COMPOSITIONS FOR PHARMACOLOGICAL SUPPLY, FOR THE OCULAR ADMINISTRATION OF THERAPEUTIC AGENTS, AND METHODS OF USE THEREFOR

Abstract

The present invention relates to a drug delivery composition comprising: one or more capsules, each having a tubular conformation with two closing ends, wherein each capsule independently comprises a two-layer wall and at least one luminal compartment; and one or more therapeutic agents, each contained within one or more of the luminal compartment(s); wherein each two-layer wall comprises an inner layer and an outer layer; wherein the inner layer comprises chitosan; and wherein the outer layer comprises poly(β-caprolactone) (PCL); and wherein the one or more therapeutic agents have a net negative charge at any pH within pH 6.0 to pH 7.4

Description

COMPOSITIONS FOR PHARMACOLOGICAL DELIVERY, FOR OCULAR ADMINISTRATION OF THERAPEUTIC AGENTS, AND METHODS OF USE THEREOF CROSS REFERENCE WITH RELATED REQUESTS This application claims the benefit of priority of United States Provisional Patent Application No. 62 / 803,388, filed February 8, 2019, the disclosure of which is incorporated herein by reference in its entirety. FIELD OF THE INVENTION This disclosure relates to drug delivery compositions and, more particularly, to compositions containing one or more multilayer drug delivery capsules, for delivery of therapeutic agents to the eye. BACKGROUND OF THE INVENTION Age-related macular degeneration (AMD) is the fourth most common cause of blindness in the world, after cataracts, premature birth and glaucoma. In the United States, there are more than 11 million people diagnosed with wet AMD. It is estimated that this figure will double in 30 years. Consequently, much work has been done to understand the pathogenesis of the disease and to develop therapeutic methods. It is widely known that overexpression of vascular endothelial growth factor (VEGF), in conjunction with aging, stimulates neovascularization in the choroid, leading to irreversible retinal damage during bleeding and scarring of newly formed blood vessels. The current gold standard treatment for wet AMD is a monthly intravitreal injection of anti-VEGF, such as bevacizumab or ranibizumab, to inhibit VEGF and prevent angiogenesis. However, frequent injections often lead to infections, increased intraocular pressure, and rhegmatogenous retinal detachment, as well as patient compliance problems. New devices, such as implants and micro / nanoparticles, for long-term drug delivery into the eye have recently been reported. Unfortunately, these implants require surgical procedures for implantation and removal. Furthermore, currently known implant devices tend to be off-target and reduce pharmacological efficacy. Although microparticles or nanoparticles are relatively small in size, appropriate for injection into the eye with a 30-gauge needle, currently disclosed microparticles or nanoparticles release therapeutic agents, such as anti-VEGF therapeutics, in a rapid release window due to to biodegradation, of known particle compositions, in the first three months. Therefore, despite significant efforts directed at the treatment of AMD or other ophthalmic disorders, there is still a paucity of methods and compositions that minimize the deleterious azcAnn / Lznz / E / YiAi side effects of currently available treatment regimens. Furthermore, there is a need for drug delivery systems and compositions that can be biodegradable and control drug release for up to nine months or more after intravitreal injection. A need still exists for improved therapeutic strategies for the treatment of AMD and other ocular diseases, which require the delivery of therapeutic agents directly to the eye. These and other needs are met by the present disclosure. SUMMARY OF THE INVENTION Consistent with the purpose(s) of the present disclosure, as embodied and broadly described herein, the disclosure, in one aspect, relates to compositions, devices, and processes for the delivery of protein therapeutic agents, e.g., the delivery intravitreal delivery of a protein therapeutic agent to the eye. The disclosed drug delivery compositions comprise a capsule having a bilayered wall and a therapeutic agent contained therein. In a further aspect, the present disclosure relates to methods of treating an ophthalmic disease or disorder. Thus, in one aspect, there is provided a composition for drug delivery, comprising: one or more capsules each having a tubular conformation with two closing ends, wherein each capsule or capsules independently comprise a multi-layered wall and at least one luminal compartment; and one or more therapeutic agents, each initially presented within one or more of the luminal compartment(s); wherein each multi-layer wall independently comprises at least one inner layer and one outer layer; wherein each inner layer comprises a first polymer that has a net positive charge under physiological conditions; and wherein each outer layer independently comprises a second polymer that differs from the first polymer. In some embodiments, the drug delivery composition may comprise two or more capsules. In some embodiments, a different therapeutic agent is initially presented within each of the two or more capsules. In other embodiments, the same therapeutic agent is initially presented within each of the two or more capsules. In some embodiments, at least one or the capsule(s) comprise two or more luminal compartments. In some embodiments, a different therapeutic agent is initially presented within each of the two or more luminal compartments. In other embodiments, the same therapeutic agent is initially presented within each of the two or more luminal compartments. QzcRnn / ίζηζ / Ε / γίΛΐ In some aspects, the first polymer may comprise a chitosan, a polyethyleneimine, a protamine, a polypropylimine, a poly L lysine, a poly L arginine, a poly D lysine, a poly D arginine, a cellulose, a dextran, a poly( amidoamine), poly(2-(dimethylamino)ethyl methacrylate), derivatives thereof or combinations thereof. In some embodiments, the first polymer may comprise a chitosan or derivatives thereof. In some embodiments, the first polymer comprises fibers having an average diameter of from about 50 nm to about 1000 nm. In some aspects, the second polymer can comprise a biodegradable polymer. In some embodiments, the second polymer comprises a poly(s-caprolactone) (PCL), a polylactic acid (PLA), a polyglycolic acid (PGA), a polylactide-coglycolide (PLGA), a polyester, a poly(ortho ester) , a poly(phosphazine), a poly(phosphate ester), a gelatin, a collagen, a polyethylene glycol (PEG), derivatives thereof or combinations thereof. In some embodiments, the second polymer comprises PCL. In other embodiments, the second polymer comprises PLA. In some embodiments, the second polymer comprises fibers having an average diameter of from about 100 nm to about 2000 nm. In some aspects, the capsule(s) each independently have a length of about 0.1 cm to about 5 cm. In some embodiments, the capsule(s) each independently have an internal diameter of from about 100 µm to about 2000 µm. In some embodiments, the capsule(s) each independently have an external diameter of about 50 µm to about 300 µm greater than the internal diameter of the capsule itself. In some embodiments, each multilayer wall has a wall thickness of from about 25 µm to about 150 µm. In some embodiments, each outer layer may further comprise pores having an average pore diameter of from about 100 nm to about 10,000 nm. In some embodiments, each or each drug delivery capsule has a surface charge measured as a zeta potential at pH 7.4 of about -25 mV to about 25 mV. In some embodiments, the therapeutic agent(s) each have a net negative charge within a pH range of about 6.0 to about 7.4. In some embodiments, at least one of the therapeutic agent(s) is an antiVEGF agent. In some embodiments, the anti-VEGF agent is a therapeutic antibody, eg, bevacizumab, ranibizumab, IBI305, or combinations thereof. In some embodiments, the anti-VEGF agent is a VEGF decoy receptor, eg, aflibercept. In some embodiments, the anti-VEGF agent is a tyrosine kinase inhibitor, eg, lapatinib, sunitinib, axitinib, pazopanib, or combinations thereof. In some embodiments, the therapeutic agent(s) may comprise an anti-inflammatory agent, such as cyclosporine, a steroid or non-steroidal anti-inflammatory drug, an antimicrobial agent, an immunomodulatory drug, an ocular hypotensive agent, a neuroprotective agent, a gene therapy, a viral vector therapy, an alpha adrenergic agonist, an azcftnn / Lznz / E / YiAi beta adrenergic agonist, or combinations thereof. In another aspect, there is provided a method of treating an ophthalmic disorder in a subject in need thereof, comprising injecting, into the subject's eye, a therapeutically effective amount of the drug delivery composition described herein. In some modalities, the ophthalmologic disorder may comprise acute macular neuroretinopathy, Behcet's disease, neovascularization including choroidal neovascularization, diabetic uveitis, histoplasmosis, infections such as fungal or viral infections, macular degeneration such as acute macular degeneration (AMD), including Wet AMD, non-exudative AMD, and exudative AMD, edema such as macular edema, cystoid macular edema, and diabetic macular edema, multifocal choroiditis, ocular trauma involving a posterior ocular site or location, ocular tumors, retinal disorders such as vein occlusion central retinal disease, diabetic retinopathy (including proliferative diabetic retinopathy), proliferative vitreoretinopathy (PVR), retinal arterial occlusive disease, retinal detachment, uveitic retinal disease, sympathetic ophthalmia, Vogt Koyanagi-Harada (VKH) syndrome, uveal diffusion, an ocular condition caused or influenced by laser eye treatment, posterior eye conditions caused or influenced by photodynamic therapy, photocoagulation, radiation retinopathy, epiretinal membrane disorders, branch retinal vein occlusion, anterior ischemic optic neuropathy, nondiabetic retinal dysfunction retinopathic, retinitis pigmentosa, cancer and glaucoma. In some embodiments, the ophthalmologic disorder comprises wet age-related macular degeneration (wet AMD), neovascularization, or macular edema. In some embodiments, injection of the described compositions into a subject's eye comprises injection into the vitreous chamber of the eye. In other embodiments, injection of the described compositions into a subject's eye comprises intravitreal injection, subconjunctival injection, sub-Tenon injection, retrobulbar injection, or suprachoroidal injection. Also provided are methods of creating the capsule(s), as used in the drug delivery compositions described herein, wherein the method comprises: forming a first layer of the first polymer on a conductive rod, wherein forming the first layer comprises electrospinning using a first solution comprising the first polymer in at least one organic solvent, and wherein electrospinning is performed using a voltage difference of approximately 10 kVa to approximately 30 kV; and forming a second layer of the second polymer in the first layer, wherein the formation of the second layer comprises electrospinning, onto the first layer formed, a second solution comprising the first polymer and optionally a porogen, and wherein the electrospinning is performed when using a voltage difference of approximately 10 kVa approximately 30 kV. Also disclosed are kits comprising one of: (a) a disclosed drug delivery composition, (b) a disclosed drug delivery composition in a sterile package, or (c) a prefilled syringe or needle comprising a disclosed azcAnn / ίζηζ / Ε / γίΛΐ drug delivery composition, and instructions for administering the drug delivery composition to treat an ophthalmic disease or disorder, as described herein. Other systems, methods, attributes, and advantages of the present disclosure will be or become apparent to one skilled in the art upon examination of the following drawings and detailed description. All such additional systems, methods, attributes, and advantages are intended to be included within this description, to fall within the scope of the present disclosure, and to be protected by the accompanying claims. In addition, all optional and preferred attributes and modifications of the described embodiments are usable in all aspects of the disclosure taught herein. Furthermore, the individual attributes of the dependent claims, as well as all optional and preferred attributes and modifications of the described embodiments, are combinable and interchangeable with one another. azcRnn / ιζηζ / Ε / γίΛΐ BRIEF DESCRIPTION OF THE FIGURES Many aspects of the present disclosure can be better understood with reference to the following drawings. Components in the drawings are not necessarily to scale, and instead emphasis is placed on clearly illustrating the principles of the present disclosure. Furthermore, in the drawings, like reference numerals designate corresponding parts throughout the several views. Figure 1A shows a representative process disclosed, comprising the following steps: a) two layers of chitosan and PCL nanofibers collected on the rotating rod using electrospinning; b) rod covered with two layers sintered at 100 °C in a vacuum furnace for approximately 3 hours; c) rod removal to create a central hollowed-out cylinder; d) porous structure in PCL layer generated by salt leaching; and e) therapeutic loading to the capsule followed by end sealing. The bilayer capsules then prepared can be used in studies such as (such as step f) titration of drug release to an appropriate buffer, eg PBS at 37°C, or used for delivery of a loaded drug to a target. suitable, for example, the eye by (such as step g) intravitreal injection. Figure 1B shows a schematic cross-sectional representation of a disclosed two-layer capsule, and a schematic representation of intravitreal injection of a disclosed two-layer capsule. Figure 2 shows a representative schematic representation of a chitosan and PCL fibrous mat formed using the disclosed techniques (see panel A). The Figure also shows representative scanning electron micrograph (SEM) images as follows: (panel B) representative SEM image of chitosan-fibrous mat cross section of bilayer PCL; and (panel C) representative SEM images of PCL and chitosan nanofibrous layer with a diameter of 932.57 ±399.42 nm and 331.61 ± 186.19 nm, respectively. Figure 3 shows representative photographic images of the disclosed bilayer capsules. The left panel of the Figure shows a photographic image of two capsules, one with a diameter of 1,645 mm and the other with a diameter of 260 pm. The middle panel of the Figure shows a representative SEM image of a PCL single layer capsule with internal diameter of 260 pm. The right panel shows a representative SEM image of a PCL chitosan bilayer capsule with a membrane thickness of 89.85 ± 4.27 pm. The image in the right panel shows, in this representative example, that a fibrous mat layer of chitosan is associated with the outer PCL layer, and that the chitosan layer takes up approximately 25% of the full wall thickness. Figure 4 shows representative images of the disclosed PCL membranes prepared using the indicated concentrations of HEPES salt, where the images show the surface or cross-sectional view of a disclosed PCL membrane, as indicated. The images show that increasing the sodium salt ratio of HEPES resulted in larger pores in the PCL membrane. Interconnecting pores within the membrane can be bypassed with a salt concentration above 5.0%. Arrow: Characteristic interconnecting pores within PCL films after leaching of salts. Each image has a scale bar displayed in the lower left corner of the image. Figure 5 shows images and data pertaining to the characterization of a disclosed two-layer capsule. Panel a shows a representative schematic of a two-layer structure, after salt leaching and washing. Panel b shows a representative SEM image of a disclosed bilayer membrane, before and after salt leaching. As shown, a porous structure was generated by salt leaching, and the fibrous chitosan structure was lost after washing with saturated sodium bicarbonate solution. A two-layered porous structure was observed in its cross section. Panel c shows a representative FTIR spectrum of the chitosan layer and PCL layer after salt leaching. As shown, a significant peak at 1752 cm'1 was assigned to the carbonyl group in PCL. A large cluster at 3478 cm'1 was the hydroxyl group on chitosan. Figure 6 shows data pertaining to the effect of porous and bilayer structure on protein release from a disclosed bilayer capsule. Data were obtained, as described herein below, from a reported representative chitosan-PCL bilayer capsule (labeled Ch-PCL in the graph legend) and PCL single-layer capsules ( labeled PCL in the graph legend), encapsulating BSA or bevacizumab, as described herein, determined from incubation in PBS. The percentage values, shown with the labels "Ch-PCL" or "PCL" in the graph legend, indicate the % w / v used to prepare the two-layer or single-layer capsule. Panel a shows a representative BSA release profile from a 1645 mm internal diameter bilayer capsule, and a representative BSA release profile from a 260 µm internal diameter bilayer capsule. . Panel b shows a representative bevacizumab release profile from a 1645 mm internal diameter bilayer capsule, and a representative azcftnn / Lznz / E / YiAi bevacizumab release profile from the profile from a two-layer capsule. layers of 260 pm internal diameter. Compositions for drug delivery show less cumulative release than single-layer capsules at each point in time. (# = p < 0.05). The data also show that increasing salt concentration was associated with increased cumulative release at each time point (* = p<0.05). Figure 7 shows data pertaining to the effect of porous and bilayer structure on protein release from a disclosed bilayer capsule. In this Figure, trend lines have been fitted to the data with the fit parameters shown. Data were obtained, as described herein below, from a reported representative chitosan-PCL bilayer capsule (labeled Ch-PCL in the graph legend) and PCL single-layer capsules ( labeled PCL in the graph legend), encapsulating BSA or bevacizumab, as described herein, determined from incubation in PBS. The percentage values, shown with the labels "Ch-PCL" or "PCL" in the graph legend, indicate the % w / v used to prepare the two-layer or single-layer capsule. Panel a shows a representative BSA release profile from a 1645 mm internal diameter bilayer capsule, and a representative BSA release profile from a 260 µm internal diameter bilayer capsule. . Panel b shows a representative bevacizumab release profile from a 1645 mm internal diameter bilayer capsule, and a representative bevacizumab release profile from a 260 µm internal diameter bilayer capsule. . The data shows that the disclosed bilayer capsules can achieve near zero order release kinetics. Figure 8 shows a test scheme for assessing the potential toxicity of a disclosed capsule, and data obtained from the test. Panel a shows an assay scheme to assess in vitro cytotoxicity using ARPE-19 cells by a direct contact method. Panel b shows in vitro toxicity data for capsules prepared with 10.0% HEPES salt, 7.5% HEPES salt, and 5.0% HEPES salt by the direct contact method. Panel c shows an assay scheme to assess in vitro cytotoxicity using ARPE-19 cells by an extract exposure method. Panel d shows the in vitro cytotoxicity of capsule extracts prepared under different conditions. Each bar, at a different point in time and salt concentration, represents the mean measurement of three independent samples. The error bars show the standard deviation. As described above, data were obtained using a reported representative chitosan-PCL bilayer capsule (labeled Ch-PCL in the graph legend) and PCL single-layer capsules (labeled PCL in the graph legend). of graph). The data show no significant difference in cell viability between cells treated with PCL or chitosan-PCL extract (p > 0.05), nor a significant observed difference over time (p > 0.05). Figure 9 shows representative fluorescent photomicrograph images and data pertaining to the inhibition of cell tubule length in VEGF-treated HUVEC cells, ozcRnn / ιζηζ / Ε / γΐΛΐ exposed to bevacizumab delivered using either a single-layer PCL capsule or a disclosed two-layer capsule. Cells were labeled using Calcien AM®. Panel a shows representative fluorescent images showing HUVEC treated at 5 ng VEGF in the absence (left) and presence (right) of 10 mg native bevacizumab in cell culture media. The data show significant disruption of cellular tubules in cells in the presence of bevacizumab, compared to the control group. Panel b shows representative fluorescent images showing inhibition of cellular tubules in cells exposed to 10 mg bevacizumab released from single-layer PCL-chitosan-PCL 260 µm diameter drug delivery devices for 1-week exposure. , 1 month, 3 months and 9 months, as indicated. Panel c shows the inhibition of mean tubular length in the indicated groups, analyzed quantitatively using ImageJ software. Data are presented as mean ± SD, n = 3. Data show that a significant difference was noted for tubular length of HUVECS from the bevacizumab-treated group eluted from the single-layer capsule, compared to that of the bevacizumab-treated group. two-layer capsules (* = p < 0.05). The data also show that a significantly different HUVECS tubular inhibition capacity of eluted bevacizumab was observed over time compared to that of free native bevacizumab (# = p < 0.05). Figure 10 shows results obtained from studies evaluating the injection of a representative disclosed bilayer capsule into an ex vivo porcine eye model. Panel a shows a schematic representation of the injection of a two-layered capsule into the vitreous by means of a hypodermic needle. Panel b shows a capsule preloaded on a 21 gauge needle, which was injected posterior to 3 mm from the limbus into the porcine eye ex vivo (see middle panel). After injection, the ex vivo porcine eye was dissected, and the intact capsule was observed intact in the vitreous of the ex vivo porcine eye (see right panel). Figure 11 shows a comparison of the biodegradation of PCL single layer capsules and double layer capsules, as described herein, during one year of incubation. Panel a shows representative images of scanning electron micrographs (SEM) prepared with different concentrations of salts. Increased pore size in PCL membranes was observed in all samples after nine months. The cross-sectional image (see right panel) shows that the capsule remained intact for a period of one year. Panel b shows representative SEM images of bilayered capsules. The fibrous scaffold could be seen in the porous chitosan layer. The intact bilayer structure is shown from the cross-sectional image (see right panel). Figure 12 shows the UV-visible absorption spectrum of bevacizumab diluted in PBS at different concentrations. Panel a shows the absorbance of diluted bevacizumab as measured by UV-Vis spectroscopy. Panel b shows the standard curve of bevacizumab as measured by a plate reader. The minimum concentrate that can be detected by UV-Vis spectroscopy and the plate reader is 5 pg / ml. azcRnn / ιζηζ / Ε / γίΛΐ Figure 13 shows the effect of the bilayered, porous structure of the capsules described herein on bevacizumab release when assayed by ELISA. Bilayer capsules, described herein, and PCL single-layer capsules encapsulating bevacizumab, were incubated in PBS. The release profile of bevacizumab was obtained for capsules with an internal diameter of 260 pm. The reported bilayer capsules effectively retained protein within the capsule for at least nine months, and have a lower cumulative release than single-layer capsules at each time point (# = p < 0.05). . Increasing the concentration of salts also increases the cumulative release at each point in time (* = p < 0.05). The release profile acquired by ELISA is consistent with the results determined by UV-Vis spectroscopy. Figure 14 shows the stability of free native bevacizumab before and after lyophilization and bevacizumab eluted from the single-layer capsule and the two-layer capsule described herein, for the first three months. Panel a shows SEC-HPLC chromatograms of free native bevacizumab, lyophilized bevacizumab, and in-device bevacizumab. Panel b shows SEC-HPLC chromatograms of bevacizumab eluted from the single-layered capsule and the double-layered capsule, incubated at physiological temperature for one and three months. Figure 15 shows the biodegradation of chitosan-PCL bilayer capsules exposed to PBS for three weeks. Representative SEM images of 260 pm internal diameter bilayer capsules prepared with 10% HEPES salts are provided, representing the more porous structure. Cross-sectional and internal images show that the capsule lost its internal chitosan layer when directed exposed to PBS after three weeks, while biodegradation was not significant when the chitosan layer was coated with PCL. The thickness of the two-layer capsule was 73.23 ± 3.62 pm. Additional advantages of the disclosure will be set forth in part in the description that follows, and in part will be obvious from the description, or may be learned by practice of the disclosure. The advantages of the disclosure will be realized and achieved by means of the elements and combinations particularly highlighted in the appended claims. Both the foregoing general description and the following detailed description are to be understood to be exemplary and explanatory only, and are not restrictive of disclosure as claimed. DETAILED DESCRIPTION OF THE INVENTION Many modifications and other modalities, disclosed in this document, will come to the mind of a person skilled in the art to which the disclosed compositions and methods pertain, having the benefit of the teachings presented in the preceding descriptions and in the following. associated drawings. Therefore, it will be understood that the disclosures are not to be limited to the specific embodiments disclosed, and that modifications and other embodiments are intended to be included within the scope of the appended claims. The skilled artisan will recognize many variants and adaptations of the azcftnn / Lznz / E / YiAi aspects described in this document. These variations and adaptations are intended to be included in the teachings of this disclosure, and to be encompassed by the claims herein. Although specific terms are used in this document, they are used in a generic and descriptive sense only, and not for purposes of limitation. As will be apparent to those skilled in the art upon reading this disclosure, each of the individual modalities described and illustrated herein has discrete components and attributes, which can be readily separated or combined with the attributes of any of the others. various modalities, without departing from the scope or spirit of this disclosure. Any indicated method may be carried out in the order of events indicated, or in any other order that is logically possible. That is, unless expressly stated otherwise, it is in no way intended to be construed that any method or aspect defined in this document requires its steps to be performed in a specific order. Accordingly, in cases where a method claim does not specifically state, in the claims or descriptions, that the steps are to be limited to a specific order, no order is in any way intended to be inferred, in any sense. This is valid for any possible non-express basis of interpretation, including questions of logic regarding the arrangement of stages or operational flow, the simple meaning derived from the grammatical organization or punctuation, or the number or type of aspects described in the specification. All publications mentioned in this document are incorporated herein by reference, to disclose and describe the methods and / or materials in connection with which the publications are cited. The publications set forth in this document are provided solely for release prior to the filing date of this application. Nothing in this document should be construed as an admission that the present invention is not entitled to antedate such publication, by virtue of prior invention. Furthermore, the publication dates provided in this document may differ from the actual publication dates, which may require independent confirmation. Although aspects of this disclosure may be described and claimed in a particular legal class, such as the systems legal class, this is for convenience only and one skilled in the art will understand that each aspect of this disclosure may be described and claimed in any legal class. It will also be understood that the terminology used in this document is for the purpose of describing particular aspects only, and is not intended to be limiting. Unless otherwise defined, all technical and scientific terms used in this document have the same meaning as is commonly understood by a person skilled in the art to which the disclosed compositions and methods pertain. It is further understood that terms such as those defined in commonly used dictionaries are to be interpreted as having a meaning that is consistent with their azcRnn / Lznz / E / YiAi meaning in the context of the relevant specification and technique, and are not to be construed in a idealized or excessively formal sense, unless expressly defined in this document. Before describing the various aspects of the present disclosure, the following definitions are provided and should be used, unless otherwise indicated. Additional terms may be defined elsewhere in this disclosure. Definitions As used in this document, "comprising" shall be construed as specifying the presence of the indicated attributes, integers, stages, or components as referred to, but does not prohibit the presence or addition of one or more attributes, integers, stages. or components, or groups thereof. Furthermore, each of the terms "by", "comprising", "comprising", "comprising of", "include", "includes", "included", "involve", "involves", "involved" and " such as” is used in its open, non-limiting sense, and may be used interchangeably. Furthermore, the term "comprising" is intended to include examples and aspects covered by the terms "consist essentially of" and "consist of". Similarly, the term "consist essentially of" is intended to include examples encompassed by the term "consist of". As used in the specification and appended claims, the singular forms "a", "an" and "the" include plural referents, unless the context clearly dictates otherwise. Thus, for example, reference to "a drug delivery composition," "a therapeutic agent," or "a clinical condition" includes, but is not limited to, two or more such drug delivery compositions, therapeutic agents, or clinical conditions, and the like. It should be noted that proportional relationships, concentrations, amounts, and other numerical data may be expressed in this document in a range format. It will further be understood that the extremes of each of the intervals are significant, both relative to the other extreme and independently of the other extreme. It is also understood that there are a number of values ​​disclosed herein, and that each value is also disclosed herein as "about" that particular value, in addition to the value itself. For example, if the value "10" is reported, then "about 10" is also reported. Ranges may be expressed herein as from "about" a particular value, and / or to "about" another particular value. Similarly, when the values ​​are expressed as approximations, by the use of the antecedent "approximately", it will be understood that the particular value forms one more aspect. For example, if the value "about 10" is reported, then "10" is also reported. When an interval is expressed, one more aspect includes from that particular value and / or to the other particular value. For example, in cases where the stated range includes one or both limits, ranges excluding either or both included limits are also included in the disclosure, for example, the phrase “x to y” includes the range from 'x' to 'y' , as well as the interval greater than 'x' and less than 'y'. The interval can also be expressed as an upper bound, for example, 'about x, y, z, or less' and should be interpreted to include the specific intervals of 'about x', αζακηη / ιζηζ / Ε / γίΛΐ 'about y' and 'about z', as well as the intervals 'less than x', 'less than y', and 'less than z'. Likewise, the phrase 'about x, y, z, or more' y should be interpreted to include the specific ranges of 'about x', 'about y', and 'about z', as well as the ranges of 'more than x' , 'more than y' and 'more than z'. In addition, the phrase "about 'x' to 'y'", where 'x' and 'y' are numerical values, includes "about 'x' to about 'y'". It will be understood that this interval format is used for convenience and brevity, and thus should be interpreted flexibly to include not only numerical values ​​explicitly indicated as interval limits, but also to include all individual numerical values ​​or subintervals. spanned within that range, as if each numeric value and subrange were explicitly stated. To illustrate, a numerical range of "about 0.1% to about 5%" should be interpreted to include not only the explicitly stated values ​​from about 0.1% to about 5%, but also to include individual values ​​(for example, about 1%, about 2%, about 3%, and about 