Drug-loaded microbead compositions, embolic compositions and related methods

Abstract

To provide microbeads for chemoembolization, methods for preparing the microbeads, and embolization therapy using the microbeads.SOLUTION: Drug-loaded microbead compositions include microbeads of a water-swellable polymer material, and a complex of a carrier and a therapeutic agent chemically bonded to the carrier. The complex is embedded in the polymer material. The therapeutic agent is not chemically bonded to the water-swellable polymer material. The drug-loaded microbead composition has a water content of less than 1 wt.% based on the total weight of the drug-loaded microbead composition. The drug-loaded microbead composition may be rehydrated to form an embolization composition for use in embolization therapy. Methods for preparing the drug-loaded microbead composition and the embolization composition include loading a therapeutic agent into a water-swellable polymer material to form microbeads, and then removing water from the microbeads.SELECTED DRAWING: None

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001]

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 62 / 607,080, filed December 18, 2017, the entire disclosure of which is incorporated herein by reference. [Technical Field]

[0002] FIELD OF THE DISCLOSURE

[0002] This disclosure relates to microbeads for chemoembolization, methods of preparing the microbeads, and methods of using the microbeads. [Background technology]

[0003] Embolization therapy is a minimally invasive procedure performed by interventional radiologists. A typical treatment may involve entering the vasculature through a small incision in, for example, an arm or leg, and reaching the treatment site through the use of a guidewire and catheter, optionally aided by imaging techniques such as fluoroscopy. The embolic agent at the treatment site occludes blood vessels, blocking blood flow from the treatment site to the tumor downstream, resulting in tumor necrosis and / or shrinkage.

[0004] The choice of embolic agent for embolization therapy depends on the desired clinical outcome and the specific properties of the embolic agent. Clinically used embolic agents generally have drawbacks. First, embolic agents are provided without preloaded drug, meaning that physicians must order the embolic agent from a pharmacy well in advance of surgery, typically at least 24 hours before surgery. Second, embolic agents have suboptimal pharmacokinetic release profiles that cause the release of drug to the target treatment site to cease after only a few days, typically within about three days of implantation.

[0005]

[0005] Thus, there is a continuing need for embolic agents and embolic therapies that allow for high efficiency in the preparation of embolic agents and also provide sustained, long-term delivery of therapeutic agents to the embolization site. Summary of the Invention

[0006]

[0006] Accordingly, embodiments of the present disclosure include a drug-loaded microbead composition, a method for preparing the drug-loaded microbead composition, an embolic composition prepared from the drug-loaded microbead composition, a method for preparing the embolic composition, and a method for treating disease with the embolic composition.

[0007]

[0007] According to an embodiment, a drug-loaded microbead composition may include microbeads made of a water-swellable polymeric material and a conjugate including a carrier and a therapeutic agent chemically bonded to the carrier. In the drug-loaded microbead composition, the conjugate is embedded within the polymeric material. The drug-loaded microbead composition has a water content of less than 1 wt. % based on the total weight of the drug-loaded microbead composition.

[0008]

[0008] According to embodiments, a method for preparing a drug-loaded microbead composition may include dissolving a carrier and a therapeutic agent in an aqueous solvent to form an initial mixture containing a complex of the carrier and the therapeutic agent. The method may further include combining the initial mixture with a first solvent composition in which the therapeutic agent is less soluble than in the aqueous solvent to form a second mixture, and rapidly stirring the second mixture to form particles of the complex in the second mixture. The method may further include combining the particles of the complex with a hydrogel of a water-swellable polymeric material to form a hydrogel mixture; combining the hydrogel mixture with the second solvent composition to form a synthesis mixture; and rapidly stirring the synthesis mixture to form drug-loaded microbeads in the synthesis mixture; and recovering the drug-loaded microbeads from the synthesis mixture. The method may include removing water from the drug-loaded microbeads to form a hydrogel mixture. The method may further comprise forming a drug-loaded microbead composition having a water content of less than 1 wt. % based on the total weight of the drug-loaded microbeads in the drug-loaded microbead composition.

[0009] According to an embodiment, a method for preparing a drug-loaded microbead composition may include dissolving a carrier and a therapeutic agent in an aqueous solvent to form an initial mixture containing a complex of the carrier and the therapeutic agent; combining the initial mixture with a hydrogel solution of a water-swellable polymeric material to form a hydrogel mixture; combining the hydrogel mixture with a solvent composition to form a synthesis mixture; rapidly stirring the synthesis mixture to form drug-loaded microbeads in the synthesis mixture; and recovering the drug-loaded microbeads from the synthesis mixture. The method may further include drying the drug-loaded microbeads to form a drug-loaded microbead composition having a water content of less than 1 wt. % based on the total weight of the drug-loaded microbeads in the drug-loaded microbead composition.

[0010] According to embodiments, an embolic composition may include a drug-loaded microbead composition according to any embodiment of the present disclosure in combination with an aqueous solution in an amount sufficient to swell the drug-loaded microbeads of the drug-loaded microbead composition, wherein the swelled drug-loaded microbeads have a water content of 50% to 95% by weight, based on the total weight of the drug-loaded microbeads.

[0011] According to embodiments, a method for preparing an embolic composition may include adding a drug-loaded microbead composition according to any embodiment of the present disclosure, or a drug-loaded microbead composition produced by a method for preparing a drug-loaded microbead composition according to any embodiment of the present disclosure, to an aqueous solution in an amount sufficient to swell the drug-loaded microbeads of the drug-loaded microbead composition to form a ready-to-inject solution. In the embolic solution produced by such a method, the swollen drug-loaded microbeads have a water content of 50% to 95% by weight, based on the total weight of the drug-loaded microbeads. The method may further include loading the ready-to-inject solution into an injection device.

[0012]

[0012] According to embodiments, a method of treating a disease may include a step of delivering an embolic composition according to any embodiment of the present disclosure intravenously to a subject in need of embolic therapy. [Brief explanation of the drawings]

[0013] [Figure 1]

[0013] A graph showing in vivo drug release versus time for (A) drug-loaded microbeads in an embolic composition according to one or more embodiments of the present disclosure; (B) a comparative embolic composition containing microbeads of biocompatible sulfonic acid-modified poly(vinyl alcohol) (PVA) loaded with doxorubicin; and (C) a comparative embolic composition containing microbeads of acrylate sodium alcohol copolymer formed by polymerization of vinyl acetate and methyl acrylate and loaded with doxorubicin.

[0014]

[0014] Additional features and advantages of the embodiments described in this specification will be set forth in the detailed description that follows, and in part will become readily apparent to those skilled in the art from that description, or will be learned by practicing the embodiments described in this specification, including the detailed description that follows, the claims, and the accompanying drawings.

[0015] It is to be understood that both the foregoing general description and the following detailed description are intended to describe various embodiments and provide an overview or framework for understanding the nature and character of the claimed subject matter. The accompanying drawings are included to provide a further understanding of the various embodiments and are incorporated into and constitute a part of this specification. The drawings illustrate various embodiments described herein and, together with the description, serve to explain the principles and features of the claimed subject matter. It helps to explain the behavior. DETAILED DESCRIPTION OF THE INVENTION

[0016]

[0016] Embodiments of the present disclosure relate to drug-loaded microbead compositions, methods for preparing the drug-loaded microbead compositions, embolic compositions prepared from the drug-loaded microbead compositions, methods for preparing the embolic compositions, and methods for treating disease using the embolic compositions. The drug-loaded microbead compositions include microbeads pre-loaded with a therapeutic agent. When included in an embolic composition and delivered to a subject as part of embolic therapy, the embolic composition can provide continuous release of the drug to a target treatment site for at least 7 days, at least 14 days, at least 21 days, or at least 30 days after implantation.

[0017] The drug-loaded microbead composition may comprise microbeads loaded with a therapeutic agent or a complex of a therapeutic agent and a carrier. The microbeads may be beads or microbeads of a water-swellable polymeric material, such as a polymeric material capable of forming a hydrogel.

