Product containing a granular composition for maintaining the form of gel particles, method for producing the same, and process for forming a granular slurry

Abstract

The present invention discloses a product, which comprises a granular composition of gel particles, particularly microgel particles. The composition comprises an intercellular carbohydrate matrix (lattice / network) containing the gel particles. The present invention provides a method for manufacturing such a product comprising a granular composition of gel particles, particularly microgel particles, the method comprising forming an aqueous slurry comprising the gel particles and a water-soluble carbohydrate compound. The slurry is shaped into the product and the shaped slurry is solidified.

Description

Technical Field

[0001] The present invention relates to products containing a particulate composition for maintaining the morphology of gel particles, particularly in the form of micro-gel particles. The present invention further relates to a method for manufacturing such solid products and a process for forming a particulate slurry containing gel particles. In this regard, it should be noted that the present invention particularly relates to gel particles enclosed and confined by a hydrophilic polymer network. In this regard, a gel refers to a hydrogel composition containing a polymer network that can contain a substantial amount of water, for example, more than 50% by weight, typically more than 90% by weight (hydrophilic).

Background Art

[0002] Gel particles are found in many products and markets, including food, life sciences, and cosmetics. The formation of products and devices containing such gel particles generally requires the use of binders or the dispersion of gel particles in a continuous medium. Known microgel particles include microcapsules containing a fluid core surrounded by a shell made of hydrogel. These hydrogel particles are produced under aqueous conditions and contain a relatively high concentration of an aqueous medium, which may exceed 90% in total. This poses a problem in terms of the shelf life because the activation and decomposition of gel particles and / or their contents generally occur in an aqueous environment. Therefore, it is necessary to preserve gel particle compositions and their ingredients.

[0003] The storage of gel particles depends on whether they are in a wet or dry state. When storing in the wet state, one or more additives may be added to prevent or at least delay the reaction of the particles and their contents. Examples of such storage additives include, for example, ethanol, salt solutions, and parabens. However, adding these compounds may cause unintended side effects with respect to health and the environment, and may also impair the properties of the gel particles. Furthermore, storing in the wet state generally results in the form of liquid emulsions or soft particle aggregates, with limited mechanical robustness, limited ability to supply a predetermined number of materials in a single step, and prevention of presenting the particle aggregates in a distinct macroscopic shape.

[0004] When storing in the dry state, substantially all of the water content can be removed from the gel particle composition. Examples of this process include solvent evaporation and freeze-drying. It has been found to be difficult to remove water from the gel particle composition without affecting the original form or properties of the gel particles. The pressure applied to the gel particles from the formation of ice crystals during freezing, or the sublimation process during solvent evaporation, often proves sufficient to deform the gel particles and / or impair the macrostructure, integrity of the gel particles, and the contents of the gel particles. Accordingly, the gel particle material needs to be optimized to withstand the storage process, which results in limitations on the materials that can be used for the gel particles. In particular, the gel particles should be able to withstand the freezing of their liquid contents and the removal of any liquid contents during the drying step in order to achieve storage in the dry state.

[0005] To enable the storage of gel particles in a dry state, it is known to modify the particle composition during manufacturing. For example, crosslinkable moieties that irreversibly preserve the shape of the gel particles may be included in the chemical composition. However, this requires additional steps such as the treatment of the particles with dangerous crosslinking chemicals such as glutaraldehyde or formalin, or the photoinduced crosslinking of acrylic acid moieties by irradiation with ultraviolet (UV) light. Also, the composition and exposure to UV light may damage the components within the gel particles. Furthermore, UV exposure is an in situ process that needs to be performed individually during manufacturing or on relatively small composition volumes limited by the maximum light penetration depth. Also, this process is irreversible and results in a hard composition that may not be suitable for the target application.

[0006] Chemical crosslinking can be used to induce preservation by introducing covalent crosslinking functional groups into the chemical structure of the shell compound of the gel particles. Covalent crosslinks are generally stronger than other types of bonds such as ionic crosslinks and can be made strong enough to withstand lyophilization of the gel particles. However, introducing covalent crosslinking moieties such as methacrylate (MA) groups or dialdehyde (DA) groups complicates the manufacturing process in terms of chemistry and increases the manufacturing cost.

[0007] Another problem is the macrostructure of the product cast from the particulate microparticle composition, i.e., the preservation of the shape. The formation of such products generally requires compression to the irreversible aggregation point of the dry particles (standard tablet compression) or lyophilization of the composition. Thereby, the shape of the macrostructure is preserved, but only some of the particle component properties such as taste, texture and / or active ingredients are retained. The shape of the particles is likely to change irreversibly during compression, for example, by disintegration, rupture or plastic deformation.

[0008] Also, such a storage method is only carried out once and the structure easily collapses after (re)hydration. The latter is widely used as a method for dissolving tablets. However, even if the composition containing flexible gel particles is re-frozen or compressed after (re)hydration, the same result cannot be obtained. With each (re)hydration cycle, the properties easily change and the solution contains irregularly shaped gel particles instead of the initial form during production.

[0009] By sintering the composition having a carbohydrate phase, the shape retention of individual microparticles can be improved. However, sintering is an irreversible process and generally the particles are bonded to the sintered phase. As a result of such a process, the product loses the ability to remove clogging and the system cannot return to the granular suspension state.

Summary of the Invention

[0010] One of the objects of the present invention is to provide a product containing gel particles that satisfy the above limitations, particularly in terms of enabling multiple storage and (re)hydration cycles while substantially retaining the shape and component properties, and particularly a granular composition substantially consisting of such gel particles.

