Delivery system and device

Abstract

The present invention provides a product capable of releasing one or more active ingredients, the product comprising a superporous hydrogel structure formed by freeze-drying. The present invention also relates to a method for manufacturing said product and various uses of said product.

Description

Technology Field

[0001] The present invention relates to a product capable of releasing one or more active ingredients. Ideally, the product is used as a delivery system and / or delivery device suitable for ingestion by humans and / or animals. The present invention also relates to a method for manufacturing said product. Inventive uses of said product are also disclosed herein. Background Technology

[0002] Gastric retention drug delivery systems have been developed to address problems arising from the poor gastric absorption and bioavailability of certain orally administered drugs and other active ingredients. Gastric retention drug delivery systems can also be used to improve the absorption and bioavailability of certain orally administered drugs in the upper small intestine.

[0003] A gastric retention type drug delivery system allows an orally administered drug or other active ingredient to be retained in the upper gastrointestinal tract (e.g., stomach) for a longer period than provided by the normal timeline of digestion, thereby increasing the amount of drug or active ingredient absorbed (e.g., in the stomach or upper GIT).

[0004] The motility motor complex (or motility myoelectric complex or motility motor complex or motility myoelectric complex or MMC) is a wave of electrical activity that sweeps through the stomach and small intestine in regular cycles during fasting. This motor complex triggers powerful, explosive peristaltic waves, also known as clearing waves, which facilitate the transport of undigested material, such as bone, fiber, and foreign substances, from the stomach through the small intestine, past the ileocecal sphincter, and into the colon. MMC waves occur every 45 to 180 minutes during the interdigestive phase (i.e., between meals) and are the cause of the rumbling sounds experienced when hungry.

[0005] Therefore, to remain in the stomach for a longer period than this, the gastric retention drug delivery system must be mechanically robust enough to withstand, for example, the forces applied by the gastric muscles during the normal gastric muscle peristalsis cycle as well as the motility complex between the third phase of the digestive tract.

[0006] Conventional gastric retention drug delivery systems are based on various technologies, including floating systems (FTS), high-density systems (HDS), mucosal adhesion systems (MCS), magnetic systems (MAGS), and extensible systems (EXS). Each of these systems is briefly summarized below. However, for a deeper understanding, readers are encouraged to refer to the following review article: 'Features and Facts of a Gastroretentive Drug Delivery System-A Review'; Turk J Pharm Sci. 2022 Aug; 19(4): 476-487.

[0007] Commercial examples of MCS include Xifaxan® (Rifaximin), developed by Lupin (India). Commercial examples of EXS include Accordion Pill®, developed by Intec Pharma Ltd., Lyndra's LYNX™ drug delivery platform, or Depomed's AcuForm. TM Includes the platform.

[0008] Floating systems (FTS) contain cavities or gas-generating agents to provide products that float and possess buoyancy within the stomach. However, these systems suffer from inadequate mechanical properties and are therefore rapidly destroyed by gastric MMC waves. Additionally, FTS are known to exit the stomach earlier than desired, making them unsuitable for allowing orally administered drugs or other active ingredients to remain in the upper gastrointestinal tract for extended periods.

[0009] High-density systems (HDS) utilize weight as a retention mechanism. Therefore, to ensure gastric retention of the drug in the stomach, the density of the drug must exceed the density of normal gastric contents (1.004 g / mL). Because these systems lack emphasis on mechanical properties, the gastric retention time of these systems is generally short, depending on the size of the formulation (reportedly up to 25 hours). However, the size of the formulation is limited by the requirements of oral formulations. Additionally, as discussed in 'Nanomaterials: An Improvised Drug Delivery System through the Gastroretentive Drug Delivery System'; Mater. Proc. 2023, 14(1), 63, HDS involve the use of weights in combination with formulation strategies such as coating with weights or mixing with iron, zinc oxide, or barium sulfate, which can cause the formulation to settle in the stomach and delay action due to the high density of the formulation. Formulations of this system are difficult, and no such commercially available formulations exist.

[0010] Mucosal adhesion systems (MCS) utilize the adhesive properties of the system to deliver drugs to specific parts of the body (e.g., the gastric mucosa) for extended periods. For this purpose, bioadhesive or mucosal adhesion polymers, such as those described in 'Features and Facts of a Gastroretentive Drug Delivery System—A Review'; Turk J Pharm Sci. 2022 Aug; 19(4): 476-487, are typically used. However, as stated in this review article, the gastric retention time of mucosal adhesion systems is typically short, with one reported example showing a retention time of 6 hours. Additional disadvantages include: high gastric humidity conditions that can reduce the bioadhesion of the MCS; and, furthermore, the higher risk of MCS adhering to the esophagus, which can cause collateral lesions. See: Current State and Future Perspectives on Gastroretentive Drug Delivery Systems Pharmaceutics 2019, 11(4), 193.

[0011] Magnetic Aggregation Systems (MAGS) include magnetic particles within an orally administered drug device and an external magnet to anchor the device. While MAGS can potentially exhibit long gastric retention times, they require external support equipment. Furthermore, the long-term use of magnets and the forces exerted on the stomach wall by MAGS are not well understood and may cause unwanted side effects.

[0012] An expandable system (EXS) is a device that expands in volume within the gastric environment, for example by swelling or unfolding, to a volume large enough to prevent the device from slipping out of the stomach. Further information on this type of system can be found in the following review article: Current State and Future Perspectives on Gastroretentive Drug Delivery Systems Pharmaceutics 2019, 11(4), 193.

[0013] The expandable system must reach a size larger than the diameter of the pylorus (preferably ≥25 mm, more preferably >30 mm) in a short time (within 45 minutes, preferably within 30 minutes, more preferably within 10 minutes). Cassily et al. in "Twenty-four hour ambulatory antroduodenal manometry in normal subjects (co-operative study)" Neurogastroenterol. Motil. 2008. 12, 231-238 SmartPill TM They studied gastric emptying and their study showed a strong correlation between the occurrence of Phase III MMC between the digestive system and the exit of non-digestible pills. For SmartPill™ (diameter >7 mm), exit with an approximately 300 kcal meal was 261 ± 22 minutes (first Phase III MMC @ 239 ± 23 minutes). When administered with water alone, gastric retention time was 92 ± 44 minutes (first Phase III MMC @ 87 ± 30 minutes). For non-digestible particles smaller than 7 mm, early exit without Phase III MMC is experienced (Stotzer et al. Neurogastroenterol Motil. 2000; 12, 415-9).

[0014] Therefore, any expandable gastric retention drug delivery system must have a diameter much larger than 7 mm (preferably ≥25 mm, more preferably >30 mm) to be retained in the stomach for any given time. Additionally, it is necessary for such a drug delivery system to achieve this size within a few minutes after swallowing.

[0015] However, conventional swelling devices, in particular, tend to struggle due to the conflict between swelling speed and mechanical properties, and devices that swell faster have substandard mechanical properties that lead to accelerated degradation of the device by the MMC waves above. Once the swelling device is degraded to a sufficiently small size, it is removed from the stomach by the MMC waves. Some expandable systems (particularly unfolding systems) exhibit long gastric retention times, but they require high-temperature processing during manufacturing, which limits the active ingredients that can be used within the system. Additionally, as stated in *Current State and Future Perspectives on Gastroretentive Drug Delivery Systems Pharmaceutics 2019, 11(4), 193*, expandable systems have several limitations, such as difficulties in storing polymers that are easily hydrolyzed and biodegradable, difficulties in manufacturing and potentially not cost-effective, difficulties in maintaining structural integrity, and the potential to cause intestinal obstruction, intestinal adhesions, and gastropathies.

[0016] Finally, swelling systems and / or expansion systems known in the art include double-mesh hydrogels and superporous hydrogels (SPH). Such systems are discussed, for example, in 'Features and Facts of a Gastroretentive Drug Delivery System-A Review'; Turk J Pharm Sci. 2022 Aug; 19(4): 476-487.

[0017] Ultraporous hydrogels have a porous, hydrophilic cross-linked structure that is hard, brittle, and insoluble in water when dried. When immersed in an aqueous medium, SPH can absorb the aqueous fluid up to several times its own weight, swelling in size to become a soft gel material. SPH typically has a three-dimensional network made of a hydrophilic polymer material having numerous pores.

[0018] In 2017, Liu et al. developed a double-mesh hydrogel dispersed with lumefantrin (an antimalarial), which doubled the release time of the free form (Nat Commun 8, 124 (2017)). This system was also tested with insulin, rifampicin, and dimethyl sulfoxide and exhibited size-dependent in vitro release rates. Although this system achieved an average gastric retention time of 9 days in pigs, its commercial application is limited due to the swelling rate; to achieve gastric retention, a pre-swollen hydrogel inserted into an endoscope measuring Φ2.8 cm × 5 cm with a volume of 22 ml was used in in vivo porcine tests. Therefore, this device is not suitable for oral administration.

[0019] In 2014, Nagpal et al. demonstrated a proof of concept as a drug delivery system by loading verapamil HCl as a model drug into SPH created using a gas blowing method to generate multiple pores. Int J Pharma Investig , 3, 131(2013)). Their test showed an initial burst release of verapamil during the first hour before release continued for the next 24 hours. However, since generating SPH through gas blowing results in random pore formation, the resulting hydrogel has insufficient mechanical strength and limited gastric retention time.

[0020] WO 2019 / 016560 A1 discloses a process for manufacturing SPH through a freeze-drying process, which produces SPH that achieves a rapid swelling rate and excellent high swelling volume. This disclosure also discloses a multi-component product formulation of a "core-shell" type on page 10, lines 5 through 12. In a preferred embodiment, a first component (which is an SPH according to the disclosure of WO 2019 / 016560 A1) is used to form the "shell," and a second component (which is one or more gently swelling non-hyperporous hydrogels) is used to form the "core."

[0021] WO 2021 / 069751 A1 discloses a process for manufacturing SPH through a freeze-drying process, which produces SPH that improves processability as well as a rapid swelling rate and excellent high swelling volume. This disclosure also teaches SPH for use in oral formulations in which one or more pharmaceuticals and / or dietary supplements are incorporated into the oral formulation as additional separate components to a plasticized hydrogel material. In one embodiment, one or more pharmaceuticals and / or dietary supplements may be additional separate components to the SPH, or in an alternative embodiment, one or more pharmaceuticals and / or dietary supplements may be part of the hydrogel material structure. In such cases where one or more pharmaceuticals and / or dietary supplements may be part of the hydrogel material structure, the pharmaceuticals and / or dietary supplements may be attached to one or more hydrophilic polymer chains forming the hydrogel material.

[0022] Accordingly, this disclosure specifically refers only to oral formulations in which one or more medicinal products and / or health functional foods may be attached to one or more hydrophilic polymer chains forming an SPH, and there is a disclosure or teaching in this prior art in which one or more medicinal products and / or health functional foods may be located within a multi-component product formulation, e.g., in a "core-shell" format. In particular, there is no disclosure regarding the manufacture of such multi-component products, or any data disclosing the effect of the release of one or more medicinal products and / or health functional foods from such multi-component products, particularly in gastric environments. It is also not known from this prior art whether one or more medicinal products and / or health functional foods must be included in the "shell" or "core" of such multi-component products to achieve long-term retention in gastric environments and enable the effective release of one or more medicinal products and / or health functional foods.

[0023] Therefore, the present invention aims to overcome the disadvantages of the aforementioned prior art.

[0024] In particular, the object of the present invention is to provide a novel product capable of releasing one or more active ingredients within an environment, ideally when exposed to a gastric environment. Ideally, the novel product will thus function as a delivery system and / or delivery device and, preferably, will have a gastric retention time of 12 hours or more in a gastric environment to allow for long-term delivery of active ingredients, such as pharmaceuticals and / or health functional foods. Accordingly, the approach of the present invention will contrast with products of the prior art having a gastric retention time of less than 12 hours, thereby enabling an increase in the amount of active ingredients absorbed in such a gastric environment.

[0025] The methods of the present invention will also enable the efficient and cost-effective production of products. Furthermore, the methods of the present invention allow temperature-sensitive active substances (e.g., biological agents) to be loaded into products by avoiding high temperatures, in contrast to the approaches of the prior art discussed above.

[0026] The present invention achieves these objectives by providing a product capable of releasing one or more active ingredients, wherein the product comprises a superporous hydrogel structure and the superporous hydrogel structure comprises a core region comprising one or more active ingredients. Ideally, the product is a multi-component product (i.e., a "core-shell" type) having a shell region and a core region.

[0027] Advantageously, as the product comprises a hydrogel material (i.e., an ultraporous hydrogel structure) ideally prepared by freeze-drying, this enables a long gastric retention time due to the product's mechanical rigidity, high volume swelling ratio, and high swelling rate. In practice, the long gastric retention time provided by the product of the present invention improves the absorption of the active ingredient by allowing one or more active ingredients to be delivered and retained in the environment, preferably the gastric environment (e.g., the stomach), for at least 12 hours, preferably at least 24 hours (preferably up to 7 days, ideally up to 14 days). Furthermore, because the product comprises a hydrogel material (i.e., an ultraporous hydrogel structure), the product (preferably acting as a delivery system and / or delivery device for drugs or vitamins) will typically decompose and be excreted from the body. Additionally, the product is compatible with a wide range of active ingredients, such as pharmaceuticals and / or health functional foods discussed below. The product is ideally used as a gastric retention type delivery system for one or more active medicinal ingredients, as discussed in detail below.

[0028] The term "ultraporous hydrogel" (SPH), as used herein, refers to a porous, hydrophilic, cross-linked structure that is hard, brittle, and insoluble in water when dried. When immersed in an aqueous medium, an SPH can absorb the aqueous fluid up to several times its own weight, swell in size, and become a soft gel material. SPH typically has a three-dimensional network made of a hydrophilic polymer material having numerous pores.

[0029] The average pore diameter of the newly formed SPH (i.e., SPH that has not undergone a compression step) is ideally greater than 100 μm to about ≤3 mm, optionally up to about ≤2 mm, and additionally optionally up to about ≤1 mm.

[0030] Preferably, the ultraporous hydrogel has a pore structure in which the pores of the pore structure have an average maximum dimension of at least 100 μm.

[0031] It will be understood that the broad term "hyperporous hydrogel" may include "compressed hyperporous hydrogel" or "uncompressed hyperporous hydrogel" or both compressed and uncompressed hyperporous hydrogels. A compressed hyperporous hydrogel is a hyperporous hydrogel exposed to compressive forces suitable for collapsing at least some of the pores of the hyperporous hydrogel structure. An uncompressed hyperporous hydrogel is a hyperporous hydrogel not exposed to such forces.

[0032] Preferably, the product comprises a compressed ultraporous hydrogel. The compressed ultraporous hydrogel can be easily distinguished from the uncompressed ultraporous hydrogel by various techniques, including scanning electron microscopy. Indeed, as discussed below, Figures 23 and 24 illustrate the visual difference between the porous structures of the compressed ultraporous hydrogel and the uncompressed ultraporous hydrogel.

[0033] The term “maximum dimension” is a parameter measured using a scanning electron microscope (SEM) and is defined as half the cross-sectional perimeter of a single pore of the pore structure of the superporous hydrogel as defined herein. Thus, if any cross-section of a single pore as illustrated by the SEM has a perimeter of 200 μm or more, the pore has a maximum dimension of at least 100 μm.

[0034] The term “average maximum dimension” refers to the arithmetic mean of a measurement sample obtained according to the definition of the term “maximum dimension.” In one embodiment, the average maximum dimension is the arithmetic mean of a sample of at least 10 pores, preferably at least 10 adjacent or interconnected pores.

[0035] Preferably, the pores of the pore structure have an average maximum dimension of at least 150 μm, optionally at least 200 μm or at least 250 μm.

[0036] Preferably, the pores of the pore structure of the ultraporous hydrogel have a maximum dimension of >10 μm to 5 mm. More preferably, the ultraporous hydrogel comprises a compressed structure having pores having a maximum dimension of >10 μm to 3 mm, optionally >30 μm to 2.1 mm.

