Plasticized super-porous hydrogel

Abstract

The present invention provides a method for preparing a plasticized superporous hydrogel material, which comprises subjecting an initial hydrogel material to treatment with an acidic solution, optionally treatment with a monovalent metal salt solution, freeze-drying and plasticization. Optionally, the method of the present invention prepares a molded plasticized superporous hydrogel material body in which one or more through-holes are formed. The plasticized superporous hydrogel material of the present invention can be formulated into a suitable oral dosage form for appetite suppressants and for delivering drugs and / or nutraceuticals to a human or animal body.

Description

Field of the Invention

[0001] The present invention relates to a method for preparing a hydrogel material that can be operated more easily and reliably and has an increased swelling volume and an increased swelling rate compared to known hydrogel materials. The hydrogel material prepared by the method of the present invention is particularly suitable for use as or in oral dosage capsules, for example as an appetite suppressant for humans and animals. Additionally, the hydrogel material prepared by the method of the present invention, when used by itself (as made) and when used in a suitable dosage formulation, can contain, incorporate, or encapsulate one or more drugs, nutraceuticals, or foreign substances for elution or otherwise delivery in a human or animal body, or generally elution or otherwise delivery into any application based on a liquid (preferably aqueous) medium. Background of the Invention

[0003] As discussed by H. Omidian et al. in "Recent developments in superporous hydrogels" in J. Pharm. & Pharmacol. 2007, 59:317 - 327, superporous hydrogels (SPHs) are porous hydrophilic crosslinked structures that, when dry, are hard and brittle and insoluble in water. However, when immersed in an aqueous medium, they can absorb up to many times their own weight of aqueous fluid, swell in size, and become soft and deformable gel materials. SPHs generally have a three - dimensional network made of hydrophilic polymer materials with many pores having an average size greater than 100 μm up to about 1 or 2 mm. It is these pores that, by connecting together to form an open channel structure, utilize capillary action to absorb water very rapidly. Maximum swelling is usually achieved within a fraction of a minute, and the SPH swells to an equilibrium size.

[0004] The recently published patent application WO2019016560 (A1) describes a method for softening (plasticizing or imparting ductility) dry superporous hydrogel materials without the need for them to swell. The method further describes forming a plasticized superporous hydrogel material sheet by applying a compressive force to flatten / collapse the hydrogel pores without breaking the bonds that hold the three - dimensional network structure together. Oral dosage formulations can be prepared by cutting samples from the superporous hydrogel material sheet, folding / rolling these samples, and then inserting them into the casing for an oral dosage capsule. Such oral dosage formulations will dissolve or rupture when contacted with an aqueous medium (e.g., gastric juice when the capsule is swallowed by a human or animal), and then the superporous hydrogel contained inside will rapidly swell to many times its original size. These formulations are disclosed as useful alternatives for preparing excellent appetite suppressants and gastric balloons for the treatment of obesity.

[0005] The present invention seeks to provide a rapid, cost-effective and reliable method for preparing a super-porous hydrogel material having excellent physical properties (including swelling volume, swelling rate and overall strength), and importantly, the super-porous hydrogel material can be easily manipulated, for example to facilitate their direct shaping or to facilitate their insertion into the outer shell of an oral dosage formulation. The aim of the method of the present invention is to avoid the need to form a plasticized super-porous hydrogel sheet (e.g., by applying a high compressive force to the plasticized super-porous hydrogel material) and to avoid the need to cut hydrogel samples from the sheet and then roll them up before inserting them into the outer shell of an oral dosage capsule. Thus, ideally, the super-porous hydrogel prepared by the method of the present invention will be able to be cast into a mold and then directly manipulated, for example, into the outer shell (shell) of an oral dosage capsule. Alternatively, the super-porous hydrogel prepared by the method of the present invention will be able to be directly cast or compressed into a lozenge-shaped dosage formulation for direct oral administration.

[0006] The present invention further provides a super-porous hydrogel material which, once swallowed and swollen, will on the one hand have mechanical robustness such that the product made therefrom can be retained in the stomach of a human or animal for a limited period of time, e.g., 1 to 4 weeks, without degrading and / or digesting, and can thus be used for appetite suppressant and appetite control applications in overweight / obese animal or human patients, or as a delivery vehicle for controlled release drugs or nutraceuticals in animals or humans. On the other hand, over time, e.g., after 1 to 4 weeks, it will begin to naturally decompose or disintegrate and be naturally excreted from the body. A suitable appetite suppressant will ideally be a tablet or other suitable oral dosage form designed to be taken at home and not requiring a hospital or healthcare facility. More ideally, the appetite suppressant of the present invention will not require surgery, endoscopy or radiation to insert, fit or check the correct placement of the appetite suppressant formulation in the patient's body. Advantageously, such an appetite suppressant formulation will be effective for several days or weeks at a time before being terminated by auto-degradation or by ingestion of an approved chemical or natural food source and then excreted. More advantageously, it is an object of the present invention to provide an appetite suppressant which will also allow the patient to be able to ingest more or less doses of one or more super-porous hydrogels and also to be able to terminate the effect of the ingested appetite suppressant product at will. Thus, the present invention also provides a method for decomposing the appetite suppressant formulation of the present invention once ingested by a patient, and provides an appetite suppressant product customized according to the desired strength and duration of the weight control process.

[0007] In another aspect, the present invention provides a plasticized superporous hydrogel material for oral dosage formulations (such as dosage capsules), which may additionally comprise one or more drugs and / or nutraceuticals, which drugs and / or nutraceuticals are designed to be eluted or otherwise delivered into a human or animal body, such as once the capsule is located at a specific location within the body (such as in the stomach or intestine). Desirably, the drug / nutraceutical will be eluted / delivered over an extended period of time. In one embodiment, it is contemplated that one or more drugs and / or nutraceuticals are incorporated into the plasticized hydrogel material as additional separate components in the oral dosage formulation. In this embodiment, the drugs and / or nutraceuticals may be used alone or in combination with one or more additives. Alternatively, the drugs and / or nutraceuticals may be associated with or contained within a separate drug delivery device such as a liposome. In yet a further embodiment, the drugs and / or nutraceuticals may be part of the hydrogel material structure, such as the drugs and / or nutraceuticals may be attached to one or more hydrophilic polymer chains that form the hydrogel material. As used herein, the term "nutraceutical" shall be construed to include any food supplement, mineral, or vitamin that provides enhanced health benefits when ingested by a human or animal.

[0008] In a preferred embodiment, the present invention provides a method for preparing a plasticized superporous hydrogel material, which comprises the following steps:

[0009] a) forming an initial hydrogel material without using a foaming agent or other foaming methods, wherein the initial hydrogel material comprises one or more selected from an interpenetrating network structure, a semi-interpenetrating network structure, and a simple crosslinked structure, and the structure is formed by providing a mixture comprising one or more hydrophilic polymers and / or copolymers and subjecting the mixture to polymerization and / or crosslinking conditions;

[0010] b) recovering the resulting initial hydrogel material formed in step a) and treating it with an acidic solution comprising one or more acids and having a pH range of <1 to ≤3;

[0011] c) treating the initial hydrogel material formed in step a) with a solution of ≥0M to ≤0.5M of one or more monovalent metal salts either simultaneously with or after treating step b);

[0012] d) using freeze-drying to dry the resulting wet initial hydrogel material to produce a dried superporous hydrogel material;

[0013] e) treating the resulting dried superporous hydrogel material to plasticize its structure; and

[0014] f) recovering the resulting plasticized superporous hydrogel material.