4%) and subranges (for example, about 0.5% to about 1.1%; about 5% to about 2.4%; about 0.5% to about 3.2%, and about 0.5% to about 4.4%, and other possible subintervals) within the indicated interval. As used in this document, the terms "approximately", "approximately", "in or approximately", and "substantially", mean that the quantity or value in question may be the exact value or a value that provides equivalent results or effects. a as stated in the claims or taught in this document. That is to say, it will be understood that the quantities, sizes, formulations, parameters, and other quantities and characteristics are not and need not be exact, but may be approximate and / or greater or lesser, as desired, reflecting the tolerances, factors of conversion, rounding, measurement error and the like, and other factors known to those skilled in the art, so that equivalent results or effects are obtained. In some circumstances, the value that provides equivalent results or effects cannot be reasonably determined. In these instances it is generally understood, as used herein, that "about" and "at or about" mean the indicated nominal value ± 10% variation, unless otherwise indicated or inferred. In general, an amount, size, formulation, parameter, or other amount or characteristic is "about," "about," or "at or about," whether or not it is expressly stated to be such. It will be understood that, in cases where "about", "approximate" or "at or about" is used before a quantitative value, the parameter also includes the specific quantitative value itself, unless otherwise specifically indicated. As used herein, "effective amount" may refer to the amount of a disclosed compound or pharmaceutical composition provided herein that is sufficient to effect a conducive or desired biological, emotional, medical, or clinical response, of a cell, tissue, system, animal or human. An effective amount can be administered in one or more administrations, applications, or dosages. The term may also include, within its scope, azcRnn / Lznz / E / YiAi in amounts effective to enhance or restore substantially normal physiological function. As used herein, the term "therapeutically effective amount" refers to an amount that is sufficient to achieve the desired therapeutic result or to have an effect on undesirable symptoms, but is generally insufficient to give rise to adverse side effects. . The specific therapeutically effective dose level, for any particular patient, will depend on a variety of factors, including the disorder being treated and the severity of the disorder, the specific composition employed, age, body weight, general health, the sex and diet of the patient, the time of administration, the route of administration, the rate of excretion of the specific compound used, the duration of treatment, the drugs used in combination or coinciding with the specific compound used, and similar factors within of the knowledge and experience of the healthcare professional, and which may be well known in the medical arts. In the case of treatment of a particular disease or condition, in some cases, the desired response may be inhibitory to the progression of the disease or condition. This may involve only slowing the progression of the disease temporarily. However, in other cases, it may be desirable to stop the progression of the disease permanently. This can be monitored by routine diagnostic methods known to a person skilled in the art, for any particular disease. The desired response to treatment of the disease or condition can also delay the onset, or even prevent the onset of the disease or condition. For example, it is within the skill of the art to initiate dosages of a compound at levels less than those required to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved. If desired, the effective daily dose may be divided into multiple doses for purposes of administration. Accordingly, single dose compositions may contain these amounts or submultiples thereof, to constitute the daily dose. The dosage can be adjusted by the individual physician in case of any contraindication. It is generally preferred to use a maximum dose of the pharmacological agents of the invention (alone or in combination with other therapeutic agents), ie, the highest safe dose according to sound medical judgment. It will be understood by those skilled in the art, however, that a patient may insist on a lower or tolerable dose for medical, psychological, or virtually any other reason. A response to a therapeutically effective dose of a disclosed drug delivery composition can be measured by determining the physiological effects of the treatment or medication, such as the decrease or absence of disease symptoms after administration of the treatment or drug agent. . Other assays will be known to one skilled in the art, and can be used to measure the level of response. The amount of a treatment can be varied, for example, by increasing or decreasing the amount of a disclosed compound and / or pharmaceutical composition, by changing the disclosed compound and / or pharmaceutical composition being administered, by changing the route of administration, by changing dosing time, etc. The azcRnn / Lznz / E / YiAi dosage may vary and may be administered in one or more daily dose administrations, for one or several days. Guidance to appropriate dosages for particular classes of pharmaceuticals can be found in the literature. As used herein, the term "prophylactically effective amount" refers to an amount effective in preventing the onset or onset of a disease or condition. As used in this document, the term "prevent" or "prevent" refers to impeding, avoiding, obviating, preventing, stopping, or hindering something from occurring, especially by anticipated action. It will be understood that, in cases where reduce, inhibit or prevent are used in this document, unless specifically indicated otherwise, the use of the other two words is also expressly disclosed. As used in this document, the terms "optional" or 'Optionally' mean that the event or circumstance subsequently described may or may not occur, and that the description includes cases where the event or circumstance occurs and cases where it does not. As used herein, "therapeutic agent" can refer to any substance, compound, molecule, and the like, that may be biologically active or otherwise induce a pharmacological, immunogenic, biological, and / or physiological effect on a subject by which is administered by local and / or systemic action. A therapeutic agent can be a primary active agent or, in other words, the component or components of a composition to which all or part of the effect of the composition is attributed. A therapeutic agent can be a secondary therapeutic agent or, in other words, the component or components of a composition to which an additional part and / or other effect of the composition is attributed. The term, therefore, encompasses those compounds or chemicals traditionally considered drugs, vaccines, and biopharmaceuticals, including molecules such as proteins, peptides, hormones, nucleic acids, gene constructs, and the like. Examples of therapeutic agents are described in recognized literature references, such as the Merck Index (14th Edition), the Physicians' Desk Reference (64th Edition), and The Pharmacological Basis of Therapeutics (12th Edition), and include, without limitation, drugs, vitamins, mineral supplements , substances used for the treatment, prevention, diagnosis, cure, or mitigation of a disease or condition, substances that affect the structure or function of the body, or prodrugs, which become biologically active or more active after they have been placed in a physiological environment. For example, the term "therapeutic agent" includes compounds or compositions for use in all major therapeutic areas, including, but not limited to, adjuvants, anti-infective agents such as antibiotics and antiviral agents, analgesics and combinations of analgesics, anorectic agents, anti-inflammatories, anti-epileptic agents, local and general anesthetics, hypnotics, sedatives, antipsychotic agents, neuroleptic agents, antidepressants, anxiolytics, antagonists, neuron blocking agents, anticholinergic and cholinomimetic agents, antimuscarinic and muscarinic agents, antiadrenergics, antiarrhythmics, antihypertensive agents, hormones and nutrients, antiarthritics, antiasthmatic agents, azcAnn / Lznz / E / YiAi anticonvulsants, antihistamines, antiemetics, antineoplastics, antipruritics, antipyretics, antispasmodics, cardiovascular preparations (including calcium channel blockers, beta-blockers, beta-agonists and antiarrhythmics), antihypertensives, diuretics, vasodilators, central nervous system stimulants, cough and cold preparations, decongestants, diagnostic agents, hormones, bone growth stimulants and inhibitors of bone resorption, immunosuppressants, muscle relaxants, psychostimulants, sedatives, tranquilizers, proteins, peptides and fragments of nucleic acid molecules (polymeric forms of two or more nucleotides, either ribonucleotides (RNA) or deoxyribonucleotides (DNA), including double-stranded and simple, gene constructs, expression vectors, antisense molecules, and the like), small molecules (eg, doxorubicin), and other biologically active macromolecules such as, eg, proteins and enzymes. The agent can be a biologically active agent used in medical, including veterinary, and agricultural applications, such as with plants, as well as other areas. The term therapeutic agent also includes, without limitation, drugs, vitamins, mineral supplements, substances used for the treatment, prevention, diagnosis, cure, or mitigation of a disease or condition, or substances that affect the structure or function of the body, or prodrugs. , which become biologically active or more active after they have been placed in a predetermined physiological environment. It will be understood that, in this document, the disclosure of a therapeutic agent also discloses a pharmaceutically acceptable salt, pharmaceutically acceptable ester, pharmaceutically acceptable amide, prodrug forms, and derivatives of the therapeutic agent. The term "pharmaceutically acceptable salts", as used herein, means salts of the main active agents that are prepared with acids or bases that are tolerated by a biological system, or are tolerated by a subject, or are tolerated by a biological system and are tolerated by a subject when administered in a therapeutically effective amount. When the compounds of the present disclosure contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of these compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable basic addition salts include, but are not limited to, sodium, potassium, calcium, ammonium, organic amino, magnesium salt, lithium salt, strontium salt, or a similar salt. When the compounds of the present disclosure contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of these compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include, but are not limited to, those derived from inorganic acids such as hydrochloric, hydrobromic, nitric, carbonic, carbonic monoacid, phosphoric, phosphoric monoacid, phosphoric diacid, sulfuric, sulfuric monoacid, hydriodic or phosphoric and the like, as well as salts derived from relatively non-toxic organic acids such as acetic, propionic, azcRnn / ιζηζ / Ε / γίΛΐ ¡sobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic , benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are amino acid salts such as arginate and the like, and organic acid salts such as glucuronic or galacturonic acids and the like. The term "pharmaceutically acceptable ester" refers to esters of compounds of the present disclosure that are hydrolyzed in vivo and includes those that are readily broken down in the human body to leave the parent compound or a salt thereof. Examples of pharmaceutically acceptable non-toxic esters of the present disclosure include C 1 to C 6 alkyl esters and C 5 to C 7 cycloalkyl esters, although C 1 to C 4 alkyl esters are preferred. with conventional methods. Pharmaceutically acceptable esters can be attached onto hydroxy groups by reaction of the hydroxy group-containing compound with acid and an alkylcarboxylic acid, such as acetic acid, or with acid and an arylcarboxylic acid, such as benzoic acid. In the case of compounds containing carboxylic acid groups, pharmaceutically acceptable esters are prepared from compounds containing carboxylic acid groups by reaction of the compound with a base, such as triethylamine, and an alkyl halide, for example , with methyl iodide, benzyl iodide, cyclopentyl iodide or alkyl triflate. They can also be prepared by reacting the compound with an acid, such as hydrochloric acid, and an alcohol, such as ethanol or methanol. The term "pharmaceutically acceptable amide" refers to non-toxic amides of the present disclosure, derived from ammonia, C 1 to C 6 primary alkylamines, and C 1 to C 6 dialkyl secondary amines. In the case of secondary amines, the amine may also be in the form of a 5- or 6-membered heterocycle containing a nitrogen atom. Amides derived from ammonia, C 1 to C 3 primary alkyl amides and C 1 to C 2 secondary dialkyl amides, are preferred. Amides of the disclosed compounds can be prepared according to conventional methods. Pharmaceutically acceptable amides can be prepared from primary or secondary amine group-containing compounds by reacting the amino group-containing compound with an alkyl anhydride, aryl anhydride, acyl halide, or aroyl halide. In the case of compounds containing carboxylic acid groups, pharmaceutically acceptable amides are prepared from compounds containing carboxylic acid groups by reaction of the compound with a base, such as triethylamine, a dehydrating agent such as dicyclohexyl carbodiimide, or carbonyl diimidazole, and an alkylamine, dialkylamine, for example, with methylamine, diethylamine and piperidine. They may also be prepared by reacting the compound with an acid, such as sulfuric acid, and an alkylcarboxylic acid, such as acetic acid, or with acid and an arylcarboxylic acid, such as benzoic acid, under dehydrating conditions, such as with added molecular sieves. . The composition may contain a compound of the present disclosure in the form of a pharmaceutically acceptable prodrug. The term "pharmaceutically acceptable prodrug" or "prodrug" represents those azcAnn / ίζηζ / Ε / γίΛΐ prodrugs of the compounds of the present disclosure that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and other animals without undue toxicity, irritation, allergic response and the like, consistent with a reasonable risk / benefit ratio, and effective for their intended use. The prodrugs of the present disclosure can be rapidly transformed in vivo to a parent compound having a structure of a disclosed compound, for example, by hydrolysis in blood. A comprehensive discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, V. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press (1987). As used in this document, "equipment" means a collection of at least two components that constitute equipment. Together, the components constitute a functional unit for a given purpose. Individual member components may be physically packaged together or separately. For example, a piece of equipment comprising an instruction to use the equipment may or may not physically include the instruction with other individual member components. Instead, the instruction may be provided as a separate member component, either in paper form or in electronic form, which may be provided on a computer-readable memory device or downloaded from an Internet web site, or as a recorded presentation. As used in this document, “instruction” or “instructions” means documents that describe relevant materials or methodologies belonging to a piece of equipment. These materials may include any combination of the following: background information, list of components and their availability information (purchasing information, etc.), brief or detailed protocols for using the kit, troubleshooting, references, technical support, and any other related document. Instructions may be provided with the equipment or as a separate member component, either in paper form or in electronic form, which may be provided on a computer-readable memory device or downloaded from an Internet web site, or as a recorded presentation. Instructions can comprise one or multiple documents, and are intended to include future updates. As used interchangeably herein, "subject", "individual" or "patient" can refer to a vertebrate organism, such as a mammal (eg, human). "Subject" can also refer to a cell, a population of cells, a tissue, organ or organism, preferably human, and constituents thereof. As used herein, the terms "treat" and "treatment" can refer generally to obtaining a desired pharmacological and / or physiological effect. The effect may be, but need not be, prophylactic in terms of preventing or partially preventing a disease, symptom or condition thereof, such as an ophthalmic disorder. The effect may be therapeutic in terms of a partial or complete cure of a disease, condition, symptom, or adverse effect attributed to the disease, disorder, or condition. The term "treatment", azcRnn / ίζηζ / Ε / γίΛΐ as used herein, may include any treatment of an ophthalmological disorder in a subject, in particular a human, and may include one or more of the following: (a) prevent the disease from occurring in a subject who may be predisposed to the disease, but has not yet been diagnosed as having it, (b) inhibit the disease, that is, arrest its development, and (c) alleviate the disease, that is say, mitigate or ameliorate the disease and / or its symptoms or conditions. The term "treatment" as used herein can refer to therapeutic treatment alone, prophylactic treatment alone, or both therapeutic and prophylactic treatment. Those in need of treatment (subjects in need thereof) may include those who already have the disorder and / or those in whom the disorder is to be prevented. As used herein, the term "treat" can include inhibition of the disease, disorder, or condition, eg, preventing its progress, and alleviating the disease, disorder, or condition, eg, causing regression of the disease. , disorder and / or condition. Treatment of the disease, disorder or condition may include ameliorating at least one symptom of the particular disease, disorder or condition, even if the underlying pathophysiology is not affected, for example, such as treatment of a subject's pain by administration of an analgesic agent, even if this agent does not treat the cause of the pain. As used herein, "dose," "unit dose," or "dosage" may refer to physically discrete units suitable for use in a subject, each unit containing a predetermined amount of a given compound and / or pharmaceutical composition. known to him, calculated to produce the desired response or responses in association with his administration. As used herein, "therapeutic" can refer to treating, curing, and / or ameliorating a disease, disorder, condition, or side effect, or slowing the rate of progression of a disease, disorder, condition, or side effect. As used herein, nomenclature for compounds, including organic compounds, can be determined by using common name, IUPAC, IUBMB, or CAS recommendations for nomenclature. When one or more stereochemical attributes are present, the CahnIngold-Prelog rules for stereochemistry can be used to designate the stereochemical priority, E / Z specification. and the like. One skilled in the art can easily ascertain the structure of a compound if a name is determined, either by systemic reduction of the compound structure using naming conventions, or by commercially available software such as CHEMDRAW™ (Cambridgesoft Corporation, USA). ). Unless otherwise specified, temperatures referenced in this document are based on atmospheric pressure (ie, one atmosphere). Compositions for drug delivery that have therapeutic or clinical utility are described herein. Also described herein are methods of preparing or producing the disclosed drug delivery compositions. Also described herein are methods of administering the disclosed drug delivery compositions to a subject in need thereof. In some aspects, the subject may have a clinical or pathological azcAnn / Lznz / E / YiAi condition, such as an ophthalmologic disorder. Other compositions, compounds, methods, attributes, and advantages of the present disclosure will be or become apparent to one skilled in the art upon examination of the following drawings, detailed description, and examples. All of these additional compositions, compounds, methods, attributes, and advantages are intended to be included within this description, and are within the scope of the present disclosure. Compositions for drug delivery Vascular endothelial growth factor (VEGF) is an essential regulator involved in abnormal angiogenesis, and aids in rapid tumor growth and the formation of wet age-related macular degeneration (AMD) (see Holmes, D.I.R. and I. Zachary , The vascular endothelial growth factor (VEGF) family: angiogenic factors in health and disease. Genome biology, 2005. 6(2): pp. 209-209; Shibuya, M., Vascular Endothelial Growth Factor (VEGF) and Its Receptor ( VEGFR) Signaling In Angiogenesis: A Crucial Target for Anti- and Pro-Angiogenic Therapies, Genes & Cancer, 2011. 2(12): pp. 1097-1105 and Ferrara, N., Role of vascular endothelial growth factor in the regulation of angiogenesis. Kidney International, 1999. 56(3): pp. 794-814). Antiangiogenic strategies have been proposed to decelerate wet AMD (see Ferrara, N., et al., Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. 2004. 3(5): p. 391; and Niu, G. and X. Chen, Vascular endothelial growth factor as an anti-angiogenic target for cancer therapy. Current drug targets, 2010. 11(8): p. 1000-1017). The humanized monoclonal antibody, anti-VEGF, has been used in ophthalmology for the self-medication treatment of wet AMD (see Ferrara, N., et al., Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. 2004 3(5): p.391 and Presta, L.G., et al., Humanization of an antl-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders, 1997. 57(20): p.4593 -4599). Treatment of this age-related retinal disease currently relies on the use of antiangiogenic agents to slow or stop progression. Intravitreal injection of anti-VEGF therapeutic agents, such as bevacizumab and ranibizumab, is the current gold standard treatment for wet AMD and prevents VEGF from initiating subretinal choroidal neovascularization (CNV) and irreversible retinal damage caused by bleeding and scarring of newly formed blood vessels (see Delplace, V., S. Payne, and M.J.J.o.C.R. Shoichet, Delivery strategies for treatment of age-related ocular diseases: From a biological understanding to biomaterial Solutions. 2015. 219: p. 652-668; and Ohr, M. and P.K.J.E.o.o.p. Kaiser, Intravitreal aflibercept injection for neovascular (wet) age-related macular degeneration. 2012. 13(4): p. 585-591). Bevacizumab, for example, has been widely used to treat wet AMD because of its relatively low cost. However, the short half-life of these protein therapeutic agents in the vitreous often requires frequent intravitreal injections, up to monthly, to maintain effectiveness in the eye (see Hárd, A.L. and A.J.A.p. Hellstróm, On safety, pharmacokinetics and dosage of bevacizumab in ROP treatment-a review. 2011. 100(12): p. 1523-1527; and Stewart, M.W., et al., Pharmacokinetic rationale for dosing every 2 weeks versus 4 weeks with intravitreal ranibizumab, bevacizumab, and aflibercept azcAnn / Lznz / E / YiAi (vascular endothelial growth factor Trap-eye). Retina, 2012. 32(3): p. 434-457). Unfortunately, this modality often results in side effects including pain, infection, endophthalmitis, elevated intraocular pressure, inflammation, retinal detachment, and cataract formation (see Sampat, K.M. and S.J.J.C.o.i.o. Garg, Complications of intravitreal injections. 2010. 21(3 ): pp. 178-183). The main obstacle to treatment is the high cost associated with each injection, which places a burden on patients and families to receive treatment on a monthly basis (see Heimes, B., et al., Compliance von Patienten mit altersabhángiger Makuladegeneration unter Anti- VEGF-Therapie Der Ophthalmologe, 2016. 113(11): p.925-932). Therefore, there is a clear need for an easier and more efficient treatment for wet AMD. Conventional delivery systems, in the form of implants and particles, have been developed to achieve controlled release for the treatment of potential AMD (see Delplace, V., S. Payne, and M.J.J.o.C.R. Shoichet, Delivery strategies for treatment of age-related ocular diseases: From a biological! understanding to biomaterial Solutions. 2015. 219: pp. 652-668; Radhakrishnan, K., etal., Protein delivery to the back of the eye: barriers, carriers and stability of anti-VEGF proteins. 2017. 22(2): 416423; Imperiale, J.C., G.B. Acosta, and A.J.J.o.C.R. Sosnik, Polymer-based carriers for ophthalmic drug delivery. 2018; and Lee, S.S., et al., Biodegradable implants for sustained drug release in the eye. 2010. 27(10): pp. 2043-2053). Compared with micro / nanoparticle-based systems, implants have greater stability and effective drug loading, due to their larger size (see Kim, Y.C., et al., Ocular delivery of macromolecules. Journal of Controlled Release, 2014. 190: pp. 172-181). However, most implant-based treatments are accompanied by injection difficulties, as additional surgeries are required for implantation and removal for non-biodegradable infraocular implants (see Silva, G.R.d., et al., Implants as drug delivery devices for the treatment of eye diseases. Brazilian Journal of Pharmaceutical Sciences, 2010. 46: p. 585-595). These are associated with postoperative complications, as well as increased cost. Furthermore, long-term sustained release, from particles or implants, has been challenging due to insufficient physical and chemical retention of drug. For example, poly(lactic-co-glycolic acid) (PLGA), one of the most commonly used polymers for drug delivery, is characterized by rapid hydrolytic degradation, often leading to a maximum therapeutic release of 90 days. (see Li, F., et al., Controlled release of bevacizumab through nanospheres for extended treatment of age-related macular degeneration. 2012. 6: p. 54; and Sousa, F., et al., A new paradigm for antiangiogenic therapy through controlled release of bevacizumab from PLGA nanoparticles. 2017. 7(1): p. 3736). Additional drawbacks include the formation of acidic byproducts that can induce inflammation and aggravate foreign body reactions (see Lu, L., M.J. Yaszemski, and A.G.J.B. Mikos, Retinalpigment epithelium engineering using synthetic biodegradable polymers. 2001. 22(24): p 3345-3355). Disclosed herein is a composition for drug delivery comprising multi-layered, biodegradable, injectable capsules loaded with a therapeutic agent, eg, bevacizumab, to achieve a higher drug loading rate and azcAnn / Lznz / E / YiAi longer term drug release duration than conventionally available injectable drug delivery devices. To achieve highly sustainable and controllable drug release, disclosed herein are, for example, compositions for drug delivery comprising a nanoporous PCL outer shell and chitosan inner layer, to achieve physical capture and electrostatically based chemisorption, respectively. To load an amount of therapeutic agent sufficient for long-term drug release, up to at least one year, a hollow structure encapsulated by the hybrid two-layer shell was used. More specifically, the entire composition for drug delivery is prepared by combining material processing technologies including electrospinning, sintering, and salt leaching. The disclosed methods provide a central hollow cylindrical microrod with high aspect ratios to enable feasibility of injection via a 21 gauge or smaller needle for delivery of intravitreal implants. By optimizing the chemical and physical structures of the capsules, using the disclosed methods, stable and controlled release of protein therapeutic agents can be obtained for more than ten months, using the disclosed drug delivery composition. By reducing the frequency of injections through a small gauge needle, the disclosed drug delivery composition can potentially improve the quality of life of patients with wet AMD. Thus, in one aspect, there is provided a composition for drug delivery, comprising: one or more capsules each having a tubular conformation with two closing ends, wherein each capsule or capsules independently comprise a multi-layered wall and at least one luminal compartment; and one or more therapeutic agents, each initially presented within one or more of the luminal compartment(s); wherein each multi-layer wall independently comprises at least one inner layer and one outer layer; wherein each inner layer independently comprises a first polymer that has a net positive charge under physiological conditions; and wherein each outer layer independently comprises a second polymer that differs from the first polymer. In some embodiments, the drug delivery composition may comprise two or more capsules, for example two capsules, three capsules, four capsules, five capsules, six capsules, seven capsules, eight capsules, nine capsules, ten capsules, or more. In these embodiments, the two or more capsules may comprise the same composition for the multi-layered wall of each capsule, or they may differ in composition. In some embodiments, the same therapeutic agent, or a different therapeutic agent, may initially be presented within each of the two or more capsules. azcAnn / ίζηζ / Ε / γίΛΐ In some embodiments, each capsule, in the drug delivery composition, may independently comprise two or more luminal compartments, eg, two luminal compartments, three luminal compartments, four luminal compartments, or more. In some embodiments, the same therapeutic agent, or a different therapeutic agent, may initially be presented within each of the two or more luminal compartments within a single capsule. In some embodiments, each capsule independently has a length of from about 0.1 cm to about 5 cm, for example, from 0.5 cm to about 3 cm, or from 1 cm to about 3 cm. In some embodiments, each capsule independently has a length of approximately 0.1 cm to 5 cm, 0.5 cm to 5 cm, 1 cm to 5 cm, 2 cm to 5 cm, 3 cm to 5 cm, 4 cm to 5 cm, from 0.1 cm to 4 cm, from 0.5 to 4 cm, from 1 cm to 4 cm, from 2 cm to 4 cm, from 3 cm to 4 cm, from 0.1 cm to 3 cm, from 0.5 cm to 3 cm , from 1 cm to 3 cm, from 2 cm to 3 cm, from 0.1 cm to 2 cm, from 0.5 cm to 2 cm, from 1 cm to 2 cm, from 0.1 cm to 1 cm, from 0.5 to 1 cm or from 0.1 to 0.5 cm. In some embodiments, the multi-layered wall has a wall thickness of from about 25 pm to about 150 pm, for example, from about 70 pm to about 100 pm, from about 75 pm to about 95 pm, or from about 80 pm to about 90 p.m.In some embodiments, the multi-layered wall has a wall thickness of about 50 pm to about 150 pm, about 55 pm to about 150 pm, about 60 pm to about 150 pm, about 65 pm to about 150 pm, about 70 pm to about 150 pm, from about 75 pm to about 150 pm, from about 80 pm to about 150 pm, from about 90 pm to about 150 pm, from about 95 pm to about 150 pm, from about 100 pm to about 150 pm, from approximately 110 pm to approximately 150 pm, from approximately 125 pm to approximately 150 pm, from approximately 140 pm to approximately 150 pm, from approximately 50 pm to approximately 140 pm, from approximately 55 pm to 140 pm, from approximately 60 pm to approximately 140 pm, from approximately 65 pm to approximately 140 pm, from approximately 70 pm to approximately 140 pm, from approximately 75 pm to approximately 140 pm, from approximately 80 pm to approximately 140 pm, from approximately 90 pm to approximately 140 pm, from approximately 95 pm to approximately 140 pm, from approximately 100 pm to approximately 140 pm, from approximately 110 pm to approximately 140 pm, from approximately 125 pm to approximately 140 pm, from approximately 50 pm to 125 pm, from approximately 55 pm to 125 pm, from approximately 60 pm to approximately 125 pm, approximately 65 pm to approximately 125 pm, approximately 70 pm to approximately 125 pm, approximately 75 pm to approximately 125 pm, approximately 80 pm to approximately 125 pm, approximately 90 pm to approximately 125 pm, from approximately 95 pm to approximately 125 pm, from approximately 100 pm to approximately 125 pm, from approximately 110 pm to azcftnn / Lznz / E / YiAi approximately 125 pm, from approximately 50 pm to 110 pm, from approximately 55 pm to 110 pm, from approximately 60 pm to approximately 110 pm, from approximately 65 pm to approximately 110 pm, from approximately 70 pm to approximately 110 pm, from approximately 75 pm to approximately 110 pm, from approximately 80 pm to approximately 110 pm, from approximately 90 pm to approximately 110 pm, from approximately 95 pm to approximately 110 pm, from approximately 100 pm to approximately 110 pm, from approximately 50 pm to approximately 100 pm, from approximately 55 pm to approximately 100 pm, from approximately 60 pm to approximately 100 pm, from approximately 65 pm to approximately 100 pm, from approximately 70 pm to approximately 100 pm, from approximately 75 pm to approximately 100 pm, from approximately 80 pm to approximately 100 pm, from approximately 90 pm to approximately 100 pm, from approximately 