WO2013129551A1 - Solid composition - Google Patents

Description

Solid composition

The present invention relates to a solid composition. More specifically, the present invention relates to a solid composition containing a polysaccharide containing galactosamine and glucuronic acid, which has high hardness and excellent breakage resistance.

Polysaccharides containing galactosamine and glucuronic acid are biopolymers that are particularly distributed in cartilage tissue. Polysaccharides containing galactosamine and glucuronic acid protect the cornea surface, treat or prevent sensorineural hearing loss (acoustic trauma), chronic nephritis, neuralgia, arthralgia, low back pain, shoulder periarthritis (fifty shoulders), open laparotomy It is used to prevent post-surgical adhesions and is blended in many pharmaceuticals and foods.

For example, Patent Document 1 discloses a composition used for treatment of connective tissues of humans and animals, which includes a glycosaminoglycan such as chondroitin, which is a polysaccharide containing galactosamine and glucuronic acid, and an amino sugar such as glucosamine. Is disclosed. Patent Document 2 contains chondroitin sulfate, which is a polysaccharide containing galactosamine and glucuronic acid, L-carnitines and / or glucosamine, and an excipient as a composition suitable for prevention and treatment of joint disorders. A composition is disclosed.

On the other hand, polysaccharides containing galactosamine and glucuronic acid, and salts thereof, are inferior in compression moldability, are hard to produce when made into a solid composition, and are prone to wear or breakage in production processes and distribution. There was a problem that it was easy to do. When a large amount of binders, excipients and the like are used to improve the compression moldability of the solid composition, the above problem is solved, but the solid composition becomes large and difficult to take, or There is a problem that the number or amount of the solid composition to be taken becomes large and the production cost is high, and it is difficult to take.

In contrast, a polysaccharide salt containing galactosamine and glucuronic acid, which is inferior in compression moldability such as sodium chondroitin sulfate, is prepared using a solution in which an excipient and a binder are dissolved or suspended. It has been reported that a tablet without tableting trouble can be produced by granulating and tableting the obtained granule (see Patent Document 3).

However, this production method is not a simple method, and the development of more useful means is required.

JP-T 9-503197 JP 2000-53569 A JP 2007-137802 A

An object of the present invention is to provide a solid composition containing a polysaccharide containing galactosamine and glucuronic acid, which has high hardness and excellent breakage resistance.

As a result of repeated studies by the present inventors, high hardness can be obtained by blending cellulose, cellulose derivatives, and / or dextrin with a polysaccharide containing galactosamine and glucuronic acid having a specific average molecular weight, or a salt thereof. It has been found that a solid composition can be obtained, and the present invention has been completed.

That is, the present invention relates to the following [1] to [8].
[1] (A) at least one selected from the group consisting of galactosamine and glucuronic acid-containing polysaccharides, and salts thereof;
(B) containing at least one selected from the group consisting of cellulose, cellulose derivatives, and dextrins,
A solid composition in which the weight average molecular weight of component (A) is 1000 to 20000 Da.
[2] The component (A) includes at least one selected from the group consisting of chondroitin, chondroitin sulfate A, chondroitin sulfate C, chondroitin sulfate D, chondroitin sulfate E, chondroitin sulfate K, and salts thereof. ] The solid composition of description.
[3] The solid composition according to [1] or [2], wherein the component (A) includes a sodium salt of a polysaccharide containing galactosamine and glucuronic acid.
[4] The solid composition according to any one of [1] to [3], wherein the component (B) includes at least one selected from the group consisting of cellulose, hydroxypropylcellulose, and dextrin.
[5] The solid composition according to any one of [1] to [4], which contains 0.01 to 100 parts by weight of component (B) with respect to 1 part by weight of component (A).
[6] The solid composition according to any one of [1] to [5], further comprising (C) at least one selected from the group consisting of glucosamine, glucosamine derivatives, and salts thereof.
[7] In the raw material for the solid composition, together with at least one selected from the group consisting of (A) a polysaccharide containing galactosamine and glucuronic acid, and a salt thereof, (B) from cellulose, cellulose derivative, and dextrin A method for increasing the hardness of a solid composition, comprising blending at least one selected from the group consisting of:
[8] In the raw material for the solid composition, together with at least one selected from the group consisting of (A) a polysaccharide containing galactosamine and glucuronic acid, and salts thereof, (B) cellulose, cellulose derivative, and dextrin A method for suppressing breakage of a solid composition, comprising blending at least one selected from the group consisting of:

The solid composition of the present invention has an excellent effect of having high hardness and excellent breakage resistance while containing a polysaccharide containing galactosamine and glucuronic acid which are inferior in compression moldability, or a salt thereof.

FIG. 1 is a diagram showing the results of Test Example 2. FIG. 2 is a diagram showing the results of Test Example 11.

The solid composition of the present invention is selected from the group consisting of (A) at least one selected from the group consisting of polysaccharides containing galactosamine and glucuronic acid, and salts thereof, and (B) cellulose, cellulose derivatives, and dextrins. The component (A) has a weight average molecular weight of 1000 to 20000 Da. The “solid composition” of the present invention is not particularly limited as long as it is a solid composition, and includes, for example, a solid composition that can be dissolved or suspended for internal use. Details will be described later.

<(A) component>
The polysaccharide containing galactosamine and glucuronic acid used in the present invention is not particularly limited as long as it contains galactosamine and glucuronic acid as constituent sugars. For example, N-acetyl-D-galactosamine and D-glucuronic acid are included. What is contained as a constituent sugar is illustrated. In the present specification, a polysaccharide containing galactosamine and glucuronic acid is sometimes referred to as polysaccharide A.

Specifically, for example, chondroitin, chondroitin sulfate A (chondroitin 4-sulfate), chondroitin sulfate C (chondroitin 6-sulfate), chondroitin sulfate D (sulfated chondroitin 6-sulfate, chondroitin E, chondroitin E) 6-sulfate), chondroitin sulfate K and the like. Of these, chondroitin, chondroitin sulfate A, chondroitin sulfate C, chondroitin sulfate D, and chondroitin sulfate E are preferable, and chondroitin sulfate A, chondroitin sulfate C, and chondroitin sulfate D are more preferable.

