Sustained-release silica hydrogel composite for treating ophthalmic conditions and method of using the same

Abstract

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

Description

Technical Field

[0001] Cross - Reference to Related Applications

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 357,631, filed Jun. 30, 2022, which is hereby incorporated by reference in its entirety for all purposes. Reference to Electronic Sequence Listing

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

[0002]

[0003] The present disclosure relates to a sustained - release silica hydrogel composite containing an anti - complement agent and methods of using it to treat ophthalmic conditions.

Background Art

[0003]

[0004] Age - related macular degeneration (“AMD”) is a disease characterized by progressive degenerative abnormalities in the macula, an area in the center of the retina. Age - related macular degeneration is a complex and slowly progressive eye disorder that can lead to distortion and / or blind spots (scotomas), changes in dark adaptation (diagnosis of rod cell health), changes in color interpretation (diagnosis of cone cell health), vision loss, or irreversible blindness.

[0004]

[0005] AMD is typically a disease of the elderly and is the leading cause of blindness in people over 50 years old in developed countries. In the United States, approximately 6% of people aged 65 - 74 and 20% of people over 75 are estimated to be affected by AMD. Due to the increasing average life expectancy in both developed and developing countries, the elderly portion of the general population is expected to increase at the largest rate in the coming decades. Without adequate preventive or treatment measures, the number of cases of AMD associated with vision loss is expected to increase in parallel with the aging population.

[0005]

[0006] Non-exudative AMD is the non-neovascular ("atrophic") form of the disease ("atrophic AMD"). Atrophic AMD accounts for approximately 90% of all AMD cases. Atrophic AMD can be characterized by degeneration of the macula and, if progression continues over several years, may ultimately result in atrophy of the central retina with loss of central vision. Atrophic AMD is a major cause of moderate and severe loss of central vision and is bilateral in most patients. In atrophic AMD, thinning of the retinal pigment epithelial cells (RPE) in the macula occurs along with other age-related changes to the adjacent retinal tissue layers.

[0006]

[0007] When neovascularization occurs in non-exudative AMD, the disease is referred to as exudative AMD, which is the neovascular ("exudative") form of the disease, and the non-exudative AMD remains present in the patient and potentially progresses. Exudative AMD can suddenly cause a substantial loss of central vision, often.

[0007]

[0008] Recent advances in imaging technology, specifically optical coherence tomography (“OCT”), and more specifically spectral domain optical coherence tomography (“SD-OCT”), have provided the ability to reproducibly and reliably measure morphological changes in the eyes of subjects indicative of the disease state of AMD and to monitor the progression of the disease 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”), geographic atrophy (“GA”), and / or neovascular geographic atrophy (“nGA”). See, for example, 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.

[0008]

[0009] Administration of a drug to treat an ocular condition such as those described above has been achieved, in some cases, by intravitreal administration that requires monthly dosing. There is a need for sustained release ocular dosage forms that include anti-complement agents that can be administered at longer intervals, thereby providing greater patient comfort, satisfaction, and / or compliance. Such compositions must also exhibit adequate characteristics to be suitable for administration via the ocular route.

Summary of the Invention

Means for Solving the Problems

[0009]

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

[0010]

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

[0011]

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

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

[0012]

[0014] In some embodiments of the composite provided herein, the anti-C5 agent is pegylated. In some embodiments of the composite provided herein, the anti-C5 agent is not pegylated.

[0013]

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

[0016] Provided herein is a method for improving, treating, or reducing the severity of symptoms 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.

[0014]

[0017] Provided herein is a method for preventing or delaying the 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.

[0015]

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

[0016]

[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, geographic atrophy neovasculosa, geographic atrophy, or exudative age-related macular degeneration.

[0017]

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

[0018]

[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.

[0019]

[0022] In some embodiments of the methods provided herein, the sustained release silica hydrogel composite is administered to a subject at a frequency such that the period between administrations is at least about 3 months. In some embodiments of the methods provided herein, the sustained release silica hydrogel composite is administered to a subject at a frequency such that the period between administrations is about 4 months, about 5 months, or about 6 months.

[0020]

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

[0021]

[0024] In some embodiments, the microparticles comprise from 60 to 75% by weight silica content and from 2.5 to 5.0%, 5 to 10%, 10 to 15%, 15 to 20%, 20 to 25%, or 25 to 30% by weight anti-C5 agent. In some embodiments, the microparticles comprise from 60 to 72% by weight silica content and from 2.5 to 25% by weight anti-C5 agent. In some embodiments, the microparticles comprise from 64 to 68% by weight silica content and from 15 to 19% by weight anti-C5 agent.

[0022]

[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 not pegylated.

Brief Description of the Drawings

[0023]

Figure 1A

[0026] Figure 1A shows the particle size distribution of an exemplary particulate formulation.

Figure 1B

[0027] Figure 1B shows the D10 value, D50 value, and D90 value of Formulations #01 to #03.

Figure 2

[0028] Figures 2A and 2B show the in vitro dissolution data of Formulations #04 to #06.

Figure 3

[0029] Figures 3A and 3B show the in vitro dissolution data of Formulations #07 to #09. These experiments analyzed the effect of API (active pharmaceutical ingredient) loading.

Figure 4

[0030] Figures 4A and 4B show the in vitro dissolution data of Formulation #02 - repeated, Formulation #10, and Formulation #11. These experiments analyzed the effect of batch size.

Figure 5A

[0031] Figure 5A shows the pH measurements of the particulate and hydrogel formulations in Tables 1 and 2.

Figure 5B

[0032] Figure 5B shows the D10 value, D50 value, and D90 value of the particulate formulation in Table 1.

Figure 5C

[0033] Figure 5C shows the particle size distribution of the particulate formulation in Table 1.

Figure 6A

[0034] Figure 6A shows the SEM (scanning electron microscope) imaging of the particulate formulation in Table 1 at the first image magnification.

Figure 6B

[0035] Figure 6B shows the SEM imaging of the particulate formulation in Table 1 at the second image magnification.

Figure 7

[0036] Figure 7 shows the in vitro release of API and the degradation of the silica matrix in Particles #01 to #03 in Table 3.

Figure 8A

[0037] Figure 8A shows the degradation of the silica matrix of the particulate and hydrogel formulations in Tables 1 and 2.

Figure 8B

[0038] Figure 8B shows the API release of the particulate formulations and hydrogel formulations in Tables 1 and 2.

Figure 8C

[0039] Figure 8C shows a graph indicating the relationship between the degradation of the silica matrix and API dissolution.

Figure 9

[0040] Figure 9 shows a graph indicating the exposure of the eye tissues of Dutch belted rabbits by the PK formulation. The solid line from top to bottom represents the vitreous SR depot (1 mg), retinal SR depot (1 mg), and RPE / choroid SR depot (1 mg). "IVT" = intravitreal. "SR" = sustained release.

Figure 10

[0041] Figures 10A to 10D show data from the analysis of the stability of the PK formulation after 8 weeks (8W) at 2 - 8°C. Figure 10A shows the degradation of silica. Figure 10B shows the release of API. Figure 10C shows the total silica content (wt.-%) in the hydrogel depot. Figure 10D shows the total API content (wt.-%) in the hydrogel depot.

Figure 11

[0042] Figures 11A to 11D show data from the analysis of the stability of the PK formulation after 8 weeks (8W) at room temperature. Figure 11A shows the degradation of silica. Figure 11B shows the release of API. Figure 11C shows the total silica content (wt.-%) in the hydrogel depot. Figure 11D shows the total API content (wt.-%) in the hydrogel depot.

Figure 12-1

[0043] Figures 12A to 12D show data from the analysis of the degradation of formulation #11. "1W" = 1 week.

Figure 12-2

[0043] Figures 12A to 12D show data from the analysis of the degradation of formulation #11. "1W" = 1 week.

