JP5415837B2 - Method for producing granules and tablets from a powdery functional substance having inferior compression moldability - Google Patents

Description

  The present invention relates to a method for producing granules and tablets from a powdery functional substance having poor compression moldability, and in particular, a method for producing tablets whose content and tablet hardness can sufficiently withstand distribution from glucosamine powder having poor compression moldability. About.

  Examples of dosage forms for ingesting functional substances that are active ingredients of pharmaceuticals and health foods include powders, granules, capsules and tablets. Of these, tablets are the most commonly used because they are easy to handle and take.

  In general, a tablet is a mixed powder containing a functional substance and optional components such as a binder, an excipient, a disintegrant and a lubricant (in some cases, granulated by adding water and / or an organic solvent, The granulated granules) are produced by quantitatively flowing them from a hopper into a mortar of a tablet machine and compressing them with an upper punch and a lower punch.

  Tablets are compressed and molded in this way. Therefore, when the functional substance powder has inherently inferior compression moldability, the higher the ratio, the more difficult it is to form a tablet with an appropriate hardness. It is necessary to increase the amount to compensate for compression moldability. Here, the compression moldability indicates a property that particles of powder are bonded to each other when pressure is applied to the powder, and refers to a characteristic capable of pressing an amorphous powder into a specific shape.

  However, when the amount of the binder contained in the tablet is increased, the content of the functional substance in the tablet is correspondingly reduced. Conversely, if the amount of the binder used is reduced in order to increase the content of the functional substance, the hardness of the tablet is lowered to a desired level or less.

  In Patent Document 1, glucosamine granules having physical properties suitable for tableting can be obtained from crystal powder of glucosamine that is not suitable for tableting, and by using this glucosamine granule, by ordinary compression molding, Techniques for obtaining glucosamine tablets that are homogeneous and have moderately high hardness are described.

  However, even in this technique, a relatively large amount of binder must be used when granulating glucosamine crystal powder and molding into tablets, and the glucosamine content of the manufactured glucosamine tablets is about 65% by mass. Only.

  Patent Document 2 discloses granules exhibiting fluidity suitable for tableting by spraying and granulating an aqueous solution of water-soluble cellulose on powder obtained by mixing pranlukast hydrate with a fluidizing agent. Techniques for manufacturing are described. However, the powder of pranlukast hydrate has adhesion and aggregation properties and is not inferior in compression moldability.

  Therefore, this technique does not require increasing the binder to supplement compression moldability and does not describe the need to achieve high tablet hardness with a small amount of binder. Moreover, the tablet is not actually manufactured, and it is not shown that the hardness of the tablet and the content of the active ingredient are increased.

JP2006-36644 JP2007-211005

  The present invention solves the above-mentioned conventional problems, and its object is to obtain a tablet with high hardness from a powdery functional substance having inferior compression moldability by using as little binder as possible. is there.

The present invention includes a step of uniformly adhering a refined granulating binder to a powdery functional substance having inferior compression moldability; and particles of the functional substance to which the granulating binder is adhered Granulating by bringing into contact;
A process for producing granules, wherein both steps may be performed simultaneously,
Provided is a method for producing granules, wherein the granulating binder is a water-soluble cellulose derivative.

  In one certain form, the said water-soluble cellulose derivative is at least 1 type selected from the group which consists of a hydroxypropyl cellulose and a hydroxypropyl methylcellulose.

  In one certain form, the said powdery functional substance is glucosamine.

  In one certain form, the said powdery functional substance is a mixture of coarse particles and fine particles having an average particle size of 1/3 or less of the average particle size of the coarse particles.

  In one certain form, the mixing ratio of the said coarse particle and a fine particle is 50-500 mass parts of fine particles with respect to 100 mass parts of coarse particles.

  In one certain form, the said functional substance is glucosamine, and the average particle diameter of a coarse particle is 180 micrometers or more.

  In one certain form, the granulating binder is used in such an amount that the content in the granules is 10% by mass or less.

  The present invention also provides granules obtained by any of the above methods.

The present invention also includes a step of filling the tablet containing the granule into a cylindrical mortar; and a step of compressing the granule filled in the mortar with an upper punch and a lower punch;
The manufacturing method of the tablet including this is provided.

  Moreover, this invention provides the tablet obtained by the said method.

  In one certain form, content which combined the binder, the excipient | filler, the disintegrating agent, and the lubricant in the said tablet is 10 mass% or less.

