Product comprising conformal particulate composition of gel particles, method of making same, and process of forming particulate slurry

Abstract

Products comprising a conformal particulate composition of gel particles, methods of making the same, and processes of forming a particulate slurry. The product comprises a particulate composition of gel particles, in particular microgel particles. The composition comprises a carbohydrate matrix (lattice / network) between cells containing the gel particles. A method of making such a product of a particulate composition comprising gel particles, in particular microgel particles, comprises forming an aqueous slurry comprising the gel particles and a water-soluble carbohydrate. The slurry is shaped into the product, and the shaped slurry is cured.

Description

Technical Field

[0001] The present invention relates to a product comprising a conformal granular composition of gel particles, in particular microgel particles. The invention also relates to a method for making such a solid product and a process for forming a granular slurry comprising gel particles. In this respect, it should be noted that the present invention particularly relates to gel particles surrounded and confined by a hydrophilic polymer network. In this respect, gel refers to a hydrogel composition comprising a (hydrophilic) polymer network, which network may contain a significant amount of water, for example more than 50% by weight of water, typically even more than 90% by weight of water. Background Art

[0002] Gel particles are present in countless products and markets, including food, life sciences, and cosmetics. Forming products and devices containing such gel particles typically involves the use of a binder or dispersing them in a continuous medium. Known microgel particles include microcapsules that contain a fluid core surrounded by a shell made from a hydrogel. These hydrogel gel particles are produced under aqueous conditions and contain a relatively high concentration of aqueous medium, which can be as high as over 90%. Since activation and degradation of the gel particles and / or their contents typically occur in an aqueous environment, this leads to shelf life challenges. Therefore, there is a need to preserve the gel particle compositions and their ingredients.

[0003] The storage of gel particles can be affected by the wet or dry state. For wet storage, one or more additives can be added, which prevent or at least delay the reactivity of the particles and their contents. Examples of such storage additives are, for example, ethanol, saline solutions and parabens. However, the addition of these compounds may cause unexpected side effects in terms of health and environment, and may also damage the properties of the gel particles. In addition, wet storage usually leads to liquid emulsions or soft particle aggregates, which limits mechanical robustness, limits the ability to provide a predetermined amount of material in a single step, and prevents the ability to present particle aggregates in a clear macroscopic shape.

[0004] In the case of dry storage, substantially all of the water can be removed from the gel particle composition. Examples of this process are solvent evaporation and freeze drying. Removing water from a gel particle composition without affecting the original shape or properties of the gel particles has proven to be challenging. The formation of water crystals during the freezing process, or the stress imposed on the gel particles by the sublimation process during the solvent evaporation process, is often sufficient to deform them and / or damage the macrostructure, its integrity and contents. Therefore, the gel particle material needs to be optimized to withstand the storage process, which places restrictions 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, as well as the removal of any liquid contents during the drying step, to achieve dry storage.

[0005] In order to enable the gel particles to be preserved in a dry state, it is known that the composition of the particles can be changed during the production process. For example, crosslinkable parts can be included in the chemical composition, which irreversibly maintain the shape of the gel particles. However, this requires additional steps, such as treating the particles with harmful crosslinking chemicals (such as glutaraldehyde or formalin, etc.), or photo-induced crosslinking of the acrylate parts by ultraviolet (UV) light radiation. In addition, exposure of the composition and UV light may damage the components in the gel particles. In addition, UV exposure is an in-situ process, which needs to be carried out separately during the production process or in a relatively small volume of the composition that is limited by the maximum light penetration depth. In addition, this process is irreversible and leads to a more rigid composition, which may be incompatible with 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 crosslinking is generally stronger than other types of bonds (e.g., ionic crosslinking) and can make the gel particles strong enough to withstand freeze drying. However, the introduction of covalent crosslinking moieties (e.g., methacrylate (MA) or dialdehyde (DA) groups) chemically complicates the production process and increases production costs.

[0007] Another problem is to maintain the macrostructure, i.e. the shape, of the product cast from the granular particulate composition. The formation of such products usually involves compression of the dry granules to the point of irreversible agglomeration (standard tablet compression) or freeze drying of the composition. Thus, the macrostructural shape is maintained, but only part of the constituent properties of the granules, such as flavor, texture and / or active ingredient, are retained. During the compression process, the shape of the granules may undergo irreversible changes, such as their collapse, cracking or plastic deformation.

[0008] Furthermore, this preservation method can only be performed once, and the structure tends to collapse upon (re)hydration. The latter is widely used as a method for dissolving tablets. However, refreezing or compressing a composition containing flexible gel particles does not produce the same results when (re)hydrated. With each (re)hydration cycle, the properties tend to shift to a solution containing randomly shaped gel particles, rather than their initial form when produced.

[0009] Sintering a composition having a carbohydrate phase can improve the shape retention of individual particles. However, sintering is an irreversible process and the particles are usually bound by sintering. As a result of this process, the product loses its ability to unjam and the system can no longer return to a granular suspension state. Summary of the invention

[0010] One of the objects of the present invention, among others, is to provide a product comprising a granular composition comprising, in particular essentially consisting of, gel particles, which product meets the above-mentioned limitations since it allows multiple storage and (re)hydration cycles while substantially maintaining its shape and compositional properties.

