JP2015160840A - Granule comprising hyaluronic acid, tablet produced using the same and swelling inhibition method - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a tablet or the like that inhibits its swelling while comprising hyaluronic acid or salt thereof.SOLUTION: A granule comprises the following component (A) and component (B): (A) at least one selected from the group consisting of hyaluronic acid and salt thereof; and particles (B) with an average particle diameter of 30-150 μm, the ratio between an average major axis (L) and an average minor axis (D) (average L/D) of 1-3, and an average repose angle of 50° or less, and having irregularities on the surfaces.

Description

  In the present invention, at least one selected from the group consisting of hyaluronic acid and a salt thereof, an average particle diameter of 30 to 150 μm, a ratio of an average major axis (L) and an average minor axis (D) (average L / D) The present invention relates to a granulated product containing 1 to 3, an average angle of repose of 50 ° or less and particles having irregularities on the surface, a tablet produced using the granulated product, and a method for suppressing swelling of the tablet.

  Hyaluronic acid and its salts can hold a lot of water due to its unique molecular structure. Hyaluronic acid and its salts having such characteristics are widely present in the body of animals such as skin and cartilage in a state of having a lot of moisture, thereby playing a role such as giving water retention and elasticity to the skin, for example. (Patent Document 1, Non-Patent Document 1). However, since hyaluronic acid and its salts in the body tend to decrease with aging, for example, the elasticity of skin and cartilage decreases with aging, which contributes to skin wrinkle formation and cartilage loss. It has become.

  On the other hand, many beauty / health-related products containing hyaluronic acid and its salts have been sold for the purpose of anti-aging. However, in a tablet containing hyaluronic acid or a salt thereof, hyaluronic acid or a salt thereof in the tablet easily absorbs moisture in the air. Therefore, if the content is high, the tablet swells and cracks. Furthermore, hyaluronic acid and its salts are low in fluidity and dispersibility, and therefore, there is a tendency that hyaluronic acid and its salts are unevenly present in the product manufacturing process and final product. If it does so, moisture content will increase locally in a tablet by localization of hyaluronic acid and its salt with high hygroscopicity, and this will bring about expansion and a crack of a tablet further.

  In addition, for the purpose of preventing such swelling and cracking, the content of hyaluronic acid and its salts in the tablets is reduced to increase the content of excipients, coating the tablets, and capsules other than tablets. However, in order to increase the cost of commercialization and make it difficult to take tablets, and to take the desired amount of hyaluronic acid and its salts There is concern that problems such as having to take a large number of tablets and capsules will arise.

  For this reason, it is important to provide a more desirable product that contains hyaluronic acid and its salts, but is suppressed in swelling.

JP 2008-99562 A

Takushi Yoshida et al. New Rem. & Clin. Vol. 58, NO. 8, p. 143-155, 2009

  Then, an object of this invention is to provide the tablet etc. by which swelling was suppressed, containing hyaluronic acid and its salt.

As a result of intensive studies by the inventor in view of the problem, the present inventor sometimes describes at least one selected from the group consisting of hyaluronic acid and salts thereof (hereinafter referred to as “component (A)”, “hyaluronic acid, etc.”). The average particle diameter is 30 to 150 μm, the ratio of the average major axis (L) to the average minor axis (D) (average L / D) is 1 to 3, the average angle of repose is 50 ° or less, and When a granulated product is produced using particles having irregularities on the surface (hereinafter sometimes referred to as “component (B)”) and a tablet is produced using the granulated product, the swelling of the tablet can be suppressed. I found. The present invention has been completed as a result of further studies based on this finding, and is described below.
Granulated product and tablet Item 1. Granules containing the following component (A) and component (B);
(A) At least one selected from the group consisting of hyaluronic acid and salts thereof (B) Average particle diameter is 30 to 150 μm, ratio of average major axis (L) to average minor axis (D) (average L / D) Particles having an average angle of repose of 50 ° or less and irregularities on the surface.
Item 2. Item 2. The granulated product according to Item 1, wherein the component (B) is a particle having a structure in which primary particles are aggregated.
Item 3. Item 3. The granulated product according to Item 1 or 2, wherein the component (B) is at least one selected from the group consisting of cellulose and starch.
Item 4. The tablet obtained by shape | molding the granulated material in any one of claim | item 1-3.
Item 1. Method for inhibiting tablet swelling A method for suppressing swelling of a tablet containing the following component (A), comprising a step of forming a granulated product obtained by bringing the following component (A) and component (B) into contact with each other;
(A) At least one selected from the group consisting of hyaluronic acid and salts thereof (B) Average particle diameter is 30 to 150 μm, ratio of average major axis (L) to average minor axis (D) (average L / D) Particles having an average angle of repose of 50 ° or less and irregularities on the surface.
Item 2. Item 2. The tablet swelling suppression method according to Item 1, wherein the component (B) is a particle having a structure in which primary particles are aggregated.
Item 3. Item 3. The tablet swelling suppression method according to Item 1 or 2, wherein the component (B) is at least one selected from the group consisting of cellulose and starch.

