Hydrogel as oral delivery dosage form, and method for producing and using the same

Abstract

To provide a hydrolyzable hydrogel as an oral dosage form into which a nutrient component and / or a therapeutic component are encapsulated for nutrient purpose, pharmaceutical purpose, and / or veterinary purpose, and can be orally delivered to a patient in need of the hydrogel.SOLUTION: Provided is a hydrogel matrix including: a backbone including a single component polymer chain or a multicomponent polymer chain; and a hydrolyzable binding site which is covalently bonded to two or more of the polymer chains, and connects the chains.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 893,529, filed August 29, 2019, the entire contents of which are incorporated herein by reference.

[0002] The present disclosure generally relates to the use of hydrolytically degradable cross-linked polymer gels (also called disintegrating hydrogels) as oral dosage forms that can encapsulate and orally deliver nutritional and / or therapeutic ingredients to patients in need thereof for nutritional, pharmaceutical, and / or veterinary purposes. [Background technology]

[0003] Environmentally responsive hydrogels have been previously used for many purposes, including, but not limited to, drug delivery (US9644039B2), three-dimensional cell culture media (PM Kharkar, KL Kiick, & AM Kloxin, Chem. Soc. Rev., 2013, 42,7335), subterranean oil recovery (US20070281870A1, US20070277981A1), and curing epoxy resins (US10214479B2). Environmentally responsive polymers have also been designed for targeted drug delivery (US20090220615A1) (C. Dingels, SS Muller, T. Steinbach, C. Tonhauser, H. Frey, Biomacromolecules 2013, 14, 448).

[0004] The chemical structure of the crosslinker that allows it to react with environmental conditions varies depending on the application and the corresponding reaction time scale. Examples of chemical structures used in the life sciences include silyl ethers, pentaerythritol, trimethyl orthoformate, and ketal functional groups covalently linked with hydroxyethyl (meth)acrylate as terminal groups (US20070281870A1; US20070277981A1; S. Kim, O. Linker, K. Garth, KR Carter. Polym. Degrad. Stab. 2015, 121, 303), ketal groups linked with amines as terminal groups that are crosslinked via diepoxides (US10214479B2), poly-hydroxyl polymers crosslinked with ketals, e.g., poly(vinyl alcohol), poly(hydroxyethyl methacrylate), and polysaccharides using aldehydes, ketones, acetals, and / or vinyl ethers (US9644039B2), and trehalose diacrylate with additional short linkages such as benzyl or hydroxyethyl groups (M. Burek, S. Waskiewicz, A. Lalik, I. Wandzik, Polym. Chem. 2018, 9, 3721), cyclic acetals crosslinked via thiol-ene click chemistry (K. Wang, J. Lu, R. Yin, L. Chen, S. Du, Y. Jiang, Q. Yu, Mater. Sci. Eng. C 2013, 33, 1261; K. Wang, NAN Zhang, J. Lu, R. Yin, JUN Nie, Q. Yu, J. Polym. Mater. 2014, 31, 89) or free radical polymerization methods (S. Kaihara, S. Matsumura, JP Fisher, Macromolecules 2007, 40, 7625), acetone (VT Huynh, S. Binauld, PL De Souza, MH Stenzel, Chem. Mater. 2012, 24, 3197) or benzaldehyde derivatives (US7056901 B2; N. Murthy, Y.X. Thng, S.These include di-hydroxyethyl methacrylamide ketals formed with hydroxyethyl acrylate (Y. Wang, J. Zheng, Y. Tian, ​​W. Yang, J. Mater. Chem. B 2015, 3, 5824; S. Luan, Y. Zhu, X. Wu, Y. Wang, F. Liang, S. Song, ACS Biomater. Sci. Eng. 2017, 3, 2410), and silyl ethers coupled with di-hydroxyethyl acrylate (MC Parrott, JC Luft, JD Byme, JH Fain, ME Napier, and JM DeSimone, J. Am. Chem. Soc. 2010, 132, 17928). Research has also demonstrated the synthesis of non-crosslinked polymers containing silyl ether functional groups that can be subjected to acid-catalyzed hydrolysis to break the polymer down into smaller polymers (P. Shieh, H.V.T. Nguyen and J.A. Johnson, Nature Chem. 2019, 11, 1124). Summary of the Invention