[0015] It is known to use blowing agents or other foaming methods in the polymerization / copolymerization and crosslinking processes of the prior art. Although this produces "super-porous" hydrogels, the Applicant has found that the efficiency of this process and the quality of the final super-porous hydrogels are impaired. First, the use of a blowing agent or other foaming method during the polymerization step would require separating the super-porous hydrogel product material from the polymer reaction mixture and then drying it. The normal methods of achieving drying are air drying or oven drying. However, as described below, we have found that this process is too slow to ensure that all solvents (usually water) are removed quickly enough to prevent pore collapse. Second, the pore size is determined by the size of the bubbles generated by the blowing agent or provided by the foaming method, and since it is difficult to control the size of these bubbles, it is difficult to control the pore size. Third, the use of a blowing agent or other foaming agent and the subsequent separation / drying of the resulting super-porous hydrogel constitute two steps, whereas the present invention only requires a single freeze-drying step to achieve super-porosity and drying. Finally, fourth, the use of a blowing agent typically uses sodium carbonate or sodium bicarbonate to generate carbon dioxide as the pore-forming gas. However, this requires the polymerization step to be carried out under acidic conditions. This may be convenient for systems for preparing acrylic-based polymers, however, this is not the case when using acrylamide-based or amide-based polymers.

[0016] The ideal initial hydrogel used in the method of the present invention is a "co-hydrogel", i.e., a hydrogel comprising two or more crosslinked interpenetrating backbones formed from one or more hydrophilic polymers and / or copolymers. When the hydrogel comprises two or more crosslinked interpenetrating backbones, the swelling rate and subsequent decomposition rate of the resulting plasticized super-porous hydrogel material can be advantageously controlled much more easily compared to hydrogels made with a single crosslinked backbone.

[0017] The hydrophilic polymer and / or copolymer can be derived from naturally occurring polymers and monomers, from synthetic polymers and monomers, or from a mixture of naturally occurring and synthetic polymers and monomers. Preferably, the one or more hydrophilic polymers are hydroxylated polymers, and more preferably, the hydrophilic polymers are selected from C1-C6-alkyl celluloses, hydroxy-C1-C6-alkyl celluloses, hydroxy-C1-C6-alkyl-C1-C6-alkyl-celluloses. Further preferably, the one or more hydrophilic polymers are selected from methyl cellulose, ethyl cellulose, n-propyl cellulose, hydroxyethyl cellulose, hydroxy-n-propyl cellulose, hydroxy-n-butyl cellulose, hydroxypropyl methyl cellulose, ethyl hydroxyethyl cellulose, carboxymethyl cellulose, carboxymethyl starch, chitosan, alginate, cationic dextran, (e.g., dextran sulfate, dextran phosphate, dimethylamino dextran, diethylamino dextran, cationic dextrin, polyetherimide, heparin, hyaluronic acid, chondroitin, chondroitin sulfate, heparan sulfate, polygalacturonic acid, polyanuronic acid, polygalacturonic acid, polyarabinic acid, and polylysine). In some cases, the one or more hydrophilic polymers can be prepared by polymerization and / or copolymerization of one or more monomers selected from C1-C6-alkenyl amides (e.g., to prepare polyacrylamide) and C1-C6-alkenoic acids (e.g., to prepare acrylic acid). Other possible preferred polymers include poly(acrylamide), poly(2-acrylamido-2-methyl-1-propanesulfonic acid), and poly(N-isopropylacrylamide).

[0018] Particularly advantageously, the one or more hydrophilic polymers and / or copolymers used in the method of the invention are at least partially derived from amine monomers and / or acrylamide monomers and / or monomers containing an amine moiety and / or monomers containing an acrylamide moiety, optionally together with a polymer of a monomer containing a plurality of OH-groups and / or a monomer containing a plurality of OH-groups. Suitable materials containing multiple -OH groups include alginate, chitosan, and other sugar- or carbohydrate-containing materials. Advantageously, the crosslinking agent contains calcium. Preferably, the one or more hydrophilic polymers are not derived from acrylic acid monomers or monomers containing an acrylic acid moiety.

[0019] The initial hydrogel is preferably prepared using one or more of the hydrophilic polymers and / or one or more monomers as described above, optionally in combination with one or more other components selected from biocompatible polymers and mechanically strong hydrogels.

[0020] Suitable biocompatible polymers include one or more selected from the following: polyallyl alcohol, polyvinyl alcohol, polyacrylic acid, polyethylene glycol, and poly(N-vinyl-2-pyrrolidone) (PVP), and these can be copolymerized with one or more other polymers such as acrolein.

[0021] Ideally, one or more hydrophilic polymers (discussed above) for preparing the initial hydrogel will be selected to impart suitable mechanical properties or toughness to the final product, or alternatively, a suitable mechanically strong hydrogel can be added to the initial hydrogel once it is formed, or to a mixture of one or more monomers used to prepare the initial hydrogel. Such strong materials include non-superporous and slowly swelling hydrogels, also known as superabsorbent polymers (SAP), which are hydrophilic networks that can absorb and retain large amounts of water or aqueous solutions. Preferably, they can absorb up to 100,000% water. Further preferably, one or more mechanically strong slowly swelling non-superporous hydrogels are selected from double network hydrogels (DN), nanocomposite hydrogels (NC), topological hydrogels (TP), and macromolecular composite hydrogels (MMC). Particularly useful slowly swelling non-superporous hydrogels include, but are not limited to, poly(2-acrylamido-2-methyl-1-propanesulfonic acid) (PAMPS)-polyacrylamide (PAAm) double network hydrogels, agarose-2-hydroxyethyl methacrylate (HEMA) double network hydrogels, alginate-PAAm double network hydrogels, poly(N-isopropylacrylamide), and poly(N-isopropylacrylamide)-laponite nanocomposite hydrogels. Although the swelling rate of such slowly swelling non-superporous hydrogels is limited, they may still have a reasonable swelling capacity of up to 15 - 20 times in terms of the volume increase from the dry gel to the fully swollen state. Non-superporous hydrogels can still maintain a maximum engineering compressive strength of 2 - 3 MPa or greater when reaching their swelling equilibrium, yet generally have a limited volume swelling ratio. Suitable non-superporous hydrogels can exhibit a high overall swelling capacity but a slower swelling rate than the high volume swelling superporous hydrogels of the present invention.

[0022] Samples of the initial hydrogel material are preferably made by a casting molding method, which may include filling a mold of suitable shape and size with a mixture of polymers and / or monomers as described above (along with one or more optional other components as discussed above), and subjecting the mixture to the addition of one or more crosslinking agents and / or radiation (e.g., with high-energy ionizing radiation such as electron beam (e-beam), γ or x-ray radiation), and / or other conditions suitable for producing a crosslinked polymeric and / or copolymeric interpenetrating network or semi-interpenetrating network or simple crosslinked structure of the hydrogel (e.g., sulfur vulcanization or other suitable chemicals, optionally in combination with heating and / or increased pressure). However, it is important to control the degree of crosslinking such that it does not affect the swelling volume ratio of the product. Ideally, the demolded initial porous hydrogel is a single piece, generally sized from 15 mm × 25 mm to 40 mm × 60 mm. The single piece (sample or body) of the initial porous hydrogel will have any suitable shape and / or size, and will preferably be a cubic, cuboid, oval, pill-shaped, bead-shaped, spherical, cylindrical, rod-shaped, or irregular-shaped body. In an alternative method, the initial hydrogel material will be molded or extruded into, for example, a long cylinder or tube of a pre-designed diameter and then cut into the desired length after curing (crosslinking).

[0023] The separately molded or cut-extruded sample of the initial hydrogel material preferably has an internal body portion (which may be solid or hollow) and an outer surface, which is the outer boundary of the internal body portion formed against the inside of the mold or extrusion die.

[0024] Alternatively, the sample of the initial hydrogel material may be non-molded, but will also preferably have an internal body portion and an outer surface that is the outer boundary of the internal body portion, and the internal body portion has an internal structure comprising a plasticized super-porous hydrogel material.

[0025] The processing steps described below will apply equally to non-molded and molded (including casting molding and non-casting molding) (e.g., made, or in sheet form or extruded or otherwise compressed) initial hydrogel materials.

