JP7792227B2 - Granular carrier, granular pharmaceutical composition and absorbent article containing the same, and method for producing the granular carrier - Google Patents

Description

The present invention relates to a granular carrier, a granular pharmaceutical composition and an absorbent article containing the same, and a method for producing the granular carrier.

Superabsorbent polymers (SAPs) absorb water upon contact with it and instantly become a transparent hydrated gel. This gel is a functional polymer that retains water without releasing water even when pressure is applied. Superabsorbent polymers have a wide range of uses. For example, in the field of hygiene products, they are used as highly absorbent materials in absorbent articles such as disposable diapers and sanitary napkins. Superabsorbent polymers are also used as carriers in gel formulations to absorb and support aqueous liquid compositions containing chemicals such as fragrances and deodorants. Gel formulations containing such carriers made of superabsorbent polymers are widely used in stationary air fresheners and deodorants because they eliminate the risk of liquid spilling from the container and have excellent design characteristics.

Currently, polyacrylic acid-based SAPs are the mainstream of superabsorbent polymers (SAPs) due to their ease of synthesis, cost, and other factors. However, because polyacrylic acid-based SAPs are made from petroleum, their production costs are affected by fluctuations and increases in crude oil prices, and they also emit a large amount of _CO2 during production and disposal. In particular, when used in diapers, acrylic acid-based SAPs are discarded in a water-absorbed state, so incineration requires a large amount of energy and emits particularly large amounts of _CO2 . Furthermore, when acrylic acid-based SAPs are disposed of in landfills, they are not biodegradable, which can lead to problems such as soil contamination.

The fact that polyacrylic acid-based SAPs are the mainstream of superabsorbent polymers (SAPs) could potentially cause environmental problems. With demand for disposable diapers expected to grow rapidly in emerging countries in the future, there is a desire to use biodegradable natural polymers as superabsorbent polymers. In light of this situation, superabsorbent polymers made from plant-derived materials such as polysaccharides have been proposed.

For example, Patent Documents 1 to 3 propose a cellulose-based SAP consisting of a crosslinked polymer of carboxymethyl cellulose (CMC) or CMC salt as a biodegradable, highly absorbent polymer to replace polyacrylic acid-based SAP. CMC is a water-soluble cellulose derivative synthesized by etherifying the hydroxyl groups of cellulose with chloroacetic acid or the like. Its aqueous solution exhibits anionic properties and has high viscosity and excellent dispersibility, making it widely used as a thickener, dispersant, and stabilizer.

CMC is neither toxic nor allergenic, and is also used as a food additive and pharmaceutical binder. Its physical properties depend strongly on the degree of substitution (DS), which is the average number of carboxymethyl groups substituted per glucose residue (monomer), and one example states that a DS of >0.55 indicates water solubility. For example, Patent Document 1 uses CMC and CMC salts with a degree of substitution of 1.1 or more (see claim 1, etc.), while Patent Document 2 uses CMC salts with a degree of substitution of 0.65 to 1.4 (see claim 1, etc.).

JP 2011-140534 A International Publication No. 2012/147256 Japanese Patent Application Laid-Open No. 2008-285611

Stationary products in which gel formulations such as fragrance compositions and deodorant compositions are filled in containers are currently on the market. Many of these products use granular gel formulations, in which a liquid composition containing various chemicals is supported on a gel carrier made of a highly absorbent polymer. Many of these products utilize air exposure to the surface of the granular gel formulation, allowing the various chemicals supported on the gel carrier to function. That is, if the chemical supported on the gel carrier is a volatile chemical such as a fragrance, the surface of the granular gel formulation is exposed to air to volatilize the volatile chemical. Furthermore, if the chemical supported on the gel carrier is a non-volatile chemical, such as a deodorant that uses a chemical reaction to eliminate odors, the surface of the granular gel formulation is exposed to air, bringing the malodorous molecules into contact with the non-volatile deodorant, resulting in the decomposition and deodorization of the malodorous molecules through a chemical reaction.

For this reason, in order for the drug carried by the gel carrier in a granular gel formulation to function efficiently, it is desirable for air to flow easily when the granular gel formulation is filled into a container. To facilitate air flow, it is preferable that the gaps between the granular gel formulations are uniform and of a certain size. For this reason, it is desirable for the granular gel formulations to be uniform in size and nearly spherical in shape.

Furthermore, considering that granular gel formulations such as fragrance compositions and deodorant compositions are distributed as stationary products filled in containers, it is desirable for the granular gel formulation to also have excellent gel strength. Furthermore, in such products, the granular gel formulation is often filled in a transparent or translucent container so that it can be seen from the outside. A granular gel formulation that is uniform in size and nearly spherical in shape not only enables the above-mentioned chemicals to function efficiently, but is also preferable from an aesthetic standpoint. From an aesthetic standpoint, it is even more desirable for the granular gel formulation to also have excellent transparency.

Meanwhile, a conventional method for producing cellulose-based SAP involves polymerizing CMC and/or CMC salt in an aqueous solution using a crosslinking agent (hereinafter referred to as "aqueous solution polymerization"). For example, a crosslinking agent is added to an aqueous CMC salt solution prepared by dissolving CMC or CMC salt in an aqueous sodium hydroxide solution, and a crosslinking reaction is carried out to produce a hydrogel, which uniformly gels the aqueous solution. The hydrogel is then pulverized and subjected to a sorting process such as classification to form a cellulose-based SAP (see, for example, paragraph 0035 of Patent Document 1, paragraph 0024 of Patent Document 2, and paragraph 0044 of Patent Document 3).

Crushed gel particles (crushed gel) refined by crushing are typically fragmented with sharp edges, and most of the particles are irregularly shaped and far from spherical. When filled into a container, cellulose-based SAP consisting of a collection of small, irregularly shaped gel fragments tends to be in close contact with each other, making it difficult for air to flow. Furthermore, cellulose-based SAP consisting of a collection of small, irregularly shaped gel fragments is undesirable from an aesthetic standpoint.