[0005] Quick Overview The present disclosure relates to the chemical composition, methods of manufacture, and use of cross-linked polymeric materials known as hydrogels as final dosage forms for the oral delivery of compounds of nutritional, therapeutic, and / or veterinary value, including, but not limited to, supplements, cell-based therapies, and active pharmaceutical ingredients, to patients in need thereof. The hydrogels contain two major components: backbone chains and hydrolytically degradable linkages that connect or cross-link the backbone chains. This design uniquely facilitates both (1) the mechanically and chemically stable encapsulation of payload materials, such as food-grade or pharmaceutical-grade materials, within the hydrogel pore spaces between the backbone chains, and (2) the rapid disintegration of the hydrogel structure through degradation of the degradable linkages (either by acid-catalyzed hydrolysis or enzyme-catalyzed cleavage) in acidic and / or neutral fluids, including, but not limited to, the gastrointestinal fluids of the stomach and GI tract. Hydrogels are produced by polymerizing hydrolytically degradable crosslinkers containing degradable linkages covalently bonded to polymerizable groups, which are converted into backbone chains upon completion of the polymerization reaction. For purposes of this disclosure, a hydrolytically degradable crosslinker (sometimes simply referred to as a crosslinker) is defined as a multifunctional chemical entity containing hydrolytically degradable linkages (sometimes simply referred to as linkages), which are chemical entities containing one or more hydrolytically degradable functional groups covalently bonded to two or more polymerizable functional groups. When a linkage is degraded, the covalent bond attaching it to the crosslinker's polymerizable functional groups remains. Thus, the backbone chain is formed by the crosslinker's polymerizable functional groups and any additional polymerizable monomers (sometimes simply referred to as monomers) present in solution during the polymerization reaction. The hydrophilic nature of the crosslinker's linkage moiety and its hydrolysis products allows the release of the water-soluble polymer with a graft / comb structure along with the payload material from the hydrogel pores. Importantly, the chemical structure of the crosslinker includes a biocompatible chemical structure that ensures low toxicity, such as, but not limited to, poly(ethylene glycol) (also known as PEG).If the backbone chains also contain hydrophobic alkyl chains, such as octadecyl acrylate, the released comb polymers have surfactant characteristics that help improve the solubility of the hydrogel payload, especially pharmaceutical and / or food-grade contents. [The present invention 1001] a backbone comprising a single-component polymer chain or a multi-component polymer chain; a hydrolytically degradable linkage covalently bonded to and connecting two or more of the polymer chains; A hydrogel matrix comprising: [The present invention 1002] 1001. The hydrogel matrix of the present invention, wherein the single-component or multi-component polymer chains are comprised of monomers selected from methacrylic acid, methyl methacrylate, ethyl methacrylate, butyl methacrylate, dimethylaminoethyl methacrylate, methacrylamide, hydroxyethyl methacrylate, 2-(methacryloyloxy)ethyltrimethylammonium chloride, poly(ethylene glycol) methacrylate, cetyl methacrylate, lauryl methacrylate (or acrylate derivatives of any methacrylate component), polymerizable surfactants, hydrolyzable surfactant monomers, 2-acrylamido-2-methylpropanesulfonic acid, vinylphosphonic acid, N-vinylcaprolactam, N-vinylpyrrolidone, vinyl acetate, and vinyl alcohol, alone or as copolymers in any combination thereof. [The present invention 1003] The joint is At least one functional group that degrades within 5 minutes to 12 hours at pH 0-8, causing a transformation from a cross-linked hydrogel into multiple polymer chains The hydrogel of the present invention 1001, comprising: [The present invention 1004] The hydrogel of the present invention 1003, wherein degradation occurs within 10 minutes to 2 hours. [The present invention 1005] The hydrogel of the present invention 1003, wherein degradation occurs within 15 to 60 minutes. [The present invention 1006] The hydrogel of the present invention 1003, wherein degradation occurs under acidic and / or neutral conditions in the pH range of 1-7. [The present invention 1007] The hydrogel of the present invention 1003, wherein degradation occurs under acidic and / or neutral conditions in the pH range of 1-5. [The present invention 1008] The hydrogel of the present invention 1003, wherein degradation occurs under acidic and / or neutral conditions in the pH range of 1-4. [The present invention 1009] The hydrogel of the present invention 1003, wherein the hydrolytically degradable functional group contained within the linkage is selected from acetal, anhydride, boronic ester, enamine, hydrazone, imide, imine, ketal, oxime, alkylsilyl ether, polysiloxane, or silyl ether groups. [The present invention 1010] 1001. The hydrogel of the present invention, wherein the hydrolytically degradable linkage comprises at least one of a ketal or acetal functional group as the acid-labile degradable functional group. [The present invention 1011] 1001. The hydrogel of the present invention, wherein the hydrolytically degradable linkage is PEG-based. [The present invention 1012] Hydrolytically degradable bonds Hydrolytically degradable crosslinkers consisting of two or more polymerizable functional groups and a covalently bonded linkage The hydrogel of the present invention 1001, which is formed by polymerizing [The present invention 1013] The hydrolytically degradable crosslinker A central poly(ethylene glycol) segment with a molecular weight of 150 g / mol or greater, with acetal functional groups attached to both terminal hydroxyl groups and bearing PEG methacrylate with a molecular weight of 174 g / mol or greater. The hydrogel of the present invention 1012, comprising: [The present invention 1014] 1012. The hydrogel of claim 10, wherein the hydrolytically degradable crosslinker comprises triethylene glycol di[ethyl-1-methacryloyloxypoly(ethylene glycol) acetal]. [The present invention 1015] The hydrolytically degradable crosslinker acetone di[methacryloyloxypoly(ethylene glycol)] ketal or acetaldehyde acryloyloxyethanol methacryloyloxypoly(ethylene glycol) acetal, with or without triethylene glycol di[ethyl-1-methacryloyloxypoly(ethylene glycol) acetal], or a combination thereof The hydrogel of the present invention 1012. [The present invention 1016] 1012. The hydrogel of claim 10, wherein the hydrolytically degradable crosslinker is di[methacryloyloxypoly(ethylene glycol)]dimethylsilyl ether, methacryloyloxypoly(ethylene glycol)methacryloylpropyldimethylsilyl ether, or poly(ethylene glycol)di[methacryloylpropyldimethylsilyl ether], or a combination thereof. [The present invention 1017] 1001. A hydrogel of the present invention, comprising 0.1 mol % to 100 mol % of a crosslinker, the remainder being composed of polymer chains of any composition. [The present invention 1018] 1001. A hydrogel of the present invention, comprising 0 mol % to 50 mol % of a crosslinker, with the remainder being composed of polymer chains of any composition. [The present invention 1019] 1001. A hydrogel of the present invention, comprising 0 mol % to 40 mol % of a crosslinker, with the remainder being composed of polymer chains of any composition. [The present invention 1020] 1001. A hydrogel of the present invention, comprising 10 mol % to 30 mol % of a crosslinker, the remainder being composed of polymer chains of any composition. [The present invention 1021] 1001. A hydrogel according to the present invention, comprising 20 mol% triethylene glycol di[ethyl-1-methacryloyloxypoly(ethylene glycol) acetal] crosslinker, 40 mol% methyl methacrylate, and 40 mol% dimethylaminoethyl methacrylate. [The present invention 1022] 1001. A hydrogel of the present invention comprising 100 mol % triethylene glycol di[ethyl-1-methacryloyloxypoly(ethylene glycol) acetal] crosslinker and formed from a 25 vol % precursor solution in a solvent containing 5 vol % photoinitiator. [The present invention 1023] The hydrogel of the present invention 1001, wherein the hydrolyzable hydrogel encapsulates a payload comprising a nutritional supplement, an active pharmaceutical ingredient, or a cell-based supplement or therapy such that the hydrogel can serve as an oral dosage form for these materials. [The present invention 1024] The active pharmaceutical ingredient contained within the voids of the hydrogel is of the following chemical class: Kinase inhibitors, statins, hormones, antioxidants, macrolides, NSAIDs, anti-infectives, retinoids, cannabinoids, anthracyclines, and hyperlipidemic agents The hydrogel of the present invention 1023, which is a component of one of the above. [The present invention 1025] 1023. A hydrogel of the present invention, wherein the pharmaceutically active ingredient has a lipophilic partition coefficient in the range of 0.5 to 10.5, a melting temperature in the range of -54°C to 301°C, and / or a molecular weight in the range of 174 g / mol to 1203 g / mol. [The present invention 1026] The hydrogel of the present invention 1023, wherein the active pharmaceutical ingredient is present in a content of 1 wt% to 90 wt%, 10 wt% to 70 wt%, and 20 wt% to 60 wt%. [The present invention 1027] 1001. The hydrogel of the present invention, wherein the polymer chains contain 1% to 50%, or 5% to 25%, or 10% to 20% by molar of hydrophobic ligands covalently bonded to said polymer chains. [The present invention 1028] Self-emulsifying or spontaneous micelle-forming lipid solutions that may contain organic solvents, hydrophobic solvents (oils), surfactants, and cosurfactants, either alone or in any possible combination. The hydrogel of the present invention 1001, which defines a void containing [The present invention 1029] The hydrogel of the present invention 1028, wherein the lipid solution also contains an active pharmaceutical ingredient. [The present invention 1030] The hydrogel of the present invention 1001, further comprising a payload encapsulated between the polymer chains of the backbone. [The present invention 1031] The hydrogel of the present invention 1030, wherein the payload comprises one or more of a food-grade material, a supplement, a pharmaceutical nutraceutical, a therapeutic agent, an active ingredient, or a combination thereof. [Brief explanation of the drawings]