[0026] Once prepared, the initial hydrogel material is preferably washed with a suitable solvent (ideally distilled water) to remove any unreacted hydrophilic polymer and / or monomer from the initial hydrogel. The initial hydrogel material is then treated with at least one acidic material (preferably by immersion in an acidic solution) for up to 14 days, preferably for 7 to 14 days, and further preferably then subjected to a daily procedure of rinsing with water (ideally distilled water) and re-treatment with fresh acidic material, or preferably re-immersion in a fresh acidic solution. Generally, the volume of the acidic solution used for soaking the initial hydrogel sample is 15 to 50 ml per initial hydrogel sample, which will cause the sample of the initial hydrogel material to swell. As described in the following specific examples, acid treatment advantageously i) improves the swelling rate of the target plasticized superporous hydrogel material, ii) allows control of the percentage change in swelling volume, iii) allows control of the porosity in the target superporous hydrogel, and iv) allows control of the degree of ductility (also referred to herein as "ease of processing" or "processability") of the target superporous hydrogel.

[0027] However, it is important that the acidic treatment step includes treating the separated initial hydrogel material formed in step a) with at least one acidic material having a pH range of <1 to ≤3, further preferably a pH range of <1 to <3, highly preferably a pH range of 1 to <3, and most preferably a pH range of 1 to 2.8. The Applicant has found it advantageous to use a pH in the range of <1 to ≤3 to protonate the hydrogel and thereby obtain larger pore sizes during the freeze-drying step. Additionally, we have observed that the final plasticized superporous hydrogel obtained by the present invention reaches the desired swelling rate and degree of swelling at low pH (e.g., in the stomach) and the desired rate and degree of decomposition (when required) at high pH (e.g., in the duodenum).

[0028] It has been found that treating the initial hydrogel material with an acid solution having a pH higher than 3 causes the target plasticized superporous hydrogel material to lose its structural integrity, i.e., the body of the target superporous hydrogel (SPH) material made from the initial hydrogel treated with an acidic solution of pH > 3 loses its defined shape (this is particularly evident in the case of cast-molded hydrogel materials). In addition, the target superporous hydrogel also becomes less porous, which in turn reduces the swelling rate. Specifically, as the pH increases from >3 to pH 9, the SPH body gradually becomes more distorted and less porous, it becomes very distorted at pH 10 and pH 11, and becomes a gel-like substance or a highly viscous fluid at pH 12 and higher. Ideally, the acid solution for treating the initial hydrogel comprises an aqueous solution of one or more acidic materials. The one or more acidic materials can be inorganic acids and / or organic acids. It has been found that stronger acids are more beneficial than weaker acids, and materials with a pKa in the range of -15 to 3.5 are preferred. A pKa in the range of -15 to 3.0 is particularly preferred, a pKa in the range of -15 to 2.5 is further preferred, and a pKa in the range of -15 to 1 is highly preferred. Suitable inorganic acids include hydrochloric acid, sulfuric acid, nitric acid, and hydrofluoric acid. Suitable organic acids include citric acid, oxalic acid, tartaric acid, maleic acid, malic acid, and toluenesulfonic acid. An acidic aqueous solution of 1 - 100 mM is preferred, and an acidic aqueous solution of 80 - 90 mM is further preferred.

[0029] The one or more acidic materials can be derived from substances obtained or extracted from animals or humans, or acidic materials made from compositions that mimic these substances, such as an acidic solution containing gastric juice and / or mimicking gastric juice is particularly preferred. The mimicking gastric juice is preferably prepared without pepsin and preferably contains 0.2% / weight sodium chloride and 0.7% / weight hydrochloric acid per liter of water and has a pH of about 1.2.

[0030] While treating the initial hydrogel material with at least one acidic material as described above, or alternatively after said treatment, the initial hydrogel material is optionally further treated with a solution containing one or more monovalent metal salts, which are preferably selected from sodium salts, potassium salts, and lithium salts. We have found that this metal salt treatment enables control of the plasticization step, which in turn determines the processing properties of the target material and will ultimately affect the manufacturing cost.

[0031] Any water-soluble monovalent metal salt can be used, such as chlorides, bromides, iodides, nitrates, sulfates, and carbonates. Sodium chloride and potassium chloride are particularly suitable. The presence of the monovalent metal salt solution is found to affect and advantageously control the processing properties (i.e., processability and handleability) of the ultimately plasticized superporous hydrogel. In particular, it is found that the improvement in the further processing and handling of the ultimately superporous hydrogel is proportional to the concentration of the monovalent metal salt up to a maximum value of 0.5 M; when the concentration exceeds 0.5 M, the ultimately plasticized superporous hydrogel becomes too soft to be easily processed within a reasonable time frame (desired from 1 minute to less than 60 minutes). Ideally, the monovalent metal salt solution will be a solution of >0 M to ≤0.5 M, preferably it is a solution of >0 M to ≤0.25 M, and further preferably >0 M to ≤0.14 M.

[0032] In a particularly advantageous method of the present invention, before freeze-drying to remove the solvent from the structure and produce a dry superporous hydrogel material, in addition to treating with a solution of an alkali metal salt (especially chloride) of <0.2 M (preferably a 0.13 M solution), the initial hydrogel material is also treated with an acidic solution having a pH in the range of 1 to 2.

[0033] The initial hydrogel naturally contains pores defined by the network / crosslinked structure, but these pores are filled with a solvent (such as water) for the polymerization reaction to form the initial hydrogel material. Generally, the thinner the mixture of monomers / polymers for preparing the initial hydrogel, the larger the pore size. Generally, the density of the initial hydrogel is about 1.30 g / cm 3 .

[0034] It is important not to allow the resulting treated initial hydrogel to dry, for example, at room temperature or above room temperature, because this will cause the treatment liquid(s) to evaporate too slowly from the swollen pores of the treated initial hydrogel material, and any moisture in the structure will cause the pores to collapse; when the desired pores are lost, the swelling rate will be greatly reduced.

[0035] However, the target material is a plasticized "superporous" hydrogel material, so it will generally have a pore volume of 70 - 90% and a density of about 0.7 - 0.8 g / cm 3The general density is such that it is necessary to enlarge / expose the pores initially formed in the structure of the initial hydrogel (the general average size of its largest dimension being from 100 μm to 1000 μm, ideally from 200 μm to 500 μm) up to a maximum of 5 mm. When enlarging the pore size, it is crucial to form the desired enlarged pore size and then "fix" that size as quickly and effectively as possible. Thus, either after the step of treating with an acidic solution as described above, or if used, after the step of treating with a solution containing one or more monovalent metal salts, the initial hydrogel is subjected to a freeze-drying process. Advantageously, freeze-drying is a rapid and effective drying process that quickly removes water, especially the water retained in the pores as described above, before the pores have time to collapse.

[0036] The freeze-drying step is preferably carried out by first initially freezing the initially hydrogel treated with the acid (and optionally monovalent metal) solution in a conventional freezer or using an ultra-low temperature freezer (-20 °C to -86 °C), which causes the liquid (preferably water) in the pores to crystallize and expand (e.g., through hydrogen bond interactions). The lower the freezing temperature used during the initial freezing process, the smaller the crystals and the smaller the final pore size. Before undergoing the initial freezing process, the acid-treated hydrogel sample is preferably placed in a mold that is 1.5 to 2.5 times larger in diameter than the initial hydrogel sample before pre-acid / metal salt treatment. The frozen sample is then freeze-dried using a freeze-drying apparatus (-50 °C to -80 °C) until all the inter-pore solution is removed to produce a super-porous hydrogel material with the desired pore size (0.1 mm to 5 mm, preferably 0.5 mm to 1.0 mm). Highly preferably, the super-porous hydrogel material prepared by the method of the present invention will preferably contain the same number of pores per unit weight as the initial hydrogel from which it is prepared.