Figure 13

[0044] Figures 13A and 13B show data from the rheological evaluation of the composite depot.

Figure 14-1

[0045] Figures 14A to 14C show data from experiments analyzing the dissolution profiles of various formulations and the particle size distribution of the microparticles.

Figure 14-2

[0045] Figures 14A - 14C show data from experiments analyzing the dissolution profiles of various formulations and the particle size distributions of the fine particles.

Figure 15-1

[0046] Figures 15A - 15C show data from experiments analyzing the dissolution profiles of various formulations and the particle size distributions of the fine particles.

Figure 15-2

[0046] Figures 15A - 15C show data from experiments analyzing the dissolution profiles of various formulations and the particle size distributions of the fine particles.

Figure 16-1

[0047] Figures 16A - 16C show data from experiments analyzing the dissolution profiles of various formulations and the particle size distributions of the fine particles.

Figure 16-2

[0047] Figures 16A - 16C show data from experiments analyzing the dissolution profiles of various formulations and the particle size distributions of the fine particles.

Figure 17-1

[0048] Figures 17A - 17C show data from experiments analyzing the dissolution profiles of various formulations and the particle size distributions of the fine particles.

Figure 17-2

[0048] Figures 17A - 17C show data from experiments analyzing the dissolution profiles of various formulations and the particle size distributions of the fine particles.

Figure 18A

[0049] Figures 18A - 18B show data from experiments analyzing the dissolution profile of silica in various formulations (Figure 18A) and the dissolution profile of the API (Figure 18B).

Figure 18B

[0049] Figures 18A - 18B show data from experiments analyzing the dissolution profile of silica in various formulations (Figure 18A) and the dissolution profile of the API (Figure 18B).

Mode for Carrying Out the Invention

[0024]

[0050] One aspect of the present disclosure relates to a sustained release silica hydrogel composite comprising an anti-complement agent (such as an anti-C5 agent or an anti-C3 agent) and a method of using the same to treat ophthalmic conditions. The sustained release silica hydrogel composites provided herein have characteristics of favorable API delivery in the eye over time, stability, and low accumulation of the residual matrix. These composites provide an unexpected advantage of a direct relationship between silica and API dissolution. Thus, the matrix that controls drug release does not remain in the eye for a long time after the API has dissolved. Further, the composites provided herein have the beneficial property of shear thinning of the depot formulation of the composite, which enables administration using a narrow bore or gauge needle that is advantageous for intravitreal drug delivery.

[0025] Anti-complement agent

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

[0026]

[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 suppresses the activity or production of the C5 complement protein or a variant thereof. An anti-C5 agent can reduce or suppress the conversion of the C5 complement protein into its component polypeptides C5a and C5b. An anti-C5 agent can also reduce or suppress the activity or production of C5a and / or C5b.

[0027]

[0053] In some embodiments, the anti-C5 agent is an anti-C5 aptamer. An aptamer is a nucleic acid molecule that has specific binding affinity for a molecule through interactions other than the well-known Watson-Crick base pairs. Aptamers, like peptides generated by phage display or monoclonal antibodies (“mAbs”), can specifically bind to a selected target and modulate the activity of the target. For example, the binding aptamer can block the ability of its target to function. Aptamers may or may not be PEGylated. In some embodiments, the aptamer may contain one or more 2'-sugar modifications, such as 2'-O-alkyl (e.g., 2'-O-methyl or 2'-O-methoxyethyl) or 2'-fluoro modifications.

[0028]

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

[0029]

[0055] Furthermore, exemplary C5-specific aptamers may also include the aptamers disclosed in PCT Publication No. WO2007 / 103549, which are incorporated by reference in their entirety. For example, exemplary C5-specific aptamers include aptamer 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), 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 (SEQ ID 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 may be included.,

[0030]

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

[0057] In some embodiments, ARC186 (SEQ ID NO: 26) may include 21 pyrimidine residues of ARC186 having a 2'-fluoro modification. Most of the purines (14 residues) have a 2'-OMe modification except for 3 2'-OH purine residues.

[0031]

[0058] In some embodiments, the anti-C5 aptamer may also include different mixtures of 2'-fluoro modifications and 2'-H modifications. In some embodiments, the anti-C5 aptamer is ARC330. ARC330 (SEQ ID NO: 34) contains 7 2'-H modifications, 14 pyrimidine residues having a 2'-fluoro modification, 14 purine residues having a 2'-OMe modification, and 3 2'-OH purine residues.

[0032]

[0059] In some embodiments, the aptamer may be PEGylated, for example, it may be conjugated to a polyethylene glycol moiety (PEG) by a linker. The PEG moiety may have a molecular weight greater than about 10 kDa, such as 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 by 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 PEG moiety of about 40 kDa is a branched PEG moiety. The branched PEG moiety of about 40 kDa can be, for example, 1,3-bis(mPEG-[about 20 kDa])-propyl-2-(4'-butamide), or 2,3-bis(mPEG-[about 20 kDa])-propyl-1-carbamoyl. In some embodiments, the aptamer may not be PEGylated.

[0033]

[0060] Unless otherwise specified or clear from the context, the term "about" means within 10% above or below the reported numerical value (except when such a number is greater than 100% or less than 0% of the numerical value considered). When used in conjunction with a range or a series of numerical values, the term "about" applies to the endpoints of the range or each of the enumerated numerical values, unless otherwise indicated. In this application, the terms "about" and "approximately" are used interchangeably.

[0034]

[0061] In some embodiments, the aptamer has a structure

[0035]

Chemical formula

[0036] The compound ARC187 or a pharmaceutically acceptable salt thereof, wherein the aptamer = fCmGfCfCGfCmGmGfUfCfUfCmAmGmGfCGfCfUmGmAmGfUfCfUmGmAmGfUfUfUAfCfCfUmGfCmG-3T (SEQ ID NO: 1), wherein fC and fU = 2'-fluoronucleotides, mG and mA = 2'-OMe nucleotides, and all other nucleotides are 2'-OH, where 3T represents inverted deoxythymidine. In some embodiments, each 20 kDa mPEG of the above structure has a molecular weight of about 20 kDa.

[0037]

[0062] In some embodiments, the aptamer is the compound ARC1905 having the following structure,

[0038]

Chemical formula

[0039] or a pharmaceutically acceptable salt thereof, wherein the aptamer = fCmGfCfCGfCmGmGfUfCfUfCmAmGmGfCGfCfUmGmAmGfUfCfUmGmAmGfUfUfUAfCfCfUmGfCmG-3T (SEQ ID NO: 1), wherein fC and fU = 2'-fluoronucleotides, mG and mA = 2'-OMe nucleotides, and all other nucleotides are 2'-OH, where 3T represents inverted deoxythymidine. In some embodiments, each 20 kDa mPEG of the above structure has a molecular weight of about 20 kDa. As shown in the figure, the above structure has a hexylamino linker.

[0040]

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

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

[0041]

[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, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, camphorsulfonate, pamoate, phenylacetate, trifluoroacetate, acrylate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoate, naphthalene-2-benzoate, isobutyrate, phenylbutyrate, α-hydroxybutyrate, butyne-1,4-dicarboxylate, hexyne-1,4-dicarboxylate, caprate, caprylate, cinnamate, glycolate, heptanoate, hippurate, malate, hydroxymaleate, malonate, mandelate, mesylate, nicotinate, phthalate, teraphthalate, propiolate, propionate, phenylpropionate, sebacate, suberate, p-bromobenzenesulfonate, chlorobenzenesulfonate, ethylsulfonate, 2-hydroxyethylsulfonate, methylsulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, naphthalene-1,5-sulfonate, xylenesulfonate, and tartarate salts. The term "pharmaceutically acceptable salts" includes, but is not limited to, hydrates of the compounds provided herein, and may also refer to salts of antagonists provided herein that have carboxylic acid functional groups or hydrogen phosphate functional groups, and acidic functional groups such as, but not limited to, bases.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-, bis-, or tris-(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine, or tris-(hydroxymethyl)methylamine such as mono-, bis-, or tris-(2-OH-lower alkylamine); N,N-di-lower alkyl-N-(hydroxyl-lower alkyl)-amine such as N,N-dimethyl-N-(2-hydroxyethyl)amine or tri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; and amino acids such as arginine and lysine.