[0006] [Figure 1] FIG. 1 is a schematic representation of the polymerization and subsequent hydrolysis reaction of the collapsing hydrogels described herein. [Figure 2] FIG. 1 is a schematic illustration of drug loading and release of payload within a collapsing hydrogel. [Figure 3] Dissolution profiles of vitamin E (tocopherol) encapsulated in hydrogels composed of 25% vol. acetal crosslinker at various drug loading levels were dissolved in 0.1 M HCl solution (pH = 1). The ratio of the final concentration of vitamin E to its intrinsic solubility (X_sat) varied with the drug loading level. [Figure 4] Dissolution profile of fenofibrate encapsulated in hydrogels composed of 20% acetal crosslinker by volume and 0%, 15%, or 10% surfactant by volume, dissolved in 0.1 M HCl solution (pH=1). [Figure 5]This is the dissolution profile of progesterone encapsulated in a hydrogel composed of 20% by volume acetal crosslinker and 15% or 10% by volume surfactant, dissolved in 0.1 M HCl solution (pH=1). [Figure 6] Figure 1 shows the dissolution profile of lumefantrine concentrations released into simulated gastric fluid from disintegrating hydrogel tablets constructed with 25% acetal crosslinker by volume at several different drug loading levels compared to pure crystalline lumefantrine (labeled "in buffer"). For comparison, this figure includes the dissolution profile of pure crystalline lumefantrine released into a hydrogel tablet solution (labeled "polymer solution") that had been pre-disintegrated in simulated gastric fluid. [Figure 7] Dissolution profiles of diflunisal concentrations after release as pure crystalline material in simulated gastric fluid at both low and high drug loading levels compared to release from a collapsing hydrogel constructed with 25% acetal crosslinker by volume. [Figure 8] 10 is a dissolution profile of clofazimine concentration after release as pure crystalline material in simulated gastric fluid compared to release from a collapsing hydrogel constructed with 25% acetal crosslinker by volume. [Figure 9] Dissolution profiles of retinoic acid concentrations after release as pure material in simulated gastric fluid at both low and high drug loading levels compared to release from a collapsing hydrogel constructed with 25% acetal crosslinker by volume. [Figure 10] Dissolution profile of Coenzyme Q10 concentration after release as pure crystalline material in simulated gastric fluid compared to release from a disintegrating hydrogel composed of 25% acetal crosslinker, 0.7% methyl methacrylate, 2.2% dimethylaminoethyl methacrylate, and 1.1% butyl methacrylate by volume. [Figure 11]Figure 11 shows the dissolution profile of albendazole concentrations after release as pure crystalline material in simulated gastric fluid compared to the release from disintegrating hydrogels composed of 25% acetal crosslinker by volume and 30% silyl ether crosslinker by volume. [Figure 12] 1 shows the dissolution profile of amphotericin B concentration after release as pure crystalline material in simulated gastric fluid compared to the release from a collapsing hydrogel composed of 25% acetal crosslinker by volume and a collapsing hydrogel composed of 30% silyl ether crosslinker by volume. [Figure 13] 10 is a dissolution profile of eicosapentaenoic acid concentration after release as pure material in simulated gastric fluid compared to release from a disintegrating hydrogel constructed with 25% acetal crosslinker by volume. [Figure 14] 10 is a dissolution profile of atorvastatin concentration after release as pure crystalline material in simulated gastric fluid compared to release from a disintegrating hydrogel constructed with 25% acetal crosslinker by volume. [Figure 15] 10 is a dissolution profile of ibuprofen concentration after release as pure crystalline material in simulated gastric fluid compared to release from a disintegrating hydrogel constructed with 25% acetal crosslinker by volume. [Figure 16] 10 is a dissolution profile of nilotinib concentration after release as pure crystalline material in simulated gastric fluid compared to release from a collapsing hydrogel constructed with 25% acetal crosslinker by volume. [Figure 17] 10 is a dissolution profile of anthraquinone concentrations after release as pure crystalline material in simulated gastric fluid compared to release from a disintegrating hydrogel constructed with 25% acetal crosslinker by volume. [Figure 18] 10 is a dissolution profile of cannabidiol concentration after release as pure crystalline material in simulated gastric fluid compared to release from a collapsing hydrogel constructed with 25% acetal crosslinker by volume. [Figure 19]Pazopanib concentration profile upon transfer to fasted simulated intestinal fluid after release as pure crystalline material in simulated gastric fluid compared to release from a collapsing hydrogel constructed with 25% vol acetal crosslinker. DETAILED DESCRIPTION OF THE INVENTION

[0007] Detailed Description This disclosure relates to the chemical composition, methods of manufacture, and use of cross-linked polymeric materials known as hydrogels as final dosage forms for the oral delivery of compounds of nutritional, therapeutic, and / or veterinary value, including, but not limited to, supplements, cell-based therapies, and active pharmaceutical ingredients, to patients in need thereof. Hydrogels contain two major components: backbone chains and hydrolytically degradable linkages that connect or cross-link the backbone chains. This design uniquely facilitates both (1) the mechanically and chemically stable encapsulation of payload materials, such as food-grade or pharmaceutical-grade materials, within the hydrogel pore spaces between the backbone chains, and (2) the rapid disintegration of the hydrogel structure via degradation of the degradable linkages (either by acid-catalyzed hydrolysis or enzyme-catalyzed cleavage) in acidic and / or neutral fluids, including, but not limited to, the gastrointestinal fluids of the stomach and GI tract. Hydrogels are produced by polymerizing hydrolytically degradable crosslinkers containing degradable linkages covalently bonded to polymerizable groups, which are converted into backbone chains upon completion of the polymerization reaction. For purposes of this disclosure, a hydrolytically degradable crosslinker (sometimes simply referred to as a crosslinker) is defined as a multifunctional chemical entity containing hydrolytically degradable linkages (sometimes simply referred to as linkages), which are chemical entities containing one or more hydrolytically degradable functional groups covalently bonded to two or more polymerizable functional groups. When a linkage is degraded, the covalent bond attaching it to the crosslinker's polymerizable functional groups remains. Thus, the backbone chain is formed by the crosslinker's polymerizable functional groups and any additional polymerizable monomers (sometimes simply referred to as monomers) present in solution during the polymerization reaction. The hydrophilic nature of the crosslinker's linkage moiety and its hydrolysis products allows the release of the water-soluble polymer with a graft / comb structure along with the payload material from the hydrogel pores. Importantly, the chemical structure of the crosslinker includes a biocompatible chemical structure that ensures low toxicity, such as, but not limited to, poly(ethylene glycol) (also known as PEG).If the backbone chains also contain hydrophobic alkyl chains, such as octadecyl acrylate, the released comb polymers have surfactant characteristics that help improve the solubility of the hydrogel payload, especially pharmaceutical and / or food-grade contents.

[0008] Before describing the compositions and methods of the present invention in further detail, it should be understood that the invention is not limited to the particular processes, compositions, or methodologies described, as these processes, compositions, or terminology may vary. It should also be understood that the methodologies used herein are intended to describe particular versions or embodiments only, and are not intended to limit the scope of the present invention, which is limited only by the appended claims. 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. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of the present invention, preferred methods, devices, and materials will now be described. All publications mentioned herein are incorporated by reference in their entirety. Nothing herein should be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention.

[0009] It should also be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, a reference to a "combustion chamber" is a reference to "one or more combustion chambers" and equivalents thereof known to those skilled in the art, and so forth.

[0010] As used herein, the term "about" means +10% or -10% of the numerical value of the number with which it is being used. Thus, "about 50" means "within the range of 45 to 55."

[0011] The present disclosure relates to the chemical composition, manufacturing methods, and use of cross-linked polymeric materials known as hydrogels as final dosage forms for the oral delivery of payloads, which may contain compounds of nutritional, therapeutic, and / or veterinary value, including, but not limited to, supplements, probiotics, cell-based therapies, and active pharmaceutical ingredients. Hydrogels contain two major components: backbone chains and hydrolytically degradable linkages connecting the backbone chains. This design uniquely facilitates both (1) mechanically and chemically stable encapsulation of the payload within the hydrogel pore spaces between the polymer chains and (2) rapid disintegration of the hydrogel structure through degradation of the linkages (either by acid-catalyzed hydrolysis or enzyme-catalyzed cleavage) in acidic and neutral fluids, including, but not limited to, the gastrointestinal fluids of the stomach and GI tract. Even as the linkages degrade, the covalent bonds attaching them to the polymerizable functional groups of the crosslinker remain. Thus, the backbone chains are formed by the polymerizable functional groups of the crosslinker and any additional monomers present in solution during the polymerization reaction. The hydrophilicity of the crosslinker ensures hydration of the crosslinker and subsequent degradation in aqueous solutions, resulting in the release of the water-soluble polymer with a graft / comb structure along with the payload material in the hydrogel pores. In this way, payloads that are poorly or insoluble in water can be delivered to an aqueous environment. If the backbone chain also contains a hydrophobic alkyl chain, such as methyl methacrylate, ethyl methacrylate, butyl methacrylate, dodecyl methacrylate, or octadecyl methacrylate, or their acrylate derivatives, the released branched polymer will have amphiphilic characteristics (similar to surfactants). This amphiphilic characteristic helps improve the solubility of the hydrogel payload. Some embodiments include the following:

[0012] Hydrogel matrices containing hydrolytically degradable crosslinkers can disintegrate into water-soluble degradation products in acidic to neutral buffers. For rapid release, degradation should occur within 2 hours, but release at specific GI tract locations can be tailored by adjusting the degradation rate and pH sensitivity.

[0013] A sufficiently hydrophobic, hydrolytically degradable hydrogel matrix is ​​used to encapsulate a payload, such as an organic liquid solution, within the matrix and subsequently release it for nutritional and / or therapeutic effect.

[0014] The chemical structure of the amphiphilic polymer released upon hydrogel degradation provides surfactant-like characteristics that can improve the solubility of payloads released from the hydrogel simultaneously with the hydrogel degradation products. Examples of amphiphilic polymer structures include, but are not limited to, a hydrophobic polymer backbone (e.g., polymethacrylic acid) branched with hydrophilic chains (e.g., polyethylene glycol) or a hydrophilic polymer backbone (e.g., polyvinylpyrrolidone) branched with hydrophobic chains (e.g., butyl acrylate).