  According to the present invention, moisture absorption by hyaluronic acid or the like can be suppressed. For this reason, according to this invention, the swelling in a tablet can be suppressed and also the crack resulting from swelling of a tablet can be suppressed. According to the present invention, it is possible to provide a tablet with suppressed swelling without worrying about high hygroscopic properties such as hyaluronic acid.

FIG. 1 is a microscopic observation of the adhesion of hyaluronate to cellulose and starch.

Hereinafter, the present invention will be described in more detail.
1. Granulated product The granulated product of this invention contains the following (A) component and (B) component. That is, the granulated product of the present invention comprises (A) at least one selected from the group consisting of hyaluronic acid and salts thereof, and (B) an average particle size of 30 to 150 μm, an average major axis (L) and an average minor axis. The ratio (average L / D) to (D) is 1 to 3, the average angle of repose is 50 ° or less, and the surface has irregularities on the surface.
Component (A) The component (A) is at least one selected from the group consisting of hyaluronic acid and salts thereof. Hyaluronic acid and salts thereof may be natural products or synthetic products, and their origin may be any of animals, microorganisms and the like. Examples of the salt of hyaluronic acid include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium and magnesium, and metal salts such as aluminum. The salt of hyaluronic acid is preferably an alkali metal salt, more preferably a sodium salt.

  The molecular weight of the component (A) is not particularly limited, but preferably a weight average molecular weight of 1000 to 300,000 is exemplified, more preferably 3000 to 10,000.

  The component (A) may be a commercially available product, and examples thereof include hyaluronic acid LM (manufactured by NC Corporation), hyalopure (manufactured by Maruha Nichiro Foods Co., Ltd.), and hyabest (manufactured by QP Corporation). These may be used alone or in combination of two or more.

Content of (A) component in a granulated material is not restrict | limited unless the effect of this invention is prevented. For example, the total content of the component (A) in the granulated product is preferably 5 to 50% by weight, more preferably 10 to 40% by weight, still more preferably 15 to 35% in the granulated product. Weight percent is exemplified. Usually, a tablet comprising a granulated product containing the component (A) at a concentration within this range swells and breaks easily due to the absorption of moisture in the air, but it swells when granulated with the component (B) described later. And can be made into a tablet which is hard to break.
Component (B) The component (B) has an average particle size of 30 to 150 μm, an average major axis (L) to average minor axis (D) ratio (average L / D) of 1 to 3, and an average angle of repose of 50 °. It is the following and is a particle | grain which has an unevenness | corrugation on the surface. Here, the unevenness is not limited as long as the effect of the present invention can be obtained, and examples of one particle having a height difference on at least a part of the surface thereof, and the average particle diameter of the particle is 30 to 150 μm. From this, what can observe the unevenness | corrugation in a microscope (magnification 100-1000 times) is illustrated. As an example of the particles having such irregularities, the particles having irregularities shown in FIGS. According to such particles, for example, the component (A) can be preferably attached around the component (B) as described later.

  Although it does not restrict | limit as long as the effect of this invention is acquired as such (B) component, More preferably, 50-150 micrometers is more preferable as an average particle diameter, More preferably, 80-150 micrometers is illustrated. Further, the component (B) is not limited as long as the effect of the present invention is obtained, but the average L / D is more preferably 1 to 2.5, still more preferably 1 to 2, particularly preferably 1 to 1.5. Illustrated. The component (B) is not limited as long as the effect of the present invention is obtained, but the average angle of repose is more preferably 45 ° or less, and further preferably 40 ° or less. The lower the average angle of repose, the higher the fluidity and the better. Therefore, the lower limit is not particularly limited, but it can be used if it is 10 ° or more. (B) As a component, what has these characteristics is still more preferable. When (B) component which has this characteristic is granulated with the said (A) component, (A) component will be especially easy to adhere to the surface, and will become easy to disperse | distribute in a tablet.

