparticle-silica sol suspension. The resulting suspension was then transferred into a pre-filled syringe for primary packaging.

[0158] A silica sol with an R value of 400 was prepared as described above. The pH of the silica sol was adjusted to 3 with 0.5 M NaOH. Next, silica microparticles with 17.7 wt % encapsulated avacincaptad pegol were mixed with the silica sol to achieve a 42.7 wt % suspension. This step was performed under high shear mixing to minimize the presence of microparticle aggregates. After mixing, the microparticle suspension was transferred from the reservoir syringe to the pre-filled syringe via a needle. Finally, the filled syringe was placed in a vertical rotation at room temperature for 6 days.

[0159] Table 6 shows representative formulations of hydrogel compositions of the present disclosure. Table 6

[0160] In this regard, the effective load of the anti-C5 agent was 4.6 ± 0.3 (mg / 50µl). In addition, the oligonucleotide equivalent was 1.1 ± 0.0 (mg / 50µl), where a factor of 0.23 was used for conversion. In addition, the residues were mainly water and trace amounts of ethanol from TEOS hydrolysis, where n=3 for PK.

[0161] Figure 5A The pH measurements of the microparticles and hydrogel formulations are shown in Tables 5 and 6. In this regard, the pH measurements of the microparticles can be used as an aid in predicting the final pH of the hydrogel, which has an impact on the gelation kinetics (generally, the higher the pH, the faster the gelation process).

[0162] Figure 5B The D10, D50 and D90 values ​​of the microparticle formulations in Table 5 are shown. Figure 5C The particle size distribution of the microparticle formulations in Table 5 is shown. In this regard, Figure 5C As shown, the particle size distribution is very narrow, with the vast majority of particles below 10 μm, predicted to be adequate for injectability. Example 4: SEM morphology of microparticles

[0163] The particles were predominantly spherical in shape and their sizes were visually consistent with static light scattering size measurements. Fig. 6ASEM imaging at a first image magnification is shown for the microparticle formulations in Table 5. Specifically, the figure depicts SEM imaging at the following parameters: Magnification = 1.00 KX; EHT = 3.00 kV; Aperture Size = 20.00 μm; WD = 6.6 mm; Signal A = SE2; Image Pixel Size = 117.2 nm. Figure 6B SEM imaging of the microparticle formulations in Table 5 at a second image magnification is shown. Specifically, the figure depicts SEM imaging at the following parameters: magnification = 5.00KX; EHT = 3.00kV; aperture size = 20.00μm; WD = 6.7mm; signal A = SE2; image pixel size = 23.44nm. In this regard, Fig. 6A and Figure 6B As shown in Figure 2, the particles appear smooth and spherical. In addition, visually, the particle size appears consistent with the particle size distribution measurements, for example, the vast majority of particles are less than 5 μm in diameter. Finally, as Figure 5C As shown in the particle size distribution diagram in , no discernible agglomerates of particles can be seen. Example 5: In vitro release of anti-C5 agents from silica composites

[0164] Figure 7 The in vitro release of avacincaptad pegol from microparticles #01-#03 and the degradation of the silica matrix in Table 1 are shown. In this regard, as shown, the API release rate is affected by the API loading in the microparticles. In addition, the API is effectively encapsulated by the silica matrix, as shown by the very low release at the 1 hour time point. In addition, the release of the API is controlled by the degradation of the silica matrix.

[0165] Fig. 8A The silica matrix degradation of the microparticles and hydrogel formulations in Tables 5 and 6 is shown. Figure 8B The API release from microparticles and hydrogel formulations is shown in Tables 5 and 6. In this regard, Fig. 8A and Figure 8B API release and silica matrix degradation occurred at a dissolution volume of 50 ml. In addition, the microparticles were stored at ambient temperature for one week before fabrication of the composite hydrogels in order to deliberately alter the silica matrix degradation and API release kinetics. Fig. 8A and Figure 8B As shown, the microparticles appear to retain the silica matrix degradation and API release rate, respectively. In addition, the API release rate was not affected by preparing the silica composites relative to the silica microparticles.

