JP6940356B2 - N-Acetylglucosamine tablets - Google Patents

Description

The present invention relates to tablets containing 95% by mass or more of N-acetylglucosamine.

N-Acetylglucosamine (N-acetyl-D-glucosamine, GlcNAc) is a monosaccharide in which the 2-position hydroxyl group of glucose is replaced with an acetylamino group. Chemically, it can be easily prepared by acetylating the 2-amino group of glucosamine.
Industrially, the shells of crabs, shrimp, etc. are heat-treated in an aqueous solution of sodium hydroxide to remove proteins, and then chitin obtained by removing ash with hydrochloric acid is used as a raw material, which is hydrolyzed with hydrochloric acid to produce glucosamine. It is then produced by acetylating it with acetic anhydride. As other methods, a method of hydrolyzing chitin obtained through a deproteinization step with an alkali and a decalcification step with hydrochloric acid with concentrated hydrochloric acid (see Patent Document 1), and using concentrated hydrochloric acid of 30% or more for chitin. A method of obtaining N-acetylglucosamine by hydrolyzing at a reaction temperature of 5 ° C. or higher and 30 ° C. or lower and setting the reaction time to 48 hours or longer and 96 hours or lower (see Patent Document 2), partial addition of chitin with an acid. There is a method of selectively obtaining N-acetylglucosamine by cold crystallization from a mixture containing 90% by weight or more of N-acetylglucosamine and chitin oligosaccharide after decomposition (see Patent Document 3).

N-acetylglucosamine has been confirmed to have clinical effects such as improvement of joint pain and improvement of skin moisturizing property, and has been widely used as a health food and supplement in recent years. In order to use it as a supplement tablet, it is necessary to add various excipients to N-acetylglucosamine to form a tablet.
Patent Document 4 describes a tablet containing cellulose powder and lactose as excipients and containing 40% by mass of N-acetylglucosamine. Patent Document 5 describes an orally rapidly disintegrating tablet containing 39.1% by mass of N-acetylglucosamine, which is a mixture of crystalline cellulose and N-acetylglucosamine.
However, N-acetylglucosamine has a powder property with very poor moldability, and in order to obtain a tablet having a high N-acetylglucosamine content, a bond such as lactose or microcrystalline cellulose is used as an excipient. It was necessary to add a large amount of the agent to 30% by mass or more. Therefore, the tablet containing N-acetylglucosamine naturally has a limit in the amount of N-acetylglucosamine to be blended.

According to Patent Document 6, N-acetylglucosamine in which water-soluble cellulose is attached to glucosamine powder particles is granulated and then tableted to obtain a tablet containing 94% by mass of N-acetylglucosamine. Have been described. In the prior art, it has been considered difficult to add a higher content of N-acetylglucosamine. Further, it has been considered that the tablet of Document 6 has a high degree of abrasion and is unsuitable for practical distribution.

JP-A-2009-167140 Japanese Unexamined Patent Publication No. 2012-217396 Japanese Unexamined Patent Publication No. 2009-191001 Japanese Unexamined Patent Publication No. 2001-48789 Japanese Unexamined Patent Publication No. 2016-41662 Japanese Patent No. 5415837

An object of the present invention is to provide a tablet containing 95% by mass or more of N-acetylglucosamine. Another object is to provide the manufacturing method.

The main configuration of the present invention is as follows.
(1) A tablet containing 95% by mass or more of N-acetylglucosamine, having a tablet hardness of 10 kgf or more and an abrasion degree of 0.5% or less.
(2) A method for producing an N-acetylglucosamine-containing tablet, which comprises tableting a complex containing 95% by mass or more of N-acetylglucosamine and 0.5 to 4% by mass of a porous inorganic substance.
(3) A complex containing 95% by mass or more of N-acetylglucosamine and 0.5 to 4% by mass of a porous inorganic substance forms a mixture of N-acetylglucosamine and a porous inorganic substance by repeating impact, compression, and shearing. The method according to (2), which is a complexed powder.
(4) The method according to (3), wherein the porous inorganic substance is any substance selected from silicon, silicon oxide, silicon dioxide, calcium silicate, and calcium phosphate.