[0011] To achieve this object, according to the invention, a product of the type mentioned in the opening paragraph is characterized in that the composition comprises a solid structure of gel particles which are bound to one another via a substantially dry or dry carbohydrate matrix between the gel particles.

[0012] Thus, the present invention provides a carbohydrate interstitial matrix that provides a binding structure between the gel particles, thereby holding the gel particles together. Thus, the carbohydrate layer provides conformal consistency and structure to the final product. The carbohydrate matrix responsible for this structural cohesion provides this structural support to the product and provides an interstitial protective barrier for the individual gel particles captured in the structure. In particular, the total water (moisture) content of the dried conformable product is less than 50% by weight, more particularly less than 15% by weight, even more particularly less than 10% by weight, even more particularly less than 5% by weight.

[0013] In particular, the product maintains the shape and size of the gel particles while also retaining their macroscopic shape, particularly during freeze drying and (re)hydration. In the dry state, because the product behaves as a solid material, it can be easily manipulated, e.g. transported, packaged, managed or cut into small pieces. However, it also allows multiple freeze drying cycles without any loss of properties on both scales. In particular, the present invention enables long-term storage and transportation of tablets composed of materials that could not previously be freeze dried without compromising the properties and / or integrity of the product, particularly the gel particles captured therein, under ambient conditions.

[0014] In this context, it should be noted that the terms hydration or rehydration used in this application may refer to aqueous solutions as well as non-aqueous solutions or liquids. These expressions may also be used interchangeably with terms such as activation and reactivation or moistening and remoistening.

[0015] In another aspect of the present invention, a method for manufacturing a solid product of a granular composition comprising gel particles (especially microgel particles) is characterized in that an aqueous slurry comprising the gel particles and a water-soluble carbohydrate is formed, wherein the slurry is shaped, especially molded, and more especially compressed into the product, and the shaped slurry comprising the gel particles and the water-soluble carbohydrate is dehydrated and solidified to form the product.

[0016] In a specific embodiment, the method according to the invention is characterized in that the shaping is solidified by at least substantially removing the water content of the shaping, in particular by drying, more in particular by freeze drying. In particular, the total water (moisture) content of the solidified and dried product is less than 50% by weight, more in particular less than 15% by weight, even more in particular less than 10% by weight, even more in particular less than 5% by weight.

[0017] Although a number of techniques may be used to shape the slurry into the product, another embodiment of the method according to the invention is characterized in that the slurry is shaped by molding, additive printing or extrusion before solidification.

[0018] By using a liquid activator which dissolves or disperses the carbohydrate lattice structure, it is possible to obtain again a substantially unchanged original slurry. To this end, the process according to the invention for forming a slurry of a granular composition comprising gel particles, in particular microgel particles, is characterized in that a product according to the invention is provided and is subjected to a liquid activator.

[0019] A preferred embodiment of the product according to the invention is characterized in that the carbohydrate matrix is ​​water-soluble. Being water-soluble, the carbohydrate matrix can be decomposed simply by (re)hydration with an aqueous liquid activator. By using tap water or an aqueous solution as a hydrating agent, a slurry is obtained that is compatible with many industrial applications, including applications in the cosmetics industry, the food industry, the nutraceutical industry or the pharmaceutical industry, such as edible compounds for oral drug delivery or active substance (e.g. vitamins or probiotics / antibiotics) intake.

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

[0021] Therefore, according to a preferred embodiment of the process for forming a slurry of the present invention, it is characterized in that the aqueous liquid activator comprises an aqueous carbohydrate solution, in particular a polycarbohydrate or polysaccharide solution, more particularly a sugar solution, even more particularly an aqueous solution of dextran, dextrin, maltodextrin, trehalose, lactose, glucose, dextrose, sucrose, fructose, maltose, isomaltose, sorbitol, mannitol, lactitol, xylitol and / or erythritol. This carbohydrate solution can be re-set in the composition as a reinforcing matrix when the slurry is solidified once, for example by drying, in particular freeze drying. This can allow multiple (re)hydration cycles while at least substantially retaining the initial properties of the slurry composition, in particular the initial properties of the gel particles contained therein.

[0022] According to another embodiment of the product of the present invention, it is characterized in that the gel particles comprise a hydrogel, more particularly a hydrophilic polymer network, more particularly, the hydrogel comprises one or more polysaccharides selected from the group consisting of agar, alginate, chitosan, dextran, poly(ethylene glycol), collagen, gelatin, hyaluronic acid, carrageenan, silk protein, fibronectin, poly-l-lysine (PLL), cellulose, graphene, polyethyleneimine (PEI), polyamidoamine (PAA), dextran sulfate, silk, silk protein, pectin, K-carrageenan, lota carrageenan, gellan gum, guar gum, tragacanth gum, xanthan gum, gum arabic, karaya gum, locust bean gum or sodium carboxymethylcellulose (S-CMC). All of these materials are preferably used as materials of natural origin and / or materials of synthetic origin, including recombinant proteins and / or derivatives of these materials, wherein the polymer network particularly comprises a calcium alginate network. Another embodiment of the method and capsule has achieved particularly successful results in this respect, wherein the gel particles comprise a crosslinked or interpenetrating alginate network, in particular a calcium crosslinked alginate network.