The present invention aims to provide a granular carrier that is both highly absorbent and biodegradable, has a substantially spherical shape, uniform particle size, and excellent strength and transparency, as well as a granular pharmaceutical composition and absorbent article that contain this granular carrier. The present invention also aims to provide a simple method for producing this granular carrier.

According to a first aspect of the present invention, there is provided a granular carrier comprising a crosslinked salt of carboxyalkyl cellulose, the viscosity of which, as a 1% by mass aqueous solution, at 25°C is in the range of 5 mPa·s to 300 mPa·s, and the granular carrier is a gel particle derived from dispersed particles in a reversed-phase suspension.

In an embodiment of the first aspect of the present invention, the dispersion medium of the reversed phase suspension may be a low-polarity organic solvent having a dielectric constant of 10 or less.

In another embodiment of the first aspect of the present invention, the dispersion medium of the reverse phase suspension may be liquid paraffin or silicone oil.

In another embodiment of the first aspect of the present invention, the viscosity of the carboxyalkyl cellulose and/or its salt may be 5 mPa·s or more and 100 mPa·s or less.

In another embodiment of the first aspect of the present invention, the granular carrier is used to carry a drug.

A second aspect of the present invention provides a granular drug composition comprising a granular carrier according to the first aspect and a liquid composition supported on the granular carrier and containing at least one drug selected from drugs having aromatic, deodorizing, deodorizing, insect repellent, insecticidal, or antifungal properties.

In an embodiment of the second aspect of the present invention, the granular pharmaceutical composition may be an air freshener composition or a deodorant composition.

According to a third aspect of the present invention, there is provided an absorbent article comprising the granular carrier according to the first aspect.

According to a fourth aspect of the present invention, there is provided a method for producing a granular carrier comprising gel particles containing a crosslinked product of a carboxyalkyl cellulose salt, the method comprising:
A carboxyalkyl cellulose and/or a salt thereof having a viscosity of 5 mPa s or more and 300 mPa s or less in a 1 mass% aqueous solution at 25°C is dissolved in an alkaline aqueous solution to prepare a carboxyalkyl cellulose salt aqueous solution;
The present invention provides a method for producing a granular carrier, which comprises preparing a mixture of the above-mentioned aqueous solution of a carboxyalkyl cellulose salt and a crosslinking agent, dispersing the mixture in a low-polarity organic solvent to form a suspension, and allowing crosslinking polymerization of the carboxyalkyl cellulose salt to proceed in the suspension to form dispersed particles containing crosslinked bodies of the carboxyalkyl cellulose salt, wherein the low-polarity organic solvent has a relative dielectric constant of 10 or less at 25°C and a kinematic viscosity of 10 ^mm2 /s or more at 37.8°C.

In an embodiment of the fourth aspect of the present invention, the low-polarity organic solvent may be liquid paraffin or silicone oil.

In another embodiment of the fourth aspect of the present invention, the kinematic viscosity of the low-polarity organic solvent at 37.8° C. may be 10 mm ² /s or more and 100 mm ² /s or less.

In another embodiment of the fourth aspect of the present invention, the cross-linking polymerization of the carboxyalkyl cellulose salt in the suspension is carried out under stirring at a rotation speed of 50 rpm or more and 500 rpm or less.

In another embodiment of the fourth aspect of the present invention, the viscosity of the carboxyalkyl cellulose and/or its salt may be 5 mPa·s or more and 100 mPa·s or less.

In another embodiment of the fourth aspect of the present invention, the mass ratio (X/Y) of the carboxyalkyl cellulose and/or its salt (X) to the crosslinking agent (Y) in the mixture may be in the range of 10/2 to 10/5.

In another embodiment of the fourth aspect of the present invention, the crosslinking agent may be a compound having two or more epoxy groups in the molecule.

In another embodiment of the fourth aspect of the present invention, the granular carrier is used to carry a drug.

In another embodiment of the fourth aspect of the present invention, the granular carrier is used as a water-absorbing material in an absorbent article.

The present invention provides a granular carrier that is both highly absorbent and biodegradable, has a substantially spherical shape and uniform particle size, and exhibits excellent strength and transparency, as well as a granular pharmaceutical composition and absorbent article that contain this granular carrier. The present invention also provides a simple method for producing this granular carrier.

FIG. 1 is a flow diagram showing an example of a method for producing a granular carrier according to an embodiment of the present invention. 2 is a photograph of the granular carrier 12 produced in Example 3-4 of the [Examples]. (a) shows the dry gel particles, and (b) shows the water-absorbed gel particles. 3A is a photograph comparing the particle shape of the granular carrier according to the embodiment of the present invention with the particle shape of crushed gel particles for comparison, where (a) is the crushed gel particles (dry state) produced in Example 4-1 of the [Example], and (b) is the granular carrier 2 (dry state) produced in Example 1-2 of the [Example]. 3B is a photograph comparing the particle shape of the granular carrier according to the embodiment of the present invention with the particle shape of crushed gel particles for comparison, where (a) is the crushed gel particles (water-absorbed state) produced in Example 4-1 of the [Examples], and (b) is the granular carrier 2 (water-absorbed state) produced in Example 1-2 of the [Examples]. FIG. 4 is a particle size distribution showing the relationship between the particle diameter D (mm) and the frequency (mass %) of the granular carrier 2 produced in Example 1-2 of the [Example].

Embodiments of the present invention will be described below with reference to the drawings. The embodiments described below further embody any of the above aspects.

The granular carrier according to an embodiment of the present invention is a gel particle containing a crosslinked carboxyalkyl cellulose salt. As described below, the gel particle is derived from dispersed particles formed by suspension polymerization (i.e., reverse-phase suspension polymerization) in a suspension using a low-polarity organic solvent as the dispersion medium. The granular carrier derived from dispersed particles obtained through the formation of crosslinked carboxyalkyl cellulose salt by reverse-phase suspension polymerization is approximately spherical in shape, has a uniform particle size, and exhibits excellent strength and transparency. According to the manufacturing method according to an embodiment of the present invention, a granular carrier having these properties can be easily obtained without undergoing the steps of crushing the gel body, classifying, etc., required in the conventional manufacturing methods described above.