[0042]

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

[0043]

[0068] Formulations for injection include sterile aqueous or non-aqueous solutions, suspensions, emulsions, or gels. In some embodiments, the formulation for injection is a sol. In some embodiments, the formulation for injection is a hydrogel. Various aqueous carriers such as water, buffered water, physiological saline, etc. can be used. Such formulations can also contain excipients such as preservatives, wetting agents, buffering agents, emulsifying agents, dispersing agents, and suspending agents.

[0044]

[0069] In some embodiments, excipients for a composition comprising an anticomplement 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, monobasic sodium phosphate, dibasic sodium 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 sorbitan fatty acid esters such as polysorbate 20 and polysorbate 80. Suitable preservatives include, but are not limited to, benzyl alcohol, ascorbic acid / salt / ester, butylhydroxytoluene, 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, one or more pH adjusters are present in an amount effective to adjust the pH to 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, one or more pH adjusters are present in an amount effective to adjust the pH to 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, one or more pH adjusters are present in an amount effective to adjust the pH to about 6.8 to about 7.8. In some embodiments, the composition does not contain a preservative. In some embodiments, the composition does not contain an antibacterial agent. In some embodiments, the composition does not contain a bacteriostatic agent.

[0045] Silica

[0070] Silica (silicon dioxide, SiO₂) is a versatile substance that can be obtained naturally and synthetically prepared in many forms. Silica can be prepared / modified into many different structures by the fuming method or wet synthesis methods, resulting in different properties with respect to both texture characteristics and (surface) chemical properties. For example, silica can be prepared by the sol-gel method. Sol-gel-derived SiO₂ and other SiO₂-based materials can generally be prepared from alkoxides, alkyl alkoxides, amino alkoxides, or inorganic silicates that form sols containing partially hydrolyzed silica species and / or fully hydrolyzed silicic acid by hydrolysis. The resulting condensation reaction of Si(OH)₄-containing species leads to an increase in siloxane bonds and the formation of larger silica species. These silica species oligomerize / polymerize to form small particles, turning the reaction solution into a sol.

[0046]

[0071] Silica prepared by the sol-gel method can be processed into a three-dimensional structure by casting (e.g., monolithic rods), spinning (fibers), dip-coating / squeeze-spinning (coatings), or by preparing particles of different sizes. In some embodiments, the particles are prepared by spray drying, which results in particles or spheres that are mostly on the micrometer scale, or by growing and increasing the particles in the sol under alkaline conditions, resulting in a colloidal silica dispersion, i.e., submicron, nanoscale particles in solution. The liquid in the colloidal dispersion can be evaporated, and the resulting powder of colloidal particles is typically washed and dried several times. The particles are sometimes also prepared, for example, by grinding a monolith to a desired size. All conventional sol-gel processing methods include a step of drying and / or heat treating the structure to somewhat reduce the amount of solution / solvent such as water and alcohol. In some embodiments, the silica particles are prepared by spray drying or liquid-phase synthesis, by cutting and spinning or pulling up silica fibers, by molding or casting a silica monolith, and, when necessary to obtain a defined particle size, by grinding the molded or cast silica monolith.

[0047]

[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, where the solid phase, such as silica itself and / or partially or fully hydrolyzed silica, is the continuous phase and the liquid, such as water, ethanol, and silica precursor residues, is uniformly dispersed in the structure. The gel is viscoelastic, with elastic properties predominating, and the viscoelasticity is indicated 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 is non-flowing at rest but is flowing 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”.

[0048]

[0073] In some embodiments, the sol can be a homogeneous mixture of at least one liquid phase and one solid phase, i.e., a colloidal dispersion, where the liquid phase, such as water, ethanol, and silica precursor residues, is the continuous phase and the solid phase, such as colloidal particles of silica and / or partially or fully hydrolyzed silica and / or aggregates of said particles, is uniformly dispersed in the liquid phase, and the sol can be characterized by having distinct flow properties and the liquid phase predominating.

[0049] Composition comprising an anti-complement agent and silica

[0074] In some embodiments, an exemplary composition for treating an ophthalmic condition is a particulate composition comprising a silica content in the range of 30 - 90%, in preferred embodiments in the range of 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%, in preferred embodiments in the range of 1 - 10%, 10 - 20%, 20 - 30%, 20 - 55%, 30 - 40%, 40 - 50%, or 50 - 60%, and a silica precursor residue content in the range of 1 - 40%, in preferred embodiments in the range of 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 particulate composition comprises a silica content in the range of 64 - 68%, an anti-C5 agent content in the range of 15 - 19%, and a silica precursor residue content in the range of 14 - 18%. In some embodiments, the particulate 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, and the aptamer has the fCmGfCfCGfCmGmGfUfCfUfCmAmGmGfCGfCfUmGmAmGfUfCfUmGmAmGfUfUfUAfCfCfUmGfCmG-3T (SEQ ID NO: 1) nucleotide sequence of, where 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 the silica precursor. In some embodiments, the silica precursor is tetraethyl orthosilicate ethyl silicate (TEOS), and the hydrolysis product is ethanol.

[0050]

[0075] In some embodiments, the sustained-release silica hydrogel composite has a silica content in the range of 10 to 50%, preferably in the range of 10 to 30%, 20 to 50%, 20 to 25%, 25 to 30%, 30 to 35%, 35 to 40%, 40 to 45%, or 45 to 50%, an anti-C5 agent content in the range of 1 to 30%, or 1 to 50%, and in a more preferred embodiment, in the range of 1 to 5%, 5 to 10%, 5 to 30%, 10 to 15%, 15 to 20%, 20 to 25%, or 25 to 30%, and a water and silica precursor residue content in the range of 40 to 80%, preferably in the range of 40 to 50%, 50 to 60%, 55 to 70%, 60 to 70%, or 70 to 80%. In some embodiments, the silica composite has a silica content in the range of 24 to 34%, an anti-C5 agent content in the range of 6 to 9%, and a water and silica precursor residue content in the range of 61 to 69%. In some embodiments, the silica composite has a silica content in the range of 10 to 30%, an anti-C5 agent content in the range of 5 to 30%, and a water and silica precursor residue content in the range of 55 to 70%. In some embodiments, the anti-C5 agent comprises a C5-specific aptamer, and the aptamer has the fCmGfCfCGfCmGmGfUfCfUfCmAmGmGfCGfCfUmGmAmGfUfCfUmGmAmGfUfUfUAfCfCfUmGfCmG-3T (SEQ ID NO: 1) nucleotide sequence of, where fC and fU are 2'-fluoronucleotides, mG and mA are 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 water and the silica precursor. In some embodiments, the silica precursor is TEOS and the hydrolysis product is ethanol. In some embodiments, the silica hydrogel composite is silica-based microparticles containing an anti-C5 agent, and the microparticles are one of dispersed, suspended, or contained within the silica-based hydrogel.

[0051]

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

[0052]

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

[0053]

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

[0054]

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

[0055]

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

[0056]

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

[0057]

[0082] In some embodiments, the sustained release silica hydrogel composite comprises silica microparticles dispersed in a silica sol hydrogel. In some embodiments, the sustained release silica hydrogel composite is a depot formulation, and the depot formulation is microparticles suspended in a silica sol hydrogel. In some embodiments, the depot formulations provided herein exhibit thixotropy. The depot formulations can be filled into a container closure system, such as a syringe for administration. Provided herein is a syringe comprising the sustained release silica hydrogel composite disclosed herein.