95 pm to about 100 pm, about 50 pm to about 95 pm, about 55 pm to about 95 pm, about 60 pm to about 95 pm, about 65 pm to about 95 pm, about 70 pm to about 95 pm, about 75 from approximately 90 pm to approximately 95 pm, from approximately 50 pm to approximately 90 pm, from approximately 55 pm to approximately 90 pm, from approximately 60 pm to approximately 90 pm, from about 65 pm to about 90 pm, about 70 pm to about 90 pm, about 75 pm to about 90 pm, about 80 pm to about 90 pm, about 50 pm to 80 pm, about 55 pm to 80 pm , from approximately 60 pm to approximately 80 pm, from approximately 65 pm to approximately 80 pm, from approximately 70 pm to approximately 80 pm, from approximately 75 pm to approximately 80 pm, from approximately 50 pm to 75 pm, from approximately 55 pm to 75 pm, about 60 pm to about 75 pm, about 65 pm to about 75 pm, about 70 pm to about 75 pm, about 50 pm to 70 pm, about 55 pm to 70 pm, about 60 pm to about 70 pm, from about 65 pm to about 70 pm, from about 50 pm to 65 pm, from about 55 pm to 65 pm, from about 60 pm to about 65 pm, from about 50 pm to 60 pm, from about 55 pm to 60 pm and from about 50 pm to about 55 pm. In some embodiments, the thickness of the inner layer can vary from about 1 pm to about 100 pm. In some embodiments, the thickness of the inner layer can range from about 100 nm to about 990 nm, for example, about 100 nm, 200 nm, 300 nm, 400 nm, 500 nm, 600 nm, 700 nm, 800 nm, 900 nm or 990nm. In some embodiments, the thickness of the outer layer can vary from about 1 pm to about 100 pm. In some embodiments, the thickness of the outer layer can range from about 100 nm to about 990 nm, for example, about 100 nm, 200 nm, 300 nm, 400 nm, 500 nm, 600 nm, 700 nm, 800 nm, 900 nm or 990nm. azcRnn / Lznz / E / YiAi In some embodiments, the tubular conformation of the drug delivery capsule has an internal diameter of from about 100 μιτι to about 1000 pm, for example, from about 100 pm to about 1000 pm, from about 100 pm to about 500 pm, or from 100 pm at about 300 pm. In some embodiments, the tubular conformation of the drug delivery capsule has an internal diameter of from about 100 pm to about 2000 pm, from about 200 pm to about 2000 pm, from about 300 pm to about 2000 pm, from about 400 pm to from approximately 2000 pm, from approximately 500 pm to approximately 2000 pm, from approximately 600 pm to approximately 2000 pm, from approximately 700 pm to approximately 2000 pm, from approximately 800 pm to approximately 2000 pm, from approximately 900 pm to approximately 2000 pm, from approximately 1000 pm to approximately 2000 pm, approximately 1500 pm to approximately 2000 pm, approximately 100 pm to approximately 1500 pm, approximately 200 pm to approximately 1500 pm, approximately 300 pm to approximately 1500 pm, approximately 400 pm to approximately 1500 from approximately 500 pm to approximately 1500 pm, from approximately 600 pm to approximately 1500 pm, from approximately 700 pm to approximately 1500 pm, from approximately 800 pm to approximately 1500 pm, from approximately 900 pm to approximately 1500 pm, from approximately 1000 from approximately 100 pm to approximately 1000 pm, from approximately 200 pm to approximately 1000 pm, from approximately 300 pm to approximately 1000 pm, from approximately 400 pm to approximately 1000 pm, from approximately 500 pm to approximately 1000 pm, from approximately 600 pm to approximately 1000 pm, from approximately 700 pm to approximately 1000 pm, from approximately 800 pm to approximately 1000 pm, from approximately 900 pm to approximately 1000 pm, from approximately 100 pm to approximately 900 pm, from approximately 200 pm to approximately 900 pm, from approximately 300 pm to approximately 900 pm, from approximately 400 pm to approximately 900 pm, from approximately 500 pm to approximately 900 pm, from approximately 600 pm to approximately 900 pm, from approximately 700 pm to approximately 900 pm, from approximately 800 pm to approximately 900 pm, from approximately 100 pm to approximately 800 pm, from approximately 200 pm to approximately 800 pm, from approximately 300 pm to approximately 800 pm, from approximately 400 pm to approximately 800 pm, from approximately 500 pm to approximately 800 pm, from approximately 600 pm to approximately 800 pm, from approximately 700 pm to approximately 800 pm, from approximately 100 pm to approximately 700 pm, from 200 pm to approximately 700 pm, from approximately 300 pm to approximately 700 pm, from approximately 400 pm to approximately 700 pm, from about 500 pm to about 700 pm, from about 600 pm to about 700 pm, from azcRnn / Lznz / E / YiAi about 100 pm to about 600 pm, from about 200 pm to about 600 pm, from about 300 pm to about 600 pm, from about 400 pm to about 600 pm, from about 500 pm to about 600 pm, from about 100 pm to about 500 pm, from about 200 pm to about 500 pm, from about 300 pm to about 500 pm, from about 400 pm to about 500 pm , from approximately 100 pm to approximately 400 pm, from 200 pm to approximately 400 pm, from approximately 300 pm to approximately 400 pm, from approximately 100 pm to approximately 300 pm, from 200 pm to approximately 300 pm and from approximately 100 pm to approximately 200 p.m. In some embodiments, the tubular conformation has an outer diameter about 100 pm to about 300 pm greater than the internal diameter, for example, about 100 pm to about 300 pm, 150 pm to about 300 pm, 200 pm to about 300 pm, about 250 pm to about 300 pm, about 100 pm to about 250 pm, about 150 pm to about 250 pm, about 200 pm to about 250 pm, about 100 pm to about 200 pm, about 150 pm to about 200 pm or about 100 pm at approximately 150 pm greater than the internal diameter. In some embodiments, the first polymer may comprise a chitosan, a polyethyleneimine, a protamine, a polypropyleneimine, a poly L lysine, a poly L arginine, a poly D lysine, a poly D arginine, a cellulose, a dextran, a poly( amidoamine), poly(2-(dimethylamino)ethyl methacrylate), derivatives thereof or combinations thereof. In some embodiments, the first polymer comprises a chitosan or derivative thereof. The chitosan may have a degree of deacetylation of from about 60% to about 90%, or a degree of deacetylation of at least about 70%, at least about 75%, or at least about 80%. In some embodiments, the first polymer has a molecular weight of about 50 kDa to about 500 kDa, for example, about 100 kDa to about 500 kDa, about 100 kDa to about 400 kDa, about 200 kDa to about 400 kDa, from about 300 kDa to about 400 kDa or from about 310 kDa to about 375 kDa. In some embodiments, the first polymer has a molecular weight of about 10 kDa or more, for example, about 15 kDa or more, about 20 kDa or more, about 30 kDa or more, about 40 kDa or more, about 50 kDa or more. , about 60 kDa or more, about 70 kDa or more, about 90 kDa or more, about 90 kDa or more, or about 100 kDa or more. In some embodiments, the first polymer, as used in the inner layer, comprises fibers. In some embodiments, the fibers can be from about 50 nm to about 1000 nm in diameter, eg, from about 100 nm to about 400 nm. In azcftnn / Lznz / E / YiAi some embodiments, the fibers may have a diameter of from about 50 nm to about 1000 nm, from about 100 nm to about 1000 nm, from about 200 nm to about 1000 nm, from about 400 nm to about 1000 nm, from about 600 nm to about 1000 nm, from about 800 nm to about 1000 nm, from about 50 nm to about 800 nm, from about 100 nm to about 800 nm, from about 200 nm to about 800 nm, from about 400 nm to about 800 nm, about 600 nm to about 800 nm, about 50 nm to about 600 nm, about 100 nm to about 600 nm, about 200 nm to about 600 nm, about 400 nm to about 600 nm, from about 50 nm to about 400 nm, from about 100 nm to about 400 nm, from about 200 nm to about 400 nm, from about 50 nm to about 200 nm, from about 100 nm to about 200 nm, or from about 50 nm to about 100 nm. In some embodiments, the second polymer may comprise a poly(s-caprolactone) (PCL), a polylactic acid (PLA), a polyglycolic acid (PGA), a polylactide-coglycolide (PLGA), a polyester, a poly(ortho ester ), a poly(phosphazine), a poly(phosphate ester), a gelatin, a collagen, a polyethylene glycol (PEG), derivatives thereof, and combinations thereof. In other embodiments, the second polymer may comprise PLGA, PCL, PLA, PGA, PEG, polysorbate, poly(s-caprolactone-thioethyl ethylene phosphate) (PCLEEP), polyvinyl alcohol (PVA), or combinations thereof. In some embodiments, the second polymer comprises PLGA, PCL, PLA, PGA, or combinations thereof. In some embodiments, the second polymer can comprise PLGA, PCK, PLA, or combinations thereof. In some embodiments, the second polymer comprises PLGA. In some embodiments, the second polymer comprises PCL. In some embodiments, the second polymer comprises PLA. In some embodiments, the second polymer has a molecular weight of about 50 kDa to about 500 kDa, for example, about 100 kDa to about 500 kDa, about 100 kDa to about 400 kDa, about 200 kDa to about 400 kDa, from about 300 kDa to about 400 kDa or from about 310 kDa to about 375 kDa. In some embodiments, the second polymer has a molecular weight of about 10 kDa or more, for example, about 15 kDa or more, about 20 kDa or more, about 30 kDa or more, about 40 kDa or more, about 50 kDa or more. , about 60 kDa or more, about 70 kDa or more, about 90 kDa or more, about 90 kDa or more, or about 100 kDa or more. In some embodiments, the second polymer is biodegradable in vivo and well tolerated throughout the duration of the composition's presence and degradation. In some embodiments, under physiological conditions, the second polymer is degraded by random catenary cleavage, giving rise to a two-phase degradation. Initially, as the molecular weight decreases, the physical structure is not significantly affected. Degradation occurs throughout the polymeric material, and proceeds until a critical molecular weight is reached, when the degradation products become small enough to be solubilized. At this point, the structure begins to become significantly more porous and hydrated. In some embodiments, the second polymer has a molecular weight of about 90 kDa or more, and does not degrade until after 6 months or more in a subject's eye. In some embodiments, the molecular weight of the biodegradable polymer is selected in order to fine-tune the degradation time of the material in vivo. In some embodiments, the second polymer may comprise a combination of a high molecular weight polymer and a low molecular weight polymer. In some embodiments, the high molecular weight polymer can be about 25 kDa or more (for example, about 30 kDa or more, 40 kDa or more, 50 kDa or more, 60 kDa or more, 70 kDa or more, 80 kDa or more). or more, 90 kDa or more, or 100 kDa or more) and the low molecular weight polymer can be about 20 kDa or less (for example, 15 kDa or less, 10 kDa or less, 8 kDa or less, 6 kDa or less, or 4 kDa or less). In some embodiments, the proportional ratio of high molecular weight polymer to lower molecular weight polymer is between about 1:9 and about 9:1, for example, between about 2:8 and about 8:2, between about 2: 8 and about 6:4, or between about 2:8 and about 1:1. In some embodiments, the outer layer of the second polymer, as used in the outer layer, comprises fibers. In some embodiments, the fibers may have a diameter of from about 100 nm to about 2000 nm, for example, from about 500 nm to about 1000 nm. In some embodiments, the fibers may have a diameter of from about 100 nm to about 2000 nm, from about 250 nm to about 2000 nm, from about 500 nm to about 2000 nm, from about 750 nm to about 2000 nm, from about 1000 nm to about 2000 nm, about 1500 nm to about 2000 nm, about 100 nm to about 1500 nm, about 250 nm to about 1500 nm, about 500 nm to about 1500 nm, about 750 nm about 1500 nm, about 1000 nm to about 1500 nm, from about 100 nm to about 1000 nm, from about 250 nm to about 1000 nm, from about 500 nm to about 1000 nm, from about 750 nm to about 1000 nm, from about 100 nm to about 750 nm, from from about 250 nm to about 750 nm, from about 500 nm to about 750 nm, from about 100 nm to about 500 nm, from about 250 nm to about 500 nm, or from about 100 nm to about 250 nm. In some embodiments, the outer layer may further comprise pores. In other embodiments, azcRnn / Lznz / E / YiAi the outer layer does not comprise pores. In some embodiments, the outer layer comprises pores having an average pore diameter of from about 1 nm to about 990 nm, for example, from about 1 nm to about 100 nm, from about 2 nm to about 700 nm, from about 3 nm at about 400 nm, from about 5 nm to about 200 nm, or from about 7 nm to about 50 nm. In some embodiments, the outer layer comprises pores having an average pore diameter of about 100 nm to 1000 nm, eg, 350 nm to 650 nm.In some embodiments, the outer layer comprises pores having an average pore diameter of about 100 nm to about 1000 nm, 200 nm to about 1000 nm, 300 nm to about 1000 nm, about 400 nm to about 1000 nm, from about 450 nm to about 1000 nm, from about 500 nm to about 1000 nm, from about 550 nm to about 1000 nm, from about 600 nm to about 1000 nm, from about 650 nm to about 1000 nm, from about 700 nm to about 1000 nm, from about 800 nm to about 1000 nm, from about 900 nm to about 1000 nm, from about 100 nm to about 900 nm, from 200 nm to about 900 nm, from 300 nm to about 900 nm, from about 400 nm to from about 900 nm, from about 450 nm to about 900 nm, from about 500 nm to about 900 nm, from about 550 nm to about 900 nm, from about 600 nm to about 900 nm, from about 650 nm to about 900 nm, from from about 700 nm to about 900 nm, from about 800 nm to about 900 nm, from about 100 nm to about 800 nm, from about 200 nm to about 800 nm, from about 300 nm to about 800 nm, from about 400 nm to about 800 nm , from about 450 nm to about 800 nm, from about 500 nm to about 800 nm, from about 550 nm to about 800 nm, from about 600 nm to about 800 nm, from about 650 nm to about 800 nm, from about 700 nm to about 800 nm, from about 100 nm to about 700 nm, from about 200 nm to about 700 nm, from about 300 nm to about 700 nm, from about 400 nm to about 700 nm, from about 450 nm to about 700 nm, from about 500 nm to about 700 nm, about 550 nm to about 700 nm, about 600 nm to about 700 nm, about 650 nm to about 700 nm, about 100 nm to about 650 nm, 200 nm to about 650 nm , from about 300 nm to about 650 nm, from about 400 nm to about 650 nm, from about 450 nm to about 650 nm, from about 500 nm to about 650 nm, from about 550 nm to about 650 nm, from about 600 nm to about 650 nm, about 100 nm to about 600 nm, about 200 nm to about 600 azcftnn / Lznz / E / YiAi nm, about 300 nm to about 600 nm, about 400 nm to about 600 nm, about 450 nm to about 600 nm, about 500 nm to about 600 nm, about 550 nm to about 600 nm, about 100 nm to about 550 nm, 200 nm to about 550 nm, 300 nm to about 550 nm, about 400 nm to about 550 nm, from about 450 nm to about 550 nm, from about 500 nm to about 550 nm, from about 100 nm to about 500 nm, from 200 nm to about 500 nm, from 300 nm to about 500 nm, from from about 400 nm to about 500 nm, from about 450 nm to about 500 nm, from about 100 nm to about 450 nm, from about 200 nm to about 450 nm, from about 300 nm to about 450 nm, from about 400 nm to about 450 nm , from about 100 nm to about 400 nm, from about 200 nm to about 400 nm, from about 300 nm to about 400 nm, from about 100 nm to about 300 nm, from about 200 nm to about 300 nm, and from about 100 nm to about 200nm. In some embodiments, the average pore size is similar to the size of the therapeutic agent, in such a way that the therapeutic agent(s) are diffused by individual file diffusion or hindered diffusion through nanopores. Pores may not be necessary when the desired therapeutic agent is of a sufficiently small size (eg, having a molecular weight of less than 500) such that it can easily diffuse through the outer layer of the capsule. In some embodiments, the first polymer or second polymer composition can provide a melting temperature of between about 50°C and about 70°C. In some embodiments, the composition of the first polymer or second polymer is selected to provide a glass transition temperature (Tg) of between about -50°C and about -80°C. In some embodiments, each or the capsule(s) may independently have a surface charge measured as a zeta potential at pH 7.5 of about -25 mV to about 25 mV, eg, about -20 mV to about 20 mV, about -15 mV to approximately 15 mV, approximately -10 mV to approximately 10 mV, approximately -5 mV to approximately 5 mV, approximately -1 mV to approximately 1 mV, approximately -0.5 mV to approximately 0.5 mV, or approximately -0.1 mV to about 0.1mV. In some embodiments, the composition of the first polymer and second polymer is selected such that 50% of the mass, for one or more of the layers, remains after at least three months when subjected to physiological conditions. If possible, the rate of degradation of one or more of the layers can be accelerated by fine-tuning these aspects of capsule production, such as the thickness or porosity of the layer, or by increasing the hydrophilicity of the polymer composition used to produce it. the layer(s). Therapeutic Agents azcAnn / ίζηζ / Ε / γίΛΐ In a further aspect, the present disclosure also provides one or more therapeutic agents that can be used in the compositions disclosed herein. In some embodiments, the therapeutic agent(s) each have a net negative charge within a pH range of about 6.0 to about 7.4. As used herein, a "therapeutic agent" refers to one or more therapeutic agents, active ingredients, or substances that can be used to treat a medical condition of the eye or cancer. Therapeutic agents are typically ophthalmically acceptable, and are provided in a form that does not cause adverse reactions when the compositions disclosed herein are placed in an eye. As discussed herein, therapeutic agents can be released from the disclosed compositions in a biologically active form. For example, therapeutic agents can retain their three-dimensional structure when released from the system into an eye. It is further understood that, as used herein, the term "therapeutic agent" includes any biologically active compound or composition of synthetic or naturally occurring matter which, when administered to an organism (human or non-human animal), induces a pharmacological, immunogenic and / or physiological effect desired by local and / or systemic action. The term, therefore, encompasses those compounds or chemicals traditionally considered drugs, vaccines, and biopharmaceuticals, including molecules such as proteins, peptides, hormones, nucleic acids, gene constructs, and the like. Examples of therapeutic agents are described in recognized literature references, such as the Merck Index (14th Edition), the Physicians' Desk Reference (64th Edition), and The Pharmacological Basis of Therapeutics (12th Edition), and include, without limitation, drugs, vitamins, mineral supplements , substances used for the treatment, prevention, diagnosis, cure, or mitigation of a disease or condition, substances that affect the structure or function of the body, or prodrugs, which become biologically active or more active after they have been placed in a physiological environment. For example, the term "therapeutic agent" includes compounds or compositions for use in all major therapeutic areas, including, but not limited to, adjuvants, anti-infective agents such as antibiotics and antiviral agents, analgesics and combinations of analgesics, anorectic agents, anti-inflammatories, anti-epileptic agents, local and general anesthetics, hypnotics, sedatives, antipsychotic agents, neuroleptic agents, antidepressants, anxiolytics, antagonists, neuron blocking agents, anticholinergic and cholinomimetic agents, antimuscarinic and muscarinic agents, antiadrenergics, antiarrhythmics, antihypertensive agents, hormones and nutrients, antiarthritics, antiasthmatic agents, anticonvulsants, antihistamines, antiemetics, antineoplastics, antipruritics, antipyretics, antispasmodics, cardiovascular preparations (including calcium channel blockers, beta-blockers, beta-agonists, and antiarrhythmics), antihypertensives, diuretics, vasodilators, central nervous system stimulants , cough and cold preparations, decongestants, diagnostic agents, hormones, bone growth stimulants and inhibitors of bone resorption, azcRnn / Lznz / E / YiAi immunosuppressants, muscle relaxants, psychostimulants, sedatives, tranquilizers, proteins, peptides and fragments of nucleic acid molecules (polymeric forms of two or more nucleotides, either ribonucleotides (RNA) or deoxyribonucleotides (DNA), including double-stranded and simple, gene constructs, expression vectors, antisense molecules, and the like), small molecules (eg, doxorubicin), and other biologically active macromolecules such as, eg, proteins and enzymes. The agent can be a biologically active agent used in medical, including veterinary, and agricultural applications, such as with plants, as well as other areas. The term therapeutic agent also includes, without limitation, drugs, vitamins, mineral supplements, substances used for the treatment, prevention, diagnosis, cure, or mitigation of a disease or condition, or substances that affect the structure or function of the body, or prodrugs. , which become biologically active or more active after they have been placed in a predetermined physiological environment. In some embodiments, the therapeutic agent may comprise an agent useful in the treatment of an ophthalmic disorder or eye disease, such as: beta-blockers including timolol, betaxolol, levobetaxolol, and carteolol; miotics including pilocarpine; carbonic anhydrase inhibitors; serotonergic; muscarinics; dopamine agonists; adrenergic agonists including apraclonidine and brimonidine; antiangiogenesis agents; anti-infective agents including quinolones such as ciprofloxacin and aminoglycosides such as tobramycin and gentamicin; non-steroidal and steroidal anti-inflammatory agents such as suprofen, diclofenac, ketorolac, rimexolone and tetrahydrocortisol; growth factors such as EGF; immunosuppressive agents; and antiallergic agents including olopatadine; prostaglandins such as latanoprost; 15 keto latanoprost; travoprost; and unoprostone isopropyl. In some embodiments, the therapeutic agent is selected from the group consisting of an anti-inflammatory agent, a calcineurin inhibitor, an antibiotic, a nicotinic acetylcholine receptor agonist, and an antilymphangiogenic agent. In some embodiments, the anti-inflammatory agent may be cyclosporine. In some embodiments, the calcineurin inhibitor may be voclosporin. In some embodiments, the antibiotic may be selected from the group consisting of amikacin, gentamicin, kanamycin, neomycin, netilmicin, streptomycin, tobramycin, teicoplanin, vancomycin, azithromycin, clarithromycin, dirithromycin, erythromycin, roxithromycin, troleandomycin, amoxicillin, ampicillin, azlocillin , carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, nafcillin, penicillin, piperacillin, ticarcillin, bacitracin, colistin, polymyxin B, ciprofloxacin, enoxacin, gatifloxacin, levofloxacin, lomefloxacin, moxifloxacin, norfloxacin, ofloxacin, trovaf loxacin, mafenide, sulfacetamide, sulfamethizole, sulfasalazine, sulfisoxazole, trimethoprim, cotrimoxazole, demeclocycline, doxycycline, minocycline, oxytetracycline, and tetracycline. In some embodiments, the nicotinic acetylcholine receptor agonist may be any of pilocarpine, atropine, nicotine, epibatidine, lobeline, or imidacloprid. In some embodiments, the antilymphangiogenic agent may be an azcAnn / ίζηζ / Ε / γίΛΐ antibody to vascular endothelial growth factor C (VEGF-C), an antibody to VEGF-D, or an antibody to VEGF-3. In some aspects, the therapeutic agent may be selected from: a beta-blocker including levobunolol (BETAGAN), timolol (BETIMOL, TIMOPTIC), betaxolol (BETOPTIC), and metipranolol (OPTIPRANOLOL); alpha agonists such as apraclonidine (IOPIDINE) and brimonidine (ALPHAGAN); carbonic anhydrase inhibitors such as acetazolamide, methazolamide, dorzolamide (TRUSOPT), and brinzolamide (AZOPT); prostaglandins or prostaglandin analogues such as latanoprost (XALATAN), bimatoprost (LUMIGAN), and travoprost (TRAVATAN); miotic or cholinergic agents such as pilocarpine (ISOPTO CARPINE, PILOPINE) and carbachol (ISOPTO CARBACHOL); epinephrine compounds such as dipivephrine (PROPINE); forskolin; or neuroprotective compounds such as brimonidine and memantine; a steroid derivative such as 2-methoxyestradiol or analogs or derivatives thereof; or an antibiotic. The term "VEGF" refers to a vascular endothelial growth factor that induces angiogenesis or an angiogenic process, including, but not limited to, increased permeability. As used herein, the term "VEGF" includes the various subtypes of VEGF (also known as vascular permeability factor (VPF) and VEGF-A) that arise, for example, by alternative splicing editing of the VEGF-gene. A / VPF including VEGF121, VEGF165 and VEGF189. Still further, as used herein, the term "VEGF" includes VEGF-related angiogenic factors, such as PIGF (placental growth factor), VEGF-B, VEGF-C, VEGF-D, and VEGF-E, which act via a related VEFG receptor (ie, VEGFR) to induce angiogenesis or an angiogenic process. The term "VEGF" includes any member of the class of growth factors that bind to a VEGF receptor, such as VEGFR-1 (Flt-1), VEGFR-2 (KDR / Flk-1), or VEGFR-3 ( FLT-4). The term "VEGF" can be used to refer to a "VEGF" polypeptide or to a gene or nucleic acid encoding "VEGF". The term "anti-VEGF agent" refers to an agent that reduces or inhibits, partially or totally, the activity or production of a VEGF. An anti-VEGF agent can reduce or inhibit, directly or indirectly, the activity or production of a specific VEGF, such as VEGF165. Furthermore, "anti-VEGF agents" include agents that act on a VEGF ligand or its cognate receptor, in order to reduce or inhibit a signal from VEGF-associated receptors. Non-limiting examples of "anti-VEGF agents" include antisense molecules, ribozymes, or RNAi that target a VEGF nucleic acid; anti-VEGF aptamers, anti-VEGF antibodies to VEGF itself or its receptor, or soluble VEGF receptor decoys that prevent the binding of a VEGF to its cognate receptor; antisense molecules, ribozymes or RNAi that target a cognate VEGF receptor (VEGFR) nucleic acid; anti-VEGFR aptamers or anti-VEGFR antibodies that bind to a cognate VEGFR receptor; and VEGFR tyrosine kinase inhibitors. In some embodiments, the therapeutic agent may comprise an anti-VEGF agent. Representative examples of anti-VEGF agents include ranibizumab, bevacizumab, aflibercept, KH902 QzcRnn / ιζηζ / Ε / γΐΛΐ VEGF-Fc receptor, fusion protein, antibody to 2C3, ORA102, pegaptanib, bevasiranib, SIRNA-027, decursin, decursinol, picropodophyllin, guggulsterone, PLG101, eicosanoid LXA4, PTK787, pazopan ib, axitinib, CDDO-Me, CDDO-lmm, shiconin, beta hydroxyusovalerylshiconin, GM3 ganglioside, DC101 antibody, Mab25 antibody, Mab73 antibody, 4A5 antibody, 4E10 antibody, 5F12 antibody, VA01 antibody, BL2 antibody, related protein with VEGF, sFLT01, sFLT02, Peptide B3, TG100801, sorafenib, antibody to G6-31, a fusion antibody, and an antibody that binds to a VEGF epitope. Additional non-limiting examples of anti-VEGF agents useful in the present methods include a substance that specifically binds to one or more of a human vascular endothelial growth factor-A (VEGF-A), human vascular endothelial growth factor -B (VEGF-B), human vascular endothelial growth factor-C (VEGF-C), human vascular endothelial growth factor-D (VEGF-D) and human vascular endothelial growth factor-E (VEGF-E), and an antibody that binds to an epitope of VEGF. In various aspects, the anti-VEGF agent is the ranibizumab antibody or a pharmaceutically acceptable salt thereof. Ranibizumab is commercially available under the trademark LUCENTIS. In another embodiment, the anti-VEGF agent is the antibody bevacizumab or a pharmaceutically acceptable salt thereof. Bevacizumab is commercially available under the trademark AVASTIN. In another embodiment, the anti-VEGF agent is aflibercept or a pharmaceutically acceptable salt thereof. Aflibercept is commercially available under the trademark EYLEA. In one embodiment, the anti-VEGF agent is pegaptanib or a pharmaceutically acceptable salt thereof. Pegaptanib is commercially available under the trademark MACUGEN. In another embodiment, the anti-VEGF agent is an antibody or antibody fragment that binds to an epitope of VEGF, such as an epitope of VEGF-A, VEGF-B, VEGF-C, VEGF-D, or VEGF-E. . In some embodiments, the VEGF antagonist binds to a VEGF epitope, in such a way that the binding of VEGF and VEGFR is inhibited. In one embodiment, the epitope encompasses a component of the VEGF three-dimensional structure shown, in such a way that the epitope is exposed on the surface of the folded VEGF molecule. In one embodiment, the epitope is a linear amino acid sequence of VEGF. In various aspects, the therapeutic agent may comprise an agent that blocks or inhibits VEGF-mediated activity, for example, one or more antisense VEGF nucleic acids. The present disclosure provides for the therapeutic or prophylactic use of nucleic acids comprising at least six nucleotides that are antisense to a gene or cDNA encoding VEGF, or a portion thereof. As used herein, a VEGF "antisense" nucleic acid refers to a nucleic acid capable of hybridizing, by virtue of some sequence complementarity, to a portion of an RNA (preferably mRNA) encoding VEGF. The antisense nucleic acid may be complementary to a coding and / or non-coding region of an mRNA encoding VEGF. These antisense nucleic acids have utility as compounds that prevent VEGF expression, and can be used in the treatment of diabetes. The antisense nucleic acids of the disclosure are oligonucleotides, αζακηη / ιζηζ / Ε / γΐΛΐ double-stranded or single-stranded RNA or DNA, or a modification or derivative thereof, and can be administered directly to a cell or produced intracellularly by transcription of introduced exogenous sequences. VEGF antisense nucleic acids are at least six nucleotides long, and preferably are oligonucleotides ranging from 6 to about 50 oligonucleotides. In specific aspects, the oligonucleotide is at least 10 nucleotides, at least 15 nucleotides, at least 100 nucleotides, or at least 200 nucleotides. Oligonucleotides can be DNA or RNA, or chimeric mixtures, derivatives, or modified versions thereof, and can be single-stranded or double-stranded. In addition, the antisense molecules can be polymers that are mimics of nucleic acids, such as RNA, morpholino oligonucleotides, and LNA. Other types of antisense molecules include short double-stranded RNAs, known as siRNAs, and short hairpin RNAs and long dsRNAs (>50 bp but usually h 500 bp). In various aspects, the therapeutic agent may comprise one or more ribozyme molecules designed to catalytically cleave gene mRNA transcripts encoding VEGF, thereby preventing translation of the target gene mRNA and thus expression of the gene product. Ribozymes are enzymatic RNA molecules capable of catalyzing the specific cleavage of RNA. The mechanism of ribozyme action involves sequence-specific hybridization of the ribozyme molecule to complementary target RNA, followed by an endonucleolytic cleavage event. The composition of ribozyme molecules must include one or more sequences complementary to the target gene mRNA, and must include the well-known catalytic sequence responsible for mRNA cleavage. For this sequence see, for example, US Patent No. 5,093,246. Although ribozymes that cleave mRNA at site-specific recognition sequences can be used to destroy mRNAs encoding VEGF, the use of hammerhead ribozymes is preferred. Hammerhead ribozymes cleave mRNAs at locations dictated by flanking regions, which form complementary base pairs with the target mRNA. The only requirement is that the target mRNA has the following two base sequence: 5'-UG-3'. The construction and production of hammerhead ribozymes is well known in the art. The ribozymes of the present disclosure also include RNA endoribonucleases (hereinafter "Cech-like ribozymes"), such as those that occur naturally in Tetrahymena thermophila (known as IVS, or L-19 IVS RNA). Cech-like ribozymes have an eight base pair active site that hybridizes to a target RNA sequence, where it occurs after cleavage of the target RNA. The disclosure covers Cech-like ribozymes that target eight base pair active site sequences, which occur in the gene encoding VEGF. In further aspects, the therapeutic agent can comprise an antibody that inhibits VEGF, such as bevacizumab or ranibizumab. In still more aspects, the therapeutic agent may comprise an agent that inhibits VEGF activity, such as a VEGF-stimulated tyrosine kinase, examples of which include, but are not limited to, lapatinib, sunitinib, sorafenib, axitinib, and pazopanib. azcRnn / ιζηζ / Ε / γίΛΐ The term "anti-RAS agent" or "anti-renin-angiotensin system agent" refers to an agent that reduces or inhibits, partially or totally, the activity or production of a renin-angiotensin system (RAS) molecule. Non-limiting examples of "anti-RAS" or "anti-renin-angiotensin system" molecules are one or more of an angiotensin converting enzyme (ACE) inhibitor, an angiotensin receptor blocker, and a renin inhibitor. In some embodiments, the therapeutic agent may comprise a renin-angiotensin system (RAS) inhibitor. In some embodiments, the renin-angiotensin system (RAS) inhibitor is one or more of an angiotensin converting enzyme (ACE) inhibitor, an angiotensin receptor blocker, and a renin inhibitor. Non-limiting examples of angiotensin converting enzyme (ACE) inhibitors, which are useful in the present invention, include, but are not limited to: alacepril, alatriopril, altiopril calcium, ancovenin, benazepril, benazepril hydrochloride, benazeprilat, benzazepril , benzoylcaptopril, captopril, captoprilcysteine, captoprilglutathione, ceranapril, ceranopril, ceronapril, cilazapril, cilazaprilat, converstatin, delapril, delaprildiacid, enalapril, enalaprilat, enalquiren, enapril, epicaptopril, phoroxymitin, fosfenopril, fosenopril, fosenopril sodium , fosinopril, fosinopril sodium, fosinoprilat , fosinoprilic acid, glycopril, hemorphin-4, idapril, imidapril, indolapril, indolaprilat, libenzapril, lisinopril, liciumin A, liciumin B, mixanpril, moexipril, moexiprilat, moveltipril, muracein A, muracein B, muracein C, pentopril, perindopril, perindoprilat , pivalopril, pivopril, quinapril, quinapril hydrochloride, quinaprilat, ramipril, ramiprilat, spirapril, spirapril hydrochloride, spiraprilat, spiropril, spirapril hydrochloride, temocapril, temocapril hydrochloride, teprotide, trandolapril, trandolaprilat, utibapril, zabicipril, zabi ciprilat, zofenopril , zofenoprilat, pharmaceutically acceptable salts thereof, and mixtures thereof. Non-limiting examples of angiotensin receptor blockers, which are useful in the present invention, include, but are not limited to: irbesartan (US Patent No. 5,270,317, incorporated herein by reference in its entirety), candesartan ( US Patent Nos. 5,196,444 and 5,705,517, hereby incorporated by reference in their entirety), valsartan (US Patent No. 5,399,578, herein incorporated by reference in their entirety), and losartan (US Patent No. 5,138,069 , incorporated herein by reference in its entirety). Non-limiting examples of renin inhibitors, which can be used as therapeutic agents, include, but are not limited to: aliskiren, ditekiren, enalkiren, remikiren, terlakiren, ciprokiren, and zankiren, pharmaceutically acceptable salts thereof, and mixtures thereof. The term "steroid" refers to compounds belonging to or related to the following illustrative families of compounds: corticosteroids, mineralocorticosteroids, and sex steroids (including, for example, potentially androgenic or estrogenic, or antiandrogenic and antiestrogenic molecules). These include, for example, prednisone, prednisolone, methyl prednisolone, triamcinolone, fluocinolone, aldosterone, spironolactone, danazol (otherwise known as OPTINA), and others. In some embodiments, the therapeutic agent may comprise a spheroid. The terms “peroxisomal proliferator-activated receptor gamma agent”, “azcftnn / Lznz / E / YiAi agent” PPAR-γ", "PPARG agent" or "PPAR-gamma agent", refer to agents that act directly or indirectly on the peroxisomal proliferator-activated receptor. This agent can also influence PPAR-alpha, "PPARA" activity. In some embodiments, the therapeutic agent may comprise a modulator of macrophage polarization. Illustrative modulators of macrophage polarization include peroxisomal proliferator-activated receptor gamma (PPAR-g) modulators, including, for example, PPAR-gamma / alpha agonists, partial agonists, antagonists, or combined agonists. In some embodiments, the therapeutic agent may comprise a PPAR gamma modulator, including PPAR gamma modulators that are full agonists or partial agonists. In some embodiments, the PPAR gamma modulator is a member of the thiazolidinedione (TZD, or glitazone) class of drugs. By way of non-limiting example, the PPAR gamma modulator can be one or more of rosiglitazone (AVANDIA), pioglitazone (ACTOS), troglitazone (REZULIN), netoglitazone, rivoglitazone, ciglitazone, or rhodanine. In some modalities, the PPAR gamma modulator is one or more of irbesartan and telmesartan. In some embodiments, the PPAR gamma modulator is a non-steroidal anti-inflammatory drug (NSAID, such as, for example, ibuprofen) or an indole. Known inhibitors include the experimental agent GW-9662. Additional examples of PPAR gamma modulators are described in WIPO Publication Nos. WO / 1999 / 063983, WO / 2001 / 000579, in Nat Rev Immunol. 