In an embodiment of the present invention, the carboxyalkyl cellulose or salt thereof used as the raw material is preferably a carboxyalkyl cellulose or salt thereof having an alkyl group having 1 to 3 carbon atoms, for example, from the standpoint of production costs, etc., and specific examples include carboxymethyl cellulose, carboxyethyl cellulose, carboxybutyl cellulose, or salts thereof. The carboxyalkyl cellulose and/or salt thereof can be used alone or in combination of two or more types.

In an embodiment of the present invention, it is important to select carboxyalkyl cellulose and/or its salts as raw materials, whose viscosity in a 1% by weight aqueous solution is within a specified range. The longer the polymer chain of the carboxyalkyl cellulose, the higher the viscosity when dissolved, making it difficult to handle when injected into the low-polarity organic solvent used as a dispersion medium. This may adversely affect the uniformity of the particle shape and particle size of the resulting granular carrier. On the other hand, the longer the polymer chain of the carboxyalkyl cellulose, the greater the water absorption capacity, which means that when the granular carrier of this embodiment is used as a drug carrier, it can carry a large amount of drug. However, if the water absorption capacity is too high, problems such as a decrease in gel strength and increased syneresis may occur. From these perspectives, an embodiment of the present invention uses carboxyalkyl cellulose and/or its salts whose viscosity in a 1% by weight aqueous solution is 5 mPa·s or more and 300 mPa·s or less.

Here, the viscosity of a 1% by mass aqueous solution of carboxyalkyl cellulose and/or its salt is the viscosity value measured using a Brookfield viscometer after preparing 200 mL of an aqueous solution of carboxyalkyl cellulose so that the solids content is 1% by mass. Hereinafter, the viscosity of a 1% by mass aqueous solution of carboxyalkyl cellulose and/or its salt measured under these conditions will be simply referred to as the "viscosity of carboxyalkyl cellulose." The viscosity of carboxyalkyl cellulose is preferably from 10 mPa·s to 100 mPa·s, and more preferably from 20 mPa·s to 50 mPa·s.

In addition, in an embodiment of the present invention, the average degree of etherification (average degree of substitution, DS) of the carboxyalkyl cellulose used as the raw material may be, for example, 0.5 to 1.5. Using a carboxyalkyl cellulose with an average degree of etherification in this range can easily improve the water absorption and strength of the gel. The average degree of etherification (average degree of substitution) refers to the average degree of substitution of hydroxyl groups at the 2nd, 3rd, and 6th positions of the glucose units that make up the cellulose.

Figure 1 is a flow diagram showing an example of a method for producing a granular carrier according to an embodiment of the present invention. The production method shown in Figure 1 includes step S1 of dissolving carboxyalkyl cellulose and/or a salt thereof in an alkaline aqueous solution to prepare a carboxyalkyl cellulose salt aqueous solution; step S2 of preparing a mixture of the carboxyalkyl cellulose salt aqueous solution obtained in step S1 with a crosslinking agent; step S3 of dispersing the mixture obtained in step S2 in a low-polarity organic solvent to form a suspension (reverse phase suspension), and proceeding with crosslinking polymerization of the carboxyalkyl cellulose salt in this suspension to form dispersed particles containing crosslinked carboxyalkyl cellulose salt; and step S4 of filtering, washing, and drying the dispersed particles formed in step S3 from the suspension.

As mentioned above, the manufacturing method shown in FIG. 1 is one example. In other examples, the manufacturing method according to the present invention may further include other steps not shown in FIG. 1. Furthermore, step S4 is an optional step that is performed as needed, as described below. Therefore, in yet another example, the manufacturing method according to the present invention may not include step S4.

In step S1, carboxyalkyl cellulose and/or its salt is added (injected) into the alkaline aqueous solution and completely dissolved while stirring at room temperature to prepare a carboxyalkyl cellulose salt aqueous solution. The time required to prepare the carboxyalkyl cellulose salt aqueous solution in step S1 can be set as appropriate, but in one example, it can be set to 1 to 5 hours. After adding the carboxyalkyl cellulose to the alkaline aqueous solution, a degassing treatment can be performed, if necessary, by reducing the pressure or by allowing it to stand at normal pressure for a predetermined period of time.

The carboxyalkyl cellulose and/or salt thereof used in step S1 may be obtained by carboxyalkylating cellulose such as pulp as a starting material using a conventional method, or commercially available carboxyalkyl cellulose and/or salt thereof may be used.

The carboxyalkyl cellulose salt contained in the carboxyalkyl cellulose salt aqueous solution obtained in step S1 may be, for example, an alkali metal salt or alkaline earth metal salt of carboxyalkyl cellulose. In this case, the alkaline aqueous solution to which the carboxyalkyl cellulose and/or its salt is added is an alkaline aqueous solution containing an alkali metal or alkaline earth metal. Examples of carboxyalkyl cellulose salts include sodium salts, potassium salts, and calcium salts. In this case, the alkaline aqueous solution to which the carboxyalkyl cellulose is added is an aqueous solution of sodium hydroxide, potassium hydroxide, or calcium hydroxide. According to one example, sodium carboxymethyl cellulose (CMC-Na) is used as the carboxyalkyl cellulose and/or its salt, and sodium hydroxide is used as the alkaline aqueous solution to prepare the CMC-Na aqueous solution in step S1.

In step S2, the carboxyalkyl cellulose salt aqueous solution obtained in step S1 is mixed with a crosslinking agent to prepare a mixture of the carboxyalkyl cellulose salt aqueous solution and the crosslinking agent. Hereinafter, when simply referring to the "mixture," this refers to the mixture of the carboxyalkyl cellulose salt aqueous solution and the crosslinking agent prepared in step S2.