INDUSTRIAL APPLICABILITY The present invention provides a tablet containing 95% by mass or more of N-acetylglucosamine and a method for producing the same. The tablet of the present invention is a tablet containing 95% by mass or more of N-acetylglucosamine, which has been difficult to provide in the past. Further, since the tablet of the present invention is an extremely hard tablet, the degree of abrasion measured by the Japanese Pharmacopoeia is 0.5% or less, and the tablet is not worn during production or transportation.

5 is an observation image of the composite particle of Example 1 at 50 times, 1000 times, and 4000 times (from the left) by a scanning electron microscope. 5 is an observation image of the N-acetylglucosamine particles used in Example 1 at 50 times, 1000 times, and 4000 times (from the left) by a scanning electron microscope. It is a graph which shows the test result which compared the tableting suitability when the excipient was added to the composite particle of Example 2 and the case where the excipient was added to the commercially available N-acetylglucosamine powder.

The present invention relates to a tablet containing 95% by mass or more of N-acetylglucosamine and a method for producing the same. Further, the tablet of the present invention is characterized in that composite particles having a structure in which fine particles of porous inorganic substances and fine particles of N-acetylglucosamine are aggregated on the particle surface of N-acetylglucosamine are used as the main raw material of the tablet. doing. Furthermore, the structure in which fine particles of porous inorganic substance and fine particles of N-acetylglucosamine are aggregated on the particle surface of N-acetylglucosamine referred to in the present specification means that N-acetylglucosamine composed of fine particles and the porous inorganic substance are used. , A state in which N-acetylglucosamine particles, which are the core, are aggregated on the surface and physically bonded.
N-acetylglucosamine is usually produced by chemically or enzymatically hydrolyzing chitin that constitutes the shell of crustaceans. Crystals with a particle size of 50 mesh or less are widely used. Such N-acetylglucosamine can be obtained as a commercially available product (for example, manufactured by Mitsubishi Chemical Foods Co., Ltd.). Further, granules may be formed by a known granulation operation using water as a binder.
The composite particle in the present invention means a state in which a plurality of particles are bonded by a physical force.

Examples of the porous inorganic substance used in the present invention include fine particles such as silica (silicon oxide, silicon dioxide), calcium silicate and calcium phosphate, natural inorganic substances such as wollastonite and zeolite, and artificial inorganic substances such as artificial zeolite. .. These porous inorganic substances may be used alone, or two or more kinds may be appropriately mixed and used. In the present invention, fine particles of silica and calcium phosphate, which have historically been widely used as pharmaceutical raw materials, are preferable, and amorphous silica powder used as a food additive is particularly preferable. Silica, also called "silicic anhydride" or "silicon dioxide", is insoluble and is not digested, absorbed and excreted in the body, so it is not harmful to the body.
In the present invention, "silicon oxide or silicon dioxide", which is a term used for pharmaceutical products, is used synonymously with silica.
The porous inorganic substance used as the raw material of the present invention preferably has an average particle size of 10 μm or less.

In the composite particles used in the present invention, N-acetylglucosamine and the porous inorganic substance are pulverized into fine particles by repeatedly applying impact, compression, and shearing forces to the above-mentioned mixture of N-acetylglucosamine powder and the porous inorganic substance. At the same time, N-acetylglucosamine pulverized into fine particles and a porous inorganic substance are aggregated (composite) on the surface of N-acetylglucosamine crystals or particles. N-acetylglucosamine and the porous inorganic substance are mixed in advance at a ratio of 96 to 99.5% by mass of N-acetylglucosamine and 4 to 0.5% by mass of the porous inorganic substance, and then complexed.
Further, an apparatus for simultaneously combining fine particles while preparing them by repeating impact, compression, and shearing is commercially available under the name of a dry compounding apparatus, and this apparatus can be used. As the dry compounding device, "Nobilta NOB (product name)" manufactured by Hosokawa Micron Co., Ltd. can be exemplified. In Nobilta NOB, while the rotor rotates at high speed in the mixing container, impact, compression, and shearing forces are applied to the raw material to make the raw material finer, and the surface shape of the finer particles is processed to automatically produce composite particles. It is an apparatus for manufacturing (see Japanese Patent Application Laid-Open No. 2010-180099).