  The tablet of the present invention has a high content and high hardness despite containing a powdery functional substance that is inferior in compression moldability. That is, since the blending ratio of so-called additives other than the functional substance in the tablet can be reduced, the content of the functional substance can be increased. As a result, it is possible for the user to obtain the benefit of reducing the daily dosage when the tablet dosage form is the same, or reducing the tablet dosage form when the daily dosage is the same.

It is a graph which shows the relationship between the hardness of the tablet of this invention, and tableting pressure.

The granule production method and the granule functional substance are substances that exhibit an intended action in the body after ingestion into the human body, and are concepts including active ingredients in pharmaceuticals and health foods. The functional substance that is the subject of the present invention is a powdery functional substance, in particular, a powdery functional substance that is inferior in compression moldability.

  The functional substance in the form of powder that is inferior in compression moldability is inherently small in the nature of the powder particles themselves to bind to each other. As a result, it is difficult to improve the content of the functional substance itself in the tablet. Specifically, for example, in the conventional tablet manufacturing method, even when used alone, the content in the tablet could not be increased beyond 60%, 70% or 75%, and the powdery functionality The substance falls under the category of inferior compression moldability.

  For example, the content of glucosamine in the tablet is limited to about 70%.

  The functional substance tableted by the method of the present invention may contain components other than the powdery functional substance having poor compression moldability.

  Examples of such a functional substance (that is, a component other than a powdery functional substance having poor compression moldability) include, for example, calcium, chitosan, chitin, hyaluronic acid, ceramide, chondroitin sulfate, N-acetylglucosamine, collagen, MSM, Red ginger extract, western willow, various polyphenols (from apple, tea, guava, pine, grape etc.), amino acids such as arginine, taurine, glutamic acid, histidine, branched chain amino acids (leucine, isoleucine, valine) used. Also, imidazole compounds such as histidine, 1-methylhistidine, 3-methylhistidine, anserine, carnosine, homocarnosine, and valenin can be used in combination. Others, octacosanol, citric acid, acetic acid, chitin dimer, chitin pentamer, chitosan hexamer, oligoglucosamine, eicosapentaenoic acid, docosapentaenoic acid, docosahexaenoic acid, red pepper, ginseng, beer yeast, baker's yeast, yeast zinc, yeast Examples include selenium.

  However, the powdery functional substance inferior in compression moldability constitutes the main component of the functional component to be tableted. The main component here means a component constituting 60% by mass or more, preferably 70% by mass or more, more preferably 80% by mass or more of the functional component to be tableted.

  The granulating binder refers to a binder used for the purpose of granulating functional substance particles. Granulation refers to the formation of aggregated secondary particles by combining a plurality of primary particles of a functional substance. Granules are composed of secondary particles, and their particle size is generally tens to hundreds of times that of primary particles.

  The granulating binder is preferably one having excellent safety for human body and high ability to bind powder particles. Moreover, the thing which is refined | miniaturized and tends to adhere to the powder particle | grains uniformly is preferable. A specific example of such a granulating binder is a water-soluble cellulose derivative.

  A water-soluble cellulose derivative is a water-soluble polymer in which hydrogen bonds are lost by substituting part of the hydrogen atoms of the hydroxyl group of cellulose with methyl, ethyl, propyl, hydroxypropyl or hydroxyethyl groups. It is. Examples include hydroxymethylcellulose, hydroxymethylethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), hydroxypropylmethylcellulose phthalate (HPMCP), and hydroxypropylmethylcellulose acetate succinate (HPMCAS). One or more of these can be appropriately blended and used. Preferred water-soluble cellulose derivatives are hydroxypropylcellulose and hydroxypropylmethylcellulose. A particularly preferred water-soluble cellulose derivative is hydroxypropylmethylcellulose.

  The granulating binder is made into an aqueous liquid by, for example, dissolving in water or an aqueous medium, and finely sprayed by spraying this aqueous solution. Moreover, the sprayed aqueous liquid of the granulating binder is sprayed on the powder of the functional substance, so that it adheres uniformly to the particles of the powder. At that time, generally, the powder of the functional substance is flowed so that the aqueous liquid of the granulating binder is uniformly brought into contact with the particles. The powder of the functional substance may be fluidized by stirring, or may be simultaneously heated and dried. Fluidization and drying may be performed simultaneously by blowing hot air into the functional substance powder.

  The amount of the granulating binder used is 10% by mass or less, preferably 2 to 8% by mass, more preferably 3 to 6% by mass, and further preferably 3 to 5% by mass with respect to the granules to be obtained. Adjusted. When the amount of the granulating binder is larger than this, it becomes difficult to sufficiently improve the content of the functional substance in the tablet. Moreover, granulation time becomes long and is unsuitable for manufacture.