[0011] To achieve the above object, the product of the type described in the opening paragraph according to the present invention is characterized in that the composition includes a solid structure of the gel particles bonded to each other by a substantially dry or dried carbohydrate matrix between the gel particles.

[0012] Accordingly, the present invention provides a carbohydrate interstitial matrix that holds gel particles together by providing a binding structure between the gel particles. Thus, the carbohydrate layer imparts consistency and structure to maintain the form to the final product. The carbohydrate matrix responsible for this structural binding provides structural support to the product and an interstitial protection shield to the individual gel particles trapped within the structure. In particular, the total water (moisture) content of the dry form-retaining product is less than 50% by weight, particularly less than 15% by weight, more specifically less than 10% by weight, and even more specifically less than 5% by weight.

[0013] In particular, the product retains its macroscopic shape while preserving the shape and size of the gel particles during lyophilization and (re)hydration. Since the product behaves as a solid material under its dry state conditions, operations such as transportation, packaging, administration, or cutting into smaller fragments can be easily performed. And it is also possible to perform multiple lyophilization cycles without losing properties on two scales. In particular, the present invention enables storing and transporting tablets made of conventional materials that cannot be lyophilized without impairing the properties and / or integrity of the product, particularly the gel particles trapped therein, for a long period under room temperature conditions.

[0014] Here, it should be noted that when used in the present application, the expressions hydration or rehydration may refer not only to aqueous solutions but also to non-aqueous solutions or liquids. Also, these expressions may be used interchangeably with expressions such as activation and reactivation, or wetting and rewetting.

[0015] In a further aspect of the present invention, a method for manufacturing a solid product containing a granular composition of gel particles, particularly microgel particles, comprises forming an aqueous slurry containing the gel particles and a water-soluble carbohydrate compound, shaping the slurry into the product, particularly molding, more specifically compressing, and dehydrating and solidifying the shaped slurry containing the gel particles and the water-soluble carbohydrate compound to form the product.

[0016] In certain embodiments, the method according to the present invention solidifies the formed slurry by at least substantially removing the aqueous content of the formed slurry, in particular by drying, more specifically by freeze-drying. In particular, the total water (moisture) content of the solidified and dried product is less than 50% by weight, in particular less than 15% by weight, more specifically less than 10% by weight, and even more specifically less than 5% by weight.

[0017] Many techniques may be used to form the slurry into the product, but in a more specific embodiment of the method according to the present invention, prior to solidification, the slurry is formed by molding, additive printing or extrusion.

[0018] The original slurry is retrieved again without substantial modification by using a liquid activator that dissolves or disperses the carbohydrate lattice structure. To that end, the process for forming a slurry comprising a particulate composition of gel particles, in particular microgel particles, according to the present invention provides a product according to the present invention, characterized in that the product is exposed to a liquid activator.

[0019] In a preferred embodiment of the product according to the present invention, the carbohydrate matrix is characterized by being water-soluble. By the carbohydrate matrix being water-soluble, the carbohydrate matrix can be easily decomposed by (re)hydration with an aqueous liquid activator. By using fresh water or an aqueous solution as the hydrating agent, slurries suitable for many industrial applications are obtained, including applications in the cosmetic industry, food industry, nutraceutical industry, or pharmaceutical industry (e.g., edible compounds used for oral drug delivery or ingestion of active agents such as vitamins or pro- / antibiotics).

[0020] Thus, in a specific embodiment of the product according to the present invention, the carbohydrate matrix comprises an amorphous matrix of at least one polycarbohydrate or polysaccharide compound. More specifically, the polycarbohydrate or polysaccharide compound comprises at least one sugar compound. More specifically, the sugar compound comprises dextran, dextrin, maltodextrin, trehalose, lactose, glucose, dextrose, sucrose, fructose, maltose, isomaltose, sorbitol, mannitol, lactitol, xylitol and / or erythritol.

[0021] Accordingly, in a preferred embodiment of the process for forming a slurry according to the present invention, the aqueous liquid activator is an aqueous carbohydrate solution, in particular a polycarbohydrate or polysaccharide solution, more specifically a sugar solution, and even more specifically an aqueous solution of dextran, dextrin, maltodextrin, trehalose, lactose, glucose, dextrose, sucrose, fructose, maltose, isomaltose, sorbitol, mannitol, lactitol, xylitol and / or erythritol. Such a carbohydrate solution can, for example, rearrange the reinforcing matrix within the composition when the slurry is subsequently solidified by drying, in particular freeze-drying. This enables multiple (re)hydration cycles to be carried out many times while at least substantially retaining the initial properties of the slurry composition, in particular the gel particles contained therein.

[0022] In a further specific embodiment of the product according to the present invention, the gel particles comprise a hydrogel, more specifically, a hydrophilic polymer network, and more specifically, the hydrogel comprises agar, alginic acid, chitosan, dextran, polyethylene glycol, collagen, gelatin, hyaluronic acid, carrageenan, fibroin, fibronectin, polyethylenimine (PLL), cellulose, graphene, polyethyleneimine (PEI), poly(amidoamine) (PAA), dextran sulfate, silk, silk fibroin, pectin, K-carrageenan, ι-carrageenan, gellan gum, guar gum, tragacanth gum, xanthan gum, acacia gum, karaya gum, locust bean gum or sodium carboxymethyl cellulose (S-CMC). These materials are all preferably applied as naturally derived materials and / or synthetically derived materials (including recombinant proteins and / or derivatives of these materials), and the polymer network particularly comprises a calcium alginate network. In this regard, in a further specific embodiment of the method and the capsule, good results are obtained, and the gel particles comprise a crosslinked or interpenetrating alginic acid network, particularly a calcium crosslinked alginic acid network.