[0037] Optionally, the ultraporous hydrogel comprises an incompressed structure having pores having a maximum dimension of >100 μm to 5 mm, optionally >200 μm to 3 mm.

[0038] To clarify, "maximum dimension" and "average maximum dimension" are defined in the same way for both compressed and uncompressed ultraporous hydrogels.

[0039] However, if the product comprises an uncompressed ultraporous hydrogel, the pores of the pore structure of the uncompressed ultraporous hydrogel will preferably further exhibit an average pore diameter of at least 100 μm. Additionally preferably, the pores of the pore structure have an average pore diameter of at least 150 μm, optionally at least 200 μm, or at least 250 μm.

[0040] As used herein, the term “average pore diameter” is defined as the longest straight wall-to-wall dimension over any cross-section of the pore. That is, if the longest straight wall-to-wall dimension over any cross-section of the pore is 100 μm, the pore is considered to have a pore diameter of 100 μm. For example, if the pores of the superporous hydrogel are substantially spherical, the term “pore diameter” refers to the actual diameter of the pores. Alternatively, if the pores of the superporous hydrogel have a substantially elliptical cross-section, the term “pore diameter” refers to the major axis of the elliptical cross-section. It will be understood that the shapes described above are provided for illustrative purposes only.

[0041] It will be understood that the above-described pore size definitions relate to the product according to the present invention. It will be further understood that if the product according to the present invention is immersed in a fluid containing water, e.g., simulated gastric juice or water, the size of the pores may increase. A preferred simulated gastric juice may comprise a mixture of a salt solution (e.g., sodium chloride, ideally 0.2 wt%) and an acid solution (e.g., hydrochloric acid, ideally pH 1-2).

[0042] Preferably, the ultraporous hydrogel structure comprises one or more selected from an interpenetrating network structure, a semi-interpenetrating network structure, and a simple cross-linked structure. Ideally, the ultraporous hydrogel structure comprises an interpenetrating network structure.

[0043] As used herein, the term “core region” refers to a substantially central portion of a hydrogel structure that includes and / or does not include a hydrogel material region. Optionally, the core region includes a void or cavity region and / or includes one or more active ingredients and / or one or more excipients. Thus, one or more active ingredients and / or one or more excipients are ideally associated (directly or indirectly) with the core region of the ultraporous hydrogel structure.

[0044] Preferably, one or more active ingredients may be located in and / or retained by the core region of the superporous hydrogel structure (e.g., retained within the core region) without being chemically connected (e.g., bonded) to a part of the core region of the superporous hydrogel structure itself (e.g., without using covalent chemical bonds). This includes, for example, preferably not being chemically attached to one or more hydrophilic polymer chains forming the superporous hydrogel structure. The term "chemically connected" refers to cases of covalent bonds resulting from a chemical reaction, and thus any electrostatic (e.g., ionic) or other charge-based interactions (e.g., van der Waals forces) are not included in this sense. In practice, active ingredients not chemically bonded to the hydrogel material may, for example, form electrostatic interactions with the hydrogel material.

[0045] Alternatively or additionally, one or more active ingredients may be located in a core region of the hydrogel material and maintained therein (e.g., maintained within the core region) without being physically connected (e.g., bonded) to the hydrogel material itself (e.g., without using an adhesive to connect one or more active ingredients to the hydrogel material itself).

[0046] Ideally, one or more active ingredients can be located and retained (partially or completely) within the core region of the ultraporous hydrogel structure. For example, one or more active ingredients can be retained within the core region by the elastic action or properties of the ultraporous hydrogel material.

[0047] Preferably, substantially all of one or more active ingredients are located within the core region of the ultraporous hydrogel structure. That is, one or more active ingredients are preferably not substantially present in regions other than the core region (e.g., the shell region of the ultraporous hydrogel structure or the shell region of the product). It will be understood that this limitation applies prior to any subsequent use of the product (i.e., prior to any selective intake by the patient). Advantageously, this results in a product with a more consistent release rate of the active ingredients.

[0048] Preferably, the core region may include one or more additional components in addition to one or more active ingredients. For example, it may include one or more excipients, which are discussed in more detail below.

[0049] As used herein, the term “shell region” refers to a part of the hydrogel structure located on the outer perimeter of the core region. In particular, the “shell region” may partially or completely surround the core region to provide a “core-shell” structure.

[0050] The ultraporous hydrogel material is preferably used in the shell region. Accordingly, in one embodiment, the product comprises an ultraporous hydrogel structure, the ultraporous hydrogel structure comprises a shell region and a core region, the shell region comprises an ultraporous hydrogel material, and the core region comprises one or more active ingredients. That is, the ultraporous hydrogel material is included in the "shell region" and one or more active ingredients are included in the "core region." However, as specified above, the "core region" is not limited to only one or more active ingredients and may include a region comprising the ultraporous hydrogel material and / or a region not comprising the ultraporous hydrogel material (e.g., a void or cavity region). Additionally, the "shell region" may comprise one or more additional components in addition to the ultraporous hydrogel material.

[0051] Preferably, the ultraporous hydrogel structure comprises a shell region that at least partially surrounds a core region, and at least a portion of the shell region of the ultraporous hydrogel structure substantially does not contain the active ingredient. Additionally, preferably, the entire shell region of the ultraporous hydrogel structure substantially does not contain the active ingredient. It will be understood that these limitations apply prior to any subsequent use of the product (i.e., prior to any selective intake by the patient). Advantageously, this results in a product with a more consistent release rate of the active ingredient.

[0052] Preferably, the core region comprises a body separated from the ultraporous hydrogel structure. That is, the core region comprises a body comprising one or more active ingredients, said body not being an extension of the surrounding ultraporous hydrogel structure. The body may or may not further comprise a hydrogel structure and / or an ultraporous hydrogel structure. However, if the body comprises a hydrogel structure and / or an ultraporous hydrogel structure, the structure of the body does not form a single porous structure continuous with the surrounding ultraporous hydrogel structure. Preferably, the shell region at least partially surrounds the body. Ideally, the shell region completely surrounds the body.

[0053] The main body may further include one or more excipients. One or more preferred excipients (optional two or more excipients) may include, but are not limited to, a penetration promoter, a filler material, a binder, a diluent, a buffer, a thickener or gelling agent, a stabilizer, a solubilizer, a surfactant, a disintegrant, a lubricant, a lubricant, a coloring agent, a contrast agent (for radiography), a preservative, a suspending agent, an emulsifier, a film-forming agent or coating agent, an antioxidant, an isotonic agent, an emission control agent, a radioactive material, and combinations thereof.

[0054] The body may optionally be in a solid state, a liquid state, or a mixture of solid and liquid.

[0055] Preferably, the core region comprises one or more cavities in which the hydrogel material is substantially empty before one or more active ingredients are loaded. Ideally, one or more cavities are loaded with one or more active ingredients. As used herein, the term “cavity” is intended to mean any empty space within the hydrogel material that is not considered a ‘pore’ of the hydrogel structure. That is, the term “cavity” does not include any of the multiple pores inherent to the hydrogel structure created by chemical or physical means during one or more processing steps, but instead refers to an empty space intentionally created by separate means (e.g., by using a specific mold or by cutting the hydrogel). Accordingly, the term may also include “pocket,” “pouch,” “chamber,” “void,” etc.

[0056] After the compression step, one or more cavities may have dimensions of < 25 mm × < 10 mm × < 10 mm. However, before the compression step, one or more cavities may have dimensions of up to 35 mm × 35 mm × 35 mm. Ideally, before the compression step, one or more cavities may have dimensions of approximately 20 mm × 20 mm × 20 mm. Thus, before the compression step, the dimensions may be approximately 10 mm × 10 mm × 10 mm to approximately 35 mm × 35 mm × 35 mm.

[0057] In one embodiment, after the compression step, one or more cavities will optionally accommodate a cylindrical or spherical tablet having a length of about 25 mm and a diameter of about 8 mm.

[0058] Preferably, the core region, and optionally one or more cavities may further include one or more excipients discussed in more detail below.

[0059] The core region may include one or more cavities, and ideally, one or more cavities may be loaded with two or more active ingredients, or in some cases, three or more active ingredients. The two or more active ingredients, or in some cases, three or more active ingredients, may each be the same active ingredient, but may be contained within separate delivery means, for example, such as capsules or pills. Alternatively, the cavities may include a first active ingredient and a second active ingredient (optional, a third active ingredient), wherein the first active ingredient is different from the second active ingredient (optional, the third active ingredient is different from the first and second active ingredients).

[0060] The core region may include two or more cavities, or in some cases, three or more cavities. Each of the two or more cavities, or each of the three or more cavities, may be loaded with one or more active components. In one embodiment, the core region may include two or more cavities, wherein one of the two or more cavities is loaded with a first active component and the other of the two or more cavities is loaded with a second active component. In this case, the first active component may be the same as or different from the second active component. Thus, in one embodiment, all of the two or more cavities, or optionally all of the three or more cavities, may each contain different active components.

[0061] Preferably, the total volume of one or more cavities is ≥0.17 µL and ≤2 mL. As used herein, the term “total volume” refers to the combined volume of one or more cavities. Optionally, one or more cavities have a maximum combined volume of at least 100 µL and ≤3 mL, optionally ≤2 mL, and additionally optionally ≤1 mL. Optionally, one or more cavities have a maximum combined volume of at least ≥0.17 µL and ≤3 mL, and additionally optionally ≤1 mL.

[0062] In one preferred embodiment, the total volume of one or more cavities is >4.2 µL and ≤2 mL. In this preferred embodiment, it will be understood that this does not overlap with the pore size of a preferred superporous hydrogel comprising a compressed structure having pores having a maximum dimension of >100 µm to 1 mm.

[0063] Additionally, one or more cavities may include one or more passages that allow fluid communication from an opening on the side of the product to one or more cavities. A passage may be considered as a passage between an opening on the side of the product and one or more cavities located within a substantially central portion of the ultraporous hydrogel structure. Advantageously, these one or more passages enable one or more active ingredients to be easily loaded into one or more cavities. Accordingly, one or more passages preferably include an opening on the side of the product to enable one or more active ingredients to be easily loaded into one or more cavities. Ideally, these passages exist before one or more active ingredients are loaded into one or more cavities during the manufacture of the product of the present invention. This is because these passages can be sealed or closed after one or more active ingredients are loaded into one or more cavities. In one embodiment, the opening is closed after one or more cavities are loaded with one or more active ingredients. The opening and / or passages are preferably sealed by the installation of a plug comprising a biologically inert material and an adhesive; optionally by the use of an adhesive, thread, or staple; or by the elastic action of the ultraporous hydrogel material; Optionally, it may be closed by the application of compressive force after freeze-drying treatment; or by any other means available to a person of ordinary skill.

[0064] The shell region may include one or more incisions. These one or more incisions may be made in the shell region of the hydrogel material so that one or more active ingredients can be loaded into the core region.

[0065] Preferably, the ultraporous hydrogel comprises a compressed structure having pores with a maximum dimension of >100 μm to 5 mm. More preferably, the ultraporous hydrogel comprises a compressed structure having pores with a maximum dimension of >100 μm to 2 mm, optionally >100 μm to 1 mm.

[0066] As used herein, the term “capable of releasing one or more active ingredients” means that one or more active ingredients contained in the product are released into the environment, preferably into the gastric environment after ingestion. Preferably, such release occurs by the diffusion or elution of the active ingredients through a plurality of pores that expand in size as a result of swelling of the ultraporous hydrogel within the gastric environment. Preferably, a material or particle having a diameter of ≤500 μm may be freely released from the core region once the ultraporous hydrogel has swollen. In some cases, a material or particle having a diameter of up to 200 μm may be freely released from the core region once the ultraporous hydrogel has swollen. In one embodiment, the diameter may be about 200 μm to about 500 μm, or about 300 μm to about 500 μm.

[0067] As used herein, the term “active ingredient” means any active ingredient selected from the group consisting of medicinal ingredients, health functional food ingredients, and combinations thereof.

[0068] The term “medicinal component” as used herein is intended to include any active component that provides an effect on humans or animals to treat a disease. Such active components are known in the art as “active medicinal components (APIs).” The scope of the term “medicinal component” also includes radiopharmaceuticals suitable for use in humans or animals to treat or diagnose a disease.

[0069] The term “health functional food ingredient” as used herein is intended to include any dietary supplement or ingredient, mineral, or vitamin that provides health-promoting benefits when consumed by humans or animals. To avoid any doubt, health functional food ingredients as defined herein also include, within the scope thereof, probiotic ingredients, prebiotic ingredients, yeast, symbiotic ingredients, antioxidants, phytochemicals, fatty acids, and amino acids.

[0070] Preferably, the active ingredient as a health functional food ingredient includes a vitamin.

[0071] The term "probiotic" as used herein is intended to mean "live microorganisms that provide health benefits to a host when administered in appropriate amounts."

[0072] The term “prebiotic” as used herein is intended to mean “a non-digestible food component that has a beneficial effect on the host by selectively stimulating the growth and / or activity of one or a limited number of bacterial species already established in the colon, and thus consequently improves the health of the host.”

[0073] The term "symbiotic" as used herein is intended to mean "a mixture of probiotics and prebiotics that have a beneficial effect on the host by improving the survival and colonization of live microbial dietary supplements in the host's gastrointestinal tract" (Andersson et al., 2001).

[0074] The definitions of “probiotic,” “prebiotic,” and “symbiotic” are defined in accordance with those reported by the World Health Organization (WHO) in October 2001, which is an accredited body that would be understood by a person skilled in the art at the time of filing this application. In particular, reference is made to page 5, Section 3, and pages 20 to 21, Section 8.4 of the WHO report on the assessment of the health and nutritional properties of probiotics in food, including active lactic acid bacteria-containing milk powder, held from October 1 to 4, 2001.

[0075] Preferably, one or more active ingredients are suitable for gastric release in combination with one or more excipients, such as one or more permeation promoters. Optionally, one or more active ingredients may have a narrow absorption range in the upper gastrointestinal tract. In some embodiments, one or more active ingredients may lose their therapeutic effect in the intestines (e.g., colon and / or small intestine) (e.g., by degradation). Alternatively or additionally, one or more active ingredients may have a negative or harmful effect when released in the intestines (e.g., colon and / or small intestine). An example of an active ingredient that may have a negative or harmful effect when released in the intestines includes an antibiotic for treating Helicobacter pylori (H. pylori).

[0076] Optionally, one or more active ingredients may be heat-unstable and / or heat-sensitive.

[0077] Optionally, one or more active ingredients may be suitable for use in treating a condition where appetite control and / or any weight loss resulting from appetite control is not a negative side effect. Preferably, one or more active ingredients may be suitable for use in treating a condition where appetite control and / or any weight loss resulting from appetite control enhances the therapeutic effect of one or more active ingredients.

[0078] Optionally, one or more active ingredients may comprise one or more macromolecules having a molecular weight greater than 1000 g / mol. These macromolecules may not be released from the microporous or mesoporous system, but may be released through the pores of the ultraporous hydrogel.

[0079] In one embodiment, the medicinal ingredient and / or health functional food ingredient may be selected from one or more of the group consisting of low molecular weight substances, peptides, proteins, oligonucleotides, one or more cells (e.g., probiotics and / or yeast), and oligopeptides. Preferably, the medicinal ingredient and / or health functional food ingredient may be selected from one or more of the group consisting of low molecular weight substances and peptides.

[0080] Desired peptides may include glucagon-like peptides, particularly glucagon-like peptide receptor agonists such as semaglutide.

[0081] The desirable low molecular weight may have a molar mass of less than 500 g / mol, ideally less than 250 g / mol, and preferably about 125 g / mol to about 250 g / mol.

[0082] Preferably, the active ingredient as a medicinal ingredient includes a drug.

[0083] The preferred active ingredient may be selected from among obesity-related drugs, and in particular, may be selected from drugs having one or more mechanisms of action including, but not limited to, appetite control, increased energy expenditure, regulation of intestinal hormones, regulation of intestinal microbiota, and reduction of fat absorption.