2011 Oct 25; 11(11):750-61, or agents identified using the methods of WO / 2002 / 068386, the contents of which are hereby incorporated by reference in their entirety. In some embodiments, the PPAR gamma modulator is a "dual", "balanced" or "pan" PPAR modulator. In some embodiments, the PPAR gamma modulator is a glitazar, which binds to two or more PPAR isoforms, eg, muraglitazar (Pargluva), tesaglitazar (Galida), and aleglitazar. In some embodiments, the therapeutic agent may comprise semapimod (CNI-1493), as described in Bianchi, et al. (March 1995). Molecular Medicine (Cambridge, Mass.) 1(3): 254-266, the contents of which are hereby incorporated by reference in their entirety. In some embodiments, the therapeutic agent may comprise a migration inhibitory factor (MIF) inhibitor. Illustrative MIF inhibitors are described in WIPO Publication Nos. WO 2003 / 104203, WO 2007 / 070961, WO 2009 / 117706, and US Patent Nos. 7,732,146 and 7,632,505, and 7,294,753 7,294,753 , whose content is incorporated by hereby by your reference in its entirety. In some embodiments, the MIF inhibitor is (S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester (ISO-1), isoxazoline, p425 (J. Biol. Chem. , 287, 30653-30663), epoxyazadyradione or vitamin E. In some embodiments, the therapeutic agent may comprise a chemokine receptor 2 (CCR2) inhibitor, as described, for example, in US Patent and Publication No.: US Patent No. 7,799,824, US Patent No. 8,067,415, US 2007 / 0197590, US 2006 / 0069123, US 2006 / 0058289 and US 2007 / 0037794, the contents of which are hereby incorporated by azcRnn / Lznz / E / YiAi by reference in their entirety. In some embodiments, the CCR2) inhibitor is maraviroc, cenicriviroc, CD192, CCX872, CCX140, 2-((¡sopropylaminocarbonyl)amino)-N-(2-((cis-2-((4(methyl) )benzoyl)amino)cyclohex¡l)amino)-2-oxoethyl)-5-(trifluoromethyl)-benzamide, vicriviroc, SCH351125, TAK779, Teijin, RS-504393, compound 2, compound 14 or compound 19 (Tweets ONE 7(3): e32864). In some embodiments, the therapeutic agent may comprise an agent that modulates autophagy, microautophagy, mitophagy, or other forms of autophagy. In some embodiments, the therapeutic agent may comprise sirolimus, tacrolimis, rapamycin, everolimus, bafilomycin, chloroquine, hydroxychloroquine, spautin-1, metformin, perifosin, resveratrol, trichostatin, valproic acid, Z-VADFMK, or others known to those skilled in the art. subject. Without intending to be bound by theoretical considerations, the agent that modulates autophagy, microautophagy, mitophagy, or other forms of autophagy, may alter the recycling of intracellular components, for example, but not limited to, cellular organelles, mitochondria, endoplasmic reticulum, lipid, or others. Without further wishing to be bound by theory, this agent may or may not act via microtubule-associated protein 1A / 1B-light chain 3 (LC3). In some embodiments, the therapeutic agent may comprise an agent used to treat cancer, ie, a cancer drug or anti-cancer agent. Exemplary cancer drugs may be selected from antimetabolite anticancer agents and antimitotic anticancer agents, and combinations thereof, for a subject. Various antimetabolite and antimitotic anticancer agents, including individual agents or combinations of these agents, can be employed in the methods and compositions described herein. Antimetabolic anticancer agents typically structurally resemble natural metabolites, which are involved in the normal metabolic processes of cancer cells, such as nucleic acid and protein synthesis. The antimetabolites, however, differ sufficiently from the natural metabolites in such a way that they interfere with the metabolic processes of cancer cells. In the cell, antimetabolites are confused with the metabolites they resemble, and are processed by the cell in a manner analogous to normal compounds. The presence of the "decoy" metabolites prevents cells from carrying out vital functions, and the cells are unable to grow and survive. For example, antimetabolites may exert cytotoxic activity by substituting these rogue nucleotides in cellular DNA, thereby disrupting cell division, or by inhibiting critical cellular enzymes, preventing DNA replication. In one aspect, therefore, the antimetabolite anticancer agent is a nucleotide or nucleotide analog. In certain aspects, for example, the antimetabolite agent may comprise purine (eg guanine or adenosine) or analogs thereof, or pyrimidine (cytadine or thymidine) or analogs thereof, with or without an associated sugar moiety. Suitable antimetabolite anticancer agents, for use in the present disclosure, can be broadly classified according to the metabolic process they affect, and can include, but are not limited to, azcftnn / Lznz / E / YiAi, acid derivatives and analogs. folic, pyrimidines, purines and cytidine. Thus, in one aspect, the antimetabolite agent(s) are selected from the group consisting of cytidine analogues, folic acid analogues, purine analogues, pyrimidine analogues, and combinations thereof. In a particular aspect, for example, the antimetabolite agent is a cytidine analog. According to this aspect, for example, the cytidine analog may be selected from the group consisting of cytarabine (cytosine arabinoside), azacitidine (5-azacytidine), and salts, analogs, and derivatives thereof. In another particular aspect, for example, the antimetabolite agent is a folic acid analogue. Folic acid analogues, or antifolates, generally work by inhibiting dihydrofolate reductase (DHFR), an enzyme involved in the formation of nucleotides, and when this enzyme is blocked, nucleotides are not formed, disrupting DNA replication and cellular division. According to certain aspects, for example, the folic acid analog may be selected from the group consisting of denopterin, methotrexate (ametopterin), pemetrexed, pteropterin, raltitrexed, trimetrexate, and salts, analogs, and derivatives thereof. In another particular aspect, for example, the antimetabolite agent is a purine analogue. Purine-based antimetabolite agents work by inhibiting DNA synthesis, for example, by interfering with the production of purine-, adenine-, and guanine-containing nucleotides, which arrests DNA synthesis and consequently cell division. Purine analogues can also be incorporated into the DNA molecule itself during DNA synthesis, which can interfere with cell division. According to certain aspects, for example, the purine analog may be selected from the group consisting of acyclovir, allopurinol, 2-aminoadenosine, arabinosyl adenine (ara-A), azacitidine, azathyprin, 8-aza-adenosine, 8-fluoro -adenosine, 8-methoxy-adenosine, 8-oxo-adenosine, cladribine, deoxycoformycin, fludarabine, gancilovir, 8-aza-guanosine, 8-fluoro-guanosine, 8-methoxy-guanosine, 8oxo-guanosine, guanosine diphosphate, guanosine diphosphate -beta-L-2-aminofucose, guanosine diphosphate-Darabinose, guanosine diphosphate-2-fluorofucose, guanosine diphosphate fucose, mercaptopurine (6-MP), pentostatin, thiamiprine, thioguanine (6-TG), and salts, analogs, and derivatives of the same. In yet another particular aspect, for example, the antimetabolite agent is a pyrimidine analog. Similar to the purine analogues discussed above, pyrimidine-based antimetabolite agents block the synthesis of pyrimidine-containing nucleotides (cytosine and thymine in DNA, and cytosine and uracil in RNA). By acting as "decoys", pyrimidine-based compounds can prevent nucleotide production, and / or can be incorporated into a growing DNA strand and lead to its termination. According to certain aspects, for example, the pyrimidine analogue may be selected from the group consisting of ancitabine, azacitidine, 6-azauridine, bromouracil (eg, 5-bromouracil), capecitabine, carmofur, chlorouracil (eg, 5-chlorouracil ), cytarabine (cytosine arabinoside), cytosine, dideoxyuridine, 3'-azido-3'-deoxythymidine, 3'-dideoxycytidine-2'-ene, 3'-deoxy-3deoxythymidine -2'-ene, dihydrouracil, doxifluridine, enocitabine, floxuridine, 5-fluorocytosine, 2-azcRnn / ιζηζ / Ε / γίΛΐ fluorodeoxycytidine, 3-fluoro-3'-deoxythym¡ne, fluorouracil (for example, 5-fluorouracil ( also known as 5-FU), gemcitabine, 5-methylcytosine, 5-propynylcytosine, 5-propynylthymine, 5-propynyluracil, thymine, uracil, uridine, and salts, analogs, and derivatives thereof.In one aspect, the pyrimidine analog it is other than 5-fluorouracil In another aspect, the pyrimidine analog is gemcitabine or a salt thereof. In certain aspects, the antimetabolite agent is selected from the group consisting of 5-fluorouracil, capecitabine, 6-mercaptopurine, methotrexate, gemcitabine, cytarabine, fludarabine, pemetrexed, and salts, analogs, derivatives, and combinations thereof. In other aspects, the antimetabolite agent is selected from the group consisting of capecitabine, 6-mercaptopurine, methotrexate, gemcitabine, cytarabine, fludarabine, pemetrexed, and salts, analogs, derivatives, and combinations thereof. In a particular aspect, the antimetabolite agent is other than 5-fluorouracil. In a particularly preferred aspect, the antimetabolite agent is gemcitabine or a salt thereof (eg, gemcitabine HCI (Gemzar®)). Other antimetabolite anticancer agents may be selected, but not limited to, from the group consisting of acanthifolic acid, aminothiadiazole, brequinar sodium, Ciba-Geigy CGP-30694, cyclopentyl cytosine, cytarabine phosphate and stearate, cytarabine conjugates, Lilly DATHF, Merrel Dow DDFC, dezaguanine, dideoxycytidine, dideoxyguanosine, didox, Yoshitomi DMDC, Wellcome EHNA, Merck & Co. EX-015, fazarabine, fludarabine phosphate, N-(2'-furanid¡l)-5-fluorouracil, Daiichi Seiyaku FO- 152, 5-FU-fibrinogen, isopropyl pyrrolizine, Lilly LY-188011; Lilly LY-264618, Methobenzaprim, Wellcome MZPES, Norespermidine, NCI NSC-127716, NCI NSC-264880, NCI NSC-39661, NCI NSC612567, Warner-Lambert PALA, Pentostatin, Pyritrexim, Plicamycin, Asahi Chemical PL-AC, Takeda TAC- 788, tiazofurin, Erbamont TIF, tyrosine kinase inhibitors, Taiho UFT, and uricitin, among others. In one aspect, the antimitotic agent is a microtubule inhibitor or a microtubule stabilizer. In general, microtubule stabilizers, such as taxanes and epothilones, bind to the inner surface of the beta-microtubule chain and enhance microtubule assembly by promoting the nucleation and elongation phases of the polymerization reaction, and by reducing the critical concentration of tubulin subunits required for microtubule assembly. Unlike microtubule inhibitors, such as the vinca alkaloids, which prevent microtubule assembly, microtubule stabilizers, such as taxanes, decrease lag time and dramatically change the dynamic equilibrium between tubulin dimers and polymers. of microtubules towards polymerization. In one aspect, therefore, the microtubule stabilizer is a taxane or an epothilone. In another aspect, the microtubule inhibitor is a vinca alkaloid. In some embodiments, the therapeutic agent may comprise a taxane, or derivative or analog thereof. The taxane may be a naturally derived compound or a related form, or it may be a chemically synthesized compound or derivative thereof, with antineoplastic properties. Taxanes are a family of terpenes, including but not limited to paclitaxel (Taxol®) and docetaxel (Taxotere®), which are primarily derived from the Pacific yew, Taxus QZCRnn / 1 7Π7 / Β / ΥΙΛΙ brevifolia, and which have activity against certain tumors, in particular breast and ovarian tumors. In one aspect, the taxane is docetaxel or paclitaxel. Paclitaxel is a preferred taxane, and is considered an antimitotic agent that promotes microtubule assembly from tubulin dimers, and stabilizes microtubules by preventing depolymerization. This stability results in inhibition of the normal dynamic reorganization of the microtubule network, which is essential for vital interphase and mitotic cell functions. Also included are a variety of known taxane derivatives, including hydrophilic derivatives and hydrophobic derivatives. Taxane derivatives include, but are not limited to, galactose and mannose derivatives described in International Patent Application No. WO 99 / 18113; piperazino and other derivatives described in WO 99 / 14209; taxane derivatives described in WO 99 / 09021, WO 98 / 22451, and US Patent No. 5,869,680; 6-thio derivatives described in WO 98 / 28288; sulfenamide derivatives described in US Patent No. 5,821,263; deoxygenated paclitaxel compounds such as those described in US Patent No. 5,440,056; and taxol derivatives described in US Patent No. 5,415,869. As noted above, it further includes paclitaxel prodrugs including, but not limited to, those described in WO 98 / 58927; WO 98 / 13059; and US Patent No. 5,824,701. The taxane can also be a taxane conjugate such as, for example, paclitaxel-PEG, paclitaxel-dextran, paclitaxel-xylose, docetaxel-PEG, docetaxel-dextran, docetaxel-xylose, and the like. Other derivatives are mentioned in "Synthesis and Anticancer Activity of Taxol Derivatives", D.G.I. Kingston et al., Studies in Organic Chemistry, vol. 26, entitled "New Trends in Natural Products Chemistry" (1986), Atta-ur-Rabman, P.W. le Quesne, Eds. (Elsevier, Amsterdam 1986), among other references. Each of these references is hereby incorporated by reference herein in its entirety. Various taxanes can be readily prepared using techniques known to those skilled in the art (see also WO 94 / 07882, WO 94 / 07881, WO 94 / 07880, WO 94 / 07876, WO 93 / 23555, WO 93 / 10076; US Nos. 5,294,637; 5,283,253; 5,279,949; 5,274,137; 5,202,448; 5,200,534; 5,229,529; and EP 590,267) (each of which is hereby incorporated by reference herein in its entirety), or obtained from a diversity from commercial sources including, for example, Sigma-Aldrich Co., St. Louis, Mo. Alternatively, the antimitotic agent may be a microtubule inhibitor, and in a preferred aspect, the microtubule inhibitor is a vinca alkaloid. In general, vinca alkaloids are mitotic spindle poisons. Vinca alkaloid agents act during mitosis when chromosomes divide and begin to migrate along the mitotic spindle tubules toward one of its poles, prior to cell separation. Under the action of these spindle poisons, the spindle becomes disorganized by dispersal of chromosomes during mitosis, which affects cell reproduction. According to certain aspects, for example, the vinca alkaloid is selected from the group consisting of vinblastine, vincristine, vindesine, vinorelbine, and salts, analogs, and derivatives thereof. The antimitotic agent can also be an epothilone. In general, members of the azcRnn / Lznz / E / YiAi class of epothilone compounds stabilize microtubule function, according to mechanisms similar to those of taxanes. Epothilones can also lead to cell cycle arrest at the G2-M transition phase, leading to cytotoxicity and eventually apoptosis. Suitable epithiolones include epothilone A, epothilone B, epothilone C, epothilone D, epothilone E, and epothilone F, and salts, analogs, and derivatives thereof. A particular epothilone analog is an epothilone B analog, ixabepilone (Ixempra™). In certain aspects, the antimitotic anticancer agent is selected from the group consisting of taxanes, epothilones, vinca alkaloids, and salts and combinations thereof. Thus, for example, in one aspect, the antimitotic agent is a taxane. More preferably, in this regard, the antimitotic agent is paclitaxel or docetaxel, and even more preferably paclitaxel. In another aspect, the antimitotic agent is an epothilone (eg, an epothilone B analog). In another aspect, the antimitotic agent is a vinca alkaloid. Examples of cancer drugs, which may be used in the present disclosure, include, but are not limited to: thalidomide, platinum coordination complexes such as cisplatin (cis-DDP), oxaliplatin, and carboplatin, anthracenediones such as mitoxantrone, substituted ureas such as hydroxyurea, methylhydrazine derivatives such as procarbazine (N-methylhydrazine, MIH), adrenocortical depressants such as mitotane (ο,ρ'-DDD) and aminoglutethimide, mRXR agonists such as bexarotene, and tyrosine kinase inhibitors such as sunitimib and imatinib. Examples of additional cancer drugs include alkylating agents, antimetabolites, natural products, hormone and antagonists, and miscellaneous agents. Alternate names are indicated in parentheses. Examples of alkylating agents include nitrogen mustards such as mechlorethamine, cyclophosphainide, ifosfamide, melphalan sarcolysin) and chlorambucil; ethyleneimines and methylmelamines such as hexamethylmelamine and thiotepa; alkyl sulfonates such as busulfan; nitrosoureas such as carmustine (BCNU), semustine (methyl-CCNU), lomustine (CCNU) and streptozocin (streptozotocin); DNA synthesis antagonists such as estramustine phosphate; and triazines such as dacarbazine (DTIC, dimethyltriazenoimidazolecarboxamide) and temozolomide. Examples of antimetabolites include folic acid analogues such as methotrexate (ametopterin); pyrimidine analogues such as fluorouracin (5-fluorouracil, 5-FU, SFU), floxuridine (fluorodeoxyuridine, FUdR), cytarabine (cytosine arabinoside), and gemcitabine; purine analogues such as mercaptopurine (6-mercaptopurine, 6-MP), thioguanine (6-thioguanine, TG) and pentostatin (2'-deoxycoformycin, deoxycoformycin), cladribine and fludarabine; and topoisomerase inhibitors, such as amsacrine. Examples of natural products include vinca alkaloids such as vinblastine (VLB) and vincristine; taxanes such as paclitaxel, protein-bound paclitaxel (Abraxane) and docetaxel (Taxotere); epipodophyllotoxins such as etoposide and teniposide; camptothecins such as topotecan and irinotecan; antibiotics such as dactinomycin (actinomycin D), daunorubicin (daunomycin, rubidomycin), doxorubicin, bleomycin, mitomycin (mitomycin C), idarubicin, epirubicin; enzymes such as L-asparaginase; and biological response modifiers such as interferon alpha and interleukin 2. Examples of hormones and antagonists include azcftnn / Lznz / E / YiAi lutein-releasing hormone agonists such as buserelin; adrenocorticosteroids such as prednisone and related preparations; progestins such as hydroxyprogesterone caproate, medroxyprogesterone acetate and megestrol acetate; estrogens such as diethylstilbestrol and ethinyl estradiol and related preparations; estrogen antagonists such as tamoxifen and anastrozole; androgens such as testosterone propionate and fluoxymesterone and related preparations; androgen antagonists such as flutamide and bicalutamide; and gonadotropin-releasing hormone analogues such as leuprolide. The alternate names and trade names of these and other examples of cancer drugs, and their methods of use, including dosage and administration regimens, will be known to a person skilled in the art. In some aspects, the anti-cancer agent may comprise a chemotherapeutic agent. Suitable chemotherapeutic agents include, but are not limited to, alkylating agents, antibiotic agents, antimetabolic agents, hormonal agents, plant-derived agents and their synthetic derivatives, antiangiogenic agents, differentiation-inducing agents, cell growth arrest-inducing agents, inducers of apoptosis, cytotoxic agents, agents that affect cellular bioenergetics, i.e., that affect cellular ATP levels and the molecules / activities that regulate these levels, biological agents, e.g., monoclonal antibodies, kinase inhibitors, and factor inhibitors cells and their receptors, gene therapy agents, cell therapy, eg, stem cells, or any combination thereof. According to these aspects, the chemotherapeutic agent is selected from the group consisting of cyclophosphamide, chlorambucil, melphalan, mechlorethamine, ifosfamide, busulfan, lomustine, streptozocin, temozolomide, dacarbazine, cisplatin, carboplatin, oxaliplatin, procarbazine, uramustine, methotrexate, pemetrexed, fludarabine, cytarabine, fluorouracil, floxuridine, gemcitabine, capecitabine, vinblastine, vincristine, vinorelbine, etoposide, paclitaxel, docetaxel, doxorubicin, daunorubicin, epirubicin, idarubicin, mitoxantrone, bleomycin, mitomycin, hydroxyurea, topotecan, irinote canine, amsacrine, teniposide, erlotinib hydrochloride and combinations thereof. Each possibility represents a separate aspect of the invention. According to certain aspects, the therapeutic agent may comprise a biological drug, in particular an antibody. According to some aspects, the antibody is selected from the group consisting of cetuximab, anti-CD24 antibody, panitumumab, and bevacizumab. Therapeutic agents, as used in the present disclosure, may comprise peptides, proteins such as hormones, enzymes, antibodies, monoclonal antibodies, antibody fragments, monoclonal antibody fragments, and the like, nucleic acids such as aptamers, siRNA, DNA, RNA, antisense or the like nucleic acids, antisense or the like nucleic acid analogues, low molecular weight compounds or high molecular weight compounds, receptor agonists, receptor antagonists, partial receptor agonists and partial receptor antagonists. Additional representative therapeutic agents may include, but are not limited to, azcAnn / ίζηζ / Ε / γίΛΐ peptide drugs, protein drugs, desensitizing materials, antigens, factors, growth factors, anti-infective agents such as antibiotics, antimicrobial agents, antiviral, antibacterial substances , antiparasitic, antifungal and combinations thereof, antiallergenic, steroids, androgenic steroids, decongestants, hypnotics, steroidal anti-inflammatory agents, anticholinergic sympathomimetics, sedatives, miotics, psychic energizers, tranquilizers, vaccines, estrogens, progestational agents, humoral agents, prostaglandins, analgesics , antispasmodics, antimalarials, antihistamines, cardioactive agents, nonsteroidal anti-inflammatory agents, antiparkinsonian agents, antialzheimer's agents, antihypertensive agents, beta adrenergic blocking agents, alpha adrenergic blocking agents, nutritional agents, and the benzophenanthridine alkaloids. The therapeutic agent may further be a substance capable of acting as a stimulant, a sedative, a hypnotic, an analgesic, an anticonvulsant, and the like. Additional therapeutic agents may comprise CNS-active drugs, neuroactive drugs, inflammatory and anti-inflammatory drugs, renal and cardiovascular drugs, gastrointestinal drugs, antineoplastics, immunomodulators, immunosuppressants, hematopoietic agents, growth factors, anticoagulant, thrombolytic and antiplatelet agents, hormones, Hormonally active agents, hormone antagonists, vitamins, ophthalmic agents, anabolic agents, antacids, antiasthmatic agents, anticholesterolemic and antilipidic agents, anticonvulsants, antidiarrheals, antiemetics, antimanic agents, antimetabolite agents, antinausea agents, antiobesity agents, antipyretic and analgesic agents, antispasmodics, antithrombotic agents, antitussive agents, antiuricemic agents, antianginal agents, antihistamines, appetite suppressants, biologic agents, cerebral dilators, coronary dilators, bronchodilators, cytotoxic agents, decongestants, diuretics, diagnostic agents, erythropoietic agents, expectorants, gastrointestinal sedatives, hyperglycemic agents, hypnotics, hypoglycemic agents, laxatives, mineral supplements, mucolytic agents, neuromuscular drugs, peripheral vasodilators, psychotropics, stimulants, thyroid and antithyroid agents, tissue growth agents, uterine relaxants, vitamins, antigenic materials, etc. Other classes of therapeutic agents include those cited in Goodman & Gilman's The Pharmacological Basis of Therapeutics (McGraw Hill), as well as therapeutic agents listed in the Merck Index and The Physicians' Desk Reference (Thompson Healthcare). Other therapeutic agents include androgen inhibitors, polysaccharides, growth factors (eg, vascular endothelial growth factor-VEGF), hormones, antiangiogenic factors, dextromethorphan, dextromethorphan hydrobromide, noscapine, carbetapentane citrate, chlorpheniramine maleate chlorphenidanol hydrochloride, phenindamine tartrate, pyrilamine maleate, doxylamine succinate, phenyltoloxamine citrate, phenylephrine hydrochloride, phenylpropanolamine hydrochloride, pseudoephedrine hydrochloride, ephedrine, codeine phosphate, codeine sulfate morphine, mineral supplements, cholestyramine, N-acetylprocainamide, acetaminophen , aspirin, azcRnn / Lznz / E / YiAi ibuprofen, phenylpropanolamine hydrochloride, caffeine, guaifenesin, aluminum hydroxide, magnesium hydroxide, peptides, polypeptides, proteins, amino acids, hormones, interferons, cytokines, and vaccines. Other examples of therapeutic agents include, but are not limited to, peptide drugs, protein drugs, desensitizing materials, antigens, anti-infective agents such as antibiotics, antimicrobial agents, antiviral, antibacterial, antiparasitic, antifungal substances and combinations thereof, antiallergens, steroids androgenic, decongestants, hypnotics, steroidal anti-inflammatory agents, anticholinergics, sympathomimetics, sedatives, miotics, psychic energizers, tranquilizers, vaccines, estrogens, progestational agents, humoral agents, prostaglandins, analgesics, antispasmodics, antimalarials, antihistamines, antiproliferatives, anti-VEGF agents, agents cardioactives, nonsteroidal anti-inflammatory agents, antiparkinsonian agents, antihypertensive agents, β adrenergic blocking agents, nutritional agents, and the benzophenanthridine alkaloids. The agent may further be a substance capable of acting as a stimulant, sedative, hypnotic, analgesic, anticonvulsant, and the like. Other representative therapeutic agents include, but are not limited to, analgesics such as acetaminophen, acetylsalicylic acid, and the like; anesthetics such as lidocaine, xylocaine and the like; anorectics such as dexadrine, phendimetrazine tartrate and the like; antiarthritics such as methylprednisolone, ibuprofen and the like; antiasthmatics such as terbutaline sulfate, theophylline, ephedrine and the like; antibiotics such as sulfisoxazole, penicillin G, ampicillin, cephalosporins, amikacin, gentamicin, tetracyclines, chloramphenicol, erythromycin, clindamycin, isoniazid, rifampin and the like antifungals such as amphotericin B, nystatin, ketoconazole and the like; antivirals such as acyclovir, amantadine and the like; anticancer agents such as cyclophosphamide, methotrexate, etretinate, paclitaxel, taxol and the like; anticoagulants such as heparin, warfarin and the like; anticonvulsants such as sodium phenyloin, diazepam and the like; antidepressants such as isocarboxazid, amoxapine and the like; antihistamines such as diphenhydramine HCI, chlorpheniramine maleate and the like; hormones such as insulin, progestins, estrogens, corticosteroids, glucocorticoids, androgens, and the like; tranquilizers such as thorazine, diazepam, chlorpromazine HCI, reserpine, chlorodiazepoxide HCI, and the like; antispasmodics such as belladonna alkaloids, dicyclomine hydrochloride and the like; vitamins and minerals such as essential amino acids, calcium, iron, potassium, zinc, vitamin B12 and the like; cardiovascular agents such as prazosin HCI, nitroglycerin, propranolol HCI, hydralazine HCI, pancrelipase, succinic acid dehydrogenase and the like; peptides and proteins such as LHRH, somatostatin, calcitonin, growth hormone, glucagon-like peptides, growth hormone-releasing factor, angiotensin, FSH, EGF, bone morphogenic protein (BMP), erythropoietin (EPO), interferon, interleukin, collagen , fibrinogen, insulin, Factor VIII, Factor IX, Enbrel®, Rituxam®, Herceptin®, alpha glucosidase, Cerazyme / Ceredose®, vasopressin, ACTH, human serum albumin, gamma globulin, structural proteins, blood product proteins, complex proteins, enzymes, antibodies, monoclonal antibodies, and the like; prostaglandins; nucleic acids; carbohydrates; fats; narcotics such as morphine, codeine and Qzcpnn / Lznz / E / YiAi similar, psychotherapeutic; antimalarials, L-dopa, diuretics such as furosemide, spironolactone and the like; antiulcer drugs such as rantidine HCI, cimetidine HCI and the like. The therapeutic agent can also be an immunomodulator, including, for example, cytokines, interleukins, interferon, colony-stimulating factor, tumor necrosis factor, and the like; immunosuppressants such as rapamycin, tacrolimus and the like; allergens such as cat dander, birch pollen, house dust mites, grass pollen and the like; antigens from bacterial organisms such as Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, Streptococcus pyrogenes, Corynebacterium diphteriae, Listeria monocytogenes, Bacillus anthracis, Clostridium tetani, Clostridium botulinum, Clostridium perfringens, Neisseria meningitides , Neisseria gonorrhoeae, Streptococcus mutans, Pseudomonas aeruginosa, Salmonella typhi , Haemophilus parainfluenzae, Bordetella pertussis, Francisella tularensis, Yersinia pestis, Vibrio Chole rae, Legionella pneumophila, Mycobacterium tuberculosis, Mycobacterium leprae, Treponema pallidum, Leptspirosis interrogans, Borrelia burgddorferi, Campylobacter jejuni and the like; virus antigens such as smallpox, influenza A and B, respiratory syncytial, parainfluenza, measles, HIV, SARS, varicella-zoster, herpes simplex 1 and 2, cytomeglavirus, Epstein-Barr, rotavirus, rhinovirus, adenovirus, papillomavirus, poliovirus, mumps, rabies, rubella, coxsackievirus, equine encephalitis, Japanese encephalitis, yellow fever, Rift Valley fever, lymphocytic choriomeningitis, hepatitis B and the like; antigens from these fungal, protozoan and parasitic organisms such as Cryptococcus