Hydrogel drug delivery implant

Abstract

Materials and methods for treating a patient, optionally a patient suffering from an ocular disease, comprising providing a set of particles comprising a first biodegradable material that is a hydrogel or xerogel and a therapeutic agent wherein the first material has a release rate for the therapeutic agent measured in a physiological solution prior to biodegradation and the second material has a release rate for the therapeutic agent measured in a physiological solution prior to biodegradation. And forming, ex vivo or in situ, a second hydrogel on the tissue of the patient at a site of intended use, optionally on or near the eye, said second hydrogel at least partially coating the set of particles. The agent is released to treat the patient.

Description

[0001] This application is a divisional application of a patent application filed on December 10, 2015, with application number 201580075658.1 (PCT / US2015 / 064975), and with the invention name: "Hydrogel Drug Delivery Implant".

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims priority to U.S. Provisional Application No. 62 / 089,994, filed December 10, 2014, which is hereby incorporated by reference. Technical Field

[0004] The technical field relates to compositions for treating the body and includes pharmaceutically acceptable implant systems comprising a collection of pharmaceutically acceptable covalently cross-linked hydrogel particles having a therapeutic agent disposed within the surrounding hydrogel. Background Art

[0005] Implants that deliver drugs in therapeutically effective doses over time are used in many fields. The science of controlled drug release is diverse both in terms of the range of scientific disciplines it encompasses and in terms of its scope of application. BRIEF DESCRIPTION OF THE DRAWINGS

[0006] Figure 1 is a schematic diagram of the process for preparing hydrogel-encapsulated hydrogel particles containing therapeutic agents.

[0007] Figure 2 It shows Figure 1 Schematic diagram of the release of therapeutic agents in the embodiment of FIG;

[0008] Figure 3 Depicts eyes using hydrogels, such as Figure 1 The hydrogel is placed in the eye;

[0009] Figure 4 is a graph of experimental results data; and

[0010] Figure 5 Two curves are depicted showing delayed release caused by coating Detailed description

[0011] Hydrogel particles are used to control the release of therapeutic agents over time. Typically, the particles are placed at the site where the agent is to be delivered, and the agent is released as the hydrogel reacts with physiological fluids at that site. In areas such as the eye, a higher concentration of the agent in the hydrogel is generally desirable because of the limited space in, on, or within the eye. Even in areas where space is not limited, it is desirable to keep the treatment volume close to its minimum necessary volume to optimize the delivery system. However, the inventors have discovered that incorporating a certain amount of additional hydrogel into these systems can be helpful; this hydrogel preferably does not contain the agent to be delivered.

[0012] As an example, refer to Figure 1 and Figure 2 . The hydrogel 100 or organogel 100' is formed by cross-linking the precursor 102 around the therapeutic agent 104. The hydrogel 100 or organogel 100' can be formed into particles or into larger hydrogels / organogels that can be processed into particulates. The hydrogel 100 or organogel 100' can be used directly, made into a xerogel, or otherwise processed into particles 108, which are hydrogels or xerogels. The hydrogel 110 (or organogel) is formed by the precursor 102 surrounding the particles 108. The hydrogel 110 (or organogel) can be made into a xerogel that can then be rehydrated. When the hydrogel is in an aqueous solution, the agent in the hydrogel particles 108 is released, and any xerogel can become a hydrogel when exposed to an aqueous solution. The hydrogel particles provide for diffusion of the agent 104 outward into the hydrogel 110. The hydrogel 110 does not change the release rate, or provides minimal change in the release rate of the agent. In short, in use, hydrogel 108 can be formed ex vivo, and hydrogel 110 can be formed ex vivo or in situ. The term "in situ" refers to the site where the hydrogel is intended to be used, such as on a patient's tissue. The hydrogel interacts with the body's physiological fluids and releases the agent over time.

[0013] Figure 5 Two sets of controlled-release curves are depicted. The coated sample, represented by the dashed line, delayed the release of the drug. The delay is the time difference between the release curves of the coated and uncoated samples. At a given cumulative release percentage, the delay percentage can be calculated by measuring the delay at that point and dividing it by the time required for the cumulative release of the uncoated sample. These are hypothetical curves. Actual data are expected to show variations in the curves; however, a skilled artisan can easily generate a sufficient amount of data to accurately compare coated and uncoated samples, thereby confirming accurate measurements.

[0014] There are a variety of methods to quantify the similarity between coated and uncoated release profiles. Often, it may be helpful to study the profile within a limited range of cumulative release percentages, as the release in the earliest and latest parts of the profile may only account for a small portion of the total released amount. Therefore, options include evaluating the release rate at a given cumulative percentage of released dose, for example, at 50%. An alternative might be some other point, for example, between 10% and 90%; those skilled in the art will immediately recognize that all ranges and values within this range are contemplated and supported, for example, 20%, 25%, 33%, 60%, 67%, etc. Another option is to measure the delay (maximum delay, average delay, mean delay) over the entire range, for example, from 10% to 90%; those skilled in the art will immediately recognize that all ranges and values within this range are contemplated and supported, for example, 20% to 60%, 10% to 50%, 33% to 67%, 15% to 95%.

[0015] In another embodiment, a first material is coated with a second material, the first material comprising a hydrogel or a xerogel that will become a hydrogel, and the second material is a hydrogel, a xerogel, or a precursor that becomes a hydrogel by crosslinking after exposure to physiological or other aqueous solutions. The precursor coating can be dried, stored as a powder, a melt, or mixed with a binder or other excipients such as plasticizers, salts, lubricants, etc.

[0016] Precursor materials

[0017] Hydrogels are made from precursors. The precursors are selected based on the desired properties of the resulting hydrogel. There are a variety of suitable precursors for preparing hydrogels and / or organogels. The term precursor refers to those that form the hydrogel or organogel matrix through crosslinking. While other materials may also be present in the hydrogel or organogel, such as therapeutic agents or fillers, they are not precursors. The term matrix applies to hydrogels, organogels, and xerogels. Such matrices include those having a solvent content greater than about 20% w / w; the skilled artisan will recognize that all ranges and values within the specified ranges are contemplated, including 20% to 99%, 80% to 95%, at least 50%, etc., where the percentages are w / w and water is the solvent for the hydrogel and liquid organic is the solvent for the organogels.

[0018] The precursors can be dissolved in an organic solvent to form an organogel. An organogel is a non-crystalline, non-glassy solid material composed of a liquid organic phase embedded in a three-dimensional cross-linked network. The liquid can be, for example, an organic solvent, mineral oil, or vegetable oil. The solubility and size of the solvent are important characteristics for the elastic properties and hardness of the organogel. Alternatively, the precursor molecules themselves can form their own organic matrix, eliminating the need for a third organic solvent. Removal of the solvent (if used) from the organogel provides a xerogel, i.e., a dried gel. Xerogels formed, for example, by freeze-drying, can have a high porosity (at least about 20%), a large surface area, and a small pore size. Xerogels made from hydrophilic materials form hydrogels when exposed to aqueous solutions. Xerogels with high porosity hydrate faster than denser xerogels. Hydrogels are materials that are insoluble in water and retain a significant portion (greater than 20%) of water within their structure. In fact, water contents exceeding 90% are often known. Hydrogels can be formed by cross-linking water-soluble molecules to form a network of essentially infinite molecular weight. Hydrogels with a relatively high water content are generally soft, pliable materials. Hydrogels and drug delivery systems such as those described in U.S. Publication Nos. 2009 / 0017097, 2011 / 0142936, and 2012 / 0071865 may be adapted for use with the materials and methods herein, following the guidance provided herein; these references are incorporated herein by reference for all purposes, and in the event of a conflict, the present specification controls.

[0019] Organogels and hydrogels can be formed from natural, synthetic, or biosynthetic polymers. Natural polymers can include glycosaminoglycans, polysaccharides, and proteins. Some examples of glycosaminoglycans include dermatan sulfate, hyaluronic acid, chondroitin sulfate, chitin, heparin, keratan sulfate, keratin sulfate, and derivatives thereof. Typically, glycosaminoglycans are extracted from natural sources and purified and derived. However, they can also be synthetically manufactured or synthesized by modified microorganisms (e.g., bacteria). These materials can be synthetically modified to become partially soluble or water-swellable or hydrogel states from a naturally soluble state. This change can be achieved by a variety of well-known techniques, such as by conjugating or replacing ionizable or hydrogen-bonded functional groups such as carboxyl and / or hydroxyl or amine groups with other more hydrophobic groups.

[0020] In some embodiments, the present invention relates to the preparation of the present invention and the preparation of the present invention.For example, the carboxyl group on hyaluronic acid can be esterified with alcohol to reduce the solubility of hyaluronic acid. Such method is used to produce sheet (sheet), fiber and the fabric based on hyaluronic acid that form hydrogel by multiple manufacturers (for example Genzyme Corp., Cambridge, MA) of hyaluronic acid product.Other natural polysaccharides also form hydrogel when contacting with aqueous environment, and described polysaccharide such as carboxymethyl cellulose or oxidized regenerated cellulose, natural gum, agar, agarose, sodium alginate, carrageenan, fucoidan (fucoidan), furcellaran (furcellaran), laminarin, hypnea (hypnea), eucheuma (eucheuma), gum arabic, gum ghatti, gum karaya, gum tragacanth, locust bean gum, arabinogalactan (arbinoglactan), pectin, amylopectin, gelatin, hydrophilic colloid (for example with the cross-linked carboxymethyl cellulose gum or alginate gum of polyol (for example propylene glycol)) etc.

[0021] Synthetic organogels or hydrogels can be biostable or biodegradable. Examples of biostable hydrophilic polymeric materials are poly(hydroxyalkyl methacrylates), poly(electrolyte complexes), poly(vinyl acetate) cross-linked with hydrolyzable or otherwise degradable bonds, and water-swellable N-vinyl lactams. Other hydrogels include those known as Hydrophilic hydrogels, acidic carboxyl polymers (Carbomer resins are high molecular weight, allyl pentaerythritol-crosslinked, acrylic acid-based polymers modified with C10-C30 alkyl acrylates), polyacrylamide, polyacrylic acid, starch graft copolymers, acrylate polymers, ester-crosslinked polyglucans. Such hydrogels are described, for example, in U.S. Patent No. 3,640,741 to Etes, U.S. Patent No. 3,865,108 to Hartop, U.S. Patent No. 3,992,562 to Denzinger et al., U.S. Patent No. 4,002,173 to Manning et al., U.S. Patent No. 4,014,335 to Arnold, and U.S. Patent No. 4,207,893 to Michaels, all of which are incorporated herein by reference; in the event of a conflict, the present specification controls.

[0022] Hydrogels and organogels can be made from precursors. The precursors are cross-linked to each other. Crosslinks can be formed by covalent bonds or physical bonds. Examples of physical bonds are ionic bonds, hydrophobic associations of precursor molecule fragments, and crystallization of precursor molecule fragments. The precursors can be triggered to react to form a cross-linked hydrogel. The precursors can be polymerizable and include a cross-linking agent, which is typically, but not always, a polymerizable precursor. A polymerizable precursor is thus a precursor having functional groups that react with each other to form a polymer and / or matrix made of repeating units. The precursor can be a polymer.

[0023] Some precursors therefore react by chain growth polymerization (also known as addition polymerization), and involve linking together monomers with double or triple chemical bonds. These unsaturated monomers have additional internal bonds that can break and link with other monomers to form repeating chains. A monomer is a polymerizable molecule having at least one group that reacts with other groups to form a polymer. A macromonomer (or macromer) is a polymer or oligomer having at least one reactive group, often at the end, that can act as a monomer; each macromonomer molecule is linked to the polymer through the reaction of the reactive groups. Therefore, macromonomers with two or more monomers or other functional groups tend to form covalent crosslinks. Addition polymerization is involved in the manufacture of, for example, polypropylene or polyvinyl chloride. One type of addition polymerization is living polymerization.

[0024] Some precursors therefore react via condensation polymerization, which occurs when monomers are bonded together through a condensation reaction. Typically, these reactions are achieved by reacting molecules with alcohol, amine, or carboxylic acid (or other carboxyl derivative) functional groups. When an amine reacts with a carboxylic acid, an amide or peptide bond is formed, and water is released. Some condensation reactions follow nucleophilic acyl substitution, for example, as described in U.S. Patent No. 6,958,212, which is incorporated herein by reference to the extent it does not conflict with the specific disclosure herein. Some precursors react via a chain growth mechanism. A chain growth polymer is defined as a polymer formed by the reaction of a monomer or macromer with a reactive center. A reactive center is a specific site within a chemical compound that is the initiator of a reaction involving that chemical compound. In chain growth polymer chemistry, this is also the propagation point for extending the chain. Reactive centers are typically free radical, anionic, or cationic in nature, but can also take other forms. Chain growth systems include free radical polymerization, which involves the processes of initiation, propagation, and termination. Initiation is the production of free radicals necessary for growth, such as those produced by a free radical initiator (e.g., an organic peroxide molecule). Termination occurs when the free radicals react in a way that prevents further growth. The most common method of termination is through coupling, where two free radical species react with each other to form a single molecule. Some precursors react by a step-growth mechanism and are polymers formed by a step-by-step reaction between the functional groups of the monomers. Most step-growth polymers are also classified as condensation polymers, but not all step-growth polymers release condensates. Monomers can be polymers or small molecules. Polymers are high molecular weight molecules formed by combining many small molecules (monomers) in a regular pattern. Oligomers are polymers with less than about 20 monomer repeat units. Small molecules generally refer to molecules less than about 2000 Daltons. The precursor may thus be a small molecule such as acrylic acid or vinyl caprolactam, a larger molecule containing a polymerizable group such as acrylate-terminated polyethylene glycol (PEG-diacrylate), or other polymers containing ethylenically unsaturated groups such as those described in U.S. Pat. No. 4,938,763 to Dunn et al., U.S. Pat. Nos. 5,100,992 and 4,826,945 to Cohn et al., or U.S. Pat. Nos. 4,741,872 and 5,160,745 to DeLuca et al., which are incorporated herein by reference to the extent they are not inconsistent with the specific disclosure herein.

[0025] In order to form a covalently cross-linked hydrogel, precursors must be covalently cross-linked together. Generally, a polymeric precursor is a polymer that is bonded to other polymeric precursors at two or more points, wherein each point is a connection (linkage) to the same or different polymers. Precursors with at least two reactive centers (e.g., in free radical polymerization) can be used as cross-linking agents because each reactive group can participate in the formation of different growing polymer chains. In the case of functional groups without reactive centers, cross-linking requires three or more such functional groups on at least one precursor type. For example, many electrophilic-nucleophilic reactions consume electrophilic and nucleophilic functional groups, so that a third functional group is needed for the precursor to form a cross-link. Such precursors can therefore have three or more functional groups and can be cross-linked by precursors with two or more functional groups. Cross-linked molecules can be cross-linked via ions or covalent bonds, physical forces, or other attractive forces. However, covalent cross-linking will generally provide stability and predictability in the reaction product structure.

[0026] In some embodiments, each precursor is multifunctional, meaning that it contains two or more electrophilic or nucleophilic functional groups, such that a nucleophilic functional group on one precursor can react with an electrophilic functional group on another precursor to form a covalent bond. At least one precursor contains more than two functional groups, such that as a result of the electrophilic-nucleophilic reaction, the precursors combine to form a cross-linked polymeric product.