  In the present invention, the average particle size of the component (B) is measured as follows. For example, after the component (B) is dispersed in water, the particle size of the component (B) is measured with a laser diffraction particle size distribution meter (LA-910, manufactured by Horiba, Ltd.), and the particles having an accumulated volume of 50% are average particles. It can be a diameter.

  In the present invention, the average L / D is measured as follows. For example, the major axis (L) and minor axis (D) of 400 components (B) can be measured with an optical microscope image, and the average value can be taken as the average L / D.

  In the present invention, the average angle of repose is measured as follows. For example, it can be measured using a Sugihara style angle of repose measuring instrument (slit size depth 10 × width 50 × height 14 mm, protractor installed at a position of width 50 mm). For example, using a quantitative feeder, the dynamic self-fluidity when the component (B) is dropped into the slit at 3 g / min is measured, and the angle between the bottom of the device and the porous material forming layer is the repose angle.

  The component (B) is not limited as long as the effects of the present invention can be obtained, but those having a structure in which primary particles are aggregated (aggregated structure) are exemplified. In the present invention, the aggregated structure includes those having a structure in which the aggregated structure of primary particles is further aggregated.

  Further, the component (B) is not limited as long as the above conditions are satisfied and the effect of the present invention is obtained, and any component such as an organic substance or an inorganic substance may be used. Examples thereof include cellulose and starch. As the component (B), commercially available products may be used. For example, porous crystalline cellulose such as Theolas KG-802, Theolas FU-F711, Theolas FU-F702 (all manufactured by Asahi Kasei Chemicals Co., Ltd.), Perfiller 102 (Freund Porous starch such as Sangyo Co., Ltd.). These may be used alone or in combination of two or more.

  Content of (B) component in a granulated material is not restrict | limited unless the effect of this invention is prevented. For example, the total content of the component (B) in the granulated product is preferably 50 to 95% by weight in the granulated product, more preferably 60 to 90% by weight, still more preferably 65 to 85%. Weight percent is exemplified.

  Moreover, the content rate of (A) component and (B) component is not restrict | limited unless the effect of this invention is prevented. For example, with respect to 1 part by weight of the total amount of component (A), the amount of component (B) is preferably 0.1 parts by weight or more, more preferably 0.5 parts by weight or more, even more preferably 1 part by weight or more. Preferably it is 2 parts by weight or more. Although an upper limit is not specifically limited, 10 weight part or less is illustrated, Preferably it is 8 weight part or less.

Moreover, content of the (A) component and (B) component in a granulated material is not restrict | limited unless the effect of this invention is prevented. For example, the content in these granulated materials is the total amount of the component (A) and the component (B), preferably 10 to 100% by weight, more preferably 15 to 100% by weight in the granulated material, More preferably, 20 to 100% by weight is exemplified.
Silicon dioxide In the present invention, the granulated product can further contain silicon dioxide. By containing silicon dioxide, moisture absorption of the component (A) can be further suppressed. The silicon dioxide is not limited as long as the effects of the present invention can be obtained, but preferably silicon dioxide having a structure in which primary particles are aggregated (aggregated structure) is exemplified. In the present invention, the aggregated structure includes those having a structure in which the aggregated structure of primary particles is further aggregated.

  Although it will not restrict | limit as long as the effect of this invention is acquired as silicon dioxide, Preferably an average particle diameter is 1-10 micrometers, More preferably, what is 2-7 micrometers is illustrated.

  Commercially available silicon dioxide may be used, for example, silo page 720, silo page 721, silo page 760, silo page 770 (all manufactured by Fuji Silysia Chemical Co., Ltd.), Carplex CS-500 (DSL Japan Co., Ltd.) Company-made). These may be used alone or in combination of two or more.

  The content of silicon dioxide in the granulated product is not limited as long as the effect of the present invention is not hindered. In the case of containing silicon dioxide, for example, the content of silicon dioxide in the granulated product is preferably 0.05 to 5% by weight, more preferably 0.05 to 4% by weight, and still more preferably 0.1%. -3.5 wt% is exemplified.