[0084] Most preferably, the medicinal ingredient may be one or more selected from the group consisting of metformin (N,N-dimethylbiguanide), carbidopa (N-amino-α-methyl-3-hydroxy-L-tyrosine monohydrate), levodopa (L-3,4-dihydroxyphenylalanine) and semaglutide.

[0085] Metformin, often sold under the name Glucophage®, is a first-line treatment for type 2 diabetes, particularly for overweight humans. It is also used to treat polycystic ovary syndrome.

[0086] Carbidopa is often Lodosyn TM It is sold under the name ) and is intended for the treatment of Parkinson's disease. Levodopa is often referred to as Sinemet™ or Pharmacopa TM It is sold under names such as Atamet™ and Stalevo™. It is also intended for the treatment of Parkinson's disease.

[0087] Semaglutide is often sold under the names Ozempic™, Rybelsus™, and Wegovy™. Semaglutide is a GLP-1 peptide (specifically a GLP-1RA peptide) (i.e., similar to the hormone glucagon-like peptide-1) and is used to treat type 2 diabetes and obesity by managing human blood glucose levels.

[0088] In a highly preferred embodiment, the medicinal ingredient comprises a glucagon-like peptide receptor agonist, such as glucagon-like peptide, particularly semaglutide, and is preferably used together with one or more permeation promoters such as salcaprosate sodium (SNAC, sodium 8-(2-hydroxybenzamido)octanoate).

[0089] Alternatively, a desirable dietary supplement ingredient may include a cobalt-containing or iron-containing dietary supplement, which is preferably a vitamin. In particular, a highly desirable dietary supplement ingredient may include vitamin B12 (also known as cobalamin). In one embodiment, when the dietary supplement ingredient includes vitamin B12, it may be used with or without a permeation promoter such as sodium salcaprosate (SNAC, sodium 8-(2-hydroxybenzamido)octanoate).

[0090] One or more medicinal ingredients and / or one or more health functional food ingredients may be used in combination with one or more excipients. These ingredients may contribute to introducing additional or increased stabilization to one or more medicinal ingredients and / or one or more health functional food ingredients, or to enhancing the therapeutic properties of such one or more medicinal ingredients and / or one or more health functional food ingredients.

[0091] Preferably, the product comprises one or more excipients located in the core region of the product. Optionally, one or more active ingredients may be mixed with one or more excipients, optionally closely mixed, and the mixture is located in the core region of the product. Preferably, the shell region does not comprise one or more excipients.

[0092] As explained above, one or more cavities may further include one or more excipients.

[0093] In some cases, two or more excipients may be used together with one or more medicinal ingredients and / or one or more health functional food ingredients.

[0094] One or more preferred excipients (optional two or more excipients) may include, but are not limited to, permeation promoters, filler materials, binders, diluents, buffers, thickeners or gelling agents, stabilizers, solubilizers, disintegrants, lubricants, lubricants, coloring agents, contrast agents (for radiography), preservatives, suspending agents, emulsifiers, film-forming agents or coating agents, antioxidants, isotonic agents, release modifiers, and combinations thereof.

[0095] The most desirable excipient comprises one or more permeation promoters. As used herein, "permeation promoter" refers to a chemical compound that ideally improves the absorption of one or more active ingredients across the gastric mucosa. A desirable permeation promoter comprises sodium salcaprosate (SNAC, sodium 8-(2-hydroxybenzamido)octanoate).

[0096] Ideally, the product of the present invention can release one or more active ingredients in an environment, preferably in a gastric environment (e.g., the upper gastrointestinal tract, particularly the stomach), preferably for an extended period. Preferably, this will be at least 12 hours, more preferably at least 24 hours, up to 7 days in some cases, and up to 14 days in others. Thus, the present invention will provide a product that can be used as a delivery system or delivery device, ideally suitable for the treatment of humans and / or animals. Preferably, the product will be suitable for oral administration. Preferably, the product will be capable of retention in the stomach (i.e., gastric retention) for at least 12 hours, more preferably at least 24 hours, up to 7 days in some cases, and up to 14 days in others.

[0097] To exhibit a long gastric retention time of 12 hours or more, at least 24 hours, up to 7 days, or up to 14 days, the product preferably has mechanical properties in the gastric environment that prevent the product from being prematurely emptied from the stomach. As such, the product exhibits a nominal stress at the point of break (measured using a force meter calibrated to pressure units) of preferably at least 100 N, ideally at least 300 N, after being immersed in simulated gastric fluid for 1 hour. Additionally, or alternatively, the product exhibits a nominal stress at the point of break (measured using a force meter calibrated to pressure units) of at least 100 N, additionally optionally at least 300 N, after being immersed in simulated gastric fluid for 7 days.

[0098] Preferably, the product is fatigue-resistant and can withstand more than 1,800 cycles of compression repetitions of 10 N to 20 N at 37°C SGF. In one embodiment, the product is fatigue-resistant and can withstand more than 9,000 cycles of compression repetitions of 10 N to 20 N at 37°C SGF. In one embodiment, the product is fatigue-resistant and can withstand more than 25,200 cycles of compression repetitions of 10 N to 20 N at 37°C SGF. The compression repetitions are preferably performed using a compression plate of a mechanical testing machine to apply a compressive force to the product until it reaches 10 N to 20 N. After reaching 10 N to 20 N, the compression plate is removed from the product, the application of compressive force to the product is stopped, and one cycle is completed. If the product can recover its original shape and mechanical properties at the time of the last compression cycle and / or thereafter, the product is considered to be fatigue-resistant (i.e., withstand compression repetition cycles).

[0099] Preferably, the product exhibits a maximum true stress at the breaking point (measured using a force meter) of at least 50 kPa, ideally at least 200 kPa, after immersion in simulated gastric fluid for 1 hour. Additionally or alternatively, the product also exhibits a maximum true stress at the breaking point (measured using a force meter) of at least 50 kPa, additionally optionally at least 200 kPa, after immersion in simulated gastric fluid for 7 days.

[0100] Preferably, the product comprises a superporous hydrogel structure formed by freeze-drying. In particular, it is desirable for the product to comprise a superporous hydrogel structure having a pore structure formed by freeze-drying. A superporous hydrogel structure having a pore structure formed by freeze-drying exhibits an improved pore structure compared to a superporous hydrogel structure having a pore structure formed by other methods, such as gas blowing. The pore structure of the superporous hydrogel is formed by a freeze-drying process as follows: A liquid reaction mixture (i.e., an initial mixture of monomers and preferably crosslinking agents) adopts a regular solvation arrangement for thermodynamic reasons during polymerization. Subsequently, during the freeze-drying process, this water freezes in situ and sublimates out of the hydrogel, resulting in the formation of thin polymer wall structures (i.e., pores) having a specific size and distribution in regions that previously contained ice crystals. These pores are often adjacent to or connected to neighboring pores and are often separated only by thin polymer walls between the pores. Therefore, the pore structure of the resulting ultraporous hydrogel structure is formed during the freeze-drying process. That is, the hydrogel becomes ultraporous through the freeze-drying process.

[0101] In contrast, ultraporous hydrogel structures having pore structures formed by other methods, such as gas blowing, have different pore structures and distribution patterns. The pores of ultraporous hydrogels formed by gas blowing are often generally separated and independent, and contain a large volume of polymer material separating each pore.

[0102] The pore structure formed by freeze-drying imparts improved mechanical properties to the ultraporous hydrogel as discussed above, and consequently, the ultraporous hydrogel structure formed by freeze-drying can exhibit a longer gastric retention time than the ultraporous hydrogel structure formed by other methods such as gas blowing.

[0103] Ideally, the product comprises a superporous hydrogel structure having a pore structure formed by freeze-drying without using a gas blowing agent. Advantageously, the product thus has a regular pore structure as described above.

[0104] Alternatively, the product may comprise an ultraporous hydrogel structure formed by a blowing agent, a foaming agent, or other foaming means discussed below. As a further alternative, the product may comprise an ultraporous hydrogel structure formed by 3D printing. The product may also comprise an ultraporous hydrogel structure formed by a freezing step followed by one or more drying steps selected from the group consisting of supercritical drying, vacuum drying, microwave drying, conventional heat drying, and combinations thereof. The product may also comprise an ultraporous hydrogel structure formed by freeze-thaw. Alternative methods may also include salt leaching or solvent casting methods.

[0105] Preferably, the ultraporous hydrogel comprises a structure comprising a mixture of hydrophilic polymers crosslinked by one or more crosslinking agents.

[0106] Preferably, the mixture of hydrophilic polymers comprises one or more hydrophilic polymers made from an alkenylamide-containing monomer (preferably acrylamide) and a polysaccharide. Ideally, the acrylamide-containing monomer comprises acrylamide, and the polysaccharide comprises an alginate.

[0107] Hydrophilic polymers and / or copolymers may 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.

[0108] Preferably, one or more hydrophilic polymers comprise hydroxylated polymers, and additionally preferably, the hydrophilic polymers are selected from C1-C6-alkylcellulose, hydroxy-C1-C6-alkylcellulose, and hydroxy-C1-C6-alkyl-C1-C6-alkyl-cellulose. Highly preferred polymers include alginate-containing compounds such as sodium alginate or alginic acid, and chitosan.

[0109] Preferably, one or more hydrophilic polymers comprise polymers produced by the polymerization and / or copolymerization of one or more monomers selected from C1-C6-alkenylamide (e.g., to make polyacrylamide) and C1-C6-alkenyl acid (e.g., to make acrylic acid). Highly preferred polymers comprise poly(acrylamide), poly(2-acrylamido-2-methyl-1-propanesulfonic acid), and poly(N-isoacrylamide). Most preferably, one or more hydrophilic polymers comprise polyacrylamide.

[0110] It is particularly advantageous for the ultraporous hydrogel structure to be derived from one or more hydrophilic polymers and / or copolymers, preferably with one or more polysaccharides, that are at least partially derived from amine-containing monomers and / or alkenylamide-containing monomers and / or acryloyl-containing monomers.

[0111] Preferably, one or more hydrophilic polymers and / or copolymers are derived from one or more amine-containing monomers and / or alkenylamide-containing monomers and / or acryloyl-containing monomers, and / or polymers selected from polyacrylamide, poly(N-isopropylacrylamide), and polyacrylic acid.

[0112] Preferably, one or more polysaccharides include alginate-containing compounds such as sodium alginate or alginic acid, and chitosan.

[0113] Ideally, the ultraporous hydrogel structure is derived from polyacrylamide and sodium alginate.

[0114] Ideally, the ultraporous hydrogel comprises a structure crosslinked by one or more crosslinking agents. That is, ideally, the ultraporous hydrogel comprises multiple polymer chains, each polymer chain being connected to one or more other polymer chains by one or more crosslinking agents to provide a crosslinked structure. One or more crosslinking agents preferably crosslink the polymer chains by chemical means (e.g., covalent bonding) and / or physical means (e.g., electrostatic attraction).

[0115] Preferably, one or more crosslinking agents comprise salts of divalent metal cations such as barium, calcium, magnesium, and iron. A preferred crosslinking agent comprises a salt of a divalent metal cation selected from calcium and / or barium. Exemplary crosslinking agents are one or more selected from the group consisting of calcium sulfate, calcium chloride, and barium sulfate.

[0116] Alternatively or additionally, one or more crosslinking agents comprise one or more acryloyl groups and / or one or more acrylamide groups and / or one or more amine groups and / or one or more olefin groups and / or one or more aldehyde groups. Particularly preferably, one or more crosslinking agents comprise amine-reactive difunctional crosslinking agents and / or multi-olefin crosslinking agents. Highly preferably, one or more crosslinking agents comprise one or more acryloyl groups and / or one or more acrylamide groups. Ideally, one or more crosslinking agents comprise one or more acrylamide groups.

[0117] One or more crosslinking agents are preferably selected from monofunctional aldehydes such as acetaldehyde or formaldehyde, difunctional aldehydes such as glutaraldehyde or glyoxal, N,N'-bis(acryloyl)cystamine (BAC), N,N'-bis(acryloyl)cystine (BISS), N,N-methylenebis(acrylamide) (MBA), ethylene glycol diacrylate (EGDA), poly(ethylene glycol diacrylate) (PEGDA), ethylene glycol dimethacrylate (EDGDMA), N,N'-ethylenebisacrylamide (EBAA), and polyethyleneimine (PEI). Preferably, the crosslinking agent comprises N,N'-bis(acryloyl)cystamine (BAC) or N,N-methylenebis(acrylamide) (MBA). Ideally, the crosslinking agent includes N,N'-bis(acryloyl)cystamine (BAC).

[0118] In a particularly preferred embodiment, the ultraporous hydrogel comprises a structure crosslinked by two or more crosslinking agents. Preferably, the first crosslinking agent comprises one or more divalent metal salts, and the second crosslinking agent comprises one or more crosslinking agents. Particularly preferably, the first crosslinking agent comprises calcium and / or calcium ions, and the second crosslinking agent comprises N,N'-bis(acryloyl)cystamine (BAC) or N,N-methylenebis(acrylamide) (MBA). Ideally, the first crosslinking agent comprises calcium sulfate, and the second crosslinking agent comprises N,N'-bis(acryloyl)cystamine (BAC).

[0119] Preferably, the product produces a swollen hydrogel having a diameter of ≥25 mm within 30 minutes, including the swelling power released when exposed to gastric fluid, and ideally ≥30 mm within 30 minutes. Since this diameter is larger than the patient's pyloric diameter, the product will not pass out of the stomach.

[0120] Preferably, the pores of the porous structure have an average maximum dimension of ≥250 μm after being immersed in simulated gastric fluid for at least one hour. Very preferably, the pores of the porous structure have an average maximum dimension of ≥450 μm, optionally ≥600 μm, after being immersed in simulated gastric fluid for at least one hour. Ideally, the pores of the porous structure have an average maximum dimension of ≥700 μm after being immersed in simulated gastric fluid for at least one hour.

[0121] Optionally, the pores of the porous structure have a maximum dimension of ≥100 μm to 5 mm after being immersed in simulated gastric fluid for more than one hour. Additionally, optionally, the pores of the porous structure have a maximum dimension of ≥100 μm to 3 mm after being immersed in simulated gastric fluid for more than one hour.

[0122] As used herein, the simulated gastric juice has a pH of 1-2 and contains a mixture of a salt solution (e.g., sodium chloride, ideally 0.2 wt%) and an acid solution (e.g., hydrochloric acid).

[0123] In a further embodiment, the present invention aims to provide an easy, cost-effective, and reliable method for making a product that can be ideally used as a delivery system or delivery device suitable for ingestion by humans and / or animals. Accordingly, the present invention also, in another embodiment, provides a method for manufacturing a product, wherein the product is capable of releasing one or more active ingredients and preferably has an ultraporous hydrogel structure formed by freeze-drying, wherein the ultraporous hydrogel structure comprises a core region containing one or more active ingredients, and the method comprises

[0124] a) A step of loading one or more active ingredients into a core region before or after freeze-drying.

[0125] Preferably, one or more active ingredients include those defined above.

[0126] Preferably, a product produced by the method defined herein is a product according to the present invention. Accordingly, the features applied to the product can be equally applied to a product produced by the method defined herein.

[0127] Preferably, the pore structure of the ultraporous hydrogel structure is formed by freeze-drying. Ideally, the pore structure of the ultraporous hydrogel structure is formed by freeze-drying without using a gas blowing agent. Advantageously, the resulting product thus has a regular pore structure as described above.

[0128] Preferably, step a) includes loading one or more active ingredients into a core region such that substantially all of the one or more active ingredients are located within the core region. That is, preferably, the one or more active ingredients are loaded into the core region such that the one or more active ingredients are not substantially present in a region other than the core region (e.g., a shell region of the ultraporous hydrogel structure or a shell region of the product). Accordingly, it is preferable that the one or more active ingredients are not loaded by immersing the hydrogel and / or ultraporous hydrogel in an aqueous solution containing the one or more active ingredients.