[0023] A further specific embodiment of the product according to the present invention is characterized in that the gel particles comprise microcapsules having a core surrounded by a hydrophilic polymer network. The microcapsules have a shell containing calcium alginate of a first molecular weight and calcium alginate of a second molecular weight, and the second molecular weight is greater than the first molecular weight.

[0024] The core may contain at least one active, pharmaceutically, cosmetically, biologically active or activatable material from the group including biological agents, antioxidants, vitamins, hormones, vaccines, microbiotics, probiotics, prebiotics, nucleic acids, antibiotics, enzymes, proteins, fungi, yeasts, bacteria, plant cells, mammalian cells and stem cells, and may contain other active compounds protected from the surroundings to preserve them, i.e., to prevent or reduce their activation and extend their shelf life or expiration date.

[0025] In certain embodiments, the microcapsules may have a fluid core. The fluid core may contain a mixture of immiscible liquids such as water-in-oil emulsions or oil-in-water emulsions. The fluid core may contain at least one liquid that does not mix mainly with water, in particular oils, in particular ether oils, macerated oils and / or essential oils, or waxes that further add pleasant sensory properties advantageous for the product. Examples of suitable organic lipophilic compounds include, for example, vegetable oils and vegetable oil derivatives such as sunflower oil, corn oil, castor oil, coconut oil, avocado oil, sweet almond oil, carophyllum oil, lanolin, sesame oil, olive oil, jojoba oil, soybean oil, cottonseed oil, rapeseed oil, peanut oil, linseed oil, luridisa oil, and essential oils such as imortel, lavender, German chamomile, neroli, peppermint oil, rosemary, rose oil, tea tree oil, dwarf pine, juniper berry, chestnut extract, birch leaf extract, hay seed extract, ethyl acetate, camphor, menthol, rosemary extract, eucalyptus oil, and macerated oils, and fatty acids such as stearic acid, palmitic acid, behenic acid, myristic acid, lauric acid, capric acid, and fatty acid derivatives such as fatty acid esters with short-chain alcohols such as isopropyl myristate, isopropyl palmitate, isopropyl stearate, dibutyl adipate, and medium-chain and long-chain fatty acids and their esters with polyols such as propylene glycol, and Animal oils such as tallow, marine oils such as fish oil and seaweed oil, or mixtures thereof, nut oils, seed oils, waxes such as paraffin wax, carnauba wax, candelilla wax, beeswax, microcrystalline wax, ozokerite wax, triglycerides, and the like.

[0026] In a further specific embodiment, the microcapsule has a core that is at least partially solid. The core, which is completely solid or partially solid, may include a mixture of a hydrophobic material and a hydrophilic material. In a specific embodiment, the hydrophilic material is heterogeneously distributed throughout the hydrophobic core, and more specifically, the mixture includes pockets of the hydrophilic material within the hydrophobic material, or alternatively, the mixture includes pockets of the hydrophobic material within the hydrophilic material.

[0027] In a further specific embodiment, the core that is at least partially solid includes a degradable material, particularly a biodegradable material, and specifically includes a polymer, and the polymer is selected from the group consisting of polylactic acid (PLA), polyglycolic acid (PGA), poly(ε-caprolactone) (PCL), lactic acid-glycolic acid copolymer (PLGA), trimethylene carbonate (TMC), and modified forms of these materials, particularly block copolymers including polyethylene glycol (PEG) as one of the blocks, and more specifically, PEG-PLA, PEG-PLGA, PEG-PGA, or PEG-PCL. Other materials include polyorthoesters (POE), particularly the fourth generation POE (POE IV).

[0028] In a further specific embodiment, such a product according to the present invention provides a sustained release composition that releases a bioactive agent. More specifically, the core that is at least partially solid undergoes degradation under physiological conditions, and more specifically, is partially or completely degraded by hydrolysis. The degradation may be the result of bulk erosion or surface erosion. By hydrolyzing in an aqueous environment, the core is eroded, and thus the active agent trapped therein is liberated and released.

[0029] In a further specific embodiment, one or more active agents are released from the core by the decomposition, and more specifically, the active agent is delivered to the environment by the decomposition. The decomposition and / or the delivery may be carried out in a timely controlled manner, specifically, it may be carried out during a time period of at least one day, more specifically, at least one week, and more specifically, at least one month or more.

[0030] The product according to the present invention is characterized by comprising gel microparticles or microgels suitable for administration by intramuscular, intravenous, subcutaneous, intra-articular or intraperitoneal injection. The product according to the present invention is characterized by being wholly or partly suitable for administration to the eye, nose, mouth, gastrointestinal tract or vaginal cavity.

[0031] In a further specific embodiment of the product according to the present invention, the gel particles are characterized by having a size in the range of 1 micron to 5 millimeters, specifically in the range of 1 micron to 500 microns. In particular, these particles have a coefficient of variation of size of less than 10%, preferably less than 5%. In the case of non-spherical particles, the above size refers to the Feret diameter.

[0032] A further specific embodiment of the product according to the present invention is characterized in that at least a part of the gel particles is functionalized with one or more compounds selected from the group consisting of nucleic acids (aptamers), proteins and peptides, so as to be capable of interacting with biological cells.

[0033] The gel particles may be biological cell carriers or cell - adhesive microparticles. These particles may contain a surface with a positive charge, for example, due to the presence of a polyelectrolyte such as polylysine. Alternatively, the microparticles may be functionalized with a cell - adhesive (natural) polymer, or a protein such as gelatin (gelatin), collagen, fibronectin or laminin, or a polymer containing a cell - interaction - binding peptide sequence containing arginine - glycine - aspartic acid (RGD), a cell - cadherin - binding peptide sequence containing histidine - alanine - valine (HAV), or a combination of all of the above.