Moreover, the content rate of (A) component and silicon dioxide is not restrict | limited unless the effect of this invention is prevented. For example, silicon dioxide is preferably 0.01 parts by weight or more, more preferably 0.05 parts by weight or more, and further preferably 0.1 parts by weight or more with respect to 1 part by weight of the total amount of component (A). Although an upper limit is not specifically limited, 1 weight part or less is illustrated, Preferably it is 0.8 weight part or less.
The granulated product of the present invention such as a method for producing a granulated product has a structure in which the component (A) is attached around the component (B). The granulated product of the present invention is not limited as long as it has the structure, and can be easily obtained by bringing the component (A) and the component (B) into contact with each other by mixing or the like. From the viewpoint that the component (A) has a characteristic of easily absorbing moisture, the contact is preferably performed by dry mixing or the like, and a conventionally known treatment such as dry granulation may be performed as necessary.

  Usually, since the granulated product of the present invention adheres to the periphery of the (B) component as described above, the granulated product is bulky than the size of the (B) component itself, As shown in the Example mentioned later, (A) component covers so that at least one part surrounding (B) component may be wrapped. More preferably, the granulated product of the present invention is exemplified by a structure in which the component (A) covers the entire component (B) so as to enclose the component (B), more preferably the component (A) covers the component (B) as a whole. The structure which covers without gap is illustrated. What is necessary is just to observe this structure by arbitrary methods, for example, as shown in the Example mentioned later, the method of fractionating the granulated material of this invention by sieving etc. and observing using a microscope is illustrated.

  In addition, since the granulated product of the present invention has the component (A) attached around the component (B), the fluidity and dispersibility of the granulated product are, for example, those of the component (A) itself. It is higher than fluidity and dispersibility. The fluidity and dispersibility may be observed by an arbitrary method. For fluidity, for example, as shown in the examples described later, the granulated material is collected in a container such as a glass bottle, and the inside of the bottle is changed by changing the inclination of the bottle. A method of observing the quality of the fluidity by moving the solid matter of the product by visual observation is exemplified. Moreover, about dispersibility, as shown in the Example mentioned later, the method of fractionating the granulated material of this invention and observing using a microscope is illustrated.

The granulated product of the present invention is not limited to this, and the size of the granulated product is appropriately set depending on the type of the component (A) and the component (B) to be used, the content and ratio of each component, the contact time thereof, and the like. Good. From the viewpoint of producing a tablet using the granulated product of the present invention, as an indication of the size of the granulated product of the present invention, an average particle size of 10 to 1000 μm is exemplified, and the obtained granulated product is more easily obtained. More preferably, an average particle diameter of 100 to 800 μm is exemplified from the viewpoint of tablets. What is necessary is just to measure the magnitude | size of the granulated material of this invention by the conventionally well-known arbitrary methods, for example, the method of measuring using a microscope is illustrated.
Optional Other Components The granulated product of the present invention may contain other components that can be used pharmaceutically and / or foodologically as necessary, as long as the effects of the present invention are not hindered. Such optional other ingredients include binders, disintegrants, lubricants, absorption enhancers, adsorbents, surfactants, fillers, preservatives, stabilizers, buffers, pH adjusters, dispersants, Excipients such as plasticizers are exemplified. Although not limiting the present invention, such excipients include maltose, methylcellulose, potassium phosphate, polyvinylpyrrolidone, hydroxypropylcellulose, hypromellose, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, poly Oxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, crospovidone, povidone, purified talc, stearate, polyethylene glycol, lactose, sucrose, sodium chloride, glucose, calcium carbonate, kaolin, sodium hydrogen phosphate, glycerin Examples include fatty acid esters. When these excipients are contained, the content of the excipient in the granulated product is preferably 10 to 90% by weight, more preferably 10 to 85% by weight in the granulated product, as a total amount. More preferably, it is 20 to 80% by weight.

  In addition, the granulated product of the present invention includes components such as amino acids, vitamins, herbal medicines, herbal medicines, plant extracts, collagen, glucosamine, chondroitin sulfate, dietary fiber, inorganic salts and the like as optional other components. You may make it contain.

  These optional components may be added after the (A) component and the (B) component are brought into contact with each other by mixing or the like, or may be mixed together when the (A) component and the (B) component are mixed. . Those optional components, contents, and the like may be appropriately set by those skilled in the art within a range not impeding the effects of the present invention.