[0027] Precursor can have biologically inert and hydrophilic part, for example, core.In the case of branched polymers, core refers to the adjacent part of the molecule that is attached to the arm extending from the core, and wherein arm has functional group, and it is often in the end of branch.Hydrophilic molecule, for example precursor or precursor part has the solubility of at least 1g / 100mL in aqueous solution.Hydrophilic part can be for example polyether, for example polyalkylene oxide such as polyethylene glycol (PEG), polyethylene oxide (PEO), polyethylene oxide-to-polypropylene oxide (PPO), copolyethylene oxide block or random copolymer and polyvinyl alcohol (PVA), poly (vinyl pyrrolidone) (PVP), polyamino acid, dextran or protein.Described precursor can have polyalkylene glycol part and can be based on polyethylene glycol, wherein at least about 80 % by weight or 90 % by weight of said polymer include polyethylene oxide repeats.Described polyether, and more particularly, poly (oxyalkylene) or poly (ethylene glycol) or polyethylene glycol are hydrophilic normally. As is customary in these arts, the term PEG is used to refer to PEO with or without hydroxyl end groups.

[0028] The precursor can also be a polymer (or macromer), which is a molecule with a molecular weight ranging from one thousand to several million. However, a hydrogel or organogel can be made from at least one precursor as a small molecule of about 1000 Da or less (or less than or equal to 2000 Da). When a polymer is reacted in combination with a small molecule (about 1000 Da or less / 200 Da or less), the polymer preferably has a molecular weight at least 5 to 50 times that of the small molecule, and preferably less than about 60,000 Da; the skilled artisan will immediately understand that all ranges and values within the explicitly stated ranges are contemplated. A more preferred range is a polymer having a molecular weight of about seven to thirty times that of the crosslinker, with a most preferred range being about ten to twenty times the molecular weight. In addition, polymers with molecular weights of 5,000-50,000 are useful, as are molecular weights of 7,000-40,000 or 10,000-20,000. These have some of the advantages of small molecules, such as diffusivity for completing the reaction.

[0029] Some macromer precursors are cross-linkable, biodegradable, water-soluble macromers described in U.S. Patent No. 5,410,016 to Hubbell et al., which is incorporated herein by reference in its entirety to the extent not inconsistent with the specific disclosure herein. These macromers are characterized by having at least two polymerizable groups separated by at least one degradable region.

[0030] Synthetic precursors can be used. Synthetic refers to molecules not found in nature or not generally found in humans. Some synthetic precursors do not contain amino acids that occur in nature or do not contain amino acid sequences that occur in nature. Some synthetic precursors are polypeptides that are not found in nature or not generally found in humans, for example, dimerization, trimerization or tetramerization of lysine. Some synthetic molecules have amino acid residues, but only have one, two or three adjacent amino acids or clusters thereof separated by non-natural polymers or groups. Polysaccharides or their derivatives are therefore not synthetic.

[0031] Alternatively, natural proteins or polysaccharides can be used with these methods, such as collagen, fibrinogen, albumin, alginate, hyaluronic acid and heparin. These natural molecules can further include chemical derivatization, for example, synthetic polymer modification. The natural molecules can be cross-linked via their natural nucleophiles or cross-linked after they are derivatized with functional groups, for example, as in U.S. Patent Nos. 5,304,595, 5,324,775, 6,371,975 and 7,129,210, each of which is incorporated herein by reference to the extent that it does not conflict with the contents clearly disclosed herein. Natural refers to molecules found in nature. Natural polymers, such as proteins or glycosaminoglycans such as collagen, fibrinogen, albumin and fibrin, can be cross-linked using reactive precursors with electrophilic functional groups. Natural polymers commonly found in the body are proteolytically degraded by proteases present in the body. Such polymers can react or derive with activatable functional groups via functional groups such as amines, thiols or carboxyl groups on their amino acids. Although natural polymers can be used in hydrogels, their gelation time and ultimate mechanical properties must be controlled by appropriate introduction of additional functional groups and selection of suitable reaction conditions such as pH.

[0032] Precursors can be made with hydrophobic moieties, provided that the resulting hydrogel retains a desired amount of water, for example, at least about 20%. In some cases, the precursor remains soluble in water because it also has a hydrophilic moiety. In other cases, the precursor is dispersed (suspended) in water but is still reactive to form a cross-linked material. Some hydrophobic moieties may include multiple alkyl groups, polypropylene, alkyl chains, or other groups. Some precursors with hydrophobic moieties are sold under the trade names PLURONIC F68, JEFFAMINE, or TECTRONIC. The hydrophobic moiety of a hydrophobic molecule or copolymer, etc., is one that is sufficiently hydrophobic to cause molecules (e.g., polymers or copolymers) to aggregate to form micelles or microphases containing hydrophobic domains in an aqueous continuous phase; or when tested alone, is sufficiently hydrophobic to precipitate from an aqueous solution of water at a temperature of about 30 to about 50 degrees Celsius and a pH of about 7 to about 7.5, or otherwise change phase when present therein.

[0033] The precursor may have, for example, 2-100 arms, each arm having a terminal end, keeping in mind that some precursors may be dendrimers or other highly branched materials. An arm on a hydrogel precursor refers to a linear chain of chemical groups that connects a crosslinkable functional group to a polymer core. Some embodiments are precursors having 3-300 arms; the skilled artisan will immediately understand that all ranges and values within the explicitly stated ranges are contemplated, such as 4-16, 8-100, or at least 6 arms.

[0034] Thus, a hydrogel can be made, for example, from a multi-arm precursor having a first set of functional groups and a low molecular weight precursor having a second set of functional groups. For example, a six-arm or eight-arm precursor can have hydrophilic arms, such as polyethylene glycol terminated with a primary amine, wherein the arms have a molecular weight of about 1,000 to about 40,000; the skilled artisan will immediately understand that all ranges and values within the explicitly stated ranges are contemplated. Such precursors can be mixed with relatively smaller precursors, such as molecules having a molecular weight of about 100 to about 5000, or no more than about 800, 1000, 2000, or 5000, having at least about three functional groups, or about 3 to about 16 functional groups; the skilled artisan will understand that all ranges and values between these explicitly stated values are contemplated. Such small molecules can be polymeric or non-polymeric and can be natural or synthetic.

[0035] Precursors that are not dendrimers can be used. Dendrimers are highly branched, radially symmetrical polymers in which atoms are arranged in numerous arms and sub-arms radiating outward from a central core. Dendrimers are characterized by their structural integrity (e.g., based on both symmetry and polydispersity) and require specific chemical methods for synthesis. Thus, a skilled artisan can readily distinguish dendrimer precursors from non-dendrimer precursors. Dendrimers have a specific shape that typically depends on the solubility of their component polymers in a given environment and can vary significantly depending on the solvent and solutes surrounding them, such as changes in temperature, pH, or ion content.

[0036] The precursor can be a dendrimer, for example, as disclosed in U.S. Publication Nos. 2004 / 0086479 and 2004 / 0131582 and PCT Publication Nos. WO07005249, WO07001926, and WO06031358, or their U.S. equivalents; dendrimers can also be useful as multifunctional precursors, for example, as disclosed in U.S. Publication Nos. 2004 / 0131582 and 2004 / 0086479 and PCT Publication Nos. WO06031388 and WO06031388; each of these U.S. and PCT applications is incorporated herein by reference in its entirety to the extent not inconsistent with the specific disclosure herein. Dendrimers are highly ordered, have a high surface area to volume ratio, and present numerous end groups for potential functionalization. Embodiments include multifunctional precursors that are not dendrimers.

[0037] Some embodiments include precursors consisting essentially of oligopeptide sequences of no more than five residues, such as amino acids containing at least one amine, thiol, carboxyl, or hydroxyl side chain. The residues are amino acids, such as those found in nature or derived therefrom. The backbone of such oligopeptides can be natural or synthetic. In some embodiments, peptides of two or more amino acids are combined with synthetic backbones to make the precursors; some embodiments of such precursors have a molecular weight in the range of about 100 to about 10,000 or about 300 to about 500. The skilled artisan will immediately understand that all ranges and values between these explicitly stated ranges are contemplated.

[0038] Precursors can be prepared to contain no amino acid sequences that can be present in the enzyme cleavage of the introduction site, including sequences that do not contain those that are easily attached to metalloproteinases and / or collagenases. In addition, precursors can be manufactured to contain no all amino acids, or no amino acid sequences that are more than about 50, 30, 20, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 amino acids. Precursors can be non-proteins, meaning that they are not naturally occurring proteins and can not be made by making naturally occurring protein cracking, and can not be made by adding synthetic materials to proteins. Precursors can be non-collagenous, non-fibrinous, non-fibrinogen and non-albumin, meaning that they are not one of these proteins and are not chemical derivatives of one of these proteins. The use of non-protein precursors and the limited use of amino acid sequences may be useful for avoiding immune responses, avoiding unwanted cell recognition and avoiding the danger associated with using proteins derived from natural sources. Precursors can also be non-sugar (does not contain sugar) or substantially non-sugar (does not contain sugar exceeding about 5% weight / weight of the precursor molecular weight). Thus, the precursor may, for example, exclude hyaluronic acid, heparin, or gellan. The precursor may also be non-proteinaceous and non-sugar. The term protein as used herein is a broad term referring to polypeptides; the term protein fragment may be used to refer to sequences shorter than the complete sequence of the wild-type protein: a precursor or therapeutic agent may be a protein fragment.

[0039] Peptides can be used as precursors. Generally, peptides with less than about 10 residues are preferred, but larger sequences (such as proteins) can be used. The technician will immediately understand that each range and value within these clear and distinct ranges are included, such as 1-10, 2-9, 3-10, 1, 2, 3, 4, 5, 6 or 7. Some amino acids have nucleophilic groups (such as primary amines or thiols) or can be derived to introduce nucleophilic groups or electrophilic groups (such as carboxyl or hydroxyl) when necessary. If the polyamino acid polymers produced by synthesis are not found in nature and are designed to be different from naturally occurring biomolecules, they are generally considered to be synthetic.

[0040] Some organogels and hydrogels are made with precursors containing polyethylene glycol. Polyethylene glycol (PEG, also known as polyethylene oxide when present at a high molecular weight) refers to a polymer having the repeating group (CH2C2O)n (where n is at least 3). A polymeric precursor having polyethylene glycol therefore has at least three of these repeating groups connected to one another in a straight line. The polyethylene glycol content of a polymer or arm is calculated by summing up all the polyethylene glycol groups on the polymer or arm, even if they are interrupted by other groups. Thus, an arm having at least 1000 MW of polyethylene glycol has enough CH2C2O groups to reach a total of at least 1000 MW. As is customary in these fields, a polyethylene glycol polymer does not necessarily refer to a molecule terminated by a hydroxyl group. The symbol k is used to abbreviate molecular weight in thousands, for example, 15K means 15,000 molecular weight, i.e., 15,000 daltons. NH2 refers to amine termination. SG refers to succinimidyl glutarate. SS refers to succinimidyl succinate. SAP refers to succinimidyl adipate. SAZ refers to succinimidyl azelate. SS, SG, SAP, and SAZ are succinimidyl esters having ester groups that degrade by hydrolysis in water. Thus, hydrolytically degradable or water-degradable refers to a material that spontaneously degrades in vitro in excess water in the absence of any enzymes or cells to mediate degradation. Degradation time refers to the effective disappearance of the material as judged by the naked eye. Trilysine (also abbreviated as LLL) is a synthetic tripeptide. PEG and / or hydrogels, and compositions comprising the same, can be provided in a pharmaceutically acceptable form, meaning that they are highly purified and free of contaminants, such as pyrogens.

[0041] hydrogel structure

[0042] The structure of the hydrogel and the material composition of the hydrogel precursor determine its properties. Precursor factors include, for example, biocompatibility, water solubility, hydrophilicity, molecular weight, arm length, number of arms, functional groups, distance between crosslinks, degradability, and the like. The choice of reaction conditions also affects the structure and properties of the hydrogel, including the choice of solvent, reaction scheme, reactant concentration, solid content, and the like. A particular property or combination of properties can be achieved in a variety of ways. On the other hand, some properties affect each other, such as increasing crosslink distance or solid content, which can increase brittleness. Strength can be increased by increasing the number of crosslinks, but this may reduce swelling. Technicians will appreciate that the same material can be used to make matrices with a wide range of structures, each with very specific mechanical properties and performance, and therefore the realization of specific properties should not be assumed based solely on the general type of precursor involved.

[0043] The spacing between the molecular chains of the hydrogel (matrix) affects some of the properties of the hydrogel, including the rate of molecular diffusion. The crosslink density can be controlled by selecting the total molecular weight of the precursor used as the crosslinker and other precursors, and the number of functional groups available for each precursor. Compared to a higher molecular weight between crosslinks, such as 500,000, a lower molecular weight between crosslinks, such as 200, will produce a higher crosslink density; the skilled person will immediately understand that all ranges and values within this range are contemplated and supported, such as 200 to 250,000, 500 to 400,000, etc. The crosslink density can also be controlled by the total solids percentage of the crosslinker and functional polymer solution. Another way to control the crosslink density is to adjust the stoichiometry of nucleophilic functional groups to electrophilic functional groups. A one-to-one ratio gives the highest crosslink density. Precursors with longer distances between crosslinkable sites generally form softer, more compliant, and more elastic gels. Therefore, increasing the length of the water-soluble segment (e.g., polyethylene glycol) can enhance elasticity to produce the desired physical properties. Thus, some embodiments relate to precursors having water-soluble fragments with molecular weights ranging from 2,000 to 100,000; the skilled artisan will readily appreciate that all ranges and values within the explicitly stated ranges are contemplated, for example, 5,000 to 35,000. Thus, embodiments include crosslinked materials (organogels, hydrogels, xerogels, (first) materials disposed within a film or coating of a second material, or second materials for encapsulation) with molecular weights of at least 2,000, at least 4,000, or 2,000 to 250,000; the skilled artisan will readily appreciate that all ranges and values between the explicitly stated ranges are contemplated, for example, any of the following may serve as upper or lower limits: 3,000, 5,000, 10,000, 500,000, 100,000. The solids content of a hydrogel (or xerogel or organogel from which a hydrogel can be derived) can affect its mechanical properties and biocompatibility and reflects a balance between competing requirements. Relatively low solids contents are useful, for example, between about 2.5% and about 20%, and those skilled in the art will immediately understand that this range includes all ranges and values therebetween, for example, about 2.5% to about 10%, about 5% to about 15%, or less than about 15%. The solids content and the distance between crosslinks are measured at the equilibrium moisture content of the material in water. Thus, embodiments include materials (organogels, hydrogels, xerogels, (first) materials placed in a film or coating of a second material, or second materials for encapsulation) having a solids content of about 2.5% to about 20%, and those skilled in the art will immediately understand that all ranges and values within the explicitly stated ranges are contemplated. The percentage solids content is measured at the equilibrium moisture content.

[0044] One way to construct materials to control or minimize sustained release is to design hydrogels with different diffusion rates for the agent. Typically, the molecular weight (MW) of the agent is the controlling variable. Several approaches exist to relate hydrogel properties to diffusion. These include free volume theory, hydrodynamic theory, barrier theory, combinatorial theory, and parameters such as mesh size, screening conditions, and the distribution of openings between chains (Amsden, Macromolecules (1998) 31: 8382-8395). In practice, however, hydrogels can be made with varying spacing between crosslinks and specific molecules tested to produce a hydrogel that provides a desired diffusion rate. In general, a larger distance between crosslinks relative to the size of the molecule provides a high diffusion rate, a smaller distance between crosslinks relative to the size of the molecule provides slow diffusion, and a distance between crosslinks smaller than the size of the molecule provides essentially no diffusion. The molecular weight of a molecule is often a useful measure of its size. Other factors may be important and should be considered when preparing hydrogels: for example, interactions between the molecule and the hydrogel, such as affinity or charge-charge, and solvent effects, such as the hydrophobicity of the molecule.