In the composite particles of powder and porous inorganic material composed of N-acetylglucosamine particles, N-acetylglucosamine composed of fine particles and porous inorganic material composed of fine particles are strongly applied to the particle surface of N-acetylglucosamine by physical force. It is a composite particle having a bonded structure. Both N-acetylglucosamine and porous inorganic material (for example, silicon dioxide) particles aggregated on the particle surface of N-acetylglucosamine have a maximum directional diameter of 0.1 to 2.8 μm, and these particles are physical. It is bound to the particle surface of N-acetylglucosamine with a strong force. This structure can be confirmed by observing the composite particles with a scanning electron microscope.

The composite particles of the present invention are prepared by the above-mentioned dry composite device, and can be obtained as powders or granules having a desired particle size by sieving them.
It can also be used after being granulated again by a normal granulation method.
In order to use it as a raw material for the formulation by the tableting method, it is sieved and classified so that the particle size is 10 to 750 μm, the medicinal properties and other components are added and mixed, and the tablets are tableted to obtain a fast-disintegrating tablet. Obtainable. In the composite particles of the present invention, the particle size of the constituent particles can be adjusted to 10 to 750 μm.

When the composite particles of the present invention are made into tablets, excipients such as cellulose and calcium stearate, lubricants, and other active ingredients (physiologically active ingredients) can be added as needed.
The tableting may be any general tableting device such as a rotary tableting machine used for producing tablets. In the case of tablets having a diameter of 8 to 9 mm, the tableting pressure at the time of tableting is preferably 1000 kgf, and the tablets containing the composite particles of the present invention do not cause tableting problems such as capping during production.
The obtained tablets have an abrasion degree of 0.5% or less when 20 tablets are tested at 25 rpm for 10 minutes using the apparatus described in the Japanese Pharmacopoeia "Tablet Abrasion Degree Test Method".

Hereinafter, the present invention will be described in more detail with reference to Examples.
<Production example of bulk powder of pharmaceutical product: Production of composite particles having a structure in which a composite of N-acetylglucosamine composed of fine particles and a porous inorganic substance composed of fine particles is aggregated on the particle surface of N-acetylglucosamine>

1. 1. Raw materials used N-acetylglucosamine powder: N-acetylglucosamine average particle size (median diameter) 122.8 μm (Koyo Chemical Co., Ltd.)
Silicon oxide (silicon dioxide, fine silicon dioxide, light anhydrous silicic acid): silopage 720 average particle size (median diameter) 4.2 μm (Fuji Silysia Chemical Ltd.)

2. Equipment used Nobilta NOB-MINI (manufacturing equipment)

3. 3. Production method N-acetylglucosamine and silicon oxide are powder-mixed at the blending ratio% shown in Table 1 below, 20 g of this mixture is charged into a composite production apparatus, and N-acetylglucosamine composed of fine particles is placed on the surface of N-acetylglucosamine particles. And a composite particle in which a precise mixture of porous inorganic substances was bonded was produced.
As a manufacturing apparatus, a dry compounding apparatus “Novirta NOB-MINI” manufactured by Hosokawa Micron Co., Ltd. was used. In "Nobilta NOB-MINI", a rotor with blades rotates at a high speed of 40 m / s or more in a horizontal cylindrical mixing container, and impact, compression, and shear forces act uniformly on each particle. It is designed to be. It is a device that can simultaneously proceed with fine particle formation and compounding by adjusting the rotation speed and operation time. The main body casing has a water-cooled jacket structure, and even if high energy is applied, the rise in product temperature can be suppressed. According to the instruction manual for this device, composite particles were prepared by repeating impact, compression, and shearing under the treatment conditions of a jacket temperature of 15 ° C. and a load of 0.01 kW · min / g. The load amount indicates the amount of energy applied to 1 g of the raw material charged into the processing apparatus or the amount of electric power (W · min).
The load amount referred to here is an index of how much energy is applied to the raw material.

For comparison, N-acetylglucosamine and silicon oxide were powder-mixed at a ratio of% in Table 2 below, passed through a 32 mesh sieve, and then powder-mixed again to prepare a powder.