Polysaccharide A is obtained by extraction and purification from animal cartilage (eg, cartilage such as horse, cow, pig, chicken, eel, shark, ray, trout, carp, cod, salmon, squid, etc.) or collagen. Refined products obtained from shark cartilage, salmon cartilage and the like are exemplified. Moreover, not only the polysaccharide A obtained by refinement | purification but what pulverized the animal cartilage containing the polysaccharide A, and a synthetic product can also be used. Among these, purified polysaccharide A is preferable from the viewpoints of safety and absorbability. Polysaccharide A is commercially available or can be produced according to known methods.

The "(A) a salt of a polysaccharide containing galactosamine and glucuronic acid" in the present invention may be any pharmacologically (pharmaceutically) or physiologically acceptable salt of polysaccharide A. Examples of the pharmacologically or physiologically acceptable salt include organic acid salts, inorganic acid salts (for example, hydrochloride, sulfate, nitrate, hydrobromide, phosphate, etc.), salts with organic bases. (For example, salts with organic amines such as methylamine, triethylamine, triethanolamine, morpholine, piperazine, pyrrolidine, tripyridine, picoline, etc.), salts with inorganic bases [for example, ammonium salts; alkali metals (sodium, potassium, etc.) And alkaline earth metals (calcium, magnesium, etc., salts with metals such as aluminum, etc.). Preferably, it is a sodium salt of polysaccharide A, and examples thereof include chondroitin sulfate A sodium, chondroitin sulfate C sodium, and chondroitin sulfate D sodium.

As the salt of polysaccharide A, one synthesized according to a known method may be used, or a commercially available product may be used.

Polysaccharide A and salts thereof can be used alone or in any combination of two or more. Among them, it is preferable to use at least one selected from the group consisting of chondroitin, chondroitin sulfate A, chondroitin sulfate C, chondroitin sulfate D, chondroitin sulfate E, chondroitin sulfate K, and salts thereof, chondroitin sulfate A sodium, Chondroitin sulfate C sodium and chondroitin sulfate D sodium are more preferable. The total content of chondroitin sulfate A sodium, chondroitin sulfate C sodium, and chondroitin sulfate D sodium in component (A) is preferably 10% by weight (W / W)% or more, more preferably 20W / W% or more, and 50W / W. % Or more is more preferable.

The polysaccharide A and a salt thereof used in the present invention have a weight average molecular weight of 1000 to 20000 Da, preferably 1500 Da or more, more preferably 2000 Da or more, still more preferably 3000 Da or more, further preferably 5000 Da or more, preferably It is 20000 Da or less, more preferably 15000 Da or less. Further, it is 1000 to 20000 Da, preferably 1500 to 20000 Da, more preferably 2000 to 15000 Da, still more preferably 3000 to 15000 Da, and further preferably 5000 to 15000 Da. Usually, a polysaccharide containing galactosamine and glucuronic acid existing in a living body has a weight average molecular weight of about 50000 Da, and thus polysaccharide A and a salt thereof used in the present invention have a low molecular weight. In addition, in this specification, the weight average molecular weight of (A) component is calculated | required by the static light-scattering method, and can be specifically measured by the method as described in the below-mentioned Example. Moreover, when (A) component consists of a some polysaccharide, it is preferable that the weight average molecular weight as the whole (A) component contained in a solid composition becomes in the said range.

As a method for obtaining the above-mentioned molecular weight polysaccharide A and a salt thereof, any conventionally known method can be used without any particular limitation. For example, an alkaline treatment method in which a polysaccharide containing galactosamine and glucuronic acid and a salt thereof are decomposed and extracted with an alkaline solution, a neutral salt treatment method in which a polysaccharide containing galactosamine and glucuronic acid and a salt thereof are extracted with a neutral salt solution, Examples thereof include an enzyme treatment method in which a polysaccharide containing galactosamine and glucuronic acid and a salt thereof are reacted with a proteolytic enzyme such as a protease or pronase for degradation and extraction, or a combination thereof. Among these, the alkali treatment method and the enzyme treatment method are preferred, and the enzyme treatment method is more preferred because of the high recovery rate of polysaccharides containing low molecular weight galactosamine and glucuronic acid, and salts thereof. Moreover, it is preferable that the low molecular weight polysaccharide salt containing galactosamine and glucuronic acid is formed into a salt obtained by reducing the molecular weight of a polysaccharide containing galactosamine and glucuronic acid in advance. In addition, when polysaccharide A and its salt have a substituent, when the molecular weight is lowered, the position of the substituent and the ratio thereof do not substantially vary.

The treatment liquid (extract) containing the galactosamine and glucuronic acid-containing polysaccharide and its salt obtained by the above method may be subjected to removal of insoluble matter by centrifugation, filtration, etc. Filter aids may be used. Moreover, removal of a turbid component, deodorizing, decoloring, degreasing, etc. can also be performed by performing the activated carbon process etc. which use about 2.5 weight% activated carbon with respect to the extract which removed the insoluble matter. Further, it may be solidified and powdered once by a method such as spray drying (spray drying), evaporation drying, freeze drying and the like.

In the solid composition of the present invention, the content of at least one selected from the group consisting of polysaccharides containing galactosamine and glucuronic acid and salts thereof is preferably 0.001 W / W% or more, and 0.005 W / W. % Or more is more preferable, 0.01 W / W% or more is more preferable, 99 W / W% or less is preferable, 97 W / W% or less is more preferable, and 95 W / W% or less is more preferable. Further, 0.001 to 99 W / W% is preferable, 0.005 to 97 W / W% is more preferable, and 0.01 to 95 W / W% is more preferable. Further, since the solid composition of the present invention uses the component (A) having a low molecular weight, it becomes possible to increase the content of the component (A). For example, the content of the component (A) is preferably 30 W / W% or more. More preferably, it can be 50 W / W% or more. The “content of at least one selected from the group consisting of galactosamine and glucuronic acid-containing polysaccharides and salts thereof” refers to the content of the component (A) contained in the solid composition of the present invention. When there are a plurality of components (A), it means the total content.