[0045] Thus, embodiments include a biomedical sustained release system for a patient comprising a collection of particles comprising a first biodegradable material that is a hydrogel or xerogel and a therapeutic agent, wherein the first material has a first release rate for the therapeutic agent measured in a physiological solution before biodegradation, and a second material (before biodegradation) that is delayed in release in a predetermined amount and optionally contains no therapeutic agent until the agent diffuses from the particles into the second hydrogel. Reference may be made to, for example, the already described methods of Figure 5 The controlled release curve shown in Figure 2 is used to describe the predetermined release amount. The release rate from the hydrogel was measured in vitro in a large amount of physiological solution, which is much larger than the hydrogel, so that the drug cannot accumulate in the solution and reduce the effective release rate. The solution used for testing is a phosphate buffer solution with a pH of 7.4, which is osmotic equilibrium with physiological conditions, as is common in the art. In addition, pH 7.2 is commonly used to specifically simulate the environment of ocular tissue.

[0046] Various therapeutic agents are described herein; they can be incorporated into these systems. Their sizes are known or readily determined. Their release rates can be readily determined. The agent may be those specifically described herein or may have a molecular weight less than about 450 kDa or within the range of 200 to about 450 kDa; skilled artisans will readily understand that all ranges and values within this range are contemplated, e.g., about 500 to about 250 kDa, about 100 to about 180 kDa, up to about 205 kDa, about 100 to about 255 kDa, etc. The release rate reflects the state of the system at the time of implantation. These systems may be biodegradable, and relative rates may vary over time as degradation occurs. However, since the release rate through the secondary material is very high, passage of the molecule is permitted and control of the delivery process is not necessary. The state of the particles within the hydrogel coating and the agent within the particles both control the release of the agent. The coating may affect the release rate, but only incidentally.

[0047] In practice, the second material, which in vivo is a hydrogel that at least partially coats the first hydrogel, plays a role in biocompatibility. It has been observed that loading hydrogel particles with pharmaceutical agents, specifically proteins not derived from in vivo animal models, can cause some undesirable biological effects, demonstrating a lack of biocompatibility. However, the same material, when coated with a hydrogel, is more biocompatible. The rabbit eye is a highly sensitive model used to demonstrate these effects. Without being bound by a particular theory, it is theorized that macrophages or other immune system cells may respond more effectively to the particles than to a bulk coating of the second material. Compared to a sheet coating, particles have a higher surface area and are more similar to the surface of cells, viruses, or tissues. Alternatively, the particles may contain the pharmaceutical agent, but may not be fully coated with all the pharmaceutical molecules, so that immune system cells can interact with them before the hydrogel degrades. The size of the outer encapsulating hydrogel can keep all cells out while allowing the pharmaceutical agent from the particles to diffuse quickly and freely. As used herein, the term "encapsulate" refers to the coating applied to all particles to be injected or otherwise placed in the patient's body. As will be apparent, embodiments include selecting a second material having a lower value of one or more of the following relative to the first material (e.g., particles): molecular weight, solids content, spacing of crosslinks, and persistence in vivo. The first material (hydrogel, etc.) can be in the form of particles and be a collection of particles having a specific size range or distribution as described elsewhere herein. Particles are useful for drug delivery, however, other objects can be coated, for example, drug implants, implantable materials, rods, rods having a size of at least 1 mm, punctal plugs, etc.

[0048] Example 1 shows a comparison of the release kinetics of therapeutic agents from in situ formed hydrogel coatings. This study employed rapidly degrading hydrogel particles; this conveniently resulted in a high rate of release of the therapeutic agent, thereby testing the effect of encapsulating the particles in the hydrogel coating to allow passage of the agent. A small but manageable difference in release rate was observed, with both formulations completely releasing in less than a week. This suggests that for particulate hydrogel-based protein delivery systems designed for sustained release, relatively high-release hydrogels can be overlayed to form a combined system. In Example 2, the encapsulated hydrogel of Example 1 was observed to have a significant impact on improving biocompatibility. The hydrogel particles coated with the encapsulated hydrogel showed a significantly lower inflammatory response than OTX-14 around the retina (Table 2).

[0049] functional groups

[0050] Precursors for covalent cross-linking have functional groups that react with each other outside the patient or in situ to form materials by covalent bonds. The functional groups are typically polymerizable, encompassing a wide range of free radical, addition, and condensation polymerizations and also groups for electrophilic-nucleophilic reactions. Aspects of polymerization are discussed in the precursor section herein.

[0051] Thus, in some embodiments, the precursor has a polymerizable group that is activated, for example, by photoinitiation or redox systems as used in the field of polymerization, or has an electrophilic functional group, such as a carbodiimidazole, a sulfonyl chloride, a chlorocarbonate, an n-hydroxysuccinimidyl ester, a succinimidyl ester, or a sulfasuccinimidyl ester, or as described in U.S. Patent Nos. 5,410,016 or 6,149,931, each of which is incorporated herein by reference in its entirety to the extent not inconsistent with the explicit disclosure herein. Nucleophilic functional groups can be, for example, amines, hydroxyls, carboxyls, and thiols. Another class of electrophiles is acyl groups, for example, as described in U.S. Patent No. 6,958,212, which describes, inter alia, a Michael addition reaction formula for reacting polymers.

[0052] Some functional groups, such as alcohols or carboxylic acids, generally do not react with other functional groups (e.g., amines) under physiological conditions (e.g., pH 7.2-11.0, 37° C.). However, such functional groups can be made more reactive by using activating groups, such as N-hydroxysuccinimide. Some activating groups include carbonyldiimidazole, sulfonyl chloride, aryl halide, sulfosuccinimidyl ester, N-hydroxysuccinimidyl ester, succinimidyl ester, epoxide, aldehyde, maleimide, imidate, etc. N-hydroxysuccinimide ester or N-hydroxysulfosuccinimide (NHS) group is a useful group for cross-linking proteins or amine-containing polymers (e.g., amino-terminated polyethylene glycol). The advantage of the NHS-amine reaction is that the reaction kinetics are favorable, but the gelation rate can be adjusted by pH or concentration. The NHS-amine cross-linking reaction results in the formation of N-hydroxysuccinimide as a by-product. Sulfonated or ethoxylated forms of N-hydroxysuccinimide have relatively increased solubility in water and therefore they can be rapidly cleared from the body. The NHS-amine crosslinking reaction can be carried out in an aqueous solution and in the presence of a buffer such as a phosphate buffer (pH 5.0-7.5), a triethanolamine buffer (pH 7.5-9.0), or a borate buffer (pH 9.0-12), or a sodium bicarbonate buffer (pH 9.0-10.0). Due to the reaction of the NHS group with water, it is preferred to prepare an aqueous solution of the NHS-based crosslinker and the functional polymer just prior to the crosslinking reaction. The reaction rate of these groups can be slowed by maintaining these solutions at a lower pH (pH 4-7). A buffer may also be included in the hydrogel introduced into the body.

[0053] In some embodiments, each precursor contains only nucleophilic functional groups or only electrophilic functional groups, as long as both nucleophilic and electrophilic precursors are used in the cross-linking reaction. Thus, for example, if the cross-linking agent has a nucleophilic functional group such as an amine, the functional polymer may have an electrophilic functional group such as N-hydroxysuccinimide. On the other hand, if the cross-linking agent has an electrophilic functional group such as sulfosuccinimide, the functional polymer may have a nucleophilic functional group such as an amine or a thiol. Thus, functional polymers such as proteins, poly (allylamine) or amine-terminated di- or multifunctional poly (ethylene glycol) can be used.

[0054] One embodiment has reactive precursor species each having from 2 to 16 nucleophilic functional groups and reactive precursor species each having from 2 to 16 electrophilic functional groups; the skilled artisan will immediately understand that all ranges and values within the explicitly stated ranges are contemplated, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 groups.

[0055] The functional group can be, for example, an electrophile that can react with a nucleophile, a group that can react with a specific nucleophile (e.g., a primary amine), a group that forms an amide bond with a material in a biological fluid, a group that forms an amide bond with a carboxyl group, an activated acid functional group, or a combination thereof. The functional group can be, for example, a strong electrophilic functional group, meaning an electrophilic functional group that effectively forms a covalent bond with a primary amine in an aqueous solution at pH 9.0 at room temperature and pressure and / or an electrophilic group that reacts via a Michael-type reaction. Strong electrophiles can be either non-participating or participating in Michael-type reactions.

[0056] Michael-type reactions refer to the 1,4 addition of nucleophiles to conjugated unsaturated systems. The addition mechanism can be purely polar or proceed through a free radical-like intermediate; Lewis acids or appropriately designed hydrogen-bonding species can act as catalysts. The term conjugated can refer to the permutation of carbon-carbon, carbon-heteroatom, heteroatom, or heteroatom multiple bonds with single bonds, or to the attachment of functional groups to macromolecules such as synthetic polymers or proteins. Michael-type reactions are discussed in detail in U.S. Patent No. 6,958,212, which is incorporated herein by reference in its entirety to the extent not inconsistent with the specific disclosure herein.

[0057] Examples of strong electrophiles that do not participate in Michael-type reactions are: succinimide, succinimidyl esters, or NHS-esters. Examples of Michael-type electrophiles are acrylates, methacrylates, methyl methacrylate, and other unsaturated polymerizable groups.

[0058] Initiation system

[0059] Some precursors use initiator reactions. The initiator group is a chemical group that can initiate a free radical polymerization reaction. For example, it can exist as an independent component or as a pendent group on the precursor. The initiator group includes thermal initiators, photoactivatable initiators and oxidation-reduction (redox) systems. Long-wave UV and visible light photoactivatable initiators include, for example, ethyl eosin (eosin) groups, 2,2-dimethoxy-2-phenylacetophenone groups, other acetophenone derivatives, thioxanthone groups, benzophenone groups, and camphorquinone groups. Examples of thermally reactive initiators include 4,4'azobis(4-cyanovaleric acid) groups and analogs of benzoyl peroxide groups. Several commercially available low-temperature free radical initiators, such as V-044 available from Wako Chemicals USA, Inc., Richmond, Va., can be used to initiate free radical crosslinking reactions at body temperature to form a hydrogel coating with the aforementioned monomers.

[0060] Metal ions can be used as oxidizing agents or reducing agents in redox initiation systems. For example, ferrous ions can be used in combination with peroxides or hydroperoxides to initiate polymerization, or as part of a polymerization system. In this case, ferrous ions will serve as reducing agents. Alternatively, metal ions can serve as oxidizing agents. For example, ceric ions (the 4+ valence state of cerium) interact with a variety of organic groups (including carboxylic acids and carbamates) to transfer electrons to the metal ion and leave initiating free radicals on the organic group. In such systems, metal ions act as oxidizing agents. Potentially suitable metal ions for either role are any transition metal ions, lanthanides, and actinides that have at least two readily accessible oxidation states. Particularly useful metal ions have at least two states separated by only one difference in charge. Among these, the most commonly used are ferric iron / ferrous iron; cupric / cuprous; ceric / ceric; cobalt / cobalt; vanadates V to IV; permanganates; and manganese / manganese. Peroxygen-containing compounds may be used, such as peroxides and hydroperoxides, including hydrogen peroxide, t-butyl hydroperoxide, t-butyl peroxide, benzoyl peroxide, cumene peroxide.

[0061] An example of an initiating system is a combination of a peroxy compound in one solution and a reactive ion, such as a transition metal, in another solution. In this case, when the moieties containing two complementary reactive functional groups interact at the site of application, no external polymerization initiator is required and the polymerization proceeds spontaneously and without the application or use of external energy.

[0062] Precursor coating

[0063] Embodiments include medical devices having at least a portion of a precursor coating that forms a hydrogel in situ when exposed to an aqueous solution. The term medical device is broad and includes drug delivery devices, drug depots for delivering drugs, intraocular drug depots, implantables, prostheses, and objects made to contact physiological fluids. An example is a tear plug, an intraocular drug depot, or a fiber for a medical device, wherein the plug or fiber is completely or partially coated with a precursor. The method of applying the coating includes immersing the device or the portion to be coated in a melt of a polymer (precursor) that forms the coating. In the absence of a solvent, the polymer melts at a temperature not exceeding the polymer melting temperature, such as about 100°C. The plug or a portion thereof is immersed in the melt. The melt is cooled to a solid that is solid at 37°C. Instead of immersing the plug in the melt, the melt can be applied in other ways, such as by brushing, rolling, dripping the melt onto the plug, and the like. In the context of polymers, the term melt refers to a polymer that is in a liquid state but is insoluble in a solvent, or a polymer that acts as its own solvent. Other substances may be present in the melt, but they are not solvents for the melt. It should be understood that small amounts of solvent may be present in concentrations that do not interfere with dissolving the majority of the polymers in the melt, for example, up to 10% by weight of the total weight. A skilled artisan will readily appreciate that all ranges and values between the specified ranges are contemplated, with any of the following being upper or lower limits: 0.1, 0.2, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10% by weight per total weight. Auxiliary agents may be present in the melt to help adjust its melting point. For example, agents that reduce the bonding between the polymers may be added to lower the melting point; these agents may be nonsolvents or solvents. Such agents may be added in amounts up to 10% by weight per total weight. A skilled artisan will readily appreciate that all ranges and values between the specified ranges are contemplated, with any of the following being upper or lower limits: 0.1, 0.2, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10% by weight per total weight. Additionally, branched polymers can be used to adjust the melting temperature.

[0064] Examples of polymers that melt at a temperature suitable for immersing the punctal plug or other device without damage include PEG, the melting point of which is related to the MW of the PEG. PEGs of about 8,000 MW have been tested and are useful. Other MWs of PEG are, for example, from about 2,000 to about 100,000 (unless otherwise specified, the MW of a polymer represents the weight average molecular weight). Generally, the polymer or polymer mixture is selected to set the desired melting temperature and target dissolution time.

[0065] The method of applying a precursor coating to a punctal plug or other device comprises exposing the punctal plug or other device to a solution comprising a polymer forming the coating, wherein the polymer is dissolved in a solvent that is not a solvent for the punctal plug. The solvent is typically non-aqueous and is an organic solvent. Examples of organic solvents are dimethyl carbonate, dimethylformamide dimethyl sulfoxide, n-methylpyrrolidone, dimethyl sulfoxide, ethyl lactate, N-dicyclohexylcarbodiimide. Other solvents that may be used are alcohols such as ethanol, isopropyl alcohol, 1,2-propylene glycol, and 1,4-butanediol.

[0066] The precursor coating can be made using water to dissolve the coating material, creating a solution that is sprayed onto the stopper to form a water-soluble coating, a process known as fluidized bed. Another configuration can use the coating material dissolved in a non-aqueous solvent to form a non-aqueous solution.

[0067] The precursor coating is not necessarily a melt. The precursor can be placed in a suitable solvent and applied to a stopper or other device, or applied in dry form. The coating can contain excipients such as adhesives, non-reactive materials or non-reactive polymers, plasticizers, buffers, developers, dyes or salts.