[0015] Suitable hydrogel matrices comprise single- or multi-component backbone polymer chains connected by hydrolytically degradable linkages covalently bonded to the polymer chains. Single-component polymer chains are released upon hydrogel degradation when the hydrogel contains only crosslinkers, whereby the backbone chains consist of the polymerizable functional groups of the crosslinkers. Multi-component polymer chains are released from degradation of hydrogels containing crosslinkers and additional monomers.

[0016] Examples of chemical structures that can be used as monomers (i.e., additional polymer components) include methacrylic acid, methyl methacrylate, ethyl methacrylate, butyl methacrylate, dimethylaminoethyl methacrylate, methacrylamide, hydroxyethyl methacrylate, 2-(methacryloyloxy)ethyltrimethylammonium chloride, poly(ethylene glycol) methacrylate, cetyl methacrylate, lauryl methacrylate (or the acrylate derivative of any methacrylate component), 2-acrylamido-2-methylpropanesulfonic acid, vinylphosphonic acid, N-vinylcaprolactam, N-vinylpyrrolidone, vinyl acetate, and vinyl alcohol, alone or as copolymers in any combination thereof.

[0017] The crosslinker contains at least one hydrolytically degradable functional group within the bond that degrades under acidic and / or neutral conditions in the pH range of 0-8, 1-7, 1-5, or 1-4.

[0018] Exemplary hydrolytically degradable functional groups contained in the crosslinker include, but are not limited to, acetal, anhydride, boronic ester, enamine, hydrazone, imide, imine, ketal, oxime, alkylsilyl ether, and silyl ether functional groups.

[0019] In some embodiments, the hydrolytically degradable linker contains at least one of a ketal, acetal, alkylsilyl ether, or silyl ether functional group as the degradable functional group. In the case of multiple silyl ether functional groups, they may be separated from each other by, for example, poly(ethylene glycol), or may be constructed adjacent to each other in the form of a multi-unit segment, for example, poly(dimethylsiloxane).

[0020] In some cases, the hydrolytically degradable linkage is poly(ethylene glycol)-based.

[0021] In some embodiments, the hydrolytically degradable crosslinker comprises one or two silyl ethers, alkylsilyl ethers, or polysiloxanes as hydrolyzable functional groups. Either one silyl ether or polysiloxane can be used to covalently bond two poly(ethylene glycol) methacrylate moieties (see Formula I below). TIFF2025183290000002.tif31128In formula, z is the number of polydimethylsiloxane repeat units, where a silyl ether is represented by z=1 and a polysiloxane is represented by z≧2; w represents the number of polyethylene glycol units between the hydrolyzable functional group and the polymerizable functional group, and w≧2.

[0022] In some embodiments, z is 3 to 7, in which case cyclomethicone can be formed after hydrolysis of two alkylsilyl ether groups on either side of the linear polydimethylsiloxane entity. Thus, the z value can range from 2 to 1000, 2 to 100, 2 to 20, 3 to 20, 3 to 10, 3 to 7, 4 to 7, 4 to 6, or 4 to 5.

[0023] An embodiment containing two silyl ether groups or two polysiloxane segments separated from each other by a linker may consist of a central polyethylene glycol flanked on either side by dimethylsiloxane functional groups, each of which is also bound to a polyethylene glycol methacrylate functional group (see Formula II below). TIFF2025183290000003.tif31129

[0024] The number of repeat units in the central polyethylene glycol linker separating the two hydrolyzable groups (embodiments shown in Formula II have either a silyl ether group with z=1 or a polysiloxane group with z≧2, or a mixture of the two) is represented by parameter x, which may vary from 1 to 1,000, 1 to 100, 1 to 50, 3 to 50, 3 to 25, or 3 to 10. The number of repeat units in the polyethylene glycol chain separating the polymerizable functional group (represented by the methacrylate group in Formula II below) and the hydrolyzable group is represented by parameter y, which may vary from 1 to 1,000, 1 to 100, 1 to 50, 2 to 50, 2 to 25, 2 to 10, 3 to 25, or 3 to 10.

[0025] Certain hydrolyzable functional groups are anisotropic because they have only one covalent bond that can be hydrolyzed. One embodiment of this type of crosslinker, in which one anisotropic hydrolyzable group is an alkylsilyl ether, may consist of poly(ethylene glycol) methacrylate linked to a methacryloylpropyldimethylsilane group (see Formula III below). TIFF2025183290000004.tif33128

[0026] In Formula III, the parameter v represents the number of polyethylene glycol repeat units separating the polymerizable group (the methacrylate functional group in Formula III) and the anisotropic hydrolyzable group, and v may vary from 1 to 1,000, 1 to 100, 1 to 50, 1 to 25, 1 to 10, 2 to 50, 2 to 25, 2 to 10, 3 to 50, 3 to 25, or 3 to 10.

[0027] One embodiment containing two anisotropic hydrolyzable groups, both alkylsilyl ether groups, may consist of two methacryloylpropyldimethylsilane groups attached to a poly(ethylene glycol) moiety of any molecular weight, but preferably large enough to create a pore size large enough to load a large amount of drug (see Formula IV below). The parameter x is the same as defined above in Formula II and specifies the number of polyethylene glycol repeat units separating the two hydrolyzable groups within the crosslinker. TIFF2025183290000005.tif37135

[0028] In some embodiments, the hydrolytically degradable crosslinker contains acetal and / or ketal hydrolyzable functional groups instead of the silane-based hydrolyzable functional groups discussed above. One embodiment comprises a central poly(ethylene glycol) segment of molecular weight greater than or equal to about 150 g / mol (corresponding to a parameter x equal to or greater than 3) with acetal functional acetaldehyde groups attached to both of the terminal hydroxyl groups, which are simultaneously linked to PEG methacrylate groups of molecular weight greater than or equal to about 174 g / mol (corresponding to a parameter y equal to or greater than 2) (see Formula V below). TIFF2025183290000006.tif28131

[0029] In some embodiments, the structure of the acid-catalyzed hydrolyzable crosslinker contains two hydrolyzable ketal functional groups and two polymerizable methacrylate functional groups.

[0030] In some embodiments, the crosslinker is triethylene glycol di[ethyl-1-methacryloyloxypoly(ethylene glycol) acetal], which is equivalent to the following formula V with parameter x=3 and parameter y=9. This crosslinker forms effective collapsing hydrogels when formulated in the precursor solution (prior to polymerization of the polymerizable functional groups) at a concentration equal to or greater than about 10% by volume to ensure the formation of a mechanically stable polymer network, or at a concentration equal to or less than about 35% by volume to ensure hydrolytic collapse of the polymer network to nearly completely release the payload encapsulated within the pores of the network. Compositions containing concentrations greater than about 35% are the subject of future experimentation.

[0031] Other suitable crosslinkers include, but are not limited to, acetone di[methacryloyloxypoly(ethylene glycol)] ketal (see Formula VI below) and acetaldehyde acryloyloxyethanol methacryloyloxypoly(ethylene glycol) acetal (see Formula VII below). TIFF2025183290000007.tif60128

[0032] The parameter w is the same as that described above for hydrolyzable crosslinkers containing silane-based hydrolyzable functional groups. The embodiment shown in Formula VII is an example of an anisotropic hydrolyzable crosslinker, where the value of the parameter w on one side of the hydrolyzable functional group is 1, and on the other side, it can be any number as described in the ranges indicated above. Hydrogels made from acetaldehyde acryloyloxyethanol methacryloyloxypoly(ethylene glycol) acetal do not completely degrade when the volume fraction of the crosslinker exceeds about 20% in the precursor solution during synthesis. The exact mechanism that prevents hydrolysis (e.g., steric hindrance, fast reverse reaction, etc.) is unknown.