neoformans, Histoplasma capsulatum, Candida albicans, Candida tropicalis, Nocardia asteroids, Rickettsia rickettsii, Rickettsia typhi, Mycoplasma pneumoniae, Chlamydia psittaci, Chlamydia trachomatis, Plasmodium falciparum, Trypanasoma bruce i, Entamoeba histolytica, Toxoplasma gondii, Trichomonas vaginalis, Schistosoma mansoni and the like. These antigens may be in the form of whole killed organisms, peptides, proteins, glycoproteins, carbohydrates, or combinations thereof. In a further specific aspect, the therapeutic agent may comprise an antibiotic. The antibiotic can be, for example, one or more of amikacin, gentamicin, kanamycin, neomycin, netilmicin, streptomycin, tobramycin, paromomycin, ansamycins, geldanamycin, herbimycin, carbacephen, loracarbef, carbapenems, ertapenem, doripenem, imipenem / cilastatin, meropenem, cephalosporins (first generation), cefadroxil, cefazolin, cephalothin or cephalothin, cephalexin, cephalosporins (second generation), cefaclor, cefamandole, cefoxitin, cefprozil, cefuroxime, cephalosporins (third generation), cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cephalosporins (4th generation), cefepime, cephalosporins (5th generation), ceftobiprole, glycopeptides, teicoplanin, vancomycin, macrolides, azithromycin, clarithromycin, dirithromycin, erythromycin, roxithromycin, troleandomycin, telithromycin, spec tinomycin, monobactams, aztreonam, penicillins, amoxicillin, ampicillin, azlocillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, methicillin, nafcillin, oxacillin, penicillin, piperacillin, ticarcillin, polypeptides, bacitracin, colistin, polymyxin B, quinolones, ciprofloxacin, enoxa cina, gatifloxacin, levofloxacin , lomefloxacin, moxifloxacin, norfloxacin, azcRnn / ιζηζ / Ε / γίΛΐ ofloxacin, trovafloxacin, sulfonamides, mafenide, prontosil (old), sulfacetamide, sulfamethizole, sulfanilimide (old), sulfasalazine, sulfisoxazole, trimethoprim, tri Methoprim-Sulfamethoxazole (Cotrimoxazole) (TMP -SMX), tetracyclines including demeclocycline, doxycycline, minocycline, oxytetracycline, tetracycline and others; arsphenamine, chloramphenicol, clindamycin, lincomycin, ethambutol, fosfomycin, fusidic acid, furazolidone, isoniazid, linezolid, metronidazole, mupirocin, nitrofurantoin, platensimycin, pyrazinamide, quinupristin / dalfopristin, rifampin (rifampin in USA), thymidazole, or a combination thereof. In one aspect, the therapeutic agent can be a combination of rifampicin (rifampin in the USA) and minocycline. Growth factors useful as therapeutic agents include, but are not limited to, transforming growth factor a ("TGF-a"), transforming growth factors ("TGF-β"), platelet derived growth factors ("PDGF ”), fibroblast growth factors (“FGF”) including FGF ¡acid isoforms 1 and 2, FGF basic form 2 and FGF 4, 8, 9 and 10, nerve growth factors (“NGF”) including NGF 2.5s, NGF 7.Os, NGF beta and neurotrophins, brain-derived neurotrophic factor, cartilage-derived factor, bone growth factors (BGF), basic fibroblast growth factor, insulin-like growth factor (IGF), vascular endothelial growth factor (VEGF), granulocyte colony-stimulating factor (G-CSF), insulin-like growth factor (IGF) I and II, hepatocyte growth factor, glial neurotrophic growth factor (GDNF), stem cell factor (SCF) ), keratinocyte growth factor (KGF), transforming growth factors (TGFs) including TGF alpha, beta, beta 1, beta 2, beta 3, skeletal growth factor, bone matrix derived growth factors and derived growth factors bone, and mixtures thereof. Cytokines useful as therapeutic agents include, but are not limited to, cardiotrophin, stromal cell-derived factor, macrophage-derived chemokine (MDC), melanoma growth-stimulating activity (MGSA), macrophage inflammatory protein 1 alpha (MIP-1 alpha), 2, 3 alpha, 3 beta, 4 and 5, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9 , IL-10, IL-11, IL-12, IL-13, TNF-α and TNF-β. Immunoglobulins useful in the present disclosure include, but are not limited to, IgG, IgA, IgM, IgD, IgE, and mixtures thereof. Some preferred growth factors include VEGF (vascular endothelial growth factor), NGF (nerve growth factors), PDGF-AA, PDGF-BB, PDGFAB, bFGF, aFGF, and BGF. Other molecules useful as therapeutic agents include, but are not limited to, growth hormones, leptin, leukemia inhibitory factor (LIF), tumor necrosis factor alpha and beta, endostatin, thrombospondin, osteogenic protein 1, bone morphogenetic proteins 2 and 7. , osteonectin, somatomedin-like peptide, osteocalcin, interferon alpha, interferon alpha A, interferon beta, interferon gamma, interferon 1 alpha, and interleukins 2, 3, 4, 5 6, 7, 8, 9, 10, 11, 12,13 , 15, 16, 17 and 18. In some embodiments, the therapeutic agent is present, in the disclosed drug delivery composition, in an amount (in pg therapeutic agent per mg weight of the disclosed drug delivery composition) of about 10, about azcAnn / ίζηζ / Ε / γίΛΐ 20, about 30, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95, about 100, about 110, about 120, about 130, about 140, about 150, about 160, about 170, about 180, about 190, about 200, about 210, about 220, about 230, about 240, about 250, about 260, about 270, about 280, about 290 , about 300, about 310, about 320, about 330, about 340, about 350, about 360, about 370, about 380, about 390, about 400, about 410, about 420, about 430, about 440, about 450, about 460, about 470, about 480, about 490, or about 500; or a range of amounts of the therapeutic reagent limited by any of the preceding values; or any combination of the preceding values. In some embodiments, the therapeutic agent exhibits near zero order release kinetics over a period of at least 30 days, eg, 45 days, 60 days, 3 months, 6 months, 9 months, 1 year, or longer. The therapeutic agent may exhibit near zero-order release kinetics at the time of implantation of the drug delivery composition, or after a period thereafter, for example, the therapeutic agent begins to exhibit approximately zero-order release kinetics. 30 days after implantation of the composition for drug delivery. In other embodiments, the drug delivery composition may exhibit kinetics that deviate from zero-order kinetics. Methods of preparing the disclosed drug delivery compositions In various aspects, the disclosed drug delivery devices are prepared by the methods disclosed herein below, and as described in specific aspects in the representative Examples that follow. Thus, in one aspect, there is provided a method of preparing a drug delivery device described herein, comprising: forming a first layer comprising the first polymer on a conductive rod; and forming a second layer comprising the second polymer in the first layer. In some embodiments, the formation of a first layer comprises electrospinning using a solution of the first polymer, and a voltage difference of about 10 kV to about 30 kV. In some embodiments, the first polymer solution is from about 1% w / v to about 10% w / v in at least one organic solvent. In some embodiments, the organic solvent(s) in the first polymer solution comprise trifluoroacetic acid, dichloromethane, hexafluoroisopropanol, or combinations thereof. In some embodiments, trifluoroacetic acid and dichloromethane are present in a proportional ratio of about 1:10 to about 10:1, for example, in a proportional ratio of about 5:3 to about 10:3. In some embodiments, trifluoroacetic acid and dichloromethane are present in a proportional ratio of approximately 7:3. In some embodiments, the formation of a second layer comprises electrospinning on the first layer formed, by using a solution comprising the second polymer and, optionally, a porogen, wherein the voltage difference used for electrospinning is approximately 20 kV at about 30kV. In some embodiments, the solution comprising the second polymer and, optionally, the porogen, is from about 1% w / v to about 10% w / v, based on the total weight of the second polymer and the porogen, for example, of from about 2.5% w / v to about 10% w / v, or from about 5% w / v to about 10% w / v. In some embodiments, the solution comprising the second polymer and the porogen is a solution of 1,1,1,3,3,3,-hexafluoropropan-2-ol. In some embodiments, the proportional weight ratio of the second polymer to the porogen is about 90:100 to about 100:1, for example, about 90:100 to 99.9:0.1, 90:100 to about 95:5, or 95:5. at approximately 99.9:0.1. In some embodiments, the proportional weight ratio of the second polymer to the porogen is about 99:1, about 95:5, about 92.5:7.5, or about 90:10. In some embodiments, the weight proportional ratio of second polymer to porogen ranges from about 50:50 to about 100:0. A "porogen", as used herein, refers to any material that can be used to create a porous material, eg, porous polycaprolactone, as described herein. In some embodiments, the porogen comprises a water-soluble compound, ie, in such a way that the porogen is substantially removed from the outer layer by washing the drug delivery device with water. In some embodiments, the porogen comprises a compound selected from ([Tr¡s(hydroxymethyl)methylam¡no]propanesulfonic acid) (TAPS), (2(bis(2-hydroxyethyl)am ¡no)acetic) (Bicine), (Tris(hydroxymethyl)aminomethane) or (2-amino-2(hydroxymethyl)propane-1,3-diol) (Tris), (N -[Tris(h¡drox¡met¡l)met¡l]gl¡c¡na) (Trlcina), (acid 3-[NTr¡s(h¡droximet¡l)met¡lam¡no]-2- hidrox¡propanesulfónico) (TAPSO), (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid) (HEPES), (2-[[1,3-dihydroxy-2-(hydroxymethyl)propan-2yl acid ]amino]ethanesulfonic acid) (TES), (3-(N-morpholino)propanesulfonic acid) (MOPS), (piperazine-N,N'bis(2-ethanesulfonic acid)) (PIPES), dimethylarsenic acid, (2- (N-morpholino)ethanesulfonic acid) (MES), or salts thereof, such as the sodium salts thereof. In some embodiments, the porogen comprises HEPES sodium salt. In some embodiments, the porogen comprises a water-soluble polymer such as polyethylene glycol, polyoxyethylene copolymer, an acrylate copolymer including azcAnn / Lznz / E / YiAi quaternary ammonium groups, a polyacrylamide, a polyvinyl alcohol, hyaluronan, and polyvinylpyrrolidone. . In other embodiments, the porogen comprises gelatin, polyethylene glycol (PEG), chitosan, polyvinylpyrrolidone (PVP), polyvinyl alcohol, or agarose. In some embodiments, the method further comprises sintering the drug delivery device after formation of the outer layer. In some embodiments, sintering is comprised at a temperature of from about 50°C to about 150°C, for example, from about 90°C to about 110°C. In some embodiments, sintering comprises heating for a period of from about 1 minute to about 6 hours, eg, from about 30 minutes to about 6 hours. In some embodiments, the method further comprises washing the drug delivery device after sintering. In some embodiments, the drug delivery device is flushed with a saturated sodium bicarbonate solution, followed by deionized water. In some embodiments, the porogen is substantially removed from the drug delivery device by washing with deionized water. In some embodiments, the method further comprises drying the drug delivery device after washing. In some modalities, the drying is in vacuo. In some embodiments, drying is at a temperature of from about 50°C to about 150°C, for example, from about 90°C to 110°C. In some embodiments, drying occurs for a period of from about 1 minute to about 6 hours, for example, from about 30 minutes to about 6 hours. In other embodiments, the disclosed capsules can be made by any appropriate method, as can be readily understood by those skilled in the art. In some embodiments, the disclosed capsules can be made by asymmetric membrane formation, and a representative example of these methods is provided in Yen, C. et al. “Synthesis and characterization of nanoporous polycaprolactone membranes via thermally- and nonsolvent-induced phase separations for biomedical device application” Journal of Membrane Science 2009, 343:180-88, hereby incorporated herein by reference in its entirety for all purposes . In some embodiments, the disclosed capsules can be manufactured using three-dimensional printing. In some embodiments, the disclosed capsules can be made around methylcellulose, which is subsequently removed to form the luminal compartment. In some embodiments, the disclosed capsules can be produced by a method described by Envisia Therapeutics in WO 2015 / 085251, WO 2016 / 144832, WO 2016 / 196365, WO 2017 / 015604, WO 2017 / 015616 or WO 2017 / 015675, each one of which is hereby incorporated by reference in its entirety for all purposes. In still other embodiments, the disclosed capsules can be made by methods similar to those used in the manufacture of hollow fiber membranes, such as phase inversion, including non-solvent induced phase inversion (NIPS), evaporative induced phase inversion (solvent) (EIPS), vapor sorption induced phase inversion (VIPS) and azcRnn / ίζηζ / Ε / γίΛΐ thermally induced phase inversion (TIPS). In some embodiments, the disclosed capsules may be produced using a method similar to the methods described in US 2015 / 232506, incorporated herein by reference in its entirety for all purposes. In some embodiments, the pores may instead be formed by laser diffraction of the capsules. In some aspects, the two ends of the tubular conformation of the capsule are closed. The ends may be closed by any number of sealing techniques, such as might be appropriately selected by one skilled in the art. In some embodiments, the two ends are sealed using a high frequency tube sealing technique. In these techniques, a high frequency generates an eddy current in the wall, which heats at least the polymeric layers. When the temperature has reached the melting point of the polymer, the clamps close and the molten polymer cools and forms. In some embodiments, the two ends are sealed using hot jaw tube sealing, where heated jaws apply heat to the outside of the tubular conformation to heat the inside to seal. In some embodiments, both ends can be sealed using ultrasonic tubing sealing. In these techniques, the polymer composition of the inner layers is heated and melted by the introduced high-frequency frictional force, and they form an ultrasonic horn. The clamps are then closed around the section to be sealed, cooled and formed to seal the ends. In some embodiments, the two ends are sealed using hot air sealing, where the system heats the sealing area within the capsule with hot air, then presses and subsequently cools the ends at a subsequent station. Treatment methods using a disclosed drug delivery device Also provided herein are methods of treating a clinical condition, by administration of a disclosed drug delivery composition. A clinical condition can be a clinical disorder, disease, dysfunction, or other condition that can be ameliorated by a therapeutic composition. The term "administer" or "administration" to a subject, of a disclosed drug delivery device, includes any route of introduction or delivery to a subject of the device to perform its intended function. Administration can be accomplished by any suitable route, including orally, intranasally, parenterally (intravenously, intramuscularly, intraperitoneally, or subcutaneously), or topical. Administration includes self-administration and administration by others. In some cases, administration is by injection into the eye, including infraocular injection. In other instances, for example, in the treatment of cancer, administration may be by injection of a disclosed drug delivery composition into, adjacent to, adjacent to, or proximal to a tumor or other mass of cancer cells. It should also be appreciated that the various modes of treatment or prevention of medical diseases and conditions, as described, are intended to mean "substantial", which includes total but also less than total treatment or prevention, and where achieves a certain azcAnn / ίζηζ / Ε / γίΛΐ biologically or medically relevant result. The treatment may be continuous long-term treatment for a chronic condition, or a single or a few administrations over time for the treatment of an acute condition. The term "separate" administration refers to the administration of at least two active ingredients at the same time or substantially the same time by different routes. The term "sequential" administration refers to the administration of at least two active ingredients at different times, where the route of administration is identical or different. More particularly, sequential use refers to the full administration of one of the active ingredients before administration of the other or others begins. In this way it is possible to administer one of the active ingredients for several minutes, hours or days before administering the other active ingredient or ingredients. The term "sequential" is therefore different from "simultaneous" administration. The term "simultaneous" administration refers to the administration of at least two active ingredients by the same route, at the same time or substantially at the same time. The term "therapeutic", as used herein, means a treatment and / or prophylaxis. A therapeutic effect is obtained by the suppression, remission or eradication of a disease state. The present disclosure further provides methods of treating an ophthalmic disease or disorder, by administering a therapeutically effective amount of the compositions described herein. In some embodiments, the disclosed methods pertain to the treatment of an ophthalmic disorder comprising injecting a therapeutically effective amount of the disclosed composition into the eye of a subject. The subject may be a patient, and the patient may have been diagnosed with an ophthalmic disorder. In some aspects, the method may further comprise diagnosing a subject with an ophthalmic disorder. The ophthalmologic disorder may be acute macular neuroretinopathy, Behcet's disease, neovascularization including choroidal neovascularization, diabetic uveitis, histoplasmosis, infections such as fungal or viral infections, macular degeneration such as acute macular degeneration (AMD), including wet AMD, AMD non-exudative and exudative AMD, edema such as macular edema, cystoid macular edema, and diabetic macular edema, multifocal choroiditis, ocular trauma involving a posterior ocular site or location, ocular tumors, retinal disorders such as central retinal vein occlusion, retinopathy diabetic (including proliferative diabetic retinopathy), proliferative vitreoretinopathy (PVR), retinal arterial occlusive disease, retinal detachment, uveitic retinal disease, sympathetic ophthalmia, Vogt Koyanagi-Harada (VKH) syndrome, uveal diffusion, a posterior ocular condition caused or influenced from laser eye treatment, posterior eye conditions caused or influenced by photodynamic therapy, photocoagulation, radiation retinopathy, epiretinal membrane disorders, branch retinal vein occlusion, anterior ischemic optic neuropathy, non-retinopathic diabetic retinal dysfunction, retinitis pigmentosa , cancer and glaucoma. In certain cases, the eye disorder is azcAnn / ίζηζ / Ε / γίΛΐ wet age-related macular degeneration (wet AMD), a cancer, neovascularization, macular edema, or edema. In a further particular aspect, the ophthalmic disorder is wet age-related macular degeneration (wet AMD). In various aspects, the injection for the treatment of an ophthalmic disorder may be injection into the vitreous chamber of the eye. In some cases, the injection is an intravitreal injection, a subconjunctival injection, a sub-Tenon injection, a retrobulbar injection, or a suprachoroidal injection. "Ocular region" or "ocular site" means any area of ​​the eyeball, including the anterior and posterior segment of the eye, and generally includes, but is not limited to, any functional (for example, for vision) or structural tissue found in the eyeball, or tissue or cell layer that lines partly or completely the interior or exterior of the eyeball. Specific examples of the areas of the eyeball in an ocular region include, but are not limited to, the anterior chamber, the posterior chamber, the vitreous cavity, the choroid, the suprachoroidal space, the conjunctiva, the subconjunctival space, the episclerotic space. , the intracorneal space, the subretinal space, the sub-Tenon space, the epicorneal space, the sclera, the pars plana, surgically induced avascular regions, the macula, and the retina. “Ophthalmic disorder” can mean a disease, ailment or condition that affects or involves the eye, or a part or region of the eye. Broadly, the eye includes the eyeball, including the cornea, and other tissues and fluids that make up the eyeball, the periocular muscles (such as the oblique and rectus muscles), and the portion of the optic nerve that lies within or adjacent to it. to the eyeball. "Glaucoma" means primary, secondary and / or congenital glaucoma. Primary glaucoma can include open-angle and angle-closure glaucoma. Secondary glaucoma can occur as a complication of a variety of other conditions, such as injury, inflammation, pigment dispersion, vascular disease, and diabetes. The increased pressure of glaucoma leads to blindness, since it damages the optic nerve where it enters the eye. Thus, in a non-limiting fashion, by lowering reactive oxygen species, STC-1 or MSC, which express increased amounts of STC-1, can be used in the treatment of glaucoma and prevent or delay the onset of blindness. “Inflammation-mediated”, in relation to an ocular condition, means any condition of the eye that may benefit from treatment with an anti-inflammatory agent, and is understood to include, but is not limited to, uveitis, macular edema, acute macular degeneration, detachment disorders, ocular tumors, fungal or viral infections, multifocal choroiditis, diabetic retinopathy, uveitis, proliferative vitreoretinopathy (PVR), sympathetic ophthalmia, Vogt-Koyanagi-Harada (VKH) syndrome, histoplasmosis, and uveal diffusion. “Injury” or “damage”, in relation to an ocular condition, are interchangeable and refer to the cellular and morphological manifestations, and symptoms that result from an inflammatory-mediated condition, such as, for example, inflammation, as well as lesions. tissue damage caused by means other than inflammation, such as chemical injury, including chemical burns, as well as injury caused by infections, including, but not limited to, bacterial, viral, or fungal infections. "Infraocular" means within or under an ocular tissue. Infraocular administration of a drug delivery system includes administration of the drug delivery system to a sub-Tenon, subconjunctival, suprachoroidal, subretinal, intravitreal, anterior chamber, and similar locations. Infraocular administration of a drug delivery system precludes administration of the drug delivery system to topical, systemic, intramuscular, subcutaneous, intraperitoneal, and similar locations. "Macular degeneration" refers to any of a number of disorders and conditions in which the macula degenerates or loses functional activity. Degeneration or loss of functional activity can arise as a result of, for example, cell death, decreased cell proliferation, loss of normal biological function, or a combination of the foregoing. Macular degeneration can lead to and / or manifest as alterations in the structural integrity of the cells and / or extracellular matrix of the macula, alteration in the normal architecture of the cellular and / or extracellular matrix, and / or loss of function of the cells. macular. The cells can be any cell type normally present in or near the macula, including RPE cells, photoreceptors, and capillary endothelial cells. Age-related macular degeneration, or ARMD, is the main condition related to macular degeneration, but a number of others are known including, but not limited to, Best's macular dystrophy, Stargardt's macular dystrophy, fundus dystrophy Sorsby, Mallatia Leventinese, Doyne's comb retinal dystrophy, and RPE pattern dystrophies. Age-related macular degeneration (AMD) is described as "dry" or "wet." The wet exudative neovascular form of AMD affects approximately 10–20% of those with AMD, and is characterized by abnormal blood vessels growing under or through the retinal pigment epithelium (RPE), resulting in hemorrhage, oozing, scarring, or serous retinal detachment. Eighty to ninety percent of AMD patients have the dry form, characterized by atrophy of the retinal pigment epithelium and loss of macular photoreceptors. Drusen may or may not be present in the macula. There may also be geographic atrophy of the retinal pigment epithelium in the macula, which explains the loss of vision. There is currently no cure for any form of AMD, although some success has been obtained in attenuating wet AMD with photodynamic therapy, and especially anti-VEGF therapy. Drusen are debris-like material that accumulates with age below the RPE. Drusen are seen on funduscopic eye examination. Normal eyes may have drusen-free macules, but drusen may be abundant in the retinal periphery. The presence of soft drusen in the macula, in the absence of any loss of macular vision, is considered an early phase of AMD. Drusen contain a variety of lipids, polysaccharides, and glycosaminoglycans, along with various proteins, modified proteins, or protein adducts. There is no generally accepted azcRnn / Lznz / E / YiAi therapeutic approach that addresses drusen formation and consequently manages the progressive nature of AMD. "Ocular neovascularization" (ONV) is used in this document to refer to choroidal neovascularization, retinal neovascularization, or both. "Retinal neovascularization" (RNV) refers to the abnormal development, proliferation, and / or growth of retinal blood vessels, eg, on the retinal surface. "Subretinal neovascularization" (SRNVM) refers to the abnormal development, proliferation, and / or growth of blood vessels beneath the surface of the retina. "Cornea" refers to the transparent structure that forms the anterior part of the fibrous tunic of the eye. It consists of five layers, specifically: 1) anterior corneal epithelium, continuous with the conjunctiva; 2) anterior limiting layer (Bowman's layer); 3) substantia propria, or stromal layer; 4) posterior limiting layer (Descemet's membrane); and 5) endothelium of the anterior chamber or keratoderma. "Retina" refers to the innermost layer of the eyeball, which surrounds the vitreous body and continues posteriorly with the optic nerve. The retina is composed of layers including: 1) inner limiting membrane, 2) nerve fiber layer, 3) ganglion cell layer, 4) inner plexiform layer, 5) inner nuclear layer, 6) outer plexiform layer, 7) outer nuclear layer, 8) outer limiting membrane, and 9) a layer of rods and cones. "Retinal degeneration" refers to any hereditary or acquired degeneration of the retina and / or retinal pigment epithelium. Non-limiting examples include retinitis pigmentosa, Best's disease, RPE pattern dystrophies, and age-related macular degeneration. In various aspects, a method of treating an ophthalmic disorder may comprise treatment of various ocular diseases or conditions of the retina, including the following: maculopathies / retinal degeneration: macular degeneration, including age-related macular degeneration (ARMD), such such as non-wetting age-related macular degeneration and weeping age-related macular degeneration; choroidal neovascularization; retinopathy, including diabetic retinopathy, acute and chronic macular neuroretinopathy, central serous chorioretinopathy; and macular edema, including cystoid macular edema and diabetic macular edema. Uveitis / retinitis / choroiditis: acute multifocal placoid pigment epitheliopathy, Behcet's disease, birdshot retinochoroidopathy, infections (syphilis, Lyme disease, tuberculosis, toxoplasmosis), uveitis including intermediate uveitis (pars planitis) and anterior uveitis, multifocal choroiditis, syndrome of Multiple Vanishing White Spots (MEWDS), ocular sarcoidosis, posterior scleritis, serpigna choroiditis, subretinal fibrosis, uveitis syndrome, and Vogt-Koyanagi-Harada syndrome. Vascular diseases / exudative diseases: retinal arterial occlusive disease, central retinal vein occlusion, disseminated intravascular coagulopathy, branch retinal vein occlusion, hypertensive fundus changes, ocular ischemic syndrome, retinal arterial microaneurysms, Coats disease, parafoveal telangiectasia, occlusion hemiretinal venous, papillophlebitis, central retinal artery occlusion, branch retinal artery occlusion, carotid artery disease (CAD), ozcRnn / ιζηζ / Ε / γΐΛΐ frosty branch angitis, sickle cell retinopathy and other hemoglobinopathies, angioid streaks, vitreoretinopathy familial exudative, Eales disease. Traumatic / Surgical Conditions: Sympathetic ophthalmia, uveitic retinal disease, retinal detachment, trauma, laser beam, PDT, photocoagulation, hypoperfusion during surgery, radiation retinopathy, bone marrow transplant retinopathy. Proliferative disorders: proliferative vitreous retinopathy and epiretinal membranes, proliferative diabetic retinopathy. Infectious disorders: ocular histoplasmosis, ocular toxocariasis, ocular histoplasmosis syndrome (OHS), endophthalmitis, toxoplasmosis, HIV-associated retinal diseases, HIV-associated choroidal disease, HIV-associated uveitic disease, viral retinitis, retinal necrosis acute, progressive outer retinal necrosis, fungal retinal diseases, ocular syphilis, ocular tuberculosis, diffuse unilateral subacute neuroretinitis, and myiasis. Genetic disorders: retinitis pigmentosa, systemic disorders with associated retinal dystrophies, congenital stationary night blindness, cone dystrophies, Stargardt's disease and fundus flavimaculatus, Best's disease, retinal pigment epithelial pattern dystrophy, X-linked retinoschisis , Sorsby's fundus dystrophy, benign concentric maculopathy, Bietti's crystalline dystrophy, pseudoxanthoma elasticum. Retinal tears / holes: retinal detachment, macular hole, giant retinal tear. Tumors: Tumor-associated retinal disease, congenital RPE hypertrophy, posterior uveal melanoma, choroidal hemangioma, choroidal osteoma, choroidal metastasis, combined retinal-retinal pigment epithelium hamartoma, retinoblastoma, vasoproliferative fundus tumors, retinal astrocytoma, intraocular lymphoid tumors . Miscellaneous: internal punctate choroidopathy, acute posterior multifocal placoid pigment epitheliopathy, myopic retinal degeneration, acute retinal pigment epitheliitis and the like. An anterior ocular condition is a disease, ailment, or condition that affects or involves an anterior ocular region or site (i.e., front of the eye), such as a periocular muscle, eyelid, or anteriorly located eyeball tissue or fluid. to the posterior wall of the lens capsule or ciliary muscles. Thus, an anterior eye condition primarily affects or involves the conjunctiva, cornea, anterior chamber, iris, posterior chamber (behind the iris but in front of the posterior wall of the lens capsule), the lens, or the lens capsule and blood vessels and nerve supplying or innervating an anterior ocular region or site. Thus, a prior ocular condition may include a disease, ailment or condition such as, for example, aphakia; pseudophakia; astigmatism; blepharospasm; waterfall; conjunctival diseases; conjunctivitis including, but not limited to, atopic keratoconjunctivitis; corneal injuries including, but not limited to, injury to the corneal stromal areas; corneal diseases; corneal ulcer; dry eye syndromes; eyelid diseases; diseases of the lacrimal apparatus; blocked tear ducts; myopia; presbyopia; pupil disorders; refractive disorders and strabismus. Glaucoma may also be considered an anterior ocular condition since a clinical goal of glaucoma treatment may be to reduce the hypertension of the azcAnn / ίζηζ / Ε / γίΛΐ aqueous fluid in the anterior chamber of the eye (ie, reduce intraocular pressure). Other diseases or disorders of the eye, which can be treated in accordance with the present invention, include, but are not limited to, ocular cicatricial pemphigoid (OOP), Stevens Johnson syndrome, and cataracts. A posterior ocular condition is a disease, ailment, or condition that primarily affects or involves a posterior ocular region or site, such as the choroid or sclera (in a position posterior to a plane through the posterior wall of the lens capsule). , the vitreous humor, the vitreous chamber, retina, optic nerve (ie, optic disc), and the blood vessels and nerves that supply or innervate a posterior ocular region or site. Thus, a posterior ocular condition may include a disease, ailment or condition such as, for example, acute macular neuroretinopathy, Behcet's disease, choroidal neovascularization, diabetic retinopathy, uveitis, ocular histoplasmosis, infections such as fungal or viral infections. , macular degeneration such as acute macular degeneration, non-exudative age-related macular degeneration and exudative age-related macular degeneration, edema such as macular edema, cystoid macular edema and diabetic macular edema, multifocal choroiditis, ocular trauma involving a posterior ocular site or location, ocular tumors, retinal disorders such as central retinal vein occlusion, diabetic retinopathy (including proliferative diabetic retinopathy), proliferative vitreoretinopathy (PVR), retinal vein or arterial occlusive disease, retinal detachment, uveitic retinal disease, sympathetic ophthalmia, Vogt Koyanagi-Harada (VKH) syndrome, uveal diffusion, a posterior ocular condition caused or influenced by laser eye treatment, posterior ocular conditions caused or influenced by photodynamic