[0037] Optional further steps in the method of the present invention include forming one or more through-holes in the body of a sample of the superporous hydrogel material, the through-holes preferably having a diameter of 1 mm to 15 mm, more preferably a diameter of 3 to 6 mm, and a height preferably of about 4 mm (before the plasticization step discussed below). The ratio of the diameter of the through-hole to the diameter of the superporous hydrogel material sample is preferably from 0.75:1 to 1:30, more preferably from 0.5:1 to 1:10, and the height is preferably from 0.3:1 to 1:10. Ideally, each of the one or more through-holes includes a channel or conduit within the body of the superporous hydrogel sample that extends from a first opening in a first portion of the outer surface of the superporous hydrogel sample to a second opening formed in a second portion (preferably radially opposite) of the outer surface of the superporous hydrogel sample. Preferably, the one or more through-holes are linear. For the avoidance of doubt, such "through-holes" are not formed directly as a result of the chemical polymerization / crosslinking reaction that forms the initial hydrogel, that is, the "through-holes" are not holes formed between the crosslinked interpenetrating skeletons of the initial hydrogel material, but rather, such "through-holes" are formed as a result of a physical processing step.

[0038] In the case where the superporous hydrogel sample is a cylinder, the one or more through-holes are preferably formed to be arranged substantially parallel to the longitudinal axis of the sample. As discussed below, non-cylindrical samples of the superporous hydrogel preferably contain one or more through-holes that are formed to be arranged substantially perpendicular to, for example, during a further processing step, the direction in which a compressive force can be applied to the finally plasticized superporous hydrogel to manipulate the plasticized superporous hydrogel into a dosage capsule. The through-holes can be formed using any suitable technique, for example, the mold used to form the initial hydrogel sample can be embedded or shaped to include one or more elongated members (such as elongated cylindrical members, pins or needles) that are arranged parallel to the central axis of the mold. Alternatively, the shape of the mold can be such that a suitable through-hole can be cast into the sample body when forming the initial body of hydrogel material. Further alternatively, one or more through-holes can be drilled in the superporous hydrogel sample, for example using a 3 - 15 mm drill bit, and preferably at room temperature. Yet further alternatively, each of the one or more through-holes can be formed by extruding the initial hydrogel over a mandrel.

[0039] The function of the one or more through-holes is to make the final plasticized super-porous hydrogel sample more easily compressible and foldable when a compressive force is applied, as discussed above. Additionally, the presence of the through-holes also increases the surface area of the final plasticized super-porous hydrogel sample, and this promotes faster swelling (expansion) of the sample compared to a similar sample without the one or more through-holes; furthermore, it has been found that the final plasticized super-porous hydrogel sample with through-holes can achieve a greater final swelling volume than a similar sample without through-holes (assuming each sample has a comparable dry volume), and this is important when the final plasticized super-porous hydrogel material prepared by the method of the present invention is used in a gastric retention system.

[0040] The toughness of the final plasticized superporous hydrogel material is a particularly important property which will affect i) its ability to obtain a substantially unbroken / undamaged / undamaged structure after compression (discussed below), and ii) to ensure that the applied compressive force will be able to effectively compress the sample; a more highly plasticized superporous hydrogel will be more ductile and able to withstand operations such as rolling / folding without cracking. The dry superporous hydrogel material obtained by freeze-drying the initial hydrogel material treated with acid generally has a rigid and brittle structure and needs to be modified to increase its plasticity and, when desired, to be able to insert the hydrogel material into a 000-size dosage capsule. The use of plasticizers (such as esters, such as sebacates, adipates, terephthalates, dibenzoates, glutarates, phthalates, azelates and their blends) may be a solution to this problem (by adding such a reagent to the reaction mixture for forming the initial hydrogel or by adding such a reagent to the once-formed initial hydrogel), but this is generally not desirable, especially although not the only case, when the improved compressed hydrogel final product is to be used as a gastric appetite suppressant, where using the minimum amount of chemicals will reduce the risk of unwanted side effects. Thus highly preferably, before applying the compressive force, an alternative method is used to lower the glass transition temperature of the superporous hydrogel and thereby increase its plasticity. A favorable alternative method involves subjecting the freeze-dried superporous hydrogel to high humidity conditions (usually percent humidity >55% to ≤100%, preferably humidity in the range of 65% to ≤100%) at room temperature or preferably at an elevated temperature, for example using water vapor (i.e., a humid environment). The use of steam is beneficial. The length of time that the freeze-dried superporous hydrogel is subjected to high humidity (water vapor and as described above) is crucial for the properties of the resulting final plasticized superporous hydrogel material, and this duration depends on the original polymer composition of the initial hydrogel material (specifically, the crosslink density, water content and amount of initiator), the size and shape of the dry superporous hydrogel sample / bulk, the molar concentration of the monovalent salt solution, and the processing method used (including the freezing temperature and how the sample is frozen, i.e., in an open or sealed mold, the material of the mold, etc.). The water vapor treatment step is preferably carried out in a covered container containing a small amount of water and heated to 50 to 65 °C (preferably 60 °C) to generate the desired percentage level of humidity therein (as described above). It is important to prevent the condensation of water vapor, for example on the inner surface of the container wall or on the lid of the container, because if the superporous hydrogel sample comes into contact with any water droplets (or even visible water vapor) during the plasticization process, it will cause irreversible deformation of the sample, mainly due to the collapse of the porous structure, and this will render the final product completely unable to expand.Therefore, the inner wall surface of the capped container preferably comprises a covering of a moisture-absorbing material; this not only helps to provide a uniform humidity level within the container, but also reduces the formation of condensate water droplets and their dripping / flowing onto the superporous hydrogel sample. The superporous hydrogel sample is placed in the container and the container is tightly sealed with a lid. The sample is then retained in the container for the desired time and then immediately removed from the container and processed / manipulated as described below. If the superporous hydrogel is treated with water vapor for too long, irreversible deformation (mainly shrinkage) will occur, while insufficient treatment will result in under-plasticization of the superporous hydrogel sample. In the former case, it is unlikely to successfully compress the hydrogel as it may become elastic and spring back to its original shape when the compressive force is released. For the latter case, further machining may damage the structure of the sample. One useful advantage of treating the initial hydrogel with an acidic solution is that it reduces the duration required for water vapor treatment. For example, at 60 °C, when the initial hydrogel is acid-treated at pH 1 - 3, the typical steam treatment time is 5 to 20 minutes (preferably 5 to 12 minutes), while other identical samples of the initial hydrogel without treatment with an acidic solution would require water vapor treatment for > 20 to 60 minutes or even longer to achieve a comparable degree of plasticization. Simultaneously or after treatment with an acidic solution, the initial hydrogel material is treated with a monovalent metal salt solution, enabling further control of the duration of water vapor treatment. The Applicant has found that the material treated with a monovalent metal salt and acid only needs to be treated at 60 °C under high humidity conditions (water vapor) for 1 to at most 5 minutes, and highly preferably for 3 minutes).

[0041] Another useful advantage of treating the initial hydrogel sample with an acidic solution is that the acid-solution-treated initial hydrogel material will have larger and better-connected pores than the non-acid-treated sample; these larger and better-connected pores are more permeable and result in more efficient water absorption, i.e., such material exhibits faster swelling and a higher swelling volume, as shown in the specific examples below. In addition, during the acid treatment step, the gel swells slightly in all directions, and as a result of this swelling, more water can penetrate the polymer network and the pores of the material expand. When this slightly swollen (swollen / entrained with water) material is frozen and then freeze-dried, the pores retain their swollen size.

[0042] Once the superporous hydrogel is sufficiently plasticized, the sample is treated under appropriate humidity and temperature conditions to prevent hardening. The method of the present invention then comprises applying a compressive force, preferably a compressive force having at least one component force along the radial direction. In some cases, it is desirable to form a sheet of the plasticized superporous hydrogel by reducing the initial thickness of the plasticized superporous hydrogel to 50% or less, preferably 30% or less, and highly preferably 15% or less of the initial thickness (i.e., the thickness of the initial hydrogel is reduced by at least 50%, preferably at least 70%, and highly preferably at least 85% after compression).