<(B) component>
The cellulose, cellulose derivative, and dextrin used in the present invention are not particularly limited as long as they can be used for the solid composition.

Examples of cellulose derivatives in the present invention include hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, hydroxyethylcellulose, methylcellulose, ethylcellulose, carboxymethylethylcellulose, carboxymethylcellulose and salts thereof, cloth Carboxymethylcellulose and its sodium salt, cellulose acetate, etc. are mentioned. Hydroxypropylcellulose includes low substituted hydroxypropylcellulose.

Examples of dextrin in the present invention include dextrin, cyclodextrin, maltodextrin, poorly soluble dextrin and the like.

These may be used alone or in any combination of two or more. Among them, cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose and salts thereof, and dextrin are preferable, and cellulose, hydroxypropylcellulose, carboxy Methyl cellulose and its salts and dextrin are more preferred, and cellulose, hydroxypropyl cellulose, and dextrin are more preferred. The total content of cellulose, hydroxypropylcellulose, carboxymethylcellulose and salts thereof, and dextrins in component (B) is preferably 10% by weight (W / W)% or more, more preferably 30W / W% or more, and 50W / W%. The above is more preferable.

The cellulose used in the present invention is not particularly limited as long as it can be used for a solid composition. Examples thereof include crystalline cellulose described in the 16th revised Japanese Pharmacopoeia, microcrystalline cellulose, and powdered cellulose described in the 8th edition Food Additives Official Document. Suitable commercially available celluloses include, for example, Theolas (registered trademark) KG-801, KG-802, ST-100, ST-02, FD-101, FD-301, UF-F711, FD-F20, UF- F702, SC-900, SC-900S, RC-591S, RC-N30, CL-611S, DX-2, Avicel (registered trademark) PH-101, PH-102, PH-301, PH-302, PH-F20 RC-A591NF (all manufactured by Asahi Kasei Co., Ltd.), KC Flock (registered trademark) W-400G, 300G, 200G (all manufactured by Nippon Paper Chemicals Co., Ltd.) and the like, and Theolas KG-801, KG-802, ST- 100, FD-101, Avicel PH-101, PH-102, PH-301, and PH-302 are preferable.

The hydroxypropyl cellulose used in the present invention is not particularly limited as long as it can be used for a solid composition. Examples thereof include hydroxypropyl cellulose and low-substituted hydroxypropyl cellulose described in the 16th revised Japanese pharmacopoeia, and hydroxypropyl cellulose described in the 8th edition food additive official regulations. Examples of the low-substituted hydroxypropyl cellulose include hydroxypropyl cellulose having a hydroxypropoxy group content of about 5 to 16% by weight. Suitable commercially available products of hydroxypropyl cellulose include, for example, HPC-SSL, HPC-SL, HPC-L (all manufactured by Nippon Soda Co., Ltd.) and the like. Examples of suitable commercially available low-substituted hydroxypropylcellulose include LH-11, LH-21, LH-31, LH-22, LH-32, LH-20, LH-30, LH-32, And LH-33 (all manufactured by Shin-Etsu Chemical Co., Ltd.).

The hydroxypropyl methylcellulose used in the present invention is not particularly limited as long as it can be used for a solid composition. For example, hypromellose described in the 16th revision Japanese Pharmacopoeia, and hydroxypropylmethylcellulose described in the 8th edition food additive official regulations. Suitable commercially available products of hydroxypropyl methylcellulose include, for example, TC-5E, TC-5M, TC-5R, TC-5S, SB-4, 60SH-50, 65SH-50 (all manufactured by Shin-Etsu Chemical Co., Ltd.) Is mentioned.

The carboxymethyl cellulose and its salt used in the present invention are not particularly limited as long as they can be used for the solid composition. For example, carmellose, carmellose calcium, carmellose sodium, carmellose potassium described in the Pharmaceutical Additives Standard 2003, described in the 16th revision Japanese Pharmacopoeia, described in the 8th edition food additive official regulations Examples include carboxymethylcellulose calcium and carboxymethylcellulose sodium. Suitable commercially available products of carboxymethyl cellulose and salts thereof include, for example, Sunrose (registered trademark) SLD-F1, SLD-FM, FT-1, F04HC, F10LC, F20HC, F300HC, FF330M, FF330M-2, F01MC, F800HC (All manufactured by Nippon Paper Chemical Co., Ltd.), Serogen (registered trademark) F-5A, F-7A, F-907A, F-815A, F-SB, F-930A, F-SA, F-AG, F, F -SH, F-3H, F-BSH, F-BSH-12, F-6HS9, HE-1500F, PR-S, F-SC, AG Gum M, PM-250L, P-815C Manufactured by Pharmaceutical Co., Ltd.), Kikkolate (registered trademark) FSLV-2, F-105, F-110, F-120, F-135, F-150, F-170, -1100, F-1500, SLV-21, FTS-1, FTS-2 (all manufactured by Nichirin Chemical Industries, Ltd.).

The dextrin used in the present invention is not particularly limited as long as it can be used for a solid composition. For example, dextrins described in the 16th revised Japanese Pharmacopoeia, dextrins described in the 8th edition Food Addendum, α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, indigestible Sex dextrin is also included. Suitable commercial products of dextrin include, for example, Amicol (registered trademark) No. 3-L, No. 1, no. 5-L, No. 6-L, no. 6-H, no. 7-H, no. 10 (all manufactured by Nissho Chemical Co., Ltd.), Pine Fiber (registered trademark) C, PINEDEX # 1, Fiber Sol (registered trademark) 2 (all manufactured by Matsutani Chemical Co., Ltd.) and the like.