According to such a granulated product of the present invention, the component (A) can be preferably adhered around the component (B). Therefore, according to the present invention, a granulated product in which the component (A) is preferably attached around the component (B) can be obtained. Moreover, according to such a granulated product of the present invention, it is possible to obtain a granulated product having improved fluidity despite containing the component (A). Moreover, according to such a granulated product of the present invention, it is possible to obtain a granulated product with improved dispersibility despite containing the component (A). From these viewpoints, it can be said that the present invention provides a method for improving the fluidity and / or dispersibility of the component (A). And the below-mentioned tablet can be simply obtained by using the granulated material of this invention.
2. Tablet The present invention further provides a tablet. The tablet of this invention is not restrict | limited as long as it is manufactured using the said granulated material, For example, the said granulated material can be manufactured and shape | molded (a shaping | molding is also included). Specifically, the tablet of the present invention can be produced, for example, by tableting the granulated product, and the tablet of the present invention can be produced by kneading the granulated product and then molding it. it can. The tablet of the present invention is not limited as long as it is produced. For example, the tablet can be produced by tableting or kneading / molding after mixing any other components as necessary with the granulated product, or (A) What is necessary is just to manufacture in accordance with a conventional method, such as mixing and granulating a component, (B) component, and arbitrary other components together, and manufacturing by tableting or kneading | mixing and shaping | molding. The arbitrary other components are not limited as long as the effects of the present invention are obtained, and the above-described arbitrary various components are exemplified. Those components, contents, and the like may be appropriately set by those skilled in the art as long as the effects of the present invention are not hindered.

  The content of the component (A) in the tablet is not limited as long as the effect of the present invention is not hindered. For example, the total content of the component (A) in the tablet is preferably 5 to 50% by weight, more preferably 10 to 40% by weight, and further preferably 15 to 35% by weight in the tablet. Is done. Usually, a tablet containing the component (A) at a concentration within this range swells and breaks easily due to the absorption of moisture in the air. However, according to the present invention, the tablet can be suppressed and hardly cracked.

  Moreover, content of (B) component in a tablet is not restrict | limited unless the effect of this invention is prevented. For example, the total content of the component (B) in the tablet is preferably 50 to 95% by weight, more preferably 60 to 90% by weight, and still more preferably 65 to 85% by weight in the tablet. Is done.

  Further, the content ratio of the component (A) and the component (B) in the tablet is not limited as long as the effect of the present invention is not hindered. For example, in the tablet, the total amount of the component (B) is preferably 0.1 parts by weight or more, more preferably 0.5 parts by weight or more, further preferably 1 part by weight with respect to 1 part by weight of the total amount of the component (A). Above, especially preferably 2 parts by weight or more. Although an upper limit is not specifically limited, 10 weight part or less is illustrated, Preferably it is 8 weight part or less.

  Further, the contents of the component (A) and the component (B) in the tablet are not limited as long as the effects of the present invention are not hindered. For example, the total content of these tablets is preferably 10 to 100% by weight, more preferably 15 to 100% by weight, and still more preferably 20 to 100% by weight in the tablet.

  Further, silicon dioxide may be contained in the tablet, and the content of silicon dioxide is not limited as long as the effect of the present invention is not hindered. Silicon dioxide is described in the same manner as described above. When silicon dioxide is contained, for example, the content of silicon dioxide in the tablet is preferably 0.05 to 5% by weight, more preferably 0.05 to 4%. A weight percent, more preferably 0.1 to 3.5 weight percent is exemplified.

  Moreover, the content rate of (A) component and silicon dioxide in a tablet is not restrict | limited unless the effect of this invention is prevented. For example, silicon dioxide is preferably 0.01 parts by weight or more, more preferably 0.05 parts by weight or more, and further preferably 0.1 parts by weight or more with respect to 1 part by weight of the total amount of component (A). Although an upper limit is not specifically limited, 1 weight part or less is illustrated, Preferably it is 0.8 weight part or less.

  In addition, any other components will be described in the same manner as described above.

  The shape and size of the tablet of the present invention are not limited as long as the effect of the present invention can be obtained, and can be appropriately adjusted according to the use object, purpose of use, and the like. For example, the size of the tablet of the present invention is exemplified by a size that is easy to take. As a guideline, the diameter is preferably 20 mm or less, more preferably 5 to 10 mm. Moreover, the size which the tablet of this invention is easy to take is illustrated as thickness of the tablet, Preferably it is 10 mm or less in diameter, More preferably, 2-5 mm is illustrated as a standard.