[0129] Preferably, one or more active ingredients are loaded into the core region of the ultraporous hydrogel structure (e.g., retained within the core region) without being chemically connected (e.g., bonded) to a part of the core region of the ultraporous hydrogel structure itself (e.g., without using strong covalent chemical bonds). This includes, for example, preferably not being chemically attached to one or more hydrophilic polymer chains forming the ultraporous hydrogel structure.

[0130] Optionally, step a) includes loading one or more active ingredients with one or more excipients into the core region before or after freeze-drying. As described above, the most preferred excipient includes one or more permeation promoters.

[0131] Preferably, the method of the present invention is,

[0132] (i) When loading one or more active ingredients into the core region before freeze-drying;

[0133] a. A step of providing an initial hydrogel including a core region;

[0134] b. A step of loading one or more active ingredients into the core region of the initial hydrogel; and

[0135] c. freeze-drying the product produced in step (b) to form an ultraporous hydrogel structure comprising a core region loaded with one or more active ingredients; or

[0136] (ii) When loading one or more active ingredients into the core region after freeze-drying;

[0137] a. A step of providing an initial hydrogel including a core region;

[0138] b. freeze-drying the initial hydrogel to form an ultraporous hydrogel structure including a core region; and

[0139] c. A step of forming a superporous hydrogel structure comprising a core region loaded with one or more active ingredients by loading one or more active ingredients into a core region of the superporous hydrogel structure.

[0140] Preferably, prior to freeze-drying in either method (i) or (ii), the method comprises a step in which the initial hydrogel undergoes a washing treatment, ideally using a washing solution. This treatment may take at least 1 day, at least 7 days, for example, ideally 7 to 14 days, or in some cases up to 21 days. This treatment may also include optional flushing steps or optional steps of replacing the washing solution during the washing process.

[0141] The washing solution may comprise an acid, a base, a salt, distilled water, and / or gastric fluid (including simulated gastric fluid). A preferred washing solution has a pH of about 1-2. This may be a region of a square, cylindrical, or spherical mold. In one embodiment, this is not a region protruding outward from the initial hydrogel structure. A preferred simulated gastric fluid may comprise a mixture of a salt solution (e.g., sodium chloride, ideally 0.2 wt%) and an acid solution (e.g., hydrochloric acid, ideally pH 1-2).

[0142] Preferably, when loading one or more active ingredients into the core region before freeze-drying, the method is,

[0143] a. A step of forming an initial hydrogel by polymerizing a mixture of monomers and / or polymers around one or more central molds in the presence of a crosslinking agent;

[0144] b. A step of demolding the product produced in step (a) to provide a core region containing one or more cavities to the initial hydrogel;

[0145] c. A step of loading one or more active ingredients into one or more cavities of the initial hydrogel; and

[0146] d. The product produced in step (c) is freeze-dried to form a superporous hydrogel structure having a core region containing one or more cavities loaded with one or more active ingredients.

[0147] Additional desirable features of step (a) are discussed below (e.g., polymerization, etc.).

[0148] Preferably, the initial hydrogel is not an ultraporous hydrogel. That is, preferably, the pores of the pore structure of the initial hydrogel have an average maximum dimension of less than 100 μm. Therefore, the purpose of the freeze-drying step is to provide, at least partially, an ultraporous hydrogel (i.e., a hydrogel in which the pores of the pore structure have an average maximum dimension of at least 100 μm).

[0149] Preferably, the polymerization of step a) is carried out within an outer mold that may be cylindrical, spherical, square, or rectangular in shape. Then, a central mold may be reversibly or irreversibly attached to one inner surface of the outer mold, optionally to the inner side of the "top" or "lid." Thus, the central mold serves to assume the shape of the initial hydrogel so as to form one or more cavities, one or more passages, and one or more openings.

[0150] Preferably, the central mold comprises one or more structures that exist within a section of the initial hydrogel at use or extend through it. In particular, the one or more structures are preferably spherical, cylindrical, square, or rectangular in shape to allow for the formation of one or more cavities and / or one or more passages. Such a central mold may therefore be referred to as a cavity-forming device and / or a passage-forming device.

[0151] In one embodiment, the central mold may include at least a portion of an elongated structure to allow the formation of one or more passages into one or more cavities. The elongated structure may be a structure having an inner diameter of 100 μm to 40 mm, preferably 1 mm to 10 mm, more preferably 1 mm to 5 mm. Ideally, the structure is cylindrical and is preferably made of polypropylene. This provides one or more passages having a narrow diameter, for example, 100 μm to 40 mm, preferably 1 mm to 10 mm, more preferably 1 mm to 5 mm. Ideally, the elongated structure has a substantially straight section extending along an axis.

[0152] When using an elongated structure as a central mold, it is preferable that the elongated structure protrude outward from a central region of the initial hydrogel (associated with one or more cavities) to a region outside the initial hydrogel structure in order to provide an opening on the side of the initial hydrogel to one or more cavities. This advantageously allows one or more passages to have fluid communication between one or more cavities and the opening, thereby enabling loading one or more active ingredients into one or more cavities. The opening may have a narrow diameter, for example, 100 μm to 40 mm, preferably 1 mm to 10 mm, more preferably 1 mm to 5 mm.

[0153] In one embodiment, the central mold may include a two-part structure that may include two regions having different shapes. One region may be similar to a square, similar to a cylinder, or similar to a sphere, while the other region may be an elongated shape similar to a rectangle or similar to a cylinder. These regions may be associated with each other to allow for the formation of one or more passages into one or more cavities when in use.

[0154] In a preferred embodiment, at least a portion of the central mold may dissolve upon contact with a washing solution such as an acid, base, salt, distilled water, or gastric fluid (including simulated gastric fluid). The preferred washing solution has a pH of about 1-2. This may be a region of the mold that is square, cylindrical, or spherical in shape. In one embodiment, this is not a region protruding outward from the initial hydrogel structure. The preferred simulated gastric fluid may comprise a mixture of a salt solution (e.g., sodium chloride, ideally 0.2 wt%) and an acid solution (e.g., hydrochloric acid, ideally pH 1-2).

[0155] Accordingly, step b) may further include the use of a cleaning process, ideally using a cleaning solution, to dissolve at least the soluble portion of the central mold. This process may take at least 1 day, at least 7 days, for example, ideally 7 to 14 days, or in some cases up to 21 days. This process may also include optional flushing steps or optional steps of replacing the cleaning solution during the cleaning process.

[0156] Step b) may also include two steps, wherein Step 1 i) includes the use of a washing treatment to dissolve at least a portion of the meltable central mold, and then Step 2 ii) includes demolding the product of Step (i) produced from the remaining unmelted portions.

[0157] A portion of the mold used to form one or more cavities and is soluble can be formed from sucrose-based materials. Advantageously, these materials can dissolve upon contact with a cleaning solution.

[0158] In an embodiment where no part of the central mold is dissolved, step b) may further include the use of a cleaning treatment using a cleaning solution, ideally before or preferably after demolding. This treatment may take at least 1 day, at least 7 days, for example, ideally 7 to 14 days, or in some cases up to 21 days. This treatment may also include optional flushing steps or optional steps of replacing the cleaning solution during the cleaning process.

[0159] Step b) may further include a first step i) comprising a curing treatment performed, preferably by treatment with steam, steam, heat, or a combination thereof, before demolding. Ideal conditions include a temperature of about 30°C to 60°C. Curing may take place for about 24 to 72 hours. After demolding, a second step ii) is performed, which includes the use of a cleaning treatment as discussed above.

[0160] Step c) includes the step of loading one or more active ingredients into one or more cavities of the initial hydrogel. In a preferred embodiment, one or more cavities of the initial hydrogel are loaded with one or more active ingredients using one or more channels ideally formed using a central mold comprising at least a portion of an elongated structure as discussed above.

[0161] Ideally, one or more active ingredients are loaded into the core region of the initial hydrogel without being chemically and / or physically connected (e.g., bonded) to a part of the core region of the initial hydrogel structure itself. That is, due to the elastic properties and / or narrow passages of the initial hydrogel, one or more active ingredients are retained within one or more cavities of the initial hydrogel.

[0162] Step d) includes the step of freeze-drying the product produced in step (c) to form a superporous hydrogel structure having a core region containing one or more cavities.

[0163] Optionally, the ultraporous hydrogel may then be treated with compressive force to close the opening of one or more passages. Preferably, the ultraporous hydrogel may first be placed in a compression mold and compressive force may be applied to close the opening (i.e., the opening among one or more passages). Then, while the ultraporous hydrogel remains in the mold, it may be treated as follows.

[0164] Typically, the hydrogel is first placed in a freezer at -10°C to -50°C for at least 2 hours and up to 36 hours, preferably 8 hours to 24 hours. Then, the freeze-drying process is performed at a temperature of about -50°C. However, a temperature of about -30°C to about -50°C is acceptable. Additionally, the freeze-drying process is typically performed for at least 2 hours and up to 120 hours. In one embodiment, the freeze-drying process may be performed for 24 hours to 120 hours, ideally 48 hours to 72 hours, or in some cases 8 hours to 24 hours.

[0165] Optionally, the freeze-dried hydrogel can then be removed from the compression mold.

[0166] Following step d), the method may also include the step of substantially sealing at least a portion of one or more cavities and / or one or more passages after loading one or more active ingredients into one or more cavities. In particular, the method may include the step of substantially sealing an opening on an initial hydrogel side associated with one or more cavities, preferably by compression and / or by the application of an adhesive such as a biologically inert adhesive.

[0167] In a preferred embodiment, the step of substantially sealing comprises blocking access to one or more cavities after loading one or more active ingredients into one or more cavities. In particular, an opening to one of one or more passages and / or the passage itself may be closed by the installation of one or more plugs. Ideally, one or more plugs may comprise one or more of a biologically inert material and an ultraporous hydrogel material. Preferably, one or more plugs comprise an ultraporous hydrogel material.

[0168] An adhesive and / or sealant may be applied to one or more plugs to form a seal with one or more passages and / or the passages themselves.

[0169] The method preferably comprises one or more steps selected from: (i) treating the ultraporous hydrogel structure to plasticize its structure after freeze-drying; and (ii) compressing the resulting plasticized ultraporous hydrogel structure to provide a compressed structure having pores having an average maximum dimension of typically 100 μm to 5 mm.

[0170] Preferably, the method includes step (ii) following step (i). However, the method may include only step (i) or step (ii); or may not include both step (i) and (ii).

[0171] In the case of optional step (i), the plasticizing treatment may be performed by the use of a plasticizer, or preferably by treatment using steam, water vapor, heat, or a combination thereof. Ideal plasticizing conditions include a temperature of about 30°C to 60°C at a relative humidity of 50% to 95%.

[0172] In the case of optional step (ii), the SPH may optionally be treated with compressive force to produce a "compressed ultraporous hydrogel" (compressed SPH). This compression may preferably be performed by a process comprising one or more inserts, preferably a central insert such as a pin, wherein the insert is placed within one or more cavities using one or more passages before compression and removed after compression to ensure that one or more cavities are retained within the compressed SPH. The one or more inserts will ideally have an elongated structure such as a rod, bar, pin, or pole.

[0173] By using an insert, this assists in forming a space of appropriate size within the compressed SPH. Thus, the compression step comprises compressing a plasticized ultraporous hydrogel structure created with the insert being present in at least a portion of one or more cavities, optionally.

[0174] The pores of the pore structure of the compressed ultraporous hydrogel may have an average maximum dimension of greater than 100 μm to about ≤5 mm, optionally up to about ≤4 mm, additionally optionally up to about ≤3 mm, additionally optionally up to about ≤2 mm, and additionally optionally up to about ≤1 mm. The pores of the compressed SPH maintain a function similar to that of the pores of the uncompressed SPH, and the compressed SPH will swell to a volume similar to that of the corresponding uncompressed SPH when immersed in an aqueous medium. However, the compressed SPH may have a faster swelling rate than the uncompressed SPH.

[0175] Alternatively, in the case where one or more active ingredients are loaded into the core region after freeze-drying, the method is,

[0176] a. A step of forming an initial hydrogel by polymerizing a mixture of monomers and / or polymers around one or more central molds in the presence of a crosslinking agent;

[0177] b. A step of demolding the initial hydrogel to provide a core region containing one or more cavities to the initial hydrogel;

[0178] c. freeze-drying the product produced in step (b) to form an ultraporous hydrogel structure having a core region containing one or more cavities; and

[0179] d. Further includes the step of forming an ultraporous hydrogel structure comprising a core region loaded with one or more active ingredients by loading one or more active ingredients into one or more cavities of the ultraporous hydrogel structure.

[0180] Additional desirable features of step (a) are discussed below (e.g., polymerization, etc.).

[0181] Preferably, the polymerization of step a) is carried out within an outer mold that may be cylindrical, spherical, square, or rectangular in shape. Then, a central mold may be reversibly or irreversibly attached to one inner surface of the outer mold, optionally to the inner side of the "top" or "lid." Thus, the central mold serves to assume the shape of the initial hydrogel so as to form one or more cavities and / or one or more passages and / or one or more openings.

[0182] Preferably, the central mold comprises one or more structures that exist within a section of the initial hydrogel at use or extend through it. In particular, the one or more structures are preferably spherical, cylindrical, square, or rectangular in shape to allow for the formation of one or more cavities and / or one or more passages. Such a central mold may therefore be referred to as a cavity-forming device and / or a passage-forming device.

[0183] In one embodiment, the central mold may include at least a portion of an elongated structure to allow the formation of one or more passages into one or more cavities. The elongated structure may be a structure having an inner diameter of 100 μm to 40 mm, preferably 1 mm to 10 mm, more preferably 1 mm to 5 mm. Ideally, the structure is cylindrical and is preferably made of polypropylene. This provides one or more passages having a narrow diameter, for example, 100 μm to 40 mm, preferably 1 mm to 10 mm, more preferably 1 mm to 5 mm. Ideally, the elongated structure has a substantially straight section extending along an axis.

[0184] When using an elongated structure as a central mold, it is preferable that the elongated structure protrude outward from a central region of the initial hydrogel (associated with one or more cavities) to an outer region of the initial hydrogel structure in order to provide an opening on the side of the initial hydrogel to one or more cavities. This advantageously allows one or more passages to have fluid communication between one or more cavities and the opening, thereby enabling loading one or more active ingredients into one or more cavities. The opening may have a narrow diameter, for example, 100 μm to 40 mm, preferably 1 mm to 10 mm, more preferably 1 mm to 5 mm.

[0185] In one embodiment, the central mold may include a two-part structure that may include two regions having different shapes. One region may be similar to a square, similar to a cylinder, or similar to a sphere, while the other region may be an elongated shape similar to a rectangle or similar to a cylinder. These regions may be associated with each other to allow for the formation of one or more passages into one or more cavities when in use.

[0186] In a preferred embodiment, at least a portion of the central mold may dissolve upon contact with a washing solution such as an acid, base, salt, distilled water, or gastric fluid (including simulated gastric fluid). The preferred washing solution has a pH of about 1-2. This may be a region of the mold that is square, cylindrical, or spherical in shape. In one embodiment, this is not a region protruding outward from the initial hydrogel structure. The preferred simulated gastric fluid may comprise a mixture of a salt solution (e.g., sodium chloride, ideally 0.2 wt%) and an acid solution (e.g., hydrochloric acid, ideally pH 1-2).

[0187] Accordingly, step b) may further include the use of a cleaning process, ideally using a cleaning solution, to dissolve at least the soluble portion of the central mold. This process may take at least 1 day, at least 7 days, for example, ideally 7 to 14 days, or in some cases up to 21 days. This process may also include optional flushing steps or optional steps of replacing the cleaning solution during the cleaning process.

[0188] Step b) may also include two steps, wherein Step 1 i) includes the use of a washing treatment to dissolve at least a portion of the meltable central mold, and then Step 2 ii) includes demolding the product produced in Step (i) from the remaining unmelted portions.

[0189] A portion of the mold used to form one or more cavities and is soluble can be formed from a sucrose-based material. Advantageously, such a material can dissolve upon contact with a cleaning solution.