[0018] In the microbeads of the drug-loaded microbead composition, the therapeutic agent or therapeutic agent conjugate may be embedded within the water-swellable polymeric material. Unless otherwise noted, the term "embedded" broadly encompasses embodiments in which the water-swellable polymeric material, or a portion thereof, entirely surrounds or embeds the therapeutic agent or therapeutic agent-containing conjugate. In some embodiments, for example, "embedded" may include a shell of water-soluble polymeric material encapsulating a core holding the therapeutic agent or conjugate. In other embodiments, "embedded" may include a structure in which the therapeutic agent or conjugate is physically disposed within a matrix, network, or porous structure of the water-swellable polymeric material, which may or may not have a core within an outer shell. The therapeutic agent itself is not chemically bonded to the water-swellable polymeric material at all or directly to the polymer backbone of the water-swellable polymeric material. The drug-loaded microbead composition may have a water content of less than 1 wt. % based on the total weight of the drug-loaded microbead composition.

[0019] In various embodiments, the water-swellable polymeric material of the drug-loaded microbead composition may comprise a natural hydrogel polymer, such as, for example, chitosan or a polysaccharide, or a synthetic hydrogel polymer, such as a polyacrylate, polyamide, polyester, polysaccharide, poly(methyl methacrylate), or poly(vinyl alcohol). In some embodiments, the water-swellable polymeric material may be biodegradable. Specific examples of water-swellable polymeric materials include, but are not limited to, poly(4-hydroxybutyrate), methacrylated hyaluronic acid (hyaluronic acid, a disaccharide polymer consisting of D-glucuronic acid and N-acetyl-D-glucosamine), chitosan-alginate, poly(N-isopropylacrylamide) copolymer, poly(N-isopropylacrylamide)-alginate, poly(N-isopropylacrylamide)-peptide, poly(N-isopropylacrylamide)-α-acryloyloxy-β,β-dimethyl-γ-butyrolactone-hydrophilic Jeffamine, or poly(N-isopropylacrylamide)-poly(ethylene glycol) diacrylate-pentaerythritol tetrakis(3-mercaptopropionate). The water-swellable polymeric material of the drug-loaded microbead composition may comprise a derivative of any of the foregoing materials, or a combination of any of the foregoing materials or their derivatives. For example, a drug-loaded microbead composition may comprise a combination of multiple water-swellable polymeric materials, with each individual microbead being made from a single type of polymer, or the drug-loaded microbead composition may comprise microbeads of multiple polymeric types. Alternatively, a drug-loaded microbead composition may comprise a combination of multiple water-swellable polymeric materials, with each individual microbead of the composition being made from multiple polymer types.

[0020] In some embodiments, the drug-loaded microbead composition comprises a therapeutic agent. The therapeutic agent may be a hydrophilic therapeutic agent, or a therapeutic agent that is either water-soluble or at least partially soluble in aqueous solution. In some embodiments, the therapeutic agent may be a chemotherapeutic agent that is at least partially effective in treating a disease such as cancer. In some embodiments, the therapeutic agent may be a chemotherapeutic agent that is at least partially effective in treating a cancer such as hepatocellular carcinoma, liver cancer, prostate cancer, or breast cancer. The therapeutic agent may have one or more chemical moieties or atomic centers that have a positive or negative charge or affinity. Examples of specific therapeutic agents include, but are not limited to, doxorubicin, sorafenib, vandetanib, nivolumab, ipilimumab, regorafenib, irinotecan, epirubicin, pirarubicin, 5-fluorouracil, cisplatin, floxuridine, mitomycin C, derivatives of any of the foregoing, prodrugs of any of the foregoing, therapeutically acceptable salts or crystalline forms of any of the foregoing, or combinations of any of the foregoing. Further examples of suitable therapeutic agents include, but are not limited to, pirarubicin, mitoxantrone, tepotecan, paclitaxel, carboplatin, pemetrexed, penistatin, pertuzumab, trastuzumab, and docetaxel.

[0021]

[0021] Individual microbeads of a drug-loaded microbead composition may contain one therapeutic agent or multiple therapeutic agents. In summary, the microbeads of a drug-loaded microbead composition may include some microbeads loaded with one particular therapeutic agent or a combination of particular therapeutic agents, and other microbeads loaded with another particular therapeutic agent or a combination of particular therapeutic agents.

[0022] In some embodiments, the therapeutic agent of the drug-loaded microbead composition may be embedded within a microbead of water-swellable polymeric material, but is not chemically bonded to the water-swellable polymeric material. In some embodiments, the therapeutic agent of the drug-loaded microbead composition may be embedded within a microbead of water-swellable polymeric material, and may not be chemically bonded directly to the polymer backbone of the water-swellable polymeric material, but may be chemically bonded to functional groups of the water-swellable polymeric material. As used herein, "not chemically bonded" refers to the lack of covalent chemical bonding between the therapeutic agent and the water-swellable polymer, but does not exclude the presence of non-covalent intermolecular interactions, such as ionic or van der Waals interactions, between the therapeutic agent and the water-swellable polymeric material.

[0023] In some embodiments, the drug-loaded microbead composition comprises a complex of a carrier and a therapeutic agent. In the complex, the therapeutic agent may be chemically bound to the carrier or associated with the carrier by non-covalent means such as encapsulation or van der Waals interactions. The complex may be embedded within a water-swellable polymeric material. When the complex is embedded within a microbead, the carrier may be chemically bound to the water-swellable polymeric material, but the therapeutic agent is not chemically bound to the water-swellable polymeric material. Without intending to be bound by theory, it is believed that if the therapeutic agent is bound to or associated with the carrier but not chemically bound to the water-swellable polymeric material, the microbeads of the drug-loaded microbead composition are less susceptible to shrinkage due to the replacement of water molecules with drug molecules during drug loading. Therefore, the final particle size distribution of the drug-loaded microbeads can be more easily controlled by selecting an appropriate microbead particle size before loading with the therapeutic agent.

[0024]

[0024] When the drug-loaded microbead composition comprises a complex of a carrier and a therapeutic agent, the carrier can be any pharmaceutically acceptable compound capable of forming a complex with or encapsulating the therapeutic agent. In some embodiments, the carrier can have a charged chemical group or a chemical group having a dipole moment, which interacts with a corresponding chemical group of the therapeutic agent having an opposite charge or opposite dipole moment. When the carrier is a polymeric material, the carrier can be a material different from the water-swellable polymeric material. Non-limiting examples of suitable carriers include polysaccharides, liposomes, polymeric micelles, Pluronic®, polycaprolactone-b-methoxy-PEG, poly(aspartic acid)-b-PEG, poly(benzyl-L Examples of polysaccharides include poly(β-benzyl-L-aspartate)-β-PEG, poly(D,L-lactide)-β-methoxy-PEG, and poly(β-benzyl-L-aspartate)-β-PEG. Non-limiting examples of polysaccharides include dextran and dextran sulfate, such as sodium dextran sulfate. In one exemplary embodiment, the carrier may comprise sodium dextran sulfate having a weight-average molecular weight of about 40 kDa (kilodaltons) to about 500 kDa, about 50 kDa to about 300 kDa, about 100 kDa to about 300 kDa, or about 100 kDa to about 200 kDa.

[0025]

[0025] Drug-loaded microbead compositions according to embodiments may have a very low moisture content, such as less than 1 wt. %, less than 0.1 wt. %, less than 0.05 wt. % (500 ppm), less than 0.02 wt. % (200 ppm), less than 0.01 wt. % (100 ppm), less than 0.005 wt. % (50 ppm), less than 0.002 wt. % (20 ppm), or less than 0.001 wt. % (10 ppm) water, based on the total weight of the microbeads in the drug-loaded microbead composition. Without intending to be bound by theory, it is believed that a drug-loaded microbead composition with a very low moisture content extends the shelf life and enhances the long-term stability of the drug-loaded microbead composition. Furthermore, a water content significantly greater than 1% by weight (e.g., 2%, 3%, 5%, or 10%) based on the total weight of the drug-loaded microbead composition may result in degradation or hydrolysis of the therapeutic agent, instability or separation of the water-swellable polymer, or a combination thereof, within days or even hours, making the drug-loaded microbead composition unusable for embolization procedures even when rehydrated. The shelf life and long-term stability of compositions having a water content significantly greater than 1% by weight may not be long enough to ensure viability of the therapeutic agent over the period from manufacture of the drug-loaded microbead composition to use of the composition in an embolization procedure. The selection of the water-swellable polymer material may be correlated with the ability to remove water from the drug-loaded microbeads by freeze-drying or other drying techniques or combinations of drying techniques in amounts sufficient to prevent degradation of the therapeutic agent.