The content of at least one selected from the group consisting of cellulose, cellulose derivatives, and dextrins in the solid composition of the present invention is preferably 0.01 W / W% or more, more preferably 0.02 W / W% or more, 0.05 W / W% or more is more preferable, 99 W / W% or less is preferable, 95 W / W% or less is more preferable, and 90 W / W% or less is more preferable. Further, 0.01 to 99 W / W% is preferable, 0.02 to 95 W / W% is more preferable, and 0.05 to 90 W / W% is more preferable. The “at least one content selected from the group consisting of cellulose, cellulose derivative, and dextrin” refers to the content of the component (B) contained in the solid composition of the present invention. ) When there are a plurality of components, it means the total content.

Further, the content ratio of the total content of the component (B) is preferably 0.001 part by weight or more, more preferably 0.01 part by weight or more, further with respect to 1 part by weight of the total content of the component (A). Preferably it is 0.02 parts by weight or more, more preferably 0.05 parts by weight or more, preferably 5500 parts by weight or less, more preferably 100 parts by weight or less, still more preferably 50 parts by weight or less, even more preferably 30 parts by weight. Less than parts by weight. The amount is preferably 0.001 to 5500 parts by weight, more preferably 0.01 to 100 parts by weight, still more preferably 0.02 to 50 parts by weight, and still more preferably 0.05 to 30 parts by weight.

<(C) component>
It is preferable that the solid composition of the present invention further contains at least one selected from the group consisting of (C) glucosamine, glucosamine derivatives, and salts thereof, in addition to the components (A) and (B). . That is, as one aspect of the solid composition of the present invention, it contains (A) component, (B) component, and (C) at least one selected from the group consisting of glucosamine, glucosamine derivatives, and salts thereof. An embodiment is mentioned.

Examples of the glucosamine derivative in the present invention include N-acetylglucosamine, N-methyl-L-glucosamine and the like.

The salt of glucosamine or a glucosamine derivative may be any pharmacologically (pharmaceutically) or physiologically acceptable salt of glucosamine or a glucosamine derivative. Specific examples include inorganic acid salts such as glucosamine hydrochloride, glucosamine sulfate, and glucosamine phosphate.

Glucosamine, glucosamine derivatives, and salts thereof can be used alone or in any combination of two or more, and among them, glucosamine and glucosamine hydrochloride are preferable. The glucosamine, glucosamine derivative, and salts thereof in the present invention may be any of D-form, L-form, and DL-form.

As glucosamine, glucosamine derivatives, and salts thereof, those prepared according to known methods may be used, or commercially available products may be used. For example, glucosamine and glucosamine derivatives can be obtained by purifying shrimp, crab, squid, etc. by enzyme or hydrolysis treatment. The glucosamine, glucosamine derivative, and salts thereof used in the present invention are not particularly limited as long as they can be used for the solid composition. For example, glucosamine hydrochloride described in Quasi-drug raw material standard 2006 is mentioned. Examples of suitable commercially available products of glucosamine, glucosamine derivatives, and salts thereof include glucosamine-GM (manufactured by Protein Chemical Co., Ltd.), natural glucosamine (manufactured by Yaizu Suisan Chemical Co., Ltd.), and the like.

In the solid composition of the present invention, the content of at least one selected from the group consisting of glucosamine, glucosamine derivatives, and salts thereof is preferably 0.001 W / W% or more, more preferably 0.005 W / W% or more. Preferably, 0.01 W / W% or more is more preferable, 80 W / W% or less is preferable, 75 W / W% or less is more preferable, and 70 W / W% or less is more preferable. Further, 0.001 to 80 W / W% is preferable, 0.005 to 75 W / W% is more preferable, and 0.01 to 70 W / W% is more preferable. The “content of at least one selected from the group consisting of glucosamine, glucosamine derivatives, and salts thereof” refers to the content of the component (C) contained in the solid composition of the present invention, (C) When there are a plurality of components, it means the total content.

In addition, the content ratio of the total content of the component (C) is preferably 0.001 part by weight or more, more preferably 0.005 part by weight or more with respect to 1 part by weight of the total content of the component (A), Preferably it is 0.01 weight part or more, Preferably it is 1000 weight part or less, More preferably, it is 500 weight part or less, More preferably, it is 100 weight part or less. The amount is preferably 0.001 to 1000 parts by weight, more preferably 0.005 to 500 parts by weight, and still more preferably 0.01 to 100 parts by weight.

The content ratio of the total content of the component (C) is preferably 0.001 part by weight or more, more preferably 0.005 part by weight or more, further preferably 1 part by weight of the total content of the component (B). The amount is 0.01 parts by weight or more, preferably 1000 parts by weight or less, more preferably 500 parts by weight or less, and still more preferably 100 parts by weight or less. Further, it is preferably 0.001 to 1000 parts by weight, more preferably 0.005 to 500 parts by weight, and still more preferably 0.01 to 100 parts by weight.

In addition to the above components, the solid composition of the present invention comprises an excipient, a binder, a disintegrant, a lubricant, a sweetener, a corrigent, an antiseptic, a chelating agent, an antioxidant, a cooling agent, a coating agent, Stabilizer, fluidizer, thickener, solubilizer, thickener, buffer, fragrance, colorant, adsorbent, wetting agent, moisture-proofing agent, antistatic agent, plasticizer, antifoaming agent, surfactant A known additive such as an agent can be contained. Examples of additives include sugars such as lactose, sucrose, and mannitol; lubricants such as magnesium stearate, calcium stearate, and sucrose fatty acid ester. It can also contain vitamins, known drugs and the like. In addition, content in particular of these components is not restrict | limited, It can set arbitrarily.

The solid composition of the present invention is not particularly limited as long as it contains the component (A) and the component (B), and can be prepared according to a method known to those skilled in the art, such as a direct powder compression method or a granule compression method. it can. Moreover, there is no limitation in particular in the shape and magnitude | size of a solid composition, According to a well-known method, coating processes, such as a sugar coating and a film coat, may be performed.

In a specific method for preparing a solid composition, for example, a mixture obtained by mixing the raw material of the solid composition containing the component (A), the component (B), and, if necessary, other additives into the component (A), A method (direct compression method) in which it is put into a tableting machine as it is and processed by molding is mentioned. Moreover, after granulating according to a known method, it may be put into a tableting machine and molded.