[0068] Visualization reagents

[0069] Visualization agents can be used as powders in the xerogel / hydrogel; they reflect or emit light of a wavelength detectable by the human eye, so that when an effective amount of the agent is contained, the user applying the hydrogel can observe the object. Agents that require mechanical assistance for imaging are referred to herein as imaging agents, and examples include: radiopaque contrast agents and ultrasound contrast agents. Some biocompatible visualization agents are FD&C BLUE #1, FD&C BLUE #2, and methylene blue. These agents are preferably present in the final electrophilic-nucleophilic reactive precursor mixture at a concentration exceeding 0.05 mg / ml and preferably in a concentration range of at least 0.1 to about 12 mg / ml, and more preferably in a range of 0.1 to 4.0 mg / ml, although larger concentrations can potentially be used, up to the solubility limit of the visualization agent. The visualization agent can be covalently linked to the molecular network structure of the xerogel / hydrogel, so that visualization remains after application to the patient until the hydrogel hydrolyzes to dissolve. Visualization agent can be selected from any various non-toxic coloring materials that are applicable to medical implantable medical devices, for example FD&C BLUE dyes 3 and 6, eosin, methylene blue, indocyanine green or the coloring dye that usually exists in synthetic surgical sutures. Reactive visualization agent for example NHS-fluorescein can be used for introducing visualization agent into the molecular network structure of xerogel / hydrogel. Visualization agent can exist together with reactive precursor material for example cross-linking agent or functional polymer solution. Preferred coloring material may or may not be chemically bonded to hydrogel.

[0070] Biodegradation

[0071] Organogels and / or xerogels and / or hydrogels can be formed so that when hydrated in physiological fluids, they form a hydrogel that is water-degradable, as measured by the hydrolytic degradation of the hydrodegradable groups in vitro in excess water, losing its mechanical strength and ultimately dissipating. This test predicts hydrolysis-driven dissolution in vivo, a process that is the opposite of cell- or protease-driven degradation. However, it is worth noting that polyanhydrides or other commonly used degradable materials that degrade into acidic components tend to cause inflammation in tissues. However, hydrogels may exclude such materials and may not contain polyanhydrides, anhydride bonds, or precursors that degrade into acids or diacids. The term degradation by solvation in water, also known as dissolution in water, refers to the process by which a matrix gradually dissolves in solution, a process that cannot occur with covalently cross-linked materials and materials that are insoluble in water.

[0072] For example, electrophilic groups such as SG (N-hydroxysuccinimidyl glutarate), SS (N-hydroxysuccinimidyl succinate), SC (N-hydroxysuccinimidyl carbonate), SAP (N-hydroxysuccinimidyl adipate), or SAZ (N-hydroxysuccinimidyl azelate) can be used, with the electrophilic group having a hydrolytically unstable ester linkage. More linear hydrophobic linkages such as pimelate, suberate, azelate, or sebacate linkages can also be used, where these linkages are less hydrolyzable than succinate, glutarate, or adipate linkages. Branched, cyclic, or other hydrophobic linkages can also be used. Polyethylene glycol and other precursors can be prepared using these groups. When water-degradable materials are used, degradation of the cross-linked hydrogel can be carried out by water-driven hydrolysis of the biodegradable segments. Polymers containing ester linkages can also be included to provide a desired degradation rate, where groups added or subtracted near the esters increase or decrease the degradation rate. Thus, degradable segments can be used to construct hydrogels with desired degradation profiles ranging from a few days to many months. For example, if polyglycolate is used as the biodegradable segment, the crosslinked polymer can be made to degrade in about 1 to about 30 days, depending on the crosslink density of the network. Similarly, a crosslinked network based on polycaprolactone can be made to degrade in about 1 to about 8 months. Degradation times generally vary depending on the type of degradable segment used, in the following order: polyglycolate < polylactic acid < polytrimethylene carbonate < polycaprolactone. Thus, degradable segments can be used to construct hydrogels with desired degradation profiles ranging from a few days to many months. Some embodiments include precursors without adjacent ester groups and / or precursors with no more than one ester group per arm of one or more precursors: controlling the number and position of esters facilitates uniform degradation of the hydrogel.

[0073] The biodegradable linkages in the organogel and / or xerogel and / or hydrogel and / or precursor can be water-degradable or enzymatically degradable. Illustrative water-degradable biodegradable linkages include polymers, copolymers, and oligomers of glycolide, dl-lactide, 1-lactide, dioxanone, esters, carbonates, and trimethylene carbonate. Illustrative enzymatically biodegradable linkages include peptide linkages that are cleavable by metalloproteinases and collagenases. Examples of biodegradable linkages include the following polymers and copolymers: poly(hydroxy acids), poly(orthocarbonates), poly(anhydrides), poly(lactones), poly(amino acids), poly(carbonates), and poly(phosphonates).

[0074] If it is desired that the biocompatible cross-linked matrix is biodegradable or resorbable, one or more precursors having biodegradable linkages between the functional groups can be used. The biodegradable linkages can also optionally serve as the water-soluble core of the one or more precursors for making the matrix. For each approach, the biodegradable linkages can be selected so that the resulting biodegradable, biocompatible, cross-linked polymer will degrade or be absorbed within the desired time period.

[0075] Aqueous sols / xerosols / organosols loaded with pharmaceutical agents prepared into granules

[0076] A method of manufacturing a therapeutic agent hydrogel or organogel is to surround the agent to form. For example, a first precursor is added to a solvent-protein mixture, and then a second precursor is added to react with the first precursor to form a cross-linked precursor. After forming a matrix in a solvent, the solvent is removed to form a xerogel. Potential methods include precipitation with a non-solvent, nitrogen drying, vacuum drying, freeze drying (freeze-drying), a combination of heat and vacuum and lyophilization. If a molten precursor is used in the absence of a third solvent, it is not necessary to use any solvent removal method. When cooling, the material forms a rubbery solid (if higher than Tg), a semi-rigid semi-crystalline material (if lower than Tm and higher than Tg) or a rigid glassy solid (if lower than Tg). These materials are denser than the xerogels formed by organic solvents. When filling the particles of other materials, such as therapeutic agents, buffer salts, visualization agents, they can be highly porous because solid particles produce and fill holes.

[0077] In some embodiments, when the precursors react, one or more pharmaceutical agents are present in a separate phase. The separated phase can be an oil (oil-in-water emulsion) or an immiscible solvent, a liposome, a micelle, a biodegradable carrier, etc. Biodegradable carriers in which the active agent can be present include: encapsulation carriers, such as microparticles, microspheres, microbeads, micropellets, wherein the active agent is encapsulated in a bioerodible or biodegradable polymer, such as the following polymers or copolymers: poly(anhydrides), poly(hydroxy acids), poly(lactones), poly(trimethylene carbonate), poly(glycolic acid), poly(lactic acid), poly(glycolic acid)-co(glycolic acid), poly(orthocarbonate), poly(caprolactone), cross-linked biodegradable hydrogel networks (such as fibrin glue or fibrin sealant), caged and trapped molecules (such as cyclodextrin), molecular sieves, etc. Microspheres made of polymers and copolymers of poly(lactones) and poly(hydroxy acids) are particularly preferred as biodegradable encapsulation carriers. The therapeutic agent or encapsulated therapeutic agent can be present in the form of a solution or suspension. Some pharmaceutical agents are highly soluble, while others are virtually insoluble in aqueous solution and form their own phase when exposed to an aqueous solvent. The therapeutic agent can be in the form of solid particles, such as a powder, in the hydrogel / organogel / xerogel. For example, a water-soluble biologic (e.g., a protein) in the solid phase can be ground or otherwise formed into a fine powder that is added to the precursor when forming the matrix. The protein or other water-soluble biological substance in the xerogel can be in the solid phase and can be fully crystalline, partially crystalline, or substantially free of crystals (meaning that more than 90% w / w is free of crystals; the skilled person will immediately recognize that all ranges and values within the specified ranges are taken into account). Protein powder refers to a powder made from one or more proteins. Similarly, a powder of a water-soluble biologic is a powder containing particles made from one or more water-soluble biologics. The powder and / or xerogel and / or organogel and / or hydrogel containing them may not contain an encapsulating material and may not contain one or more liposomes, micelles, or nanocapsules. In addition, protein particles or water-soluble bioparticles can be prepared that are free of one or more of: binders, non-peptide polymers, surfactants, oils, fats, waxes, hydrophobic polymers, polymers containing alkyl chains longer than 4 CH2 groups, phospholipids, micelle-forming polymers, micelle-forming compositions, amphiphiles, polysaccharides, polysaccharides of three or more sugars, fatty acids, and lipids. Lyophilized, spray-dried, or otherwise processed proteins are often formulated with sugars such as trehalose to stabilize the protein prepared by lyophilization or other methods. These sugars can be allowed to persist in the particles throughout the organogel / xerogel process. Particles can be made to contain from about 20% to about 100% (dry w / w) protein; the skilled artisan will immediately understand that all ranges and values within the explicitly stated ranges are contemplated, for example, from about 50% to about 80% or at least 90% or at least about 99%. Many factors can be controlled to aid in the processing and delivery of proteins without denaturation.The protein can be prepared as a powder, the particle size of which is selected based on the size of the final hydrogel / organogel / xerogel particles. The organic solvent for the protein can be selected so that it is not solvated by the organic solvent and is compatible with the protein. Another factor is oxygen, the elimination of which aids processing to avoid denaturation. Another factor is chemical reactions. These can be avoided by maintaining the protein in a solid phase and excluding the solvent that dissolves the protein until the protein is implanted.

[0078] An organogel or hydrogel can be formed and then reduced to particles, which are then treated to remove the organic or aqueous solvent to form a xerogel. For injectable forms, the organogel or hydrogel can be impregnated, homogenized, extruded, sieved, chopped, cut into pieces or otherwise reduced to a granular form. Alternatively, the organogel or hydrogel can be formed into droplets or moldings containing suspended protein particles. A method for manufacturing such particles involves producing a broken or granular material. A technique involves preparing an organogel or hydrogel with protein particles and grinding, for example, in a ball mill or with a mortar and pestle. The matrix can be chopped or cut with a knife or wire. Alternatively, the matrix can be cut in a mixer or homogenizer. Another process includes passing the organogel through a mesh, collecting the fragments, and passing them through the same mesh or other meshes until the desired size is reached.

[0079] Biologic particles or organogel particles or xerogel particles can be separated into collections having a desired size range and size distribution by various methods. The size can be very finely controlled, ranging from less than 1 micron to several millimeters, and the average particle size and particle size range can be controlled with a narrow distribution. The skilled artisan will immediately understand that all ranges and values within the clearly defined ranges are contemplated, such as about 0.1 to about 10 μm or about 1 to about 30 μm. About 1 to about 500 microns is another useful range, with sizes falling within the entire range and having an average size within the range of values and a standard deviation centered around the average, such as about 1% to about 100%. Simple methods of screening particle size include using a custom or standard mesh sieve. Another method of measuring particle size is to use a laser diffraction particle size analyzer, such as a Coulter LS200, which analyzes particles suspended in a liquid such as saline. The term particle is broad and includes spheres, discs, and irregularly shaped particles. Spherical particles are particles in which the longest central axis (a straight line through the geometric center of the particle) is no longer than twice the length of the other central axes, wherein the particles can be truly spherical or have an irregular shape. Rod-shaped particles are particles having a longitudinal central axis that is approximately twice the length of the shortest central axis. Embodiments include preparing multiple particle assemblies that have different degradation rates in vivo and mixing the assemblies to produce biomaterials with desired degradation properties.

[0080] The particles can be prepared as a collection of particles having a certain average volume, an average volume mean, or a distribution of sizes falling within a certain volume range (meaning that at least 95% w / w of the particles are distributed within this range). One embodiment is a collection of particles having one or more of the following: an average volume, an average volume mean, or a size distribution of about 0.02 μm. 3 to about 2mm 3 The skilled person will immediately understand that all ranges and values within this range are considered and supported, for example from 0.025 μm 3 Up to 1mm 3 , 0.03μm 3 Up to 1.5mm 3 etc. In addition, the total volume of all hydrogels and / or the total volume of the particle collection for use in a human injection system may have a value of about 0.005 to about 2.5 milliliters (ml); the skilled person will immediately understand that all ranges and values within this range are contemplated, for example, 0.005 to 1 ml, 0.1 ml to 1.5 ml, etc. The particles may have a diameter of from 0.01 micrometer to 2 mm (in the longest dimension if not symmetrical); the skilled person will immediately understand that all ranges and values between the explicitly stated ranges are contemplated, for example, any of the following may be used as upper or lower limits: 1, 5, 10, 20, 50, or 100 nanometers, 0.1, 0.2, 0.5, 1, 10, 20, 30, 40, 50, 100, 200, 300, 500, 1000 micrometers, 1, 1.5, or 2 millimeters. In particular, for drug delivery to targeted tissues, such as various structures of the eye, the volume that can be occupied by the drug delivery reservoir is limited. For example, the suprachoroidal space can contain up to approximately 100 μl of depot, or 200 μl if it conforms to the spatial shape. Similarly, up to 100 μl or 200 μl can be injected into the vitreous humor, as long as the depot does not intrude into the visual axis. Other sites, such as subconjunctival delivery, can accommodate larger depots because this tissue can accommodate by swelling.

[0081] Alternatively, instead of particles, the hydrogel / organogel / xerogel can be formed as or as part of a medical device or medical implant. The device can be used in vivo or on the body surface. The implant is at least partially implanted in the body, or can be completely implanted in the body. Examples of devices are intravascular or extravascular but punctal plugs, rod-shaped objects, drug delivery devices, patches, and drug depots that are in contact with at least a portion of a blood vessel or associated structure (e.g., adventitia). The hydrogel / organogel / xerogel can be formed in vitro for the device, e.g., prepared and lyophilized to prepare a xerogel, or formed in situ, e.g., by providing at least a partial coating of a precursor that forms a hydrogel in vivo when exposed to an aqueous solution.

[0082] Application

[0083] In one embodiment, a hydrogel is formed by in situ polymerization around hydrogel and / or xerogel particles, wherein the particles contain a therapeutic agent. The in situ formed hydrogel surrounds the particles and may encapsulate them. When the particles are thoroughly mixed with the encapsulating hydrogel, they are coated and, thus, encapsulated. In other cases, the particles are left in an open state and then the hydrogel is applied, which may result in only partial encapsulation of the particles.

[0084] In use, the hydrogel particles are mixed with the precursors and injected into the patient at the desired site of action. The precursors react with each other to form an encapsulated hydrogel. The particles can be made with a first diffusivity for the pharmaceutical agent, and the encapsulated hydrogel can be made with a second diffusivity. A needle, cannula, trocar, sprayer, or other applicator can be used. Administration of the hydrogel and / or xerogel can also include pre-hydration immediately before or at the time of use. Alternatively, the xerogel can be implanted unhydrated and hydrated in situ.