[0026] As mentioned above, a drug-loaded microbead composition with a very low water content can be obtained by drying techniques, which will be described in detail hereinafter with respect to the method of preparing the drug-loaded microbead composition. In this regard, the drug-loaded microbead composition can be a dry or substantially dehydrated composition of microbeads containing an embedded therapeutic agent or an embedded complex of a therapeutic agent and a carrier. The drug-loaded microbead composition can have a powder-like consistency. Thus, the drug-loaded microbead composition can be made suitable for injection into a subject to be treated by rehydrating the microbeads of the drug-loaded microbead composition to form an embolic composition, as described in more detail hereinafter. Nevertheless, the drug-loaded microbead composition can be provided in a form such that a physician need only add an aqueous solution, such as water or a physiologically buffered saline solution, to the drug-loaded microbead composition to prepare the composition for use in an embolization procedure.

[0027] The microbeads of the drug-loaded microbead composition may have any shape common to microparticles formed from hydrogel-type water-swellable polymeric materials. For example, the microparticles may be spherical or substantially spherical, or may have an oval shape with an oval or elliptical cross section about a longitudinal axis and a circular cross section about an axis perpendicular to the longitudinal axis.

[0028]

[0028] The drug-loaded microbead composition may contain an amount of therapeutic agent per unit volume of microbead in the composition that is selected to have a desired therapeutic effect or activity based on the intended use of the drug-loaded microbead composition and the particular therapeutic agent present in the individual microbeads.

[0029] The amount of therapeutic agent in an individual microbead of the drug-loaded microbead composition may vary, e.g., The amount of therapeutic agent in an individual microbead of a drug-loaded microbead composition can be adjusted through the specific techniques involved during drug loading, such as loading time, loading temperature, or the concentration of therapeutic agent in the loading solution. The amount of therapeutic agent in an individual microbead of a drug-loaded microbead composition can also be adjusted through the specific synthesis techniques used to synthesize the microbeads themselves, such as adjusting the polymer molecular weight, the degree of hydrogel crosslinking, the polymer density, or the polymer porosity of the water-swellable polymeric material. For example, if doxorubicin is the therapeutic agent, the amount of drug loaded into the drug-loaded microbeads can be adjusted relative to the number of negative charges in the polymer backbone of the water-swellable polymeric material. Similarly, if sorafenib is the therapeutic agent, sorafenib can be embedded within polymer micelles or liposomes that can be embedded within the microbead structure. The amount of therapeutic agent in an individual microbead of a drug-loaded microbead composition can also be adjusted through the selection of a carrier.

[0030] In exemplary embodiments, each individual drug-loaded microbead of the drug-loaded microbead composition comprises a water-swellable polymeric material, a therapeutic agent, a carrier, and water. Each individual drug-loaded microbead of the drug-loaded microbead composition may comprise about 30% to about 70%, about 35% to about 65%, about 40% to about 60%, about 45% to about 55%, or about 50% to about 70% by weight of the water-swellable polymeric material, based on the total weight of the individual drug-loaded microbead. In exemplary embodiments, each individual drug-loaded microbead of the drug-loaded microbead composition may comprise about 1% to about 25%, about 1% to about 20%, about 1% to about 15%, about 2% to about 25%, about 5% to about 25%, or about 10% to about 25% by weight of the therapeutic agent, based on the total weight of the individual drug-loaded microbead. In exemplary embodiments, an individual drug-loaded microbead of the drug-loaded microbead composition may comprise from about 1% to about 40% by weight, from about 1% to about 30% by weight, from about 1% to about 25% by weight, from about 1% to about 20% by weight, from about 5% to about 40% by weight, from about 10% to about 40% by weight, or from about 20% to about 40% by weight of carrier, based on the total weight of the individual drug-loaded microbead. In exemplary embodiments, the individual drug-loaded microbeads of the drug-loaded microbead compositions according to embodiments may have a very low water content, such as less than 1 wt. %, less than 0.5 wt. %, less than 0.1 wt. %, less than 0.05 wt. % (500 ppm), less than 0.02 wt. % (200 ppm), less than 0.01 wt. % (100 ppm), less than 0.005 wt. % (50 ppm), less than 0.002 wt. % (20 ppm), or less than 0.001 wt. % (10 ppm) water, based on the total weight of the individual drug-loaded microbeads in the drug-loaded microbead composition.

[0031] Having described drug-loaded microbead compositions according to various embodiments, methods for preparing the drug-loaded microbead compositions are described below.

[0032] In some embodiments, the method for preparing a drug-loaded microbead composition as described above may include dissolving a carrier and a therapeutic agent in an aqueous solvent to form an initial mixture. In the initial mixture, a complex may be formed between the carrier molecule and the therapeutic agent molecule. For example, a mixture of doxorubicin as the therapeutic agent and dextran sulfate as the carrier may form a complex between doxorubicin and dextran sulfate.

[0032]

[0033] The initial mixture containing the complex may then be combined with a first solvent composition to form a second mixture. The first solvent composition comprises a solvent or mixture of solvents in which the therapeutic agent is less soluble than in an aqueous solvent. The second mixture may be a biphasic or multiphasic mixture. The second mixture is then rapidly agitated or stirred. Rapid agitation or stirring results in the formation of complex particles in the second mixture. The second mixture may be agitated, for example, at a stirring speed of about 150 rpm to about 2000 rpm. Agitation may be continuous and may be performed for a time sufficient to form microbeads. For example, agitation may be performed continuously for a stirring time of about 1 hour to about 12 hours. If the second mixture is biphasic, particles may be formed in the phase of the second mixture in which the therapeutic agent is less soluble or least soluble. Optionally, the complex particles may be separated by any suitable method, such as filtration. It can be isolated from the second mixture by techniques.

[0033]

[0034] The particles of either the composite, still in the second mixture, or optionally after isolation from the second mixture, can then be combined with a hydrogel of a water-swellable polymeric material to form a hydrogel mixture. The hydrogel mixture is then combined with a second solvent composition to form a synthesis mixture. The second solvent composition comprises a solvent or mixture of solvents in which the therapeutic agent and / or the hydrogel are less soluble than in an aqueous solvent.

[0034]

[0035] The synthesis mixture is rapidly stirred or agitated to form drug-loaded microbeads in the synthesis mixture. The synthesis mixture can be agitated, for example, at a stirring speed of about 150 rpm to about 2000 rpm. Agitation can be continuous and can be performed for a time sufficient to form microbeads. For example, agitation can be performed continuously for a stirring time of about 1 hour to about 12 hours. Drug-loaded microbeads can be formed either when the water-swellable polymer hardens around the therapeutic agent complex or when the therapeutic agent complex is absorbed into the polymer matrix of the water-swellable polymer. The drug-loaded microbeads are then recovered from the synthesis mixture by any suitable separation technique, such as, for example, filtration.

[0035]

[0036] The drug-loaded microbeads prepared by the above-mentioned procedure may exhibit a core-shell structure in which a polymer matrix shell encapsulates a particle core and a complex is disposed in the particle core. In the core-shell structure, the therapeutic agent is not chemically bonded to the water-swellable polymer material, and the carrier may be chemically bonded to the water-swellable polymer material.

[0036]

[0037] In other embodiments, the method for preparing a drug-loaded microbead composition as described above may include dissolving a carrier and a therapeutic agent in an aqueous solvent to form an initial mixture. In the initial mixture, a complex may be formed between the carrier molecules and the therapeutic agent molecules. For example, a mixture of doxorubicin as the therapeutic agent and dextran sulfate as the carrier may form a complex between doxorubicin and dextran sulfate. The initial mixture may then be combined with a hydrogel solution of a water-swellable polymeric material to form a hydrogel mixture, without first forming complex particles as an intermediate step.

[0037]

[0038] The hydrogel mixture is then combined with a second solvent composition to form a synthesis mixture. The second solvent composition comprises a solvent or mixture of solvents in which the therapeutic agent and / or hydrogel are less soluble than in an aqueous solvent. The synthesis mixture is rapidly stirred to form drug-loaded microbeads in the synthesis mixture. Drug-loaded microbeads can be formed either when the water-swellable polymer cures in the presence of the therapeutic agent complex or when the therapeutic agent complex is absorbed into the polymer matrix of the water-swellable polymer. The drug-loaded microbeads are then recovered from the synthesis mixture by any suitable separation technique, such as filtration. Drug-loaded microbeads prepared by the above procedure can exhibit an interpenetrating network structure in which the water-swellable polymer material has a polymer matrix and the therapeutic agent / carrier complex is disposed within the porous structure of the polymer matrix. In the interpenetrating network structure, the therapeutic agent can be chemically bonded to the carrier, and the therapeutic agent / carrier complex can be disposed within the molecules of the water-swellable polymer.