[0033] Other crosslinkers include acetone di(hydroxyethyl acrylate) ketal (see Formula VIII below) and acetone di(hydroxyethyl methacrylate) ketal (see Formula IX below). Without wishing to be bound by theory, the close proximity of the hydrolyzable ketal and polymerizable functional groups in these crosslinkers slows but does not stop the acid-catalyzed hydrolysis reaction, resulting in slow drug release. Additionally, the low molecular weight of the crosslinkers reduces swelling in the presence of organic solvents, thereby reducing the payload that can be encapsulated in the hydrogel pores. TIFF2025183290000008.tif55128

[0034] The hydrogel may contain 0.1 mol % to 100 mol % crosslinker, with the remainder made up of 0% to 99.9%, or 1% to 50%, or 5% to 25%, or 10% to 20% monomer.

[0035] In one embodiment, the hydrogel composition contains 20 mol% triethylene glycol di[ethyl-1-methacryloyloxypoly(ethylene glycol) acetal] crosslinker, 40 mol% methyl methacrylate, and 40 mol% dimethylaminoethyl methacrylate.

[0036] The hydrogel composition contains 100 mole % triethylene glycol di[ethyl-1-methacryloyloxypoly(ethylene glycol) acetal] which is cured in solution to a 25 volume % hydrogel.

[0037] Hydrolytically Degradable Hydrogels Containing Active Ingredients as Oral Dosage Forms - Patent application In some cases, the hydrolyzable hydrogel contains additional inactive ingredients, including, but not limited to, solvents, oils / lipids, surfactants, and polymers, such that it can serve as a payload, including nutritional supplements, active pharmaceutical ingredients, cell-based supplements, or cell-based therapies, as well as oral dosage forms of these materials.

[0038] Hydrophobically modified hydrolytic hydrogels that degrade into surfactant-like amphiphilic molecules In some cases of collapsing hydrogels containing 100% crosslinker, the polymer chains released upon hydrolysis of the hydrolyzable functional groups contain a hydrophobic backbone, e.g., methacrylate functional groups, and a hydrophilic chain, e.g., polyethylene glycol, covalently bonded to the hydrophobic backbone in the form of a comb-like structure, which has the properties of an amphiphilic molecule.

[0039] A preferred embodiment of this chemical composition is formed by hydrolysis of a collapsing hydrogel initially composed of triethylene glycol di[ethyl-1-methacryloyloxypoly(ethylene glycol) acetal] (Formula V above), which transforms into individual poly(polyethylene glycol methacrylate) chains that are difficult to synthesize by other polymerization methods.

[0040] In some cases, the polymer chains contain from 1 mol % to 90 mol %, or from 10 mol % to 75 mol %, or from 20 mol % to 50 mol % hydrophobic monomers (or ligands covalently bonded thereto).

[0041] When such compositions are decomposed, the resulting grafted polymer chains are soluble in aqueous solutions and have the properties of amphiphilic molecules.

[0042] The chemical composition of the hydrolysis product and a schematic diagram of the process by which it is formed are shown in Figure 1. As shown, the hydrolyzable crosslinker polymerizes to form the crosslinked polymer network that constitutes the collapsed hydrogel, and the crosslinked polymer network is subsequently hydrolyzed to form the individual comb-shaped polymers. The components of the hydrolyzable crosslinker are labeled as follows: the polymerizable functional group is labeled A, the bond between the polymerizable functional groups is labeled B, and the hydrolyzable functional group within the bond is labeled C. After polymerization, the polymerizable functional group transforms into the backbone polymer chain, labeled D, of the crosslinked network that constitutes the collapsed hydrogel. Upon hydrolysis, the hydrolyzable functional group is removed to form the individual polymer chains.

[0043] In some cases, the hydrophobic ligand is a medium to large alkyl chain with a polymerizable end group. In some cases, the hydrophobic ligand is ethyl methacrylate, butyl methacrylate, octyl(capryl) methacrylate, dodecyl(lauryl) methacrylate, or octadecyl(stearyl) methacrylate, or an acrylate derivative thereof.

[0044] In some cases, the hydrophobic ligand is a nonionic surfactant, such as, but not limited to, alkyl PEG ether, PEG-PPG-PEG triblock copolymer, and fatty acid PEG ester, modified to contain a polymerizable functional group, referred to as a polymerizable surfactant. In some embodiments, these monomers contain a hydrolyzable functional group, referred to as a hydrolyzable surfactant monomer, to which both the nonionic surfactant and the polymerizable functional group are covalently bonded. In some embodiments, the surfactant is an alkyl poly(ethylene glycol) ether, such as, but not limited to, PEG-20 stearyl ether. Hydrogels containing polymerizable surfactants retain the hydrophobic character of the surfactant within the polymer, which is released after hydrolysis, whereas hydrogels containing hydrolyzable surfactant monomers release the surfactant and comb polymer separately upon decomposition of the hydrolyzable functional group.

[0045] Hydrophobically modified hydrolytic hydrogels loaded with lipid-based formulations containing active pharmaceutical ingredients In some embodiments, the hydrogel voids contain a payload comprising a self-emulsifying or spontaneous micelle-forming lipid solution, which may include organic solvents, hydrophobic solvents (oils), surfactants, and cosurfactants, either alone or in any possible combination. In some embodiments, the lipid solution payload also contains an active pharmaceutical ingredient.

[0046] Method for preparing hydrolyzable hydrogels and loading them with active ingredients Figure 2 shows a schematic diagram of drug loading and release from a payload within a collapsing hydrogel. The payload is labeled A, the linkage connecting the backbone polymer chains is labeled B, the hydrolyzable functional group within the linkage is labeled C, and the backbone polymer chain is labeled D. After loading, the payload is located within the pores of the cross-linked polymer network. After hydrolysis, the amphiphilic comb-shaped polymer chains bind to the payload, improving its solubility.

[0047] In some embodiments, hydrogels contemplated herein are produced by combining a polar (protic or aprotic) solvent with a hydrolytically degradable crosslinker and an initiator (e.g., photoinitiator, thermal initiator, etc.) in a homogeneous solution, which is then added to an inert mold of a specific shape and exposed to an initiation source (e.g., UV lamp, heating element, etc.) for the time necessary to induce sufficient polymerization of the crosslinker into a mechanically stable crosslinked hydrogel.

[0048] In some embodiments, the starting solution contains 15% to 35% by volume of the crosslinker triethylene glycol di[ethyl-1-methacryloyloxypoly(ethylene glycol) acetal] and about 5% by volume of the photoinitiator 2-hydroxy-2-methylpropiophenone dissolved in dimethylformamide, which is then dispersed in a silicone mold and exposed to a 365 nm wavelength lamp for 20 minutes.

[0049] This chemical composition of this hydrogel is shown below as Formula X. TIFF2025183290000009.tif36142

[0050] Collapsed hydrogels containing the structure shown in Formula X, in some embodiments, are compositions that are 100 mol % triethylene glycol di[ethyl-1-methacryloyloxypoly(ethylene glycol) acetal] crosslinker, which upon hydrolysis of the hydrolyzable functional groups converts to a comb polymer, particularly a poly(polyethylene glycol methacrylate) polymer, having the structure shown in Formula XI below. The molecular weight of the resulting comb polymer of this or any other composition released upon hydrogel collapse can vary from 1,000 g / mol to 1,000,000 g / mol. By-products of the collapse of hydrogels containing the structure of Formula X include triethylene glycol and acetaldehyde. TIFF2025183290000010.tif37128

[0051] In some embodiments, hydrogels contemplated herein are produced by combining a polar (protic or aprotic) solvent with a monofunctional monomer, a difunctional hydrolyzable crosslinker, and an initiator (e.g., a photoinitiator, a thermal initiator, etc.) in a homogeneous solution, which is then added to an inert mold of a specific shape and exposed to an initiation source (e.g., a UV lamp, a heating element, etc.) for a period of time necessary to induce sufficient polymerization of the functional components into a mechanically stable crosslinked hydrogel.