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

[0024] The core may comprise at least one active, pharmaceutical, cosmetic, biologically active or activatable material selected from the group consisting of: biologics, antioxidants, vitamins, hormones, vaccines, microbiota, probiotics, prebiotics, nucleic acids, antibiotics, enzymes, proteins, fungi, yeasts, bacteria, plant cells, mammalian cells and stem cells, or other active compounds that are preferably isolated from the environment to preserve them, i.e. prevent or reduce their activation and increase their shelf life or useful life.

[0025] In one embodiment, the microcapsules may have a fluid core. The fluid core may comprise a mixture of immiscible liquids, such as a water-in-oil emulsion or an oil-in-water emulsion. The fluid core may comprise at least one liquid that is predominantly immiscible with water, in particular an oil, in particular a liquid selected from essential oils, macerated oils and / or essential oils or waxes, which, in addition, adds advantageous, pleasant organoleptic properties to the product. Examples of suitable organic lipophilic compounds are, for example:

[0026] - vegetable oils, for example sunflower oil, corn oil, castor oil, palm oil, coconut oil, avocado oil, sweet almond oil, and tamanu oil, lanolin, sesame oil, olive oil, jojoba oil, soybean oil, cottonseed oil, rapeseed oil, peanut oil, linseed oil, borage oil and vegetable oil derivatives,

[0027] -Essential oils such as helichrysum, lavender, German chamomile, orange blossom, peppermint oil, rosemary, rose oil, tea tree oil, dwarf pine, juniper berry, roasted chestnut extract, birch leaf extract, hay seed extract, ethyl acetate, camphor, menthol, rosemary extract, eucalyptus oil,

[0028] - Impregnation oil,

[0029] - fatty acids, such as stearic acid, palmitic acid, behenic acid, myristic acid, lauric acid and capric acid,

[0030] - fatty acid derivatives, for example fatty acid esters with short-chain alcohols, such as isopropyl myristate, isopropyl palmitate and isopropyl stearate and dibutyl adipate; medium-chain and long-chain fatty acids and their esters with polyols, such as propylene glycol;

[0031] - animal oils, such as tallow and marine oils, such as fish oil and algae oil, or mixtures thereof;

[0032] - nut oils, seed oils, waxes such as paraffin, carnauba, candelilla, beeswax, microcrystalline wax, ozokerite; and

[0033] -Triglycerides.

[0034] In another embodiment, the microcapsule has a core that is at least partially solid. The completely solid or partially solid core may comprise a mixture of hydrophobic and hydrophilic materials. In one embodiment, the hydrophilic material is non-uniformly distributed in the hydrophobic core, more specifically, the mixture comprises pockets of the hydrophilic material in the hydrophobic material, or the mixture comprises pockets of the hydrophobic material in the hydrophilic material.

[0035] In another specific embodiment, the at least partially solid core comprises a degradable (especially biodegradable) material, especially a polymer selected from the group consisting of poly(lactic acid) (PLA), poly(glycolic acid) (PGA), poly(ε-caprolactone) (PCL), poly(lactic-co-glycolic acid) (PLGA), trimethylene carbonate (TMC), and modifications of these materials, especially block copolymers comprising poly(ethylene glycol) (PEG) as one of the blocks, more especially PEG-PLA, PEG-PLGA, PEG-PGA or PEG-PCL. Other materials are polyorthoesters (POE), especially fourth generation POE (POE IV).

[0036] In another specific embodiment, a sustained release composition is provided according to this product of the present invention, releasing a bioactive agent. More specifically, the at least partially solid core can degrade under physiological conditions, more specifically, partially or completely degraded by hydrolysis. The degradation can be the result of overall erosion or surface erosion. By hydrolysis in an aqueous environment, the core will be eroded, thereby releasing the active agent captured therein.

[0037] In another specific embodiment, the degradation results in the release of one or more active agents from the core, more specifically, the degradation results in the delivery of the active agents to the surrounding environment. The degradation and / or the delivery can occur in a timely and controlled manner, specifically over a period of at least one day, more specifically over a period of at least one week, more specifically over a period of at least more than one month.

[0038] The product according to the present invention is characterized in that the product comprises gel particles or microgels suitable for administration by intramuscular, intravenous, subcutaneous, intraarticular or intraperitoneal injection. The product according to the present invention is characterized in that the product is completely or partially suitable for administration to the eyes, nose, mouth, gastrointestinal tract or vaginal cavity.

[0039] Another embodiment of the product according to the invention is characterized in that the size of the gel particles is between 1 μm and 5 mm, in particular between 1 μm and 500 μm. In particular, the coefficient of variation of the size of these particles is less than 10%, preferably less than 5%. In the case of non-spherical particles, the above-mentioned sizes refer to their Feret diameter.

[0040] According to another embodiment of the product of the present invention, it is characterized in that at least part of the gel particles are capable of interacting with biological cells, in particular by being functionalized with one or more compounds selected from nucleic acids (aptamers), proteins and peptides.

[0041] The gel particles may be biological cell carriers or cell adhesion microparticles. These particles may have a positively charged surface, for example, due to the presence of a polyelectrolyte (e.g., poly-l-lysine). Alternatively, the microparticles may contain cell adhesion (natural) polymers or proteins, such as gelatin, collagen, fibronectin or laminin, or polymers partially functionalized by cell adhesion, such as cell integrin binding peptide sequences containing arginine-glycine-aspartic acid (RGD) or cell cadherin binding peptide sequences containing histidine-alanine-valine (HAV), or a combination of all of the above.