therapy, photocoagulation, radiation retinopathy, disorders of the epiretinal membrane, branch retinal vein occlusion, anterior ischemic optic neuropathy, non-retinopathic diabetic retinal dysfunction, retinitis pigmentosa, and glaucoma. Glaucoma can be considered a posterior ocular condition since the therapeutic goal is to prevent loss or reduce the occurrence of vision loss due to damage or loss of retinal ganglion cells or retinal nerve fibers (ie, neuroprotection). In some modalities, the ophthalmic disorder is ocular inflammation resulting from, for example, iritis, conjunctivitis, seasonal allergic conjunctivitis, acute and chronic endophthalmitis, anterior uveitis, uveitis associated with systemic diseases, posterior segment uveitis, chorioretinitis, pars planitis, syndromes masking including ocular lymphoma, pemphigoid, scleritis, keratitis, severe ocular allergy, corneal abrasion, and impaired blood-aqueous barrier. In another embodiment, the ophthalmic disorder is postoperative ocular inflammation resulting from, for example, photorefractive keratectomy, cataract removal surgery, infraocular lens implantation, vitrectomy, corneal transplantation, forms of lamellar keratectomy (DSEK, etc.), and keratotomy. radial. In various aspects, the injection for the treatment of an ophthalmic disorder may be injection into the vitreous chamber of the eye. In some cases, the injection is an intravitreal injection, subconjunctival injection, sub-Tenon injection, retrobulbar injection, or suprachoroidal azcAnn / Lznz / E / YiAi injection. In various aspects, the method for treating an ophthalmic disorder comprises administering a disclosed drug delivery device containing an amount, for example, by injection, of about 0.01 mg to about 25 mg of therapeutic agent, or about 1 mg to about 15 mg of therapeutic agent. In some embodiments, the drug delivery composition can deliver an amount of drug that maintains a concentration within the vitreous of the eye of from about 10 picomolar to about 500 picomolar, for a period of about 10 days to about 12 months. The amount of therapeutic agent in the drug delivery composition could be dependent on the amount of therapeutic agent that may reside in the capsule(s), as well as the amount necessary to achieve the desired therapeutic effect. In some embodiments, the disclosed drug delivery can protect the bioactivity of the included therapeutic agent for a period of up to 12 months. The level of bioactivity protection will be dependent on the therapeutic agent used as well as the selected composition of the disclosed capsules, but can be quantified by methods such as HPLC (to determine the amount and forms of drugs present in the eye), cellular activity assays against a positive control (such as use of the therapeutic agent alone), as well as ELISAs, to characterize forms of other therapeutic agents or to assess changes in biological activity, such as expression of transcription factors. Equipment The present disclosure also pertains to kits comprising one of: (a) the drug delivery composition as described herein, (b) the drug delivery composition as described herein in a sterile package, or (c) a prefilled syringe or needle comprising the drug delivery composition as described herein, and instructions for administering the drug delivery composition as described herein to treat a clinical condition or pathology. In a further aspect, the kits disclosed may be packaged on a daily dosage regimen (eg, card packaged, dosage card packaged, blister packs or blow molded plastics, etc.). This packaging promotes the products and increases ease of use for administration by a health care profession. This packaging can also reduce potential medical errors. The present invention also shows similar equipment, which also contains instructions for its use. In a further aspect, the present disclosure also provides a pharmaceutical package or kit, comprising one or more containers comprising the disclosed drug delivery composition. Associated with these containers may be a notification in the form prescribed by a government agency regulating the production, use or sale of pharmaceuticals or biologics, which notification reflects the agency's approval of the production, use or sale for azcRnn / Lznz / E / YiAi administration to humans. In various aspects, the kits disclosed may also comprise additional therapeutic agents, compounds, and / or products co-packaged, co-formulated, and / or co-delivered with other components. For example, a drug manufacturer, drug reseller, physician, compounding store, or pharmacist may provide a kit comprising a disclosed drug delivery composition and another component, for delivery to a patient. It is contemplated that the disclosed kits may be used in connection with the disclosed methods of production, the disclosed methods of use of or treatment, and / or the disclosed compositions. From the foregoing, it will be seen that the aspects herein are well adapted to achieve all the aims and objects stated herein above, together with other advantages which are obvious and which are inherent in the structure. Although specific elements and stages are set forth in connection with each other, it is understood that any element and / or stage provided herein is contemplated as being combinable with any other element and / or stage, regardless of the explicit provision thereof while they are still in place. within the scope provided in this document. It will be understood that certain attributes and sub-combinations are useful, and that they may be used without reference to other attributes and sub-combinations. This is contemplated and is within the scope of the claims. Since many possible aspects may be embodied without departing from the scope thereof, it is to be understood that all matter set forth herein or shown in the accompanying drawings and detailed description is to be construed as illustrative and not in a limiting sense. It will also be understood that the terminology used in this document is for the purpose of describing particular aspects only, and is not intended to be limiting. The skilled person will recognize many variations and adaptations of the aspects described in this document. These variations and adaptations are intended to be included in the teachings of this disclosure, and to be encompassed by the claims herein. Now, having described aspects of the present disclosure in general, the following Examples describe some additional aspects of the present disclosure. Although aspects of the present disclosure are described in connection with the following examples, and the corresponding text and figures, it is not intended to limit aspects of the present disclosure to this description. Rather, it is intended to cover all alternatives, modifications, and equivalents included within the spirit and scope of this disclosure. EXAMPLES The following examples are provided in order to provide those skilled in the art with a complete disclosure and description of how the compounds, compositions, azcRnn / Lznz / E / YiAi articles, devices and / or methods claimed in this document, and are intended to be strictly exemplary of the disclosure, and are not intended to limit the scope of what the inventors consider to be their disclosure. Efforts have been made to ensure accuracy with respect to figures (eg amounts, temperature, etc.), but some errors and deviations must be assumed. Unless otherwise indicated, parts are parts by weight, temperature is in °C or is at room temperature, and pressure is at or near atmospheric. Materials Chitosan (DD > 75%, Mw 310,000 to 375,000 Da), polycaprolactone (Mn 80,000), trifluoroacetic acid (TFA), 4-(2-hydroxyethyl)p¡peraz¡n-1-ethanesulfonic acid sodium salts (HEPES ) and tween 20 were purchased from Sigma-Aldrich Inc. (St. Louis, MO). 1,1,1,3,3,3-hexafluoro-2-propanol (HFP) was purchased from Oakwood Products Inc. (Estill, SC). Dichloromethane (DCM), chromatographically purified bovine serum albumin (BSA) and recombinant human VEGF protein were purchased from Fisher Scientific International Inc. (Hampton, NH). Bevacizumab (Avastin) was purchased from Genentech, Inc. (San Francisco, CA). The Bicinchoninic Acid (BOA) Protein Assay Kit and 3-(4,5dimethyl¡lt¡azol-2-¡l)-5-(3-carbox¡methoxy¡phenyl)-2-( 4-Sulfofen¡l)-2H-tetrazol¡o (MTS), goat anti-human immunoglobulin G (IgG) crystallizable fragment (Fe) secondary antibody conjugated to horseradish peroxidase (HRP), and 3,3',5 ,5'-tetramethylbenzidine (TMB) were purchased from Thermo Fisher Scientific Inc. (Waltham, MA). Human retinal pigment epithelium cell line (ARPE-19 cells, CRL2302) and DMEM:F-12 medium were purchased from the American Type Culture Collection (Rockville, MD). Human umbilical vein endothelial cells (HUVEC), 200PRF medium, low serum growth supplement, and basement membrane matrix with reduced lactose dehydrogenase-elevating virus-free growth factor (LDEV) were purchased from Thermo Fisher Scientific. Inc. (Waltham, MA). All other reagents used were of analytical grade. Capsule manufacturing Two sizes of capsules, with different internal diameters (260 pm and 1645 pm), were fabricated in this study. The 1,645mm size capsule served primarily as a preliminary model for the smaller capsules, to optimize processing conditions. The 260 pm size capsules were used for subsequent studies. The capsule manufacturing process is shown in Figure 1A. The chitosan fibrous layer was prepared by electrospinning based on previous studies with modifications (see Gu, B.K., et al., Fabrication of sonicated chitosan nanofiber mat with enlarged porosity for use as hemostatic materials. 2013. 97(1): p. 65-73). Briefly, a 5.0% (w / v) chitosan solution, prepared in a mixture of TFA and DCM at a 7:3 proportional volume ratio, was extruded through a 20-gauge stainless steel needle that was attached to the cathode of a high voltage DC generator The soil was attached to a rotating drum collector at a speed of 500 rpm, where electrospun fibers were deposited. To obtain capsules with the two different internal diameters, a 1645 mm or 260 pm diameter 315 stainless steel rod was used for fiber collection. The solution was continuously doped with azRnn / Lznz / E / YiAi at an introduction rate of 3.0 ml / h for the 1.645 mm drum collector, and 1.0 ml / h for the 260 pm drum collector, at a voltage of 25.0 kV. Humidity during electrospinning was controlled at 30%, using a glove box filled with nitrogen. To prepare the PCL nanoporous layer (see Cipitria, A., et al., Design, fabrication and characterization of PCL electrospun scaffolds—a review. 2011. 21(26): p. 9419-9453; Chaparro, F.J., et al ., Sintered electrospun polycaprolactone for controlled model drug delivery. 2019; Nam, J., et al., Modulation of embryonic mesenchymal progenitor cell differentiation via control over puree mechanical modulus in electrospun nanofibers. 2011. 7(4): p. 1516- 1524; and Chaparro, F.J., et al., Sintered electrospun poly(c-caprolactone)-poly(ethylene terephthalate) for drug delivery. Journal of Applied Polymer Science, 2019. 0(0): p. 47731), 0.5 g of a combination of PCL and HEPES sodium salts were dissolved in 10.0 g of HFP, and the solution was continuously stirred at 40 °C overnight. Five mass ratios of PCL to sodium salt of HEPES (100:0; 99:1; 95:5; 92.5:7.5; 90:10) were studied to assess the impact of salt-induced porous structure of the film. PCL on drug release. The PCL solution was continuously spiked at an introduction rate of 3.0 ml / h for the 1645 mm drum collector, and 1.0 ml / h for the 260 pm drum collector, using a syringe pump. The high voltage DC generator was set at 24.0 kV to produce PCL nanofibers by depositing onto 1645 mm, 260 µm diameter 315 stainless steel rods, with or without the chitosan layer as spun to form a two-layer film. layers and a single layer film, respectively. Electrospun capsules were sintered under vacuum at 100 °C for 3 hours to remove surface porosity using an AccuTemp digital vacuum furnace, and then the capsules were gently removed from the rod (see Chaparro, F.J., ef al., Sintered electrospun polycaprolactone for controlled model drug delivery. 2019). The samples were washed with the saturated sodium bicarbonate solution to neutralize the TFA, and then with deionized water to dissolve and remove the HEPES sodium salts. The capsules were vacuum dried overnight. The external diameter of the capsules prepared using the 1645 mm rod, before and after sintering, was measured using a digital micrometer (Keyence). The film thickness was calculated as [capsule sintered outer diameter 1,645 mm] / 2. A light microscope (Cole-Parmer) was used to acquire the images of capsules prepared using the 260 pm diameter rod. Images were analyzed by Motic Image Plus to determine the external diameter of the capsule. The film thickness was calculated as [capsule sintered outer diameter - 260 pm] / 2. Capsule characterization The morphological characteristics of the capsules were examined by scanning electron microscopy (SEM) (FEI, Cuanta 200). Chitosan fibrous layer, PCL fibrous layer, and cross section of two-layer films and one-layer films, before and after salt leaching, were fixed on carbon tape placed on aluminum mounts and coated by sprayed with a gold-palladium coating. The capsules were immersed and fractured in liquid nitrogen, to acquire the cross section azcftnn / ίζηζ / Ε / γίΛΐ for imaging. Fiber sizes and average pore sizes of the PCL layer and chitosan layer were characterized and quantified from SEM images of three samples using ImageJ (NIH). Surface chemical analysis of the electrospun samples was performed using a Fourier Transform Infrared (FTIR) spectrometer (Thermo Scientific, Nicolet Nexus 670) in the attenuated total reflectance (ATR) mode. A germanium crystal was contacted with the samples, and 100 scans were collected at a resolution of 8 cm-1. Standard peak positions at 1727 cm-1 and 1590 cm'1 were used to identify PCL (carbonite peak) and chitosan (amine band), respectively (see Elzein, T., et al., FTIR study of polycaprolactone chain organization at interfaces, Journal of Colloid and Interface Science, 2004. 273(2): pp. 381-387, and Osman, Z. and A.K. Arof, FTIR studies of chitosan acetate based polymer electrolytes, Electrochimica Acta, 2003. 48(8): p 993-999). Drug release profile and loading / encapsulation efficacy Hollow two-layer capsules with two open ends were obtained by removing the drum headers. For the 1645 mm internal diameter capsule, 2.0 mg of BSA powder (model protein) or 2.0 mg of lyophilized bevacizumab powder (Avastin, anti-VEGF), dissolved in phosphate buffered saline (PBS) at a concentration of 0.1 mg / μΙ, were loaded into the capsule which was end-sealed using a tube sealer (Doug Care Equipment, TTS-8C) (see Chaparro, F.J., et al., Sintered electrospun polycaprolactone for controlled model drug delivery. 2019; and Bernards, D.A., et al., Nanostructured thin film polymer devices for constant-rate protein delivery. 2012. 12(10): p. 5355-5361). For 260 µm internal diameter capsules, 1.0 mg of concentrated BSA or 1.0 mg of bevacizumab aqueous suspension, at a concentration of 1.0 mg / μΙ, were loaded into the capsules using a 31-gauge needle, considering the limited volume. inside the capsules. In vitro BSA release profiles, from PCL single-layer capsules and PCL-chitosan two-layer capsules, were acquired as described in the following steps. Capsules were immersed in 1 ml PBS in a 1.5 ml low-binding centrifuge tube to reduce the binding of the centrifuge tube to the eluted protein. The centrifuge tube with a submerged dish was incubated at 37°C to simulate physiological conditions. At 1h, 3h, 6h, 12h, 24h, 3 days, 1 week, 2 weeks, 1 month, and monthly thereafter, the eluent was collected (see Sousa, F., et al., A new paradigm for antiangiogenic therapy through controlled release of bevacizumab from PLGA nanoparticles. 2017. 7(1): p. 3736; Yandrapu, S.K., et al., Nanoparticles in Porous Microparticles Prepared by Supercritical Infusion and Pressure Quench Technology for Sustained Delivery of Bevacizumab Molecular Pharmaceutics, 2013. 10(12): pp. 4676-4686 and Tyagi, P., et al., Light-activated, in situ forming gel for sustained suprachoroidal delivery of bevacizumab. Molecular Pharmaceutics, 2013. 10(8 ): p.28582867). Then 1.0 ml of freshly prepared PBS was added and kept under incubation. The BSA release profile was acquired by determining the uptake of eluted BSA by BCA assay, and quantifying the concentration using a BSA protein-based standard curve. For the release of bevacizumab in vitro, from PCL single layer capsules and PCL bilayer capsules azcAnn / Lznz / E / YiAi and from PCL-chitosan bilayer capsule, over a long-term period, were determined by morphological changes. Briefly, double-end sealed capsules and double-layered double-open capsules were incubated in PBS at physiological temperature for 9 months and 3 weeks, respectively, recovered, and then vacuum-dried for characterization. The PCL outer layer, chitosan inner layer, and cross section of single-layer and double-layer capsules were examined using SEM. Major rupture and tear were assessed, and the average pore sizes of the PCL layer, prepared with different proportional ratios of HEPES sodium salt, were quantified by analyzing three different images using Image J, and compared to the size of initial pore of the capsules before incubation by one-way ANOVA with Tukey's test a posteriori, at a significance level of 0.05. Data are presented as the mean ± standard deviation. Cytotoxicity The in vitro cytotoxicity of the PCL single-layered capsule, and of the PCLchitosan two-layered capsule, were assessed by MTS assay conducted with human retinal pigmented epithelial cells (ARPE-19) (see Sur, A., et al. ., Pharmacological protection of retinal pigmented epithelial cells by sulindac involves PPAR-a. 2014. 111(47): p. 16754-16759; Andrés-Guerrero, V., et al., Novel biodegradable polyesteramide microspheres for controlled drug delivery in ophthalmology 2015. 211: pp. 105-117 and Huhtala, A., et al., In vitro biocompatibility of degradable biopolymers in cell Une cultures from various ocular tissues: extraction studies, Journal of Materials Science: Materials in Medicine, 2008. 19(2): pp. 645-649). ARPE-19 cells were grown in 48-well plates at a density of 4 x 10 4 cells / well for all experiments. The cytotoxicity assay was carried out by the direct contact method and the extract exposure method. For the direct contact method, a 1 cm PCL single-layer dish or a PCL-chitosan two-layer dish was placed in the well plate cultured with cells for 24 hours. For the extract exposure method, the 1 cm PCL single-layer dish or the PCL-chitosan two-layer dish were immersed in 1 ml of freshly prepared medium for 1 day, 3 days, 1 week, 2 weeks. and 1 month. At each time point, the conditioned medium from the capsules was transferred to the ARPE-19 cell culture, and measurements were made with incubation times of each sample with the cells for 24 hours. To perform the cytotoxicity assay, cell culture media were mixed with 20 µl of MTS reagent, followed by 3 h of incubation at 37 °C. Absorbance measurements of supernatants were obtained using a microplate reader at 490 nm. The cell viabilities of the experimental group were normalized to the control group (no treatment). All experiments were repeated in triplicate, and data were analyzed by one-way ANOVA with Tukey's test a posteriori, at a significance level of 0.05. Data are presented as the mean + standard deviation. Assessment of aggregation and antiangiogenic activity Bevacizumab stability was determined by Ultra High Performance Liquid Chromatography (UHPLC) System 300 (Thermo Fisher Scientific Inc., Waltham, MA) using an azcRnn / ιζηζ / Ε / γίΛΐ SEC column. 1000. To determine the stability of bevacizumab during the lyophilization process, 500 µL of 25 mg / mL bevacizumab (Avastin) was freeze-dried by a lyophilizer (Labconco), and the powders were further diluted in 500 µΙ PBS. Instability of concentrated bevacizumab was also assessed by diluting the aqueous suspension of bevacizumab from the device in PBS to 25 mg / mL. Free native bevacizumab before and after lyophilization, concentrated bevacizumab, and bevacizumab eluted from single-layer and double-layer capsules, at specific time points, were filtered through a 0.2 pm Whatman SPARTAN HPLC Syringe Filter (VWR International, Radnor, PA) prior to injection. Native bevacizumab monomer, aggregate, and fragment fractions were analyzed by spectral deconvolution on HPLC to separate single elution peaks. The integral areas of monomer, aggregate and fragment were normalized to the total area of ​​the HPLC peak, to obtain the percentage of each component. The average molecular weight was then calculated from the % fraction and molecular weight of each component. The antiangiogenic activity of bevacizumab released from PCL single-layer capsule and PCL-chitosan bilayer capsules were further assessed using a capillary-type tubule formation assay (see Elsaid, N., et al. , PLGA microparticles entrapping chitosan-based nanoparticles for the ocular delivery of ranibizumab. 2016. 13(9): p. 2923-2940; Arnaoutova, I. and H.K.J.N.p. Kleinman, In vitro angiogenesis: endothelial cell tube formation on gelled basement membrane extract. 2010. 5(4): p.628 and DeCicco-Skinner, K.L., et al., Endothelial cell tube formation assay for the in vitro study of angiogenesis. 2014(91). More specifically, HUVECs were exposed to VEGF (5 ng / ml), angiogenesis promoter, mixed with i) 10 pg / ml native bevacizumab, ii) 10 pg / ml bevacizumab released from PCL single-layer capsule, and iii) 10 pg / ml bevacizumab released from PCL-chitosan bilayer capsule at 1 week, 2 weeks, 1 month, 3 months, 6 months and 9 months. After 6 hours, calcein AM was added to the cells, followed by incubation for 30 min. Cells were then directly visualized using a fluorescent microscope (Nikon, Eclipse TS100) equipped with a digital camera (Qimaging). Three images were analyzed using Image J to quantify the lengths of the capillary structure formed. The total tubular lengths of the experimental groups were normalized to the VEGF-treated control group for each sample, and all experiments were repeated three times. The data were analyzed by one-way ANOVA with a posterior Tukey's test!, with a significance level of 0.05. Data are presented as the mean ± standard deviation. injection feasibility Fresh porcine eyes, obtained from a local slaughterhouse (Delaware Meats, Delaware, Ohio), were used for assessment of device injection feasibility (see Hoshi, S., et al., In Vivo and In Vitro Feasibility Studies of Infraocular Use of Polyethylene Glycol-Based Synthetic Sealant to Close Retina! Breaks in Porcine and Rabbit Eyes. 2015. 56(8): p. 4705-4711). The capsule was preloaded into a 21-gauge hypodermic needle, which was connected to a 1 mL syringe. The 21-gauge needle used in this study has an internal diameter similar to the commercialized infraocular implant injector, the Ozurdex applicator (see Lee, S.S., et al., Biodegradable implants for sustained drug release in the eye. QZCRnn / 1 7Π7 / Β / ΥΙΛΙ 2010. 27(10): ρ. 2043-2053). The infraocular injection was placed 3 mm posterior to the limbus using the syringe needle. A small volume of PBS (100 µL) was used to push the capsule into the porcine vitreous and reduce the effect of IOP elevation. After injection, the needle was withdrawn and the sclera was incised around the middle of the eye to check the placement of the capsule in the vitreous. Electrospinning of PCL and chitosan nanofibers as building blocks for IBB capsules The disclosed IBB capsule manufacturing strategy is based on a two-step coating of chitosan and PCL films onto a rod-shaped template, followed by removal of the template. Electrospinning was used to create the porous central hollowed bilayer structure, which can offer a high surface area to volume ratio for protein chemosorption and adjustable porosity for drug diffusion to achieve the desired function. Electrospinning, as a method for manufacturing nanofibers, is based on the use of electrical force to draw the charged polymer solution into nanoscopic fibers. To synthesize the chitosan nanofibers, processing parameters, including humidity and voltage, were optimized. For example, high humidity (above 30%) or low voltage (below 24 kV) caused significant spin head pressure loss and prevented the threads in the chitosan solution from forming fibers. Therefore, low humidity and relatively high voltage were used. Meanwhile, the chitosan precursor was dissolved in TFA and DCM, since the addition of TFA dissolved chitosan better, while DCM allowed timely evaporation of the solvent, both necessary for electrospinning. To place the chitosan nanofiber on the steel rod templates, the chitosan nanofibers were collected on a steel rod under rotation directly. From the SEM images shown in Figure 2, the diameter of the chitosan fibers was 331.61 ± 186.19 nm, and these fibers were highly interconnected, forming a highly porous structure to allow efficient drug diffusion. However, the chitosan fibrous mat was found to be brittle, which is consistent with reports of its low mechanical flexibility (see Jayakumar, R., et al., Biomedical applications of chitin and chitosan based nanomaterials—A short review. 2010. 82(2): pp. 227-232). To this end, a second layer of PCL was added, which not only provided physical drug capture, but also imparted improved flexibility. More specifically, on top of the chitosan nanofibers, PCL nanofibers with a diameter of 932.57 ± 399.42 nm were coated (see Baker, S.R., et al., Determining the mechanical properties of electrospun poly-εcaprolactone (PCL) nanofibers using AFM and a novel fiber anchoring technique. 2016. 59: p. 203-212). For this purpose, nanofiber-based cylinders having high surface area, high mechanical flexibility, and strong adhesion between different layers were constructed as building blocks for IBB capsules. Synthesis and characterization of injectable and bilayer microcapsules By using the two layers of nanofibers as building blocks, the capsule structure Hollow QzcAnn / ίζηζ / Ε / γίΛΐ was formed by directly removing the steel rod template after electrospinning, as shown in Figure 3. Although the two-layer PCL-chitosan nanofibrous structure could provide significant physical and electrostatic interactions with For protein therapeutics, a burst release could still occur given the significantly larger sizes of the continuous porous structures of nanofibers compared to the size of proteins (see Chaparro, F.J., et al., Sintered electrospun polycaprolactone for controlled model drug delivery. 2019). Sintering was used to melt the PCL nanofiber layer to reduce its porosity and reduce burst release of drug. On the other hand, direct coating of the PCL layer, without starting with the initial nanofibrous structure, makes it difficult to achieve the thin layered structure on top of the chitosan, which was critical for producing small, injectable capsules. The sinter-based formation mechanism of the bilayer structure was based on the relatively low melting point of PCL at 60 °C, compared to chitosan nanofibers at 220 °C. Therefore, although the PCL became mostly non-porous during the process to physically retain the drug, the chitosan remained porous to electrostatically bind the drug. Furthermore, this process also better integrated the two layers during the fusion process. From the SEM images shown in Figure 3, the fibrous chitosan layer adhered to the PCL outer layer, which stabilized the bilayer structure, since the fusion of the PCL nanofibers increases the adhesion between the layers. two layers. However, the large fiber composite scaffold can still be seen on the PCL surface after sintering. During the sintering process, the film thickness decreased by 80% due to compression and an increase in density, so capsule size can be controlled by modulating the thickness of the chitosan and PCL fibrous layers during the process. of electrospinning. After sintering the chitosan and PCL fibrous film, bilayer microcapsules with hollow structures were generated by a templating strategy and by taking advantage of the mechanical robustness of the PCL outer layer. By controlling the shape and size of the template rods, the sizes and structures of the capsules could be effectively controlled. As a proof of concept, two sizes of PCL single-layer and chitosan-PCL double-layer capsules were prepared: one with an internal diameter greater than 1,645 mm (pre-model) that could be transplanted as a scaffold, and one with an internal diameter less than 260 pm (final model) which is injectable through a 21 gauge needle. Although the hollow tempered steel rod structure primarily allowed for high volume drug loading, the two-layer membrane provided physical capture and non-covalent chemical binding, to achieve a sustainable release for a long time. In the devices used for drug release studies, the outer diameter of the 1,645 mm inner diameter capsule was approximately 1,815 mm, with a wall thickness of 89.36 ± 11.52 pm. Similarly, the external diameter of the 260 µm internal diameter capsule was approximately 430 µm, with 89.85 ± 4.27 µm of membrane thickness, which was designed to be injectable via a 21-gauge needle. capsules enhanced the azcRnn / Lznz / E / YiAi mechanical properties of the capsule, which prevented fracture during injection. However, the increase in capsule size could potentially preclude intravitreal injection. Therefore, 80 to 90 pm was determined as the wall thickness that balanced mechanical robustness as well as injection feasibility. Furthermore, membrane thickness is closely related to the rate of drug diffusion, so the difference in thickness between single-layer and double-layer capsules was controlled and minimized to reduce the impact of thickness on drug release. Modulation of the nanoporous structure of the two-layer membrane After sintering, the PCL layers became non-porous and the drug release rate was significantly limited (see Chaparro, F.J., et al., Sintered electrospun polycaprolactone for controlled model drug delivery. 2019). However, without sintering, the bilayer capsule could be highly porous, resulting in an undesirable high drug release rate. As such, a salt leaching method was employed to precisely modulate the 3D porous structure of the bilayer membrane, to enable sustainable long-term drug delivery. More specifically, varying amounts of water soluble salts (HEPES) were mixed into the nanofibers during electrospinning. Incubation of capsules in water, prior to drug loading, led to dissolution of HEPES within the films, consequently forming a porous structure again in the bilayered membrane. By modulating the HEPES concentrations in the PCL nanofibers, the porosities could be effectively controlled. As shown in Figure 4, the pore size and distribution in the PCL sintered films were highly dependent on the proportional ratio of salt to PCL masses. For example, the pores tended to be smaller and more scattered over the entire surface of the films at lower salt concentrations. However, the low amounts of salt also prevented the generation of interconnecting pores for the diffusion and release of large molecules. Table 1 shows the analytical results of pore sizes for different proportional ratios of PCL to HEPES sodium salt. For this purpose, PCL films prepared with salt concentrations above 5.0% were used in capsule production and drug release studies, because of the interconnected porous structures observed in their cross sections by SEM. TABLE 1. Porosity and pore size of PCL membranes prepared with different proportional ratios of PCL to HEPES sodium salt. ozcRnn / ιζηζ / Ε / γίΛΐ Sample Name Pore Diameter (nm) Porous Channel 0.0% HEPES Salt None No 1.0% HEPES Salt 237.26 ± 96.93 No 5.0% HEPES Salt 371.65 ± 156.77 Yes 7.5% HEPES Salt 582.21 ±302.17 Yes 10 % HEPES salt 608.55 ± 273.90 Yes To assess the changes in the bilayer structure before and after salt leaching, SEM imaging was used to observe the inner surface, outer surface, and cross section of the bilayer capsules. Before salt leaching, the PCL sintered film was rough with some HEPES sodium salt crystals embedded therein. After salt leaching, the porous structure appeared in the PCL layer, and the chitosan layer lost its fibrous structure and formed a porous layer. The average pore sizes of the chitosan layer were 802.47 ± 501.02 nm, which allowed 3D diffusion and protein interactions for sustainable release, by maximizing its interactions with the protein through electrostatic interactions. The chitosan inner layer showed a more nanoporous structure with a thickness of 25 pm, which could be due to the relatively high melting point of chitosan. In contrast, the PCL outer layer had a more compact structure with nanochannels passing through and a total thickness of 65 pm, to support protein diffusion while physically capturing drugs. These results are consistent with the morphologies collected in the individual PCL and chitosan layers. To further confirm the chemical property of the bilayer capsules after sintering and washing, FTIR spectroscopy was performed on the final capsule, shown in Figure 5. In the spectrum shown, a significant peak was assigned to 1727 cnr1 to the carbonyl group. in PCL. Peaks at 2963 cnr1 and 2995 cnr1 were C-H stretches in the PCL backbone. A large cluster could be observed at 3478 cm'1, which was attributed to vibrations of O-H stretches of hydroxyl groups, which were abundant in the chitosan backbone. Furthermore, a characteristic peak for chitosan at 1571 cm-1 was assigned to N-H stretches. These peaks provide strong evidence for the chemical property of the chitosan layer and the PCL layer, even after exposure to sintering. Therefore, the cationic chitosan remains active and is able to non-covalently chemically bind the anionic protein, bevacizumab. With SEM and FTIR, the feasibility of the reported bottom-up approach was demonstrated to synthesize nanomicrostructured hybrid capsules, which have widely adjustable pore sizes, aspect ratios, and dimensions, and which can provide optimal physical and chemical properties for drug loading and controlled drug release. protein therapeutic agents. High bevacizumab payloads and long-term sustainable drug release To confirm the high effective loading of the protein drugs that the hollow structure of the capsules allows, the efficacy of drug encapsulation was determined by breaking the drug-loaded capsules and assessing the amount of BSA and bevacizumab leaking from the capsules, respectively. BSA was used as a model protein drug, and bevacizumab is an anti-VEGF therapeutic agent used clinically to treat AMD. Considering that BSA and bevacizumab can adsorb to the chitosan layer of the bilayer capsule, the single-layer capsule and the bilayer capsule were used to assess the effective drug loading. No significant difference was found in the effective drug load between the two capsules. Based on the study, the encapsulation efficiency of BSA, of the three large capsules and three small capsules, was 100.39 ± 6.46% and 69.64 ± 7.15%, respectively. Lower encapsulation efficiency was observed for bevacizumab loading into large and small capsules, which was 52.66 ± 6.47% as assessed by azcftnn / Lznz / E / YiAi UV-Vis spectroscopy, a commonly used instrument to determine protein concentration. , which has a characteristic absorption around 280 nm, shown in Figure 12. However, a higher amount of reactive bevacizumab, 729.02 ± 84.67 pg, was quantitated by ELISA, giving approximately 70% bevacizumab encapsulation efficiency. . The lower encapsulation efficiency could be attributed to the decreased sensitivity of UV-Vis spectroscopy to bevacizumab at lower concentration and cumulative release, which can be effectively detected by ELISA. The loading capacity of the capsule is approximately 26.60 ± 1.90% w / w, which is higher than that of the most reported devices with a loading capacity of 10 to 15% (see L¡, F., et al. , Controlled release of bevacizumab through nanospheres for extended treatment of age-related macular degeneration. 