[0190] In an embodiment where no part of the central mold is dissolved, step b) may further include the use of a cleaning treatment using a cleaning solution, ideally before or preferably after demolding. This treatment may take at least 1 day, at least 7 days, for example, ideally 7 to 14 days, or in some cases up to 21 days. This treatment may also include optional flushing steps or optional steps of replacing the cleaning solution during the cleaning process.

[0191] The lavage solution may comprise an acid, a base, a salt, distilled water, or gastric juice (including simulated gastric juice). A preferred lavage solution has a pH of about 1-2. A preferred simulated gastric juice may comprise a mixture of a salt solution (e.g., sodium chloride, ideally 0.2 wt%) and an acid solution (e.g., hydrochloric acid, ideally pH 1-2).

[0192] Step b) may further include a first step i) comprising a curing treatment performed, preferably by treatment with steam, steam, heat, or a combination thereof, before demolding. Ideal conditions include a temperature of about 30°C to 60°C. Curing may take place for about 24 to 72 hours. After that, following demolding, a second step ii) is performed, which includes the use of a cleaning treatment as discussed above.

[0193] Step c) comprises freeze-drying the product produced in step (b) to form a superporous hydrogel structure having a core region containing one or more cavities. Typically, the hydrogel is first placed in a freezer at -10°C to -50°C for at least 2 hours and up to 36 hours, preferably 8 hours to 24 hours. Then, the freeze-drying process is performed at a temperature of about -50°C. However, a temperature of about -30°C to about -50°C is acceptable. Additionally, the freeze-drying process is typically performed for at least 2 hours and up to 120 hours. In one embodiment, the freeze-drying process may be performed for 24 to 120 hours, ideally 48 to 72 hours, or in some cases 8 to 24 hours.

[0194] Preferably, following step c), the method comprises step d) of loading one or more active ingredients into one or more cavities of the ultraporous hydrogel structure to form an ultraporous hydrogel structure comprising a core region loaded with one or more active ingredients. In a preferred embodiment, one or more cavities of the ultraporous hydrogel structure are loaded with one or more active ingredients using one or more channels ideally formed using a central mold comprising at least a portion of an elongated structure as discussed above.

[0195] Ideally, one or more active ingredients are loaded into the core region of the ultraporous hydrogel structure without being chemically and / or physically connected (e.g., bonded) to a part of the core region of the ultraporous hydrogel structure itself. That is, due to the elastic properties and / or narrow passages of the ultraporous hydrogel structure, one or more active ingredients are retained within one or more cavities of the ultraporous hydrogel structure.

[0196] Following step d), the method comprises, preferably, after loading, (i) treating the ultraporous hydrogel structure to plasticize its structure; and (ii) compressing the resulting plasticized ultraporous hydrogel structure to provide a compressed structure having pores having an average maximum dimension of typically 100 μm to 5 mm.

[0197] Additionally, as an intermediate step between step (i) and step (ii), the method may also include a step of substantially sealing at least a portion of one or more cavities and / or one or more passages after loading one or more active ingredients into one or more cavities. Alternatively, instead of being an intermediate step between step (i) and step (ii), this step may be performed after step d) but before steps (i) and (ii).

[0198] In particular, this step may include applying an adhesive (e.g., a biologically inert adhesive) to an opening on the side of a superporous hydrogel structure associated with one or more cavities, with or without a lid. Thus, the effect will be to substantially seal at least a portion of one or more cavities and / or one or more passages.

[0199] In a preferred embodiment, the step of substantially sealing comprises blocking access to one or more cavities after loading one or more active ingredients into one or more cavities. In particular, an opening to one of one or more passages and / or the passage itself may be closed by the installation of one or more plugs. Ideally, one or more plugs may comprise one or more of a biologically inert material and an ultraporous hydrogel material. Preferably, one or more plugs comprise an ultraporous hydrogel material.

[0200] Adhesive and / or sealant may be applied to one or more plugs to establish a seal with one or more passages and / or the passages themselves.

[0201] In an alternative embodiment, following step c) and prior to step d), the method may optionally include, after freeze-drying, (i) treating the ultraporous hydrogel structure to plasticize its structure; and (ii) compressing the resulting plasticized ultraporous hydrogel structure to provide a compressed structure having pores having an average maximum dimension typically of 100 μm to 5 mm.

[0202] Preferably, the method includes step (ii) following step (i). However, the method may include only step (i) or step (ii); or may not include both steps (i) and (ii).

[0203] Optional steps (i) and (ii) are discussed further below.

[0204] In the case of optional step (i), the plasticizing treatment may be performed by the use of a plasticizer, or preferably by treatment with steam, water vapor, heat, or a combination thereof. Ideal plasticizing conditions include a temperature of about 30°C to 60°C at a relative humidity of 50% to 95%. The treatment may be performed for 1 hour or less, 30 minutes or less, and ideally for 1 minute to 10 minutes until the ultraporous hydrogel structure becomes flexible.

[0205] In the case of the optional step (ii), the SPH may optionally be treated with a compressive force to produce a "compressed ultraporous hydrogel" (compressed SPH). This compression may preferably be performed by a process comprising one or more inserts, preferably a central insert such as a pin, wherein the insert is placed within one or more cavities using one or more passages before compression and removed after compression to ensure that one or more cavities are retained within the compressed SPH. The one or more inserts will ideally have an elongated structure such as a rod, bar, pin, or pole.

[0206] By using an insert, this assists in forming a space of appropriate size within the compressed SPH. Thus, the compression step comprises compressing a plasticized ultraporous hydrogel structure created with the insert being present in at least a portion of one or more cavities, optionally.

[0207] The compressed SPH may have an average maximum dimension of greater than 100 μm to about ≤5 mm, optionally up to about ≤4 mm, additionally optionally up to about ≤3 mm, additionally optionally up to about ≤2 mm, and additionally optionally up to about ≤1 mm.

[0208] The pores of compressed SPH maintain functions similar to those of uncompressed SPH, and when compressed SPH is immersed in an aqueous medium, it will swell to a volume similar to that of the corresponding uncompressed SPH. However, compressed SPH may have a faster swelling rate than uncompressed SPH.

[0209] After removal of the selective insert, step d) may be performed, which includes loading one or more active ingredients into one or more cavities of the compressed ultraporous hydrogel structure to form an ultraporous hydrogel structure comprising a core region loaded with one or more active ingredients.

[0210] Following step d), the method may also include the step of substantially sealing at least a portion of one or more cavities and / or one or more passages after loading one or more active ingredients into one or more cavities. In particular, the method may preferably include the step of substantially sealing an opening on the side of a superporous hydrogel structure associated with one or more cavities by using an adhesive (e.g., a biologically inert adhesive) and / or a lid and / or applying a compressive force.

[0211] In a preferred embodiment, the step of substantially sealing comprises blocking access to one or more cavities after loading one or more active ingredients into one or more cavities. In particular, an opening to one of one or more passages and / or the passage itself may be closed by the installation of a plug. Ideally, one or more plugs may comprise one or more of a biologically inert material and an ultraporous hydrogel material. Preferably, one or more plugs comprise an ultraporous hydrogel material.

[0212] An adhesive and / or sealant may be applied to one or more plugs to form a seal with one or more passages and / or the passages themselves. The process may then be completed by finishing the step of substantially sealing the openings on the sides of the ultraporous hydrogel structure by applying a compressive force.

[0213] As explained above, additional desirable features of step (a) are discussed below (e.g., polymerization, etc.).

[0214] In particular, the method comprises polymerizing a mixture of monomers and / or polymers in the presence of a crosslinking agent to form an initial hydrogel.

[0215] Preferably, the mixture of hydrophilic polymers comprises one or more hydrophilic polymers made from an alkenylamide-containing monomer (preferably acrylamide) and a polysaccharide. Ideally, the acrylamide-containing monomer comprises acrylamide, and the polysaccharide comprises an alginate.

[0216] Hydrophilic polymers and / or copolymers can be derived from naturally occurring polymers and monomers, from synthetic polymers and monomers, or from a mixture of naturally occurring polymers and synthetic polymers and monomers.

[0217] Preferably, one or more hydrophilic polymers comprise hydroxylated polymers, and additionally preferably, the hydrophilic polymers are selected from C1-C6-alkylcellulose, hydroxy-C1-C6-alkylcellulose, and hydroxy-C1-C6-alkyl-C1-C6-alkyl-cellulose. Highly preferred polymers include alginate-containing compounds such as sodium alginate or alginic acid, and chitosan.

[0218] Preferably, one or more hydrophilic polymers comprise polymers produced by the polymerization and / or copolymerization of one or more monomers selected from C1-C6-alkenylamide (e.g., to make polyacrylamide) and C1-C6-alkenyl acid (e.g., to make acrylic acid). Highly preferred polymers comprise poly(acrylamide), poly(2-acrylamido-2-methyl-1-propanesulfonic acid), and poly(N-isoacrylamide). Most preferably, one or more hydrophilic polymers comprise polyacrylamide.

[0219] It is particularly advantageous for the ultraporous hydrogel structure to be derived from one or more hydrophilic polymers and / or copolymers, preferably together with one or more polysaccharides, that are at least partially derived from amine-containing monomers and / or alkenylamide-containing monomers and / or acryloyl-containing monomers.

[0220] Preferably, one or more hydrophilic polymers and / or copolymers are derived from one or more of polymers selected from amine-containing monomers and / or alkenylamide-containing monomers and / or acryloyl-containing monomers, and / or polyacrylamide, poly(N-isopropylacrylamide), and polyacrylic acid.

[0221] Preferably, one or more polysaccharides include alginate-containing compounds such as sodium alginate or alginic acid, and chitosan.

[0222] Ideally, the ultraporous hydrogel structure is derived from polyacrylamide and sodium alginate.

[0223] Ideally, the ultraporous hydrogel comprises a structure crosslinked by one or more crosslinking agents.

[0224] Preferably, one or more crosslinking agents comprise salts of divalent metal cations such as barium, calcium, magnesium, and iron. A preferred crosslinking agent comprises a salt of a divalent metal cation selected from calcium and / or barium. Exemplary crosslinking agents are one or more selected from the group consisting of calcium sulfate, calcium chloride, and barium sulfate.

[0225] Alternatively or additionally, one or more crosslinking agents are selected from N,N'-bis(acryloyl)cystamine (BAC), N,N'-bis(acryloyl)cystine (BISS), N,N-methylenebis(acrylamide) (MBA), ethylene glycol diacrylate (EGDA), N,N'-ethylenebisacrylamide (EBAA), and polyethyleneimine (PEI). Preferably, the crosslinking agent comprises N,N'-bis(acryloyl)cystamine (BAC) or N,N-methylenebis(acrylamide) (MBA). Ideally, the crosslinking agent comprises N,N'-bis(acryloyl)cystamine (BAC).

[0226] In a particularly preferred embodiment, the ultraporous hydrogel comprises a structure crosslinked by two or more crosslinking agents. Preferably, the first crosslinking agent comprises calcium sulfate, and the second crosslinking agent comprises N,N'-bis(acryloyl)cystamine (BAC).

[0227] In a preferred embodiment, the product of the present invention comprises a compressed ultraporous hydrogel or has a compressed ultraporous hydrogel structure. Preferably, such compressed SPH will have an average maximum dimension of greater than 100 μm to about ≤5 mm, optionally up to about ≤4 mm, further optionally up to about ≤3 mm, further optionally up to about ≤2 mm, and further optionally up to about ≤1 mm.

[0228] The present invention provides a method for manufacturing a product, wherein the product is capable of releasing one or more active ingredients and has an ultraporous hydrogel structure formed by freeze-drying, the ultraporous hydrogel structure comprises a core region containing one or more active ingredients, and the method comprises

[0229] a) A step of loading one or more active ingredients into a core region before or after freeze-drying.

[0230] Alternatively, (i.e., instead of using one or more cavities), one or more active ingredients can be loaded into the core region of the ultraporous hydrogel structure. This can preferably be done by forming one or more incisions in the body of the ultraporous hydrogel material so that one or more active ingredients can be loaded inside.

[0231] The present invention also provides, in another embodiment, a product that can be obtained by a method as disclosed herein.

[0232] The present invention also provides, in another aspect, a use of the product as disclosed herein in drug delivery.

[0233] The present invention also provides, in another embodiment, a pharmaceutical composition comprising a product as disclosed herein. The pharmaceutical composition may optionally comprise one or more excipients.

[0234] The present invention also provides, in another embodiment, a medical treatment method comprising the step of administering a product as disclosed herein to a subject.

[0235] Treatment may include one or more conditions selected from gastric cancer, gastric ulcer, Helicobacter pylori infection, Parkinson's disease, polycystic ovary syndrome, metabolic diseases, obesity and obesity-related diseases, cardiovascular diseases, and vitamin B12 deficiency. Preferably, treatment may include one or more of obesity, diabetes, or non-alcoholic fatty liver disease. Very preferably, treatment may include obesity and / or diabetes. Ideally, treatment may include obesity.

[0236] Accordingly, the present invention may provide a method for preventing or treating one or more diseases as defined herein, comprising, in another embodiment, the step of administering a product as disclosed herein to a subject.

[0237] Preferably, one or more diseases are selected from gastric cancer, gastric ulcer, Helicobacter pylori infection, Parkinson's disease, polycystic ovary syndrome, metabolic disease, obesity, obesity-related disease, diabetes, cardiovascular disease, and non-alcoholic fatty liver disease. Very preferably, one or more diseases are selected from obesity, obesity-related disease, diabetes, and non-alcoholic fatty liver disease.

[0238] Preferably, the product is administered in an effective amount to cause a gastric retention period of at least 24 hours.

[0239] Preferably, the product is administered in an effective amount to cause a gastric retention period of at least 3 days.

[0240] Preferably, the product is administered in an effective amount to cause a gastric retention period of 3 to 14 days.

[0241] Preferably, the product is administered in an effective amount to cause a swollen hydrogel with a diameter of ≥25 mm within 30 minutes when the product is exposed to gastric fluid.

[0242] Preferably, the product is administered in an effective amount to cause a swollen hydrogel with a diameter of ≥30 mm within 30 minutes when the product is exposed to gastric fluid.

[0243] Preferably, the product is administered in an effective amount that results in the release of 65% or less of one or more active ingredients after 24 hours.

[0244] Preferably, the product is administered in an effective amount that results in the release of 80% or less of one or more active ingredients after 48 hours.

[0245] The present invention also provides, in another aspect, a product as disclosed herein for use as a pharmaceutical product.

[0246] The present invention also provides, in another embodiment, a product as disclosed herein for use in treatment. In particular, it is intended for use in oral administration treatment.

[0247] The present invention also provides, in other embodiments, a product as disclosed herein for use in treating one or more diseases selected from gastric cancer, gastric ulcer, Helicobacter pylori infection, Parkinson's disease, polycystic ovary syndrome, metabolic disease, obesity and obesity-related disease, cardiovascular disease and vitamin B12 deficiency. Preferably, the product may be used to treat obesity, diabetes, or non-alcoholic fatty liver disease. Most preferably, the product is intended for use in treating obesity and / or diabetes.

[0248] The present invention also provides, in another embodiment, an ultraporous hydrogel material for use in treating one or more diseases selected from gastric cancer, gastric ulcer, Helicobacter pylori infection, Parkinson's disease, polycystic ovary syndrome, metabolic diseases, obesity and obesity-related diseases, cardiovascular diseases and vitamin B12 deficiency. Preferably, the ultraporous hydrogel material may be used to treat one or more diseases selected from obesity, diabetes, or non-alcoholic fatty liver disease. Most preferably, the ultraporous hydrogel material may be used to treat non-alcoholic fatty liver disease.

[0249] Preferably, the ultraporous hydrogel material has a pore structure formed by a freeze-drying process.