[0042] Gel particles with a size between 10 and 100 μm are particularly suitable for pharmaceutical applications. For food and nutritional purposes, gel particles with a size between 100 and 500 μm can be used. In cosmetics, personal care and agriculture, the size of the gel particles is usually between 500 and 5000 μm. However, it should be understood that in any of these application areas, the size of the gel particles outside these ranges can also be selected, especially to suit a specific application.

[0043] According to another embodiment of the product of the invention, it 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 total volume of the gel particles in the granular material when swollen in water relative to the total volume of the corresponding granular material.

[0044] The volume fraction of more than 50% is particularly selected to approach or even exceed the volume fraction of random close packing (about 64% v / v), in particular to approach or even exceed the maximum packing of non-deformable spheres (about 74% v / v). In particular, the volume fraction can be in the range of 50-95% v / v, for example in the range of 60-90% v / v, in particular in the range of 75-90% v / v. In addition, the particles can be elastically deformable. In order to achieve a volume fraction of more than 74%, deformable particles can be particularly selected. The volume fraction is related to the (physical) properties of the particles. For example, the particles can form a conformal (i.e. shape-stable) product according to the present invention, and its volume fraction range can be different for a granular material comprising rigid particles and another granular material comprising weaker particles.

[0045] According to another embodiment of the product of the present invention, it is characterized in that the composition is shaped to form at least a portion of a tablet, in particular at least a portion of a tablet having a volume at least ten times the average volume of the gel particles. Such tablets may have structural gradients and compartments, resulting in further patterning of the additive over time.

[0046] In particular, the tablet may comprise a plurality of compartments, and the composition is formed into one of the compartments of the tablet. In addition, a texture or engraving may be performed on the tablet surface, and / or the tablet may be prepared to be cut or broken into different small pieces, in particular by (partial) laser cutting of a dried tablet. The tablet may exhibit a surface texture or gradient of particle accumulation, local chemical or local physical properties to facilitate the separation of the tablet into different small pieces after activation. In particular, each small piece contains a controlled amount of microgel.

[0047] In another embodiment, the product according to the invention is characterized in that the shaped slurry is cast or molded in an elastomeric compound before or after curing, or is coated with an elastomeric compound, in particular cast or molded in polydimethylsiloxane (PDMS) or is coated with polydimethylsiloxane. This elastomeric molding or coating acts like a barrel, which can capture the composition inside and can expand with the product when the product is (re)hydrated. The product in the barrel can be reactivated, in particular hydrated, by penetrating the coating and introducing a (aqueous) liquid activator through the channels thus obtained. The elastomeric structure can be sufficiently porous to allow air to flow out when the liquid enters the inner space.

[0048] In another embodiment, the microgel particle slurry can be cast, or otherwise formed or injected into a silicone 3D mold. It is then frozen by immersion in liquid nitrogen, or placed on a cold surface to freeze by directional freezing. The sample can be dried in a freeze dryer. After drying, the dried microgel tablet is shape-stable, i.e., conformal, and can be removed from the mold. Activation by liquid rehydration can be performed inside or outside the mold.

[0049] According to another specific embodiment of the product of the present invention, it is characterized in that the composition also comprises an effervescent disintegrant, particularly a carbonate compound. This effervescent agent, when in contact with a suitable liquid (particularly water), can promote product decomposition, while producing and escaping gaseous compounds, particularly oxygen or carbon dioxide. Specific applications are as food supplements, flavorings or fat-reducing products, and in cosmetics, such as (anhydrous) bath products or face creams. Specific applications also include as pharmaceutical preparations containing active pharmaceutical ingredients, agricultural products containing active agricultural chemical compounds (such as (biological) pesticides), cosmetics containing microbial compounds, or aromatic products containing natural aromatic compounds. Another specific application is as an edible product for oral delivery of active compounds (such as active drugs or nutrients, such as probiotic strains).

[0050] According to another specific embodiment of the product of the present invention, it is characterized in that the composition further comprises a plasticizer, in particular ethanol. After adding a weakening agent such as ethanol, the granular composition can become ductile.

[0051] The product may be a pharmaceutical product, wherein the gel particles contain a pharmaceutically active agent. The size of these particles is typically between 10 and 100 μm.

[0052] The product may be a cosmetic product, wherein the gel particles comprise a cosmetically active agent. The size of these particles is typically between 500 and 5000 μm.

[0053] The product may be a food product, wherein the gel particles contain a nutritional ingredient or a supplement. In this case, the size of the gel particles may typically be between 100 and 500 μm. BRIEF DESCRIPTION OF THE DRAWINGS

[0054] Hereinafter, the present invention will be described in further detail with reference to specific embodiments and accompanying drawings. In the accompanying drawings:

[0055] Figure 1 A-1F is a micrograph of the device and composition according to the present invention at a subsequent processing stage;

[0056] Figure 2 A-1F is a micrograph of a shadow device and composition according to the prior art at a subsequent processing stage.