[0058] Early AMD

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

[0059]

[0084] In some embodiments, the present disclosure relates to methods and compositions useful for subjects having 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 that are vertically oriented and determined by OCT, namely, (1) regions of hypertransmission of signals to the choroid, (2) corresponding zones of attenuation or disruption of the RPE, and (3) evidence or signs of degeneration of the overlying photoreceptors. Evidence or signs of degeneration of the overlying photoreceptors include sinking of the inner nuclear layer (“INL”) and outer plexiform layer (“OPL”), the presence of hyporeflective wedges in the Henle fiber layer (“HFL”), thinning of the outer nuclear layer (ONL), disruption of the external limiting membrane (“ELM”), and disintegration of the ellipsoid zone (“EZ”). iRORA should not be used to refer to RPE breaks.

[0060]

[0085] In some embodiments, the present disclosure relates to methods and compositions useful for subjects having risk factors for progression to iRORA. Subjects showing risk factors for progression to iRORA show some, but not all, of the signs of iRORA as described above. Further, subjects showing high-risk drusen and risk factors for progression to iRORA may also show hyperreflective lesions, heterogeneous internal reflectivity of drusen, and / or subretinal drusenoid deposits. Determination of whether a subject has risk factors for progression to iRORA is also achieved by multimodal imaging, which includes, but is not limited to, OCT. Subjects having risk factors for progression to iRORA are at risk of progressing to iRORA, cRORA, nGA, GA, and / or exudative AMD.

[0061]

[0086] Risk factors are well known in the art and include, for example, hypertension, obesity, atherosclerosis, localized deposition of acellular organic deposits 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, higher plasma fibrinogen, and / or diabetes (see, e.g., Garcia-Layana et al., Clinical Interventions in Aging 2017:12 1579-1587, the contents of which are hereby incorporated by reference in their entirety).

[0062]

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

[0063]

[0088] In some embodiments, the present disclosure relates to methods and compositions useful for a subject having nGA. nGA is an ophthalmic disease, disorder, and / or condition characterized by (i) a depression of the inner nuclear layer ("INL") and the outer plexiform layer ("OPL"), and (ii) a hyporeflective wedge-shaped band within the OPL, including within the Henle fiber layer. nGA may also be accompanied by RPE disruption and an increase in signal overtransmission to the choroid. Further, features frequently present with the depression of the OPL and INL may include damage to the inner segment ellipsoid ("ISe"), disruption of the ELM, and evidence of increased signal transmission under the Bruch's membrane. Also, features frequently present with the hyporeflective wedge-shaped band include depressions such as vortices of the OPL and INL, drusen regression, and evidence of increased signal transmission under the RPE. The onset of nGA may also be accompanied by, or preceded by, partial or complete drusen regression, such that the overlying retinal layers undergo changes characteristic of progressive atrophy. nGA may also be associated with, and / or occur concurrently with, an iRORA disease state. A subject showing nGA may have previously shown risk factors for progression to iRORA and may subsequently show cRORA and / or GA.

[0064]

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

[0065]

[0090] Furthermore, highly dangerous drusen may be characterized by other morphological features. Also, highly dangerous drusen may be characterized with respect to the maximum height and maximum diameter of the lesion, the internal reflectivity of the lesion, the presence and extent of hyperreflective lesions within the overlying retina, and the choroidal thickness both under the fovea and under the drusen. Furthermore, highly dangerous drusen may exhibit hyperreflective lesions covering the drusen, non-uniform internal reflectivity of the drusen, or a choroidal thickness of less than 135 μm below the baseline of the drusen. Furthermore, highly dangerous drusen may be soft, large, indistinct, and / or confluent.

[0066]

[0091] In some embodiments, the subject exhibits hyperpigmentation or hypopigmentation. In some embodiments, an increase in hyperpigmentation is another way of indicating disease progression. In some embodiments, hypopigmentation is associated with a particular disease state.

[0067]

[0092] SD-OCT specifically provides a reliable and reproducible method for measuring the morphology of drusen over time, as well as other features of AMD. Furthermore, SD-OCT algorithms are available for quantifying drusen features. Such algorithms can be fully automated and can reliably report drusen burden, the volume and area of drusen using cube root and square root transforms respectively, and morphological changes over time. Advances in imaging methods using SD-OCT and color fundus images have made it possible to study and measure the morphology of drusen by providing a three-dimensional, geometric evaluation. SD-OCT imaging methods also enable multimodal imaging and identify other macular features that increase the risk of vision loss, including a decrease in the internal reflectivity of drusen (identified as calcified drusen), hyperreflective lesions within the retina, and subretinal drusenoid deposits. Devices used for SD-OCT, such as Cirrus HD-OCT, are well known in the art.

[0068] Administration and Dosage

[0093] The dosage of the anticomplement agent (e.g., anti-C5 agent) for ocular administration 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 dosage of the anti-C5 agent for ocular administration 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, about 3.25 mg / eye, or about 3.50 mg / eye, or about 3.75 mg / eye, or about 4 mg / eye.

[0069]

[0094] In some embodiments, the dosage of the anticomplement agent (e.g., anti-C5 agent) for ocular administration can be about 0.3 mg / eye to about 5 mg / eye. In some embodiments, the dosage of the anticomplement agent (e.g., anti-C5 agent) for ocular administration can be about 2 mg / eye.

[0070]

[0095] The dosage of the anticomplement agent (e.g., anti-C5 agent) for ocular administration can be an amount equivalent to about 100 - 200, about 200 - 400, about 400 - 600, about 600 - 800, or about 800 - 1000 μg of oligonucleotide.

[0071]

[0096] The daily drug dosage provided by the silica complex (e.g., microparticles and silica hydrogel) can be 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.

[0072]

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

[0073]

[0098] The silica complex (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 2 months, once every 3 months, once every 4 months, once every 5 months, or once every 6 months.

[0074]

[0099] In some embodiments, the silica complex (e.g., microparticles and silica hydrogel) can be administered into or around the eye, for example, by subconjunctival injection, retrobulbar injection, intracameral injection, sub-Tenon's injection, subretinal injection, suprachoroidal injection, or intravitreal injection. In some embodiments, the silica complex is administered by intravitreal injection. In some embodiments, the silica complex is administered by suprachoroidal injection. The silica complex can be in the form of a depot.

[0075]

[0100] In some embodiments, a dosing regimen comprising a loading phase and a maintenance phase may be administered. In some embodiments, the silica complex (e.g., microparticles and silica hydrogel) can be administered in a dosing regimen comprising a loading phase and a maintenance phase. In some embodiments, the loading phase can comprise administering an anti-C5 agent, while the maintenance phase can comprise administering a silica complex (e.g., microparticles and silica hydrogel). In some embodiments, the anti-C5 agent is avacincaptad pegol. In some embodiments, the loading phase can comprise administering avacincaptad pegol at a different dose, different frequency, or a combination thereof, compared to avacincaptad pegol in the silica complex during the maintenance phase. For example, the loading phase can comprise 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, and the maintenance phase can comprise administering avacincaptad pegol in the silica complex at a dose that is 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 dose of avacincaptad pegol in the loading phase, or at a dose exceeding the dose of avacincaptad pegol in the loading phase.Alternatively, or additionally, the loading phase can include administering abataceptadopegol at a frequency with an interval between administrations of 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 2 months, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 3 months, 4 months, 5 months, or 6 months, and the maintenance phase can include administering abataceptadopegol in the silica complex at an interval between administrations that is 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 interval between administrations of the loading phase or at a frequency exceeding the interval between administrations of the loading phase. In some embodiments, the loading phase can last for a period of 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 start simultaneously with the loading phase, at any time within the loading phase, or at the end of the loading phase.