[0250] The present invention also provides, in another embodiment, a method of administration for administering a product according to the present invention to a patient suffering from one or more diseases selected from gastric cancer, gastric ulcer, Helicobacter pylori infection, Parkinson's disease, polycystic ovary syndrome, metabolic disease, obesity and obesity-related disease, cardiovascular disease and vitamin B12 deficiency. Preferably, the present invention provides a method of administration for administering to a patient suffering from one or more diseases selected from obesity, diabetes mellitus, or non-alcoholic fatty liver disease.

[0251] Preferably, the administration method comprises orally administering a first dose of the product according to the present invention to a patient in an amount that causes swelling to a size larger than the diameter of the pylorus in less than 1 hour, preferably to ≥ 25 mm within 30 minutes, and ideally to ≥ 30 mm within 30 minutes. Accordingly, preferably, the first dose is retained in the patient's stomach for at least 12 hours, preferably at least 24 hours (preferably up to 7 days, ideally up to 14 days). Optionally, the first dose is retained in the patient's stomach for several weeks (preferably at least 3 or 4 weeks, optionally up to 10 weeks).

[0252] In a preferred administration regimen for treating a patient, a first dose of one to three orally acceptable tablets, capsules, or delivery agents comprising any suitable size, preferably 000 size capsules, comprising the product according to the present invention is administered to the patient. Subsequently, a second and optionally additional subsequent doses are followed, comprising optionally up to five orally acceptable tablets, capsules, or delivery agents comprising the product according to the present invention. Preferably, the optional second and optional additional subsequent doses comprise one, two, or three orally acceptable tablets, capsules, or delivery agents comprising the product according to the present invention. The optional second and optional additional subsequent doses are delivered at time intervals of, preferably at least about 12 hours, preferably at least about 24 hours, and very preferably longer, for example, about 48 hours. The optional second and subsequent doses may be the same as or equal to the first dose, or they may be different from each other.

[0253] Optionally, the second dose is retained in the patient's stomach for at least 12 hours, preferably at least 24 hours or at least 48 hours (preferably up to 7 days). Optionally, the first dose is retained in the patient's stomach for up to 7 days (preferably at least 1 day, optionally up to 5 days).

[0254] Optionally, the subsequent dose is retained in the patient's stomach for at least 12 hours, preferably at least 24 hours or at least 48 hours (preferably up to 7 days). Optionally, the first dose is retained in the patient's stomach for up to 7 days (preferably at least 1 day, optionally up to 5 days).

[0255] Ideally, the above method will also include the intake of at least 300 kcal of food and at least 100 ml of water before and / or during and / or after the patient takes at least one of the first, second, or additional subsequent doses.

[0256] In many applications, it will be important that each ultraporous hydrogel-containing product can swell to a size larger than the pyloric diameter of the patient (human or animal) to ensure retention in the stomach.

[0257] Although the product of the present invention is not designed to obstruct the esophagus or lower gastrointestinal tract (GI tract), there is a possibility of unexpected accidents. Additionally, it is desirable that the product be easily terminated without surgical, endoscopic, or other unpleasant medical interventions. The present invention addresses these issues by using a trigger or emergency evacuation mechanism to decompose the product formulation into a form that is easily excreted by the patient. The 'decomposition trigger' may take various forms as long as it is effective and efficient during the decomposition process and is safe for the patient to use. Preferred decomposition triggers include electromagnetic waves (e.g., light, heat), mechanical waves (e.g., ultrasound), or chemical substances.

[0258] The size of the product formulation is preferably not larger than a standard 000 capsule. The product may be inserted into a capsule, tablet, or lozenge, or otherwise coated with a biologically acceptable material. Brief explanation of the drawing

[0259] The present invention will now be described with reference to the representations in the following drawings. FIG. 1a illustrates a cross-sectional view of a mold containing a hydrogel material, wherein the mold has a central portion made of a soluble material and attached to a lid by a thin rod. FIG. 1b shows a cross-sectional view of the hydrogel material of FIG. 1a after it has been removed from the mold, in which the hydrogel material still includes a soluble central part of the mold and a thin rod. FIG. 1c shows a cross-sectional view of the hydrogel material of FIG. 1b after the central part of the mold is dissolved and the thin rod is removed, leaving a cavity connected to the opening on the upper surface of the hydrogel by a passage. Figure 2a shows a cross-sectional view of a drug core just before it is inserted into the cavity of the hydrogel material of Figure 1c through an opening and a passage. FIG. 2b shows a cross-sectional view of the drug core of FIG. 2a and the hydrogel material after the drug core is inserted into the cavity. FIG. 2c shows a cross-sectional view of a hydrogel material that has undergone several process steps after the step of FIG. 2b, such as freeze-drying, plasticizing, and compression, in which the openings and passages are closed. FIG. 3a shows a cross-sectional view of a sample of a loaded, freeze-dried, and plasticized ultraporous hydrogel inserted into a hollow open-end cylindrical mold, with two push rods inserted one at each of the two open ends of the mold. FIG. 3b is a cross-sectional view of a sample of a loaded, freeze-dried, and plasticized ultraporous hydrogel inserted into a hollow open-end cylindrical mold as shown in FIG. 4a, in which two push rods compress the sample from opposite sides. FIG. 4a illustrates a cross-sectional view of a mold containing a hydrogel material, wherein the mold has a non-dissolvable central portion attached to the lid. FIG. 4b shows a cross-sectional view of the hydrogel material of FIG. 4a after being removed from the mold, in which the hydrogel material contains a cavity connected to an opening on the upper surface of the hydrogel by a passage. Figure 5a shows a cross-sectional view of a drug core just before it is inserted into a cavity of freeze-dried hydrogel material through an opening and a passage. Figure 5b shows a cross-sectional view of the hydrogel material of Figure 5a after the drug core is loaded into the cavity. FIG. 5c shows a cross-sectional view of a hydrogel material that has undergone several processing steps after the step of FIG. 5b, in which it is plasticized and compressed to close the openings and passages. FIG. 6 shows a graph of the release rate (%) of vitamin B12 over time using a buffer solution containing sodium phosphate at pH 6.8 for a tablet containing 50 wt% HPMC, 22 wt% SNAC, and 0.22 wt% vitamin B12. FIG. 7 shows a graph of the release rate (%) of vitamin B12 over time using a buffer solution containing sodium phosphate at pH 6.8 for a product loaded after freeze-drying containing a drug core comprising a tablet containing 50 wt% HPMC, 22 wt% SNAC, and 0.22 wt% vitamin B12. FIG. 8 shows a graph of the release rate (%) of vitamin B12 over time using a buffer solution containing sodium phosphate at pH 6.8 for a drug core comprising a tablet containing 60 wt% HPMC, 22 wt% SNAC, and 0.22 wt% vitamin B12. FIG. 9 shows a graph of the release rate (%) of vitamin B12 over time measured using a buffer solution containing sodium phosphate at pH 6.8 for a product loaded before freeze-drying containing a drug core comprising a tablet containing 60 wt% HPMC, 22 wt% SNAC, and 0.22 wt% vitamin B12. FIG. 10 shows a graph of the release rate (%) of vitamin B12 over time using a buffer solution containing sodium phosphate at pH 6.8 for a product loaded after freeze-drying containing a drug core comprising a tablet containing 60 wt% HPMC, 22 wt% SNAC, and 0.22 wt% vitamin B12. FIG. 11 shows a graph of the diameter swelling profile over time using simulated gastric fluid as a swelling medium for a product loaded before freeze-drying containing a drug core in the form of a placebo tablet containing 30% HPMC. FIG. 12 illustrates the dissolution of the MR tablet and the combined devices. V1-3: MR tablet, V4-6: drug delivery system. Figure 13 shows average dissolution data for MR purification and combined devices. Figure 14 shows a representative plasma concentration versus time plot for animals administered MR B12 pills. Figure 15 shows a typical plasma concentration versus time plot for animals administered CS pills. Figure 16 shows a comparative average plasma concentration versus time plot for animals administered MR and CS pills. FIG. 17 illustrates the displacement curve of a drug delivery system according to the present invention under a 100 N load. FIG. 18 illustrates the load-displacement curve of a drug delivery system according to the present invention at a load of 300 N. FIG. 19 illustrates a fatigue test for a drug delivery system according to the present invention. Figure 20 illustrates a schematic diagram of 'Path 1'. Figure 21 shows a schematic diagram of 'Path 2'. Figure 22 shows a schematic diagram of 'Path 3'. FIG. 23 shows a scanning electron microscope (SEM) image of pores of a freeze-dried superporous hydrogel made according to the process of the present invention. Figure 24 shows a scanning electron microscope (SEM) image of the pores of a compressed ultraporous hydrogel made according to the process of the present invention. FIG. 25 shows a scanning electron microscope (SEM) image of pores after a compressed ultraporous hydrogel made according to the process of the present invention has been swollen by being immersed in simulated gastric fluid for 1 hour. Figure 26 shows volume swelling data of a product according to the present invention using MBA and BaSO4 as crosslinking agents. FIG. 27 shows mechanical strength data of a product according to the present invention using MBA and BaSO4 as crosslinking agents. Specific details for implementing the invention

[0260] The abbreviations used in this document are defined as follows.

[0261] [Table 1]

[0262]

[0263] Example 1: A product is prepared (Route 01) having a superporous hydrogel structure formed by freeze-drying, capable of releasing one or more active ingredients, wherein the superporous hydrogel structure comprises a core region containing one or more active ingredients, and one or more active ingredients are loaded prior to freeze-drying.

[0264] Hydrogel Synthesis:

[0265] 25.0 g to 50.0 g (+ / - 0.1 g) of AAm, 6.0 g to 20.0 g (+ / - 0.1 g) of AL, and 99.0 mg to 132.0 mg (+ / - 1 mg) of BAC were weighed and mixed with 150 ml to 500 ml of DW. This solution was mixed with 433.0 mg to 751.0 mg (+ / - 1.0 mg) of APS in a beaker (labeled Beaker A).

[0266] In another beaker (labeled Beaker B), 150.0 mg to 250.0 mg (+ / - 1.0 mg) of CaSO4 powder, 4 ml to 10 ml of water, and 47 µl to 82 µl of TEMED were added and weighed.

[0267] The solution in beaker A was poured into the suspension in beaker B. Then, the mixture was stirred for 10 to 50 seconds and poured into a mold. As shown in FIG. 1a, each mold consisted of a cylindrical polypropylene (PP) tube (10) with an inner diameter of 10 mm to 40 mm and a meltable central mold (12) attached to an upper stopper (14) by a thin rod (16).

[0268] Samples in PP molds were placed in an incubator (preheated to 60°C) for 1 hour. Afterward, to complete polymerization, the molds were transferred to a humidity chamber at room temperature and cured for 24 to 72 hours. The resulting gelled material (initial hydrogel material) was labeled as the gel as prepared (APG, 18).

[0269] The upper stopper (14) was removed from the mold (see FIG. 1b), and the APG (18), containing the still soluble central mold (12) and thin rod (16), was removed from the tube (10) for the next washing process.

[0270] The APG (18) was soaked in a washing solution having a pH of about 1-2 for 7 to 21 days, and the sample and container were flushed with DW daily and the SGF was replaced with fresh SGF. The volume of SGF used to soak the sample was 75 ml to 150 ml per gel. As shown in FIG. 1c, the soluble central portion (12) was dissolved during the process and the thin rod (16) was removed to obtain a washed APG (20) having a cavity (22) in the core area and a narrow passage (24) including an opening (26) at the top of the washed APG.

[0271] Loading:

[0272] The washed APG (20) was discharged from the SGF, washed with deionized water, and dried. Then, as shown in FIG. 2a, a drug core (28) containing one or more active ingredients was inserted into the cavity (22) through the opening (26) and passage (24) of each washed APG (20) to obtain a loaded APG (30). Due to the elastic properties of the APG material and the narrow diameter of the passage (24), the drug core was retained within the cavity (22) as shown in FIG. 2b.

[0273] Freezing and Freeze-drying:

[0274] Each loaded APG (30) was placed directly into a PP cylindrical tube mold to compress each loaded APG and close each opening (26). As shown in FIG. 2c, the swollen gel inside the mold was placed in a freezer at -10°C to -50°C for 8 to 24 hours, then transferred to a freeze dryer and freeze-dried at -30°C to -50°C to produce a loaded freeze-dried superporous hydrogel (loaded freeze-dried SPH).

[0275] Saturation:

[0276] A loaded freeze-dried SPH sample was placed in a sample holder and left in a humidity chamber at 30°C to 60°C with a relative humidity of 50% to 75% for 1 to 10 minutes until it became flexible, thereby obtaining a plasticized loaded freeze-dried SPH (31).

[0277] compression:

[0278] As illustrated in FIGS. 3a and 3b, the plasticized loaded freeze-dried SPH (31) was carefully removed from the container and placed into a cylindrical tube (25), and then compressed by a push rod (27a and 27b) inserted into the opposite open end of the cylindrical tube (25), each having a concave end (29a, 29b), or formed directly into a capsule mold. Through this compression step, the loaded compressed SPH (32) was obtained. A schematic diagram of path 1 is shown in FIG. 20.

[0279] Example 2: A product is prepared (Route 02) having a superporous hydrogel structure formed by freeze-drying, capable of releasing one or more active ingredients, wherein the superporous hydrogel structure comprises a core region containing one or more active ingredients, and one or more active ingredients are loaded after freeze-drying.

[0280] Hydrogel Synthesis:

[0281] 25.0 g to 50.0 g (+ / - 0.1 g) of AAm, 6.0 g to 20.0 g (+ / - 0.1 g) of AL, and 99.0 mg to 132.0 mg (+ / - 1 mg) of BAC were weighed and mixed with 150 ml to 500 ml of DW. This solution was mixed with 433.0 mg to 751.0 mg (+ / - 1.0 mg) of APS in a beaker (labeled Beaker A).

[0282] In another beaker (labeled Beaker B), 150.0 mg to 250.0 mg (+ / - 1.0 mg) of CaSO4 powder, 4 ml to 10 ml of water, and 47 µl to 82 µl of TEMED were added and weighed.

[0283] The solution in beaker A was poured into the suspension in beaker B. Then, the mixture was stirred for 10 to 50 seconds and poured into a mold. As shown in FIG. 4a, each mold was composed of a cylindrical polypropylene (PP) tube (10) with an inner diameter of 10 mm to 40 mm and a central mold (34) attached to an upper stopper (14).

[0284] Samples in PP molds were placed in an incubator (preheated to 60°C) for 1 hour. Afterward, to complete polymerization, the molds were transferred to a humidity chamber at room temperature and cured for 24 to 72 hours. The resulting gelled material (initial hydrogel material) was labeled as the gel as prepared (APG, 36).

[0285] As shown in FIG. 4b, the upper plug (14) was removed from the mold, and the APG (36), which includes a cavity (22) in the core area and a passage (24) including an opening (26) on the upper side of the APG, was removed from the tube (10) for the next cleaning process.

[0286] APG (18) was soaked in a washing solution with a pH of about 1-2 for 7 to 21 days, and the sample and container were flushed with DW daily and the SGF was replaced with fresh SGF. The volume of SGF used to soak the sample was 75 ml to 150 ml per gel.

[0287] Freezing and Freeze-drying:

[0288] The expanded and acidic washed samples were removed from the SGF, washed with deionized water, and dried. Each hydrogel was placed directly into a PP cylindrical tube mold with a diameter similar to that of the swollen gel. The swollen gel inside the mold was placed in a freezer at -10°C to -50°C for 8 to 24 hours, then transferred to a freeze dryer and freeze-dried at -30°C to -50°C to produce a freeze-dried ultraporous hydrogel (freeze-dried SPH (38)).

[0289] Loading:

[0290] A drug core (28) containing one or more active ingredients was loaded into a freeze-dried SPH (38). This was done by inserting the drug core into a cavity (22) through an opening (26) of the freeze-dried SPH (38) as shown in FIG. 5a, thereby obtaining a loaded freeze-dried SPH (40) as shown in FIG. 5b.