[0057] It should be noted that some of the drawings may be purely schematic and are not necessarily drawn to the same scale. In particular, some dimensions may be more or less exaggerated in order to facilitate the clarity of any feature. Similar parts are generally indicated by the same reference numerals in all the drawings. DETAILED DESCRIPTION

[0058] Before any product, compound, composition, formulation, device, method or use is disclosed and described in this application, it should be understood that the aspects described below are not limited to specific products, compounds, compositions, formulations, devices, methods or uses, as they can certainly vary. It should also be understood that the terminology used herein is only for the purpose of describing specific aspects and is not intended to be limiting.

[0059] It must be noted that, as used in the specification and the appended 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 a mixture of two or more such agents, etc.

[0060] The present invention relates to a method for preparing a product having a granular composition, the granules of which are formed by gel particles, particularly microparticles of gel. The term "particle" as used herein is used interchangeably with "sphere", "bead", "beads" or "capsules", and particularly refers to a particle comprising a core surrounded by a barrier polymer network and / or a core-constraining polymer network of a hydrophilic gel compound or composition.

[0061] The gel particles may contain an active agent or other substance dispersed, dissolved or otherwise distributed therein. The gel particles are usually composed of substantially uniform spherical particles, although sometimes the gel particles may be irregularly shaped. The size range (diameter) of the uniform gel particles may be from submicron to millimeter. In particular, the coefficient of variation of the size of these particles is less than 10%, preferably less than 5%. For non-spherical particles, the above sizes refer to their Feret diameters.

[0062] As used herein, the term "active agent" is used interchangeably with "biologically active agent," "cosmetic active agent," "pharmaceutically active agent," or "drug," and refers to an agent that has biological activity and is used to treat, diagnose, cure, alleviate, prevent (i.e., prophylactically), ameliorate, regulate, or produce other beneficial effects on diseases, disorders, infections, etc. Active agents also include prodrugs that become biologically active or more biologically active after being placed in a predetermined physiological environment.

[0063] Various forms of active agents can be used, which can be released from gel particles into adjacent tissues or fluids. For this reason, liquid or solid active agents can be incorporated into the core of the gel particles described herein. Therefore, the active agent can be an acidic, alkaline or amphoteric salt. In some embodiments, the active agent can be a nonionic molecule, polar molecule or molecular complex that can form a hydrogen bond. The active agent can be included in the gel particles in the form of, for example, uncharged molecules, molecular complexes, salts, ethers, esters, amides, polymer drug conjugates (conjugate) or other forms to provide effective biological or physiological activity.

[0064] Examples of salts include, when the active agent has a basic group (e.g., 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, etc.) or organic acids (also referred to as organic free acids) (e.g., succinic acid, acetic acid, propionic acid, trifluoroacetic acid, etc.), etc., or the like. Examples of salts include, when the active agent has an acidic group (e.g., 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, etc.) or organic bases (also referred to as organic free bases) (e.g., organic amines such as triethylamine, basic amino acids such as arginine), etc., or the like. In addition, physiologically active peptides can form metal complex compounds (e.g., copper complexes, zinc complexes, etc.).

[0065] Examples of active agents that can be incorporated into the gel particles of this invention include, but are not limited to, biologics, antioxidants, vitamins, hormones, vaccines, microorganisms, probiotics, prebiotics, antibiotics, enzymes, proteins, fungi, yeasts, bacteria, plant cells, nucleic acids, mammalian cells, and stem cells. In some embodiments, the active agent can be water-soluble or water-dispersible. In some embodiments, the active agent can be soluble or dispersed in a solvent (e.g., an organic solvent or an inorganic solvent). The active agent can be dissolved or dispersed in an aqueous solvent. A non-limiting example of an aqueous solvent is water.

[0066] As used herein, a "core" may include a biodegradable and biocompatible polymer or lipid that captures, encapsulates, binds or otherwise contains an active agent to be released on site. Suitable biodegradable polymers include, but are not limited to, poly(glycolic acid), poly(d,l-lactic acid), poly(l-lactic acid), copolymers of the foregoing, including poly(d,l-lactic-co-glycolic acid) (PLGA), poly(aliphatic carboxylic acids), copolyoxalates, poly(caprolactone), poly(dioxanone), poly(o-carbonate), poly(acetal), poly(lactic-caprolactone), polyorthoesters, poly(glycolic-caprolactone), polyanhydrides and polyphosphazenes or derivatives thereof, or combinations thereof. In some embodiments, the biodegradable polymer comprises a block copolymer of a hydrophilic and a hydrophobic polymer.

[0067] The present invention provides a method and composition for increasing the shelf life of soft microparticles, particularly hydrogel microparticles, and capsule tablet compositions, which do not require irreversible annealing of them at a point after production, thereby avoiding modification of the microparticle material. As a result, the microparticle composition can be rehydrated and subsequently dried again for multiple cycles. Alternatively, the microparticles can be used or consumed upon first rehydration.

[0068] As an illustrative embodiment, a hydrogel composition is prepared according to the present invention. The composition is Figure 1 A-1F is shown in the continuous processing stage, and contains an aqueous solution of a water-soluble carbohydrate. In this example, a carbohydrate is selected as a saccharide, namely maltodextrin. Spherical calcium alginate microparticles are made by cross-linking 0.25% w / v sodium alginate (Wako, 1% 80-120 cP) in water with 0.2M CaCl2 in water, with an average diameter of about 100 μm, and are injected into the above-mentioned aqueous solution containing 60% w / v maltodextrin (MDX1317) for 3 hours. Figure 1 A shows a microscopic image of the initial stage of the gel composition according to the invention.