[0052] In some embodiments, the starting solution contains about 20% by volume of the crosslinker triethylene glycol di[ethyl-1-methacryloyloxypoly(ethylene glycol) acetal], about 10% by volume of an equimolar solution of dimethylaminoethyl methacrylate and methyl methacrylate, and about 5% of the photoinitiator 2-hydroxy-2-methylpropiophenone dissolved in dimethylformamide, which is then dispersed in a silicone mold and exposed to a 365 nm wavelength lamp for 20 minutes.

[0053] The chemical structure of one embodiment of the chemically crosslinked hydrogel contains the preferred acid-labile crosslinker triethylene glycol di[ethyl-1-methacryloyloxy-poly(ethylene glycol) acetal], a hydrophobic monomer (an alkyl methacrylate), and two other monomeric components (methyl methacrylate and dimethylaminoethyl methacrylate) that promote hydration, swelling, and solubilization in aqueous solution. This chemical composition of this hydrogel is shown below as Formula XII. The parameters x and y are the same as those described above, and the parameter u represents the number of repeating methyl units in the alkoxy methacrylate monomer between the methacrylate group and the terminal methyl group, which may vary from 0 to 21, or 1 to 17, or 3 to 17. The parameter R refers to any other monomeric units and / or functional groups used to initiate and terminate the polymerization process, such as the photoinitiator and solvent, respectively. TIFF2025183290000011.tif83142

[0054] This composition yields a hydrogel that, after being washed to remove unreacted monomers and photoinitiators, completely hydrolyzes and dissolves within 30 minutes when added to an aqueous buffer solution at pH 1, with the smallest dimension of the hydrogel being approximately 10 mm or less.

[0055] When exposed to aqueous acidic solutions, the crosslinked hydrogel having the composition of Formula XII transforms into individual polymer chains having the composition shown in Formula XIII due to hydrolysis of the acetal functional groups within the linkages. TIFF2025183290000012.tif90128

[0056] In some embodiments, the starting solution contains 15% to 30% by volume of the crosslinker triethylene glycol di[ethyl-1-methacryloyloxy-poly(ethylene glycol) acetal], 1% to 20% by volume of a hydrolyzable surfactant monomer, and approximately 5% by volume of the photoinitiator 2-hydroxy-2-methylpropiophenone dissolved in dimethylformamide, which is then dispersed in a silicone mold and exposed to a 365 nm wavelength lamp for 20 minutes. The resulting chemical structure of the collapsed hydrogel is shown in Formula XIV below. The parameters x, y, u, and R are the same as those described above, and the parameter q represents the number of repeating polyethylene glycol units contained in the surfactant molecule and can vary from 2 to 100 or from 4 to 20. When crosslinked hydrogels of the composition of Formula XIV are exposed to aqueous acidic solutions, they undergo hydrolysis of the acetal functional groups within the linkages to transform into individual polymer chains having the composition shown in Formula XI but with monomers having different values ​​of the parameter y, potentially as a result of the different compositions of the hydrolyzable surfactant and hydrolyzable crosslinker used during hydrogel synthesis. By-products of the breakdown of hydrogels containing the structure in Formula XIV include triethylene glycol, acetaldehyde, and the nonionic surfactant used to synthesize the hydrolyzable surfactant monomers. TIFF2025183290000013.tif56145

[0057] The method of loading dietary or pharmaceutical active ingredients into collapsing hydrogels synthesized by the above process involves dissolving the particular active ingredient in a polar (protic or aprotic) solvent, adding this solution to a mold containing the hydrogel, concentrating the active ingredient so that it enters the pore spaces of the hydrogel, and finally evaporating the solvent to remove all or essentially all of the solvent.

[0058] This process converts payloads, such as dietary ingredients or active pharmaceutical ingredients, having a melting temperature of about 20°C or higher (i.e., solid at room temperature) into nanocrystals with an average size of 10 nm to 1000 nm, 10 nm to 500 nm, 10 nm to 300 nm, 10 nm to 100 nm, 20 nm to 500 nm, 20 nm to 300 nm, 20 nm to 100 nm, less than 300 nm, less than 200 nm, less than 100 nm, or less than 50 nm.

[0059] The result of following this process is the formation of a hydrolytic hydrogel loaded with a poorly soluble drug that can subsequently release the poorly soluble drug in an acidic aqueous solution at pH 1 to a solubility greater than the saturation concentration of the drug itself in less than 240 minutes, or less than 120 minutes, or less than 90 minutes, or less than 60 minutes, or less than 40 minutes, or less than 30 minutes.

[0060] The drug loading process described above can also be accomplished using a polar (aprotic or protic) solvent containing a lipid-based formulation mixture (including, but not limited to, glycerides, surfactants, and cosurfactants, and / or cosolvents) in addition to the active pharmaceutical ingredient, such that upon solvent removal, the lipid-based formulation and active pharmaceutical ingredient become entrapped within the pore spaces of the collapsing hydrogel. The resulting collapsing hydrogel formulation releases the solubilizing polymer, lipid formulation components, and active pharmaceutical ingredient in the form of an emulsion that improves the solubility of the active pharmaceutical ingredient (see Figure 1).

[0061] Loading a collapsing hydrogel with a cell-based therapy is accomplished by adding the desired cells to a precursor solution consisting of a polar solvent, a crosslinker, and an initiator prior to the polymerization reaction. Upon subsequent exposure to an initiation source, the crosslinker polymerizes into the hydrogel, and the cells become encapsulated within the pore spaces of the hydrogel.

[0062] By controlling the concentration of the active pharmaceutical ingredient, nutritional supplement, veterinary ingredient, and / or cell-based therapy in solution during the loading process, the mass fraction of the payload within the collapsing hydrogel (i.e., the mass of the payload divided by the total mass of the payload and hydrogel) can be controlled to be 1%-99%, 5%-90%, 10%-90%, 15%-80%, 20%-70%, 20%-60%, 20%-50%, 30%-70%, 30%-60%, or 30%-50%.

[0063] The chemical versatility of hydrolytically soluble hydrogels makes them the most widely compatible oral dosage form for poorly soluble active pharmaceutical ingredients. The chemical composition of the hydrogel, including the crosslinker and any and all monomers, can be modified to maximize chemical compatibility with any chemical payload, particularly active pharmaceutical ingredients. The solvent used to dissolve the payload, such as an active pharmaceutical ingredient, and the payload concentration in that solution can also be adjusted to maximize hydrogel swelling and, consequently, the amount of payload (by mass or volume) that can be injected into the hydrogel pores. This was performed with several active pharmaceutical ingredients spanning a wide range of chemical properties critical to solubility and absorption during oral drug delivery, including lipophilic partition coefficients (LogP) ranging from 0.8 to 10.5, melting temperatures (Tm) ranging from -54°C to 301°C, molecular weights (Mw) ranging from 206 g / mol to 1203 g / mol, and aqueous solubilities (C_s) ranging from 0.01 μg / mL to 120 μg / mL. The disintegrating hydrogel oral dosage forms have also been shown to be compatible with a wide range of chemical classes, including, but not limited to, kinase inhibitors, statins, hormones, antioxidants, macrolides, NSAIDs, anti-infectives, and antihyperlipidemic agents. The drugs tested and their corresponding parameters are summarized in Table 1. In addition to the drugs listed in Table 1, examples of active pharmaceutical ingredients compatible with the hydrolytically degradable hydrogel include acetylsalicylic acid, naproxen, fenoprofen, ketoprofen, flurbiprofen, indomethacin, diclofenac, aceclofenac, mefenamic acid, tolfenamic acid, and piroxicam within the NSAID class, and vancomycin, clindamycin, erythromycin, linezolid, and tigecycline within the anti-infective class. , doxycycline, ritonavir, lopinavir, tenofovir, rilpivirine, efavirenz, itraconazole, ketoconazole, griseofulvin, and miconazole; within the antioxidant class, beta-carotene, ubiquinone, lycopene, phytomenadione, menadione, calciferol, cholecalciferol, and curcumin; within the cannabinoid class, tetrahydrocannabinol, cannabinol, cannabigerol,These include cannabichromene, cannabielsoin, and cannabicyclol, and within the hypolipidemic drug class, ethyl icosapentaenoate, docosahexaenoic acid, bempedoic acid, Within the statin class, these include rosuvastatin, fluvastatin, lovastatin, simvastatin, and pravastatin; within the kinase inhibitor class, these include vemurafenib, regorafenib, osimertinib, imatinib, sorafenib, ibrutinib, erlotinib, dasatinib, olaparib, lenvatinib, and gefitinib; within the macrolide class, these include erythromycin, daptomycin, clarithromycin, carbomycin A, spiramycin, tacrolimus, sirolimus, nystaphylococcus aureus, and nistatin. Within the retinoid class, retinol, etretinate, acitretin, bexarotene, and adapalene are included; within the steroid hormone class, estradiol, ethinyl estradiol, etonogestrel, mifepristone, testosterone, dexamethasone, prednisone, ganaxalone, brexanolone, pregnenolone, abiraterone acetate, levonorgestrel, budesonide, and fluticasone furoate are included.