[0166] Figure 8CA direct relationship between silica and API dissolution was shown. This is a surprising advantage compared to other delivery technologies where the duration of the matrix controlling drug release may be several times that of the API, resulting in matrix accumulation or retention in the eye over time. Example 6: In vivo ocular release of anti-C5 agents from silica composites

[0167] The composite formulations (using formulation #11 CSTR-3) were prepared as described in Examples 2 and 3 (the in vitro release profiles of which are shown in Fig. 8A and Figure 8B ACP release and tissue exposure following IVT dosing were evaluated in Dutch belt (DB) rabbits (shown). The study design consisted of bilateral intravitreal dosing of 1.0 mg oligonucleotide equivalents in a 50 µL dosing volume of the silica composite PK formulation. Two rabbits (4 eyes) were harvested at each of the following time points, i.e., days 1, 3, 7, 14, 28, 42, 56, and 84. Eyes were dissected and vitreous humor, retina, and retinal pigment epithelium (RPE) / choroid were harvested for tissue-specific bioanalytical analysis using a qualified two-hybrid assay. Fig. 9 The ocular PK (pharmacokinetics) of the liquid formulation administered at an IVT bolus dose for vitreous humor and retinal tissues are summarized as a comparison with a sustained release depot PK formulation. The ocular tissue PK of the PK formulation is represented by solid lines, vitreous humor (top line), retina (midline), and RPE / choroid (bottom line). The data show that a single dose of the sustained release PK formulation of Example 3 provides long-lasting and consistent ocular tissue concentrations for up to 84 days.

[0168] At the end of the study (Day 84), the remaining PK formulation depot was recovered from the vitreous humor by centrifugation and analyzed for residual silica by microwave plasma atomic emission spectroscopy (MP-AES) and avacincaptad pegol content by a qualified HPLC assay. Residual silica ranged from 0-9%, while avacincaptad pegol ranged from 0-3% of the administered dose.

[0169] The in vitro dissolution data provided an estimated duration of release based on a 30X historical in vitro-in vivo correlation (IVIVC). Figure 8B, the predicted duration to achieve ~95% release was 3x30=90 days. This was used to predict the rate of release of ACP from the depot formulation (1.0mg / 90 days=11mg / day. The terminal half-life of ACP in DB rabbits following bolus administration of the liquid formulation was used to predict steady-state vitreous humor concentrations based on a daily infusion rate of 11 micrograms / day and a terminal half-life of 3.8 days. This calculation estimated a vitreous humor steady-state concentration of ~30,000ng / mL. From days 28 to 84, the average steady-state vitreous humor concentration was measured to be 22,650ng / g. For this analysis, the vitreous humor density was approximated as 1, so the measured steady state was 75% of the predicted value. In addition, analysis of the depot formulation remnants recovered on day 84 indicated that <10% formulation remained (range 0-9%), which supports a predicted duration of approximately 3 months or 90 days. Example 7: Stability Assessment

[0170] The PK formulation of Example 3 was packaged in 0.5 mL RTF® glass LuerLock syringes with Datwyler Neoflex stoppers and evaluated for stability over 8 weeks under refrigerated (2-8°C) and room temperature storage conditions. The stability results at 2-8°C are shown in Table 1. Figures 10A-10D The stability results at room temperature are shown in Figures 11A-11D The stability data under the two storage conditions showed no changes in the silicon dioxide content, API content, or in vitro release kinetics of the PK formulation under the two storage conditions. Example 8: Aging Studies

[0171] An interesting phenomenon was observed during the storage of the ACP microparticles compared to the stability of the composite depot formulation of Example 7. A significant decrease in release rate with storage time and temperature was observed.

[0172] Figures 12A-12D It is shown that after one week of storage under refrigeration and room temperature conditions, silica ( Fig. 12A ) and ACP (upper right) dissolution rates from silica microparticles. In contrast, silica ( Fig. 12C ) and ACP ( Fig.12D ) The dissolution rate in the silica reservoir composite remained unchanged.

[0173] Aging was further studied to evaluate the effects of alternative storage conditions, including vacuum, nitrogen atmosphere, and high humidity. ACP silica-based microparticles were prepared according to the method of Example 1B at a ratio to provide 38 grams of ACP microparticles. This provided microparticles with a similar particle size distribution to the PK formulation of Example 2, and a slightly narrower particle size distribution than the microparticles of the first aging study. Table 7. Particle size distribution of ACP microparticles in PK, aging study 1, and aging study 2