[0034] Gel particles having a size of 10 - 100 microns are particularly suitable for pharmaceutical applications. For food and nutritional purposes, gel particles having a size of 100 - 500 microns may be used. In cosmetics, personal care and agriculture, the gel particles generally have a size of 500 - 5000 microns. However, it should be understood that in any of these application fields, the size of the gel particles can also be selected outside of these ranges as being particularly suitable for a particular application.

[0035] A further specific embodiment of the product according to the present invention is characterized in that the composition comprises at least 50% by volume of the gel particles and at least 10% by weight of the carbohydrate matrix. The volume fraction of the particles is defined as the relative ratio of the total volume of the gel particles when swollen with water in the granular material to the total volume of each granular material.

[0036] A volume fraction exceeding 50% is selected to approach or exceed the random close packing (about 64% v / v), and more specifically, to approach or exceed the maximum packing of non-deformable spheres (about 74% v / v). The volume fraction may particularly be in the range of 50 to 95% v / v, for example, in the range of 60 to 90% v / v, particularly in the range of 75 to 90% v / v. Further, the particles may be elastically deformable. In order to achieve a volume fraction exceeding 74%, the particles may be particularly selected to be deformable. The volume fraction is related to the (physical) properties of the particles. For example, in the case of a granular material containing hard particles, the range of the volume fraction at which the particles can form a product according to the present invention having form retention, i.e., shape stability, may be different from that of another granular material containing weaker particles.

[0037] A further specific embodiment of the product according to the present invention is characterized in that the composition is shaped to form at least a part of a tablet, particularly a tablet having a volume of at least 10 times the average volume of the gel particles. Since such a tablet has a structural gradient and compartments, a pattern of additives is further formed over time.

[0038] In particular, the tablet may include a plurality of compartments, and the composition is shaped into one of the compartments of the tablet. Further, the tablet may be textured or engraved on its surface, and / or the tablet may be manufactured to be cut or divided into separate pieces, particularly by (partially) laser cutting dry tablets. The tablet exhibits a surface texture or a gradient of particle packing, local chemical properties, or local physical properties that facilitate the splitting of the tablet into separate pieces after activation. Specifically, a controlled amount of microgel is contained in each piece.

[0039] In a further specific embodiment, the product according to the invention is characterized in that the formed slurry is cast or molded or coated with an elastomeric compound, in particular polydimethylsiloxane (PDMS), before or after solidification. Such an elastomeric molding or coating functions like a cartridge that captures the composition inside and has the ability to expand with the product while the product is (re)hydrated. The product within the cartridge can be reactivated, in particular hydrated, by introducing an (aqueous) liquid activator through the product and through the channels thus obtained by penetrating the coating. The elastomeric structure may have sufficient permeability such that liquid can enter the internal space and air can flow out.

[0040] In a specific embodiment, the microgel particle slurry may be cast, molded or injected (injected) into a silicone 3D mold. It is then frozen by immersion in liquid nitrogen or by directional freezing on a cold surface. The sample can be dried in a freeze dryer. After drying, the dried microgel tablets are stable in shape, i.e., retain their form and can be removed from the mold. Activation by rehydration with liquid can be done either inside or outside the mold.

[0041] A further specific embodiment of the product according to the invention is characterized in that the composition further comprises a foaming disintegrant, in particular a carbonate compound. Such a foaming agent promotes the disintegration of the product when in contact with a suitable liquid, in particular water, and a gaseous compound, in particular oxygen or carbon dioxide, is generated and released. Specific uses are as food supplements, fragrances or low-fat products, and as cosmetics such as (anhydrous) bath products or facial creams. Specific uses are as pharmaceutical compositions containing active pharmaceutical ingredients, or as agricultural products containing active pesticidal compounds such as (biological) pesticides, or as cosmetics containing microbial compounds, or as fragrance products containing natural fragrance compounds. Another specific use is as an edible product for oral delivery of active compounds such as active pharmaceutical ingredients or nutraceutical ingredients such as probiotic strains.

[0042] A further specific embodiment of the product according to the present invention is characterized in that the composition further comprises a plasticizer, in particular ethanol. The granular composition becomes plastic when a embrittling agent such as ethanol is added.

[0043] The product may be a pharmaceutical in which the gel particles contain a pharmaceutically active agent. These particles may typically have a size of 10 to 100 microns.

[0044] The product may be a beauty product in which the gel particles contain a cosmetic active agent. Such particles may typically have a size of 500 to 5000 microns.

[0045] The product may be a food product in which the gel particles contain a nutritional component or an adjuvant. In this case, the gel particles may typically have a size of 100 to 500 microns.

Brief Description of the Drawings

[0046] Hereinafter, the present invention will be described in more detail with reference to specific embodiments and the accompanying drawings.

[0047]

Figure 1A

Figure 1B

Figure 1C

Figure 1D

Figure 1E

Figure 1F

Figure 2A

Figure 2B

Figure 2C

Figure 2D

Figure 2E

Figure 2F

DETAILED DESCRIPTION OF THE INVENTION

[0048] It should be noted that some of the figures are drawn merely schematically and are not necessarily drawn to the same scale. In particular, certain dimensions are exaggerated somewhat for clarity of features. Throughout the figures, like parts are generally designated by like reference numerals.

[0049] Although a product, compound, composition, formulation, device, method or use has been disclosed and described in this application, it should be understood that the embodiments described below are not limited to a particular product, compound, composition, formulation, device, method or use and may vary. Also, it should be understood that the terms used in this specification are for the purpose of describing particular embodiments only and are not intended to be limiting.