[0043] The application of the compressive force causes the pores in the plasticized superporous hydrogel to collapse / flatten and is achieved by applying the compressive force using any suitable method or device, such as between one or more pairs of rollers and / or using one or more plates to apply pressure and / or using a vacuum to assist in providing at least a partial radial compressive force. As described in WO2019016560(A1), once formed, the plasticized superporous hydrogel sheet can be rolled, folded, pleated, wrinkled, wound, concertinaed, cut, extruded, and molded before being inserted into an oral dosage capsule.

[0044] In the case of molding a plasticized superporous hydrogel material, the Applicant has found it beneficial to manipulate (e.g., fold and / or squeeze) the plasticized superporous hydrogel material during its formation (i.e., directly without first forming a sheet), such as inserting it into an oral dosage capsule. As described above, the initial hydrogel material can be molded into any desired shape. In the case where the initial hydrogel and thus the plasticized superporous hydrogel is a cylindrical sample, it is desirable to form one or more through-holes or channels within the body of the superporous hydrogel, as described above. A compressive force can then be applied to the plasticized superporous hydrogel, preferably in a radial or a combined radial and axial direction, relative to the longitudinal axis of the molded plasticized superporous hydrogel material. In a preferred example, a compressive force can be applied to the molded plasticized superporous hydrogel material using an elongate rod (e.g., having an outer diameter of 3 to 15 mm, preferably 6 to 10 mm), the longitudinal axis of which is oriented parallel to the central longitudinal axis of the hydrogel sample (i.e., parallel to one or more through-holes, if present), to produce a linear indentation or compression line on the side of the outer surface of the plasticized superporous hydrogel sample. The cylindrical sample can then be folded along this compression line to form a "quasi"-cylinder, which can be squeezed using three-sided compression. Such three-sided compression (which mainly comprises opposing biaxial forces with a small component in the third axis) can be carried out, for example, by inserting the folded quasi-cylindrical sample of the plasticized superporous hydrogel into a hollow conical tube and then pushing it within the tube to further shape and compress it and to reduce its diameter to a desired size (e.g., capsule diameter). Before pushing the sample / capsule out of the open end of the conical tube (preferably having an inner diameter of 26 mm), the sample / capsule can preferably be left for 2 - 10 minutes (preferably 4 - 6 minutes) to fully fix the shape. Alternatively, the folded sample can be pushed into a cylindrical tube having two opposing open ends (e.g., having an inner diameter of 8 to 13, preferably 9 - 10 mm). Each of two push rods having concave ends can be inserted into each of the two open ends of the cylindrical tube, their concave ends being used to simultaneously squeeze the folded sample on opposite sides, thereby forming a capsule containing a lozenge-shaped compressed superporous hydrogel with dome-shaped ends. The plasticized superporous hydrogel material can also be directly molded (extruded) into a dosage capsule mold.

[0045] The folding step is most preferably carried out on samples containing one or more through-holes because they exhibit a particularly high diameter swelling ratio.

[0046] As described above, the preparation of the superporous hydrogel material involves washing the initial hydrogel with an acidic solution and then optionally treating it with a monovalent salt solution, meaning that it may not be necessary to form one or more through-holes, and thus it is not necessary to fold a sample of the superporous hydrogel material along the compression line as described above. Ideally, the plasticized superporous hydrogel samples can simply be compressed on three sides, for example by directly extruding them into a capsule mold or a gelatin capsule shell or one of the conical or cylindrical tubes described above.

[0047] Since the material is more easily deformed by an external force at a temperature above its glass transition temperature (Tg), it is preferred to apply the compression force at an elevated temperature. After applying the compression force, as described above, the elevated temperature can be reduced to, for example, ambient temperature to "set" the shape of the compression-plasticized superporous hydrogel. In addition, after machining, it is preferred to remove any residual moisture in the compression-plasticized superporous hydrogel capsule, and thus it is preferred to further dry the product (e.g., in a dryer or by lyophilization again) to ensure long-term storage stability.

[0048] The above composition is ideally suitable for providing a product formulation containing a plasticized superporous hydrogel material prepared by the method of the present invention, optionally in a compressed form, and optionally together with one or more slowly swelling non-superporous hydrogels. Preferably, the product formulation will be suitable for use as an appetite suppressant, for example to control weight gain and prevent obesity, or to deliver a drug and / or a nutraceutical to a human or an animal body.

[0049] The size of the product formulation (e.g., a capsule, a tablet or a lozenge) is preferably that of a standard 000 capsule or other forms of capsules, and the insertion of the improved superporous hydrogel prepared by the method of the present invention is preferably achieved as described above.

[0050] In many applications, it is important that each capsule containing the plasticized superporous hydrogel material can swell to a size larger than the pyloric diameter of the patient (human or animal) to ensure its retention in the stomach.

[0051] Although the product formulation of the present invention is designed not to block the esophagus or the lower digestive tract, unforeseen accidents may occur. Similarly, it is desirable that the appetite suppressant formulation can be easily terminated without surgery, endoscopy or other unpleasant medical interventions. The present invention uses a trigger or an emergency discharge mechanism to break down the product formulation into a form that can be easily excreted by the patient to solve these problems. The "decomposition trigger" can have various forms as long as it is effective and efficient during the decomposition process and can be safely used by the patient. Preferred decomposition triggers include electromagnetic waves (e.g., light, heat), mechanical waves (e.g., ultrasound) or chemicals.

[0052] Depending on the nature of the hydrogel, the decomposition trigger can be but is not limited to one of the following:

[0053] (1) A solution of a certain chemical substance or certain chemical substances containing attack crosslinking groups;

[0054] (2) An alkaline solution that reduces the mechanical strength of a pH-sensitive hydrogel;

[0055] (3) A high-intensity focused ultrasound (HIFU) device for an aqueous hydrogel composition;

[0056] (4) Thermal, light, or electrical signals transmitted by an endoscope or another capsule-like device to an occlusion point, which will trigger the response of a temperature-, light-, or electrical-sensitive hydrogel.

[0057] As an example, the hydrogels of the present invention can be designed to have reversible crosslinks that can be attacked by certain chemical substances. Although the reversible crosslinks are stable in the gastric environment, the chemical triggers are preferably substances that are not normally consumed in daily life or are present in food but in such low amounts that they do not cause immediate decomposition of the hydrogel. The amounts and concentrations should be strictly controlled within limits that can be found in regulations established by an authoritative body. Potential reversible crosslinks and their antidotes can include one or more of those in Table 1 below:

[0058] Table 1

[0059]

[0060] The improved compression-plasticized superporous hydrogel material prepared by the method of the present invention can be used for treating and / or preventing one or more medical conditions, including but not limited to obesity and diabetes. Highly preferably, such a hydrogel can be used as an appetite suppressant.

[0061] On the other hand, the present invention provides a dosing regimen for administering to a patient suffering from one or more medical conditions, such as those selected from obesity and diabetes, comprising orally administering to the patient a first dose of an orally acceptable formulation that contains the high-volume swelling hydrogel of the present invention in such an amount or quantity of sample that the sample will swell upon ingestion to fill up to 80%, preferably up to 60%, and further preferably up to 50% of the patient's gastric volume.