[0291] Sealing:

[0292] A sealing mechanism was used to create plugs by cutting sections from additional freeze-dried SPH. These plugs were inserted into the passages (24) of the main freeze-dried SPH to block access to the cavity (22). A sealant was applied to the peripheral surfaces of the plugs to establish a seal with the passages (24). The sealed assembly was then dried at room temperature for up to 3 days.

[0293] Saturation:

[0294] A sample of loaded freeze-dried SPH (40) was placed in a sample holder and left in a humidity chamber at 30°C to 60°C with a relative humidity of 50% to 75% for 1 to 10 minutes until it became flexible, thereby obtaining a plasticized loaded freeze-dried SPH (31).

[0295] compression:

[0296] The plasticized loaded freeze-dried SPH (31) was carefully removed from the container and a biologically inert bioadhesive was applied to the opening (26). Then, as shown in FIGS. 3a and 3b, the plasticized loaded freeze-dried SPH (31) was pushed into a cylindrical tube (25) and compressed by a push rod (27a and 27b) inserted into the opposite open end of the cylindrical tube (25), each having a concave end (29a, 29b), or formed directly into a capsule mold. Through this compression step, the loaded compressed SPH (32) was obtained, and as shown in FIG. 5c, the opening (26) was further closed.

[0297] A schematic diagram of path 2 is shown in Fig. 21.

[0298] Example 3: A product is prepared (Route 3) having a hyperporous hydrogel structure formed by freeze-drying, capable of releasing one or more active ingredients, wherein the hyperporous hydrogel structure comprises a core region containing one or more active ingredients, and one or more active ingredients are loaded after freeze-drying.

[0299] This route differs from route 2 in that it loads a drug core after compressing the freeze-dried SPH from route 3.

[0300] Hydrogel Synthesis:

[0301] 25.0 g to 50.0 g (+ / - 0.1 g) of AAm, 6.0 g to 20.0 g (+ / - 0.1 g) of AL, and 99.0 mg to 132.0 mg (+ / - 1 mg) of BAC were weighed and mixed with 150 ml to 500 ml of DW. This solution was mixed with 433.0 mg to 751.0 mg (+ / - 1.0 mg) of APS in a beaker (labeled Beaker A).

[0302] In another beaker (labeled Beaker B), 150.0 mg to 250.0 mg (+ / - 1.0 mg) of CaSO4 powder, 4 ml to 10 ml of water, and 47 µl to 82 µl of TEMED were added and weighed.

[0303] The solution in beaker A was poured into the suspension in beaker B. The mixture was then stirred for 10 to 50 seconds and poured into a mold. The mold was made of polyoxymethylene or acetal material with an inner diameter of 10 mm to 40 mm. The mold was designed such that a bridge was positioned at the top of the mold. The bridge enabled the central placement of a dissolvable central mold attached to the upper stopper by a thin rod, as shown in Fig. 1a.

[0304] The samples in the acetal molds were placed in an incubator (preheated to 60°C) for 1 hour. Afterward, the molds were transferred to a humidity chamber at room temperature to complete polymerization and cured for 24 to 72 hours. The resulting gelled material (initial hydrogel material) was labeled as the gel as prepared (APG).

[0305] The top stopper was removed from the mold, and the APG containing the still soluble central mold and thin rod was removed from the tube for the next washing process.

[0306] The APG was immersed in a washing solution with a pH of approximately 1-2 for 7 to 21 days, and the sample and container were flushed with DW daily and the SGF was replaced with fresh SGF. The volume of SGF used was 75 ml to 150 ml per gel. During the process, the soluble central portion dissolved, resulting in a washed APG containing a cavity in the core region and a narrow passage including an opening on the upper side of the washed APG.

[0307] Freezing and Freeze-drying:

[0308] The expanded and acidic washed samples were discharged from the SGF, washed with deionized water, and dried. Each hydrogel was placed directly into a PP cylindrical tube mold with a diameter similar to that of the swollen gel. The swollen gel inside the mold was placed in a freezer at -10°C to -50°C for 8 to 24 hours, then transferred to a freeze dryer and freeze-dried at -30°C to -50°C to produce a freeze-dried ultraporous hydrogel (freeze-dried SPH).

[0309] Saturation:

[0310] A sample of freeze-dried SPH was placed in a sample holder and left in a humidity chamber at 30°C to 60°C with a relative humidity of 50% to 75% for 1 to 10 minutes until it became flexible, thereby obtaining plasticized freeze-dried SPH.

[0311] Compression, Loading:

[0312] The plasticized freeze-dried SPH was carefully removed from the container and placed into a compression tool, and an acetal pin was positioned through the passage into the cavity of the freeze-dried SPH. Subsequently, the system was compressed with the assistance of the compression tool while the acetal pin remained inside the cavity. This created a cavity of appropriate size within the compressed SPH. A drug core containing one or more active ingredients was loaded into the cavity of the compressed freeze-dried SPH pill. This was accomplished by inserting the drug core into the cavity of the freeze-dried SPH pill to obtain an open, loaded freeze-dried SPH pill. The opening of the compressed freeze-dried SPH pill was plugged and sealed with a suitable adhesive. Compression was completed using push rods with concave ends; each push rod had a concave end, was inserted into the opposite open end of a cylindrical tube, and formed directly in a capsule mold. This step obtained a loaded, compressed SPH and further resulted in the closure of the opening.

[0313] A schematic diagram of path 3 is shown in Fig. 22.

[0314] Example 4: Dissolution test of a drug delivery system product loaded with various active ingredients.

[0315] Various vitamin B12 / HPMC drug cores were loaded onto ultraporous hydrogel structures by methods including the step of loading before or after freeze-drying. The dissolution of these products was measured by the USP Dissolution Device II in 900 mL of 50 mM sodium phosphate buffer at pH 6.8 using the parameters specified in Table 2 below.

[0316] [Table 2]

[0317] Leaching test method

[0318]

[0319] The results of these dissolution tests are shown in FIGS. 12 to 16 and Table 3 below. Examples of "bare tablets" refer to dissolution tests of bare tablets (i.e., drug cores without a hydrogel shell).

[0320] [Table 3]

[0321] Leaching test results

[0322]

[0323] These results show that products generated by loading before or after freeze-drying exhibit acceptable leaching data in the above environment.

[0324] In addition, while the tablet core (i.e., a conventional tablet) is removed from the stomach within a few hours, the product according to the present invention remains in the stomach for several days. Therefore, referring to FIGS. 12 and FIGS. 14, in the case of comparative examples, only about 20% of the vitamin B12 contained in the tablet will be released in the stomach.

[0325] As a result, a much higher proportion of vitamin B12 contained in the product of the present invention will be released while the product is in the stomach, and thus more vitamin B12 will be absorbed into the body.

[0326] Example 5: In vitro dissolution profile (2) of a drug delivery system loaded with B12

[0327] Vitamin B12 / HPMC drug cores were loaded onto ultraporous hydrogel structures by methods including lyophilization and loading. The dissolution of these products was measured by the USP Dissolution Device II in 900 mL of 50 mM sodium phosphate buffer at pH 6.8 using the parameters specified in Table 4 below.

[0328] [Table 4]

[0329] Leaching test method

[0330]

[0331] As shown in Fig. 13, the individual release profiles showed good consistency between each vessel, and the variability of the release profile of the drug delivery system (CS) was significantly improved compared to previous studies. The average release results show that the release of the drug delivery system (CS) is slower than that of the MR tablet.

[0332] Example 6: Swelling performance of a drug delivery system product

[0333] Four products containing placebo tablets prepared according to Example 1, each containing 30% HPMC, were placed in simulated gastric fluid at 37°C for 90 minutes. At 0, 10, 30, 60, and 90 minutes, each product was removed from the simulated gastric fluid, the simulated gastric fluid was wiped off the surface of the product, and the diameter of the product was measured. Then, each product was placed back into the simulated gastric fluid. The results are shown in Figure 11, where data points represent the mean value and error bars represent the standard deviation.

[0334] FIG. 11 illustrates that the device made according to Example 1 swells to a diameter of more than 30 mm within 30 minutes. As discussed above, this diameter is larger than the diameter of the patient's pylorus. Additionally, because the swelling rate is rapid, the hydrogel device will reach this size before the MMC wave begins after ingestion. Therefore, the device will not pass out of the stomach.

[0335] Example 7: Pharmacokinetic evaluation of modified-release B12 pills in a drug delivery system in a dog model

[0336] Research Protocol

[0337] A preliminary study was conducted to evaluate the safety and feasibility of administering a drug delivery system to animals. Two male Beagle dogs, 3 years of age and weighing 10 to 15 kg, were orally administered a drug delivery system as disclosed herein. 150 mL of warm water was provided after the administration of the drug delivery system. On the morning of the day of administration (before administration), the animals were restricted from daily food rations until 1 hour after administration.

[0338] Fecal Sample Collection - Feces were collected in polypropylene containers. Fecal samples were examined on a mesh grid or a clear self-sealing plastic bag to determine if swollen ultraporous hydrogels were present in the samples. Photographs of the samples were taken before and after examination.

[0339] Results - Administration was performed without any incidents of the pills being chewed or bitten. No adverse reactions to the administration of the drug delivery system were observed in the administered animals, indicating safety and tolerability. There were no effects on food intake or animal behavior throughout the study period. Fecal collection results showed that a hydrogel section was recovered from one dog on day 5. Another dog did not expel the hydrogel during the study.

[0340] Example 8: Plasma concentration of B12

[0341] A study was designed to evaluate the pharmacokinetics of vitamin B12 in male Beagle dogs after oral administration of three different release formulations.

[0342] Research Protocol

[0343] Dog - 12 non-naive male Beagle dogs, 3 years of age, weighing 10 to 15 kg.

[0344] Food intake - Animals were allowed to consume 300 g to 350 g of certified dog food 5007 (Labdiet, PMI Nutrition International) daily during the study period. On the morning of the day of administration (before administration), the animals were restricted from daily food rationing until 3 hours after administration.

[0345] Test items - 3 1 mg B12 formulations with different release profiles. Details of the formulations are specified in Table 5.

[0346] [Table 5]

[0347] Preparations evaluated in animal studies

[0348]

[0349] Route of administration - Tablets of all formulations were administered orally to dogs that had fasted for 12 hours. A group of 6 male Beagle dogs will receive a single dose of one tablet containing 1 mg Vitamin B12 MR per animal (Animal numbers - 064M, 065M, 066M, 078M, 079M, 088M). A third group of 6 male Beagle dogs will receive a single dose of one tablet containing 1 mg Vitamin B12 binding system: B12 MR+OMPGEL per animal (068M, 069M, 097M, 098M, 099M, 100M). Prior to oral administration (approximately 30 minutes prior to administration), all animals will receive a single intramuscular (IM) dose of pentagastrin at a target dose level of 6 μg / kg.

[0350] Sample Collection - After oral administration of each tablet, a blood sample (approx. 1 mL) was collected in a tube containing lithium heparin anticoagulant by venipuncture from the jugular vein. Details of the blood collection times are in Table 5. The collected samples were analyzed using the Siemens Healthineers Immulite 2000 XPi immunoassay system employing chemiluminescent enzyme immunoassay. The analyzable detection range is 150 pg / mL to 1000 pg / mL.

[0351] For dogs administered the combination system, fecal samples were collected from the floor of the enclosure at time intervals specified in Table 6.

[0352] [Table 6]

[0353] Animal study design details

[0354]

[0355] result

[0356] The B12 value prior to administration was considered to be at an endogenous level and was subtracted from subsequent measurements to obtain accurate analytical data.

[0357] As can be seen in Figure 14, a significant level of variability was observed in all animals administered modified-release tablets, suggesting inconsistencies in gastric passage. Additionally, some samples showed a double peak, which may indicate fecal ingestion due to a lack of precautions in the enclosure design.

[0358] In the case of the drug delivery system, one sample (97M) was prematurely expelled from the dog before 24 hours. The other sample (100M) showed significantly delayed development. These two hydrogels were considered outliers because they did not match the expected behavior.

[0359] As a result of plasma concentration analysis, the remaining four samples of dogs administered the drug delivery system (OMPGEL+B12) showed peak concentrations at 6 hours (Figs. 15; 16). The plasma concentration spectra of the animals at 068M, 069M, 098M, and 099M showed a consistent trend, indicating low variability in the degree of absorption. The observed consistency of drug release further supports the concept of effective gastric passage.

[0360] A comparative analysis of the two systems was performed by plotting the averages of MR and CS plasma concentrations, excluding outliers.

[0361] [Table 7]

[0362] PK summary for the test group

[0363]

[0364] Comparative analysis of the modified-release system and the combined system revealed that the time required to reach peak concentration shifted to the right from 2 hours to 6 hours. This shift is consistent with the swelling kinetics of OMPGEL in a physiological environment, supporting the delayed-release function. Additionally, the combined system showed slightly higher B12 concentrations compared to the modified-release system (Fig. 13). The area under the curve (AUC) of the combined system increased by 47%, demonstrating favorable pharmacokinetic characteristics (Table 7). These results suggest the potential for improved bioavailability and increased duration of treatment.

[0365] Estimated upper retention

[0366] A total of 8 OMPGELS were administered to dogs, and 87.5% of the OMPGELS showed a gastric retention period of at least 3 days, 62.5% showed a maximum gastric retention exceeding 14 days, and no hydrogel residue was collected in the stool even after 14 days. Only one system (12.5%) failed to deploy correctly (<24 h).

[0367] Example 9:

[0368] Mechanical Test-I

[0369] To evaluate the mechanical robustness of the drug delivery system, a pre-swollen sample was secured in a 12 cm × 12 cm Petri dish containing 50 mL of simulated gastric fluid (SGF) and placed on a Mecmesin Multitest 2.5i instrument platform. A compressive load of 100 N was applied to the system at room temperature. The system successfully withstood this load, showing no signs of cracking or other structural damage. To ensure the reproducibility of the results, this process was repeated for three samples (Fig. 17). These results confirm the unwavering stability of the system and its suitability for long-term gastric retention.

[0370] Mechanical Test-II

[0371] To evaluate the mechanical robustness of the drug delivery system, a pre-swollen sample was secured in a 12 cm × 12 cm Petri dish containing 50 mL of simulated gastric fluid (SGF) and placed on a Mecmesin Multitest 2.5i instrument platform. A compressive load of 300 N was applied to the system at room temperature. The system successfully withstood this load, showing no signs of cracking or other structural damage. To ensure the reproducibility of the results, this process was repeated for three samples (Fig. 18). These results confirm the unwavering stability of the system and its suitability for long-term gastric retention.

[0372] Fatigue test (FT)

[0373] The loaded drug delivery system was pre-swelled in simulated gastric fluid and placed in a 12 cm × 12 cm Petri dish mounted on a Mecmesin Multitest 2.5i instrument platform. At room temperature, 7,000 cycles were applied to the drug delivery system with a 10 N load while maintaining a 50 mL SGF volume in the Petri dish. This experiment was performed to demonstrate the robustness of the drug delivery system. The perfect overlap of the load-versus-displacement curves between the initial and final cycles further confirmed that the system remains highly stable even under prolonged repetitive stress (Fig. 19). This study demonstrated that the system possesses unwavering stability even when exposed to the harshest conditions.

[0374] Example 10: SPH pore circumference

[0375] FIGS. 23 to 25 show scanning electron microscope (SEM) images of a superporous hydrogel prepared according to any one of Examples 1 to 3 without a loading step.

[0376] FIG. 23 illustrates a cross-section of a superporous hydrogel immediately after freeze-drying (i.e., before any compression or plasticization process is performed). The average perimeter of the pores in the cross-section of the superporous hydrogel shown in FIG. 23 is 1596.0 μm, which means that the pores of the superporous hydrogel in FIG. 23 have an average maximum dimension of 798.0 μm.

[0377] FIG. 24 illustrates a cross-section of a compressed ultraporous hydrogel (i.e., an ultraporous hydrogel after the "compression" step of any one of Examples 1 to 3). The average perimeter of the pores in the cross-section of the compressed ultraporous hydrogel shown in FIG. 24 is 998.7 μm, which means that the pores of the compressed ultraporous hydrogel in FIG. 24 have an average maximum dimension of 499.3 μm.