The carboxyalkyl cellulose salt aqueous solution and the crosslinking agent are mixed preferably at 10°C to 80°C, more preferably 20°C to 50°C, while stirring, for example, using a static mixer. At temperatures higher than 80°C, the crosslinking reaction proceeds too quickly, making it difficult to obtain uniform, spherical gel particles in the subsequent step S3. At temperatures lower than 10°C, the viscosity of the mixture increases, making it difficult to handle when the mixture is added to the low-polarity organic solvent in the subsequent step S3. The crosslinking reaction of the carboxyalkyl cellulose salt begins immediately after the crosslinking agent is added to the carboxyalkyl cellulose salt aqueous solution in step S2, and the viscosity begins to increase. Therefore, the time between adding the crosslinking agent to the carboxyalkyl cellulose salt aqueous solution and adding the mixture to the low-polarity organic solvent can be appropriately set, taking into account factors such as ease of handling when adding the mixture to the low-polarity organic solvent in the subsequent step S3. According to one example, the reaction temperature can be adjusted within the above range, with a target time of 30 minutes or less. After stirring, degassing under reduced pressure may be performed as needed.

There are no particular limitations on the crosslinking agent used in the manufacturing method according to an embodiment of the present invention, and known compounds such as polyepoxy compounds, polyglycidyl compounds, polyaldehyde compounds, polycarboxylic acids, vinyl ether compounds, methylol compounds, polyisocyanates, polyoxazoline compounds, polyvinyl compounds, polyacrylate compounds, polymethacrylate compounds, polyhalogen compounds, methylenebisacrylamide, epichlorohydrin, polyacid anhydrides, methylenebisacrylamide, and glycidyl methacrylate can be used.

Specific examples of preferred crosslinking agents include (a) compounds having two or more hydroxyl groups in the molecule, (b) compounds having two or more polymerizable double bonds, and (c) compounds having two or more epoxy groups.

(a) Examples of compounds having two or more hydroxyl groups in the molecule include ethylene glycol, diethylene glycol, triethylene glycol, polyethylene glycol, glycerin, polyglycerin, propylene glycol, diethanolamine, polyoxypropylene, sorbitan fatty acid esters, trimethylolpropane, pentaerythritol, 1,3-propanediol, and sorbitol.

(b) Examples of compounds having two or more polymerizable double bonds in the molecule include bis(meth)acrylamide, allyl(meth)acrylamide, diethylene glycol diacrylate, trimethylolpropane triacrylate, polyethylene glycol diacrylate, and ethoxylated trimethylolpropane triacrylate.

(c) Examples of compounds having two or more epoxy groups in the molecule include polyglycidyl ethers such as ethylene glycol diglycidyl ether (EGDE), polyethylene glycol diglycidyl ether, polypropylene glycol diglycidyl ether, glycerin triglycidyl ether, glycerol polyglycidyl ether, polyglycerol polyglycidyl ether, trimethylolpropane polyglycidyl ether, sorbitol polyglycidyl ether, pentaerythritol polyglycidyl ether, resorcinol diglycidyl ether, neopentyl glycol diglycidyl ether, and hydrogenated bisphenol A diglycidyl ether.

Of these, from the viewpoint of reactivity and the water absorption performance of the resulting granular carrier, (b) compounds having two or more polymerizable double bonds in the molecule and (c) compounds having two or more epoxy groups in the molecule are preferred, (c) compounds having two or more epoxy groups in the molecule are more preferred, polyglycidyl ethers are even more preferred, and ethylene glycol diglycidyl ether (EGDE) is particularly preferred.

The blending weight ratio of carboxyalkyl cellulose and/or its salt to the crosslinking agent can be set as appropriate. From the standpoint of the shape, transparency, and strength of the granular carrier, the blending weight ratio (X/Y) of carboxyalkyl cellulose and/or its salt (X) to the crosslinking agent (Y) is preferably in the range of 10/2 ≧ X/Y ≧ 10/5, and more preferably in the range of 10/2 > X/Y ≧ 10/4.

In step S3, the mixture obtained in step S2 is added (injected) into a low-polarity organic solvent and dispersed to form a suspension (reverse phase suspension), and dispersed particles containing crosslinked carboxyalkyl cellulose salt are formed by crosslinking polymerization in this suspension.

The low-polarity organic solvent used as the dispersion medium in step S3 is a low-polarity organic solvent with a dielectric constant of 10 or less at 25°C, and is less polar than the above-mentioned mixture of dispersoids. Therefore, the suspension prepared in step S3 is a reversed-phase suspension, and the cross-linking polymerization of the carboxyalkyl cellulose salt is reversed-phase suspension polymerization. Here, the dielectric constant is the dielectric constant at 25°C measured using a capacitance meter. According to one example, it is more preferable that the low-polarity organic solvent used as the dispersion medium has a dielectric constant of 3 or more and 6 or less.

Examples of low-polarity organic solvents with a relative dielectric constant of 10 or less include aliphatic hydrocarbons, alicyclic hydrocarbons, aromatic hydrocarbons, liquid paraffin, and silicone oil, which can be used alone or in combination of two or more.

The low-polarity organic solvent used in step S3 is further a viscous fluid having a kinematic viscosity of 10 mm ² /s or more at 37.8°C. When the dispersion medium is a viscous fluid, it is possible to suppress the aggregation of the generated spherical gel particles and the adhesion between the spherical gel particles, thereby suppressing clumping of the spherical gel particles. A low-polarity organic solvent having a kinematic viscosity of 10 mm ² /s or more is important for obtaining high-quality granular carriers that are spherical in shape and have uniform particle sizes.

Here, the kinematic viscosity is the kinematic viscosity measured by a vibration viscometer at 37.8°C. According to one example, the low-polarity organic solvent used as the dispersion medium has a kinematic viscosity of 10 mm ² /s or more and 100 mm ² /s or less, according to another example, 15 mm ² /s or more and 80 mm ² /s or less, and according to yet another example, 20 mm ² /s or more and 50 mm ² /s or less.

Among the specific examples of low-polarity organic solvents with a dielectric constant of 10 or less, liquid paraffin and silicone oil are viscous fluids and are therefore particularly preferred as the low-polarity organic solvents used in step S3.