  Subsequently, the particles of the functional material to which the binder for granulation is adhered are brought into contact with each other to be adhered to each other and granulated. For example, when a powder of a functional substance is flowed while spraying an aqueous solution of a granulating binder, particles of the functional substance to which the granulating binder is attached come into contact with each other to cause granulation. In this case, the finely divided granulating binder is uniformly attached to the functional substance particles, and the functional substance particles to which the granulating binder is adhered are simultaneously brought into contact with each other. It will be.

  The powdery functional substance has an average particle size of 60 to 200 μm, preferably 65 to 185 μm, more preferably 70 to 170 μm. If the average particle size of the functional substance is less than 60 μm, the cohesiveness becomes strong and the powder tends to be agglomerated, and the powder does not flow and prevents the particles from contacting each other. When the average particle size of the functional substance exceeds 200 μm, the gap between the particles becomes large when forming into a tablet, and it becomes difficult to sufficiently improve the content of the functional substance in the tablet. Moreover, since the contact area of particle | grains becomes small, it will become a granule inferior to compression moldability.

  The powdered functional substance is preferably packed as densely as possible in the molded tablet. This is because it is effective in improving the content of the functional substance in the tablet. For this purpose, for example, a filling form in which fine particles having relatively small dimensions are closely packed in gaps between coarse particles having relatively large dimensions is preferable. In such a case, the particle diameter of the fine particles is theoretically 1/6 to 1/3 with respect to the particle diameter of the coarse particles.

  In order to realize a finely packed form, the functional substance in powder form has coarse particles having a particle size larger than that of a general one and fine particles so that the particle size is closely packed in the gaps between the coarse particles. It is preferable to mix and use the particles. The average particle size of the fine particles is preferably 1/3 or less, for example, 1/6 to 1/3, or 1/5 to 1/4 with respect to the average particle size of the coarse particles. However, the lower limit of the average particle size of the fine particles is not particularly limited.

Greater when fine particles than 1/3 the average particle size to the average particle size of the coarse particles of the fine particles is not close-packed in the gap between the coarse particles to sufficiently improve the content of the functional substance in the tablet It becomes difficult.

  Note that the accuracy of the particle size of the fine particles need not be strict. For example, even if the average particle size of the fine particles is 1/3 or more than the average particle size of the coarse particles, the particle size changes due to friction and compression between the particles in the process of preparing granules and forming into tablets. As a result, it is acceptable if the size is such that the fine particles are closely packed in the gaps between the coarse particles.

  The average particle size of the coarse particles is, for example, 180 to 300 μm, preferably 200 to 260 μm, more preferably 210 to 240 μm. When the average particle size of the coarse particles exceeds 300 μm, the balance with the fine particles is lost, and the granules are inferior in compression moldability. The average particle size of the fine particles is, for example, 20 to 100 μm, preferably 30 to 90 μm, and more preferably 40 to 80 μm.

  Here, the average particle size means the volume average particle size (MV) of the primary particles. For example, a commonly used laser diffraction type particle size distribution measuring device (for example, “Microtrac particle size analyzer manufactured by Nikkiso Co., Ltd.”). MT3300EX ").

  When the particle size of the functional substance is expressed as a mesh, the coarse particles have a size that has passed, for example, 16 to 50 mesh, preferably 20 to 45 mesh, more preferably 30 to 40 mesh. The fine particles are, for example, 50 to 180 mesh, preferably 60 to 150 mesh, more preferably 80 mesh to 100 mesh. Here, the mesh is a unit representing the size of the mesh of the sieve net (JIS Z8801) and the size of particles passing through it. The meaning of the numerical value is the number of meshes per inch of sieve mesh.

  The mixing ratio of the coarse particles and the fine particles is appropriately adjusted so that the fine particles are densely packed in the gaps between the coarse particles in consideration of both particle sizes. Generally, it is 50-500 mass parts of fine particles with respect to 100 mass parts of coarse particles, Preferably it is 100-400 mass parts, More preferably, it is 200-300 mass parts.

  The powdery functional substance has a bulk density of 0.45 to 0.61 g / ml, preferably 0.46 to 0.60 g / ml, more preferably 0.47 to 0.59 g / ml. If the bulk density of the functional substance is less than 0.45 g / ml, the cohesiveness becomes strong and the powder tends to be agglomerated, and the powder does not flow and prevents the particles from contacting each other. When the bulk density of the functional substance exceeds 0.61 g / ml, a gap between particles becomes large when forming into a tablet, and it becomes difficult to sufficiently improve the content of the functional substance in the tablet. Moreover, since the contact area of particle | grains becomes small, it will become a granule inferior to compression moldability.