2012. 6: p. 54; and Badiee, P., et al., Ocular implant containing bevacizumab-loaded chitosan nanoparticles intended for choroidal neovascularization treatment. Journal of Biomedical Materials Research Part A, 2018. 106(8): p.2261-2271). Using the model drug BSA, the ability of the exemplary capsule to modulate the drug release profile was exposed, by altering the surface morphology and porosity of the capsules, as shown in Figure 6. As a proof of concept, we prepared single-layer and double-layer capsules with internal diameters of 1,645 mm and 260 pm, and samples prepared with 5%, 7.5% and 10% salt leaching conditions were also investigated. Figure 6 shows the BSA release profile from single layer and double layer capsules for both sizes. As expected, in 1645 mm internal diameter PCL single layer capsules, burst release occurred within the first month, and more than 75% of the loaded BSA eluted from the capsules, significantly limiting the duration of drug release. Due to the higher proportional ratio of surface area to volume, the burst release period was shortened to two weeks in the 260 µm internal diameter capsules, and the cumulative percentage release is similar to that of the 1645 mm id capsule. internal diameter during this period. As such, the drug diffusion rate of the small capsule was promoted. However, a steady release was followed by burst release in both capsule sizes. The maximum period of pharmacological release from the single layer capsule was approximately five months for the 1645 mm internal diameter capsule, and three months for the 260 µm internal diameter capsules prepared with 10% salt. The effect of the sodium salt of HEPES was also investigated. A higher concentration of salts resulted in a faster release rate due to the greater interconnectivity of pores. Burst release slowed but was still uncontrollable in capsules with lower salt concentrations. In contrast, PCL-chitosan bilayer capsules did not show obvious evidence of burst release. The bilayer capsules significantly slowed the release of BSA. The release profiles of the bilayer capsule showed high linearity, which is summarized in Figure 7. After one month, the 1645 mm internal diameter bilayer capsule showed a greater ability to retain BSA within the device. , with approximately 15% released from the loaded BSA, which was 60% less release in the same period, compared to the PCL single-layer azcRnn / Lznz / E / YiAi capsule. Similarly, the 260 pm internal diameter bilayer capsules significantly reduced burst release. Only 25% of the BSA eluted from the 260 µm internal diameter bilayer capsules, which was larger than the 1645 mm capsules due to the relatively larger area at volume for diffusion. The chitosan layer was effective in limiting drug diffusion, and the porosity of the PCL coating did not play a vital role in controlling BSA release. There was no significant difference between the diameters of single-layer and double-layer capsules (p > 0.05), so the effect of thickness on drug release was negligible in these studies. Theoretically, the bilayer structure has the potential to control drug release for at least one year for capsules in both sizes, based on cumulative release data. After extensively investigating and optimizing the porous structures of the bilayer capsules, the bilayer structure capsules were used and leached with 10% HEPES to load and release bevacizumab, the target drug for the clinical treatment of AMD. Consistent with BSA pharmacological release experiments, a sustained release profile was successfully achieved for one year and nine months with no initial burst release evident in the 1645 mm and 260 pm capsules, respectively. Interestingly, there was a further reduction in burst release of bevacizumab compared to BSA, during drug delivery based on bilayer capsules. This could be due to the increased molecular weight and lower effective charge of bevacizumab compared to BSA. In this condition, the pore size dominates the diffusion rate of bevacizumab. Higher molecular weight bevacizumab can be difficult to elute from the capsule with limited pore channels. This explains why the total release of single layer capsules and two layer capsules, prepared with 5% HEPES salt, have similar release kinetics. Furthermore, the capsules prepared by 5% HEPES salt have the lowest release rate compared to the other two capsules with larger pores within the membrane. It is discernible that near zero-order release kinetics were achieved with the 260 pm internal diameter bilayer capsule loaded with bevacizumab after burst release, shown in Figure 7 (p < 0.05). Simple UV absorption was used to titrate and quantify the amount of bevacizumab, but could not specify the reactive bevacizumab or differentiate the background of disintegrated polymers from the capsules over time. Therefore, the bevacizumab eluted from the 260 pm capsules was determined again by ELISA. Figure 13 shows that the general trend of bevacizumab release was consistent with previous results determined by UV-Vis. For example, the long-term cumulative release of bevacizumab from single-layer capsules made of 5% HEPES salt was approximately 160 pg as assessed by UV-Vis, which was the same as characterized by ELISA for nine months. Therefore, when comparing the release result of UVVis and ELISA, the release profile acquired by UV-Vis was reliable, which can provide a general release trend of bevacizumab from single-layer and double-layer capsules. Similarly, capsules prepared with 5% salt had a relatively slower AzcAnn / Lznz / E / YiAi release rate compared to those with 7.5% and 10% salt over nine months. Based on these considerations, bilayer capsules with higher HEPES salt concentrations (7.5% and 10%) were then identified and used for long-term anti-VEGF release. Meanwhile, the high drug loading capacity and stable drug release profiles, over periods of nine months, strongly indicate the potential of the exemplary bilayer capsules as a versatile platform for delivering anti-VEGF therapeutic agents. Biodegradation of capsules The in vitro degradation of the PCL single-layer capsule and the chitosan-PCL two-layer capsule was studied. By placing the capsules with two closed ends in PBS at 37 °C, for nine months, the capsules were recovered and characterized by SEM. The mechanical integrity of the entire device is primarily determined by the PCL layer, which is slowly subject to ester bond hydrolysis (see Darwis, D., et al., Enzymatic degradation of radiation crosslinked poly (ε-caprolactone). Polymer Degradation and Stability, 1998. 62(2): pp. 259-265). Therefore, it is critical to assess the erosion and degradation of the PCL layer over time. From the characteristic SEM images shown in Figure 11, the single-layered capsule and the double-layered capsule remained intact after a nine-month incubation. However, the pores on the PCL membrane surface became larger and more scattered after nine months compared to the initial capsule, indicating slow degradation of the PCL membrane. Table 2 summarizes the analytical pore size of the capsules under different HEPES salt conditions. Pores on the PCL surface increased significantly by approximately 180 nm in diameter on average (p < 0.05), but the entire device maintained integrity with no obvious cracks or breaks. The two-layer capsule was also characterized. After nine months, the chitosan layer was still tightly adhered to the PCL layer, and the fibers were still well defined and intact. The fibrous scaffold of the chitosan surface layer was still evident, without significant changes. Furthermore, the membrane thickness of the one-layer capsule and the two-layer capsule was in the range of 80 pm to 90 pm, which is similar to their original thickness before incubation. However, the significant decrease in thickness and the loss of chitosan fibers were observed when the capsules were immersed with two open ends in PBS at physiological temperature for three weeks, as shown in Figure 15. This is probably caused by the slow degradation of chitosan when directly exposed to water in the long term (see Kean, T. and M. Thanou, Biodegradation, biodistribution and toxicity of chitosan. Advanced Drug Delivery Reviews, 2010. 62(1): p. 3-11 and Onishi, H. and Y. Machida, Biodegradation and distribution of water-soluble chitosan in mice. Biomaterials, 1999. 20(2): p. 175-182). Furthermore, due to the weak mechanical properties of chitosan, the inner fibrous chitosan membrane can become brittle under shear forces during long-term incubation in water, resulting in significant loss of chitosan (see Sangsanoh, P. and P.J.B. Supaphol, Stability improvement of electrospun chitosan nanofibrous membranes in neutral or weak basic aqueous Solutions. 2006. 7(10): pp. 2710-2714 and Chen, Z., et al., Mechanical properties of electrospun collagen-chitosan QZCRnn / 1 7Π7 / Β / ΥΙΛΙ complex single fibers and membrane. Materials Science and Engineering: C, 2009. 29(8): p. 2428-2435). Therefore, the hydrophobic layer of PCL is capable of protecting the inner chitosan layer against rupture, and further reducing the deterioration of the entire device. TABLE 2. Porosity and pore size of PCL membranes prepared with different proportional ratios of PCL to HEPES sodium salt after incubation for one year. A significant increase in PCL pore size was found at different salt concentrations during incubation for nine months (p < 0.05). QZCRnn / 1 7Π7 / Β / ΥΙΛΙ Sample Name Pore Diameter (nm) Increment (nm) 5.0% HEPES Salt 550.83 ± 243.33 179.81 ± 16.71 7.5% HEPES Salt 662.00 ± 238.43 79.79 ±22.26 10% HEPES Salt 935.17 ±331 .41 326.62 ± 24.82 Cytotoxicity One of the most critical properties for any drug delivery device is acceptable biocompatibility in the presence of target cells or tissues, both in the short and long term. To this end, the cytotoxicity of exemplary bilayered capsules was investigated using retinal pigment epithelial cells (ARPE-19), since they are among the most prevalent cells in the retina and are highly sensitive to toxic and exogenous materials. by the methods of direct contact and exposure to extracts. Using a standard mitochondrial activity measurement assay, cell viability of RPE cells with and without single-layer and double-layer capsule treatment was measured. From the results shown in Figure 8, both the PCL single-layer capsule and the PCL-chitosan two-layer capsule showed negligible toxicity to RPE cells during direct incubation for 24 hours. Both PCL and chitosan have been reported to have acceptable biocompatibility in infraocular applications (see Kim, J., et al., Long-term intraocular pressure reduction with intracameral polycaprolactone glaucoma devices that deliver a novel antiglaucoma agent. 2018. 269: p. 45-51, and Wassmer, S., et al., Chitosan microparticles for delivery of proteins to the retina. Acta Biomaterialia, 2013. 9(8): p. 7855-7864). Similarly, the extracts from both capsules also did not influence cell viability for one month, shown in Figure 8. More than 95% viability was also found for the two-layer capsules, even at time points as long as one month. These results collectively indicate negligible cytotoxicity to retinal pigment epithelial cells, and suggest the potential of bilayer capsules for preclinical evaluation in ophthalmic models in future studies. Stability of released VEGF inhibitors and therapeutic effects on antiangiogenesis A major issue preventing the development of long-term sustained protein delivery systems is protein aggregation and degradation in aqueous environments. Bevacizumab is unstable under physiological conditions and is prone to degradation and aggregation in the body over time (see Courtois, F., et al., Rational design of therapeutic mAbs against aggregation through protein engineering and incorporation of glycosylation motifs applied to bevacizumab. mAbs, 2016. 8(1): pp. 99-112; Oliva, A., M. Llabrés, and J.B. Fariña, Capability measurement of size-exclusion chromatography with a light-scattering detection method in a stability study of bevacizumab using the process capability indices. Journal of Chromatography A, 2014. 1353: pp. 89-98; Latypov, R.F., et al., Elucidation of acidinduced unfolding and aggregation of human immunoglobulin lgG1 and lgG2 Fe. Journal of Biological Chemistry, 2012. 287(2): 1381-1396 and Bakri, S.J., et al., Six-month stability of bevacizumab (Avastin) binding to vascular endothelial growth factor after withdrawal into a syringe and refrigeration or freezing, Retina, 2006. 26 (5): pp. 519-522). Furthermore, the device is loaded with high concentrated bevacizumab purchased from freeze drying. Aggregation and loss of activity can occur at high concentrations or during the lyophilization process (see Varshochian, R., et al., The protective effect of albumin on bevacizumab activity and stability in PLGA nanoparticles intended for retinal and choroidal neovascularization treatments. European Journal of Pharmaceutical Sciences, 2013. 50(3): pp. 341-352). This becomes somewhat critical since bevacizumab aggregates may not be released from the implant at the same rate as the monomer. Therefore, the bevacizumab stability study was necessary to assess bevacizumab aggregation and fragmentation during device fabrication, and device incubation over time using HPLC. The analytical aggregation and fragmentation of bevacizumab are summarized in Table 3, and the HPLC spectrum is shown in Figure 14. To confirm the stability of bevacizumab during lyophilization, the HPLC spectrum of lyophilized bevacizumab was compared with that of commercial bevacizumab. , Avastin. About 16% of aggregates formed in the free native bevacizumab, and a slight increase in bevacizumab aggregates was observed during the lyophilization cycle. Also, aggregation in concentrated solutions was assessed by dilution in PBS, immediately followed by HPLC characterization. However, no changes of bevacizumab aggregates were observed, indicating that the proteins are quite stable in concentrated solutions, further proving that the exemplary device can slow down the release of bevacizumab monomer. The long-term potency of bevacizumab released from the single-layer capsule and double-layer capsule was also assessed. The percentage of aggregates varied between 11% and 16% for both capsules over three months, and bevacizumab was also found to be subject to fragmentation during long-term incubation. However, bevacizumab potency was still maintained at a high level during this period, shown in Table 3. Bevacizumab monomer, eluted from the capsule of a 260 pm internal diameter PCL layer, occupied 84% in one month. , and this figure decreased slightly to 79% in three months. Similarly, the bevacizumab monomer released from the 260 pm internal diameter chitosan-PCL bilayer capsule was 82% for the first three months. This enhanced stability could be due to the adhesion to chitosan by ionically binding to the glycoprotein, and increasing its bioavailability. Additionally, the hydrophobic PCL layer slowed down the fragmentation process by reducing fluid exchange through the capsule. As such, the long-term potency of released bevacizumab is well preserved, suggesting the acceptable potential of the exemplary capsules for the treatment of AMD without frequent injections. azcAnn / ίζηζ / Ε / γίΛΐ TABLE 3. Analytical aggregation and fragmentation of free native bevacizumab before and after lyophilization, and bevacizumab eluted from single-layer capsule and double-layer capsule at 1 month and 3 months. azcAnn / Lznz / E / YiAi Sample Name Light Chain Heavy Chain Heavy + Light Avastin - Heavy Avastin - Light Avastin Aggregate MW (kDa) Native Bevacizumab 0% 0% 0% 0% 0% 84% 16% 161 Lyophilized Bevacizumab 0% 0% 0% 0% 0 % 81% 19% 162 Bevacizumab in device 0% 0% 0% 0% 0% 81% 19% 165 PCL_1 month 0% 0% 4% 0% 0% 84% 11% 155 PCL_3 month 0% 0% 5% 0% 0% 79% 16% 157 Ch-PCL 1 month 0% 3% 2% 3% 0% 82% 11% 154 Ch-PCL _3 month 0% 0% 6% 0% 0% 83% 11% 154 While HPLC provides clear information on bevacizumab monomer and aggregation, delivered by exemplary capsules, ELISA characterizes the potency and quantity of VEGF-reactive bevacizumab released over the long term, to ensure its effects on angiogenesis. Therefore, a bevacizumab ELISA was conducted to determine the reactive bevacizumab released from the 260 pm internal diameter capsule over time. After one month, the release rate of active bevacizumab remained around 20 pg / mL per month, which is similar to the amount of bevacizumab determined by UV-Vis. Furthermore, the percentage bioactivity of the eluted bevacizumab was also calculated from the comparison of the percentage cumulative release measured by ELISA with that determined by UV / Vis. From the result, bevacizumab released from single-layer capsules could maintain its bioactivity greater than 90% during the period of nine months, which indicates its potential in protecting the protein. A fluctuation of bioactivity was observed in the two-layer capsule, which remained at around 80%. The lower percentage bioactive could be caused by the increased background of the absorbance effect of UV-VIS, by the slow biodegradation of the inner layer during a long-term period of incubation, as already mentioned. However, both results strongly support the high bioactivity of the protein protected by the one-layer capsule and two-layer capsule. In this regard, the exemplary hollow bilayer capsule, which physically protects the drug, has the potential to overcome this barrier to sustained release. In addition, bevacizumab eluted from PCL single-layer and PCLchitosan double-layer capsules was assessed for its inhibitory effect on VEGF-induced tubule growth in a tube formation assay using HUVEC, as shown. in Figure 9. At a concentration of 10 pg / ml, the native positive control bevacizumab caused 93.15 ± 1.49% inhibition of tubule length. Bevacizumab eluted from single-layer and double-layer capsules, after one month, led to approximately 13.33 ± 6.51% and 12.33 ± 4.63% tube formation of the 260 pm internal diameter capsule and 1.645 mm capsule. internal diameter, respectively, which was more effective compared to conventional injection of native bevacizumab. A slight increase in the formation of tube lengths appeared after three months, due to the loss of bioactivity caused by long-term incubation at physiological temperature. However, there was no significant difference in the antiangiogenetic properties of bevacizumab eluted from the bilayer capsule and that eluted from the single-layer capsule (p > 0.05). The slow drug diffusion is expected to retard the breakdown process of bevacizumab by enzymes that significantly protected the protein within the capsule. In general, the anti-angiogenic bioactivity was well maintained at a high level for nine months, suggesting the potential protective effects of the capsule towards long-term drug delivery. injection feasibility In addition to high drug loading capacity, sustained release of protein therapeutic agents, and maintenance of anti-VEGF bioactivity, these capsules can also be made injectable. To demonstrate this, injection feasibility tests were conducted by delivering 10 mm long capsules to porcine vitreous humor ex vivo, via a 21 gauge needle through the sclera, shown in Figure 10. Capsules with a external diameter of 430 µm were used in this study since they are of a similar size to the commercialized infraocular implant, Ozurdex, with 460 µm in diameter and 6 mm in length. The Ozurdex applicator is equipped with a 22-gauge TSK needle (see Chan, A., L.-S. Leung, and M.S. Blumenkranz, Critical appraisal of the clinical utility of the dexamethasone intravitreal implant (Ozurdex®) for the treatment of macular edema related to branch retinal vein occlusion or central retinal vein occlusion.Clinical Ophthalmology (Auckland, NZ), 2011. 5: p.1043;Arcinue, C.A., O.M. Cerón, and C.S. Foster, A comparison between the fluocinolone acetonide (Retisert) and dexamethasone (Ozurdex) intravitreal implants In uveitis.Journal of ocular pharmacology and therapeutics, 2013. 29(5): pp. 501-507 and Querques, L., et al., Repeated intravitreal dexamethasone implant (Ozurdex®) for retinal vein occlusion. Ophthalmologica, 2013. 229(1): p. 21-25). The internal diameter of the needle is approximately 500 pm, which might fit the exemplary capsule (see Meyer, C.H., et al., Penetration force, geometry, and cutting profile of the novel and old Ozurdex needle: the MONO study. Journal of Ocular Pharmacology and Therapeutics, 2014. 30(5): pp. 387-391). More specifically, in clinical applications, the anti-VEGF loaded capsule could typically be delivered by the similar applicator intravitreal, which may avoid invasive open surgery. Therefore, the advanced drug delivery system, based on the exemplary bilayer capsules, could be quite compatible with the currently used clinical strategy. In this study, to address the critical challenges of long-term therapy for the treatment of wet AMD, a polymer-based microstructured delivery platform was designed and developed to achieve sustainable anti-VEGF release in vitro. Sustainable protein release was achieved by designing and optimizing the chitosan-PCL bilayer microcapsule structures, using a combined chemistry and materials design approach. Critical attributes of these azcftnn / Lznz / E / YiAi chitosan-PCL microcapsules included: size, PCL shell porosity, and hollow structures for simple and pure drug loading. PCL-chitosan microcapsules were synthesized by a novel combination of electrospinning, sintering, and salt leaching. In preliminary studies it was observed that the chitosan fibers lost their structure after the leaching of salts. It was considered that the formation of trifluoroacetate salts, during the fiber preparation, accelerated the chitosan dissolution process with the use of TFA and DCM as solvents, for which reason a necessary neutralization step with sodium bicarbonate solution was required during washing, to reduce the effect of acid salts on the bioactivity of bevacizumab (see Sangsanoh, P. and P.J.B. Supaphol, Stability improvement of electrospun chitosan nanofibrous membranes in neutral or weak basic aqueous Solutions. 2006. 7(10): p. 2710-2714). The membrane thickness was correlated with the period of drug release. Theoretically, a thicker membrane resulted in slower drug diffusion. Although increasing the capsule size could potentially help achieve slower drug release, the larger size of the microcapsules would preclude injection through a small-gauge needle. Therefore, to make the injectable capsule for clinical application, a thinner membrane was required. A chitosan layer was added to address this problem. In this study, all capsules had a thickness between 80 and 95 pm, which minimized the influence of thickness in exploring the relationship between the drug release rate and the chitosan-PCL composite. After optimizing these important factors to control drug release, microcapsule performance was evaluated and optimized for sustainable anti-VEGF release. Bevacizumab has been used clinically in the treatment of wet AMD since 2004 (see Michels, S., et al., Systemic bevacizumab (Avastin) therapy for neovascular age-related macular degeneration: twelve-week results of an uncontrolled open-label clinical study 2005. 112(6): p.1035-1047.e9). Theoretically, the isoelectric point (pl) of bevacizumab is 7.8 (see Nomoto, H., et al., Pharmacokinetics of bevacizumab after topical, subconjunctival, and intravitreal administration in rabbits. 2009. 50(10): p. 4807-4813) . Its net charge, calculated from the pl, should be slightly positive at pH 7.4, which has been reported by numerous studies. However, protein aggregates in water and other organic solvents, typically used during device fabrication, have the potential to reduce bioactivity and cause undesirable side effects (see Varshochian, R., et al., Albuminated PLGA nanoparticles containing bevacizumab intended for ocular neovascularization treatment.Journal of Biomedical Materials Research Part A, 2015. 103(10): pp. 3148-3156;Courtois, F., et al., Rational design of therapeutic mAbs against aggregation through protein engineering and incorporation of glycosylation motifs applied to bevacizumab. mAbs, 2016. 8(1): pp. 99-112 and Varshochian, R., et al., The protective effect of albumin on bevacizumab activity and stability in PLGA nanoparticles intended for retinal and choroidal neovascularization treatments European Journal of Pharmaceutical Sciences, 2013. 50(3): p.341-352). Therefore, PBS is widely used to suspend bevacizumab, to maintain its stability and azcRnn / ιζηζ / Ε / γίΛΐ bioactivity. Bevacizumab has been reported to have a net negative charge in PBS at pH 7.4, suggesting binding to chitosan and may provide a more sustainable release from the exemplary capsule (see Li, S.K., et al., Effective electrophoretic mobilities and charges of anti-VEGF proteins determined by capillary zone electrophoresis. 2011. 55(3): pp. 603-607; and García-Quintanilla, L., et al., Pharmacokinetics of Intravitreal Anti-VEGF Drugs in Age-Related Macular Degeneration Pharmaceutics, 2019. 11(8): p. 365). Binding of regulator ions in PBS to bevacizumab increases its hydrophilicity, which further increases its stability and causes the difference between the theoretical and experimental net charge of the protein (see Li, S.K., et al., Effective electrophoretic mobilities and charges of antiVEGF proteins determined by capillary zone electrophoresis. 2011. 55(3): p. 603-607; and Chopra, P., J. Hao, and S.K.J.I.j.o.p. Li, lontophoretic transport of charged macromolecules across human solera. 2010. 388(1-2 ): pp. 107-113). Consequently, bevacizumab has a negative charge in the vitreous body and capsule, and it is therefore hypothesized that this protein could be retained by the positively charged chitosan via electrostatic attraction. Similarly, BSA is a negatively charged protein in water, with an isoelectric point of about 4.7. BSA could bind cationic ions and raise its surface charge under physiological conditions (in PBS). However, BSA still remains negatively charged in PBS since these ions have a minor effect on the charge of BSA, as previously reported (see Li, S.K., et al., Effective electrophoretic mobilities and charges of anti-VEGF proteins determined by capillary zone electrophoresis. 2011. 55(3): pp. 603-607; and alis, A., et al., Measurements and Theoretical Interpretation of Points of Zero Charge / Potential of BSA Protein. Langmuir, 2011. 27(18 ): p.11597-11604). By providing a combined electrostatic interaction between bevacizumab or BSA and chitosan, and a protective effect from the PCL shell, a desirable sustained drug release profile could be achieved. In this study, the release rate, for a similar effective load of bevacizumab, was also significantly improved. The average effective load of the reported devices ranged from 500 pg to 1000 pg (see Li, F., et al., Controlled release of bevacizumab through nanospheres for extended treatment of age-related macular degeneration. 2012. 6: p. 54; and Varshochian, R., et al., Albuminated PLGA nanoparticles containing bevacizumab intended for ocular neovascularization treatment.Journal of Biomedical Materials Research Part A, 2015. 103(10): p.3148-3156). However, these devices had limitations, including not being injectable or not sustaining release for three months. The drug loading capacity of these devices was not as expected. Furthermore, the bioactivity of anti-VEGF can be influenced during the manufacturing process in these devices, due to the interaction of the therapeutic agent with solvents or high temperatures. However, the drug load was processed after the device was manufactured, which prevented drug loss and deactivation, which commonly occurs when using conventional preparation methods, such as emulsion. Therefore, the capsules designed herein ensured an effective drug loading of 700 pg of bevacizumab, because of the confined space in the injectable capsule and the large molecular weight of bevacizumab. The template rod can be selectively increased to azcAnn / Lznz / E / YiAi to enlarge the internal space and enhance drug loading. In addition, in the drug product, bevacizumab dry powder could be accurately replaced and loaded under the microscope, and further enhance drug loading efficiency and stability of bevacizumab. In addition, other lower molecular weight therapeutic agents, comparable to the model drug BSA, can be evaluated using the exemplary device and have the potential to further increase effective drug loading significantly (see Rosenfeld, P.J., et al., Optica! Coherence tomography findings after an intravitreal injection of bevacizumab (Avastin®) for neovascular age-related macular degeneration. 2005. 36(4): p. 331-335). Bilayer capsules can efficiently control the rate of drug release, utilizing the electrostatic interaction between protein and polymer therapeutics, which may address many of the current issues associated with the clinical treatment of wet AMD. It also provides an alternative method for some diseases, which require long-term treatment with protein therapeutic agents, such as colorectal and breast cancers, as well as some brain tumors. However, optimization of device fabrication methods may still be needed for the requirements of different protein therapeutic agents, which could have great potential for ophthalmic, cancer, and other biomedical applications. In conclusion, a polymer-based delivery platform for controlled release of anti-VEGF has been developed, which is based on a two-layer microstructure that synergistically combines electrostatic binding between chitosan and anti-VEGF with a hydrophobic layer. protective of PCL, to provide an effective pathway to modulate polymer-protein interactions for controlled therapeutic release. The bilayer structure was characterized in detail, and the capsular yield for protein delivery was further determined. Most importantly, the exemplary designed delivery platform significantly improved the long-term release of anti-VEGF in vitro, compared to most current devices, supporting its potential to treat AMD. In future studies, evaluation and reoptimization of the therapeutic effect of anti-VEGF loaded devices in an in vivo model of AMD is required. It will be apparent to those skilled in the art that various modifications and variations may be made to the present disclosure, without departing from the scope or spirit of the disclosure. Other disclosure modalities will be apparent to those skilled in the art from consideration of the specification, and from the disclosure practice disclosed herein. The specification and examples are intended to be considered exemplary only, with the true scope and spirit of the disclosure indicated by the following claims.