[0069] For comparison, similar alginate microparticles were injected into demineralized water to provide a control gel composition. This shadow composition contained a hydrogel of 0.25% (w / v) sodium alginate microparticles cross-linked with calcium and injected into water. Figure 2 A-2F is shown in the sequential processing stages. Figure 2 A shows a microscopic image of the initial stage of this gel composition for comparison.

[0070] The two starting gel compositions were molded separately to form tablets, respectively. Figure 1 B and 2B. A cup-shaped mold was used to receive the microgel slurry without applying any stress to the slurry itself. Both tablets were disc-shaped with a diameter of about 20 mm and a thickness of about 5 mm. The total volume of each tablet exceeded one million times the average volume of the gel particles.

[0071] The cup containing the microgel slurry is inverted onto a screen or sieve with mesh size smaller than the microgel particles. The slurry is concentrated by removing part of the aqueous solution until a sufficiently high microgel / liquid volume fraction is reached to produce a ductile, shape-stable, and tightly packed slurry. For calcium alginate microparticles, the volume fraction is above about 74%. The molded product is then cured by immersion in liquid nitrogen, as shown in FIG. Figure 1 C and 2C. In addition to this rapid freezing by immersion in liquid nitrogen, the product can also be directionally frozen on a cold surface at temperatures below -80°C.

[0072] Already in this frozen state, the carbohydrate matrix is ​​responsible for maintaining its shape Figure 1 The product of C provided consistency. The control product of 2C had lost some of its consistency. After drying, this difference became even more pronounced. Figure 1 It is clear from the comparison between D and 2D that the carbohydrate forms a carbohydrate amorphous matrix between the gel particles. This carbohydrate lattice and network maintains the shape and consistency of the molded product, i.e. Figure 1 Tablets shown in D. On the other hand, the shadow product lacks such a carbohydrate structure and completely disintegrates into a microparticle powder.

[0073] The dried product is injected into a liquid (e.g. water) again, and the rehydrated shadow product ( Figure 2 E) immediately forms an unshaped gel slurry, while products containing an enhanced carbohydrate matrix ( Figure 1 E) still retains its macroscopic shape and integrity. The latter is also true at the microscopic scale, as Figure 1 F and 2F. Obviously, after a complete freeze-drying and rehydration cycle, the microparticles Figure 1 The microparticles in the control composition that underwent the same treatment steps were severely damaged. Figure 1 If more liquid, such as water, is added to the product E, when its volume fraction drops below the 74%, the macrostructure will eventually break down into a slurry or dilute suspension of individual particles.

[0074] It has been shown that Figure 1 As shown in A-1F, the product according to the present invention can be repeatedly subjected to multiple rehydration and drying cycles without substantially affecting the macroscopic shape of the product or the microscopic integrity of the soft calcium alginate-gel particles contained therein.

[0075] Although only with reference to limited number of embodiments to explain the present invention in more detail, it should be understood that the present invention is not limited to these embodiments. For the skilled person, on the contrary, many other embodiments and changes are feasible within the scope of the present invention without requiring any creative skills or labor.

[0076] Similar results were obtained by rapid freezing of tablets having a total volume at least 10 times the volume of the particle units. It appears that particulate compositions consisting of hydrogel particle units can be injected, molded, frozen, dried, and reconstituted by rapid cooling to below -80°C in a freezer or on a freezing surface.

[0077] According to the present invention, products in other shapes than tablets can be produced by soft microscopic gel particles. Due to the reinforced carbohydrate lattice, even products with complex geometries can be preserved after drying and rehydration or activation.

[0078] Similar results can be obtained using microgel particles or microgel fibers of different sizes, shapes and / or compositions. In particular, hemispherical microparticles of the order of 1 mm are able to maintain their hemispherical shape when frozen, dried and rehydrated. In particular, the microparticles can be injected into a plasticizer (e.g., a 70% ethanol solution) to improve the flexibility and deformability of the product.

[0079] In particular, by adding a suitable plasticizer or other weakening agent, the rehydrated or reactivated product can deliver an extrudable, jettable (3D printing) or injectable (drug) slurry. The product can be formed from micron-sized gel particles into strips with customized cross-sections to fit the microchannels of a microfluidic device, the materials used for the microfluidic device (such as glass, silicon or polymers such as PDMS (polydimethylsiloxane)) are processed by etching or molding processes. Similarly, this product can be formed into a column, which can be easily (pre)loaded into a syringe for injection purposes.

[0080] The microparticle carbohydrate subunits may comprise all types of physically (e.g. ionically) and / or chemically (i.e. covalently) crosslinked hydrogel beads, including agar, alginate, chitosan, dextran, poly(ethylene glycol), collagen, gelatin, hyaluronic acid, carrageenan, silk protein, fibronectin, poly-l-lysine (PLL), cellulose, graphene, polyethyleneimine (PEI), poly(amidoamine) (PAA), dextran sulfate, silk, silk protein, pectin, K-carrageenan, Iota carrageenan, gellan gum, guar gum, tragacanth gum, xanthan gum, gum arabic, karaya gum, locust bean gum or sodium carboxymethylcellulose (S-CMC). All of these are preferably used as materials of natural origin and / or materials of synthetic origin, including recombinant proteins and / or derivatives of these materials, wherein the polymer network particularly comprises a calcium alginate network. For example, similar results were obtained with 5% (w / v) of 1 to 500 μm water-swollen gelatin particles cross-linked with formaldehyde and injected into 60% maltodextrin (MDX13-17; ie, the aqueous solution).