  As described above, in the granulated product of the present invention, the component (A) is preferably adhered around the component (B), and the fluidity and dispersibility of the granulated product are thereby improved by the flow of the component (A) itself. Higher than dispersibility and dispersibility. Therefore, in the tablet obtained by using the granulated product of the present invention, the localization of the component (A) is more significant than the tablet manufactured without preferably attaching the component (A) around the component (B). Is suppressed. As described above, in the tablet of the present invention, moisture absorption and further swelling of the component (A) are suppressed. Further, the degree of cracking is further reduced in the tablet of the present invention. For this reason, the skin of the tablet of the present invention is not essential. However, the tablet of the present invention is a tablet with a normal coating as required, such as sugar-coated tablets, gelatin-encapsulated tablets, film-coated tablets, double tablets, multilayer tablets, capsules, hyaluronic acid, etc. It is good also as a solid form which controlled (for example, rapid release property, sustained release property, etc.). These can be prepared by a conventionally known method.

  In addition, in this way, the tablet of the present invention suppresses moisture absorption itself and further swelling and cracking despite containing the component (A). The degree of moisture absorption suppression of the tablet of the present invention may be evaluated by a conventionally known method. As an example of the method, for example, as shown in the examples described later, the tablet is allowed to stand for 2 hours in a constant temperature and humidity chamber (room temperature 25 ° C., relative humidity 60%), and then the tablet is measured using a moisture measuring device. It can be evaluated by measuring the moisture absorption rate. It can be determined that moisture absorption is suppressed as the moisture absorption rate is low. As another example of the method, the degree of swelling and the degree of cracking in the tablet of the present invention are visually observed, and it can be evaluated that moisture absorption is suppressed as the degree of swelling and the degree of cracking are smaller. What is necessary is just to observe visually, for example about the grade of the swelling in a tablet, and also the grade of a crack.

  The tablet of this invention is good also as a pharmaceutical, a quasi-drug, a beauty food, health food (nutrient functional food, food for specified health), and a supplement based on the effect | action of (A) component.

  The dose of the tablet of the present invention may be appropriately set depending on the use of the tablet, the age of the administration subject, sex, degree of symptoms, etc., but the total amount of hyaluronic acid and the like per day for one adult (body weight 60 kg) The dose is usually about 10 to 1000 mg, preferably about 50 to 500 mg. Moreover, what is necessary is just to divide and administer the tablet of this invention 1 to several times a day.

According to such a tablet of the present invention, the content of the component (A) in the tablet can be increased without worrying about the high hygroscopic properties and localization of the component (A). For this reason, according to this invention, although it is a tablet, (A) component can be ingested efficiently. Moreover, since the content rate of the excipient | filler etc. in a tablet can be reduced, the deterioration of the tablet production cost and ease of drinking can be suppressed.
3. The present invention further includes a method for suppressing swelling of a tablet containing the component (A), further comprising a step of forming a granulated product obtained by bringing the component (A) and the component (B) into contact with each other. provide.

  The component (A), component (B), contact, granulated product, molding, tablet and the like in the method are also described in the same manner as described above. In this method, as described above, tablets are coated tablets, such as sugar-coated tablets, gelatin-encapsulated tablets, film-coated tablets, double tablets, multilayer tablets, capsules, hyaluronic acid and the like (eg, rapid release). Solid forms with controlled release, sustained release, etc.) may be used, and these are also explained in the same manner.

  According to such a method of the present invention, swelling of the tablet containing the component (A) can be suppressed. Further, by using such a method of the present invention, it is possible to provide a tablet in which the content of the component (A) in the tablet is increased without worrying about the high hygroscopic property of the component (A). In spite of being a tablet, the component (A) can be efficiently ingested. In addition, by using such a method of the present invention, the content ratio of excipients and the like in the tablet can be reduced, and since the coating is not essential, the cost to commercialize tablets and the ease of drinking are deteriorated. Can be suppressed.

  Moreover, according to such a method of the present invention, it is possible to suppress moisture absorption in the tablet despite containing the component (A), and further to reduce the degree of cracking. Accordingly, the present invention provides a method for reducing moisture absorption and / or cracking of a tablet containing the component (A), comprising the step of forming a granulated product obtained by bringing the component (A) and the component (B) into contact with each other. It can be said that it provides.