Other specific methods for preparing the solid composition include, for example, a mixture obtained by mixing the raw material of the solid composition containing the component (A), the component (B), and, if necessary, other additives into the component (A). May be granulated by a granulation method such as an extrusion granulation method, a rolling granulation method, a fluidized bed granulation method, a spray-drying granulation method, or a crushing granulation method.

The solid composition of the present invention thus obtained has a high hardness. For example, in the case of a tablet having a diameter of 5 to 15 mm, the hardness is preferably 5 Sc or more, more preferably 7 Sc or more, and further preferably 8 Sc or more. For example, in the case of a tablet having a diameter of 8 to 10.5 mm, its hardness is preferably 6.5 to 40 Sc, more preferably 10 to 20 Sc. The hardness in the present invention can be measured by the method described in the examples below, but is designed assuming the tablet diameter and the thickness of the tablet obtained after tableting. It is not limited.

The solid composition of the present invention can be widely used for, for example, pharmaceuticals, quasi drugs, foods and the like. The food includes food for specified health use, functional nutritional food, food for the elderly, special purpose food, functional food, health supplement (supplement), confectionery tablets, and the like.

The solid composition of the present invention is preferably used as an internal preparation, more preferably an oral internal preparation.

The solid composition of the present invention is not particularly limited as long as it is a solid composition. Specifically, fine granules, granules, pills, tablets (plain tablets, dragees, orally disintegrating tablets) Chewable tablets (chewable), effervescent tablets, troches, film-coated tablets, etc.) and dry syrups are exemplified, and fine granules, granules, and tablets are preferred.

The solid composition of the present invention can be suitably used for diseases for which the administration of component (A) is desired. For example, it can be used to improve and / or prevent symptoms in chronic nephritis, neuralgia, joint pain, low back pain, shoulder periarthritis (fifty shoulders) and the like.

As the administration subject of the present specification, preferably, a human who needs an action for improving chronic nephritis, neuralgia, joint pain, low back pain, and shoulder periarthritis (fifty shoulders) can be mentioned. In addition, since the solid composition of the present invention is a safe composition, patients who have other diseases or general healthy persons can also be administered, and animals such as pets can also be used. There may be.

The dose of the solid composition of the present invention may be an amount such that the desired effect of the present invention can be obtained, and its form, administration method, purpose of administration and age of the subject of administration of the composition, It is set appropriately according to weight and symptoms and is not constant. For example, a preferable dose is an amount such that component (A) is 50 to 400 mg / dose per adult. Moreover, administration may be performed once or divided into several times within one day within a desired dose range, and the period is also arbitrary. In the present specification, “administration” means “administration” and / or “intake”.

The solid composition of the present invention contains at least one selected from the group consisting of polysaccharides containing galactosamine and glucuronic acid, which are inferior in compression moldability, and salts thereof, and has high hardness and resistance to breakage. It has the effect of being excellent in. Therefore, the present invention also provides a method for increasing the hardness of a solid composition comprising at least one selected from the group consisting of polysaccharides containing D-galactosamine and -glucuronic acid, and salts thereof, and the solid composition There is also provided a method for suppressing breakage of objects.

As a method for increasing the hardness of the solid composition, specifically, (A) a polysaccharide containing galactosamine and glucuronic acid in a solid composition, more specifically, a raw material for the solid composition, and a salt thereof There is no particular limitation as long as at least one selected from the group consisting of (B) cellulose, cellulose derivatives, and dextrin is blended with at least one selected from the group consisting of.

Further, as a method for suppressing breakage of the solid composition, specifically, (A) a polysaccharide containing galactosamine and glucuronic acid in the solid composition, more specifically in the raw material for the solid composition, and There is no particular limitation as long as at least one selected from the group consisting of (B) cellulose, a cellulose derivative, and dextrin is blended with at least one selected from the group consisting of the salt.

In addition, in the hardness increasing method and the breakage suppressing method of the solid composition, the blending of the component (A) and the component (B) may be simultaneous or separate, and the order thereof is not particularly limited. In addition, in these methods, the types of components (A) and (B) to be used, their contents, and their content ratios, the types of components added and blended, preparation methods, uses, formulation forms, The administration target is the same as that of the solid composition of the present invention.

Hereinafter, the present invention will be described based on examples, but the present invention is not limited to these examples. In addition, the polysaccharide containing galactosamine and glucuronic acid in each test example is a commercial product obtained by purifying shark cartilage, and is compatible with the standard of sodium chondroitin sulfate of the pharmaceutical additive standard 2003, chondroitin sulfate C sodium And a polysaccharide containing sodium chondroitin sulfate D (for convenience, “sodium chondroitin sulfate (Na)”) (weight average molecular weight of about 30000 Da) is decomposed by an enzyme treatment method using a degrading enzyme, and each weight average molecular weight is determined. What was possessed was extracted and used. The unit of component content in each table is W / W%.

[Weight average molecular weight of polysaccharides and salts thereof containing galactosamine and glucuronic acid]
The weight average molecular weight of the polysaccharide containing galactosamine and glucuronic acid, and a salt thereof can be measured by a static light scattering method. Specifically, a dynamic light scattering photometer [DLS-8000 (Otsuka Electronics Co., Ltd.)] is used under the following conditions. A sample is dissolved in purified water to prepare a concentration of 10 mg / mL. This solution is further diluted with purified water to prepare concentrations of 2, 4, 6, 8 mg / mL. Static light scattering measurements at 20, 30, 40, 60, 90, 120, and 150 degrees at 25 ° C. and dn / dc measurements that are intrinsic refractive index increments, and from the Zimm square root plot and Debye plot, the weight average molecular weight Is calculated. Before the scattering measurement, the sample is filtered with a filter having a pore size of 0.22 μm. The dn / dc measurement can be performed with a DRM-3000 manufactured by Otsuka Electronics.