[0050] It should be noted that, as used in this specification and the claims, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an active agent" includes mixtures of two or more such active agents and the like.

[0051] The present invention relates to a method for manufacturing a product having a granular composition in which particles are formed by gel particles, particularly gel microparticles. As used herein, the term "particle" is interchangeable with "sphere", "bead", "pearl" or "capsule", and in particular refers to a particle containing a core surrounded by a hydrophilic gel compound or a polymer network for shielding and / or core encapsulation of a composition.

[0052] The gel particles may contain an active agent or other substances dispersed, dissolved or otherwise distributed therein. The gel particles may, in some cases, have an irregular shape, but generally consist of spherical and substantially uniform particles. The uniform gel particles can have a size (diameter) in the range from submicron to millimeter. In particular, these particles have a coefficient of variation of size of less than 10%, preferably less than 5%. In the case of non-spherical particles, the above size refers to the Feret diameter.

[0053] As used herein, the term "active agent" is interchangeable with "bioactive agent", "cosmetic active agent", "pharmaceutical active agent" or "drug", has biological activity, and is used to treat, diagnose, cure, relieve, prevent (i.e., prophylactically), improve, regulate diseases, disorders, infections, etc. or refers to a drug having other preferred effects. The active agent also includes prodrugs that have biological activity or have higher biological activity after being placed in a given physiological environment.

[0054] Various forms of the active agent that can be released from the gel particles into the adjacent tissue or body fluid can be used. For this purpose, a liquid active agent or a solid active agent can be incorporated into the core of the gel particles described herein. Thus, the active agent may be an acidic salt, a basic salt or an amphoteric salt. In some embodiments, the active agent may be a nonionic molecule, a polar molecule, or a molecular complex capable of hydrogen bonding. The active agent may be included in the gel particles in the form of a non-charged molecule, a molecular complex, a salt, an ether, an ester, an amide, a polymer-drug complex, or other forms that provide effective biological or physiological activity.

[0055] Examples of salts include, when the active agent has a basic group such as an amino group, salts with inorganic acids (also referred to as inorganic free acids) (e.g., carbonic acid, bicarbonic acid, hydrochloric acid, sulfuric acid, nitric acid, boric acid), salts with organic acids (also referred to as organic free acids) (e.g., succinic acid, acetic acid, propionic acid, trifluoroacetic acid), and the like. Examples of salts include, when the active agent has an acidic group such as a carboxyl group, salts with inorganic bases (also referred to as inorganic free bases) (e.g., alkali metals such as sodium and potassium, alkaline earth metals such as calcium and magnesium), salts with organic bases (also referred to as organic free bases) (e.g., organic amines such as triethylamine, basic amino acids such as arginine), and the like. Further, the bioactive peptide may form a metal complex compound (e.g., a copper complex, a zinc complex, etc.).

[0056] Examples of active agents that can be incorporated into the gel particles in this specification include, but are not limited to, biological agents, antioxidants, vitamins, hormones, vaccines, probiotics, prebiotics, antibiotics, enzymes, proteins, fungi, yeasts, bacteria, plant cells, nucleic acids, mammalian cells, and stem cells. In some embodiments, the active agent may be water-soluble or water-dispersible. In some embodiments, the active agent may be soluble or dispersible in a solvent such as an organic solvent or an inorganic solvent. The active agent may be dissolved or dispersed in an aqueous solvent. A non-limiting example of the aqueous solvent is water.

[0057] As used herein, "core" may include a biodegradable and biocompatible polymer, or a lipid that captures, encapsulates, binds, or otherwise contains an agent released in situ. Suitable biodegradable polymers include, but are not limited to, the aforementioned copolymers including polyglycolic acid, poly(D,L-lactic acid), poly(L-lactic acid), poly(D,L-lactide-co-glycolide) (PLGA), poly(aliphatic carboxylic acids), copolyoxalates, polycaprolactone, polydioxanone, poly(orthocarbonates), polyacetals, poly(lactic acid-caprolactone), polyorthoesters, poly(glycolic acid-caprolactone), polyanhydrides, polyphosphazines, or derivatives thereof, or combinations thereof. In some embodiments, the biodegradable polymer includes a block copolymer of a hydrophilic polymer and a hydrophobic polymer.

[0058] The present invention provides a method and composition for extending the shelf life of soft microparticles, particularly hydrogel particles, and a capsule tablet composition that does not require an irreversible annealing process at the time after manufacture and avoids modification of the microparticle material. As a result, the microparticle composition may be rehydrated and then subjected to a plurality of drying cycles. Alternatively, the microparticles may be used or consumed at the time of the first rehydration.

[0059] As an illustrative embodiment, a hydrogel composition was produced according to the present invention. This composition is shown in the sequential processing steps in FIGS. 1A-1F and includes an aqueous solution of a water-soluble carbohydrate compound. In this example, the sugar compound was selected as the carbohydrate compound, i.e., maltodextrin. Spherical calcium alginate microparticles with an average diameter of about 100 microns, prepared with 0.25% w / v sodium alginate in water (Wako, 1% at 80-120 cP) and crosslinked with 0.2 M CaCl2 in water, were immersed in an aqueous solution containing 60% w / v maltodextrin (MDX13-17) in water for 2 hours. FIG. 1A shows a microscopic image of the starting stage of the gel composition according to the present invention.

[0060] For comparison, similar alginate microparticles are immersed in deionized water to obtain a control gel composition. This shadow composition comprises an aqueous gel of 0.25% (w / v) sodium alginate microparticles crosslinked with calcium and immersed in water. This shadow composition is shown in the sequential processing steps in FIGS. 2A - 2F. FIG. 2A shows a microscopic image of the starting stage of the gel composition provided for comparison.