[0038]

[0039] Whether the drug-loaded microbeads are prepared with or without the intermediate step of forming particles of a complex between a therapeutic agent and a carrier, the aforementioned methods for preparing a drug-loaded microbead composition further include removing water from the drug-loaded microbeads to form a drug-loaded microbead composition having a water content of less than 1 wt. % based on the total weight of the drug-loaded microbead composition. In some embodiments, water removal can include lyophilization, followed by an optional additional drying step involving temperature change (heating or cooling), flowing air, vacuum, or a combination thereof. The drug-loaded microbeads can have an average synthesis volume upon recovery from the synthesis mixture and an average final volume after water removal. The average final volume can be in the range of about 10% to about 75% of the average synthesis volume, such as about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, or about 75% of the average synthesis volume.

[0039]

[0040] Freeze-drying of drug-loaded microbeads can be performed by any procedure commonly used for drying particulate matter. For example, drug-loaded microbeads can be placed in semi-stoppered glass vials and then placed on a cooled, temperature-controlled shelf in a freeze dryer. The shelf temperature is lowered, and the sample is frozen to a specified temperature. After complete freezing, the pressure in the dryer can be reduced to a specified pressure to initiate primary drying. During primary drying, the shelf temperature is controlled at a constant low temperature, and water vapor is gradually removed from the frozen mass by sublimation. Secondary drying can be initiated by increasing the shelf temperature and further reducing the chamber pressure, so that water absorbed in the semi-dried mass can be removed until the residual moisture content is reduced to a desired level.

[0040]

[0041] Freeze-drying of drug-loaded microbeads can also be performed by atmospheric freeze-drying, which involves rapidly circulating very dry air over the frozen drug-loaded microbeads. The circulating dry gas improves heat and mass transfer from the frozen microbeads. Atmospheric spray-drying can promote the formation of small-diameter microbeads as a free-flowing powder while avoiding the formation of a dry cake. The free-flowing powder can then facilitate rehydration of the drug-loaded microbead composition when preparing the embolic composition.

[0041]

[0042] The drug-loaded microbeads of the drug-loaded microbead composition described above, or prepared by the method described above, may exhibit physical or mechanical properties that are advantageous for their use, storage, transport, or subsequent rehydration to form the embolic composition.

[0042]

[0043] For example, it was previously described that in the drug-loaded microbead compositions and embolic compositions according to embodiments of the present disclosure, the therapeutic agent in the microbeads is not chemically bonded to the water-swellable polymer. Without intending to be bound by theory, it is believed that the lack of direct chemical bonding between the therapeutic agent and the water-swellable polymer results in the swollen diameter of the water-swellable polymer microbeads being substantially the same when loaded with a therapeutic agent as when not loaded with a therapeutic agent, whether before the therapeutic agent is loaded into the microbeads or after the therapeutic agent is eluted from the microbeads.

[0043]

[0044] In contrast, certain hydrogel polymer microbeads not according to embodiments of the present disclosure have an original diameter in a swollen state without drug loading, which has been observed to shrink by as much as 5% or 10% when drug is loaded into the polymer matrix of the microbeads. Without intending to be bound by theory, it is believed that this shrinkage occurs because the addition of drug molecules to the microbeads creates chemical bonds between the drug and the microbead polymer, which in turn limits the amount of water that can be present in the microbead polymer, which causes the microbead polymer to swell.

[0044]

[0045] In clinical practice, when such microbead compositions are prepared for injection into patients, the shrinkage observed in some hydrogel polymer microbeads not according to embodiments of the present disclosure is reversed because some amount of drug elutes from the microbeads during preparation. The reversal of shrinkage is manifested as an increase in microbead diameter despite the drug being removed or eluted. Such diameters can be large enough to clog microcatheters used to inject the microbeads. The observed problem of microcatheter clogging is averted by drug-loaded microbead compositions and embolic compositions according to embodiments of the present disclosure, in which the therapeutic agent is not chemically bonded to the water-swellable polymeric material. This is thought to be avoided.

[0045]

[0046] By way of further illustration, the mechanical properties of the drug-loaded microbead composition can be tailored by adjusting the properties or synthesis method of the water-swellable polymeric material. For example, the compressive strength of the drug-loaded microbeads can be adjusted by varying the crosslinking agent used to prepare the microbeads, or by modifying the density or molecular weight of the water-swellable polymeric material through polymer synthesis techniques known and understood by those skilled in the art of polymer synthesis. In some embodiments, the drug-loaded microbeads of the drug-loaded microbead composition can have physical and mechanical properties selected such that the drug-loaded microbeads recover more than 85% of their diameter after being compressed to 50% of their initial diameter.

[0046]

[0047] The drug-loaded microbeads of the drug-loaded microbead composition described above, or prepared by the method described above, may be provided to a physician along with instructions for rehydrating the drug-loaded microbead composition to form an embolic composition ready for use in embolic therapy. Accordingly, embodiments of the present disclosure include embolic compositions and methods for preparing embolic compositions.

[0047]

[0048] The embolic composition may include a drug-loaded microbead composition according to any embodiment of the present disclosure or a drug-loaded microbead composition prepared by a method embodied in the present disclosure. The embolic composition may further include an aqueous solution in an amount sufficient to swell the drug-loaded microbeads of the drug-loaded microbead composition. Depending on the amount of aqueous solution, the swollen drug-loaded microbeads may have a water content of about 50% to about 99% by weight, about 60% to about 95% by weight, about 70% to about 95% by weight, about 80% to about 95% by weight, about 90% to about 95% by weight, about 80% to about 99% by weight, about 90% to about 99% by weight, or about 95% to about 99% by weight, based on the total weight of the drug-loaded microbeads. The aqueous solution may be any pharmaceutically acceptable solution, such as a physiologically buffered saline solution.

[0048]

[0049] In exemplary embodiments, the swollen individual drug-loaded microbeads of the embolic composition comprise a water-swellable polymeric material, a therapeutic agent, a carrier, and water. The swollen individual drug-loaded microbeads of the embolic composition may comprise about 3% to about 10%, about 3% to about 7%, about 3.5% to about 6.5%, about 4% to about 6%, about 4.5% to about 5.5%, or about 5% to about 7% by weight of the water-swellable polymeric material, based on the total weight of the swollen individual drug-loaded microbeads. In exemplary embodiments, the swollen individual drug-loaded microbeads of the embolic composition may comprise about 0.1% to about 2.5%, about 0.1% to about 2%, about 0.1% to about 1.5%, about 0.2% to about 2.5%, about 0.5% to about 2.5%, or about 1% to about 2.5% by weight of therapeutic agent, based on the total weight of the swollen individual drug-loaded microbeads. In exemplary embodiments, the swollen individual drug-loaded microbeads of the embolic composition may comprise about 0.1% to about 4%, about 0.1% to about 3%, about 0.1% to about 2.5%, about 0.1% to about 2%, about 0.5% to about 4%, about 1% to about 4%, or about 2% to about 4% by weight of carrier, based on the total weight of the swollen individual drug-loaded microbeads. In exemplary embodiments, the swollen individual drug-loaded microbeads of the embolic compositions according to embodiments may have a water content of about 50% to about 99% by weight, about 50% to about 97% by weight, about 50% to about 96% by weight, about 60% to about 95% by weight, about 70% to about 95% by weight, about 80% to about 95% by weight, about 90% to about 95% by weight, about 80% to about 99% by weight, about 90% to about 99% by weight, or about 95% to about 99% by weight, based on the total weight of the individual drug-loaded microbeads.

[0049]

[0050] The swollen microbeads of the embolic composition may have an average diameter of about 5 μm to about 1200 μm as measured by dynamic light scattering (DLS). In this context, the diameter of an individual particle is taken to be the widest measurement obtained from a first point on the surface of the microbead through the center of mass of the microbead to a second point on the surface of the microbead opposite the first point. A particular particle size distribution of microparticles can be selected or tailored to suit the particular treatment for which the embolic composition is intended to be used. The average diameter of the microbeads of the embolic composition can be selected by any suitable particle size selection method, either before or after the therapeutic agent is loaded into the microbeads. In some embodiments, the swollen microbeads of the embolic composition can have an average diameter of, for example, about 40 μm to about 800 μm, about 40 μm to about 100 μm, about 40 μm to about 75 μm, about 75 μm to about 100 μm, about 100 μm to about 200 μm, about 200 μm to about 300 μm, about 300 μm to about 400 μm, about 400 μm to about 500 μm, about 600 μm to about 700 μm, or any subset of any of the foregoing ranges. In some embodiments, the swollen microbeads can have an average diameter with a narrow particle size distribution, such as, for example, 40 μm ± 20 μm, 40 μm ± 10 μm, 40 μm ± 5 μm, or 40 μm ± 1 μm.