Test example 1
The solid compositions of Example 1 and Comparative Examples 1 to 4 were prepared. Specifically, each component described in Table 1 was weighed and then mixed by a conventional method to obtain a mixed powder. The obtained mixed powder was tableted (tablet pressure 10 kg) using a tabletop tablet molding machine (manual pump manufactured by Riken Seiki Co., Ltd.) to obtain tablets (diameter 9 mm, one tablet 300 mg). The tablet is 9 mm in diameter and R-shaped.

About the obtained tablet, the hardness of the tablet was evaluated. That is, using a tablet hardness tester (manufactured by Pharmatest), the tablet was pressed in the diameter direction of the tablet, and the weight (Sc) when the tablet was broken was measured to obtain the tablet hardness. Further, the amount of increase in hardness (Sc) of each tablet relative to the tablets of Comparative Examples 1 to 3 was calculated using the following formula (1). The results are shown in Table 1.
Hardness increase (Sc) = Tablet hardness (Sc) −Comparative tablet hardness (Sc) (1)

Note that cellulose is Theorus FD-101 (manufactured by Asahi Kasei Co., Ltd.), and D-mannitol and sucrose fatty acid ester comply with food additive standards.

Compared to the solid composition containing neither sodium chondroitin sulfate nor cellulose (Comparative Example 1), the solid composition containing only sodium chondroitin sulfate having a weight average molecular weight of about 5000 Da (Comparative Example 2) has a tablet hardness of 1.8 Sc. The solid composition (Example 1) containing cellulose together with sodium chondroitin sulfate having a weight average molecular weight of about 5000 Da as compared with the tablet containing only cellulose (Comparative Example 3) was 5.8 Sc. A more noticeable increase in the hardness of the solid composition, an increase in tablet hardness, was observed.

Similarly, the solid composition containing only cellulose (Comparative Example 3) has an increase in tablet hardness of 9.0 Sc as compared to the solid composition containing neither sodium chondroitin sulfate nor cellulose (Comparative Example 1). However, in comparison with the solid composition containing only sodium chondroitin sulfate having a weight average molecular weight of about 5000 Da (Comparative Example 2), the solid composition containing cellulose together with sodium chondroitin sulfate having a weight average molecular weight of about 5000 Da (Example 1). A more noticeable increase in the hardness of the solid composition was observed, with an increase in tablet hardness of 13.0 Sc.

On the other hand, in the solid composition (Comparative Example 4) containing cellulose together with sodium chondroitin sulfate having a weight average molecular weight of about 30000 Da, the tablet hardness was lower than that of the solid composition containing only cellulose (Comparative Example 3). .

From these results, it was revealed that the hardness of the solid composition was significantly increased by containing low molecular weight sodium chondroitin sulfate and cellulose.

Test example 2
The solid compositions of Examples 2 to 5 and Comparative Example 5 were prepared, and the hardness of the tablets was evaluated in the same manner as in Test Example 1. The cellulose was Theorus FD-101 (manufactured by Asahi Kasei Co., Ltd.), and the same D-mannitol and sucrose fatty acid ester as in Test Example 1 were used. The results are shown in Table 2 and FIG.

In comparison with tablets containing sodium chondroitin sulfate having a weight average molecular weight of about 30000 Da together with cellulose (Comparative Example 5), tablets containing sodium chondroitin sulfate having a weight average molecular weight of about 5000 to 15000 Da together with cellulose (Examples 2 to 5). A significant increase in tablet hardness was observed (see FIG. 1).

From the above results, it was found that the hardness of the solid composition was remarkably increased by containing sodium chondroitin sulfate having a specific molecular weight together with cellulose.

Test example 3
The solid compositions of Examples 6 to 9 and Comparative Examples 6 to 9 were prepared, and the hardness of the tablets was evaluated in the same manner as in Test Example 1. The cellulose was Theorus FD-101 (manufactured by Asahi Kasei Co., Ltd.), and the same D-mannitol and sucrose fatty acid ester as in Test Example 1 were used. The results are shown in Tables 3 and 4. Table 4 also shows the results of Example 2 and Comparative Example 5.

The tablet hardness of the solid composition (Examples 6 to 7) containing 40 to 60 W / W% of chondroitin sulfate having a weight average molecular weight of about 5000 Da together with 10 W / W% of cellulose contains only 10 W / W% of cellulose. It increased remarkably compared with the tablet hardness of the solid composition (Comparative Example 6). On the other hand, the tablet hardness of the solid composition (Comparative Example 8) containing 10 W / W% cellulose and 60 W / W% chondroitin sulfate having a weight average molecular weight of about 30,000 Da is the same as that of Comparative Example 6. It was about the same. The tablet hardness of the solid composition (Comparative Example 7) containing 10 W / W% cellulose and 40 W / W% chondroitin sulfate having a weight average molecular weight of about 30,000 Da is significantly higher than that of the solid composition of Comparative Example 6. Diminished.

The tablet hardness of the solid composition (Examples 2 and 8 to 9) containing 20 to 60 W / W% sodium chondroitin sulfate having a weight average molecular weight of about 5000 Da together with 20 W / W% cellulose is 20 W / W%. Compared with the tablet hardness of the solid composition containing only cellulose (Comparative Example 9), it increased significantly. On the other hand, the tablet hardness of the solid composition (Comparative Example 5) containing 20 W / W% cellulose and 40 W / W% chondroitin sulfate having a weight average molecular weight of about 30,000 Da is the same as the solid composition of Comparative Example 9. Compared to a decrease.

Test example 4
The solid compositions of Examples 10 to 11 and Comparative Examples 10 to 13 were prepared, and the hardness of the tablets was evaluated in the same manner as in Test Example 1. The cellulose was Theorus FD-101 (manufactured by Asahi Kasei Co., Ltd.), and the same D-mannitol and sucrose fatty acid ester as in Test Example 1 were used. The results are shown in Table 5.