[0061] The compositions at both starting stages are molded to form tablets as shown in FIGS. 1B and 2B respectively. A cup-shaped mold that can receive the slurry with little pressure on the microgel slurry itself was used. Both tablets have a disc shape with a diameter of about 20 millimeters and a thickness of about 5 millimeters. The total volume of each tablet exceeds one million times the average volume of the gel particles.

[0062] The cup containing the microgel slurry is placed upside down on a sieve or strainer with a mesh size smaller than the microgel particles. The slurry is concentrated by removing a portion of the aqueous solution until the microgel / liquid volume fraction is sufficient to obtain a plastic, shape-stable, and gapless slurry. In the case of calcium alginate microparticles, this exceeds a volume fraction of about 74%. Then, the molded product is solidified by immersing it in liquid nitrogen as shown in FIGS. 1C and 2C respectively. In addition to immersing in liquid nitrogen for rapid freezing, the product may be directionally frozen on a cold surface below minus 80 degrees.

[0063] The carbohydrate matrix already in this frozen state provides consistency to the product in FIG. 1C that maintains its shape. The control product in FIG. 2C has already lost some of its consistency. Upon drying, this difference becomes more prominent. As is clear from comparing FIGS. 1D and 2D, the carbohydrate compound forms a carbohydrate amorphous matrix between the gel particles. This carbohydrate lattice and network maintain the shape and consistency of the molded product, i.e., the tablet shown in FIG. 1D. On the other hand, the shadow product lacks such a carbohydrate structure and completely disintegrates into fine particle powder.

[0064] When the dried product is immersed again in a liquid such as water, the rehydrated shadow product (Figure 2E) immediately forms a formless gel slurry, while the product containing the reinforcing carbohydrate matrix (Figure 1E) still maintains its macroscopic shape and integrity as long as the volume fraction of the microparticles usually exceeds about 74%. The latter is the same even at the microscopic scale, as shown in the microscopic images of Figures 1F and 2F respectively. Apparently, the microparticles remain substantially unchanged between the stages in Figures 1A and 1F after undergoing a complete freeze-drying and rehydration cycle. On the other hand, the microparticles in the control composition that have undergone the same processing steps are considerably damaged. When a liquid such as water is further added to the product in Figure 1E and the volume fraction is below the 74%, the macroscopic structure finally collapses into a slurry or dilute suspension of individual microparticles.

[0065] As shown in Figures 1A to 1F, the product according to the present invention can withstand multiple rehydration and drying cycles without substantially affecting the macroscopic shape of the product and the macroscopic integrity of the soft calcium alginate gel particles contained in the product.

[0066] Although the present invention has been described in more detail with reference to only a limited number of embodiments, it should be understood that the present invention is not limited to these embodiments. Those skilled in the art can realize many other embodiments and variations within the scope of the present invention without the need for creative skills or labor.

[0067] Similar results can be obtained when tablets with a total volume at least 10 times the unit volume of the particles are shock-frozen. By rapidly cooling to below -80 degrees on a freezer or freezing surface, it is possible to immerse, mold, freeze, dry, and reconstitute a granular composition composed of hydrogel particle units.

[0068] According to the present invention, products with shapes other than tablets can be manufactured using soft gel microparticles. Even for products with complex geometric shapes, they remain preserved after drying, rehydration, or activation due to the lattice of the reinforcing carbohydrate.

[0069] Similar results are obtained for microgel particles or microgel fibers with different sizes, shapes and / or compositions. In particular, hemispherical microparticles on the order of 1 millimeter can maintain their hemispherical shape after freezing, drying and rehydration. In particular, in order to improve the flexibility and deformability of the product, the microparticles may be immersed in a plasticizer such as a 70% ethanol solution.

[0070] In particular, the rehydrated or reactivated product may deliver a slurry that is extrudable or jetable (3D printing) or injectable (pharmaceutical ingredient) by adding a suitable plasticizer or other embrittling agent. This product may be formed from micron-scale gel particles as a bar having a customized cross-section that fits into the microchannels of a microfluidic device etched or molded in a material such as a polymer such as glass, silicon or PDMS (polydimethylsiloxane). Similarly, such a product may be formed in a column that can be easily (pre)loaded into a syringe for injection purposes.

[0071] The microparticle carbohydrate subunits may include all types of hydrogel beads crosslinked physically (e.g., ionic bonds) and / or chemically (i.e., covalently), and the hydrogel beads include agar, alginic acid, chitosan, dextran, polyethylene glycol, collagen, gelatin, hyaluronic acid, carrageenan, fibroin, fibronectin, polyethylenimine (PLL), cellulose, graphene, polyethyleneimine (PEI), poly(amidoamine) (PAA), dextran sulfate, silk, silk fibroin, pectin, K-carrageenan, ι-carrageenan, gellan gum, guar gum, tragacanth gum, xanthan gum, acacia gum, karaya gum, locust bean gum, or sodium carboxymethyl cellulose (S-CMC). These are all preferably applied as naturally derived materials and / or synthetically derived materials (including recombinant proteins and / or derivatives of these materials), and the polymer network particularly includes a calcium alginate network. As an example, similar results were obtained for 1 - 500 micron 5% (w / v) water-swollen gelatin particles crosslinked by formaldehyde and immersed in 60% maltodextrin (MDX 13 - 17, i.e., the aqueous solution).