<Structural observation with scanning electron microscope>
The composite particles obtained above were observed with a scanning electron microscope S-3400 (manufactured by Hitachi High-Technologies Corporation), and their structures were evaluated. FIG. 1 shows observation images of 50 times, 1000 times, and 4000 times the composite particles of N-acetylglucosamine and silicon oxide of Example 1. In addition, in order to evaluate the structure, FIG. 2 shows observation images of 50 times, 1000 times, and 4000 times the N-acetylglucosamine used in Example 1.
As can be understood by comparing FIGS. 1 and 2, the composite particle of the present invention has a structure in which powder of agglomerates composed of fine particles and fine particles are agglomerated on the surface. On the other hand, the particles of N-acetylglucosamine used as a raw material had a smooth surface.
The fine particles are aggregated on the surface of the N-acetylglucosamine particles, and it has been confirmed that the fine particles are N-acetylglucosamine and silicon oxide finely pulverized by the complexing treatment. Since the particle size of the fine particles of N-acetylglucosamine is about 1 μm, it is expected that they are mixed at the micro level.
Therefore, it was confirmed that the particles constituting the complex powder of the present invention have a structure in which N-acetylglucosamine composed of fine particles and silicon oxide are aggregated on the particle surface of N-acetylglucosamine.

<Evaluation of particle size of fine particles>
The particle size of the fine particles found in the composite particles of the present invention was measured by the maximum diameter in a fixed direction. For 300 arbitrary particles in the observation image of 4000 times the complex of N-acetylglucosamine and silicon oxide of Example 1 of FIG. 1, the maximum in a fixed direction using the image analysis software WinROOF (manufactured by Mitani Corporation). The diameter was calculated. The measurement results are shown in Table 3 below.

From Table 3, it was confirmed that the maximum diameter in the directional direction of the fine particles observed in the composite particles of the present invention was 0.12 to 2.75 μm.

<Evaluation of tablet processing suitability (1)>
1% by mass of calcium stearate as a lubricant was added to 99 parts by mass of each of the powders of Examples and Comparative Examples, the powders were mixed, and then tableting was performed with a single-shot tableting machine N-30E (manufactured by Okada Seiko Co., Ltd.). .. The tablet shape was 8 mm, 10R, 200 mg / tablet, and the tableting pressure was 600, 900, 1200 kgf. The hardness and disintegration time of the obtained tablets were measured. The hardness was measured using the New Speed Checker TS-75N (manufactured by Okada Seiko Co., Ltd.). As for the disintegration time, the disintegration time in water was measured according to the method described in the "Disintegration Test Method" of the Japanese Pharmacopoeia for tablets molded to have a hardness of about 7 kgf. The measurement results are shown in Tables 4 and 5 below.

In the example (product of the present invention), a dramatic increase in hardness was confirmed by using silicon oxide to form a complex as compared with the tablet using the powder of the comparative example having the same composition. In addition, the disintegration time of the tablet using the powder of the example was within 10 minutes, showing excellent disintegration property. On the other hand, since the tablet using the powder of the comparative example did not have a hardness of 7 kgf, the measurement of the disintegration time was omitted.
No increase in hardness was confirmed in the tablets using the powder complexed without blending the silicon oxide of Comparative Example 1.
From this test, it was confirmed that the composite particles composed of N-acetylglucosamine and silicon oxide of the present invention have preferable tablet processing suitability.

<Evaluation of tablet processing suitability (2) (Comparison test with excipients)>
In order to evaluate the effect of the composite particles of the present invention, a tablet formed from a powder obtained by mixing 99% by mass of the composite powder of Example 2 with 1% by mass of calcium stearate as a lubricant, and the following. The hardness of the tablets formed from the powder mixed with the powder having the composition shown in Table 6 was similarly measured, and the measurement results are shown in FIG.

As is clear from FIG. 3, when a powder obtained by adding an excipient to the composite particles of Example 2 (corresponding to about 3% as an excipient) is used, the tablet hardness equivalent to that of the powder containing 23% excipient is obtained. Indicated.

From the above Examples and Comparative Examples, it was clarified that the composite particles composed of N-acetylglucosamine and silicon oxide of the present invention can reduce the excipient required for tableting by 20% or more. Therefore, the size of the tablet can be reduced, and other physiologically active ingredients can be added without affecting the N-acetylglucosamine content.