[0085] Materials as described herein can be used to deliver drugs or other therapeutic agents (such as imaging agents or markers). One application method is to apply a mixture of xerogel / hydrogel particles and other materials (such as therapeutic agents, buffers, promoters, initiators) to the site of action by needles, microneedles, cannulas, catheters or hollow wires. The mixture can be delivered, for example, by using a manually controlled syringe or a mechanically controlled syringe (such as a syringe pump). Alternatively, a double syringe or multi-barrel syringe or multi-chamber system can be used to mix xerogel / hydrogel particles at or near the site with a hydration fluid and / or other agents. Some locations require a cautious application method, such as in the eye. A fine needle can be used, and / or a needle of limited length. If helpful, work can be performed under magnification using a stereoscope, guided imaging or robot (such as described by Eindhoven University of Technology). Precursor solution and particle assembly can be prepared with a size and lubricity that can be manually injected by a small gauge needle. The hydrophilic hydrogel crushed into spherical particles of about 40 to about 100 microns in diameter is small enough to be manually injected through a 30-gauge needle. A hypertonic solvent and / or osmotic agent that increases the osmotic pressure can be used to facilitate passage of the particles / solution through the needle.

[0086] The application of hydrogels and / or organogels and / or xerogels can be directly applied to the site of interest. Embodiments of the present invention include application at or near the eye. The structure of the mammalian eye can be divided into three main layers or membranes: the tunica fibrosus, the tunica vascularis, and the tunica neuropil. The tunica fibrosus, also known as the ocular fibrous membrane, is the outer layer of the eyeball consisting of the cornea and the sclera. The sclera extends from the cornea (the clear front part of the eye) to the optic nerve at the back of the eye. The sclera is a fibrous, elastic, and protective tissue composed of tightly packed collagen fibers that contains about 70% water. Overlying the tunica fibrosus is the conjunctiva. The conjunctiva is the membrane that covers the sclera (the white part of the eye) and lines the inside of the eyelid. The conjunctiva is typically divided into three parts: (a) the palpebral or tarsal conjunctiva, which is the conjunctiva lining the eyelids; the palpebral conjunctiva folds back at the superior and inferior fornixes to become the bulbar conjunctiva, (b) the forniceal conjunctiva: the conjunctiva where the inner portion of the eyelid and the eyeball meet, (c) the bulbar or conjunctiva: the conjunctiva that covers the eyeball, above the sclera. This area of the conjunctiva is tightly (firmly) attached and moves with the movement of the eyeball. The conjunctiva effectively surrounds, covers, and is attached to the sclera. It has cellular tissue and connective tissue, is somewhat elastic, and can be removed, pulled off, or otherwise taken down to expose the surface area of the sclera.

[0087] The tunica vascularis, also known as the ocular tunica, is the central vascularized layer that includes the iris, ciliary body, and choroid. The choroid lies between the retina and the sclera. The choroid contains blood vessels that supply oxygen to retinal cells and remove respiratory waste products. The choroid is connected to the ciliary body at the front of the eye and is attached to the edge of the optic nerve at the back of the eye. The tunica neuritis, also known as the optic nerve membrane, is the internal sensory organ that includes the retina. The retina contains light-sensitive rods and cones and their associated neurons. The retina is a relatively smooth (but curved) layer. It has two distinct points: the fovea and the optic disc. The fovea is a depression in the retina directly opposite the lens that is densely packed with cones. The fovea is part of the macula. The optic disc is the point on the retina where the optic nerve penetrates the retina to connect to the nerve cells within it. The mammalian eye can also be divided into two main segments: the anterior segment and the posterior segment. The anterior segment consists of the anterior chamber and the posterior chamber.

[0088] The cornea and lens help converge light to focus on the retina. The lens behind the iris is a raised, flexible disk that focuses light onto the retina via the second humor. It is attached to the ciliary body via a ring of suspensory ligaments called the zonule of Zinn. The iris, between the lens and the first humor, is a pigmented ring of fibrovascular tissue and muscle fibers. Light enters the eye, passes through the cornea, and enters the first of the two humors (the aqueous humor). About two-thirds of the total refractive power of the eye comes from the cornea, which has a fixed curvature. The aqueous humor is a transparent substance that connects the cornea of the eye to the lens, helps maintain the convex shape of the cornea (needed for light focusing in the lens), and provides nutrients to the corneal endothelium. The posterior segment is behind the lens and in front of the retina. It includes a transparent membrane in front and structures behind it, including the vitreous humor, the retina, and the optic nerve.

[0089] Figure 3 FIG3 is a cross-section of an eye 300 and depicts a cornea 302, which is optically clear and allows light to pass through the iris 304 and penetrate the lens 306. Anterior chamber 308 is located beneath cornea 302, and posterior chamber 310 is located between iris 304 and lens 306. Ciliary body 312 is attached to lens 306. Conjunctiva 312 overlies sclera 314. Vitreous body 316 contains a jelly-like vitreous humor, within which vitreous cavity 318 is also located. Fovea 320 is located in the macula, and retina 322 overlies choroid 324. Various delivery points of eye 300 are depicted. One area is focal 350. Another area is within the vitreous, as shown at 352, 354, and 356; locations 352 and 356 are outside the focal area of the lens, and location 356 is located at the edge of the retina in contact with the inner edge of the eye. Location 358 is located outside the eye and on the sclera. In use, the hydrogel 108, 110 or the hydrogel 108 and the precursor 102 are delivered, for example, using a syringe, catheter (not shown), or other device. When the precursors are delivered, they are selected so that they form the hydrogel 110 in situ at the intended site of use. The therapeutic agent is released from the hydrogel.

[0090] Other positions can be selected.The position of drug delivery library includes the surface of anterior chamber, posterior chamber, vitreous body, sclera, under conjunctiva, cornea or conjunctiva, scleral surface, sclera, under sclera or sclera and under conjunctiva and between the bulbar conjunctiva (subconjunctiva) of the position of contact conjunctiva, palpebral conjunctiva or tarsal conjunctiva or under, on eyelid, upper fornix, lower fornix, bulbous conjunctiva and fornix conjunctiva.Other positions are located between choroid, choroid and sclera, between retina and choroid or its combination.

[0091] The hydrogel can be placed at a site suitable for delivering the agent for the pathology to be treated. The choice of dosage, implant size, and location is influenced by factors such as the time interval between repeated applications, patient comfort or compliance, and the dose received at the target tissue. In general, diseases of the posterior segment of the eye can be treated using drugs such as local, systemic, intraocular, and subconjunctival delivery routes. Systemic and topical delivery methods (referring to eye drops and non-adhesive materials) are insufficient for delivering therapeutic drug levels to treat posterior segment diseases: these drug delivery methods face diffusion and drug dilution problems due to inherent structural barriers of the intraocular and systemic systems, resulting in significant patient side effects (due to multiple daily dosing), poor bioavailability, and compliance issues. Transdermal drug delivery using ocular hydrogel implants located in the subconjunctival, sclera, suprachoroidal, retrobulbar, or sub-Tenon locations can potentially provide a safer and more robust retinal drug delivery system compared to local and systemic routes. For example, steroids such as dexamethasone and tramadol can be mixed with hydrogel precursors to form sustained-release drug implants. The liquid hydrogel can then be injected in situ into the subfascial capsule, where it can provide a constant or regulated drug release profile over a three- to four-month period. The minimally invasive procedure can be performed in a doctor's office or during cataract surgery under local anesthesia to treat chronic eye diseases.

[0092] In some embodiments, the eyelid is held back with a retractor, and the user creates a small buttonhole in the conjunctiva approximately 5-6 mm from the lower nose / nasal margin and dissects the conjunctiva from the fascial sac down to the exposed sclera. Next, a 23-gauge blunt-tipped cannula 86 (e.g., 15 mm in length) is inserted through the opening and the liquid drug implant is injected at the intended site of administration. The cannula is then removed and the conjunctiva is closed with a cautery device. One advantage of a hydrogel implant with three-dimensional integrity is that it tends to resist cellular infiltration and can prevent the topically applied drug from being prematurely engulfed and cleared from the site. Instead, it remains intact until delivery. In contrast, microparticles, liposomes, or pegylated proteins tend to be rapidly cleared from the body by the reticuloendothelial system before a biological effect occurs.

[0093] Delivering therapeutic amounts of drugs to the retina for posterior segment diseases remains a challenge. Although intravitreal injections of anti-VEGF drugs into the vitreous cavity have shown promise in preventing, and in some cases reversing, chronic age-related diseases such as macular degeneration, these techniques and procedures are not without risks and side effects. Intravitreal administration of therapeutic agents into the vitreous cavity can cause cataracts, endophthalmitis, and retinal detachment. This treatment regimen requires many patients to receive intraocular injections of anti-VEGF drugs monthly for 12 months, thereby increasing the risk of infection, vitreous wicks, and retinal detachment. Embodiments involving in situ hydrogel biodegradable drug implants containing hydrogel particles will provide an effective alternative treatment for posterior segment diseases and are expected to reduce the common side effects associated with repeated intravitreal injections. For intravitreal implants, for example, a subretinal cannula is used to inject a hydrogel precursor and hydrogel particles into the vitreous cavity approximately 2.5 mm behind the limbus through a ciliary ring incision, which can be performed as needed after dissection or after cleaning the conjunctiva in other cases. A 25, 27 or 30 gauge secondary subretinal cannula 94 (or other suitable cannula) is then inserted into the eye and positioned at the desired target site, where a flowable precursor is introduced to form a hydrogel in situ. The precursor then forms a readily absorbed gel that adheres to the desired target site.

[0094] The drug reservoir of the in situ hydrogel drug delivery implant can be designed for controlled, long-term drug release, for example, for about 1 to about 3 months; and can optionally be targeted for the treatment of posterior segment diseases, including, for example, age-related macular degeneration, diabetic retinopathy, diabetic macular edema, and cystic macula. The device can be loaded with a payload of drugs for various types of therapeutic agents for various conditions, some of which include, for example, steroids, antibiotics, NSAIDS, and / or anti-angiogenic agents, or combinations thereof. In situ implantation can improve the efficacy and pharmacokinetics of effective therapeutic agents in the treatment of chronic posterior ocular diseases and minimize side effects for patients in a variety of ways. First, the implant can be placed in the vitreous cavity at the specific disease site, avoiding local or systemic routes, thereby improving drug bioavailability. Second, the implant maintains local therapeutic concentrations at the specific target tissue site for an extended period of time. Third, the number of intravitreal injections will be significantly reduced compared to various conventional systems, thereby reducing the patient's risk of infection, retinal detachment, and transient visual disturbances (white spots suspended in the vitreous), which can occur until the drug in the vitreous moves down to the lower wall of the eye and away from the central vitreous or macula. Conventionally injected drug boluses form in the vitreous and displace the vitreous humor until they disperse. Dispersion typically takes a significant amount of time because the vitreous humor is quite viscous. The bolus can therefore interfere with vision, particularly in response to sudden acceleration (such as when the patient stands up or turns their head quickly) so that the drug moves to the periphery of the eye.

[0095] The hydrogel can be formed in, on, or under the scleral tissue with or without the presence of the conjunctiva. The hydrogel can be bonded to the sclera or other tissues, placed therein to promote drug diffusion through the intended tissue, or provide a stable reservoir to guide the therapeutic agent as needed. In some embodiments, the conjunctiva of the eye can be removed, immersed, dissected, or plucked so that the tissue can be lifted from the sclera to access a specific area of the sclera for implantation or injection of the hydrogel. In other embodiments, the hydrogel is injected into or onto the choroid. The hydrogel is formed in situ, layered, and adhered to the target site. In some embodiments, the hydrogel comprises at least 50%, 75%, 80%, 90%, or 99% w / w water-soluble precursor (calculated by measuring the weight of the hydrophilic precursor and dividing by the weight of all precursors, so that the weight of water or solvent or non-hydrogel components is ignored) to enhance the non-adhesive properties of the hydrogel. In some embodiments, this hydrophilic precursor essentially comprises polyethylene oxide. In some embodiments, agents that reduce tissue adhesion mediated by biological mechanisms including cell mitosis, cell migration, or macrophage migration or activation are included, such as anti-inflammatory agents, anti-mitotic agents, antibiotics, PACLITAXEL, MITOMYCIN, or paclitaxel.

[0096] In some embodiments, the conjunctiva can be punctured or penetrated with a needle, catheter, or trocar, and the precursor introduced into the space between the sclera and conjunctiva, or other spaces within the eye. In some cases, the conjunctiva can be punctured to access a natural potential space between tissues that is filled with the precursor, such as the potential space of the choroid. In other cases, a potential or actual space is mechanically created using a needle, trocar, dilator, or the like, which disrupts the adhesion between tissue layers, allowing for the introduction of the precursor. The conjunctiva is sufficiently elastic to allow useful amounts of precursor to be introduced or forced into such natural or created spaces. Similarly, in the case of intravitreal hydrogel formation, relatively large volumes can also be used. Thus, in some cases, the amount is between about 0.001 and about 5 ml; the skilled artisan will readily understand that all ranges and values within the explicitly stated ranges are contemplated, such as about 1 ml, about 0.005, 0.01, 0.025, or 0.05 ml, or from 0.002 ml to about 1 or 2.5 ml.

[0097] Furthermore, the hydrogel can be easily removed, whether intraocular or periocular, using a vitrectomy cutter if the implant is located in the vitreous cavity, a manual I / A syringe and cannula if the implant is located on the sclera, or an irrigation / aspiration handpiece. This contrasts with the major surgical procedure required to remove some conventional non-absorbable implants.

[0098] In some aspects, the in situ formation of the hydrogel allows the hydrogel to gel or cross-link in place so that it does not flow out through the needle's conduit and does not spread outside the eye through the incision after the needle or cannula is removed. The shape-stable hydrogel thus formed can effectively deliver drugs and can be advantageously of well-controlled size, shape, and surface area. Small needles can be used to inject the material because soluble or flowable precursors can be used instead of already formed materials. In contrast, alternative materials that cannot be quickly and firmly cross-linked after introduction tend to flow out of the incision. Materials that cannot be covalently cross-linked can creep or weep as the material continues to reorganize, causing some or all of the material to flow out.

[0099] Drugs or therapeutic agents for delivery

[0100] Therapeutic agents include, for example, agents for treating conditions that may be caused by inflammatory or abnormal vascular lesions, retinal vein occlusion, geographic atrophy, retinitis pigmentosa, retinoblastoma, and the like.

[0101] The therapeutic agent can be those such as anti-angiogenic, anti-VEGF, blocking VEGFR1, blocking VEGFR2, blocking VEGFR3, anti-PDGF, anti-angiogenesis, sunitinib, E7080, Takeda-6d, Tivozanib, Regorafenib, Sorafenib, Pazopanib, Axitinib, Nintedanib, Cediranib, Vetalanib, motesanib, macrolides, sirolimus, everolimus, tyrosine kinase inhibitors (TKIs), imatinib ( GLEEVAC), gefitinib (IRESSA), toceranib (PALLADIA), erlotinib (TARCEVA), lapatinib (TYKERB), nilotinib, bosutinib, neratinib, lapatinib, vatalanib, dasatinib, erlotinib, gefitinib, imatinib, lapatinib, lestaurtinib, nilotinib, semaxanib, toceranib, and vandetanib.

[0102] The therapeutic agent may include a macromolecule, such as an antibody or antibody fragment. The therapeutic macromolecule may include a VEGF inhibitor, such as ranibizumab, the commercially available Lucentis TMThe active ingredient in VEGF (vascular endothelial growth factor) inhibitors can cause the restoration of abnormal blood vessels and improve vision when released into the vitreous humor of the eye. Examples of VEGF inhibitors include Lucentis TM (ranibizumab), Eylea TM (Aflibercept or VEGFTrap), Avastin TM (bevacizumab), Macugen TM (Pegaptanib). It can also deliver platelet-derived growth factor (PDGF) inhibitors, such as Fovista TM , anti-PGDF aptamer.