[0076]

[0101] In some embodiments, abicipar pegol can be administered in a dosing regimen that includes a loading phase with a dose of about 2 mg / eye administered once a month for up to 1 year, followed by a maintenance phase with 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, or about 3.75 mg / eye, or about 4 mg / eye of abicipar pegol in the silica complex 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, or once every 26 weeks. In some embodiments, abicipar pegol can be administered in a dosing regimen that includes a loading phase with a dose of about 4 mg / eye administered once a month for up to 1 year, followed by a maintenance phase with a dose of about.3 mg / eye, or about.5 mg / eye, or about.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 of abicipar pegol in the silica complex 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, or once every 26 weeks.In some embodiments, abicipar pegol is administered in a dosing regimen that includes a loading phase with a dose of about 2 mg / eye administered once a month for a period of about six months, followed by a maintenance phase in which abicipar pegol in the silica complex is administered once every eight weeks, once every nine weeks, once every ten weeks, once every eleven weeks, once every twelve weeks, once every thirteen weeks, once every fourteen weeks, once every fourteen weeks, once every fifteen weeks, once every sixteen weeks, once every seventeen weeks, once every eighteen weeks, once every nineteen weeks, once every twenty weeks, once every twenty-one weeks, once every twenty-two weeks, once every twenty-three weeks, once every twenty-four weeks, once every twenty-five weeks, or once every twenty-six weeks at 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.

[0077]

[0102] The amount of the silica complex (e.g., microparticles and silica hydrogel) administered to the subject can range from about 10 to about 2000 μL, or from about 25 to about 2000 μL. In some embodiments, the silica complex can be administered intravitreally or peribulbar, for example, by subconjunctival injection, retrobulbar injection, intracameral injection, sub-Tenon's injection, subretinal injection, suprachoroidal injection, or intravitreal injection. In some embodiments, the silica complex can be administered by intravitreal injection. In some embodiments, the silica complex can be administered by suprachoroidal injection.

[0078]

[0103] In the present disclosure, any range of concentrations, ratios, proportions, or integers is to be understood to include any integer value within the recited range, and, where appropriate, fractions thereof (such as tenths and hundredths of an integer), unless otherwise indicated.

[0079] Numbered embodiments

[0104] Notwithstanding the appended claims, the present disclosure describes the following numbered embodiments.

[0080]

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

[0081]

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

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

[0082]

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

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

[0083]

[0110] Embodiment 6. The sustained-release silica hydrogel composite of any one of Embodiments 1 to 5, comprising silica fine particles dispersed in a silica sol hydrogel.

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

[0084]

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

[0113] Embodiment 9. A sustained-release silica hydrogel composite according to any one of Embodiments 1 to 7, wherein the anti-C5 agent is not pegylated.

[0085]

[0114] Embodiment 10. A syringe containing a sustained-release silica hydrogel composite according to any one of Embodiments 1 to 9.

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

[0086]

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

[0087]

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

[0088]

[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, geographic atrophy, geographic atrophy, or exudative age-related macular degeneration.

[0089]

[0119] Method according to any one of Embodiments 11 to 14, wherein the sustained-release silica hydrogel complex is administered to a subject by subconjunctival injection, retrobulbar injection, intracameral injection, sub-Tenon's injection, subretinal injection, suprachoroidal injection, or intravitreal injection.

[0090]

[0120] Method according to any one of Embodiments 11 to 14, wherein the sustained-release silica hydrogel complex is administered to a subject by intravitreal injection.

[0121] Method according to any one of Embodiments 11 to 14, wherein the sustained-release silica hydrogel complex is administered to a subject by suprachoroidal injection.

[0091]

[0122] Method according to any one of Embodiments 11 to 17, wherein the sustained-release silica hydrogel complex is administered to a subject at a dose of about 0.3 mg / eye to about 5 mg / eye.

[0123] Method according to any one of Embodiments 11 to 17, wherein the sustained-release silica hydrogel complex is administered to a subject at a dose of about 2 mg / eye.

[0092]

[0124] Method according to any one of Embodiments 11 to 19, wherein the sustained-release silica hydrogel complex is administered to a subject at a frequency such that the period between administrations is at least about 3 months.

[0125] Method according to any one of Embodiments 11 to 19, wherein the sustained-release silica hydrogel complex is administered to a subject at a frequency such that the period between administrations is about 4 months, about 5 months, or about 6 months.

[0093]

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

[0094]

[0127] Embodiment 23. The formulation of Embodiment 22, wherein 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%.

[0095]

[0128] Embodiment 24. The formulation of Embodiment 22, wherein the microparticles contain a silica 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 contain a silica content in the range of 64 - 68% and an anti-C5 agent in the range of 15 - 19%.

[0096]

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

[0131] Embodiment 27. The formulation according to any one of Embodiments 22 - 25, wherein the anti-C5 agent is not pegylated.

[0097]

[0132] The present disclosure is further illustrated by the following examples, which are intended to be merely illustrative of the present disclosure and are in no way limiting.

Examples

[0098] Example 1A: Preparation of silica microparticles containing an anti-C5 agent using a semi-batch reactor process

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

[0099]

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

[0100]

[0135] TEOS was hydrolyzed in a batch reactor. The preparation of silica microparticles having encapsulated abaciclib captad pegol 15% (w / w) was initiated along with the production of silica sol. The sol was prepared by mixing tetraethyl orthosilicate (TEOS, Sigma Aldrich), a silica precursor, with milli-Q water (Merck Millipore) and 0.1 M hydrochloric acid (HCl, Merck Titripur). The molar ratio of water to TEOS, designated as the R value, was 5. Using 0.1 M HCl stock, the pH of the final mixture was adjusted to a value of 2. The hydrolysis reaction was carried out for 25 minutes at room temperature (21 - 23 °C) under continuous stirring. The silica sol was diluted with milli-Q water to an R value of 55 - 66 and the pH was adjusted to 3.0 ± 0.1 using 0.1 M sodium hydroxide (NaOH, Merck Titripur) solution. Next, 33.58 ml of the aqueous abaciclib captad pegol solution was added to the silica sol and mixed. Finally, the pH of the silica sol containing abaciclib captad pegol was adjusted to 6.0 ± 0.1 with 0.1 M NaOH solution. The R value of the final silica sol with soluble abaciclib captad pegol was 100 with respect to the components other than 0.1 M NaOH.

[0101]

[0136] The sol containing silica and ACP was injected into a spray dryer (SD, Buchi B - 290) at an outlet temperature between 52 - 66 °C to obtain spray - dried silica microparticles containing abaciclib captad pegol. The ACP - silica microparticles were stored at 4 - 8 °C until further processing.

[0102]

[0137] Using the described semi - batch process, formulations were prepared with varying drug load of the API, first R value or major R value, and batch size as outlined in Table 1.

[0103]

Table 1

[0104]

[0138] The feasibility formulations (microparticles) #01 - #11 (Table 1A and Table 1B) were characterized by light scattering particle size distribution, scanning electron microscopy, and in vitro dissolution. The results suggested that an increase in API loading accelerated in vitro dissolution (Figure 3A, Figure 3B). The first R value had no measurable effect on the light scattering particle size distribution or in vitro dissolution. The semi-batch process could be reproducibly prepared in the laboratory, and the batch size was increased.

[0105]

Table 2

[0106]

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

[0107]

[0140] In addition 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. That is, API loading = m API / m SiO2 Furthermore, the pH coincides with the pH of the API-sol mixture at the start of spray drying. Additionally, the inlet / outlet temperature coincides with the spray drying inlet air temperature and the spray drying outlet air temperature.

[0108]

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

[0109]

[0142] Figure 1B shows the D10 value, D50 value, and D90 value of Formulations #01 to #03. In this regard, the particle size distribution is suitable for injection with a narrow gauge needle. For example, the particle size values for D10, D50, and D90 can be those at one of 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, or 10% of the inner diameter or lumen size of the needle.