[0081] The gel particle subunits can be formed into various forms, including solid matrices, core / shell capsules, multi-core capsules, compartmentalized capsules, compartmentalized particles. The gel particles can contain active agents, which are released immediately or over time (delayed release) once the product is activated, such as hydrolyzed. When stored in a dry state, the active agent can contain active cosmetics, cosmetics, nutritional additives, nutritional supplements, pharmaceutical active ingredients, agricultural chemical ingredients or other ingredients, such as pigments or soy lecithin.

[0082] For example, the methods and capsules according to the invention can be used in embodiments wherein the active compound comprises at least one vitamin, in particular selected from the group consisting of thiamine, riboflavin, niacin, pantothenic acid, pyridoxine, biotin, folic acid, cyanocobalamin, lipoic acid, ascorbic acid, lecithin, glycyrrhizic acid, retinol, retinyl palmitate, tocopherol, tocopherol acetate, salicylic acid, benzoyl peroxide and azelaic acid and / or their derivatives, more particularly ascorbic acid and / or its derivatives.

[0083] As another example, the methods and capsules according to the present invention can be used in embodiments wherein the active compound comprises at least one antioxidant, particularly selected from the group consisting of polyphenols, thiol-based components, sulfites and their derivatives. These active compounds can be used, for example, as nutritional supplements or for pharmaceutical treatments, etc., in which case they are likely to be administered orally. The microparticles and / or microparticle-loaded tablets can be formulated to survive the acidic environment of the human stomach to be digested in a more downstream portion of the user's gastrointestinal tract to release their contents. In particular, probiotics and prebiotics can be administered particularly effectively in this manner.

[0084] Other applications of the microparticles according to the invention may be paints, carbon capture, fillers, building materials (concrete), smart materials responsive to stress and / or temperature.

[0085] In particular, microparticles can include microgel capsules containing biologically active compounds (e.g., enzymes, cells, proteins, and pharmaceutical agents). Mammalian cells, stem cells, yeast, plant seeds, fungi, bacteria, or other living microorganisms can be added to the liquid activator. The carbohydrate spaces between the hydrogel subunits form a proliferation structure for such active additives.

[0086] The composition or product can be used as an assembly part of a larger granular composition or product, in particular for the production of multi-component products such as tablets. In addition, other activators besides water can also be used for injection and reactivation of products and compositions. By adding excess activators, the final product may decompose. The decomposition time may depend on the macroscopic shape and size of the product, as well as the shape and size of the constituent microscopic gel particles.

[0087] The mass uniformity of the dried tablets can meet the pharmacopoeial standards for pharmaceutical applications. A total of 75 tablets of the same size were produced by freeze-drying a mixture of microparticles and an interstitial carbohydrate matrix. The microparticles are water-swellable microgels made of calcium-crosslinked alginate (0.25 wt. % alginate, cross-linked using 0.2 M CaCl2 in water). The interstitial carbohydrate matrix contains an aqueous solution of maltodextrin with 60% maltodextrin. Of these particles, 22 were randomly selected and weighed three times using a high-precision weight scale. None of the tablets deviated by more than 10% from the average mass specified in the pharmacopoeial standard for the mass uniformity of uncoated tablets.

[0088] The product may include an effervescent disintegrant for loading or releasing one or more active compounds in certain applications, including pharmaceutical effervescent tablets, food applications such as beverages, or health or personal care applications such as bathing. For this reason, for example, an acid or carbonate compound may be added. The hydrogel particles may be used as active ingredient (e.g., drug, food, or beauty) carriers with a controlled passive release profile customized to the application when activated while maintaining the shelf life of their properties.

[0089] Before freezing or after drying, functional devices (e.g., sensors and / or actuators) can be embedded in or on the surface of the composition. The product can be embedded or encapsulated with an elastomeric matrix such as PDMS to provide a flexible shell. The product can be rehydrated in the PDMS shell.

[0090] The surface gradient of the product can determine the flow of liquids added after drying. In addition, the gradient of the carbohydrate network or granular properties of the composition in the dried product can determine the flow of liquids added after drying.

[0091] In particular, the carbohydrate network of the composition can control the capillary flow path for liquids added after drying.

Claims

1. A product comprising a shape-preserving granular composition of gel particles, in particular microgel particles, characterized in that The composition comprises a solid structure of the gel particles which are bound to each other by a substantially dry or dry 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 or 2, characterized in that The carbohydrate matrix comprises an amorphous matrix of at least one polycarbohydrate or polysaccharide compound, more particularly, the polycarbohydrate or polysaccharide compound comprises at least one saccharide compound.

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

5. Product according to any one of the preceding claims, characterized in that The gel particles comprise a hydrogel, in particular a hydrophilic polymer network.