  Here, the bulk density means the powder mass per unit bulk volume, and is determined by filling the powder in a container with a known volume and measuring the mass. The bulk density may be measured, for example, according to an operation described in the Japanese Pharmacopoeia.

  There is no particular limitation on the granulator used for granulating the powdered functional substance, and for example, a fluidized bed granulator, a stirring granulator, an extrusion granulator, or the like can be used.

  In the method of the present invention, a granulating sub-base material may be blended within a range that does not significantly affect the physical properties of the granules and the content of the functional material. The auxiliary base material may be pre-mixed before granulation and then granulated, or may be added after granulation. At that time, starch, dextrin and other starch degradation products, carrageenan, agar, alginic acid, guar gum, chitosan, xanthan gum and other polysaccharides, sugar, glucose, lactose, maltose and other monosaccharides, disaccharides, fructooligosaccharides, malto-oligosaccharides, iso Oligosaccharides such as maltooligosaccharide, galactooligosaccharide, chitin oligosaccharide and chitosan oligosaccharide, sugar alcohols such as maltitol, sorbitol, xylitol and erythritol, crystalline cellulose and the like can be used as the auxiliary base material for granulation. In addition to the sugars, components such as thickeners and emulsifiers that are commonly used for preparing granular preparations can be used as the auxiliary base material for granulation.

  By mixing these sub-base materials for granulation as appropriate and granulating, the productivity during granulation and / or tableting can be increased, and the shape stability of granule products is further improved. can do. The amount of the granulation sub-base material is not particularly defined, but may be adjusted to such an extent that the content of the functional substance is not lowered. Generally, the content in the granule is adjusted to 20% by mass or less, preferably 10% by mass or less.

  The granules thus obtained are dried as necessary to remove the contained water and organic solvent. The drying temperature is 20 to 90 ° C, preferably 30 to 85 ° C, more preferably 65 to 80 ° C.

  The obtained granule has a content of components other than the functional substance of 3 to 10% by mass and a bulk specific gravity of 25 to 40 g / ml, more preferably 28 to 35 g / ml. Further, the water content is preferably 3.0% by mass or less, and more preferably 2.0% by mass or less. Furthermore, the granules may be appropriately sized to 16-22 mesh.

The tablet manufacturing method and tablet- dried granules are sized, if necessary, and added with the necessary base materials (for example, binders, excipients, disintegrants, lubricants, etc.) to manufacture tablets. To obtain a tableting powder, which is compression-molded into tablets. As a necessary base material, what is generally used in order to make a granule or a tablet can be used. Specifically, starch degradation products such as starch and dextrin, polysaccharides such as carrageenan, agar, alginic acid, guar gum, chitosan and xanthan gum, monosaccharides such as sugar, glucose, lactose and maltose, disaccharides, fructooligosaccharides, maltooligosaccharides , Oligosaccharides such as isomaltoligosaccharide, galactooligosaccharide, chitin oligosaccharide, chitosan oligosaccharide, sugar alcohols such as maltitol, sorbitol, xylitol, erythritol, celluloses such as crystalline cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone Synthetic polymers such as gum arabic, agar, pullulan, fine silicon oxide, pregelatinized starch, partially pregelatinized starch, CMC-Ca, sodium starch glycolate, magnesium stearate, stearin Calcium, stearate, sucrose fatty acid esters, hydrogenated oils, vegetable oils and the like.

  These substrates are used singly or in combination of two or more, but it is desirable to use them divided into tableting binders, excipients, disintegrants and lubricants according to their functions. The tablets produced as described above may be appropriately provided with a coating process for applying film coating or sugar coating.

Tablets are produced, for example, by filling tablet powder into a cylindrical mortar, grinding the granule filled in the mortar to a fixed amount with a grinding plate, and compressing it with upper and lower scissors. A known tableting machine can be used without any limitation. The tableting pressure may be adjusted so that the tablet hardness is sufficient to withstand circulation.

  The tablet thus obtained has a total content of components other than the functional substance (for example, binder, excipient, disintegrant, lubricant, etc.) of 15% by mass or less, more preferably, for example, 5 -10 mass%, and the tablet hardness in that case is 3-10 kgf. In the present specification, the term “binder” includes both a granulating binder and a tableting binder.