EXAMPLES Hereinafter, although an Example is shown and this invention is demonstrated in detail, this invention is not limited to these.
Test example 1
1. Preparation of Granulated Product and Tablet According to the composition (weight ratio) shown in Table 1, each component was mixed and sieved (mesh size: 500 μm) to obtain a granulated product. Each obtained granulated product was compression-molded (tablet pressure: 15 kN) with a table breath machine (trade name: TB-20H, manufactured by NP System Co., Ltd.) to produce tablets (180 mg per tablet).
2. Evaluation method of granulated product and tablet The adhesion of hyaluronate to cellulose and starch was evaluated by observing each prepared granulated product with a microscope. Specifically, each granulated product produced was observed with a microscope (trade name: VHX-D510, manufactured by Keyence Corporation) (lens magnification Z50 × 200), and the hyaluronate was entirely on the cellulose and starch without any gaps. Those that adhered were evaluated as “◎”, those that adhered as a whole, “◯”, those that adhered partially as “Δ”, and those that did not adhere as “x”.

  Moreover, it evaluated about the fluidity | liquidity and dispersibility of each produced granulated material. Specifically, 5 g of each obtained granulated product was collected in a 50 ml glass bottle, and the solid in the bottle was moved by changing the inclination of the bottle, and the quality of the fluidity was visually observed. Using the granulated product obtained in Comparative Example 2 as a criterion for “×” having very poor fluidity, “◯” indicates that fluidity is good, “△” indicates that it is poor, and “×” indicates that it is very poor. It was evaluated in three stages. Each granule was observed with a microscope (trade name: VHX-D510, manufactured by Keyence Corporation) (lens magnification Z50 × 200), and the granule obtained in Comparative Example 2 had very poor dispersibility. As a criterion for “x”, a grade having good dispersibility was evaluated in three grades: “◯”, bad grade “Δ”, and very poor grade “x”.

Moreover, the moisture absorption rate and swelling of each produced tablet were evaluated. Specifically, each of the produced tablets was allowed to stand for 2 hours at room temperature of 25 ° C. and a relative humidity of 60% using a thermo-hygrostat (trade name: LH21-15M, manufactured by Nagano Science Co., Ltd.). Thereafter, the moisture absorption rate of the tablets was measured using a moisture measuring device (trade name: Aqua Arab, manufactured by Decagon Devices, Inc.). In addition, by visually observing the degree of swelling of the tablet, “○” indicates that the tablet does not swell, “Δ” indicates that the tablet swells in part, and indicates that the tablet swells as a whole. Evaluated as “x”.
3. The results are shown in Table 1 and FIG.

  As shown in Table 1, when hyaluronate and fibrous cellulose were mixed (Comparative Examples 2 to 4), substantially no adhesion of hyaluronate to fibrous cellulose was observed. Moreover, in Comparative Examples 2-4, although the moisture absorption rate fell compared with the case where only a hyaluronate salt is contained (Comparative Example 1), still the whole swelling was recognized by the tablet.

  On the other hand, when hyaluronate and porous cellulose were mixed (Examples 1 to 7, 12 to 17), hyaluronate was adhered around the porous cellulose. Moreover, in Examples 1-7 and 12-17, compared with Comparative Examples 2-4, the moisture absorption rate could further be reduced and the swelling of the tablet could also be suppressed. Moreover, in Examples 1-7 and 12-17, the fluidity | liquidity and the dispersibility were able to be improved compared with Comparative Examples 2-4.

  Moreover, also when hyaluronate and porous starch are mixed (Examples 8 to 10), hyaluronate is sufficiently adhered around the porous starch, and the moisture absorption rate can be reduced. It was also possible to suppress the swelling. Also in this case, fluidity and dispersibility could be improved as compared with Comparative Examples 2-4.

  Further, when porous cellulose and porous starch are used in combination (Example 11), hyaluronate is sufficiently adhered around porous cellulose and porous starch, and the moisture absorption rate can be reduced. Also, swelling of the tablet could be suppressed. Also in this case, fluidity and dispersibility could be improved as compared with Comparative Examples 2-4.

  Further, it was found that when silicon dioxide was used in combination, the moisture absorption suppressing effect was increased (for example, Example 6 and Example 7, Example 8 and Example 9).