[0062] In a preferred dosage regimen for treating obese or diabetic patients, an initial large first dose is administered to the patient, preferably greater than 3, preferably at least 5, and further preferably at least 20 orally acceptable tablets or capsules (any other suitable product formulation may also be used, preferably 000-sized capsules), which contain one or more of the high-volume swelling hydrogels of the present invention. Then, this is optionally followed by a second dose, and optionally followed by further subsequent doses, preferably doses containing up to 5 orally acceptable tablets or capsules (or any other suitable product formulation), which contain one or more high-volume swelling hydrogels (these hydrogels may be the same or different from those taken at the initial high dose), at time intervals of at least about 12 hours, preferably at least about 24 hours, and highly preferably longer, such as about 48 hours. Preferably, the product formulation containing the high-volume swelling hydrogel will remain in the patient's stomach for several days (1 - 7 days), further preferably for several weeks (1 - 30 weeks) or even longer. The optional second dose and subsequent doses may be the same as or different from each other.

[0063] Ideally, the above method will also include the patient ingesting about 200 ml of water (preferably warm, further preferably at about 37 °C) before and / or during and / or after the patient ingests at least one of the first, second, or further subsequent doses.

[0064] Another separate and independent invention provides a similar method for preparing a plasticized superporous hydrogel material body as described above, which includes a through-hole forming step, optionally including a monovalent metal salt treatment step, but not including an acid treatment step. It has been found that the through-hole treatment step is particularly useful because materials treated with non-acidic solutions generally have lower yields than their acid-treated counterparts, and the use of through-holes enables the final plasticized superporous hydrogel material, whether molded or not, to be folded / rolled into a desired shape for insertion into a 000-dose capsule. All other steps, features, and advantages as described above will apply to this separate invention except for the absence of acid treatment. Description of the Drawings

[0065] The present invention will now be described with reference to the representations in the following drawings, in which:

[0066] Figure 1A : A cross-sectional view of a mold containing an initial hydrogel material before sealing;

[0067] Figure 1B : Showing after sealing Figure 1A The same cross-sectional view of the same mold depicted in;

[0068] Figure 2A: An end view showing the circular end face of a cylindrical sample of a plasticized, highly porous hydrogel having a through-hole drilled along its central longitudinal axis and the circular end face of a cylindrical compression rod before it is used to compress the hydrogel sample;

[0069] Figure 2B : Showing the cylindrical compression rod for compressing Figure 2A the cylindrical sample of the plasticized, highly porous hydrogel depicted in

[0070] Figure 2C : Showing Figure 2B the cylindrical sample of the plasticized, highly porous hydrogel depicted in , which will be folded in the direction of the arrow along the compression folds formed on its surface by the cylindrical compression rod (removed);

[0071] Figure 2D : Showing the Figure 2C cylindrical sample of the plasticized, highly porous hydrogel depicted in after being folded to reduce its diameter.

[0072] Figure 3 : A cross-sectional view showing two folded cylindrical samples of a plasticized, highly porous hydrogel and a push rod inserted into a hollow conical cylindrical mold;

[0073] Figure 4A : A cross-sectional view showing a folded cylindrical sample of a plasticized, highly porous hydrogel inserted into a cylindrical mold with a hollow open end, the mold having two push rods, each inserted into one of the two open ends of the mold;

[0074] Figure 4B : Showing, as Figure 4A shown, a cross-sectional view of a folded cylindrical sample of a plasticized, highly porous hydrogel inserted into a cylindrical mold with a hollow open end, where two push rods compress the sample on opposite sides;

[0075] Figure 4C : Showing the Figure 4B compressed and folded plasticized, highly porous hydrogel sample as shown in after being demolded from the cylindrical mold with a hollow open end;

[0076] Figure 5 : A graph showing the relationship between the volume swelling ratio and time for compressed and folded plasticized, highly porous materials prepared according to Control Example 1 (#OG) and Example 2 (#NG) of the present invention, using water or simulated gastric juice as the swelling medium;

[0077] Figure 6 : A graph showing the variation of the swelling diameter curve with time for compressed and folded plasticized, highly porous materials prepared according to Control Example 1 (#OG) and Example 2 (#NG) of the present invention, using water or simulated gastric juice as the swelling medium;

[0078] Figure 7 : Show the graph of true stress versus time for the compressed-folded plasticized superporous material prepared according to Comparative Example 1 (#OG), using water or simulated gastric juice as the swelling medium;

[0079] Figure 8 : Show the graph of engineering stress versus time for the compressed-folded plasticized superporous material prepared according to Comparative Example 1 (#OG), using water or simulated gastric juice as the swelling medium;

[0080] Figure 9 : Show the bar graph of the 4-day strength of the compressed-folded plasticized superporous material prepared according to the present invention in Example 2 (#NG) in simulated gastric juice. Specific embodiments

[0081] The abbreviations used herein are defined as follows:

[0082] Table 2

[0083]

[0084] Example 1: (Control)

[0085] Example 1: (Control) Preparation of a superporous hydrogel material (PSH) in which one or more through-holes are formed to facilitate folding of the PSH to reduce its size and facilitate preparation of an oral dosage formulation. (PSH) for preparing a PSH that is folded to reduce its size and facilitate the preparation of an oral dosage formulation by forming one or more through-holes to assist in plasticization.

[0086] Synthesis and polymerization:

[0087] Weigh 16.0 g (+ / -0.1 g) of AAm and 99.0 - 132.0 mg (+ / -1 mg) of BAC and mix with 90 - 200 ml of DW. At the same time, weigh 20.0 g (+ / -0.5 g) of AAm into 6.0 g (+ / -0.1 g) of AL and mix with 160 - 290 ml DW. Mix the above two solutions with 433.0 - 751.0 mg (+ / -1.0 mg) of APS, and equally distribute the resulting solution into 8 smaller beakers (labeled Group A).

[0088] Weigh 150.0 mg (+ / -1.0 mg) of CaSO4 powder, 6.2 ml of water and 47 - 82 ul of TEMED into each of another 8 beakers (labeled Group B).

[0089] Pour the solution in one of the eight beakers in Group A together with the suspension in one of the eight beakers in Group B. Then stir the mixture (14) for 10 - 50 seconds and pour it into 4 - 8 molds (10). Each mold consists of a cylindrical polypropylene (PP) tube (12) with an inner diameter of 10 - 40 mm and tapered rubber stoppers (16, 18) that match at the top and bottom and have the same outer diameter. The rubber stoppers (16, 18) in the tube mold (10) are as Figure 1A and 1B shown.

[0090] Repeat a similar operation for all eight sets of solutions in Group A and Group B, and leave all the samples in the PP molds (10) in an incubator (preheated to 60 °C) for 1 hour. Then transfer the molds (10) to a humid chamber to cure for another 24 - 72 hours at room temperature to complete the polymerization. The resulting gel material (the initial hydrogel material) is labeled as the prepared gel (APG).

[0091] Freezing and freeze-drying:

[0092] Place the APG gel in its respective mold (both ends of the mold are sealed with rubber stoppers) in a freezer at -20 °C for 8 - 24 hours, and then transfer it to a freeze dryer to remove water from the frozen gel within 48 to 72 hours. This produces a freeze-dried superporous hydrogel (a freeze-dried SPH).

[0093] Formation of through-holes:

[0094] Drill one or more through-holes or channels with a diameter of 4 to 10 mm along the longitudinal axis of each freeze-dried SPH cylinder sample to form a drilled freeze-dried SPH. For example, use a fan to blow away the chips.

[0095] Plasticization:

[0096] Place a covered container that is half-filled with water and includes a sample rack that can float on the water in the container in an incubator at 60 °C for 24 hours. Then place the drilled freeze-dried SPH sample in the sample rack and leave it in the container for 30 to 60 minutes until it becomes ductile.

[0097] Compression:

[0098] Carefully remove the ductile (plasticized) drilled freeze-dried SPH (20, 26) from the container, and compress it from the side of the sample along the holes (22, 25) with a rod (24), and fold it along the compression line (28) to form a folded plasticized drilled freeze-dried SPH (30), as Figure 2D shown, and then extrude it through an open-ended tapered tube to reduce its size to the size of an oral dose capsule, asFigure 3 as shown, or extruded into a cylindrical tube and compressed with push rods (38a and 38b), each push rod having a concave end (40a, 40b) and each inserted into an opposite open end of the cylindrical tube (36), as Figure 4A and 4B shown, or directly molded in a capsule mold.