The tablet hardness of the solid composition (Examples 10 and 11) containing 20 W / W% sodium chondroitin sulfate having a weight average molecular weight of about 5000 Da together with 60 or 70 W / W% cellulose is also the sodium chondroitin sulfate having a weight average molecular weight of about 5000 Da. Compared with the tablet hardness of the solid composition (Comparative Examples 10 and 12) containing no sucrose, it increased remarkably. On the other hand, the tablet hardness of the solid composition (Comparative Examples 11 and 13) containing 60 W or 70% W / W% cellulose and 20 W / W% chondroitin sulfate sodium having a weight average molecular weight of about 30000 Da is Comparative Example 10 and Although a slight increase was observed in comparison with the hardness of 12, the degree of increase in the tablet hardness was low compared with the solid compositions containing sodium chondroitin sulfate having a weight average molecular weight of about 5000 Da (Examples 10 and 11). there were.

Test Example 5
The solid compositions of Examples 12 to 14 and Comparative Example 14 were prepared, and the hardness of the tablets was evaluated in the same manner as in Test Example 1. The cellulose was Theorus FD-101 (manufactured by Asahi Kasei Co., Ltd.), and the same D-mannitol and sucrose fatty acid ester as in Test Example 1 were used. The results are shown in Table 6.

The tablet hardness of the solid composition containing 20 to 60 W / W% chondroitin sulfate having a weight average molecular weight of about 5000 Da together with 5 W / W% cellulose is also the same as that of the solid composition not containing sodium chondroitin sulfate having a weight average molecular weight of about 5000 Da. Increased compared to tablet hardness (Comparative Example 14 and Examples 12-14).

Test Example 6
The solid compositions of Examples 15 to 16 and Comparative Examples 15 to 16 were prepared, and the hardness of the tablets was evaluated in the same manner as in Test Example 1. The cellulose was Theorus FD-101 (manufactured by Asahi Kasei Co., Ltd.), D-mannitol was the same as in Test Example 1, and calcium stearate and magnesium stearate were those complying with the standards for food additives. The results are shown in Table 7.

Even when the sucrose fatty acid ester used in Example 2 is replaced with calcium stearate, the tablet hardness of the solid composition containing sodium chondroitin sulfate having a weight average molecular weight of about 5000 Da together with cellulose is a solid containing only cellulose. Along with the composition and cellulose, the tablet hardness of the solid composition containing sodium chondroitin sulfate having a weight average molecular weight of about 30,000 Da was significantly increased (Comparative Examples 15 to 16 and Example 15). Similarly, when the sucrose fatty acid ester used in Example 2 is replaced with magnesium stearate, the tablet hardness of the solid composition containing sodium chondroitin sulfate having a weight average molecular weight of about 5000 Da together with cellulose is remarkably increased. (Example 16).

Test Example 7
The solid compositions of Examples 17 to 19 and Comparative Examples 17 to 19 were prepared, and the hardness of the tablets was evaluated in the same manner as in Test Example 1. The cellulose used was Theolas FD-301 and Theolas ST-100 (both manufactured by Asahi Kasei Co., Ltd.), the hydroxypropyl cellulose was HPC-L (manufactured by Shin-Etsu Chemical Co., Ltd.), and D-mannitol and sucrose fatty acid ester were as in Test Example 1. The same thing was used. The results are shown in Table 8.

The tablet hardness of the solid composition containing sodium chondroitin sulfate having a weight average molecular weight of about 5000 Da is also the weight average even in the case where Theola FD-101 used in Example 2 is replaced by Theola FD-301 and Theola ST-100. Compared to the tablet hardness of the solid composition containing sodium chondroitin sulfate having a molecular weight of about 30,000 Da (Comparative Examples 17 to 18 and Examples 17 to 18).

Even when the cellulose used in Example 2 is replaced with hydroxypropylcellulose, the tablet hardness of the solid composition containing sodium chondroitin sulfate having a weight average molecular weight of about 5000 Da is chondroitin sulfate sodium having a weight average molecular weight of about 30000 Da. Significantly increased compared to the tablet hardness of the solid composition containing (Comparative Example 19 and Example 19).

From these results, it has been clarified that a remarkable increase in hardness of the solid composition can be observed by containing low molecular weight sodium chondroitin sulfate, cellulose and derivatives thereof.

Test Example 8
The solid compositions of Comparative Example 20 and Example 20 were prepared, and the hardness of the tablets was evaluated in the same manner as in Test Example 1. The dextrin was PINEDEX # 1 (manufactured by Matsutani Chemical Co., Ltd.), and the same D-mannitol and sucrose fatty acid ester as in Test Example 1 were used. The results are shown in Table 9.

Even when the cellulose (FD-101) used in Example 7 and Comparative Example 8 was replaced with dextrin, the solid composition containing sodium chondroitin sulfate having a weight average molecular weight of about 5000 Da together with dextrin was obtained as in the case of cellulose. The tablet hardness significantly increased compared to the tablet hardness of the solid composition containing sodium chondroitin sulfate having a weight average molecular weight of about 30,000 Da together with dextrin (Comparative Example 20 and Example 20).

From these results, it has been clarified that when the low molecular weight sodium chondroitin sulfate and dextrin are contained, the hardness of the solid composition is remarkably increased.

Test Example 9
The solid compositions of Comparative Examples 21 to 23 were prepared, and the hardness of the tablets was evaluated in the same manner as in Test Example 1. The lactose was Pharmatose 200M (manufactured by DMV-Fonterra Excipients), and D-mannitol and sucrose fatty acid ester were the same as those used in Test Example 1. The results are shown in Table 10 together with the results of Comparative Example 1.

The hardness of a tablet containing sodium chondroitin sulfate having a weight average molecular weight of about 5000 Da together with lactose is that of a solid composition containing only lactose and a tablet of a solid composition containing only sodium chondroitin sulfate having a weight average molecular weight of about 5000 Da There was no significant difference from the hardness (Comparative Examples 21 to 23), and the tablet hardness of the solid composition containing only D-mannitol was comparable (Comparative Example 1).

From these results, the increase in the hardness of the solid composition by containing cellulose, cellulose derivative, and dextrin together with low molecular weight sodium chondroitin sulfate is a specific effect of cellulose, cellulose derivative, and dextrin. It became clear.