  A specific state in which hyaluronate is adhered to cellulose or starch is illustrated in FIG. In FIG. 1, (a) is the granulated product obtained in Comparative Example 1, (a) is the granulated product obtained in Comparative Example 2, (c) is the granulated product obtained in Example 7, ( D) shows the granulated product obtained in Example 8. Although not described in Table 1, (e) is the fibrous cellulose used in Comparative Example 2, (f) is the porous cellulose used in Example 7, and (g) is in Example 8. Each of the used porous starches was observed with a microscope.

  As is clear from FIG. 1, in the case of (c) or (d) where hyaluronate is mixed with porous cellulose or porous starch, there is no gap between the hyaluronate around the porous cellulose or porous starch. It turned out that it adhered as a whole. On the other hand, in the case of (i) in which hyaluronate is mixed with fibrous cellulose, it can be seen that hyaluronate was not substantially adhered around the fibrous cellulose.

The particles such as porous cellulose and porous starch used here have an average particle diameter of 30 to 150 μm, an average L / D of 1 to 3, an average angle of repose of 50 ° or less, and unevenness on the surface. Therefore, it is considered that the hyaluronate and these particles were efficiently brought into contact with each other because of such characteristics, and the hyaluronate was preferably attached to the periphery of the particles. In addition, these particles have higher fluidity than fibrous cellulose. Therefore, it is considered that the hyaluronate and the particles were uniformly and efficiently in contact with each other, and the hyaluronate was preferably adhered to the periphery of the particles. It is done. For this reason, hyaluronate was dispersed in the granulated material and did not exist in one lump. In addition, the tablet produced using the granulated product is broken so that the aggregated structure of the particles is crushed by compression during the production, and hyaluronate is evenly confined between the particles. It is thought that moisture absorption by the acid salt was suppressed.
Test example 2
Granulation in the same manner as in Test Example 1 except that hyaluronate, porous cellulose, porous starch, fibrous cellulose and silicon dioxide were mixed according to the composition (weight ratio) shown in Table 2, and then maltose was mixed. The product was prepared, and this was tableted to produce tablets (180 mg per tablet) (Examples 18 to 23 and Comparative Example 5). Subsequently, the dispersibility of each produced granulated product and the degree of swelling of each tablet were evaluated in the same manner as in Example 1. The results are shown in Table 2.

As is apparent from Table 2, even when maltose is used in addition to hyaluronate, porous cellulose and porous starch, the dispersibility of hyaluronate is improved in each obtained granulated product, Moreover, swelling was suppressed in each tablet (Examples 18 to 23). Maltose is one of the components used for the purpose of adjusting the hardness and disintegration of tablets, and even when these other components are further used, excellent tablets with suppressed swelling are used. I was able to get it. On the other hand, in the tablet (comparative example 5) using hyaluronate and fibrous cellulose in combination, the dispersibility of hyaluronate in the granulated product is poor even when maltose is used, Swelling was observed, which was not preferable.
Test example 3
Tablets (180 mg per tablet) were prepared in the same manner as in Test Example 2 except that each component was mixed according to the composition (weight ratio) shown in Table 3 (Examples 24-33 and Comparative Examples 6 and 7). Subsequently, the dispersibility of each produced granulated product and the degree of swelling of each tablet were evaluated in the same manner as in Example 1. The results are shown in Table 3.

  As is clear from Table 3, even when the blending amount of porous cellulose relative to hyaluronate is different, the dispersibility of hyaluronate is improved in the granulated product using hyaluronate and porous cellulose in combination, Swelling was suppressed in the tablets (Examples 24-33).

Claims (5)

Granules containing the following component (A) and component (B);
(A) At least one selected from the group consisting of hyaluronic acid and salts thereof (B) Average particle diameter is 30 to 150 μm, ratio of average major axis (L) to average minor axis (D) (average L / D) Particles having an average angle of repose of 50 ° or less and irregularities on the surface. The granulated product according to claim 1, wherein the component (B) is a particle having a structure in which primary particles are aggregated. The granulated product according to claim 1 or 2, wherein the component (B) is at least one selected from the group consisting of cellulose and starch. The tablet obtained by shape | molding the granulated material in any one of Claims 1-3. A method for inhibiting swelling of a tablet containing the component (A), comprising a step of forming a granulated product obtained by bringing the following component (A) and component (B) into contact with each other;
(A) At least one selected from the group consisting of hyaluronic acid and salts thereof (B) Average particle diameter is 30 to 150 μm, ratio of average major axis (L) to average minor axis (D) (average L / D) Particles having an average angle of repose of 50 ° or less and irregularities on the surface.