[0110]

[0143] The particle size distributions for Feasibility Formulations #04 to #06 are shown in Table 2. The microparticle formulations appear to be very similar. All formulations show a shoulder on the right side of the distribution, which may indicate the presence of aggregates of particles (microparticles that fused together during spray drying). The in vitro dissolution data for Feasibility Formulations #04 to #06 are shown in Figures 2A and 2B. The conclusion from the investigation of Formulations #04 to #06 is that the first R value does not affect in vitro dissolution or the particle size distribution of spray-dried microparticles.

[0111]

Table 3

[0112]

[0144] Drug Loading Evaluation 2: A second investigation of the effect of drug loading was conducted to add or supplement the particle sizes between 20% and 40% loading investigated in Formulations #02 and #03. Here, drug loadings of 25%, 30%, and 35% were investigated. The data show that Formulations #07 to #09 have release rates that fall between those of the boundary Formulations #02 and #03 with drug loadings of 20% and 40% respectively. The results support the conclusion that as the drug loading increases, the in vitro dissolution kinetics become faster but do not affect the particle size distribution of the spray-dried material.

[0113]

[0145] The particle size distributions for Feasibility Formulations #07 to #11 are shown in Table 3. All formulations show a shoulder on the right side of the distribution, which may indicate the presence of aggregates of particles. The in vitro dissolution data for Feasibility Formulations #07 to #09 are shown in Figures 3A and 3B.

[0114]

Table 4

[0115]

[0146] Scale-up. The bench-scale process was scaled based on the amount of silica raw material (TEOS) input. In vitro dissolution data for Feasibility Formulation #02 (repeated), Formulation #10, and Formulation #11 are shown in FIGS. 4A and 4B. The bench-scale scale-up study demonstrated that the input of silica can be increased by 5 times without affecting the in vitro dissolution kinetics or particle size distribution of the spray-dried substance.

[0116] Example 1B: Preparation of Further Exemplary Formulations Containing an Anti-C5 Agent

[0147] As described in more detail in the following examples, further exemplary formulations as shown in Table 4 were created and tested. Formulation Degradation Test 1 was prepared using the semi-batch process described in Example 1A that was appropriately scaled. The remaining formulations annotated as CSTR (Continuous Stirred Tank Reactor) 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 later examples.

[0117]

[0148] FIGS. 18A and 18B show that the dissolution rates of silica and the API are equivalent for Formulation #11 CSTR-1, Formulation #11 CSTR-2, and Formulation #11 CSTR-3. These data suggest that the CSTR batches have equivalent dissolution release profiles.

[0118]

Table 5

[0119]

Table 6

[0120] Example 2: Preparation of Silica Particles Containing an Anti-C5 Agent Using a Continuous Stirred Reactor Process

[0149] The product of silica particles was prepared using the following general procedure. That is, preparation of an anti-C5 agent (abatacept-captodipegol) and an NaOH solution, preparation of a silica sol by hydrolysis of TEOS in a batch reactor, mixing of component solutions (abatacept-captodipegol solution, NaOH solution, and silica sol) in a continuous stirred tank reactor, and spray drying.

[0121]

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

[0122]

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

[0123]

[0152] TEOS was hydrolyzed in a batch reactor. The preparation of silica particles having 17.7% (w / w) of encapsulated abatacept-captodipegol was started along with the production of the silica sol. The sol was prepared by mixing the silica precursor tetraethyl orthosilicate (TEOS, Sigma Aldrich) with milli-Q water (Merck Millipore) and 0.1 molar hydrochloric acid (Merck Titripur). The molar ratio of water to TEOS, designated as the R value, was 5. 0.1 M HCl was used so that the pH of the final mixture was 2. The hydrolysis reaction was carried out for 25 minutes at room temperature (21 - 23 °C) under continuous stirring.

[0124]

[0153] The prepared solutions were combined in a continuous stirred tank reactor. The prepared solutions (silica sol, avasiran captad peptide aqueous solution, and NaOH aqueous solution) were injected by a peristaltic pump (inlet pump) and mixed in a continuous stirred tank reactor (CSTR) at a target volume flow rate ratio of 1:3.21:2.83, respectively. The target average residence time of the CSTR is 3 to 5 minutes. The concentration of silica should be within 16.7 to 30.1 mg / ml, and the pH of the solution should be between 5.6 and 6.4. After mixing, the solution was injected into a spray dryer (SD, Buchi B-290) by a second peristaltic pump (outlet pump). The interval time of the flow-through reactor step between the CSTR and the SD should be 1 minute. The outlet temperature of the spray drying should be between 52 and 66 °C.

[0125]

[0154] The following spray drying parameters were used. That is, aspirator (air): 538.3 L / min, spray air flow: 11.2 L / min, nozzle type: co-current two-fluid, nozzle insert diameter: 0.7 mm, nozzle cap diameter: 1.4 mm, volume flow rate: 5.5 to 5.7 ml / min.

[0126]

[0155] The following represents the total content assay obtained from the particulate formulation over a one-week holding time.

[0127]

Table 7

[0128]

[0156] The total content assay of the microparticles indicates that no change in the substance occurred during the one-week holding time (e.g., no change greater than experimental variation / measurement accuracy). Example 3: Preparation of a silica hydrogel composite containing an anti-C5 agent

[0157] A silica hydrogel composite containing an anti-C5 agent was prepared using the following general procedure. The abacizumab-captadpegol-silica microparticles from Example 2 were mixed with a dilute silica sol (prepared separately by hydrolysis of TEOS) at the desired pH to obtain an abacizumab-captadpegol-silica microparticle-silica sol suspension. The resulting suspension was then transferred to a prefilled syringe for primary packaging.

[0129]

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

[0130]

[0159] Typical formulations for the hydrogel compositions of the present disclosure are shown in Table 6.

[0131]

Table 8

[0132]

[0160] In this regard, the payload of the anti-C5 agent is 4.6 ± 0.3 (mg / 50 μl). Further, the oligo-equivalent is 1.1 ± 0.0 (mg / 50 μl) when using a conversion of 0.23-fold. Further, the residue consists mostly of water from TEOS hydrolysis and trace amounts of ethanol, and n = 3 for PK.

[0133]

[0161] Figure 5A shows the pH measurements of the microparticle formulations and hydrogel formulations of Tables 5 and 6. In this regard, the pH measurement of the microparticles is used as an aid to predict the pH of the resulting hydrogel that can affect the gelation kinetics (generally, the higher the pH, the faster the gelation process).

[0134]

[0162] Figure 5B shows the D10 value, D50 value, and D90 value of the particulate preparation in Table 5. Figure 5C shows the particle size distribution of the particulate preparation in Table 5. In this regard, as shown in Figure 5C, the particle size distribution is very narrow, and most of the microparticles are 10 μm or less, predicting sufficient injectability.

[0135] Example 4: SEM Morphology of Microparticles

[0163] The particles are originally mainly spherical and visually consistent in size in static light scattering size measurements. Figure 6A shows the SEM imaging of the particulate preparation in Table 5 at the first image magnification. Specifically, the figure shows the SEM imaging at the following parameters. That is, mag = 1.00KX, EHT = 3.00kV, aperture size = 20.00μm, WD = 6.6mm, signal A = SE2, pixel size = 117.2nm. Figure 6B shows the SEM imaging of the particulate preparation in Table 5 at the second image magnification. Specifically, the figure shows the SEM imaging at the following parameters. That is, mag = 5.00KX, EHT = 3.00kV, aperture size = 20.00μm, WD = 6.7mm, signal A = SE2, pixel size = 23.44nm. In this regard, as shown in Figures 6A and 6B, the particles appear smooth and spherical. Furthermore, visually, the size of the microparticles appears to be consistent with the particle size distribution measurement. For example, most of the microparticles are less than 5 μm in diameter. Finally, as suggested by the particle size distribution profile in Figure 5C, no identifiable aggregates of microparticles are seen.