[0099] Example 2: Using an acidic solution to treat a precursor initial hydrogel material and forming one or more through-holes in the sample body at the stage of superporous hydrogel (SH) to further assist in processing the PSH material into a lozenge-shaped body, preparation of a superporous hydrogel material using the method of the present invention. Treatment with an acidic solution: Figure 1B

[0100] The synthesis and polymerization steps used to form the initial hydrogel material in Example 2 are exactly the same as those used in Example 1.

[0101] Freezing and freeze-drying:

[0102] Remove the rubber plugs (16, 18) from the mold (10) as Formation of through-holes: shown, and use DW to wet the interface between the APG and the PP tube (12) so that the APG can slide out of the tube for the next washing process.

[0103] Immerse the APG in SGF (pH of about 1.3) for 7 - 14 days, routinely rinsing the sample and the container with DW every day and updating the SGF. The volume of SGF used for soaking the sample is 15 - 50 ml per gel.

[0104] Plasticization:

[0105] Drain the swollen and acid - solution - washed samples from the SGF, and place each hydrogel directly into a PP cylindrical tube mold with a diameter similar to that of the swollen gel. Then place the swollen gel in the mold in a freezer at - 20°C for 8 - 24 hours, and then transfer it to a freeze - dryer to produce freeze - dried super - porous hydrogel (freeze - dried SPH).

[0106] Compression:

[0107] Drill one or more through - holes or channels with a diameter of 4 to 10 mm along the longitudinal axis of each freeze - dried SPH cylindrical sample to form the drilled freeze - dried SPH. For example, use a fan to blow away the chips.

[0108] Figure 2A

[0109] Place a covered container that is half - filled with water and includes a sample rack that can float on the water in an incubator at 60°C for 24 hours to ensure uniform temperature. Then place the freeze - dried SPH with holes in the sample rack and leave it in the container for 5 to 20 minutes until it becomes ductile.

[0110] Figure 2C

[0111] Carefully remove the malleable (plasticized) freeze-dried SPH sample from the container, and as Figure 4A and 2B shown, compress it from the side of the sample (20) along the hole (22) with a rod (24) and fold it along the compression line as Figure 4C and 2D shown. The resulting folded sample (30) of the plasticized freeze-dried superporous hydrogel is extruded into a cylindrical tube (36) with an inner diameter of 9 - 10 mm, as Figure 4A shown. Two studs (38a and 38b) (outer diameter 9 - 10 mm) with special domed concave ends (40a and 40b) are placed on both sides of the sample (30) in the tube (36) and pushed towards the center to form a round-ended hydrogel capsule (42), which is then removed from the tube as a free capsule (tablet-shaped body) (44), as Figure 4C shown.

[0112] Results:

[0113] The degree of swelling can be measured in several different ways, for example:

[0114] 1) By placing the sample before and after swelling on a calibrated grid (1 square centimeter) and recording the change in size.

[0115] 2) Using the displacement method, where first the initial volume of the dry gel is measured using the ethanol displacement method. The gel is placed in a graduated cylinder filled with pure ethanol, and is pushed down with a fine needle to just submerge it in the ethanol. The displacement of the liquid level is calculated and taken as the initial volume of the dry gel. When measuring the amount of ethanol for displacement, the gel is removed from the ethanol, dried (e.g., using a clean paper towel) and placed in a fume hood for 1 hour to evaporate the remaining ethanol before placing the gel sample in the swelling medium (e.g., water or SGF). When swelling is complete, the swollen gel volume is determined using the same liquid displacement method as immediately above but using the swelling medium as the liquid instead of ethanol. The difference between the volume of displaced ethanol and the volume of displaced swelling liquid is used to determine the swelling volume ratio of the gel.

[0116] 3) Using calipers to measure the length and diameter of the hydrogel sample before and after swelling.

[0117] Both Example 1 and Example 2 prepared compressed plasticized superporous hydrogel materials. However, compared to the hydrogel prepared using Example 1 (#OG) which takes more than 60 minutes to reach the same degree of swelling, the material prepared in Example 2 (#NG) obtained faster swelling results, with the maximum swelling size obtained within about 20 min (in SGF and water).

[0118] Summary of results:

[0119] Table 3

[0120]

[0121]

[0122]

[0123]

[0124] Example 3: Experiment to study the effect of pH on the appearance and swelling properties of a plasticized superporous hydrogel material prepared by the method of the present invention Effect on appearance and swelling properties 。

[0125] The synthesis and polymerization steps used in Comparative Example 1 were used to prepare thirteen (13) individual samples of the initial hydrogel material, each individually cast in a mold (10). Then each molded sample was treated according to the present invention as follows.

[0126] Treatment with an acidic solution:

[0127] The rubber stoppers (16, 18) were removed from Figure 1B each of the molds (10) shown, and the interface between the APG and the PP tube (12) was wetted with DW so that the APG could slide out of the tube for the next washing process.

[0128] Each APG sample was immersed in its own acidic solution, each sample having a different pH, and the pH was from 1 to 12. Thirteen APG samples were immersed in SGF (pH about 1.3) for 7 days. The volume of the acidic solution used to soak the samples was 15 - 50 ml per gel.

[0129] Freezing and freeze-drying:

[0130] The swollen and acid solution-washed samples were drained from the final acidic solution, and each acid-treated hydrogel sample was directly placed into a cylindrical tube mold with a diameter of 30 mm, which should be longer than the gel length and have only one open end. Then the swollen gel in the mold was placed in a freezer at -20 °C for 8 - 24 hours, and then transferred to a freeze dryer to produce freeze-dried superporous hydrogel (freeze-dried SPH).

[0131] Plasticization:

[0132] Each sample of the freeze-dried superporous hydrogel was plasticized using the following method. A 0.4 L covered container with an inner surface containing a moisture wicking material (e.g., a moisture-absorbing paper strip, each wetted with 1 ml of water). The container was heated to 60 °C for 5 minutes. Then the freeze-dried SPH sample was placed in the container (well away from the moisture wicking material), and the container was placed in an oven at 60 °C for 1 to 5 minutes (ideally 3 minutes) until the sample became malleable.

[0133] Compression:

[0134] Each malleable (plasticized) freeze-dried SPH sample was carefully removed from the container and compressed from the side of the sample (20) along the holes (22) with a rod (24) as shown in Figure 2A and 2B and folded along the compression line as shown in Figure 2C and 2D The resulting folded sample (30) of the plasticized freeze-dried superporous hydrogel was extruded into a cylindrical tube (36) with an inner diameter of 9 - 10 mm as shown in Figure 4A This was achieved using a crimper that applied uniform radial compression along the long axis of the sample. The degree of swelling was determined by recording the weight of each SPH material sample before swelling in distilled water at 37 °C and recording the length and diameter of each swollen sample and the percentage volume expansion over time.

[0135] The results are shown in Table 4 below. As the pH of the acidic treatment solution increased from 1 to 12, the SPH samples showed an increase in the percentage of swelling, with the initial hydrogel samples treated with acidic solutions at pH 1 to 3 recording the greatest increase. The initial hydrogel samples treated with acidic solutions at pH 4 to 11 produced SPH samples where the percentage of swelling continued to increase, but the rate of this increase tended to level off, and when using a treatment solution at pH 12, the corresponding SPH samples disintegrated.