[0378] Figure 25 shows a cross-section of a superporous hydrogel after swelling by immersion in simulated gastric fluid for 1 hour. The average perimeter of the pores in the swollen superporous hydrogel cross-section shown in Figure 25 is 1470.1 μm, which means that the pores of the swollen superporous hydrogel in Figure 25 have an average maximum dimension of 735.1 μm.

[0379] Table 8 presents the average pore area and average pore circumference for six ultraporous hydrogel samples immediately after freeze-drying (i.e., before any compression or plasticization processes were performed). The average pore area of ​​these samples is 205365.58 µm. 2 (Standard deviation 136633.65 µm 2 ) and the average pore circumference is 1813.79 μm (standard deviation 573.31 μm). Therefore, the average maximum pore size of the samples in Table 8 is 906.6 μm.

[0380] [Table 8]

[0381]

[0382] Table 9 discloses the average pore area and average pore circumference for six compressed ultraporous hydrogel samples (i.e., ultraporous hydrogels after the "compression" step of any one of Examples 1 to 3). The average pore area of ​​these samples is 8833.97 µm. 2 (Standard deviation 4735.50 µm) 2 ) and the average pore circumference is 671.62 μm (standard deviation 188.13 μm). Therefore, the average maximum pore size of the samples in Table 9 is 385.8 μm.

[0383] [Table 9]

[0384]

[0385] Table 10 presents the average pore area and average pore circumference for six ultraporous hydrogel samples after swelling by immersion in simulated gastric fluid for 1 hour. The average pore area of ​​these samples is 123,960.71 µm. 2 (Standard deviation 30453.32 µm 2 ) and the average pore circumference is 1482.16 μm (standard deviation 178.22 μm). Therefore, the average maximum pore size of the samples in Table 10 is 741.1 μm.

[0386] [Table 10]

[0387]

[0388] Example 11: N,N'-Methylenebisacrylamide (MBA) and BaSO₄ 4 crosslinking agent

[0389] A hydrogel composition was prepared by varying the MBA concentration from 0.0065% to 0.008% of the total formulation while maintaining the total crosslinking agent concentration at a constant level.

[0390] Initial Hydrogel Synthesis:

[0391] 25.0 g to 50.0 g (+ / - 0.1 g) of AAm, 6.0 g to 20.0 g (+ / - 0.1 g) of AL, and 10 mg to 100 mg (+ / - 1 mg) of MBA were weighed and mixed with 150 ml to 500 ml of DW. This solution was mixed with 433.0 mg to 751.0 mg (+ / - 1.0 mg) of APS in beaker A. In beaker B, 150.0 mg to 250.0 mg of CaSO4 powder (+ / - 1.0 mg), 4 ml to 10 ml of water, and 47 µl to 82 µl of TEMED were added and weighed. The solution from beaker A was poured into beaker B. The mixture was stirred and then poured into a mold. Each cylindrical mold had an inner diameter of 10 mm to 40 mm and included a central mold attached to an upper stopper by a thin rod.

[0392] The samples in the PP mold were cured in an incubator (25°C to 60°C) for 1 hour. Afterward, to complete the polymerization, they were transferred to a humidity chamber at room temperature and cured for an additional 24 to 72 hours. The resulting gelled material (initial hydrogel material) was labeled as the gel as prepared (APG).

[0393] The top stopper was removed from the mold, and the APG, still containing the central mold and thin rod, was removed from the tube for the next washing process.

[0394] The APG was immersed in the washing solution for 7 to 21 days, and the sample and container were flushed with deionized water daily, and the used washing solution was replaced with a new washing solution. The central mold was removed or dissolved to obtain a washed APG having a cavity in the core region and a narrow passage including an opening at the top of the washed APG.

[0395] Loading method:

[0396] The washed APGs were discharged from the washing solution. A drug core containing one or more active ingredients was inserted into the cavity through the opening and passage of each washed APG to obtain a loaded APG. Due to the elastic properties of the APG material and the narrow diameter of the passage, the drug core was retained within the cavity.

[0397] Freezing and Freeze-drying:

[0398] Each loaded APG was placed in a freezer at -10°C to -50°C for 8 to 72 hours, then transferred to a freeze dryer and freeze-dried to produce a loaded freeze-dried ultraporous hydrogel (loaded freeze-dried SPH).

[0399] Saturation:

[0400] A loaded freeze-dried SPH sample was placed in a sample holder and left in a humidity chamber at 30°C to 60°C with a relative humidity of 50% to 95% for 1 to 10 minutes until it became flexible, thereby obtaining a plasticized loaded freeze-dried SPH.

[0401] compression:

[0402] The plasticized loaded freeze-dried SPH was carefully removed from the container and compressed into a pill shape. Through this compression step, the loaded compressed SPH was obtained.

[0403] Swelling performance:

[0404] The swelling ability of the hydrogel was evaluated by measuring the changes in diameter, height, and mass when immersed in simulated gastric juice at 37°C. These results are shown in Fig. 26.

[0405] Concentrations 1, 2, 3, and 4 correspond to MBA concentrations of 0.008%, 0.0075%, 0.007%, and 0.0065% w / w in APG, respectively. All samples swelled to an average of more than 30 mm within 30 minutes, indicating the potential for gastric retention characteristics.

[0406] Mechanical strength evaluation

[0407] The mechanical strength of the hydrogel was evaluated by measuring its resistance to cracking or structural failure under controlled conditions. These results are shown in Fig. 27.

[0408] The samples were compressed with a force of 100 N using a 500 N capacity load cell. Both samples remained intact after compression. There were no cracks or fractures induced by compression. The MBA concentration-01 sample (0.008% w / w MBA) exhibited less displacement compared to the concentration-02 sample (0.0075% w / w MBA), indicating a higher compressive modulus.

Claims

Claim 1 A product capable of releasing one or more active ingredients, wherein the product comprises a superporous hydrogel structure having a pore structure formed by freeze-drying, and the superporous hydrogel structure comprises a core region comprising one or more active ingredients. Claim 2 A product according to claim 1, wherein substantially all of the one or more active ingredients are located within the core region of the ultraporous hydrogel structure. Claim 3 A product according to claim 1, wherein the superporous hydrogel structure comprises a shell region that at least partially surrounds the core region, and at least a portion of the shell region of the superporous hydrogel structure substantially does not contain an active ingredient. Claim 4 A product according to any one of claims 1 to 3, wherein the core region comprises a body separate from the ultraporous hydrogel structure. Claim 5 A product according to any one of claims 1 to 4, wherein one or more active ingredients are not chemically bonded to a part of the core region of the ultraporous hydrogel structure and are maintained by the core region of the ultraporous hydrogel structure. Claim 6 A product according to any one of claims 1 to 5, wherein the ultraporous hydrogel comprises a structure comprising a mixture of hydrophilic polymers crosslinked by one or more crosslinking agents. Claim 7 In claim 6, the mixture of hydrophilic polymers comprises one or more hydrophilic polymers made from alkenylamide-containing monomers and polysaccharides. Claim 8 In claim 7, the product wherein the alkenylamide-containing monomer comprises acrylamide and the polysaccharide comprises alginate. Claim 9 A product according to any one of claims 6 to 8, wherein the one or more crosslinking agents comprise one or more selected from one or more acryloyl groups, one or more acrylamide groups, one or more amine groups, one or more olefin groups, one or more aldehyde groups, and one or more divalent metal ions. Claim 10 In claim 9, the product comprises one or more crosslinking agents selected from N,N'-bis(acryloyl)cystamine (BAC) and / or N'-methylenebisacrylamide (MBA) and / or calcium ions. Claim 11 A product according to any one of claims 1 to 9, wherein the ultraporous hydrogel comprises a compressed structure having pores having an average maximum dimension of 100 μm to 5 mm. Claim 12 A product according to any one of claims 1 to 11, wherein the pores of the pore structure have an average maximum dimension of ≥250 μm after immersion in simulated gastric fluid for 1 hour. Claim 13 A product according to any one of claims 1 to 12, wherein the core region comprises one or more cavities (22), and one or more active ingredients are loaded into the one or more cavities (22). Claim 14 In paragraph 13, before loading one or more active ingredients into the one or more cavities (22), the one or more cavities (22) include one or more passages (24), and one end of the one or more passages (24) includes an opening (26) on the side of the product. Claim 15 A product according to claim 13 or 14, wherein the total volume of one or more cavities (22) is ≤2 mL. Claim 16 A product according to any one of claims 1 to 15, wherein the active ingredient comprises one or more medicinal ingredients. Claim 17 A product according to any one of claims 1 to 16, wherein the active ingredient comprises one or more health functional food ingredients. Claim 18 A product according to any one of claims 1 to 17, wherein the active ingredient is selected from one or more of the group consisting of metformin (N,N-dimethylbiguanide), carbidopa (N-amino-α-methyl-3-hydroxy-L-tyrosine monohydrate), levodopa (L-3,4-dihydroxyphenylalanine), glucagon-like peptide receptor agonists such as semaglutide, cobalt-containing dietary supplements such as vitamin B12, iron-containing dietary supplements, and combinations thereof. Claim 19 A product according to any one of claims 1 to 18, wherein the core region further comprises one or more excipients. Claim 20 In paragraph 19, the product comprises one or more excipients including a permeability promoter such as salcaprosate sodium. Claim 21 A product according to any one of claims 1 to 20, wherein the product produces a swollen hydrogel having a diameter of ≥25 mm within 30 minutes, including a swelling force released when the product is exposed to gastric fluid. Claim 22 A method for manufacturing a product having a superporous hydrogel structure capable of releasing one or more active ingredients and having a pore structure formed by freeze-drying, wherein the superporous hydrogel structure comprises a core region containing one or more active ingredients, the method comprising a) a step of loading one or more active ingredients into the core region before or after freeze-drying. Claim 23 In claim 22, the method comprises the step of loading one or more active ingredients into the core region such that substantially all of the one or more active ingredients are located within the core region. Claim 24 In claim 22 or 23, step a) comprises (i) loading one or more active ingredients into the core region before freeze-drying; a. A step of providing an initial hydrogel including a core region; b. A step of loading one or more active ingredients into the core region of the initial hydrogel; and c. freeze-drying the product produced in step (b) above to form an ultraporous hydrogel structure comprising a core region loaded with one or more active ingredients; or (ii) loading one or more active ingredients into the core region after freeze-drying; a. A step of providing an initial hydrogel including a core region; b. freeze-drying the initial hydrogel to form an ultraporous hydrogel structure including a core region; and c. A method further comprising the step of loading one or more active ingredients into a core region of the above-described ultraporous hydrogel structure to form an ultraporous hydrogel structure comprising a core region loaded with one or more active ingredients. Claim 25 A method according to any one of claims 22 to 24, wherein one or more active ingredients are loaded into a core region prior to freeze-drying, the method further comprises: a. polymerizing a mixture of monomers and / or polymers around one or more central molds (12, 16; 34) in the presence of a crosslinking agent to form an initial hydrogel; b. demolding the product produced in step (a) to provide a core region comprising one or more cavities (22) to the initial hydrogel; c. loading one or more active ingredients into one or more cavities (22) of the initial hydrogel; and d. freeze-drying the product produced in step (c) to form an ultraporous hydrogel structure having a core region comprising one or more cavities (22) loaded with one or more active ingredients. Claim 26 A method according to any one of claims 22 to 24, wherein one or more active ingredients are loaded into a core region after freeze-drying, the method further comprises: a. polymerizing a mixture of monomers and / or polymers around one or more central molds (12, 16; 34) in the presence of a crosslinking agent to form an initial hydrogel; b. demolding the initial hydrogel to provide a core region comprising one or more cavities (22) to the initial hydrogel; c. freeze-drying the product produced in step (b) to form an ultraporous hydrogel structure having a core region comprising one or more cavities (22); and d. loading one or more active ingredients into one or more cavities (22) of the ultraporous hydrogel structure to form an ultraporous hydrogel structure comprising a core region loaded with one or more active ingredients. Claim 27 A method according to any one of claims 24 to 26, wherein the step of demolding includes a cleaning treatment. Claim 28 A method according to any one of claims 22 to 27, further comprising, after loading, (i) a step of treating the superporous hydrogel structure to plasticize its structure; and (ii) a step of compressing the resulting plasticized superporous hydrogel structure to provide a compressed structure having pores having an average maximum dimension of 100 μm to 5 mm. Claim 29 A method according to claim 28, further comprising, prior to steps (i) and (ii), a step of substantially sealing one or more cavities, one or more openings into passages, and at least one portion selected from one or more passages. Claim 30 In paragraph 29, the method comprising the substantially sealing step including the installation of a plug. Claim 31 A method according to any one of claims 22 to 27, further comprising, after freeze-drying, (i) a step of treating the superporous hydrogel structure to plasticize its structure; and (ii) a step of compressing the resulting plasticized superporous hydrogel structure to provide a compressed structure having pores having an average maximum dimension of 100 μm to 5 mm. Claim 32 A method according to claim 31, wherein the compressing step comprises compressing the resulting plasticized ultraporous hydrogel structure into an elongated insert present in at least a portion of one or more cavities. Claim 33 A method according to claim 25 or 26, further comprising the step of, after loading one or more active ingredients into one or more cavities (22), substantially sealing one or more cavities, one or more openings into one or more passages, and at least one portion selected from one or more passages. Claim 34 In paragraph 33, the method comprising the substantially sealing step including the installation of a plug. Claim 35 A product that can be obtained by a method according to any one of paragraphs 22 through 34. Claim 36 The use of a product according to any one of paragraphs 1 through 21 or paragraph 35 in drug delivery. Claim 37 A pharmaceutical composition comprising a product according to any one of claims 1 to 21 or claim 35. Claim 38 A medical treatment method comprising the step of administering a product according to any one of claims 1 to 21 or 35 to a subject. Claim 39 A product according to any one of paragraphs 1 through 21 or 35 for use as a pharmaceutical. Claim 40 A product according to any one of claims 1 to 21 or 35 for use in treating or preventing one or more diseases selected from gastric cancer, gastric ulcer, Helicobacter pylori infection, Parkinson's disease, polycystic ovary syndrome, metabolic disease, obesity, obesity-related disease, cardiovascular disease, diabetes mellitus, and non-alcoholic fatty liver disease. Claim 41 A method of administration for administering a product according to any one of paragraphs 1 to 21 or 35 to a patient suffering from one or more diseases. Claim 42 A method for treating or preventing one or more diseases of a subject, comprising the step of administering a product according to any one of claims 1 to 21 or 35 to the subject. Claim 43 In paragraph 42, the method wherein one or more of the above diseases are selected from gastric cancer, gastric ulcer, Helicobacter pylori infection, Parkinson's disease, polycystic ovary syndrome, metabolic disease, obesity, obesity-related disease, diabetes, cardiovascular disease, and non-alcoholic fatty liver disease. Claim 44 A method according to paragraph 42 or 43, wherein the product is administered in an amount effective to cause a gastric retention period of at least 24 hours. Claim 45 A method according to any one of paragraphs 42 to 44, wherein the product is administered in an amount effective to cause a gastric retention period of at least 3 days. Claim 46 A method according to any one of claims 42 to 45, wherein the product is administered in an amount effective for causing a gastric retention period of 3 to 14 days. Claim 47 A method according to any one of claims 42 to 46, wherein the product is administered in an amount effective to produce a swollen hydrogel having a diameter of ≥25 mm within 30 minutes when the product is exposed to gastric fluid. Claim 48 A method according to any one of claims 42 to 47, wherein the product is administered in an amount effective to produce a swollen hydrogel having a diameter of ≥30 mm within 30 minutes when the product is exposed to gastric fluid. Claim 49 A method according to any one of claims 42 to 48, wherein the product is administered in an effective amount such that it causes the release of 65% or less of one or more active ingredients after 24 hours. Claim 50 A method according to any one of claims 42 to 49, wherein the product is administered in an effective amount such that it causes the release of 80% or less of one or more active ingredients after 48 hours.

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