[0174] The ACP microparticles were dispensed into glass vials and loosely capped to fully expose them to ambient storage conditions. Storage was performed at room temperature with different atmospheric conditions, including vacuum, nitrogen, and relative humidity greater than 95%. Under all storage conditions, the direct relationship between silica and ACP dissolution remained unchanged, and the dissolution rate decreased over time. The greatest change in dissolution rate occurred under nitrogen storage conditions, and the smallest change occurred in samples with a relative humidity greater than 95%. The data show that in addition to the temperature shown in the first aging study, atmospheric storage conditions also affect aging. Aging provides a tool that can be used to adjust the dissolution kinetics of ACP-based silica microparticles. Please note that the stability data of Example 7 show that aging does not occur in the final ACP composite reservoir formulation of ACP microparticles suspended in silica sol hydrogel. Example 9: Composite Reservoir Rheology

[0175] In the present disclosure, silica can be used to create a silica sol hydrogel reservoir, thereby eliminating the need to add new or additional materials or excipients to the composite reservoir formulation that may complicate biocompatibility. The rheology of the final composite reservoir is a property that may affect reservoir stability, injectability, and performance after dosing. The silica sol hydrogel forms a reservoir formulation based on silica microparticles dispersed in the silica sol hydrogel. According to the procedure of Example 1A, the microparticles were prepared using the composition of Preparation #11 at an input scale of 40 mL TEOS. Four separate composite reservoirs were prepared using the microparticles according to the method of Example 2, and the hydrogel R values ​​were 400, 350, 300 and 250, respectively. The results are shown in FIG. Fig.13A and Fig. 13B shown.

[0176] The rheological properties of the prepared composite reservoirs were evaluated. Rheological measurements of the API-silica microparticle-silica hydrogel composites were performed using an Anton Paar MCR 302 (Modular Compact Rheometer). The decrease in the hydrogel R value was associated with an increase in the storage modulus (G') and a decrease in the loss factor (tanδ) of the composite reservoirs. The results showed that the rheological properties of the composite reservoirs can be controlled by the silica content in the prepared silica sol hydrogels and that an increased silica content improves the mechanical properties of the composite reservoirs. Example 10: Formulation Development

[0177] Experiments were conducted to investigate the effect of varying the pH of the final silica sol on composite storage agent production, 1R value, 2R value and reaction time. Batches were prepared using the continuous flow reactor process of Example 2 and the compositions listed in Table 8. Table 8. Formulation development parameters

[0178] Formulations pH#1-pH#3 showed a trend towards slower release at pH 7 in dissolution profiles compared to pH 4.9-5.3 and particle size distribution. The pH 4.9-5.3 formulations had a bimodal particle size distribution, indicating that particle aggregation may occur under these processing conditions. The pH range studied had little effect on silica or drug loading. Figure 14A-Figure 14C shown.

[0179] Formulations 2R #1-2R #3 showed that the 2R value had little effect on dissolution, particle size distribution, silica, and drug loading. Figure 15A-Figure 15C shown.

[0180] Formulations Rxn #1-Rxn #3 evaluated the effect of shortening the reaction time from 10 minutes to 5 minutes. As the reaction time increased, there was a potential trend for the dissolution rate to slow down within this time range. There was little effect on drug loading and no effect on particle size distribution. Results are shown in Table 1. Figure 16A-16C shown.

[0181] Formulations 1R #1-1R #3 explored the impact of reducing the 1R value to lower values ​​previously evaluated. Precipitation was observed at a 1R value of 3, which affected the total amount of avacincaptad pegol released. Formulation 1R #3 was prepared at a pH below the target, so two of the three formulations in the sequence were affected, limiting the conclusions that can be drawn from this subset of formulations. Results are shown in Table 1. Figure 17A-Figure 17C shown. Example 11: Experimental Methods

[0182] The experimental methods of the aforementioned examples are briefly described as follows.

[0183] In vitro degradation .

[0184] Microparticle samples: In vitro degradation of silica and release of API were measured in PBS (137 mM NaCl, 2.7 mM KCl, 10 mM Na2HPO4, 1.8 mM KH2PO4) supplemented with 0.05% TWEEN80 (pH 7.4, +37°C). The microparticle or hydrogel samples analyzed were approximately 10-25 mg in size and were subjected to dissolution studies for up to 96 hours in an oscillating water bath (60 times / min).

[0185] Hydrogel Depot Samples: The buffer and conditions for the hydrogel reservoir samples were the same as for the microparticle samples described in the previous section. The weighed sample amounts for analysis ranged from approximately 15-25 mg. In addition, the sample preparation was different such that the hydrogel reservoir was dispersed into the dissolution buffer by placing a small magnet into the tank and mixing until the suspension looked homogenous. This was done to ensure that the dissolution conditions for the hydrogel reservoir were comparable to the microparticles, i.e., the shape of the hydrogel reservoir in the dissolution tank did not affect its degradation profile due to the different surface area available for dissolution.