[0136] Table 4

[0137]

[0138] Other key observations made during this experiment included: i) As the pH of the acidic solution used to process the initial hydrogel increased, the target SPH became less mechanically stable. This was observed through the loss of structural integrity in the SPH samples; when using acidic treatment solutions with a pH of 1 to 3, the SPH samples had a defined cylindrical shape, but as the pH increased to pH 11, this shape gradually became more distorted, and when the treatment solution was at pH 12, it eventually became amorphous. ii) Although swelling increased as the pH of the acidic solution used as the immersion liquid increased, the target SPH material became gradually less useful. iii) The desired hazy / translucent appearance was only observed in the SPH when the initial hydrogel forming the corresponding SPH sample was treated with an acidic solution having a pH of 1 to 3. It is understood that this haziness / translucency is caused by the porosity in the hydrogel.

[0139] Depending on the pH of the acidic solution, it was found that the time required to process each sample under high humidity conditions varied greatly.

[0140] Conclusion: The pH of the acidic solution used to process the initial hydrogel material is particularly important for ensuring good processing performance and must be less than or equal to pH 3 to provide the optimal conditions for the desired pore size and desired swelling rate while maintaining structural integrity.

[0141] Example 4: Experiment to determine the effect of pH value and treatment with potassium chloride on the swelling behavior

[0142] The synthesis and polymerization steps used in Example 1 were used to prepare twenty (20) individual samples of the initial hydrogel material, and each sample was individually cast in a mold (10). Then the samples of the initial hydrogel material were divided into four (4) batches; one batch was treated with an acidic solution having a pH of 1, another batch was treated with a solution having a pH of 1.3, another batch was treated with a solution having a pH of 2, and the remainder was treated with a solution having a pH of 7. Then five samples in each batch were treated with an aqueous solution containing 0 M to 1 M potassium chloride salt. Thereafter, each sample was freeze-dried, plasticized, and compressed as described in Example 3 above, and the resulting formed SPH samples were immersed in distilled water at 37 °C and the length in mm and diameter in mm of each swollen sample were recorded, and the change in % volume of swelling over time was recorded.

[0143] The complete experiment was repeated 4 times, and each percentage value of volume increase shown in Table 5 below is the average of four results obtained for the corresponding samples of each repeated experiment. The results show that the concentration of potassium chloride has a very small effect on the final swelling weight during soaking. In the case of samples prepared from the initial hydrogel samples treated with acidic solutions with a pH of 1 to 2, although, as expected from Experiment 3 above, much larger percentage weight increases were observed when the treatment solution was pH 7. However, quite surprisingly, it was found that the percentage change in volume after 60 minutes was affected by the potassium chloride concentration; specifically, as the potassium chloride concentration increased from 0 M to approximately 0.134 M (10 g), the percentage of volume expansion increased, and then decreased when the concentration reached approximately 0.5 M.

[0144] Conclusion: The addition of KCl from 0 to 0.134 M is a particularly useful range.

[0145] Table 5

[0146]

[0147] Example 5: Experiment to determine the effect of monovalent metal salt concentration on the processability of the target SPH material

[0148] An important property of the required plasticized super-porous hydrogel material is its ease of shaping, for example by folding / rolling / compressing, so that it can be inserted into a dose capsule shell within a reasonable time frame (desired to be more than 1 minute but less than 60 minutes) and there is a good balance between SPH materials with excellent processability and SPH materials that become too soft. The current work surprisingly determined that for a given degree of water vapor treatment (exposure to moisture: humidity percentage and duration) for plasticizing SPH samples, the "processability" (ease of folding / rolling / compressing) of SPH samples increases with increasing KCl concentration, and the SPH material becomes more "processable". However, too much KCl, generally when the metal salt concentration is higher than 0.15 M, the target SPH becomes too soft to process.

[0149] A useful result of this observation is that the addition of KCl helps to control and optimize the amount of moisture exposure (duration and / or humidity percentage) required to soften the dried SPH material samples. Compared with the case of not using KCl salt, a KCl salt concentration >0 M up to 0.15 M can reduce the humidity / shorten the duration of moisture exposure.

[0150] Conclusion: The best moisture exposure is obtained when using a monovalent salt solution of >0 M to 0.15 M.

Claims

1. A method for preparing a plasticized superporous hydrogel, comprising the following steps: a) Form an initial hydrogel material in the absence of any foaming agent or other foaming method, wherein the initial hydrogel material comprises one or more selected from the group consisting of an interpenetrating network structure, a semi-interpenetrating network structure, and a simple cross-linked structure, and the structure is formed by providing a mixture comprising acrylamide and alginate and subjecting the mixture to polymerization and / or cross-linking conditions; b) Recover the resulting initial hydrogel material formed in step a) and treat it with an acidic solution comprising one or more acids and having a pH of 1 to 2; c) Simultaneously with or after treating step b), treat the initial hydrogel material formed in step a) with a solution comprising one or more monovalent metal salts selected from the group consisting of one or more sodium salts, potassium salts, and lithium salts, in an amount of ≥0M to ≤0.5M; d) Use freeze-drying to dry the resulting wet initial hydrogel material to produce a dry, highly porous hydrogel material; e) Treat the resulting dry, highly porous hydrogel material with water vapor to plasticize its structure; and f) Recover the resulting plasticized, highly porous hydrogel material.

2. The method according to claim 1, wherein the resulting plasticized superporous hydrogel material is in the form of a separate isolated sample comprising a body having an internal structure containing the plasticized superporous hydrogel material and an outer surface, wherein each sample comprises one or more through-holes that form channels extending between a first opening in a first portion of the outer surface of the body within the internal structure of the body and a second opening in a second portion of the outer surface of the hydrogel material body.

3. The method according to any one of claims 1 or 2, wherein a separate sample of the initial hydrogel material is prepared by filling a suitable mold with a reaction mixture comprising acrylamide and alginate, then subjecting the mixture to polymerization and / or crosslinking conditions, and demolding the separate sample of the resulting initial hydrogel material.

4. The method according to claim 3, wherein the separate sample of the initial hydrogel material is of irregular shape.

5. The method according to claim 3, wherein the separate sample of the initial hydrogel material is cylindrical in shape.

6. The method according to claim 5, wherein the separate sample of the initial hydrogel material is rod-shaped.

7. The method according to claim 3, wherein the separate sample of the initial hydrogel material is oval or spherical in shape.

8. The method according to claim 3, wherein the separate sample of the initial hydrogel material is cubic or cuboid in shape.

9. The method according to claim 1 or 2, wherein step e) comprises subjecting the superporous hydrogel to humidity conditions of >50%.

10. The method according to claim 1 or 2, wherein the one or more acids are selected from inorganic acids and / or organic acids.

11. The method according to claim 1 or 2, wherein the acidic solution comprises one or more selected from gastric juice and simulated gastric juice.

12. The method according to claim 1 or 2, further comprising the step of applying a compressive force to the resulting plasticized superporous hydrogel material to reduce the volume of at least some of the pores therein.

13. The method according to claim 1 or 2, which further comprises the step of inserting the resulting plasticized superporous hydrogel material into a capsule dosage form shell to prepare a capsule dosage form.

14. The method according to claim 13, wherein before inserting into the capsule dosage form shell, one or more techniques are used to reduce the overall size of the resulting hydrogel mass, and the resulting plasticized superporous hydrogel material is inserted into the capsule dosage form shell, and the techniques are selected from: applying pressure and folding.

15. The method according to claim 14, wherein the applying pressure is extrusion.

16. The method according to claim 15, wherein the extrusion is applying bilateral and / or trilateral compression.

17. The method according to claim 14, wherein before inserting into the capsule dosage form shell, the resulting plasticized superporous hydrogel material is extruded through a hollow conical tube.

18. Use of one or more plasticized superporous hydrogels prepared by the method according to any one of claims 1 to 17 for the preparation of a formulation suitable for oral administration.

19. The use according to claim 18, which further comprises one or more drugs and / or functional nutrients.

20. An oral dosage form, which comprises one or more plasticized superporous hydrogels prepared by the method according to any one of claims 1 to 17, optionally and one or more drugs and / or functional nutrients.

21. The method according to claim 1, wherein step e) is at room temperature or at an elevated temperature.

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