[0050]

[0051] A method for preparing an embolic composition may include adding a drug-loaded microbead composition according to any embodiment of the present disclosure, or a drug-loaded microbead composition prepared by a method embodied in the present disclosure, to an aqueous solution in an amount sufficient to swell the drug-loaded microbeads of the drug-loaded microbead composition, such that the swollen drug-loaded microbeads have a water content of 50% to 99%, 50% to 90%, 50% to 75%, 60% to 99%, 75% to 99%, 75% to 95%, 75% to 90%, or 85% to 99% by weight, based on the total weight of the drug-loaded microbeads, to form a ready-to-inject solution. The aqueous solution may be any pharmaceutically acceptable solution, such as, for example, a physiologically buffered saline solution. The method may further include loading the ready-to-inject solution into an injection device, such as, for example, a syringe. The method may further include allowing the drug-loaded microbeads to swell for a rehydration period of about 5 minutes to about 60 minutes before loading the ready-to-inject solution into the injection device. In some examples, the embolic composition may contain from about 25 mg of therapeutic agent per ml of microbeads to about 150 mg of therapeutic agent per ml of microbeads.

[0051]

[0052] Embolic compositions prepared from drug-loaded microbead compositions according to embodiments of the present disclosure can be incorporated into embolization treatments or therapies intended to treat diseases such as cancer. In some embodiments, the therapeutic agent can be a chemotherapeutic agent that is at least somewhat effective in treating cancers such as hepatocellular carcinoma, liver cancer, prostate cancer, or breast cancer. Accordingly, embodiments of the present disclosure include methods of treating diseases. The methods of treating diseases can include intravenously delivering an embolic composition according to any embodiment described herein, prepared from a drug-loaded microbead composition according to any embodiment described herein, to a subject in need of embolization therapy.

[0052]

[0053] In a method for treating a disease, after an embolic composition is delivered intravenously, at least a portion of the drug-loaded microbeads flow through the subject's vasculature to the embolic site, restricting blood flow at the embolic site. The drug-loaded microbeads can then release at least 90% by weight of the therapeutic agent, based on the initial amount of therapeutic agent embedded in the microbeads before the embolic composition was delivered, to the tissue at the embolic site over a release period. In some embodiments, the release to the tissue at the embolic site can include an initial burst of drug release, during which at least 10% by weight of the therapeutic agent initially present in the drug-loaded microbeads is released to the tissue surrounding the embolic site. The initial burst can occur within 1 minute, 5 minutes, 10 minutes, 30 minutes, 60 minutes, 120 minutes, 180 minutes, 240 minutes, 300 minutes, 360 minutes, 12 hours, 18 hours, or 24 hours after the drug-loaded microbeads reach the embolic site. In some embodiments, the drug-loaded microbeads provide sustained release of the therapeutic agent to the tissue over the release period. The release period can be a long-term release period, such as at least 5 days, at least 10 days, at least 14 days, at least 28 days, or at least 42 days, etc. The end of the release period is determined from the time when the drug-loaded microbeads are either completely degraded or stop eluting the therapeutic agent into the tissue.

[0053]

[0054] Without intending to be bound by theory, it is believed that the release mechanism of the therapeutic agent from the drug-loaded microbeads of the embolic composition may be based on a dual mechanism, including ion exchange and enzymatic release. For example, in the early stages of delivery of the therapeutic agent to the embolic site, when a large amount of water is present, the therapeutic agent may be released from the drug-loaded microbeads by ion exchange. In later stages, when water becomes scarce due to closure of the container, the drug-loaded microbeads may be degraded by enzymatic methods, such as lysozyme, to release the therapeutic agent from the microbeads. In the final stages, such as 21 days after implantation, most of the water-swellable polymeric material is believed to be resorbed by the tissue surrounding the embolic site. At this stage, the water-swellable polymeric material no longer has a matrix encapsulating the therapeutic agent or the therapeutic agent-carrier complex, allowing the therapeutic agent to be completely eluted at the embolic site. It is therefore believed that the embolic composition according to embodiments of the present disclosure can increase tumor response and disease-free survival rates. Additionally, the embolic compositions according to embodiments of the present disclosure provide economic value, such as reduced physician procedure time, by eliminating the need to require a pharmacist or technician to add a therapeutic agent to unloaded microbeads. [Example]

[0054]

[0055] The following examples are offered by way of illustration only. In light of the foregoing description, those skilled in the art will appreciate that the following examples are not intended to limit the scope of the present disclosure or its many embodiments.

[0055] Example 1

[0056] The drug-loaded microbead composition of this example includes polymeric microbeads and a conjugate comprising dextran sulfate chemically bound to doxorubicin. The conjugate is encapsulated within a microbead core defined within a shell of a water-swellable polymeric material. The microbeads have particle sizes ranging from 10 μm to 2000 μm. The drug-loaded microbead composition contains approximately 25 mg of doxorubicin per ml of microbeads to approximately 150 mg of doxorubicin per ml of microbeads.

[0056]

[0057] To prepare the drug-loaded microbead composition, a dextran-doxorubicin complex is prepared by dissolving dextran sodium sulfate (molecular weight range 40 kDa to 500 kDa) and doxorubicin in an aqueous solution. The dextran-doxorubicin solution is then added to the solvent mixture with high-speed stirring to produce doxorubicin-loaded dextran particles. The doxorubicin-loaded particles are then added to a hydrogel solution of a polymeric material and encapsulated within the microbead cores using the water / oil method. In the water / oil method, the doxorubicin-loaded dextran particles are present in an aqueous solvent, to which additional solvent is added to form a biphasic mixture. The biphasic mixture contains an aqueous phase in which the doxorubicin-loaded dextran particles initially reside along with the hydrogel, and an oil phase. The biphasic mixture is rapidly mixed to incorporate the doxorubicin-loaded dextran particles into the hydrogel polymer microbeads within the oil phase of the biphasic mixture.

[0057]

[0058] After recovery from the biphasic mixture, the drug-loaded microbeads contain a significant amount of water and are in a swollen state. To prepare the drug-loaded microbead composition for packaging, the microbeads are freeze-dried to remove the water. The freeze-drying process removes more than 90%, more than 95%, more than 98%, more than 99%, more than 99.9%, or more than 99.99% by weight of the total water present in the microbeads immediately after drug loading. The freeze-dried microbeads may be further subjected to air and / or vacuum drying. Thereby, the drug-loaded microbead composition contains less than 1 wt. %, less than 0.1 wt. %, less than 0.05 wt. % (500 ppm), less than 0.02 wt. % (200 ppm), less than 0.01 wt. % (100 ppm), less than 0.005 wt. % (50 ppm), less than 0.002 wt. % (20 ppm), or less than 0.001 wt. % (10 ppm) of water, based on the total weight of the drug-loaded microbead composition.

[0058] Example 2

[0059] The drug-loaded microbead composition of this example also includes polymeric microbeads and a conjugate comprising dextran sulfate chemically bound to doxorubicin. The conjugate is encapsulated within a microbead core defined within a shell of a water-swellable polymeric material. The microbeads have particle sizes ranging from 10 μm to 2000 μm. The drug-loaded microbead composition contains about 25 mg of doxorubicin per ml of microbeads to about 150 mg of doxorubicin per ml of microbeads.

[0059]

[0060] To prepare the drug-loaded microbead composition, a dextran-doxorubicin complex was prepared by dissolving dextran sulfate sodium (molecular weight range 40 kDa to 500 kDa) and doxorubicin in an aqueous solution. Unlike Example 1, which produces doxorubicin-loaded dextran particles as an intermediate step, the dextran-doxorubicin solution was directly combined with a hydrogel solution of polymeric material to form a synthesis mixture. After vigorous mixing, drug-loaded microbeads were formed, in which the microbeads were embedded within an interpenetrating network of the water-swellable polymeric material and dextran, and doxorubicin formed a complex with the dextran without being chemically bound to the water-swellable polymeric material. The drug-loaded microbeads were then recovered from the synthesis mixture.