[0136] Example 5: In Vitro Release of Anti-C5 Agent from Silica Composite

[0164] Figure 7 shows the in vitro release of abacizumab captadopegol and the degradation of the silica matrix in microparticles #01 to #03 in Table 1. In this regard, as shown in the figure, the API release rate is affected by the API loading in the microparticles. Furthermore, the API is effectively encapsulated by the silica matrix, as indicated by the very low release at the 1-hour time point. Furthermore, the release of the API is controlled by the degradation of the silica matrix.

[0137]

[0165] Figure 8A shows the degradation of the silica matrix of the particulate and hydrogel formulations of Tables 5 and 6. Figure 8B shows the API release of the particulate and hydrogel formulations of Tables 5 and 6. In this regard, the API release and the degradation of the silica matrix in Figures 8A and 8B occurred at a dissolution volume of 50 ml. Further, the particulates were held at ambient temperature for 1 week prior to the production of the composite hydrogel, the purpose of which was to deliberately vary the degradation kinetics of the silica matrix and the API release kinetics. As shown in Figures 8A and 8B, the particulates each appear to retain the degradation rate of the silica matrix and the API release rate. Further, the API release rate is not affected by the preparation of the silica composite as compared to the silica particulates.

[0138]

[0166] Figure 8C shows the direct relationship between silica and API dissolution. This is a surprising advantage compared to other delivery technologies that the matrix controlling drug release can last several times longer than the API release, resulting in matrix accumulation or residual matrix in the eye over time.

[0139] Example 6: In Vivo Ocular Release of an Anti-C5 Agent from a Silica Composite

[0167] The complex formulation prepared as described in Examples 2 and 3, whose in vitro release profiles are shown in Figures 8A and 8B (using Formulation #11 CSTR-3), was evaluated for ACP release and tissue exposure after IVT administration in Dutch Belt (DB) rabbits. The study design included bilateral intravitreal administration of 1.0 mg of oligo equivalent in a 50 μL dosing volume of the silica complex PK formulation. Two rabbits (4 eyes) were sacrificed at each of the following time points: Day 1, Day 3, Day 7, Day 14, Day 28, Day 42, Day 56, and Day 84. The eyes were enucleated, and the vitreous humor, retina, and retinal pigment epithelium (RPE) / choroid were harvested for tissue-specific biological analysis using a qualified dual hybridization assay. Ocular PK (pharmacokinetics) is summarized in Figure 9 for the solution administered as an IVT bolus to the vitreous humor and retinal tissue as a control drug for the sustained release depot PK formulation. Ocular tissue PK for the PK formulation is shown as solid lines for the vitreous humor (top line), retina (center line), and RPE / choroid (bottom line). The data demonstrate that a single administration of the sustained release PK formulation of Example 3 provides consistent ocular tissue concentrations over the long term, up to 84 days.

[0140]

[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 the remaining silica by microwave plasma atomic emission spectrometry (MP-AES) method and for the remaining abicipaptad pegol content by a qualified HPLC assay method. The remaining silicon ranged between 0 and 9% of the administered dose, and the remaining abicipaptad pegol ranged between 0 and 3% of the administered dose.

[0141]

[0169] In vitro dissolution data showed an estimated release period of 30-fold based on historical in vitro-in vivo correlations (IVIVC). Based on Figure 8B, the predicted period until approximately 95% release is 3 × 30 = 90 days. This was used to predict the ACP release rate from the depot formulation (1.0 mg / 90 days = 11 micrograms per day). Using the terminal phase half-life of ACP in DB rabbits after bolus administration of the solution, the steady-state vitreous humor concentration was predicted based on a daily input of 11 micrograms per day and a terminal phase half-life of 3.8 days. This calculation estimated a steady-state vitreous humor concentration of approximately 30,000 ng / mL. The average measured steady-state vitreous humor concentration from day 28 to day 84 was 22,650 ng / g. In this analysis, since the density of the vitreous humor is approximated to 1, the measured steady-state is 75% of the predicted value. Furthermore, analysis of the depot formulation residue recovered on day 84 indicated that <10% (range 0 - 9%) of the formulation remained, which supports the predicted period of approximately 3 months or 90 days.

[0142] Example 7: Stability Evaluation

[0170] The PK formulation of Example 3 was packaged in a 0.5 mL RTF® glass luer lock syringe using a Datwyler Neoflex plug and evaluated for stability for 8 weeks under refrigerated (2 - 8°C) and room temperature storage conditions. The results of stability at 2 - 8°C are shown in Figures 10A - 10D. The results of stability at room temperature are shown in Figures 11A - 11D. The stability data under both storage conditions emphasize that there are no changes in the silica content, API content, or in vitro release kinetics of the PK formulation under either storage condition.

[0143] Example 8: Degradation Test

[0171] Interesting observations were made regarding the storage of ACP microparticles compared to the stability of the composite depot formulation of Example 7. A measurable decrease was the release rate observed as a function of storage time and storage temperature.

[0144]

[0172] Figures 12A - 12D show the change in the dissolution rate of silica (Figure 12A) and ACP (upper right panel) from silica microparticles after one week under refrigerated and room temperature storage conditions. In contrast, the dissolution rates of silica (Figure 12C) and ACP (Figure 12D) from silica depot complexes after one week under refrigerated and room temperature storage conditions are unchanged.

[0145]

[0173] Deterioration was further investigated and the influence of alternative storage conditions, including vacuum, nitrogen atmosphere, and high humidity, was evaluated. As a scale to obtain 38 g of ACP microparticles, ACP silica - based microparticles were prepared according to the method of Example 1B. This resulted in microparticles having a particle size distribution similar to that of the PK formulation of Example 2 and slightly narrower than that of the microparticles of the first degradation test.

[0146]

Table 9

[0147]

[0174] ACP microparticles were aliquoted into glass vials, loosely capped, and completely exposed to environmental storage conditions. Storage was carried out at room temperature under different atmospheric conditions including vacuum, nitrogen, and relative humidity above 95%. Under all storage conditions, the direct relationship between silica and ACP dissolution was maintained and the dissolution rate decreased as a function of time. The largest change in the dissolution rate was in the case of nitrogen storage conditions and the smallest change was in the case of the relative humidity sample above 95%. The data demonstrate that, in addition to temperature demonstrated in the first degradation test, atmospheric storage conditions affect degradation. Degradation provides a means that can be utilized to regulate the dissolution kinetics of ACP - based silica microparticles. Note that the stability data of Example 7 demonstrate that the degradation phenomenon does not occur in the final ACP complex depot formulation of ACP microparticles suspended in silica sol - hydrogel.

[0148] Example 9: Rheology of the Complex Depot

[0175] In the present disclosure, silica can be used to create a silica sol hydrogel depot, thus obviating the need for new or additional substances or excipients that may complicate biocompatibility in the composite depot formulation. The rheology of the final composite depot is a property that can affect the stability, injectability, and post-dose performance of the depot. The silica sol hydrogel creates a depot formulation of silica-based microparticles dispersed in the silica sol hydrogel. The microparticles were prepared according to the procedure of Example 1A using the composition of Formulation #11 on a feed scale of 40 mL of TEOS. Four separate composite depots were prepared using the microparticles according to the method of Example 2 at R-values of 400, 350, 300, and 250 of the hydrogel, respectively. The results are shown in FIGS. 13A and 13B.

[0149]

[0176] The rheology of the prepared composite depots was evaluated. Rheological measurements of the API-silica microparticle-silica hydrogel composite material were performed using an Anton Paar MCR 302 (Modular Compact Rheometer). A decrease in the R-value of the hydrogel correlates with an increase in the storage modulus (G’) and a decrease in the loss factor (tanδ) of the composite depot. The results showed that the rheology of the composite depot can be controlled by the silica content of the prepared silica sol hydrogel, and an increase in silica content improves the mechanical properties of the composite depot.