[0103] The therapeutic agent can include small molecules, such as corticosteroids and analogs thereof. For example, the therapeutic corticosteroid can include one or more of triamcinolone, triamcinolone acetonide, dexamethasone acetate, fluocinolone acetonide, fluocinolone acetonide or its analogs. Alternatively or in combination, the small molecule of the therapeutic agent can include a tyrosine kinase inhibitor, including one or more of axitinib, bosutinib, cediranib, dasatinib, erlotinib, gefitinib, imatinib, lapatinib, lestaurtinib, nilotinib, semaxanib, sunitinib, tocinib, vandetanib or vatalanib.

[0104] The therapeutic agent may include an anti-VEGF therapeutic agent. Anti-VEGF therapeutic agents and medicaments can be used to treat some cancers and age-related macular degeneration. Examples of anti-VEGF therapeutic agents suitable for use in accordance with the embodiments described herein include one or more of the following: monoclonal antibodies such as bevacizumab (Avastin TM ) or antibody derivatives such as ranibizumab (Lucentis TM ) or small molecules that inhibit VEGF-stimulated tyrosine kinases, such as lapatinib (Tykerb TM ), Sunitinib (Sutent TM ), Sorafenib (Nexavar TM ), axitinib, or pazopanib.

[0105] The therapeutic agent may comprise a therapeutic agent suitable for treating dry AMD, such as Sirolimus TM (rapamycin), Copaxone TM (glatiramer acetate), Othera TM, complement C5aR blocker, ciliary neurotrophic factor, fenretinide or rheopheresis.

[0106] Therapeutic agents may include those suitable for wet AMD, such as REDD14NP (Quark), Sirolimus TM (rapamycin), ATG003; Regeneron TM (VEGF Trap) or complement inhibitor (POT-4).

[0107] The therapeutic agent may include a kinase inhibitor, such as one or more of bevacizumab (monoclonal antibody), BIBW2992 (a small molecule targeting EGFR / Erb2), cetuximab (monoclonal antibody), imatinib (small molecule), trastuzumab (monoclonal antibody), gefitinib (small molecule), ranibizumab (monoclonal antibody), pegaptanib (small molecule), sorafenib (small molecule), dasatinib (small molecule), sunitinib (small molecule), erlotinib (small molecule), nilotinib (small molecule), lapatinib (small molecule), panitumumab (monoclonal antibody), vandetanib (small molecule), or E7080 (a small molecule targeting VEGFR2 / VEGFR2, commercially available from Esai).

[0108] Therapeutic agent can include various types of medicine. Medicine includes for example steroids, nonsteroidal anti-inflammatory drugs (NSAIDS), anticancer drugs, antibiotics, anti-inflammatory drugs (such as diclofenac), acetaminophen (such as bupivacaine), calcium channel blockers (such as nifedipine), antibiotics (such as ciprofloxacin), cell cycle inhibitors (such as simvastatin), proteins (such as insulin). Therapeutic agent includes following drug types, including for example steroids, NSAIDS, antibiotics, acetaminophen, inhibitors of vascular endothelial growth factor (VEGF), chemotherapeutic agents, antiviral drugs. The example of NSAIDS is ibuprofen, meclofenamate sodium (Meclofenamate sodium), mefenamic acid, salsalate, sulindac, tolmetin sodium, ketoprofen, diflunisal, piroxicam, naproxen, etodolac, flurbiprofen, fenoprofen calcium, indomethacin, celecoxib (celoxib), ketorolac (ketrolac) and nepafenac. The drug itself can be a small molecule, protein, RNA fragment, protein, glycosaminoglycan, carbohydrate, nucleic acid, inorganic and organic biologically active compounds, where specific biologically active agents include but are not limited to: enzymes, antibiotics, anti-tumor agents, local anesthetics, hormones, angiogenic agents, anti-angiogenic agents, growth factors, antibodies, neurotransmitters, psychotropic drugs, anti-cancer drugs, chemotherapeutic drugs, drugs affecting reproductive organs, genes and oligonucleotides or other structures.

[0109] Therapeutic agents can include proteins or other water-soluble biological agents. These include peptides and proteins. As used herein, the term protein refers to a peptide of at least about 5000 daltons. As used herein, the term peptide refers to peptides of any size. The term "oligopeptide" refers to a peptide of up to about 5000 daltons in mass. Peptides include therapeutic proteins and peptides, antibodies, antibody fragments, short chain variable fragments (scFv), growth factors, angiogenic factors, and insulin. Other water-soluble biological agents are carbohydrates, polysaccharides, nucleic acids, antisense nucleic acids, RNA, DNA, small interfering RNA (siRNA), and aptamers.

[0110] The therapeutic agent can be used as a method of treating a given condition or as part of a composition for treating a given condition. For example, AZOPT (brinzolamide ophthalmic suspension) can be used to treat elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma. BETADINE in povidone-iodine eye drops can be used to prepare irrigation for the periocular area and ocular surface. BETOPTIC (betaxolol hydrochloride) can be used to lower intraocular pressure or for chronic open-angle glaucoma and / or ocular hypertension. CILOXAN (ciprofloxacin hydrochloride ophthalmic solution) can be used to treat infections caused by susceptible strains of microorganisms. NATACYN (natamycin ophthalmic suspension) can be used to treat fungal blepharitis, conjunctivitis, and keratitis. NEVANAC (nepafenac ophthalmic suspension) can be used to treat pain and inflammation associated with cataract surgery. TRAVATAN (travoprost ophthalmic solution) can be used to lower elevated intraocular pressure—open-angle glaucoma or ocular hypertension. FML FORTE (fluorometholone ophthalmic suspension) is used to treat corticosteroid-responsive inflammation of the tarsal and bulbar conjunctiva, cornea, and anterior segment of the eye. LUMIGAN (bimatoprost ophthalmic solution) is used to reduce elevated intraocular pressure - open-angle glaucoma or ocular hypertension. PRED FORTE (prednisolone acetate) is used to treat steroid-responsive inflammation of the tarsal and bulbar conjunctiva, cornea, and anterior segment of the eye. PROPINE (dipifrine hydrochloride) is used to control intraocular pressure in chronic open-angle glaucoma. RESTASIS (cyclosporine ophthalmic emulsion) is used to increase tear production in patients, such as those with eye inflammation associated with keratoconjunctivitis sicca. ALREX (loteprednol ethyl carbonate ophthalmic suspension) is used for temporary relief of seasonal allergic conjunctivitis. LOTEMAX (loteprednol ethyl carbonate ophthalmic suspension) is used to treat steroid-responsive inflammation of the tarsal and bulbar conjunctiva, cornea, and anterior segment of the eye. MACUGEN (pegaptanib sodium injection) is used to treat neovascular (wet) age-related macular degeneration. OPTIVAR (azelastine hydrochloride) is used to treat itching of the eye associated with allergic conjunctivitis. XALATAN (latanoprost ophthalmic solution) is used to reduce elevated intraocular pressure in patients (e.g., those with open-angle glaucoma or ocular hypertension). BETIMOL (timolol ophthalmic solution) is used to treat elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma. Latanoprost is a prodrug in the free acid form that is a prostaglandin-selective FP receptor agonist. Latanoprost reduces intraocular pressure in patients with glaucoma with minimal side effects. Latanoprost has a relatively low solubility in aqueous solutions but is readily soluble in organic solvents that are commonly used in the preparation of microspheres using solvent evaporation.

[0111] Other embodiments for delivering therapeutic agents include those that specifically bind to the target peptide in vivo to prevent the target peptide from interacting with its natural receptor or other ligands. For example, AVASTIN is an antibody that binds to VEGF. and AFLIBERCEPT is a fusion protein that contains a portion of the VEGF receptor that captures VEGF. IL-1 traps that utilize the extracellular domain of the IL-1 receptor are also known; these traps block IL-1 from binding to and activating receptors on the cell surface. Embodiments of agents for delivery include nucleic acids, such as aptamers. For example, pegaptanib (MACUGEN) is a pegylated anti-VEGF aptamer. The advantage of particle and hydrogel delivery processes is that the aptamers are protected from the in vivo environment until they are released. Additional embodiments of agents for delivery include polymeric drugs, a term referring to drugs that are significantly larger than classic small molecule drugs, i.e., drugs such as oligonucleotides (aptamers, antisense primers, RNAi), ribozymes, gene therapy nucleic acids, recombinant peptides, and antibodies.

[0112] One embodiment includes extended release of a drug for allergic conjunctivitis. For example, ketotifen, antihistamines, and mast cell stabilizers can be provided in particulate form and released into the eye in an effective amount as described herein to treat allergic conjunctivitis. Seasonal allergic conjunctivitis (SAC) and perennial allergic conjunctivitis (PAC) are allergic conjunctivitis. Symptoms include itching and pink to reddish eyes. Both eye conditions are mediated by mast cells. Non-specific measures to improve symptoms typically include: cold compresses, eyewashes containing tear substitutes, and avoiding allergens. Treatment typically consists of antihistamine mast cell stabilizers, dual-mechanism antiallergic agents, or topical antihistamines. Corticosteroids may be effective, but due to side effects, they are reserved for more severe forms of allergic conjunctivitis, such as vernal keratoconjunctivitis (VKC) and atopic keratoconjunctivitis (AKC).

[0113] Moxifloxacin is the active ingredient in VIGAMOX, a fluoroquinolone approved for the treatment or prevention of bacterial infections of the eye. The dosage is typically one drop of a 0.5% solution applied three times daily for one week or longer. VKC and AKC are chronic allergic diseases in which eosinophils, conjunctival fibroblasts, epithelial cells, mast cells, and / or TH2 lymphocytes exacerbate the biochemistry and histology of the conjunctiva. VKC and AKC can be treated with drugs used to treat allergic conjunctivitis. Penetrants are agents that can also be included in gels, hydrogels, organogels, xerogels, and biomaterials as described herein. These are agents that facilitate penetration of the drug into the intended tissue. The penetrant can be selected based on the tissue's needs, for example, penetrants for the skin, penetrants for the tympanic membrane, and penetrants for the eye.

[0114] Eye disease conditions

[0115] Materials described herein can be used to deliver drugs or other therapeutic agents (such as imaging agents or markers) to the eye or near tissue. Some disease states are posterior ocular diseases. The term posterior ocular disease is recognized by those skilled in the art in these fields, and generally refers to any disease that affects the integrity of the vasculature and retina, spots or choroid, thereby causing visual clarity disorder, blindness or blindness in the posterior segment of the eye. Posterior segment disease states can be derived from age, trauma, surgical intervention and genetic factors. Some posterior ocular diseases are age-related macular degeneration (AMD), cystoid macular edema (CME), diabetic macular degeneration (DME), posterior uveitis and diabetic retinopathy. Some posterior ocular diseases are derived from unwanted angiogenesis or vascular proliferation, such as macular degeneration or diabetic retinopathy. Drug treatment selection for these and other conditions is further discussed elsewhere herein.

[0116] Reagent test kit

[0117] A kit or system for preparing a hydrogel around hydrogel / xerogel particles can be prepared such that the hydrogel / xerogel particles containing the therapeutic agent are stored in the kit along with the precursors used to make the encapsulated hydrogel. An applicator can be used in combination therewith. The kit is manufactured using medically acceptable conditions and contains components having pharmaceutically acceptable sterility, purity, and formulation. The solvent / solution can be provided in the kit or separately, or the components can be premixed with the solvent. The kit can include a syringe and / or needle for mixing and / or delivery. The kit or system can include the components described herein. Example

[0118] Some precursors are designated by the nomenclature of naxxKpppfff, where n is the number of arms, xx is the molecular weight (MW), ppp is the polymer, and fff is the functional end group. Thus, 8a15KPEGSAP refers to an 8-arm polyethylene glycol (PEG) with a MW of 15,000 g / mol = 15K PEG. Succinimidyl adipate is SAP. Succinimidyl glutarate is SG. PEG refers to polyethylene oxide and may or may not terminate in an OH group.

[0119] Example 1: Comparison of release kinetics of therapeutic agents from in situ formed hydrogel coatings.

[0120] Materials: Monoclonal antibody (Mab) bevacizumab (MW 149 kDa) entrapped in hydrogel particles. 8a15KSS = 8-arm polyethylene glycol, MW 15,000 Da, each arm capped with a succinimidyl succinate end group. 8a20KNH2 = 8-arm polyethylene glycol, MW 20,000 Da, each arm capped with a free amine (non-salt) end group. 4a20KSAZ = 4-arm polyethylene glycol, MW 20,000 Da, each arm capped with a succinimidyl benzoate end group. 8a20KNH3+Cl- = 8-arm polyethylene glycol, MW 15,000 Da, each arm capped with an ammonium hydrochloride end group. Particle-based hydrogel protein delivery system: Rapidly degrading 8a15KSS / 8a20KNH2 was used to rapidly release the protein from the interior of the hydrogel particles. Envelope: In situ formed 4a20KSAZ / 8a20KNH2 hydrogel.

[0121] method:

[0122] A spray-dried powder of bevacizumab (1.136 g; 27% activated) was suspended in 3.5 ml of 8a20KNH2 solution (11.4% in DMC), sonicated for 15 minutes, and then mixed with 3.5 ml of 8a15KSS solution (8.6% in DMC). Within 15 seconds, a mass of 8a15KSS / 8a20KNH2 organogel in DMC was formed. The organogel was then cured at room temperature for 2 hours and then reduced in size to produce a slurry of organogel particles in DMC. The bevacizumab (Bvcz)-loaded organogel particles were then dried to form particles loaded with Bvcz xerogel.

[0123] Individual samples of "uncoated" Bvcz xerogel particles were mixed with a 1% HA solution and rehydrated (4 hours) to form Bvcz hydrogel particles (10% Bvcz; 10% 8a15KSS / 8a20KNH2; 80% of a 1% HA solution). Samples were injected (using a 21G2 needle) into tared vials and weighed (15 samples: 68.2; 37.1; 36.8; 37.6; 38.5; 43.7; 47.5; 28.0; 39.5; 39.3; 42.8; 42.4; 36.1; 70.5; 77.6 mg). Individual samples were then released in 30 ml of PBS (1×; pH 7.4) and placed (3 samples / time point) for 1; 2; 3; and 9 days.

[0124] Bvcz xerogel particles with an in situ hydrogel envelope were prepared by rehydrating and mixing using syringes. Syringe A contained Bvcz xerogel particles (88.0 mg) and dried 4a20KSAZ polymer (15.3 mg); Syringe B contained 0.4% HA solution (567.5 mg); and Syringe C contained 211 mg of 3.2% 8a20KNH3+Cl- in pH 9.4 buffer (21.5 mg / ml sodium tetraborate decahydrate; 7.1 mg / ml sodium hydrogen phosphate). Using a separate kit (7 samples), Bvcz xerogel particles with an in situ hydrogel envelope were prepared by mixing syringes A and B and then mixing the contents with syringe C to form an envelope around the particles.

[0125] Each sample was transferred to PBS pH 7.4 release medium to determine the release kinetics of Bvcz and compared to that of the uncoated sample. The buffer was changed at 42, 68, 100, 119, 142, and 288 hours.

[0126] The in vitro kinetics of Bvcz sustained release from xerogel particles with and without an “in situ formed” hydrogel coating were then tested. Figure 4 Throughout the in vitro release experiments, the coating envelope remained intact, so that the protein was forced to pass through the envelope to reach the release medium.