6. The product according to claim 5, wherein: The hydrogel comprises one or more polysaccharides selected from the group consisting of agar, alginate, chitosan, dextran, poly(ethylene glycol), collagen, gelatin, hyaluronic acid, carrageenan, silk protein, fibronectin, poly-l-lysine (PLL), cellulose, graphene, polyethyleneimine (PEI), polyamidoamine (PAA), dextran sulfate, silk, silk protein, pectin, K-carrageenan, Iota carrageenan, gellan gum, guar gum, tragacanth gum, xanthan gum, gum arabic, karaya gum, locust bean gum, or sodium carboxymethylcellulose (S-CMC).

7. The product according to claim 5 or 6, characterized in that The hydrogel comprises a compound selected from the group consisting of calcium alginate, gelatin, hyaluronic acid, collagen or chitosan.

8. The product according to claim 5, 6 or 7, wherein The gel particles comprise a cross-linked or interpenetrating alginate network, in particular a calcium cross-linked alginate network.

9. Product according to any one of the preceding claims, characterized in that The gel particles comprise microcapsules having a core surrounded by a hydrophilic polymer network.

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

11. The product according to claim 9 or 10, characterized in that The microcapsules have a fluid core.

12. The product according to claim 9, 10 or 11, characterized in that The microcapsules have an at least partially solid core, in particular an essentially completely solid core.

13. The product according to claim 12, characterized in that The at least partially solid core comprises a degradable, in particular biodegradable material, specifically a polymer selected from the group consisting of poly(lactic acid) (PLA), poly(glycolic acid) (PGA), poly(ε-caprolactone) (PCL), poly(lactic-co-glycolic acid) (PLGA), and modifications of these materials, in particular block copolymers comprising polyethylene glycol (PEG) as one of the blocks, more particularly PEG-PLA, PEG-PLGA, PEG-PGA or PEG-PCL.

14. The product according to claim 12 or 13, characterized in that The core comprises a mixture of hydrophobic and hydrophilic materials, in particular at least one of said materials being non-homogeneously distributed in the core.

15. Product according to any one of the preceding claims, characterized in that At least a portion of the gel particles is capable of interacting with biological cells, in particular by being functionalized with one or more compounds selected from nucleic acids (aptamers), proteins and peptides.

16. Product according to any one of the preceding claims, characterized in that The gel particles are biological cell carriers or cell adhesion particles.

17. Product according to any one of the preceding claims, characterized in that The size of the gel particles is in the range of 1 μm to 5 mm, in particular in the range of 1 μm to 500 μm.

18. The product according to claim 17, characterized in that The gel particles contain pharmaceutically active compounds and are between 10 and 100 μm in size, and / or the particles contain nutritional ingredients or supplements and are between 100 and 500 μm in size, and / or the gel particles contain cosmetically active agents and are between 500 and 5000 μm in size.

19. Product according to any one of the preceding claims, 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.

20. The product according to any one of the preceding claims, characterized in that The composition is shaped to form at least a portion of a tablet, in particular a tablet having a volume at least ten times the average volume of the gel particles.

21. The product according to claim 20, characterized in that The tablet comprises a plurality of compartments, and the composition is formed into one of the compartments of the tablet.

22. The product according to any one of the preceding claims, characterized in that The molding paste is coated with an elastomeric compound, in particular polydimethylsiloxane (PDMS), before or after curing.

23. The product according to any one of the preceding claims, characterized in that The composition also comprises an effervescent disintegrant, particularly a carbonate compound.

24. Product according to any one of the preceding claims, characterised in that The composition may also contain a plasticizer or other weakening agent, in particular ethanol.

25. A medicinal product comprising a product of the type claimed in any one of the preceding claims, wherein: The gel particles contain a pharmaceutically active agent.

26. A cosmetic product comprising a product of the type described in any one of claims 1 to 24, wherein The gel particles contain a cosmetically active agent.

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 ingredients or supplements.

28. A method for producing a solid product comprising a granular composition of gel particles, in particular a granular composition of microgel particles, wherein: An aqueous slurry comprising the gel particles and the water-soluble carbohydrate is formed, the slurry is shaped, in particular molded, more in particular compressed into the product, and the shaped slurry comprising the gel particles and the water-soluble carbohydrate is dehydrated and solidified to form the product.

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

30. The method of claim 29, wherein: The polycarbohydrate or polysaccharide compound comprises at least one carbohydrate compound.

31. The method according to claim 30, wherein: The carbohydrate compound includes dextran, dextrin, maltodextrin, trehalose, lactose, glucose, dextrose, sucrose, fructose, maltose, isomaltose, sorbitol, mannitol, lactitol, xylitol and / or erythritol.

32. The method according to any one of claims 28 to 31, wherein: The shaping is solidified by at least substantially removing the water content of the shaping, in particular by drying, more particularly by freeze drying.

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

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

35. The method according to any one of claims 28 to 34, wherein: The slurry is shaped by molding, additive printing or extrusion before curing.

36. A process for forming a slurry comprising a granular composition of gel particles, in particular a granular composition of microgel particles, characterized in that A solid product according to any one of claims 1 to 24 is provided and is treated with a liquid activator.

37. The process according to claim 36, characterized in that An aqueous liquid activator is used and the product is hydrated.

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

39. The process according to any one of claims 36 to 38, characterized in that At least one biologically active or activatable material selected from the group consisting of mammalian cells, stem cells, fungi, yeast, bacteria and plant seeds is added to the liquid activating agent.

Images