The liquid paraffin is not particularly limited as long as it is a paraffin that is liquid at room temperature, and examples thereof include liquid saturated hydrocarbons having 12 to 50 carbon atoms, such as n-paraffin, isoparaffin, and naphthene. Commercially available products that can be used include, for example, Moresco White and Moresco Bioless (all trade names, manufactured by Matsumura Oil Research Institute), Stanol, Krystoll, Esso White Oil, and Purelex (all trade names, manufactured by Esso Oil Co., Ltd.). These may be used alone or in combination of two or more types.

The silicone oil is not particularly limited as long as it has a siloxane structure that is liquid at room temperature. Examples include polysiloxane oils such as dimethyl silicone oil. Modified silicone oils containing functional groups such as hydroxyl groups, carboxyl groups, amino groups, epoxy groups, cyano groups, mercapto groups, trifluoropropyl groups, chlorophenyl groups, and long-chain alkyl groups, or modified silicone oils modified with polyethers or alcohols, etc., can also be used. These may be used alone or in combination of two or more types.

In step S3, the aforementioned crosslinking agent may be further added to the low-polarity organic solvent to perform surface crosslinking (secondary crosslinking), which creates areas with high crosslink density on the surface layer of the gel particles. By performing surface crosslinking (secondary crosslinking), it is possible to improve gel strength while maintaining water absorption.

In step S3, the low-polarity organic solvent to which the mixture obtained in step S2 is added is at room temperature or heated. In one example, the low-polarity organic solvent is preferably heated to 30°C to 80°C, and in another example, it is more preferable that the low-polarity organic solvent be heated to 50°C to 70°C.

In step S3, the low-polarity organic solvent to which the mixture obtained in step S2 is added is stirred. Examples of stirring devices include mechanical stirrers, and examples of stirring blades include anchor-type, propeller-type, and paddle-type blades, and these can be selected appropriately. In one example, in step S3, the low-polarity organic solvent is stirred at a rotation speed of 50 to 500 rpm, in another example, at a rotation speed of 200 to 500 rpm, and in yet another example, at a rotation speed of 250 to 400 rpm.

In step S3, the mixture obtained in step S2 is added (injected) into the low-polarity organic solvent. One example of a method is to add the mixture drop by drop using a pipette from the liquid surface of the low-polarity organic solvent (hereinafter sometimes referred to as the "drop-by-drop injection method"). Another example is to continuously inject the mixture while immersing a pipette in the low-polarity organic solvent (hereinafter sometimes referred to as the "continuous injection method"). The drop-by-drop injection method is preferable because it makes it easier to obtain dispersed particles with a uniform particle size. The continuous injection method is preferable because it can be easily performed in a short amount of time.

In step S3, the time required for the cross-linking polymerization reaction of the carboxyalkyl cellulose salt can be set as appropriate. For example, it can be set to 1 to 6 hours.

The method for producing a granular carrier according to this embodiment typically includes step S4, as shown in Figure 1. Specifically, the dispersed particles containing the crosslinked carboxyalkyl cellulose salt formed in the suspension in step S3 of this embodiment are typically removed from the suspension by filtration, and are then washed, dried, or otherwise processed as necessary. Post-filtration washing can involve, for example, washing the low-polarity organic solvent adhering to the gel particle surface with an aqueous detergent solution containing a surfactant, and/or immersing the gel particles in ethanol to dehydrate and dealkalize them. Drying can be accomplished by air drying, for example. When a low-boiling-point solvent such as n-hexane is used as the low-polarity organic solvent, the solvent on the gel particle surface can be volatilized and removed without washing by using a method such as vacuum distillation.

However, in the method for producing a granular carrier according to this embodiment, step S4 is an optional step, and the dispersed particles may be distributed as a product in a dispersed state in the suspension without being removed from the suspension. In other words, the granular carrier according to this embodiment may be gel particles derived from dispersed particles that have been subjected to reverse phase suspension polymerization in the suspension formed in step S3. For example, the granular carrier may be in the form of dispersed particles present in the suspension, water-absorbed gel particles that have been removed from the suspension and not dried, or dried gel particles that have been removed from the suspension and dried.

The particle size of the granular carrier according to this embodiment is not particularly limited, but there are preferred particle sizes depending on the purpose of use. For example, when the granular carrier according to this embodiment is used to carry a drug, the average particle size of the gel particles in a water-absorbed state may be, in one example, 2 mm to 30 mm, and in another example, 2 mm to 20 mm. Here, the average particle size refers to the value measured by measuring the major axis of 30 randomly selected particles using a vernier caliper and averaging the results.

Furthermore, when the granular carrier according to this embodiment is used for carrying a drug, the average particle diameter of the gel particles in a dry state may be, for example, 0.2 mm to 6 mm, and in another example, 0.5 mm to 4 mm. Here, the average particle diameter refers to the value measured by measuring the major axis of 30 randomly selected particles using a vernier caliper and averaging the results.

The granular carrier according to this embodiment can be used in a dry state as a highly absorbent material in absorbent articles such as disposable diapers, sanitary products (such as napkins and tampons), pads (sweat pads, breastfeeding pads, incontinence pads, etc.), and pet toilets.

In another example, the granular carrier according to this embodiment is used as a drug carrier. That is, a liquid composition containing at least one drug selected from drugs having, for example, aromatic, deodorizing, deodorizing, insect repellent, insecticidal, or antifungal properties is absorbed and carried by the granular carrier composed of the dried gel particles according to this embodiment. This makes it possible to provide gel formulations such as granular drug compositions, such as granular air freshener compositions, granular deodorant compositions, granular deodorizing compositions, granular insect repellent compositions, granular insecticide compositions, and granular antifungal compositions.