[0064] [Table 1] TIFF2025183290000015.tif147154

[0065] Figures 3-19 are dissolution profiles of the payloads listed above. [Example]

[0066] Example 1 Synthesis of the di-acetal crosslinker triethylene glycol di[ethyl-1-methacryloyloxypoly(ethylene glycol) acetal] In the synthesis of the crosslinker described above, poly(ethylene glycol) divinyl ether is added to dichloromethane containing toluenesulfonic acid as a catalyst along with 2 molar equivalents of poly(ethylene glycol) methacrylate and allowed to react for 1 hour at 25°C. The reaction is quenched by adding 5 molar equivalents of triethylamine to the toluenesulfonic acid. The reaction solution is washed with an equal volume of 1 M sodium hydroxide solution to extract the toluenesulfonic acid triethylammonium salt and excess triethylamine. The remaining reaction solution is dried to remove residual water, and the product is then purified by removing the dichloromethane by evaporation.

[0067] Example 2 Synthesis of Collapsing Hydrogels Using Di-acetal-Based Crosslinkers The precursor solution was prepared by dissolving 25% by volume of the crosslinker triethylene glycol di[ethyl-1-methacryloyloxy-poly(ethylene glycol) acetal] and 5% by volume of the photoinitiator 2-hydroxy-2-methylpropiophenone in dimethylformamide. After mixing to a homogeneous solution, it was then dispensed into a silicone mold and exposed to a 365 nm wavelength lamp for 20 minutes. The semi-solid disintegrated hydrogel was then mechanically removed from the mold and immersed three times in succession in ethanol volumes five times the volume of the gel to ensure that the levels of residual monomer, photoinitiator, and dimethylformamide were well below 1% of the initial content of each component.

[0068] Example 3 Lumefantrine in collapsing hydrogel Hydrogels composed purely of triethylene glycol di[ethyl-1-methacryloyloxypoly(ethylene glycol) acetal] crosslinker were loaded with various volumes of a 200 mg / mL solution of lumefantrine in dimethylformamide, resulting in a series of hydrogels containing lumefantrine ranging from 10 wt% to 59 wt%. Tablets were dissolved in simulated gastric fluid to produce various levels of supersaturation above the natural solubility of lumefantrine. The maximum level of supersaturation achieved was 13 times the saturated concentration at a drug loading level of 29 wt%, as shown in Figure 6.

[0069] Example 4 Tocopherol (Vitamin E) in Collapsing Hydrogels Hydrogels composed purely of triethylene glycol di[ethyl-1-methacryloyloxypoly(ethylene glycol) acetal] crosslinker were loaded with various volumes of a 400 mg / mL solution of tocopherol in ethanol, resulting in a series of hydrogels containing tocopherol ranging from 30.7 wt% to 63.2 wt%. Tablets were dissolved in simulated gastric fluid to produce various levels of supersaturation above the natural solubility of tocopherol. The corresponding supersaturation levels achieved after drug release ranged from approximately 13 to approximately 74 times the saturated concentration, as shown in Figure 3.

[0070] Example 5: Loading of an active pharmaceutical ingredient into a collapsing hydrogel and release in a physiologically relevant buffer A collapsed hydrogel is first formed from 0.125 mL of a dimethylformamide solution containing 25% by volume of the crosslinker triethylene glycol di[ethyl-1-methacryloyloxypoly(ethylene glycol) acetal] and 5% by volume of the photoinitiator 2-hydroxy-2-methylpropiophenone, and then purified by washing several times with ethanol. The collapsed hydrogel is then transferred to the same solvent used to maximize dissolution of the active pharmaceutical ingredient of interest. The hydrogel is then transferred to a silicone mold and heated for a minimal time to evaporate most of the solvent absorbed into the hydrogel pores. Approximately 0.1 mL of a solution of the active pharmaceutical ingredient solubilized in a suitable solvent is then added to the silicone mold containing the hydrogel, and the mold is allowed to swell to absorb the solution. Once expanded, the solvent is removed in a vacuum oven to induce crystallization of the active pharmaceutical ingredient within the hydrogel pores. The mass of the active pharmaceutical ingredient contained in the collapsed hydrogel is experimentally determined and then normalized by the combined mass of both components to quantify the mass fraction of the active pharmaceutical ingredient. For several active pharmaceutical ingredients, these values ​​are summarized in Table 1 in the column labeled "% wt Drug."

[0071] Separately, glass vials placed on a stirring plate with a stir bar set to rotate at 150 revolutions per minute are filled with a volume (mL) of simulated gastric fluid equal to the amount (mg) of active pharmaceutical ingredient contained in the drug-loaded collapsing hydrogel. The hydrogel is added to the vial and allowed to dissolve for 2 hours. The presence of the active pharmaceutical ingredient in the aqueous solution is monitored by UV-visible spectroscopy to quantify the concentration relative to the intrinsic solubility of the active pharmaceutical ingredient in the absence of the hydrogel. The ratio of the solubility achieved upon release from the collapsing hydrogel to the solubility achieved upon dissolution without the collapsing hydrogel is supersaturation. Supersaturation values ​​for several active pharmaceutical ingredients are listed in Table 1 as "X The results are summarized in a vertical column labeled "sat."

[0072] As shown in the figure, when vitamin E (tocopherol), fenofibrate, progesterone, and lumefantrine, all poorly soluble APIs, were encapsulated in an immediate-release acid-catalyzed hydrolytic hydrogel and dissolved in 0.1 M HCl solution (pH = 1), 80% of the encapsulated drug was demonstrated to be released within 40 minutes. Due to the solubility-enhancing properties of the hydrogel degradation products, the final concentrations of each drug substance reached supersaturation levels of 74, 351, and 11 times the intrinsic solubility of each substance, respectively. Acetal hydrogels [containing 10% surfactant] {containing 15% surfactant}, designated hydrogels, were synthesized by polymerizing a precursor solution containing 25% [20%] {20%} by volume triethylene glycol di[ethyl-1-methacryloyloxy-poly(ethylene glycol) acetal] crosslinker, 0% [3.9%] {3.9%} by volume methyl methacrylate, 0% [6.1%] {6.1%} by volume dimethylaminoethyl methacrylate, and 0% [10%] {15%} by volume hydrolyzable surfactant monomer: acetaldehyde-(stearyl PEG-20 ether)-(acrylate ethylene glycol) acetal. Each drug substance was first dissolved in ethanol and loaded into the hydrogel pores by adding the organic solution to a silicone mold containing a preformed, washed hydrogel and then evaporating the solvent. Sufficient drug substance solution was added to the mold to achieve various drug loading values.

[0073] Example 6 Synthesis of Hydrolyzable Surfactant Monomer Acetaldehyde-(Stearyl PEG-20 Ether)-(Acrylate Ethylene Glycol) Acetal The synthesis of the hydrolyzable surfactant monomer acetaldehyde-(stearyl PEG-20 ether)-(acrylate ethylene glycol) acetal proceeds by first synthesizing the intermediate 2-acryloyloxy-ethanol vinyl ether. This intermediate is synthesized by combining acryloyl chloride with one molar equivalent of ethylene glycol vinyl ether and three molar equivalents of triethylamine in dichloromethane. The solution is allowed to react at 25°C for 12 hours. The resulting triethylammonium chloride salt is filtered from the solution, and the remaining trimethylamine and dichloromethane are removed by evaporation to yield the crude intermediate.