Claims

1. A drug delivery composition comprising: one or more capsules, each having a tubular conformation with two closing ends, wherein each capsule or capsules independently comprise a two-layer wall and at least one luminal compartment; and one or more therapeutic agents, each contained within one or more of the luminal compartment or compartments; wherein each two-layer wall comprises an inner layer and an outer layer; wherein the inner layer comprises a first polymer having a net positive charge under physiological conditions; and wherein the outer layer independently comprises a second polymer that differs from the first polymer.

2. The pharmacological delivery composition according to claim 1, wherein the composition is intended for injection into the eye of a subject.

3. The drug delivery composition according to claim 2, wherein the injection is into the vitreous chamber of the eye.

4. The drug delivery composition according to claim 2, wherein the injection is an intravitreal injection, a subconjunctival injection, a subtenonian injection, a retrobulbar injection, or a suprachoroidal injection.

5. The drug delivery composition according to any of claims 1 to 4, wherein the first polymer comprises chitosan, polyethyleneimine, protamine, polypropyleneimine, poly L lysine, poly L arginine, poly D lysine, poly D arginine, cellulose, dextran, poly(amidoamine), poly(2-(dimethylamino)ethyl methacrylate), derivatives thereof, or combinations thereof.

6. The drug delivery composition according to any of claims 1 to 5, wherein the first polymer comprises chitosan or a derivative thereof.

7. The drug delivery composition according to any of claims 1 to 6, wherein the second polymer comprises a poly(s-caprolactone) (PCL), a polylactic acid (PLA), a polyglycolic acid (PGA), a polylactide-coglycolide (PLGA), a polyester, a poly(ortho ester), a poly(phosphazine), a poly(phosphate ester), a gelatin, a collagen, a polyethylene glycol (PEG), derivatives thereof and combinations thereof.

8. The drug delivery composition according to any of claims 1 to 7, wherein the second polymer comprises PCL or a derivative thereof.

9. The drug delivery composition according to any of claims 1 to 8, wherein each of the capsule(s) has a length of approximately 0.1 cm to approximately 5 cm. Qzcpnn / ίζηζ / E / γίΛΐ 10. The drug delivery composition according to claim 9, wherein each of the capsule(s) has a length of approximately 0.5 cm to approximately 3 cm.

11. The drug delivery composition according to any of claims 9 or 10, wherein each of the capsule(s) has a length of approximately 1 cm to approximately 3 cm.

12. The drug delivery composition according to any of claims 1 to 11, wherein each of the capsule(s) has an internal diameter of approximately 100 pm to approximately 2000 pm.

13. The drug delivery composition according to claim 12, wherein the internal diameter is from approximately 100 pm to approximately 500 pm.

14. The drug delivery composition according to any of claims 12 or 13, wherein the internal diameter is from approximately 100 pm to approximately 300 pm.

15. The drug delivery composition according to any of claims 12 to 14, wherein each of the capsule(s) has an external diameter approximately 50 µm to approximately 300 µm greater than the internal diameter.

16. The drug delivery composition according to any of claims 1 to 15, wherein the two-layer wall has a wall thickness of approximately 25 µm to approximately 150 µm.

17. The drug delivery composition according to claim 16, wherein the wall thickness is from approximately 70 µm to approximately 100 µm.

18. The drug delivery composition according to any of claims 16 or 17, wherein the wall thickness is from approximately 75 µm to approximately 95 µm.

19. The drug delivery composition according to any of claims 16 to 18, wherein the wall thickness is approximately 80 µm to approximately 90 µm.

20. The drug delivery composition according to any of claims 1 to 19, wherein the outer layer further comprises pores having a pore diameter of approximately 100 nm to approximately 10000 nm.

21. The drug delivery composition according to claim 20, wherein the pore diameter is approximately 350 nm to 650 nm.

22. The drug delivery composition according to any of claims 1 to 21, wherein the outer layer comprises fibers having a diameter of approximately 100 nm to approximately 2000 nm.

23. The drug delivery composition according to claim 22, in azcftnn / Lznz / E / YiAi where the fibers have a diameter of approximately 500 nm to approximately 1000 nm.

24. The drug delivery composition according to any of claims 1 to 12, wherein the inner layer comprises fibers having a diameter of approximately 50 nm to approximately 1000 nm.

25. The drug delivery composition according to claim 24, wherein the fibers have a diameter of approximately 100 nm to approximately 400 nm.

26. The drug delivery composition according to any of claims 1 to 25, wherein the therapeutic agent has a net negative charge at any pH within approximately pH 6.0 to approximately pH 7.

4.

27. The drug delivery composition according to any of claims 1 to 26, wherein the therapeutic agent is an anti-VEGF therapeutic agent.

28. The drug delivery composition according to claim 27, wherein the anti-VEGF therapeutic agent is a therapeutic antibody, a therapeutic protein, or combinations thereof.

29. The drug delivery composition according to claim 28, wherein the therapeutic antibody is bevacizumab, ranibizumab, IBI305 or combinations thereof.

30. The drug delivery composition according to claim 28, wherein the therapeutic protein is a VEGF decoy receptor.

31. The drug delivery composition according to claim 30, wherein the VEGF decoy receptor is aflibercept.

32. The drug delivery composition according to claim 27, wherein the anti-VEGF therapeutic agent is a tyrosine kinase inhibitor.

33. The drug delivery composition according to claim 32, wherein the tyrosine kinase inhibitor is lapatinib, sunitinib, sorafenib, axitinib, pazopanib or combinations thereof.

34. The drug delivery composition according to claim 27, wherein the anti-VEGF therapeutic agent is an antisense nucleic acid that targets VEGF or the VEGF receptor.

35. The drug delivery composition according to any of claims 1 to 34, wherein the therapeutic agent is presented in an amount of approximately 0.01 mg to approximately 3 mg.

36. The drug delivery composition according to claim 35, wherein the therapeutic agent is presented in an amount of approximately 0.5 mg to approximately 2 mg.

37. The drug delivery composition according to any of claim 35 or 36, wherein the therapeutic agent is presented in an amount of approximately 0.5 mg to approximately 1.5 mg. azcRnn / Lznz / E / YiAi 38. The drug delivery composition according to any of claims 1 to 37, wherein the therapeutic agent exhibits near zero-order release kinetics for a period of at least 30 days.

39. The drug delivery composition according to claim 38, wherein the therapeutic agent exhibits near zero-order release kinetics for a period of at least 3 months.

40. The drug delivery composition according to claim 38, wherein the therapeutic agent exhibits near zero-order release kinetics for a period of at least 6 months.

41. The drug delivery composition according to claim 38, wherein the therapeutic agent exhibits near zero-order release kinetics for a period of at least 9 months.

42. A method for treating an ophthalmological disorder in a subject in need thereof, comprising injecting, into the subject's eye, a therapeutically effective quantity of the drug delivery composition of any of claims 1 to 41.

43. The method according to claim 42, wherein the ophthalmological disorder is acute macular neuroretinopathy, Behcet's disease, neovascularization including choroidal neovascularization, diabetic uveitis, histoplasmosis, infections such as fungal or viral infections, macular degeneration such as acute macular degeneration (AMD), including wet AMD, non-exudative AMD and exudative AMD, edema such as macular edema, cystoid macular edema and diabetic macular edema, multifocal choroiditis, ocular trauma affecting a posterior ocular site or location, ocular tumors, retinal disorders such as central retinal vein occlusion, diabetic retinopathy (including proliferative diabetic retinopathy), proliferative vitreoretinopathy (PVR), retinal arterial occlusive disease, retinal detachment, uveitic retinal disease, sympathetic ophthalmia, Vogt syndrome Koyanagi-Harada (VKH), uveal diffusion,a posterior ocular condition caused or influenced by laser eye treatment, posterior ocular conditions caused or influenced by photodynamic therapy, photocoagulation, radiation retinopathy, epiretinal membrane disorders, retinal vein branch occlusion, anterior ischemic optic neuropathy, non-retinopathic diabetic retinal dysfunction, retinitis pigmentosa, cancer, and glaucoma.

44. The method according to claim 42, wherein the ophthalmological disorder is wet age-related macular degeneration (wet AMD), neovascularization, macular edema, or edema.

45. The method according to any of claims 42 to 44, wherein the injection into the subject's eye comprises injection into the vitreous chamber of the eye.

46. ​​The method according to any of claims 42 to 44, wherein the injection into the subject's eye comprises an intravitreal injection, a subconjunctival injection, a subtenonian injection, a retrobulbar injection, or a suprachoroidal injection.

47. A method for preparing a drug delivery capsule for injection into the eye of a subject, wherein the method comprises: forming an inner layer on a conductive rod comprising a first polymer having a net positive charge under physiological conditions; and forming an outer layer on the inner layer, wherein the outer layer comprises a second polymer differing from the first polymer; wherein the formation of the inner layer comprises electrospinning using a solution of the first polymer, and a voltage difference of approximately 10 kV to approximately 30 kV; wherein the solution of the first polymer is approximately 1% w / v to approximately 10% w / v in at least one organic solvent; wherein the formation of the outer layer comprises electrospinning on the formed inner layer, using a solution comprising the second polymer and, optionally, a porogen;and wherein the voltage difference used for electrospinning is from approximately 10 kV to approximately 30 kV; wherein the solution comprising the second polymer and, optionally, the porogen, is at approximately 1% w / v to approximately 10% w / v, based on the total weight of the second polymer and the porogen; and wherein the proportional weight ratio of the second polymer to the optional porogen is from approximately 50:50 to approximately 100:

0.

48. The method according to claim 47, wherein the first polymer comprises chitosan or a derivative thereof.

49. The method according to any of claims 47 or 48, wherein the second polymer comprises PCL or a derivative thereof.

50. The method according to any of claims 47 to 49, wherein at least one organic solvent in the solution of the first polymer is a mixture of trifluoroacetic acid and dichloromethane; and wherein the trifluoroacetic acid and dichloromethane are present in a proportional ratio of approximately 1:10 to approximately 10:

1.

51. The method according to claim 50, wherein the trifluoroacetic acid and the dichloromethane are presented in a proportional ratio of approximately 5:3 to approximately 10:

3.

52. The method according to claim 51, wherein the trifluoroacetic acid and the dichloromethane are presented in a proportional ratio of approximately 7:

3.

53. The method according to any of claims 47 to 52, wherein the weight ratio of the second polymer to the porogen is approximately 90:100 to approximately 99.9:0.

1.

54. The method according to claim 53, wherein the proportional ratio in azcAnn / Lznz / E / YiAi weights of the second polymer to the porogen is approximately 90:100 to approximately 95:

5.

55. The method according to claim 53, wherein the weight ratio of the second polymer to the porogen is approximately 95:5 to approximately 99.9:0.

1.

56. The method according to any of claims 47 to 55, wherein the solution comprising the second polymer and the porogen is at approximately 2.5% w / v to approximately 10% w / v, based on the total weight of the second polymer and the porogen.

57. The method according to claim 56, wherein the solution comprising the second polymer and the porogen is at approximately 5% w / v to approximately 10% w / v, based on the total weight of the second polymer and the porogen.

58. The method according to any of claims 47 to 57, further comprising sintering the drug delivery capsule after the formation of the outer layer.

59. The method according to claim 58, wherein the sintering comprises heating to a temperature of approximately 50 °C to approximately 150 °C for a period of approximately 1 minute to approximately 6 hours.

60. The method according to claim 58, wherein the sintering comprises heating to a temperature of approximately 90 °C to approximately 110 °C for a period of approximately 30 minutes to approximately 6 hours.

61. The method according to any of claims 58 to 60, further comprising washing the drug delivery capsule after sintering.

62. The method according to claim 61, wherein the washing comprises washing the drug delivery capsule with an alkaline solution, an aqueous solution, or combinations thereof.

63. The method according to claim 61, wherein the washing comprises washing with a saturated sodium bicarbonate solution, followed by washing with deionized water.

64. The method according to any of claims 61 to 63, further comprising drying the drug delivery capsule after washing.

65. The method according to claim 64, wherein the drying is in vacuo at a temperature of approximately 50 °C to approximately 150 °C for a period of approximately 1 minute to approximately 6 hours.

66. The method according to claim 64, wherein the drying is in vacuo at a temperature of approximately 90 °C to approximately 110 °C for a period of approximately 30 minutes to approximately 6 hours.

67. A drug delivery capsule produced by the method of any of claims 47 to 66.

68. The drug delivery capsule according to claim 67, further comprising a therapeutic agent.