[0060]

[0061] After recovery from the synthesis mixture, the drug-loaded microbeads contain a significant amount of water and are in a swollen state. To prepare the drug-loaded microbead composition for packaging, the microbeads are freeze-dried to remove the water. The freeze-drying process removes more than 90%, more than 95%, more than 98%, more than 99%, more than 99.9%, or more than 99.99% by weight of the total water present in the microbeads immediately after drug loading. The freeze-dried microbeads may be further dried by air and / or vacuum. The drug-loaded microbead composition thereby contains less than 1%, less than 0.1%, less than 0.05% (500 ppm), less than 0.02% (200 ppm), less than 0.01% (100 ppm), less than 0.005% (50 ppm), less than 0.002% (20 ppm), or less than 0.001% (10 ppm) by weight of water, based on the total weight of the drug-loaded microbead composition.

[0061] Example 3

[0062] A drug-loaded microbead composition is prepared according to Example 1 or Example 2. The drug-loaded microbead composition is then mixed with a physiological buffered saline solution for a rehydration period of 5 to 40 minutes to swell the microbeads, forming embolic composition (A). The solution containing the swollen microbeads is then injected into a patient.

[0062]

[0063] To compare the in vitro doxorubicin release rate of the drug-loaded microbead compositions prepared according to Example 1 or Example 2 with the in vitro doxorubicin release rate of other microbead compositions prepared from beads of non-degradable polymeric material, two comparative samples were prepared and injected into patients. The first comparative sample (B) contained microbeads of biocompatible sulfonic acid-modified poly(vinyl alcohol) loaded with doxorubicin by adding doxorubicin in aqueous solution to unloaded microbeads and waiting approximately 24 hours before injection. The second comparative sample (C) was formed by polymerization of vinyl acetate and methyl acrylate and loaded with doxorubicin in aqueous solution to unloaded microbeads and waiting approximately 24 hours before injection. The microbeads contain sodium alcohol copolymer acrylate that are loaded with doxorubicin by waiting for a period of time.

[0063]

[0064] A comparison of the doxorubicin release rates of the three samples from injection up to 30 days after injection is shown in the figure. Embolic compositions (A) prepared from the drug-loaded microbead compositions of Example 1 or Example 2 exhibited an initial burst of doxorubicin release over the first two days, during which approximately 30% of the total doxorubicin content was released into the patient's tissues. Doxorubicin release continued through Day 14, at which point approximately 70% of the total doxorubicin content of the microbeads had been released, and approximately 90% to 100% of the total doxorubicin content of the microbeads had been released by Day 30.

[0064]

[0065] In contrast, the first sample (B) immediately releases about 20% of its doxorubicin and releases about 25% of its doxorubicin content by day 2. However, no more doxorubicin is released after day 2. Similarly, the second comparative sample (C) immediately releases about 15% of its doxorubicin and does not release any additional doxorubicin after the initial release.

[0065]

[0066] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description herein is for the purpose of describing particular embodiments only and is not intended to be limiting. As used in this specification and the appended claims, the singular forms "a," "an," and "the" are intended to include the plural forms as well, unless the context clearly dictates otherwise.

[0066]

[0067] Unless otherwise expressly stated, all numerical values ​​expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and the like used in the specification and claims should be understood to be modified in each instance by the term "about." Accordingly, unless expressly stated otherwise, the numerical properties set forth in the specification and claims are approximations that may vary depending on the desired properties sought to be obtained in embodiments of the invention. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values ​​set forth in the specific examples are reported as precisely as possible. One of ordinary skill in the art will understand that any numerical value inherently contains certain errors resulting from the measuring techniques employed to determine the values.

[0067]

[0068] It is noted that terms such as "preferably," "generally," and "typically" are not used herein to limit the scope of the claims or to imply that a particular feature is essential, essential, or even critical to the structure or function of the claimed invention. Rather, these terms are intended merely to highlight alternative or additional features that may or may not be utilized in a particular embodiment of the invention.

[0068]

[0069] It is noted that for purposes of describing and defining the present invention, the term "substantially" is used herein to represent the inherent degree of uncertainty that may result from any quantitative comparison, value, measurement, or other representation. The term "substantially" is also used herein to represent the extent to which a quantitative representation may vary from the stated basis without resulting in a change in the basic functionality of the subject matter under discussion. As such, it is used to represent the inherent degree of uncertainty that may result from any quantitative comparison, value, measurement, or other representation, and refers to an arrangement of elements or features that, in theory, would be expected to exhibit exact correspondence or behavior, but may in practice be embodied as less than exact.

[0069]