In a gel preparation consisting of such a granular pharmaceutical composition, various commonly used drugs can be used as the pharmaceutical component contained in the liquid composition absorbed and carried by the granular carrier depending on the purpose.
Specific examples of aromatic agents include animal fragrances such as musk, spirit cat fragrance, and dragon jasmine fragrance, and plant fragrances such as abies oil, accion oil, almond oil, angelica root oil, peper oil, bergamot oil, perch oil, bois rose oil, kayabuchi oil, gananga oil, capsicum oil, caraway oil, cardamom oil, cassia oil, celery oil, cinnamon oil, citronella oil, cognac oil, coriander oil, cumin oil, camphor oil, basil oil, estugolan oil, eucalyptus oil, fennel oil, garlic oil, ginger oil, grapefruit oil, hop oil, lemon oil, lemongrass oil, nutmeg oil, mandarin oil, peppermint oil, orange oil, sage oil, star anise oil, turpentine oil, rosemary oil, eucalyptus oil, anise oil, lavender oil, cumin oil, cinnamon oil, and hiba oil. Artificial fragrances such as synthetic fragrances or extracted fragrances can also be used. Specific examples include hydrocarbon fragrances such as pinene and limonene; alcohol fragrances such as linalool, geraniol, citronellol, menthol, borneol, benzyl alcohol, anise alcohol, and β-phenethyl alcohol; phenol fragrances such as anethole and eugenol; aldehyde fragrances such as n-butyraldehyde, isobutyraldehyde, hexylaldehyde, citral, citronellal, benzaldehyde, and cinnamic aldehyde; ketone fragrances such as carvone, menthone, camphor, acetophenone, and ionone; lactone fragrances such as γ-butyrolactone, coumarin, and cineole; and ester fragrances such as octyl acetate, benzyl acetate, cinnamyl acetate, butyl propionate, and methyl benzoate. These may be used alone or in any combination of two or more.

Deodorizing agents may be volatile or non-volatile, and specific examples include metal oxides such as titanium oxide and zinc oxide, flavonoid compounds, plant extracts such as catechin and polyphenols or their derivatives, cyclodextrin or its derivatives, and amine compounds. These may be used alone or in any combination of two or more.

Specific examples of deodorizing agents include carbon-based adsorbents such as activated carbon made from coconut shells, charcoal such as binchotan charcoal, and silica-based adsorbents such as zeolite, silica gel, and layered zinc aluminosilicate. These can be used alone or in any combination of two or more.

Specific examples of insecticides with insect repellent or insecticidal properties include pyrethroid insecticides such as empenthrin, transfluthrin, allethrin, fenothrin, eminence, and profluthrin, and volatile insect repellent and insecticidal ingredients such as paradichlorobenzene, naphthalene, camphor, 2-phenoxyethanol, hinokitiol, and allyl isothiocyanate. These can be used alone or in any combination of two or more.

In addition to the above-mentioned drugs, various additives can be used in the liquid composition. Specific examples include surfactants, coloring agents, preservatives, and pH adjusters.

The granular pharmaceutical composition of this embodiment can be produced, for example, by impregnating dry gel particles into a liquid pharmaceutical composition.

As described above, the granular carriers of this embodiment are gel particles derived from dispersed particles formed by reverse-phase suspension polymerization using a low-polarity organic solvent as the dispersion medium. They are approximately spherical in shape and have a uniform particle size. Therefore, a granular pharmaceutical composition obtained by loading a liquid pharmaceutical composition onto the granular carriers of this embodiment is prone to air flow when filled into a container, allowing the pharmaceutical loaded onto the granular carriers to function efficiently. Furthermore, the granular pharmaceutical composition of this embodiment also has excellent strength and transparency. Therefore, the granular carriers of this embodiment are suitable for use as pharmaceutical carriers for granular gel formulations loaded into containers in stationary products such as air fresheners and deodorants.

Example 1 CMC-Na Viscosity Example 1-1: Production of Granular Carrier 1
The raw material used was sodium carboxymethylcellulose (CMC-Na) (Daicel 1110, manufactured by Daicel Miraize Co., Ltd.) having a viscosity in the range of 10 to 20 mPa s. The viscosity here was measured by the above-mentioned method for the viscosity of a 1% by mass aqueous solution of CMC-Na at 25°C.

10.0 g of the above CMC-Na (Daicel 1110) was dissolved in 100 mL of 0.5 mol/L aqueous sodium hydroxide solution. 4.0 g of ethylene glycol diglycidyl ether (EGDE) (Denacol EX-810, manufactured by Nagase ChemteX Corporation) as a crosslinking agent was added dropwise to this solution, and after stirring for 20 minutes, the solution was degassed under reduced pressure for 5 minutes. This resulted in a mixture of an aqueous CMC-Na solution and EGDE. In this example, the mass ratio of CMC-Na to the crosslinking agent EGDE (CMC-Na/EGDE) was 10/4.

The resulting mixture was then injected into liquid paraffin (Moresco White P-100, manufactured by MORESCO Corporation; kinematic viscosity 20.5 mm ² /s) that had been heated to 60°C and stirred at a stirring speed of 250 rpm. A high-viscosity pipette was used to inject the mixture, and the tip of the pipette was immersed in the liquid paraffin while the mixture was injected. The mixture was allowed to react in the liquid paraffin for 4 hours. After the reaction, the produced gel particles were filtered off, and the liquid paraffin adhering to the surface of the gel particles was washed off with an appropriate amount of aqueous surfactant solution. The gel particles were then immersed in ethanol to dehydrate and dealkalize them, and then air-dried to obtain a white to pale yellow solid (granular carrier 1).

<Examples 1-2 to 1-6: Production of Granular Carriers 2 to 6>
Granular carriers 2 to 6 were produced in the same manner as in Example 1-1, except that CMC-Na (Daicel 1110, viscosity 10-20 mPa·s) was changed to CMC-Na shown in Table 1 below.

<Evaluation>
[Handling when pouring into liquid paraffin (ease of pouring)]
In the manufacturing process of each granular carrier, the handling properties when injecting the mixture of CMC sodium salt and EGDE into the liquid paraffin were evaluated based on the ease of drawing into the pipette and the ease of injecting from the pipette into the liquid paraffin, according to the following criteria. The evaluation results are shown in Table 1.
A: Easy to aspirate and inject.
B: Suction and injection take some time, but are not difficult.
C: Difficult to suction and inject.