[0127] Example 2: Comparison of in-vitreous tolerance of hydrogel particles with and without an envelope.

[0128] Hydrogel formulations with and without an envelope ("Encapsulated") were tested in vivo. OTX-13 represents particles with an envelope, and OTX-14 represents particles without an envelope.

[0129] Materials 8a5KSG = 8-arm polyethylene glycol, MW 5,000 Da, each arm terminated with a succinimidyl glutarate end group. 8a10KSG = 8-arm polyethylene glycol, MW 10,000 Da, each arm terminated with a succinimidyl glutarate end group. 8a5KNH2 = 8-arm polyethylene glycol, MW 5,000 Da, each arm terminated with a free amine (non-salt) end group. 4a20KSAZ = 4-arm polyethylene glycol, MW 20,000 Da, each arm terminated with a succinimidyl benzoate end group. 8a20KNH3+Cl- = 8-arm polyethylene glycol, MW 15,000 Da, each arm terminated with an ammonium hydrochloride end group.

[0130] method

[0131] Aliquots of 8a5KNH2 (30% in DMC) and 8a5KSG (30% in DMC) were mixed in a 1:1 ratio using a syringe to form a block of 8a5KSG / 8a5KNH2 organogel in DMC. The organogel block was then cured at room temperature for 2 hours and then reduced in size to produce a slurry of organogel particles in DMC. The resulting blank organogel particles in DMC were then dried to form blank 8a5KSG / 8a5KNH2 xerogel particles. Aliquots of 8a5KNH2 (20% in DMC) and 8a10KSG (40% in DMC) were mixed in a 1:1 ratio using a syringe to form a block of 8a10KSG / 8a5KNH2 organogel in DMC. The organogel block was then cured at room temperature for 2 hours and then reduced in size to produce a slurry of organogel particles in DMC. The resulting blank organogel particles in DMC were then dried to form 8a10KSG / 8a5KNH2 xerogel blank particles.

[0132] OTX-14 (uncoated) was prepared by weighing 8a5KSG / 8a5KNH2 (72.8 mg) and 8a10KSG / 8a5KNH2 (48.5 mg) xerogel blank particles in syringe A and Provisc (519.3 mg; 1% HA) in syringe B, and then mixing syringes A and B, where OTX-14 was ready for intravitreal injection.

[0133] OTX-13 (coated) was prepared by weighing 8a5KSG / 8a5KNH2 (58.7 mg) and 8a10KSG / 8a5KNH2 (42.4 mg) xerogel blank particles and 4a20KSAZ (16.2 mg) into syringe A; filling syringe B with diluted PROVISC (664.3 mg; 0.41% HA in PBS, pH 7.4); and filling syringe C with 8a20KNH3+Cl- (257 mg; 3.2% in pH 10.0 buffer: 21.5 mg / ml sodium tetraborate decahydrate; 7.1 mg / ml sodium phosphate dibasic). A single injection was prepared by mixing syringes A and B for 1 minute, then mixing with syringe C for 10 seconds to initiate the reaction. At this point, the mixture was transferred to a 100 μl syringe for intravitreal injection. 25 μl was injected. Injected rabbits were sacrificed on days 28 and 56, and eyes were collected for histopathological analysis. Any abnormalities in the tissues were scored on a semiquantitative scale of 0-5.

[0134]

[0135] At both time points, intravitreal injection of OTX-13 resulted in slightly less vitreous inflammation compared to OTX-14. Both formulations produced a similar, typically minimal, inflammatory response in the vitreous cavity surrounding the injected test material, with scattered macrophages observed within the vitreous cavity. Rarely, this inflammation minimally extended into the retina or sclera. Periretinally, OTX-13 demonstrated a significantly lower inflammatory response compared to OTX-14 (Table 2: 0.02-0.03 compared to 0.1-0.2).

[0136] Table 2

[0137]

[0138] Intravitreal injection of OTX-13 and OTX-14 resulted in similar, typically minimal fibrosis surrounding the implanted material within the vitreous cavity. Mean scores for OTX-13 were slightly decreased compared with those for OTX-14 at both time points.

[0139] Intravitreal injections of OTX-13 and OTX-14 produced similar typical minimal epithelial hyperplasia and inflammatory responses in the epithelium just anterior to the ora serrata. Mean scores for OTX-13 were slightly different compared with those for OTX-14 at both time points.

[0140] Table 3

[0141]

[0142] Further Disclosure

[0143] 1a. A biomedical sustained-release system for use in a patient, comprising:

[0144] A collection of particles and a second material that is a hydrogel or xerogel, the collection of particles comprising a first biodegradable material that is a hydrogel or xerogel and a therapeutic agent, wherein the first material has a release rate for the therapeutic agent in a physiological solution before biodegradation, and the second material at least partially coats the collection of particles. Alternatively, an implant, a medical device, a drug reservoir, an intraocular drug reservoir, a fiber, a xerogel fiber, a prosthesis, an object in contact with a physiological fluid, or a biomaterial comprising a first hydrogel or xerogel material is coated with the second material. Similarly, a biomedical sustained-release system for a patient comprises a collection of particles and a second material that is a hydrogel or xerogel, the collection of particles comprising a first biodegradable material that is a hydrogel or xerogel and a therapeutic agent, wherein the first material has a first release rate for the therapeutic agent measured in a physiological solution before biodegradation, and the second material at least partially coats the collection of particles. The release can be, for example, from a few days to a few months, such as six days to 365 days; the skilled person will immediately understand that all ranges and values between the explicitly stated limits are contemplated, for example, any of the following can be used as an upper or lower limit: 6, 14, 30, 60, 90, 120, 180, 240, 300 or 360 days.

[0145] 1b. A biomedical sustained-release system for use in a patient, comprising: a first biodegradable material that is a hydrogel or xerogel and a therapeutic agent, wherein the first material has a release rate for the therapeutic agent measured in a physiological fluid prior to biodegradation; and a second material that is a hydrogel or xerogel at least partially coating the first material, wherein the second material delays the release rate of the therapeutic agent by no more than 20% at 50% w / w release of the therapeutic agent. Alternatively, an implant, medical device, drug reservoir, intraocular drug reservoir, fiber, xerogel fiber, prosthesis, object in contact with physiological fluid, or biological material comprising the first hydrogel or xerogel material is at least partially coated with the second material.

[0146] 1c. The system of claim 1b, wherein the first material and the second material are xerogels.

[0147] 1d. The system of claim 1b, wherein the second material comprises precursors that react with each other in response to a physiological solution to form a covalently cross-linked hydrogel.

[0148] 1e. The system of any one of 1b-1d, wherein the first material is in the form of a rod, a punctal plug, an intraocular drug reservoir or an intraocular implant having a size in the range of 1-10 mm, or a monolithic (single-piece) medical implant or a combination thereof.

[0149] 2. The system of 1 (see 1a, 1b, 1c, etc.), wherein the second material delays the release rate of the pharmaceutical agent by no more than 20% when measured at 50% w / w release of the pharmaceutical agent.

[0150] 3. A system as described in 1 or 2, wherein the solids content of the second material is lower than the solids content of the particles or other coating and is in the range of about 2.5% to about 20%, including all ranges and values therebetween, such as about 2.5% to about 10%, about 5% to about 15%, or less than about 10%-20%.

[0151] 4. A system as described in any of 1-3, wherein the hydrogel is covalently cross-linked and the molecular weight between cross-links of the second material is lower than the distance between cross-links of the particles or other coating and is at least 2000, at least 4000, or 2000-250,000; the skilled person will immediately understand that all ranges and values between the explicitly stated limits are contemplated, for example, any of the following can be used as upper or lower limits: 3000, 5000, 10,000, 500,000, 100,000.

[0152] 5. The system of any one of 1-4, wherein the molecular weight of the therapeutic agent is in the range of about 200 Da to about 400 kDa, or wherein the therapeutic agent has a molecular weight (MW) of no more than about 250 kDa. Alternatively, the molecular weight of the agent is no more than about 205 kDa.

[0153] 6a. The system of any one of 1-5, wherein the release rate measured at 50% w / w release of the agent is delayed by no more than 10%, or - by no more than about 15%, about 5%, or about 1%.

[0154] 6b. The system of any one of 1-5, wherein the release rate is described as a graph of the cumulative percentage (w / w) of the agent released over time, wherein the delay at all points of the graph between 10% and 50% w / w cumulative release is no more than about 20%, or - no more than about 1%, about 5%, or about 10%.

[0155] 6c. The system of any one of 1-5, wherein the release rate is described as a graph of the cumulative percentage (w / w) of the pharmaceutical agent released over time, wherein the delay at all points on the graph between 0% and 90% w / w cumulative release is no more than about 20%, or - no more than about 1%, about 5%, about 10%, or about 15%.

[0156] 7. The system of any one of 1-6, wherein the second material encapsulates the first material and the collection of particles.

[0157] 8. The system of any one of 1-7, wherein the second material is free of the therapeutic agent until the agent diffuses from the particles into the second hydrogel.

[0158] 9. The system of any one of 1-8, wherein the diffusion rate of the therapeutic agent in the second material is about 4 times to about 20 times the diffusion rate of the agent through the first material.

[0159] 10. The system of any one of 1-9, wherein the therapeutic agent comprises a protein of at least about 1000 Da.

[0160] 11. The system of any one of 1-10, wherein the therapeutic agent comprises a water-soluble biologic.

[0161] 12. The system of 11, wherein the water-soluble biologic is a protein having a molecular weight of at least about 10,000 Daltons and a carbohydrate attached to the protein.

[0162] 13a. The system of any one of 1-12, wherein the therapeutic agent is a protein and the first hydrogel comprises solid particles of the protein.

[0163] 13b. The system of any one of 1-12, wherein the therapeutic agent is an aptamer and the first hydrogel comprises solid particles of the aptamer.

[0164] 14. The system of any one of 1-12, wherein the therapeutic agent is selected from a fluoroquinolone, moxifloxacin, travoprost, dexamethasone, an antibiotic, or a vestibulotoxin.

[0165] 15. The system of any one of claims 1-12, wherein the therapeutic agent comprises a small molecule drug, a protein, a nucleic acid, or a growth factor.

[0166] 16. The system of any one of 1-12, wherein the therapeutic agent comprises an anti-VEGF drug.

[0167] 17. The system of any one of 1-12, wherein the particles in the collection have a diameter of about 4 μm. 3 to about 4mm 3 Alternatively, having a diameter of about 1 micron to about 1.5 mm or a diameter of 5 to 500 microns.

[0168] 18. The system of any one of 1-12, wherein the average volume of the particles in the aggregate is about 0.02 μm 3 to about 1mm 3 .

[0169] 19. The system of any of 1-12, having a total volume of about 0.005 to about 0.2 milliliters.

[0170] 20. The system of any one of 1-12, wherein the collection of particles is dispersed within the second material.

[0171] 21. The system of 20, having a monomer having a total volume of about 0.005 and 0.1 ml and a thickness of about 0.1 to about 10,000 microns. The skilled artisan will immediately understand that all ranges and values within this range are contemplated and supported.

[0172] 22. The system of any one of 1-21, wherein the first material and the second material are hydrolytically biodegradable by water.

[0173] 23. The system of any one of 1-22, wherein the first material and the second material are synthetic.

[0174] 24. The system of any one of 1-23, wherein

[0175] The first material includes a first precursor comprising a first functional group and a second precursor comprising a second functional group, wherein the first functional group and the second functional group form a covalent crosslink, and

[0176] The second material includes a third precursor comprising a third functional group and a fourth precursor comprising a fourth functional group, wherein the third functional group and the fourth functional group form a covalent crosslink.

[0177] 25. The system of 24, wherein before the reaction, the first to fourth functional groups are selected from electrophilic groups and nucleophilic groups.

[0178] 26. The system of 25, wherein the electrophilic group comprises succinimide, succinimide ester, N-hydroxysuccinimide, maleimide, succinate, nitrophenyl carbonate, aldehyde, vinyl sulfone, azide, hydrazide, isocyanate, diisocyanate, tosyl, tresyl, or carbonyldiimidazole.

[0179] 27. The system of 25, wherein the nucleophilic group comprises a primary amine or a primary thiol.

[0180] 28. The system of any one of 24-27, wherein the first to fourth precursors are water soluble prior to covalent cross-linking.

[0181] 29. The system of any one of 24-28, wherein the first to fourth precursors are synthetic.

[0182] 30. The system of any one of 24-29, wherein the first to fourth precursors each contain no more than five amino acids.

[0183] 31. The system of any one of 24-30, wherein the first to fourth precursors are hydrophilic polymers.

[0184] 32. The system of any one of 24-31, wherein at least one of the first to fourth precursors comprises a polymer selected from the group consisting of polyethylene glycol, polyacrylic acid, polyvinyl pyrrolidone, and block copolymers thereof.

[0185] 33. The system of any one of 24-32, wherein at least one of the first to fourth precursors comprises a polymer selected from the group consisting of alginate, gellan gum, collagen, and polysaccharides.

[0186] 34. A method of treating a patient, optionally a patient suffering from an eye disease, comprising

[0187] providing a collection of particles comprising a first biodegradable material that is a hydrogel or xerogel and a therapeutic agent, wherein the first material has a release rate for the therapeutic agent in a physiological solution prior to biodegradation, and

[0188] A second hydrogel is formed in situ at the intended site of use on the patient's tissue (optionally on or near the eye) that at least partially coats the assembly of particles. The pharmaceutical agent is released to treat the patient.

[0189] 35. The method of 34, wherein the second material delays the release rate of the pharmaceutical agent by no more than 20% when measured at 50% w / w release of the pharmaceutical agent.

[0190] 36. A method as described in claim 34 or 35, wherein the solids content of the second material is lower than the solids content of the particles or other coating and is in the range of about 2.5% to about 20%, including all ranges and values therebetween, such as about 2.5% to about 10%, about 5% to about 15%, or less than about 10%-20%, as a percentage of w / w.

[0191] 37. The method of any of 34-36, wherein the hydrogel is covalently cross-linked and the molecular weight between cross-links of the second material is lower than the solids content of the particles or other coating and is at least 2000, at least 4000, or 2000-250,000; the skilled artisan will immediately understand that all ranges and values between the explicitly stated limits are contemplated, for example any of the following may be an upper or lower limit: 3000, 5000, 10,000, 500,000, 100,000.

[0192] 38. The method of any one of 34-37, wherein the second hydrogel is formed in the suprachoroidal space.

[0193] 39. The method of any one of 34-38, wherein the molecular weight (MW) of the therapeutic agent is no more than about 400 kDa. Alternatively, the molecular weight of the agent is no more than about 250 kDa.

[0194] 40a. The method of any of 34-39, wherein the release rate is delayed by no more than about 10%, or no more than about 15%, about 5%, or about 1% as measured when 50% w / w of the agent is released.

[0195] 40b. The method of any one of 34-39, wherein the release rate is described as a graph of the cumulative percentage (w / w) release of the pharmaceutical agent over time, wherein the delay at all points in the graph between 10% and 50% w / w cumulative release is no more than about 10%, or - no more than about 1%, about 5%, about 20%, or about 10%.

[0196] 40c. The method of any one of 34-39, wherein the release rate is described as a graph of the cumulative percentage (w / w) release of the pharmaceutical agent over time, wherein the delay at all points in the graph between 10% and 90% w / w cumulative release is no more than about 20%, or - no more than about 1%, about 5%, about 10%, or about 15%.