[0186] Determination of total content of silicon dioxide and ACP

[0187] Silica concentration was measured by microwave plasma atomic emission spectrometry (MP-AES) analyzing the electron emission intensity at a wavelength of 261 nm. API was analyzed using a high performance liquid chromatograph (HPLC) connected to a diode array detector (λ = 258 nm). Chromatographic separation was performed on a DNAPac PA-100, 4x250 mm, 13 µm, with a guard column DNAPac PA-100, 4x50 mm, ThermoScientific.

[0188] Particle size distribution (PSD)

[0189] The particle size distribution measurements of API-silica microparticles were performed by using the static light scattering method. The instrument used was a Sympatec HELOS BR3, using an R3 lens, which is optimal for the particle size range of 0.5 to 175 µm. The sample was prepared by weighing about 20 mg of API-silica microparticles and adding about 3 ml of Milli-Q H2O. Next, the suspension was vortexed at maximum power for 30 seconds. Then, 60 µl of the suspension was pipetted into a cuvette (V ≈ 35 ml) filled with Milli-Q H2O. Prior to the measurement, the sample was sheared with ultrasound for 20 seconds.

[0190] Manual injectability

[0191] The injectability of the silica-API microparticle-silica hydrogel composite formulation was tested by manually injecting the material. First, a 27G TUTW hypodermic needle was connected to the syringe. Next, the syringe was primed so that the material completely filled the needle hub and the excess material was wiped off the needle. Finally, the primed syringe was emptied onto a petri dish. The injection was considered successful if the movement was continuous, i.e., no transient blockage occurred during the process. The resulting material was also visually inspected.

[0192] The foregoing description is given for clearness of understanding only, and no unnecessary limitations are to be understood therefrom, as modifications within the scope of the disclosure may be obvious to one skilled in the art.

[0193] Throughout the specification, when a composition is described as including components or materials, unless otherwise stated, it is contemplated that the composition may also consist essentially of or consist of any combination of the components or materials. Similarly, when a method is described as including specific steps, unless otherwise stated, it is contemplated that the method may also consist essentially of or consist of any combination of the steps. The invention exemplarily disclosed herein may be suitably implemented in the absence of any element or step not specifically disclosed herein.

[0194] The implementation of the methods disclosed herein and their various steps can be performed manually and / or with the aid of electronic devices or automation provided by electronic devices. Although the processes have been described with reference to specific embodiments, it will be readily appreciated by those skilled in the art that other methods may be used to perform actions associated with the methods. For example, unless otherwise indicated, the order of the various steps may be changed without departing from the scope or spirit of the methods. In addition, some individual steps may be combined, omitted, or further subdivided into additional steps.

[0195] All references, articles, publications, patents, patent publications and patent applications cited herein are incorporated herein by reference in their entirety for all purposes. However, the mention of any reference, article, publication, patent, patent publication and patent application cited herein is not and should not be regarded as an admission or any form of suggestion that they constitute valid prior art or form part of the common general knowledge in any country in the world. If there is a conflict between the present disclosure and the incorporated reference, article, publication, patent, patent publication and patent application, the present disclosure shall prevail.

Claims

1. A sustained release silica hydrogel composite material, the composite material comprising: a silica content in the range of 5-35% and an anti-C5 agent in the range of 1-40%, wherein the anti-C5 agent comprises a C5-specific aptamer, wherein the aptamer comprises a nucleotide sequence of fCmGfCfCGfCmGmGfUfCfUfCmAmGmGfCGfCfUmGmAmGfUfCfUmGmAmGfUfUfUAfCfCfUmGfCmG-3T (SEQ ID NO: 1), wherein fC and fU=2' fluoro nucleotides, mG and mA=2'-OMe nucleotides, all other nucleotides are 2'-OH, and 3T represents inverted deoxythymidine.

2. The sustained release silica hydrogel composite material according to claim 1, wherein the composite material comprises a silica content in the range of 5-35% and an anti-C5 agent in the range of 5-40%.

3. The sustained release silica hydrogel composite material according to claim 1, wherein the composite material comprises a silica content in the range of 5-30% and an anti-C5 agent in the range of 1-5%, 5-10%, 10-15%, 15-20%, 20-25% or 25-30%.