[0072] The gel particle subunits can form various morphologies including solid matrices, core / shell capsules, multi-core capsules, compartmentalized capsules, and compartmentalized particles. The gel particles may contain an active agent that is released instantaneously or over time (sustained release) when the product is activated, such as by hydrolysis. The active agent may contain, while being stored in a dry state, an active cosmetic, a beauty agent, a nutritional additive, a dietary supplement, a pharmaceutical active ingredient, a pesticide ingredient, or other ingredients such as a pigment or soy lecithin.

[0073] As an example, the method and capsule according to the present invention may be used in embodiments where the active compound comprises a vitamin selected from the group consisting of at least one vitamin, in particular thiamine, riboflavin, nicotinic acid, pantothenic acid, pyridoxine, biotin, folic acid, cyanocobalamin, lipoic acid, ascorbic acid, lecithin, glycyrrhizic acid, retinol, retinol palmitate, tocopherol, tocopherol acetate, salicylic acid, benzoyl peroxide, azelaic acid and / or derivatives thereof, more specifically ascorbic acid and / or derivatives thereof.

[0074] As another example, the method and capsule according to the present invention may be used in embodiments where the active compound comprises an antioxidant selected from the group consisting of at least one antioxidant, in particular polyphenols, thiol-based components, sulfite esters and derivatives thereof. These active compounds may be used, for example, as nutritional supplements or for pharmaceutical treatment, in which case they are likely to be administered orally. The microparticles and / or microparticle-containing tablets may be formulated to withstand the acidic environment of the human stomach and be digested in the downstream part of the user's gastrointestinal tract to release their contents. Specifically, probiotics and prebiotics may be administered particularly effectively in this way.

[0075] Another use of the microparticles according to the present invention may be in the use in paints, carbon capture, fillers, building materials (concrete), smart materials that respond to pressure and / or temperature.

[0076] In particular, the microparticles may comprise micro gel-capsules containing bioactive compounds such as enzymes, cells, proteins and pharmaceuticals. Mammalian cells, stem cells, yeast, plant seeds, fungi, bacteria or other viable microorganisms can be added to the liquid activator. The carbohydrate spaces between the hydrogel subunits pattern the structure of the diffusion of such living additives.

[0077] The composition or product can be used as an assembly part of a larger granular composition or product, especially for producing multi-component products such as tablets. Also, active agents other than water may be used for the injection and reactivation of products and compositions. By adding an excessive amount of the active agent, the final product may disintegrate. The disintegration time may depend on the macroscopic shape and size of the product and the shape and size of the constituent gel microparticles.

[0078] The uniform mass of the dried tablets may comply with the pharmacopoeial standards for pharmaceutical use. By lyophilizing a mixture of microparticles and an interstitial carbohydrate matrix, a total of 75 tablets of the same size were produced. The microparticles are water-swellable microgels composed of calcium-crosslinked alginic acid (0.25 wt% alginic acid crosslinked with 0.2M CaCl2 in water). The interstitial carbohydrate matrix contains a maltodextrin solution of 60% maltodextrin in water. Twenty-two of these particles were randomly selected and weighed three times with a high-precision weighing scale. None of the tablets had a deviation exceeding 10% from the average mass described in the pharmacopoeial standard for the mass uniformity of plain tablets.

[0079] The product may contain a foaming disintegrant for transporting or releasing one or more active compounds in specific applications, including pharmaceutical effervescent tablets, food applications such as beverages, and health or personal care applications such as bathing. For this purpose, for example, an acid or carbonate compound may be added. The hydrogel particles can function as carriers for active ingredients (such as pharmaceuticals, foods, or cosmetics, etc.) with a controlled passive release profile when activated according to the application while maintaining the shelf life of their properties.

[0080] Functional devices such as sensors and / or actuators may be embedded inside or on the surface of the composition before freezing or after drying. The product may be embedded or encapsulated in an elastomeric matrix such as PDMS to provide a flexible case. The product can be rehydrated within the PDMS case.

[0081] The surface gradient of the product can affect the flow of the liquid added after drying. Also, the gradient of the carbohydrate network or particle properties of the composition within the dried product can affect the flow of the liquid added after drying.

[0082] In particular, the carbohydrate network of the composition can control the capillary flow path of the liquid added after drying.

Claims

1. A product comprising a granular composition for maintaining the shape of gel particles, particularly microgel particles, wherein the composition comprises a solid structure of the gel particles bound together by a substantially dry or dried carbohydrate matrix between the gel particles.

2. The product according to claim 1, characterized in that the carbohydrate matrix is ​​water-soluble.

3. The product according to claim 1, characterized in that the carbohydrate matrix comprises an amorphous matrix of at least one polycarbohydrate or polysaccharide compound, and more specifically, the polycarbohydrate or polysaccharide compound comprises at least one sugar compound.

4. The product according to claim 3, characterized in that the sugar compound comprises dextran, dextrin, maltodextrin, trehalose, lactose, glucose, dextrose, saccharose, fructose, maltose, isomaltose, sorbitol, mannitol, lactitol, xylitol and / or erythritol.

5. The product according to claim 1, characterized in that the gel particles include a hydrogel, more specifically, a hydrophilic polymer network.

6. The product according to claim 5, wherein the hydrogel comprises one or more polysaccharides selected from agar, alginic acid, chitosan, dextran, polyethylene glycol, collagen, gelatin, hyaluronic acid, carrageenan, fibroin, fibronectin, polyelulysine (PLL), cellulose, graphene, polyethyleneimine (PEI), poly(amideamine) (PAA), dextran sulfate, silk, silk fibroin, pectin, K-carrageenan, rotacarrageenan, gellan gum, guar gum, tragacanth gum, xanthan gum, acacia gum, karaya gum, locust bean gum, or sodium carboxymethylcellulose (S-CMC).