[0150] Example 10: Formulation Development

[0177] Experiments were conducted to explore the effect of changes in the pH, first R-value, second R-value, and reaction time of the final silica sol for the manufacture of the composite depot. Batches were prepared using the continuous flow reactor process of Example 2 and the composition as listed in Table 8.

[0151]

Table 10

[0152]

[0178] Formulations with pH values from 1 to 3 showed that the dissolution profiles tended to release more slowly at pH 7 compared to those at pH 4.9 - 5.3 and the particle size distribution of the fine particles. The formulations with pH values from 4.9 - 5.3 had a bimodal particle size distribution of the fine particles and showed potential particle aggregation under these processing conditions. The investigated pH range had a slight effect on silica or drug loading. The results are shown in Figures 14A - 14C.

[0153]

[0179] Formulations 2R#1 - 2R#3 revealed that the second R value had a slight effect on dissolution, the particle size distribution of the fine particles, silica, and drug loading. The results are shown in Figures 15A - 15C.

[0154]

[0180] Formulations Rxn#1 - Rxn#3 evaluated the effect of reaction time from 10 to 5 minutes. There was a potential tendency for a slower dissolution rate over a time range as the reaction time increased. There was a slight effect on drug loading and no effect on the particle size distribution of the fine particles. The results are shown in Figures 16A - 16C.

[0155]

[0181] Formulations 1R#1 - 1R#3 explored the effect of the main R value on a value lower than the previously evaluated value. Precipitation was observed at the main R value of 3, and this precipitation affected the total amount of abaciclib - conjugated pegol released. Since formulation 1R#3 was prepared at a pH value lower than the target pH value, this limited the conclusion that two of the three formulations of this procedure might be impaired and could be obtained from a part of this formulation. The results are shown in Figures 17A - 17C.

[0156] Example 11: Experimental Methods

[0182] The experimental methods related to the foregoing examples are briefly described as follows.

[0183] In vitro degradation

[0184] Microparticle sample: The in vitro degradation of silica and the 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% TWEEN® 80 (at pH 7.4 at +37°C). The size of the microparticle sample analyzed or the size of the hydrogel sample was approximately 10 - 25 mg, and the dissolution test was carried out for up to 96 hours in a shaking water bath (60 strokes / min).

[0157]

[0185] Hydrogel depot sample: The buffer and conditions of the hydrogel depot sample were the same as those of the microparticle sample described in the above section. The amount of sample weighed for analysis ranged from approximately 15 - 25 mg. Further, the preparation of the sample was different in that a small magnet was placed in the jar and mixed until the suspension looked homogeneous so that the hydrogel depot was dispersed in the dissolution buffer. This was done to ensure that the dissolution conditions of the hydrogel depot were equivalent to those of the microparticles, i.e., the shape of the hydrogel depot in the dissolution jar would not affect its degradation profile due to differences in the effective surface area for dissolution.

[0158]

[0186] Total content assay of silica and ACP

[0187] The concentration of silica was measured by microwave plasma atomic emission spectrometry (MP-AES), and the electron emission intensity was analyzed at a wavelength of 261 nm. The API was analyzed by high-performance liquid chromatography (HPLC) connected to a diode array detector (at λ = 258 nm). Chromatographic separation was obtained with a Thermo Scientific Guard Column DNAPac PA-100, 4×50 mm and a DNAPac PA-100, 4×250 mm, 13 μm.

[0159]

[0188] Particle size distribution (PSD)

[0189] The particle size distribution of the API silica microparticles was measured by using the static light scattering method. The equipment used was the HELOS BR3 from Sympatec, which uses an R3 lens optimal for particle sizes in the range of 0.5 to 175 μm. The sample was prepared by weighing approximately 20 mg of the API silica microparticles and adding about 3 ml of milli-Q water. Next, the suspension was vortex-mixed at full output for 30 seconds. Then, 60 μl of the suspension was pipetted and placed into a cuvette (V ≒ 35 ml) filled with milli-Q water. The sample was sheared ultrasonically for 20 seconds before measurement.

[0160]

[0190] Possibility of manual injection

[0191] The injectability of the silica API silica microparticle silica hydrogel composite formulation was tested by manually injecting the substance. First, a 27G TUTW subcutaneous needle was attached to a syringe. Next, the syringe was primed so that the substance completely filled the needle hub, and any excess substance was wiped off the needle. Finally, the primed syringe was emptied on a Petri dish. The injection was considered successful if the movement was continuous, i.e., if there was no transient blockage during the procedure. The resulting substance was also visually examined.

[0161]

[0192] The above description is given for clarity of understanding only, and unnecessary limitations should not be construed therefrom, as modifications within the scope of the present disclosure may be apparent to those skilled in the art.

[0193] Throughout the present disclosure, when a composition is described as including a component or substance, the composition may also be considered to consist essentially of, or consist of, any combination of the recited components or substances, unless otherwise stated. Similarly, when a method is described as including specific steps, the method may also be considered to consist essentially of, or consist of, a combination of the recited steps, unless otherwise stated. The invention exemplified in this specification can be preferably implemented even in the absence of any element or step not specifically disclosed herein.

[0162]

[0194] The methods disclosed in this specification, and the implementation of its individual steps, can be performed manually and / or by leveraging electronic devices or through the automation provided by electronic devices. The process is described with reference to specific embodiments, but those skilled in the art will readily understand that other methods of performing the acts associated with this method may also be used. For example, the order of the various steps can be changed without departing from the scope or spirit of the method, unless otherwise stated. Further, some of the individual steps may be combined, omitted, or further subdivided into additional steps.

[0163]

[0195] All references, papers, publications, patents, patent gazettes, and patent applications cited in this specification are hereby incorporated by reference in their entirety for all purposes. However, any reference to a reference, paper, publication, patent, patent gazette, and patent application cited in this specification is not an admission that they constitute valid prior art or form part of the common general knowledge in any country in the world or any form of suggestion or should be construed as such. In the event of any conflict between this disclosure and the references, papers, publications, patents, patent gazettes, and patent applications incorporated herein, this disclosure shall govern.

Claims

1. A sustained-release silica hydrogel composite containing silica in the range of 5 to 35% and an anti-C5 agent in the range of 1 to 40%, wherein the anti-C5 agent contains a C5-specific aptamer, and the aptamer is fCmGfCfCfCGfCmGmGfUfCfUfCmAmGmGfCGfCfUmGmAmGfUfCfUfUmGmAmGfUfUfUAfCfCfUfCmGfCmG-3T (SEQ ID NO: 1) containing the nucleotide sequence of, where fC and fU = 2'-fluoronucleotides, mG and mA = 2'-O-Me nucleotides, all other nucleotides are 2'-OH, and 3T represents inverted deoxythymidine, a sustained-release silica hydrogel composite.

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

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

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

5. The sustained-release silica hydrogel composite according to claim 1, containing silica at about 27.4% and an anti-C5 agent at about 8%.

6. The sustained-release silica hydrogel composite according to any one of claims 1 to 5, containing silica fine particles dispersed in a silica sol hydrogel.

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

2.

8. The sustained-release silica hydrogel composite 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 not pegylated.

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

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

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

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

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

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

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

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

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

20. The method according to any one of claims 11 to 19, wherein the sustained-release silica hydrogel composite is administered to the subject at a frequency such that the period between administrations is at least about 3 months.

21. The method according to any one of claims 11 to 19, wherein the sustained-release silica hydrogel complex is administered to a subject at a frequency such that the period between administrations is about 4 months, about 5 months, or about 6 months.

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

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

24. The formulation according to claim 22, wherein the microparticles contain a silica content in the range of 60 to 72% and an anti-C5 agent in the range of 2.5 to 25%.

25. The formulation according to claim 22, wherein the microparticles contain a silica content in the range of 64 to 68% and an anti-C5 agent in the range of 15 to 19%.

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

27. The formulation according to any one of claims 22 to 25, wherein the anti-C5 agent is not pegylated.

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