[Shape of granular carrier (dry gel)]
The shape of each of the resulting granular carriers (dried gels) was visually evaluated according to the following criteria. The evaluation results are shown in Table 1.
A: Spherical dry gels account for almost the entire sample, and dry gels of shapes other than spherical are hardly observed.
B: Mostly spherical dry gel. Flat or thread-like dry gel is mixed in, but not noticeable.
C: Most of the gel is thread-like, with a small amount of spherical gel.

[Transparency]
Each of the obtained granular carriers (dry gels) was immersed in ion-exchanged water to absorb the maximum amount of water possible, and the transparency of the water-absorbed gel particles was evaluated visually according to the following criteria. The evaluation results are shown in Table 1.
A: No cloudiness and high transparency overall.
B: Some parts are cloudy, but 80% or more of the product is transparent, and the product appears transparent overall.
C: Many parts are cloudy or the whole is cloudy, and the transparency is low overall.

[Strength]
One gram of each of the obtained granular carriers (dried gel particles) was filled into a 200 mL beaker, 150 mL of ion-exchanged water was added, and the mixture was left overnight to obtain water-absorbed gel particles carrying the maximum amount of water they could absorb. The water-absorbed gel particles were filtered to remove excess water, and then the water-absorbed gel particles were filled into the 200 mL beaker again. At this point, the container contained approximately six layers of particles stacked from the bottom to the top. These were used as evaluation samples, and their strength was evaluated according to the following criteria. The evaluation results are shown in Table 1.
A: The strength at which particles located at the bottom of the container and bearing a weight approximately six times their own weight maintain their spherical shape, and gaps of uniform size are formed between the particles throughout the particle-packed structure.
B: A strength in which at least some of the particles located at the bottom of the container and subjected to a weight approximately six times their own weight are unable to maintain their spherical shape, resulting in areas where no gaps are formed between the particles at the bottom. C: A strength in which the particles are unable to maintain their spherical shape even under their own weight.

Table 1 shows that granular carriers 1 to 5 of Examples 1-1 to 1-5 according to embodiments of the present invention have excellent particle shape, transparency, and strength. Furthermore, Examples 1-1 to 1-5 also have excellent handling properties when injecting the mixture into liquid paraffin, demonstrating that granular carriers (gel particles) with excellent particle shape, transparency, and strength can be easily obtained by reverse-phase suspension polymerization. On the other hand, it is clear that it is difficult to produce spherical gel particles by reverse-phase suspension polymerization in Example 1-6 (comparative example), which uses highly viscous CMC.

Example 2: CMC-Na/crosslinking agent (mass ratio)
<Examples 2-1 and 2-2: Production of Granular Carriers 7 and 8>
Granular carriers 7 and 8 were produced in the same manner as in Example 1-2 above, in which Daicel 1120 (viscosity 20 to 50 mPa s) was used as the raw material (CMC-Na), except that the blending mass ratio of CMC-Na to EGDE was changed as shown in Table 2. For each granular carrier, the dried gel shape, transparency, and strength were evaluated in the same manner as in Example 1-1. The evaluation results are shown in Table 2.

Incidentally, although Example 2-1 received a strength rating of B, the only area where gaps between particles were absent was the bottommost part of the packed particles, and air fluidity was maintained.

Example 3 Dynamic viscosity of liquid paraffin and stirring speed Examples 3-1 to 3-5: Production of granular carriers 9 to 13
Granular carriers were produced in the same manner as in Example 1-2 (granular carrier 2) above, which used Daicel 1120 (viscosity 20 to 50 mPa s) as the raw material (CMC-Na), except that the liquid paraffin and stirring speed were changed as shown in Table 3. The dried gel shape of each granular carrier was evaluated in the same manner as in Example 1-1. The evaluation results are shown in Table 3.

However, in Examples 3-1 and 3-2, in which liquid paraffin with a low viscosity (kinematic viscosity 4.51 mm ² /s) was used, the mixture accumulated at the bottom and coalesced, and granular gel particles could not be obtained.

Incidentally, although Example 3-3 received a strength rating of B, the only area where gaps between particles were absent was the bottommost part of the packed particles, and air fluidity was maintained.

Example 4 Comparison of particle shapes between granular carrier according to the embodiment and crushed gel particles Example 4-1: Production of crushed gel (crushed gel)
10.0 g of CMC-Na (Daicel 1120, Daicel Miraize Co., Ltd.) was dissolved in 100 mL of 0.5 mol/L aqueous sodium hydroxide solution. 4.0 g of EGDE (Denacol EX-810, Nagase ChemteX Corporation) was added dropwise and stirred for 20 minutes. After degassing under reduced pressure for 5 minutes, the mixture was allowed to react for 4 hours in a constant temperature bath at 60°C. After the reaction, the resulting gel-like substance was removed from the beaker and coarsely pulverized using a mixer. The resulting pulverized gel was immersed in ethanol, dehydrated and dealkalized, and then air-dried to obtain a white to pale yellow solid.

<Evaluation>
Figure 3A(a) is a photograph of the dried pulverized gel particles produced in Example 4-1, and Figure 3B(a) is a photograph of the water-absorbed state of the particles. Figure 3A(b) is a photograph of the granular carrier 2 (dried gel particles) produced in Example 1-2, and Figure 3B(b) is a photograph of the water-absorbed state of the particles.
Comparing (a) and (b) in Figure 3A and comparing (a) and (b) in Figure 3B, it is clear that the particle shape of the granular carrier in this embodiment is completely different from the particle shape of the crushed gel particles.
3A(a) and 3B(a) show that the pulverized gel particles obtained by the conventional method of pulverizing a hydrogel formed by aqueous solution polymerization are fragmented with sharp edges, and most of the particles are irregularly shaped and cannot be described as spherical. On the other hand, 3A(b) and 3B(b) show that the gel particles according to the present embodiment, which are derived from dispersed particles formed by reversed-phase suspension polymerization, are spherical in shape and have a uniform particle size. It can be seen that the production method according to the present embodiment allows high-quality gel particles to be easily obtained.