Test Example 10
The solid compositions of Examples 21 to 22 and Comparative Example 24 were prepared, and the hardness of the tablets was evaluated in the same manner as in Test Example 1. The cellulose used was Theorus FD-101 (manufactured by Asahi Kasei Co., Ltd.), the glucosamine used was glucosamine-GM (manufactured by Protein Chemical Co., Ltd.), and the same D-mannitol and sucrose fatty acid ester as those used in Test Example 1 were used. The results are shown in Table 11 together with the results of Comparative Example 9.

The tablet hardness of the solid composition containing 10 W / W% glucosamine together with cellulose (Comparative Example 24) and the tablet hardness of the solid composition containing only cellulose (Comparative Example 9) were comparable. In contrast, the tablet hardness (Example 21) of the solid composition containing 40 W / W% sodium chondroitin sulfate having a weight average molecular weight of about 5000 Da together with cellulose and 10 W / W% glucosamine was significantly increased. The tablet hardness of the solid composition (Example 22) in which the content of glucosamine was increased to 20 W / W% while the contents of cellulose and sodium chondroitin sulfate having a weight average molecular weight of about 5000 Da were the same was as that of Example 21. Increased significantly compared to.

Test Example 11 (Evaluation of degree of damage)
The solid compositions of Examples 2 and 6 and Comparative Examples 5, 6, 7, and 9 were prepared in the same manner as in Test Example 1, and the degree of breakage of the solid compositions was evaluated. Specifically, after measuring the total weight (initial weight) of the solid composition (6 tablets) from which the powder adhering to the solid composition was removed, a glass container (cocked test tube S-50, 50 mL, IWAKI The product was put on a lid and covered with a shaker (KM Shaker, manufactured by IWAKI) for 3 minutes in the long side direction (100 times / minute). After shaking, the total weight (post-test weight) of the solid composition (6 tablets) from which the powder adhering to the solid composition was removed was measured, and the degree of damage was determined by the following formula (2). The results are shown in Table 12 and FIG. The tablet is 9 mm in diameter and R-shaped.
Degree of damage (%) = (initial weight (mg) −post-test weight (mg)) / initial weight (mg) × 100 (2)

The degree of breakage of a solid composition (Example 6) containing sodium chondroitin sulfate having a weight average molecular weight of about 5000 Da together with 10 W / W% cellulose compared to a solid composition containing only 10 W / W% cellulose (Comparative Example 6). Decreased significantly. On the other hand, compared with the solid composition containing only 10 W / W% cellulose (Comparative Example 6), the degree of breakage of the solid composition containing sodium chondroitin sulfate having a weight average molecular weight of about 30000 Da together with 10 W / W% cellulose. Increased significantly (Comparative Example 7).

Similarly, compared with the solid composition containing only 20 W / W% cellulose (Comparative Example 9), the degree of breakage of the solid composition containing sodium chondroitin sulfate having a weight average molecular weight of about 5000 Da together with 20 W / W% cellulose is remarkable. (Example 2). On the other hand, compared with the solid composition containing only 20 W / W% cellulose (Comparative Example 9), the degree of breakage of the solid composition containing sodium chondroitin sulfate having a weight average molecular weight of about 30,000 Da together with 20 W / W% cellulose. Increased significantly (Comparative Example 5).

From these results, it has been clarified that the breakage of the solid composition is markedly suppressed by containing low molecular weight sodium chondroitin sulfate together with cellulose.

Formulation Examples 1-27
Solid compositions having the formulations shown in Tables 13 to 16 are prepared in the same manner as in Example 1.

Formulation examples 28-54
Prescription Examples 28 to 54 are prepared in the same manner as in Example 1 except that sodium chondroitin sulfate having a weight average molecular weight of about 5000 Da used in Formulation Examples 1 to 27 is replaced with sodium chondroitin sulfate having a weight average molecular weight of about 20000 Da.

The solid composition of the present invention has an effect that a solid composition having high hardness and excellent breakage resistance can be easily produced while containing chondroitin inferior in compression moldability. Thereby, handling of the solid composition in a series of manufacturing processes becomes easy. Moreover, the solid composition which can fully endure distribution can be obtained. Furthermore, since the blending ratio of so-called additives in the solid composition can be reduced, the solid composition can be made smaller and easier to take, or the number or amount of the solid composition to be taken is reduced, thereby reducing the production cost. It can be easy to take.

Claims (8)

(A) at least one selected from the group consisting of polysaccharides containing galactosamine and glucuronic acid, and salts thereof;
(B) containing at least one selected from the group consisting of cellulose, cellulose derivatives, and dextrins,
A solid composition in which the weight average molecular weight of component (A) is 1000 to 20000 Da. The component (A) comprises at least one selected from the group consisting of chondroitin, chondroitin sulfate A, chondroitin sulfate C, chondroitin sulfate D, chondroitin sulfate E, chondroitin sulfate K, and salts thereof. Solid composition. The solid composition according to claim 1 or 2, wherein the component (A) comprises a sodium salt of a polysaccharide containing galactosamine and glucuronic acid. The component (B) according to any one of claims 1 to 3, wherein the component comprises at least one selected from the group consisting of cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose and salts thereof, and dextrin. Solid composition. The solid composition according to any one of claims 1 to 4, comprising 0.01 to 100 parts by weight of component (B) with respect to 1 part by weight of component (A). The solid composition according to any one of claims 1 to 5, further comprising (C) at least one selected from the group consisting of glucosamine, glucosamine derivatives, and salts thereof. From the group consisting of (B) cellulose, a cellulose derivative, and dextrin, together with at least one selected from the group consisting of (A) a polysaccharide containing galactosamine and glucuronic acid, and a salt thereof in the raw material for the solid composition A method for increasing the hardness of a solid composition, comprising blending at least one selected. A group consisting of (B) cellulose, a cellulose derivative, and a dextrin, together with at least one selected from the group consisting of (A) a polysaccharide containing galactosamine and glucuronic acid, and salts thereof in the raw material for the solid composition At least 1 sort (s) selected from more is mix | blended, The method of suppressing the failure | damage of a solid composition characterized by the above-mentioned.

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