7. The product according to claim 5, characterized in that the hydrogel contains a compound from the group consisting of calcium alginate, gelatin, hyaluronic acid, collagen, and chitosan.

8. The product according to claim 5, characterized in that the gel particles include a crosslinked alginate network or an interpenetrating alginate network, particularly a calcium crosslinked alginate network.

9. The product according to claim 1, characterized in that the gel particles include microcapsules having a core surrounded by a hydrophilic polymer network.

10. The product according to claim 9, wherein the core comprises at least one biologically, pharmaceutically, and / or cosmetically active or activatable material from the group consisting of biological agents, antioxidants, vitamins, hormones, vaccines, microbiotics, probiotics, prebiotics, antibiotics, enzymes, proteins, fungi, yeasts, bacteria, plant cells, mammalian cells, and stem cells.

11. The product according to claim 9, characterized in that the microcapsule has a fluid core.

12. The product according to claim 9, characterized in that the microcapsule has a core that is at least partially solid, and in particular has a core that is substantially completely solid.

13. The product according to claim 12, wherein the core, which is at least partially solid, comprises a biodegradable material, particularly a biodegradable material, and more specifically, comprises a polymer, the polymer being selected from the group comprising polylactic acid (PLA), polyglycolic acid (PGA), poly(ε-caprolactone) (PCL), lactic acid-glycolic acid copolymer (PLGA), and modifications thereof, particularly block copolymers containing polyethylene glycol (PEG) as one of the blocks, more specifically, PEG-PLA, PEG-PLGA, PEG-PGA, or PEG-PCL.

14. The product according to claim 12, characterized in that the core comprises a mixture of a hydrophobic material and a hydrophilic material, and in particular, at least one of the materials is heterogeneously distributed throughout the core.

15. The product according to claim 1, characterized in that at least a portion of the gel particles are functionalized with one or more compounds selected from the group including nucleic acids (aptamers), proteins, and peptides, thereby enabling interaction with biological cells.

16. The product according to claim 1, characterized in that the gel particles are a biological cell carrier or cell-adhering microparticles.

17. The product according to claim 1, characterized in that the gel particles have a size in the range of 1 micron to 5 millimeters, specifically in the range of 1 micron to 500 microns.

18. The product according to claim 17, characterized in that the gel particles contain a pharmaceutically active compound and have a size of 10 to 100 microns, and / or the particles contain a nutrient or auxiliary agent and have a size of 100 to 500 microns, and / or the gel particles contain a cosmetic surfactant and have a size of 500 to 5000 microns.

19. The product according to claim 1, characterized in that the composition comprises at least 50 volume% of the gel particles and at least 10% by weight of the carbohydrate matrix.

20. The product according to claim 1, characterized in that the composition is molded to form at least a portion of tablets, particularly tablets whose volume is at least 10 times the average volume of the gel particles.

21. The product according to claim 20, wherein the tablet comprises a plurality of compartments, and the composition is molded into one of the compartments of the tablet.

22. The product according to claim 1, characterized in that the molded slurry is coated with an elastomer compound, particularly polydimethylsiloxane (PDMS), before or after solidification.

23. The product according to claim 1, characterized in that the composition further comprises a foaming disintegrant, particularly a carbonate compound.

24. The product according to claim 1, characterized in that the composition further comprises a plasticizer or other embrittlement agent, particularly ethanol.

25. A pharmaceutical product comprising a product of the type described in any one of claims 1 to 24, wherein the gel particles contain a pharmaceutically active agent.

26. A beauty product comprising a product of the type described in any one of claims 1 to 24, wherein the gel particles contain a cosmetic surfactant.

27. A food product comprising a product of the type described in any one of claims 1 to 24, wherein the gel particles contain nutritional components or supplements.

28. A method for producing a solid product containing a granular composition of gel particles, particularly microgel particles, A method comprising forming an aqueous slurry containing the gel particles and a water-soluble carbohydrate compound, molding the slurry into a product, particularly molding, and more specifically compressing, dehydrating and solidifying the molded slurry containing the gel particles and the water-soluble carbohydrate compound to form the product.

29. The method according to claim 28, wherein the water-soluble carbohydrate compound comprises at least one polycarbohydrate or polysaccharide compound.

30. The method according to claim 29, wherein the polycarbohydrate or polysaccharide compound comprises at least one sugar compound.

31. The method according to claim 30, wherein the sugar compound comprises dextran, dextrin, maltodextrin, trehalose, lactose, glucose, dextrose, saccharose, fructose, maltose, isomaltose, sorbitol, mannitol, lactitol, xylitol and / or erythritol.

32. The method according to any one of claims 28 to 31, wherein the molded slurry is solidified by drying, more specifically by freeze-drying, which removes at least substantially the aqueous contents of the molded slurry.

33. The method according to claim 32, wherein the slurry is shaped to form at least a portion of a tablet before drying.

34. The method according to claim 33, wherein the tablet comprises a plurality of compartments, and the composition is molded into one of the compartments of the tablet.

35. The method according to any one of claims 28 to 31, wherein the slurry is molded by molding, printing with additive materials, or extrusion before solidification.

36. Gel particles, especially microgels A process for forming a slurry containing a granular composition of particles, A process characterized by providing a solid product according to any one of claims 1 to 24, and exposing the product to a liquid activator.

37. The process according to claim 36, characterized in that an aqueous liquid surfactant is used to hydrate the product.

38. The process according to claim 37, characterized in that the aqueous liquid surfactant comprises an aqueous carbohydrate solution.

39. The process according to claim 36, characterized in that at least one biologically active or activatable material from the group including mammalian cells, stem cells, fungi, yeasts, bacteria, and plant seeds is added to the liquid activator.

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