Example 5 - Uniformity of particle size Granular carrier 2 (dried gel particles) obtained in Example 1-2 was classified using sieves with openings of 4 mm, 2 mm, 1 mm, and 0.25 mm to obtain particles with D (particle size) > 4 mm, 4 mm ≥ D > 2 mm, 2 mm ≥ D > 1 mm, 1 mm ≥ D > 0.25 mm, and 0.25 mm ≥ D. Figure 4 shows the results, and is a graph showing the particle size distribution of granular carrier 1-2.
From FIG. 4, it can be seen that 90% by mass or more of the frequency (mass%) of the granular carrier 2 has a particle size D in the range of 2 mm or more and less than 4 mm, and that the granular carrier 2 has excellent uniformity of particle size.

Example 6: Uniformity of particle shape and particle size Figure 2 is a photograph of the granular carrier 12 obtained in Examples 3-4. (a) shows the dried gel particles, and (b) shows the water-absorbed gel particles. From the photograph in Figure 2, it can be seen that the granular carrier 12 is dominated by roughly spherical particles and has excellent particle size uniformity.

The present invention is not limited to the above-described embodiments, and various modifications can be made in the implementation stage without departing from the spirit of the invention. Furthermore, the various embodiments may be implemented in appropriate combinations, in which case the combined effects can be obtained. Furthermore, the above-described embodiments include various inventions, and various inventions can be extracted by combining selected elements from the multiple elements disclosed. For example, if the problem can be solved and the desired effect can be obtained even if some elements are deleted from all elements shown in the embodiments, the configuration from which these elements are deleted can be extracted as an invention.

Claims (20)

A granular carrier containing a crosslinked salt of carboxyalkyl cellulose, the viscosity of which when in a 1% by weight aqueous solution at 25°C is in the range of 5 mPa·s or more and 300 mPa·s or less, and which is a gel particle derived from dispersed particles in a reverse phase suspension, and which is used as a drug carrier . 2. The granular carrier according to claim 1, wherein the average particle size in a dry state is in the range of 0.2 mm to 6 mm. 3. The granular carrier according to claim 1, wherein the average particle size in a water-absorbed state is in the range of 2 mm to 30 mm. 4. The granular carrier according to claim 1, wherein the dispersion medium of the reversed phase suspension is a low-polarity organic solvent having a relative dielectric constant of 10 or less. 5. The granular carrier according to claim 1, wherein the dispersion medium of the reversed phase suspension is liquid paraffin or silicone oil. 6. The granular carrier according to claim 1 , wherein the viscosity of the carboxyalkyl cellulose and/or salt thereof is 5 mPa·s or more and 100 mPa·s or less. 6. The granular carrier according to claim 1, wherein the viscosity of the carboxyalkyl cellulose and/or salt thereof is 5 mPa·s or more and 50 mPa·s or less. A granular pharmaceutical composition comprising a granular carrier described in any one of claims 1 to 7 and a liquid composition supported on the granular carrier and containing at least one pharmaceutical selected from pharmaceuticals having aromatic, deodorizing, deodorizing, insect repellent, insecticidal or antifungal properties. 9. The granular pharmaceutical composition according to claim 8 , which is an air freshener composition or a deodorant composition. An absorbent article comprising a granular carrier comprising a crosslinked salt of carboxyalkyl cellulose, the viscosity of which at 25°C in a 1% by mass aqueous solution is in the range of 5 mPa·s or more and 300 mPa·s or less, and the granular carrier is a gel particle derived from dispersed particles in a reverse phase suspension . The absorbent article according to claim 10, which is any one selected from the group consisting of disposable diapers, sanitary products, sweat pads, breastfeeding pads, incontinence pads, and pet toilets. A method for producing a granular carrier comprising gel particles containing a crosslinked product of a carboxyalkyl cellulose salt, comprising:
A carboxyalkyl cellulose and/or a salt thereof having a viscosity of 5 mPa s or more and 300 mPa s or less in a 1 mass% aqueous solution at 25°C is dissolved in an alkaline aqueous solution to prepare a carboxyalkyl cellulose salt aqueous solution;
The method for producing a granular carrier includes: preparing a mixture of the aqueous solution of a carboxyalkyl cellulose salt and a crosslinking agent; dispersing the mixture in a low-polarity organic solvent to form a suspension; and proceeding with crosslinking polymerization of the carboxyalkyl cellulose salt in the suspension to form dispersed particles containing crosslinked bodies of the carboxyalkyl cellulose salt, wherein the low-polarity organic solvent has a relative dielectric constant of 10 or less at 25°C and a kinematic viscosity of 10 ^mm2 /s or more at 37.8°C. The method according to claim 12 , wherein the low-polarity organic solvent is liquid paraffin or silicone oil. The kinematic viscosity of the low-polarity organic solvent at 37.8°C is 10 mm ² /s or more and 100 mm ² /s or more.
The method according to claim 12 or 13 , wherein the saturation temperature is 1000°C or less. The method according to any one of claims 12 to 14 , wherein the cross-linking polymerization of the carboxyalkyl cellulose salt in the suspension is carried out under stirring at a rotation speed of 50 rpm or more and 500 rpm or less. The method according to any one of claims 12 to 15 , wherein the viscosity of the carboxyalkyl cellulose and/or salt thereof is 5 mPa·s or more and 100 mPa·s or less. 17. The method according to claim 12 , wherein the mass ratio (X/Y) of the carboxyalkyl cellulose and/or salt thereof (X) to the crosslinking agent (Y) in the mixture is in the range of 10/2 to 10/5 . 18. The method according to claim 12 , wherein the crosslinking agent is a compound having two or more epoxy groups in the molecule. The method according to any one of claims 12 to 18 , wherein the granular carrier is used for carrying a drug. 19. The method according to any one of claims 12 to 18 , wherein the granular carrier is used as a water-absorbing material in an absorbent article.