[0197] 41. The method of any one of 34-40, wherein the second material encapsulates the first material and the collection of particles and / or wherein the second material is free of the therapeutic agent until the agent diffuses from the particles into the second hydrogel.

[0198] 42. The method of any one of 34-41, wherein the diffusion rate of the therapeutic agent in the second material is about 4 to about 20 times the diffusion rate of the agent in the first material.

[0199] 43. The method of any one of 34-42, wherein the therapeutic agent comprises a protein of at least about 1000 Da and / or wherein the therapeutic agent comprises a water-soluble biologic.

[0200] 44. The method of any one of 34-43, wherein the water-soluble biologic is a protein having a molecular weight of at least about 10,000 Daltons and a carbohydrate associated with the protein.

[0201] 45. The method of any one of claims 34-44, wherein the therapeutic agent is a protein and the first hydrogel comprises solid particles of the protein or wherein the therapeutic agent is an aptamer and the first hydrogel comprises solid particles of the aptamer.

[0202] 46. The method of any one of 34-45, wherein the therapeutic agent is selected from a fluoroquinolone, moxifloxacin, travoprost, dexamethasone, an antibiotic, or a vestibular toxin.

[0203] 47. The method of any one of 34-46, wherein the therapeutic agent comprises a small molecule drug, a protein, a nucleic acid, or a growth factor.

[0204] 48. The method of any one of 34-47, wherein the therapeutic agent comprises an anti-VEGF or anti-angiogenic drug.

[0205] 49. The method of any one of 34-48, wherein the particles in the collection have a diameter of about 4 μm. 3 to about 4mm 3 Alternatively, the diameter is from about 1 micron to about 1.5 mm or from 5 to 500 microns.

[0206] 50. The method of any one of 34-49, wherein the average volume of the particles in the collection is about 400 μm 3 to about 4mm 3 .

[0207] 51. The method of any one of 34-50, having a total volume of about 0.005 to about 2.5 milliliters.

[0208] 52. The method of any one of 34-51, wherein the collection of particles is dispersed within a second material.

[0209] 53. The method of any one of 34-52, which is a single mass having a total volume of about 0.005 and 0.1 milliliters and a thickness of about 0.1 to about 10,000 microns. The skilled artisan will immediately understand that all ranges and values within this range are contemplated and supported.

[0210] 54. The method of any one of 34-53, wherein the first material and the second material are capable of hydrolytically biodegrading by passage of water through the channel.

[0211] 55. The method of any one of claims 34-54, wherein the first material and the second material are synthetic.

[0212] 56. as the method described in any one of 34-55, wherein said first material comprises the first precursor comprising the first functional group and the second precursor comprising the second functional group, said first functional group and said second functional group form covalent crosslinking, and said second material comprises the third precursor comprising the third functional group and the fourth precursor comprising the fourth functional group, said third functional group and the fourth functional group form covalent crosslinking. Various precursors and functional groups can be the same or different from each other.

[0213] 57. The method of 56, wherein before the reaction, the first to fourth functional groups are selected from electrophilic groups and nucleophilic groups.

[0214] 58. methods as described in 56 or 57, wherein the electrophilic group is independently selected from one or more of succinimide, succinimide ester, N-hydroxysuccinimide, maleimide, succinate, nitrophenyl carbonate, aldehyde, vinyl sulfone, azide, hydrazide, isocyanate, diisocyanate, tosyl, trifluoroethanesulfonyl or carbonyldiimidazole.

[0215] 59. The method of 56 or 57, wherein the nucleophilic group comprises a primary amine or a primary thiol.

[0216] 60. The method of 56, wherein the first to fourth precursors are water-soluble before covalent cross-linking.

[0217] 61. The method of any one of claims 56-60, wherein the first to fourth precursors are synthetic.

[0218] 62. The method of any one of 56-60, wherein the first to fourth precursors each contain no more than five amino acids.

[0219] 63. The method of any one of claims 56-60, wherein the first to fourth precursors are hydrophilic polymers.

[0220] 64. The method of any one of 56-60, wherein at least one of the first to fourth precursors comprises a polymer selected from the group consisting of polyethylene glycol, polyacrylic acid, polyvinyl pyrrolidone, and block copolymers thereof.

[0221] 65. The method of any one of 56-60, wherein at least one of the first to fourth precursors comprises a polymer selected from the group consisting of alginate, gellan gum, collagen, and polysaccharides.

[0222] 66. methods as described in any one of 56-65, wherein process patient's tissue, or form hydrogel in situ on tissue.Tissue includes for example eyes, lacrimal point, intraocular, subconjunctival, sclera, suprachoroidal, posterior eyeball, eyeball fascia capsule position.

[0223] 67. Use of a system for treating an eye disease or other condition, comprising the system of any one of 1-33 or the method of any one of 34-66 above.

[0224] 68. Use of the system of any one of 1-33 or the method of any one of 34-66 for (controlled release and) delivery of a therapeutic agent to a patient.

[0225] The present invention also relates to:

[0226] 1. A method of treating a patient, comprising

[0227] providing a collection of particles comprising a first biodegradable material that is a hydrogel or xerogel and a therapeutic agent, wherein the first material has a release rate for the therapeutic agent measured in a physiological solution prior to biodegradation, and

[0228] A second hydrogel is formed in situ on the patient's tissue, at least partially coating the assembly of particles, and the pharmaceutical agent is subsequently released to treat the patient.

[0229] 2. The method of embodiment 1, wherein the solids content of the second material is lower than the solids content of the particles and is in the range of about 2.5% to about 20% w / w.

[0230] 3. The method of embodiment 1 or 2, wherein the hydrogel is covalently cross-linked and the molecular weight between the cross-links of the second material is lower than the solids content of the particle or other coating and is at least 2000 Da.

[0231] 4. The method of any one of embodiments 1-3, wherein the second material delays the release rate of the pharmaceutical agent by no more than 20% measured when the pharmaceutical agent is released at 50% w / w.

[0232] 5. The method of any one of embodiments 1-4, wherein the second material is free of the therapeutic agent until the agent diffuses from the particles into the second hydrogel.

[0233] 6. The method of any one of embodiments 1-4, wherein the agent is a protein.

[0234] 7. The method of any one of embodiments 1-6, wherein the particles have a diameter in the range of about 1 to about 100 microns in diameter.

[0235] 8. The method of any one of embodiments 1-7, wherein the collection of particles is delivered in the presence of a precursor using a syringe or catheter, wherein the precursor coats the particles and forms a hydrogel in situ.

[0236] 9. The method of any one of embodiments 1-8, wherein the tissue is an eye and the hydrogel is formed within the eye.

[0237] 10. A biomedical sustained release system for a patient, comprising

[0238] an assembly of particles comprising a first biodegradable material that is a hydrogel or xerogel and a therapeutic agent, wherein the first material, prior to biodegradation, has a release rate for the therapeutic agent as measured in a physiological solution, and

[0239] A second material that is a hydrogel or xerogel at least partially coats the collection of particles, wherein the second material delays the release rate of the agent by no more than 20% when measured at 50% w / w release of the agent.

[0240] 11. The system of embodiment 10, wherein the second material has a lower solids content than the particles, and wherein the second material has a solids content in a range from about 2.5% to about 20% w / w.

[0241] 12. The system of embodiment 10 or 11, wherein the hydrogel is covalently cross-linked and the molecular weight between cross-links of the second material is lower than the distance between cross-links of the particles and is at least 3000.

[0242] 13. The system of any one of embodiments 11-12, wherein the release rate measured when 50% w / w of the agent is released is delayed by no more than 10%.

[0243] 14. The system of any one of embodiments 11-13, wherein the therapeutic agent is a protein.

[0244] 15. A system according to any one of embodiments 11-14, wherein the first material includes a first precursor including a first functional group and a second precursor including a second functional group, wherein the first functional group and the second functional group form a covalent crosslink, and the second material includes a third precursor including a third functional group and a fourth precursor including a fourth functional group, wherein the third functional group and the fourth functional group form a covalent crosslink.

[0245] 16. The system of embodiment 15, wherein the first to fourth functional groups before the reaction are selected from electrophilic groups and nucleophilic groups.

[0246] 17. The system of embodiment 15 or 16, wherein the first to fourth precursors are water soluble prior to covalent cross-linking.

[0247] 18. A biomedical sustained-release system for a patient, comprising:

[0248] a first biodegradable material that is a hydrogel or xerogel and a therapeutic agent, wherein the first material has a release rate for the therapeutic agent measured in a physiological solution prior to biodegradation, and

[0249] A second material that is a hydrogel or xerogel at least partially coats the first material, wherein the second material delays the release rate of the pharmaceutical agent by no more than 20% when measured at 50% w / w release of the pharmaceutical agent.

[0250] 19. The system of embodiment 18, wherein the first material and the second material are xerogels.

[0251] 20. The system of embodiment 18 or 19, wherein the second material comprises precursors that react with each other in response to a physiological solution to form a covalently cross-linked hydrogel.

[0252] 21. The system of any one of embodiments 19-20, which is an intraocular drug depot.

[0253] 22. Use of the system according to any one of embodiments 11-20 to deliver a pharmaceutical agent to a patient.

Claims

1. Use of a collection of biodegradable xerogel particles and a hydrogel precursor in the preparation of an implant for treating a patient, wherein delivering the combination of the hydrogel precursor and the collection of biodegradable xerogel particles to the patient, wherein When the hydrogel precursor is combined with the particle assembly, the hydrogel precursor is covalently cross-linked in situ to form an envelope hydrogel, which encapsulates the biodegradable xerogel particle assembly to form an envelope structure. wherein the coated hydrogel is biodegradable and does not contain a therapeutic agent separate from the biodegradable xerogel particles, and wherein the biodegradable xerogel particles form biodegradable hydrogel particles upon delivery to a patient and contain a therapeutic agent, wherein the biodegradable hydrogel particles are designed to have a desired release rate of the therapeutic agent upon implantation in a patient, wherein the release rate of the therapeutic agent is measurable upon hydration in a physiological solution at 50% w / w release of the agent, whereupon the therapeutic agent is released to treat the patient, and wherein the encapsulated hydrogel delays the release rate of the therapeutic agent by no more than 20%, such that the release rate of the therapeutic agent from the encapsulated structure is approximately determined by the xerogel particles, And the biocompatibility of the envelope structure is higher than the biocompatibility of the biodegradable hydrogel particle assembly.

2. The method according to claim 1, wherein the release rate of the therapeutic agent from the encapsulated structure is not changed from an expected value.

3. Use according to claim 1 or 2, wherein the higher biocompatibility of the encapsulated structure is measured by lower inflammation at the delivery site.

4. The use according to any one of claims 1 to 3, wherein the solids content of the coated hydrogel is lower than the solids content of the biodegradable hydrogel particles and is in the range of about 2.5% to about 20% w / w.

5. The use according to any one of claims 1 to 4, wherein the molecular weight between the cross-linked bonds of the coated hydrogel is at least 2000 Da.

6. The use according to any one of claims 1 to 5, wherein the coated hydrogel does not contain the therapeutic agent until the therapeutic agent diffuses from the particle into the coated hydrogel.

7. The use according to any one of claims 1 to 3, wherein the therapeutic agent is selected from a protein, a nucleic acid, a growth factor, a fluoroquinolone, moxifloxacin, travoprost, dexamethasone, an antibiotic, a vestibular toxin, an anti-VEGF drug, an aptamer or a monoclonal antibody.

8. The use according to any one of claims 1 to 7, wherein the biodegradable hydrogel particles have a diameter in the range of about 1 to about 100 microns.

9. The use according to any one of claims 1 to 8, wherein the collection of biodegradable xerogel particles is delivered using a syringe or a catheter in the presence of a precursor, wherein the precursor coats the particles and forms a hydrogel in situ.

10. The use according to any one of claims 1 to 9, wherein the encapsulated hydrogel is formed in the eye.

11. A biomedical sustained-release composition for a patient comprising an assembly of particles comprising a first biodegradable material that is a xerogel and a therapeutic agent, wherein the assembly of particles is designed to have a desired release rate of the therapeutic agent after implantation in a patient, wherein the release rate of the therapeutic agent is measured at 50% w / w release of the agent in a physiological solution, and A second material that is a hydrogel without a therapeutic agent, which encapsulates the particles and collects them in the hydrogel of the second material to form an encapsulated structure, wherein the second material is biodegradable, The coating hydrogel delays the release rate of the therapeutic agent by no more than 20%, so that the release rate of the therapeutic agent from the coating structure is roughly determined by the particle assembly, wherein the biocompatibility of the coating structure is higher than the biocompatibility of the particle assembly.

12. The composition of claim 11, wherein the release rate of the therapeutic agent from the encapsulated structure is unchanged from an expected value.

13. A composition according to claim 11 or 12, wherein the solids content of the hydrogel of the second material is lower than the solids content of the particles and the solids content of the hydrogel of the second material is in the range of about 2.5% to about 20% w / w.

14. The composition of any one of claims 11 to 13, wherein the hydrogel of the second material is covalently cross-linked and has a molecular weight between cross-links of at least 3000 Da.

15. The composition of any one of claims 11-14, wherein the release rate of the therapeutic agent from the envelope structure is no more than 10% lower than the release rate from the collection of particles.

16. The composition of any one of claims 11-15, wherein the therapeutic agent is selected from a protein, a nucleic acid, a growth factor, a fluoroquinolone, moxifloxacin, travoprost, dexamethasone, an antibiotic, a vestibular toxin, an anti-VEGF drug, an aptamer, or a monoclonal antibody.

17. The composition of any one of claims 11 to 16, wherein the first material comprises a first precursor comprising a first functional group and a second precursor comprising a second functional group, wherein the first functional group and the second functional group form a covalent crosslink, and the second material comprises a third precursor comprising a third functional group and a fourth precursor comprising a fourth functional group, wherein the third functional group and the fourth functional group form a covalent crosslink and wherein the first to fourth functional groups before the reaction are selected from electrophilic groups and nucleophilic groups.

18. The composition of claim 17, wherein the first to fourth precursors are water soluble prior to covalent cross-linking.

19. Use of a composition according to any one of claims 11 to 18 in the preparation of an implant for delivery to a patient.

20. A biomedical sustained release system for a patient comprising a collection of xerogel particles comprising a first biodegradable material that is a xerogel, a therapeutic agent, and a hydrogel precursor for preparing a covalently cross-linked hydrogel surrounding the xerogel particles in a physiological solution. wherein the coated hydrogel is free of therapeutic agent and is biodegradable, and wherein the coated hydrogel delays the release rate of the therapeutic agent by no more than 20%, as measured when 50% w / w of the therapeutic agent is released, wherein the delay is the time between the release curves of the coated particles and the non-coated particles.

21. The system according to claim 20, further comprising one or more of: an applicator for applying the mixture of the xerogel particles and the precursor, a solvent for the hydrogel precursor, and a needle for delivering the mixture of the xerogel particles and the precursor.

22. The system of claim 20 or 21, wherein the hydrogel precursor comprises a first precursor comprising a first functional group and a second precursor comprising a second functional group, wherein the first functional group and the second functional group form covalent crosslinks in a physiological solution, and wherein the first and second precursors are water-soluble prior to covalent crosslinking.

23. The system of claim 22, wherein the encapsulating hydrogel is formed around the xerogel particles after the xerogel particles are mixed with a hydrogel precursor and the hydrogel precursor is crosslinked.

Images