<Evaluation of tablet processing suitability (3) (Confirmation of productivity by rotary tableting machine)>
The tablet processing suitability was evaluated using a rotary tableting machine. The powder to be charged into the rotary tableting machine is obtained by granulating the N-acetylglucosamine composite particles prepared in Example 2 with a 5% aqueous solution of hydroxypropyl cellulose, adding calcium stearate, and then passing through a 32 mesh sieve. Prepared by mixing for 5 minutes. This powder was designated as Example 4. For comparison, a powder having the same composition was prepared in the same manner, and this powder was designated as Comparative Example 6. The compounding ratio% of Example 4 and Comparative Example 6 is shown in Table 7 below. The amount charged was 500 g, a fluidized bed device MP-01 (manufactured by Paulek Co., Ltd.) was used for granulation, and a V-type mixer S-3 (manufactured by Tsutsui Rikagaku Kikai Co., Ltd.) was used for mixing.
The tablets of Example 4 and Comparative Example 6 are tablets containing 95.6% or more of N-acetylglucosamine powder.

実施例４、比較例６の粉末をロータリー打錠機ＶＥＬ２（株式会社菊水製作所製）で打錠し、錠剤加工適性を評価した。打錠は、撹拌フィーダーを使用し、回転速度２５ｒｐｍ、予圧１００ｋｇｆとして、打錠圧力６００及び、９００、１２００、１５００ｋｇｆで成形した。各打錠圧力により成形された錠剤の硬度及び崩壊時間を前述した方法で測定した。また、打錠圧力９００ｋｇｆで成形された錠剤の摩損度を日本薬局方に従って測定した。それぞれの測定結果を表８に示した。

The powders of Example 4 and Comparative Example 6 were tableted with a rotary tableting machine VEL2 (manufactured by Kikusui Seisakusho Co., Ltd.), and the tablet processing suitability was evaluated. For tableting, a stirring feeder was used, the rotation speed was 25 rpm, the preload was 100 kgf, and the tableting pressure was 600, 900, 1200, 1500 kgf. The hardness and disintegration time of the tablets formed by each tableting pressure were measured by the method described above. In addition, the degree of abrasion of the tablets molded at a tableting pressure of 900 kgf was measured according to the Japanese Pharmacopoeia. The results of each measurement are shown in Table 8.

Example 4 could be manufactured without any trouble at any locking pressure. Regarding the hardness of the tablets, the maximum hardness was 13.9 kgf at a tableting pressure of 900 kgf, and a decrease in hardness was confirmed at 1500 kgf. Further, a hard tablet having a hardness of 10 kgf or more was obtained in a tableting pressure range of 600 to 1200 kgf.
On the other hand, in Comparative Example 6, a sticking tendency was observed at any tableting pressure, and tablets having a damaged surface were confirmed. Regarding the hardness of the tablets, the maximum hardness of 8.1 kgf was shown at a tableting pressure of 900 kgf, and a decrease in hardness was confirmed at a tableting pressure of 1200 kgf. Since capping occurred at a locking pressure of 1500 kgf, it was difficult to mold. No tablet showing a hardness of 10 kgf was obtained at any of the tableting pressures.
The decrease in hardness mainly occurs when the upper limit of compression of the tablet is exceeded, and when a stronger pressure is applied to the tablet, capping is likely to occur, and as a result, molding becomes difficult. In Example 4, since the tableting pressure that causes a decrease in hardness is higher than that in Comparative Example 6, it is presumed that the tableting pressure that reaches the compression limit has increased.
Regarding the disintegration time and the degree of abrasion, no significant difference was confirmed between Example 4 and Comparative Example 6, and both had no problem in tablet quality.
Therefore, it was confirmed that in Example 4, it was possible to produce in a wide range at a tableting pressure of 600 to 1200 kgf, and the obtained tablet exhibited a hardness of 10 kgf or more.

It has been clarified that the tablet of the present invention is excellent in tableting processing suitability and exhibits high tablet hardness in spite of its high content of N-acetylglucosamine.

Claims (3)

A tablet containing 96 to 98% by mass of N-acetylglucosamine and 2 to 4% by mass of a porous inorganic substance, having a tablet hardness of 10 kgf or more and an abrasion degree of 0.5% or less. A mixture of 2-4 weight% of 96 to 98 wt% and a porous inorganic substance N- acetylglucosamine, impact, compression, by repeated shear characterized by tabletting powders complexed N- acetyl A method for producing a glucosamine-containing tablet. The method according to claim 2 , wherein the porous inorganic substance is any substance selected from silicon, silicon oxide, silicon dioxide, calcium silicate, and calcium phosphate.

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