[0070] It will be apparent to those skilled in the art that various modifications and variations can be made to the embodiments described herein without departing from the spirit and scope of the claimed subject matter. Accordingly, it is intended that the specification cover modifications and variations of the various embodiments described herein, provided that such modifications and variations come within the scope of the appended claims and their equivalents. In one aspect, the present invention may be as follows. [Embodiment 1] Microbeads comprising a water-swellable polymeric material; and a conjugate comprising a carrier and a therapeutic agent chemically bound to the carrier; 1. A drug-loaded microbead composition comprising: the composite is embedded within the polymer material; the drug-loaded microbead composition has a water content of less than 1 wt. % based on the total weight of the drug-loaded microbead composition; The above composition. [Aspect 2] The drug-loaded microbead composition of Aspect 1, wherein the water-swellable polymer material is a biodegradable polymer material selected from poly(4-hydroxybutyrate), methacrylated hyaluronic acid, chitosan-alginate, poly(N-isopropylacrylamide) copolymer, poly(N-isopropylacrylamide)-alginate, poly(N-isopropylacrylamide)-peptide, poly(N-isopropylacrylamide)-α-acryloyloxy-β,β-dimethyl-γ-butyrolactone-hydrophilic Jeffamine, poly(N-isopropylacrylamide)-poly(ethylene glycol) diacrylate-pentaerythritol tetrakis(3-mercaptopropionate), derivatives of any of the foregoing, or combinations of any of the foregoing. [Aspect 3] A drug-loaded microbead composition according to Aspect 1 or 2, wherein the therapeutic agent is selected from doxorubicin, sorafenib, vandetanib, nivolumab, ipilimumab, regorafenib, irinotecan, epirubicin, pirarubicin, 5-fluorouracil, cisplatin, floxuridine, mitomycin C, a derivative of any of the foregoing, a prodrug of any of the foregoing, a therapeutically acceptable salt of any of the foregoing, or a combination of any of the foregoing. [Aspect 4] A drug-loaded microbead composition according to any one of the preceding aspects, wherein the therapeutic agent is not chemically bonded to the water-swellable polymeric material. [Embodiment 5] The water-swellable polymeric material comprises a polymer matrix shell encapsulating a particle core; The complex is disposed within the particle core. 10. The drug-loaded microbead composition of any one of the preceding aspects. [Embodiment 6] The drug-loaded microbead composition of any one of the preceding embodiments, wherein the carrier is embedded within an interpenetrating network of the water-swellable polymeric material of the drug-loaded microbead. [Aspect 7] The drug-loaded microbead composition of any one of the preceding aspects, wherein the carrier is selected from liposomes, polymeric micelles, pluronics, polycaprolactone-b-methoxy-PEG, poly(aspartic acid)-b-PEG, poly(benzyl-L-glutamate)-b-PEG, poly(D,L-lactide)-b-methoxy-PEG, poly(β-benzyl-L-aspartate)-b-PEG, or dextran sulfate sodium. [Aspect 8] A drug-loaded microbead composition according to Aspect 6, wherein the carrier comprises dextran sulfate sodium. [Aspect 9] A drug-loaded microbead composition according to Aspect 8, wherein the dextran sulfate sodium has a molecular weight of about 40 kDa to about 500 kDa. [Embodiment 10] A drug-loaded microbead composition according to embodiment 7, wherein the carrier comprises a liposome. [Embodiment 11] A drug-loaded microbead composition according to embodiment 7, wherein the carrier comprises a polymer micelle. [Embodiment 12] The drug-loaded microbead composition of embodiment 7, wherein the carrier comprises Pluronic. [Aspect 13] A drug-loaded microbead composition according to Aspect 7, wherein the carrier comprises polycaprolactone-b-methoxy-PEG. [Embodiment 14] A drug-loaded microbead composition according to embodiment 7, wherein the carrier comprises poly(aspartic acid)-b-PEG. [Embodiment 15] A drug-loaded microbead composition according to embodiment 7, wherein the carrier comprises poly(benzyl-L-glutamate)-b-PEG. [Aspect 16] A drug-loaded microbead composition according to Aspect 7, wherein the carrier comprises poly(D,L-lactide)-b-methoxy-PEG. [Aspect 17] A drug-loaded microbead composition according to Aspect 7, wherein the carrier comprises poly(β-benzyl-L-aspartate)-b-PEG). [Aspect 18] A drug-loaded microbead composition according to any one of the preceding aspects, wherein the drug-loaded microbeads are substantially spherical. [Aspect 19] A drug-loaded microbead composition according to any one of the preceding aspects, wherein the drug-loaded microbeads have a diameter of about 40 μm to about 800 μm. [Embodiment 20] The individual microbeads of the drug-loaded microbead composition contain, based on the total weight of the individual microbeads, about 30% to about 70% by weight of a water-swellable polymeric material; about 1% to about 25% by weight of a therapeutic agent; About 1% by weight to about 40% by weight of a carrier; Less than 1% by weight of water 10. The drug-loaded microbead composition of any one of the preceding embodiments, comprising: [Embodiment 21] A method for preparing a drug-loaded microbead composition, comprising: dissolving a carrier and a therapeutic agent in an aqueous solvent to form an initial mixture comprising a complex of the carrier and the therapeutic agent; combining the initial mixture with a first solvent composition in which the therapeutic agent is less soluble than in the aqueous solvent to form a second mixture; rapidly stirring the second mixture to form particles of the composite in the second mixture; combining particles of the composite with a hydrogel of a water-swellable polymeric material to form a hydrogel mixture; combining the hydrogel mixture with a second solvent composition to form a synthesis mixture; rapidly stirring the synthesis mixture to form drug-loaded microbeads in the synthesis mixture; recovering the drug-loaded microbeads from the synthesis mixture; removing water from the drug-loaded microbeads to form a drug-loaded microbead composition having a water content of less than 1 wt. % based on the total weight of the drug-loaded microbeads in the drug-loaded microbead composition; The above method, comprising: [Embodiment 22] The method of embodiment 21, further comprising filtering the second mixture to recover the particles of the complex prior to combining the particles of the complex with the hydrogel solution. [Embodiment 23] The method of embodiment 21 or 22, wherein removing water comprises freeze-drying the drug-loaded microbeads. [Aspect 24] The water removal step comprises freeze-drying the drug-loaded microbeads; drying the freeze-dried drug-loaded microbeads by air, temperature change, vacuum, or any combination thereof; 23. The method of embodiment 21 or 22, comprising: [Embodiment 25] The drug-loaded microbeads have an average synthesis volume upon recovery from the synthesis mixture and an average final volume after removal of water, The average final volume is about 10% to about 75% of the average composite volume. A method according to any one of aspects 21 to 24. [Embodiment 26] A method for preparing a drug-loaded microbead composition, comprising: dissolving a carrier and a therapeutic agent in an aqueous solvent to form an initial mixture comprising a complex of the carrier and the therapeutic agent; combining the initial mixture with a hydrogel solution of a water-swellable polymeric material to form a hydrogel mixture; combining the hydrogel mixture with a solvent composition to form a synthesis mixture; rapidly stirring the synthesis mixture to form drug-loaded microbeads in the synthesis mixture; recovering the drug-loaded microbeads from the synthesis mixture; drying the drug-loaded microbeads to form a drug-loaded microbead composition having a moisture content of less than 1 wt. % based on the total weight of the drug-loaded microbeads in the drug-loaded microbead composition; The above method, comprising: [Aspect 27] The method of aspect 26, wherein removing water comprises freeze-drying the drug-loaded microbeads. [Embodiment 28] The water removal step comprises freeze-drying the drug-loaded microbeads; drying the freeze-dried drug-loaded microbeads with air, heat, vacuum, or any combination thereof; 27. The method of embodiment 26, comprising: [Embodiment 29] The drug-loaded microbeads have an average synthesis volume upon recovery from the synthesis mixture and an average final volume after removal of water, The average final volume is about 10% to about 75% of the average composite volume. A method according to any one of aspects 26 to 28. [Aspect 30] A drug-loaded microbead composition according to any one of Aspects 1 to 20, a drug-loaded microbead composition produced by the method according to any one of Aspects 21 to 25, or a drug-loaded microbead composition produced by the method according to any one of Aspects 26 to 29; an aqueous solution in an amount sufficient to swell the drug-loaded microbeads of the drug-loaded microbead composition, such that the swollen drug-loaded microbeads have a water content of 50% to 95% by weight based on the total weight of the drug-loaded microbeads; An embolic composition comprising: [Embodiment 31] The embolic composition according to embodiment 30, wherein the aqueous solution is a physiologically buffered saline solution. [Embodiment 32] The embolic composition contains swollen individual drug-loaded microbeads, each of which is about 3% to about 10% by weight of a water-swellable polymeric material; about 0.1% to about 2.5% by weight of a therapeutic agent; about 0.1 wt % to about 4.0 wt % of a carrier; About 50% to about 96% by weight of water 32. The embolic composition of embodiment 30 or 31, comprising: [Embodiment 33] A method for preparing an embolic composition, comprising: adding the drug-loaded microbead composition according to any one of Aspects 1 to 20, or the drug-loaded microbead composition produced by the method according to any one of Aspects 21 to 25, or the drug-loaded microbead composition produced by the method according to any one of Aspects 26 to 29, to an aqueous solution in an amount sufficient to swell the drug-loaded microbeads of the drug-loaded microbead composition, whereby the swollen drug-loaded microbeads have a water content of 50 wt% to 95 wt%, based on the total weight of the drug-loaded microbeads, to form an injectable solution; loading the injectable solution into an injection device; The above method, comprising: [Embodiment 34] The method described in embodiment 33, further comprising a step of swelling the drug-loaded microbeads for a rehydration time of about 5 minutes to about 60 minutes before loading the injectable solution into an injection device. [Embodiment 35] The method of embodiment 33 or 34, wherein the aqueous solution is a physiologically buffered saline solution. [Aspect 36] A method for treating a disease, comprising: delivering the embolic composition according to any one of aspects 30 to 32 into the vein of a subject in need of embolic therapy. The above method, comprising: [Embodiment 37] After the embolic composition is delivered intravenously, at least a portion of the drug-loaded microbeads flow through the vasculature of the subject to the embolization site, restricting blood flow at the embolization site; the drug-loaded microbeads release at least 90% by weight of the therapeutic agent based on the initial amount of the therapeutic agent embedded within the microbeads before the embolic composition is applied to the tissue at the embolization site over a release period; The method of embodiment 36. [Embodiment 38] The method of embodiment 37, wherein the release into the tissue at the embolization site includes an initial burst of release, during which at least 10% by weight of the therapeutic agent is released relative to the initial amount. [Embodiment 39] The method of embodiment 37 or 38, wherein the drug-loaded microbeads provide sustained release of the therapeutic agent to the tissue over the release period. [Embodiment 40] The method according to any one of embodiments 37 to 39, wherein the release period is at least 14 days. [Embodiment 41] The method of embodiment 37 or 38, wherein the release period is at least 28 days. [Aspect 42] A method according to any one of aspects 36 to 41, wherein the disease is cancer. [Aspect 43] The method described in Aspect 42, wherein the cancer is hepatocellular carcinoma, liver cancer, prostate cancer or breast cancer.

Claims

1. Microbeads comprising a water-swellable polymeric material; and a complex comprising a carrier and a therapeutic agent associated with the carrier by non-covalent means; 1. A drug-loaded microbead composition comprising: the composite is embedded within the polymer material; the drug-loaded microbead composition has a water content of less than 1 wt. % based on the total weight of the drug-loaded microbead composition; the water-swellable polymeric material is a biodegradable polymeric material selected from poly(4-hydroxybutyrate), methacrylated hyaluronic acid, chitosan-alginate, poly(N-isopropylacrylamide) copolymer, poly(N-isopropylacrylamide)-alginate, poly(N-isopropylacrylamide)-peptide, poly(N-isopropylacrylamide)-poly(ethylene glycol) diacrylate-pentaerythritol tetrakis(3-mercaptopropionate), or any combination of the foregoing; the therapeutic agent is selected from sorafenib, vandetanib, regorafenib, irinotecan, epirubicin, pirarubicin, mitomycin C, a therapeutically acceptable salt of any of the foregoing, or a combination of any of the foregoing; The carrier is dextran sulfate. The above composition.