[0074] The hydrolyzable surfactant monomer product is synthesized by combining 2-acryloyloxy-ethanol vinyl ether with one molar equivalent of the nonionic surfactant stearyl PEG-20 ether in dichloromethane, a solvent containing toluenesulfonic acid as a catalyst. The solution is allowed to react for one hour at 25°C. The reaction is quenched by adding five molar equivalents of triethylamine to the toluenesulfonic acid. The reaction solution is washed with an equal volume of 1M sodium hydroxide solution to extract the toluenesulfonic acid triethylammonium salt and excess triethylamine. The remaining reaction solution is dried to remove any remaining water, and the product is then purified by evaporating off the dichloromethane.

Claims

1. a backbone comprising a single-component polymer chain or a multi-component polymer chain; a hydrolytically degradable linkage covalently bonded to and connecting two or more of the polymer chains; A hydrogel matrix comprising:

2. 10. The hydrogel matrix of claim 1, wherein the single-component or multi-component polymer chains are comprised of monomers selected from methacrylic acid, methyl methacrylate, ethyl methacrylate, butyl methacrylate, dimethylaminoethyl methacrylate, methacrylamide, hydroxyethyl methacrylate, 2-(methacryloyloxy)ethyltrimethylammonium chloride, poly(ethylene glycol) methacrylate, cetyl methacrylate, lauryl methacrylate (or an acrylate derivative of any methacrylate component), polymerizable surfactants, hydrolyzable surfactant monomers, 2-acrylamido-2-methylpropanesulfonic acid, vinylphosphonic acid, N-vinylcaprolactam, N-vinylpyrrolidone, vinyl acetate, and vinyl alcohol, alone or as copolymers in any combination thereof.

3. The joint is At least one functional group that degrades within 5 minutes to 12 hours at pH 0-8, causing a transformation from a cross-linked hydrogel to multiple polymer chains 2. The hydrogel of claim 1, comprising:

4. 4. The hydrogel of claim 3, wherein degradation occurs within 10 minutes to 2 hours.

5. 4. The hydrogel of claim 3, wherein degradation occurs within 15 to 60 minutes.

6. 4. The hydrogel of claim 3, wherein degradation occurs under acidic and / or neutral conditions in the pH range of 1 to 7.

7. 4. The hydrogel of claim 3, wherein degradation occurs under acidic and / or neutral conditions in the pH range of 1 to 5.

8. 4. The hydrogel of claim 3, wherein degradation occurs under acidic and / or neutral conditions in the pH range of 1 to 4.

9. 4. The hydrogel of claim 3, wherein the hydrolytically degradable functional group contained within the linkage is selected from an acetal, anhydride, boronic ester, enamine, hydrazone, imide, imine, ketal, oxime, alkylsilyl ether, polysiloxane, or silyl ether group.

10. 10. The hydrogel of claim 1, wherein the hydrolytically degradable linkage comprises at least one of either a ketal or an acetal functional group as the acid-labile degradable functional group.

11. 10. The hydrogel of claim 1, wherein the hydrolytically degradable linkage is PEG-based.

12. Hydrolytically degradable bonds Hydrolytically degradable crosslinkers consisting of two or more polymerizable functional groups and a covalently bonded linkage 10. The hydrogel of claim 1, wherein the hydrogel is formed by polymerizing

13. The hydrolytically degradable crosslinker A central poly(ethylene glycol) segment with a molecular weight of 150 g / mol or greater, with acetal functional groups attached to both terminal hydroxyl groups and bearing PEG methacrylate with a molecular weight of 174 g / mol or greater.

13. The hydrogel of claim 12, comprising:

14. 13. The hydrogel of claim 12, wherein the hydrolytically degradable crosslinker comprises triethylene glycol di[ethyl-1-methacryloyloxypoly(ethylene glycol) acetal].

15. The hydrolytically degradable crosslinker acetone di[methacryloyloxypoly(ethylene glycol)] ketal or acetaldehyde acryloyloxyethanol methacryloyloxypoly(ethylene glycol) acetal, with or without triethylene glycol di[ethyl-1-methacryloyloxypoly(ethylene glycol) acetal], or a combination thereof 13. The hydrogel of claim 12, wherein

16. 13. The hydrogel of claim 12, wherein the hydrolytically degradable crosslinker is di[methacryloyloxypoly(ethylene glycol)]dimethylsilyl ether, methacryloyloxypoly(ethylene glycol)methacryloylpropyldimethylsilyl ether, or poly(ethylene glycol)di[methacryloylpropyldimethylsilyl ether], or a combination thereof.

17. 10. The hydrogel of claim 1, comprising 0.1 mol % to 100 mol % crosslinker, the remainder being composed of polymer chains of any composition.

18. 10. The hydrogel of claim 1, comprising 0 mol% to 50 mol% crosslinkers, the remainder being composed of polymer chains of any composition.

19. 10. The hydrogel of claim 1, comprising 0 mol% to 40 mol% crosslinkers, the remainder being composed of polymer chains of any composition.

20. 10. The hydrogel of claim 1, comprising 10 mol% to 30 mol% crosslinkers, the remainder being composed of polymer chains of any composition.

21. 10. The hydrogel of claim 1, comprising 20 mol% triethylene glycol di[ethyl-1-methacryloyloxypoly(ethylene glycol) acetal] crosslinker, 40 mol% methyl methacrylate, and 40 mol% dimethylaminoethyl methacrylate.

22. 10. The hydrogel of claim 1, wherein the hydrogel comprises 100 mol % triethylene glycol di[ethyl-1-methacryloyloxypoly(ethylene glycol) acetal] crosslinker and is formed from a 25 vol % precursor solution in a solvent containing 5 vol % photoinitiator.

23. 10. The hydrogel of claim 1, wherein the hydrolyzable hydrogel encapsulates a payload comprising a nutritional supplement, an active pharmaceutical ingredient, or a cell-based supplement or therapy such that the hydrogel can serve as an oral dosage form for these materials.

24. The active pharmaceutical ingredient contained within the voids of the hydrogel is of the following chemical class: Kinase inhibitors, statins, hormones, antioxidants, macrolides, NSAIDs, anti-infectives, retinoids, cannabinoids, anthracyclines, and hyperlipidemic agents 24. The hydrogel of claim 23, wherein the hydrogel is a component of one of:

25. 24. The hydrogel of claim 23, wherein the active pharmaceutical ingredient has a lipophilic partition coefficient in the range of 0.5 to 10.5, a melting temperature in the range of -54°C to 301°C, and / or a molecular weight in the range of 174 g / mol to 1203 g / mol.

26. 24. The hydrogel of claim 23, wherein the active pharmaceutical ingredient is present in a content of 1% to 90% by weight, 10% to 70% by weight, and 20% to 60% by weight.

27. 10. The hydrogel of claim 1, wherein the polymer chains contain between 1% and 50%, or between 5% and 25%, or between 10% and 20% by molar of hydrophobic ligands covalently bonded to the polymer chains.

28. Self-emulsifying or spontaneous micelle-forming lipid solutions that may contain organic solvents, hydrophobic solvents (oils), surfactants, and cosurfactants, either alone or in any possible combination.

10. The hydrogel of claim 1, wherein the hydrogel defines a void containing

29. 30. The hydrogel of claim 28, wherein the lipid solution also contains an active pharmaceutical ingredient.

30. 10. The hydrogel of claim 1, further comprising a payload encapsulated between the polymer chains of the backbone.

31. 31. The hydrogel of claim 30, wherein the payload comprises one or more of a food-grade material, a supplement, a pharmaceutical nutraceutical, a therapeutic agent, an active ingredient, or a combination thereof.

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