4. The sustained release silica hydrogel composite material according to claim 1, wherein the composite material comprises a silica content in the range of 25-30% and an anti-C5 agent in the range of 5-10%.

5. The sustained-release silica hydrogel composite material according to claim 1, wherein the composite material comprises about 27.4% silica content and about 8% anti-C5 agent.

6. The sustained-release silica hydrogel composite material according to any one of claims 1 to 5, wherein the composite material comprises silica microparticles dispersed in a silica sol hydrogel.

7. The sustained-release silica hydrogel composite material according to any one of claims 1 to 6, wherein the ratio of the silica dissolution rate to the anti-C5 agent dissolution rate of the composite material is 2:1, 1:1 or 1:

2.

8. The sustained-release silica hydrogel composite material according to any one of claims 1 to 7, wherein the anti-C5 agent is pegylated.

9. The sustained-release silica hydrogel composite according to any one of claims 1 to 7, wherein the anti-C5 agent is non-PEGylated.

10. A syringe comprising the sustained-release silica hydrogel composite material according to any one of claims 1 to 9.

11. A method for improving, treating or reducing the severity of symptoms of an ophthalmic disorder in a subject in need thereof, the method comprising administering to the subject the sustained-release silica hydrogel composite material according to any one of claims 1 to 9.

12. A method for preventing or delaying progression of an ophthalmic condition in a subject in need thereof, the method comprising administering to the subject the sustained-release silica hydrogel composite material according to any one of claims 1 to 9.

13. A method for treating or reducing the severity of an ophthalmic condition in a subject in need thereof, the method comprising administering to the subject the sustained release silica hydrogel composite material according to any one of claims 1-9.

14. The method of any one of claims 11-13, wherein the ophthalmic condition is incomplete retinal pigment epithelium (RPE) and outer retinal atrophy, complete RPE and outer retinal atrophy, neonatal geographic atrophy, geographic atrophy, or wet age-related macular degeneration.

15. The method of any one of claims 11-14, wherein the sustained release silica hydrogel composite is administered to the subject by subconjunctival, retrobulbar, intracameral, subTenon's, subretinal, suprachoroidal, or intravitreal injection.

16. The method of any one of claims 11-14, wherein the sustained release silica hydrogel composite is administered to the subject by intravitreal injection.

17. The method of any one of claims 11-14, wherein the sustained release silica hydrogel composite is administered to the subject by suprachoroidal injection.

18. The method of any one of claims 11-17, wherein the sustained release silica hydrogel composite is administered to the subject at a dose of about 0.3 mg / eye to about 5 mg / eye.

19. The method of any one of claims 11-17, wherein the sustained release silica hydrogel composite is administered to the subject at a dose of about 2 mg / eye.

20. The method of any one of claims 11-19, wherein the sustained release silica hydrogel composite is administered to the subject at a frequency such that the duration between doses is at least about three months.

21. The method of any one of claims 11-19, wherein the sustained release silica hydrogel composite is administered to the subject at a frequency such that the duration between doses is about four months, about five months, or about six months.

22. A formulation comprising a population of microparticles, the microparticles comprising: a silica content in the range of 10-70% and an anti-C5 agent in the range of 5-50%, wherein the anti-C5 agent comprises a C5-specific aptamer, wherein the aptamer comprises a nucleotide sequence of fCmGfCfCGfCmGmGfUfCfUfCmAmGmGfCGfCfUmGmAmGfUfCfUmGmAmGfUfUfUAfCfCfUmGfCmG-3T (SEQ ID NO: 1), wherein fC and fU=2' fluoro nucleotides, mG and mA=2'-OMe nucleotides, all other nucleotides are 2'-OH, and 3T represents inverted deoxythymidine.

23. The formulation of claim 22, wherein the microparticles comprise a silicon dioxide content in the range of 60-75% and an anti-C5 agent in the range of 2.5-5.0%, 5-10%, 10-15%, 15-20%, 20-25% or 25-30%.

24. The formulation of claim 22, wherein the microparticles comprise a silicon dioxide content in the range of 60-72% and an anti-C5 agent in the range of 2.5-25%.

25. The formulation of claim 22, wherein the microparticles comprise a silicon dioxide content in the range of 64-68% and an anti-C5 agent in the range of 15-19%.

26. The formulation of any one of claims 22-25, wherein the anti-C5 agent is pegylated.

27. The formulation of any one of claims 22-25, wherein the anti-C5 agent is non-PEGylated.

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