2. 10. The drug-loaded microbead composition of claim 1, wherein the therapeutic agent is not chemically bonded to the water-swellable polymeric material.

3. the water-swellable polymeric material comprises a polymer matrix shell encapsulating a particle core; The complex is disposed within the particle core. The drug-loaded microbead composition according to claim 1 or 2.

4. The drug-loaded microbead composition of any one of claims 1 to 3, wherein the carrier is embedded within an interpenetrating network of the water-swellable polymeric material of the drug-loaded microbead.

5. 5. The drug-loaded microbead composition according to claim 1, wherein the dextran sulfate is sodium dextran sulfate.

6. The drug-loaded microbead composition of any one of claims 1 to 5, wherein the drug-loaded microbeads are substantially spherical.

7. 7. The drug-loaded microbead composition of claim 1, wherein the drug-loaded microbeads have a diameter of from about 40 μm to about 800 μm.

8. The individual microbeads of the drug-loaded microbead composition have a weight ratio of: about 30% to about 70% by weight of a water-swellable polymeric material; about 1% to about 25% by weight of a therapeutic agent; about 1% to about 40% by weight of a carrier; Less than 1% by weight of water The drug-loaded microbead composition according to any one of claims 1 to 7, comprising:

9. 1. A method for preparing a drug-loaded microbead composition, comprising: dissolving a carrier and a therapeutic agent in an aqueous solvent to form an initial mixture comprising a complex of the carrier and the therapeutic agent; combining the initial mixture with a first solvent composition in which the therapeutic agent is less soluble than in the aqueous solvent to form a second mixture; rapidly stirring the second mixture to form particles of the composite in the second mixture; combining particles of the composite with a hydrogel of a water-swellable polymeric material to form a hydrogel mixture; combining the hydrogel mixture with a second solvent composition to form a synthesis mixture; rapidly stirring the synthesis mixture to form drug-loaded microbeads in the synthesis mixture; recovering the drug-loaded microbeads from the synthesis mixture; removing water from the drug-loaded microbeads to form a drug-loaded microbead composition having a water content of less than 1 wt. % based on the total weight of the drug-loaded microbeads in the drug-loaded microbead composition; Including, the therapeutic agent is selected from sorafenib, vandetanib, regorafenib, irinotecan, epirubicin, pirarubicin, mitomycin C, a therapeutically acceptable salt of any of the foregoing, or a combination of any of the foregoing; the water-swellable polymeric material is a biodegradable polymeric material selected from poly(4-hydroxybutyrate), methacrylated hyaluronic acid, chitosan-alginate, poly(N-isopropylacrylamide) copolymer, poly(N-isopropylacrylamide)-alginate, poly(N-isopropylacrylamide)-peptide, poly(N-isopropylacrylamide)-poly(ethylene glycol) diacrylate-pentaerythritol tetrakis(3-mercaptopropionate), or any combination of the foregoing; The carrier is dextran sulfate. The above method.

10. 10. The method of claim 9, further comprising filtering the second mixture to recover the particles of the composite prior to combining the particles of the composite with the hydrogel of the water-swellable polymeric material.

11. 11. The method of claim 9 or 10, wherein removing water comprises freeze-drying the drug-loaded microbeads.

12. freeze-drying the drug-loaded microbeads to remove water; further drying the freeze-dried drug-loaded microbeads by air, temperature change, vacuum, or any combination thereof; 11. The method of claim 9 or 10, comprising:

13. the drug-loaded microbeads have an average synthesis volume upon recovery from the synthesis mixture and an average final volume after removal of water; the average final volume is from about 10% to about 75% of the average composite volume; The method according to any one of claims 9 to 12.

14. 1. A method for preparing a drug-loaded microbead composition, comprising: dissolving a carrier and a therapeutic agent in an aqueous solvent to form an initial mixture comprising a complex of the carrier and the therapeutic agent; combining the initial mixture with a hydrogel solution of a water-swellable polymeric material to form a hydrogel mixture; combining the hydrogel mixture with a solvent composition to form a synthesis mixture; rapidly stirring the synthesis mixture to form drug-loaded microbeads in the synthesis mixture; recovering the drug-loaded microbeads from the synthesis mixture; drying the drug-loaded microbeads to form a drug-loaded microbead composition having a moisture content of less than 1 wt. % based on the total weight of the drug-loaded microbeads in the drug-loaded microbead composition; Including, the therapeutic agent is selected from sorafenib, vandetanib, regorafenib, irinotecan, epirubicin, pirarubicin, mitomycin C, a therapeutically acceptable salt of any of the foregoing, or a combination of any of the foregoing; the water-swellable polymeric material is a biodegradable polymeric material selected from poly(4-hydroxybutyrate), methacrylated hyaluronic acid, chitosan-alginate, poly(N-isopropylacrylamide) copolymer, poly(N-isopropylacrylamide)-alginate, poly(N-isopropylacrylamide)-peptide, poly(N-isopropylacrylamide)-poly(ethylene glycol) diacrylate-pentaerythritol tetrakis(3-mercaptopropionate), or any combination of the foregoing; The carrier is dextran sulfate. The above method.

15. The method of claim 14, wherein drying the drug-loaded microbeads comprises freeze-drying the drug-loaded microbeads.

16. Drying the drug-loaded microbeads comprises the steps of: freeze-drying the drug-loaded microbeads; further drying the freeze-dried drug-loaded microbeads with air, heat, vacuum, or any combination thereof; 15. The method of claim 14, comprising:

17. the drug-loaded microbeads have an average synthesis volume upon recovery from the synthesis mixture and an average final volume after drying of the drug-loaded microbeads; the average final volume is from about 10% to about 75% of the average composite volume; The method according to any one of claims 14 to 16.

18. A drug-loaded microbead composition according to any one of claims 1 to 8, an aqueous solution in an amount sufficient to swell the drug-loaded microbeads of the drug-loaded microbead composition, whereby the swollen drug-loaded microbeads have a water content of 50% to 95% by weight based on the total weight of the drug-loaded microbeads; An embolic composition comprising:

19. 20. The embolic composition of claim 18, wherein the aqueous solution is a physiologically buffered saline solution.

20. The embolic composition contains 100% swollen individual drug-loaded microbeads, based on the total weight of the swollen individual drug-loaded microbeads. about 3% to about 10% by weight of a water-swellable polymeric material; about 0.1% to about 2.5% by weight of a therapeutic agent; about 0.1% to about 4.0% by weight of a carrier; about 50% to about 96% by weight of water; 20. The embolic composition of claim 18 or 19, comprising:

21. 1. A method for preparing an embolic composition, comprising: adding the drug-loaded microbead composition of any one of claims 1 to 8 to an aqueous solution in an amount sufficient to swell the drug-loaded microbeads of the drug-loaded microbead composition, whereby the swollen drug-loaded microbeads have a water content of 50% to 95% by weight based on the total weight of the drug-loaded microbeads, to form an injectable solution; loading the injectable solution into an injection device; The above method, comprising:

22. 22. The method of claim 21, further comprising the step of allowing the drug-loaded microbeads to swell for a rehydration time of about 5 minutes to about 60 minutes before loading the injectable solution into the injection device.

23. 23. The method of claim 21 or 22, wherein the aqueous solution is a physiologically buffered saline solution.

24. A composition for treating a disease, comprising: The embolic composition according to any one of claims 18 to 20 is provided to a subject in need of embolic therapy. The above composition.

25. After the embolic composition is delivered, at least a portion of the drug-loaded microbeads flow through the vasculature of the subject to the embolization site and restrict blood flow at the embolization site; the drug-loaded microbeads release at least 90% by weight of the therapeutic agent based on the initial amount of the therapeutic agent embedded in the microbeads before the embolic composition is applied to the tissue at the embolization site over a release period; 25. The composition of claim 24.

26. 26. The composition of claim 25, wherein the release into the tissue at the embolization site comprises an initial burst of release during which at least 10% by weight of the initial amount of therapeutic agent is released.

27. 27. The composition of claim 25 or 26, wherein the drug-loaded microbeads provide sustained release of the therapeutic agent to the tissue over the release period.

28. The composition of any one of claims 25 to 27, wherein the release period is at least 14 days.

29. 27. The composition of claim 25 or 26, wherein the release period is at least 28 days.

30. The composition according to any one of claims 24 to 29, wherein the disease is cancer.

31. The composition of claim 30, wherein the cancer is hepatocellular carcinoma, liver cancer, prostate cancer, or breast cancer.

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