  Moreover, you may mix | blend functional substances other than the powdery functional substance which is inferior to compression moldability in the said tableting powder in the range which does not impair the hardness of a tablet. Examples of the functional substance other than the powdery functional substance inferior in compression moldability include those exemplified when the production method of the granule of the present invention is described. As described above, a preferable amount of such a functional substance used is a range in which a powdery functional substance having inferior compression moldability is the main component of the functional substance contained in the tablet.

  The following examples further illustrate the present invention, but the present invention is not limited thereto. Unless otherwise noted, the ratios and amounts of materials used are on a mass basis.

Example 1
Preparation of granules Glucosamine powder with a particle size of 83 mesh sieve (“Koyo Glucosamine 80” manufactured by Koyo Chemical Co., Ltd.) and Glucosamine powder with a particle size of 42 mesh sieve (“Koyo Glucosamine” manufactured by Koyo Chemical Co., Ltd.) ) At a mass ratio of 3/1 to obtain a functional substance for granulation. Hydroxypropyl methylcellulose (“Metroze SE-06” manufactured by Shin-Etsu Chemical Co., Ltd.) was prepared as a binder for granulation, and an 8% aqueous solution thereof was prepared to obtain a spray solution.

  Using a fluidized granulator ("Fluidized bed granulator MP-01" manufactured by POWREC Co., Ltd.), granulation was performed according to a conventional method while spraying the spray liquid uniformly on the functional material for granulation. At that time, the supply air temperature was 75 ° C., and the spray rate of the spray liquid was 6 to 10 ml / min. In addition, the amount of each component was adjusted so that the formed tablet was 100%, the functional substance was 94.48%, and the granulating binder was 4.17%.

  The obtained granulated product was dried at a temperature of 80 ° C. until the water content became 2% or less, and after drying, the particles were sized using a 16 or 20 mesh sieve to obtain glucosamine-containing granules.

Measurement of bulk density of granule The bulk density of the obtained granule was measured. The bulk density was calculated by the following formula after the granule was ground and filled into a 100 ml container, and the weight was measured.

Bulk specific gravity [g / ml] = Glucosamine granule weight [g] / 100 ml
The results are shown in Table 1.

Preparation of Tablets The obtained glucosamine-containing granules were mixed with crystalline cellulose (“Theoras UF-F702” manufactured by Asahi Kasei Chemicals Corporation) and calcium stearate (manufactured by Sakai Chemical Co., Ltd.) as a lubricant to obtain a tableting powder. The tableting powder was tableted using a tableting machine ("HT-AP12SS-U" manufactured by Hata Iron Works) to obtain 8 mm round tablets with a diameter of 250 mg. At that time, the tableting pressure was changed in the range of 5 to 15 kN. The amount of each component was adjusted such that the formed tablet was 100%, the crystalline cellulose was 0.55%, and the calcium stearate was 0.80%.

Measurement of Tablet Hardness The hardness of the tablets obtained was measured using “Tablet Breaking Strength Meter TH-303MP” manufactured by Toyama Sangyo Co., Ltd. The results are shown in FIG.

Examples 2-6, Reference Examples 1-3
A tablet was prepared and the hardness was measured in the same manner as in Example 1 except that the particle structure of the functional substance (glucosamine) was changed as shown in the column of “particle mixing ratio” in Table 1. The results are shown in FIG.

Comparative Example 1
A tablet was prepared in the same manner as in Example 1 except that it was sprayed with water instead of hydroxypropylmethylcellulose, and 4.72% of hydroxypropylmethylcellulose was added to the granulated part and granulated, and the hardness was measured. . The results are shown in FIG.

Comparative Example 2
Tablets were prepared in the same manner as in Example 1 except that dextrin (“Paindex # 100” manufactured by Matsutani Chemical Industry Co., Ltd.) was used instead of hydroxypropylmethylcellulose, and the hardness was measured. The results are shown in FIG.

  As shown in Table 1, the tablet of the comparative example could not obtain a hardness that could withstand distribution. The tablets of Examples 1 and 3 had sufficient hardness. Other examples were not as high as those in Examples 1 and 3, but the hardness to withstand circulation was obtained. Example 9 had strong powder cohesiveness and had production problems such as not flowing in a fluidized bed granulator, but showed the highest tablet hardness.

Claims (9)

A step of uniformly adhering a refined granulating binder to a powdered functional substance having inferior compression moldability; and contacting particles of the functional substance to which the granulating binder is adhered The step of granulating by
A process for producing granules, wherein both steps may be performed simultaneously,
The powdery functional substance is glucosamine in which coarse particles and fine particles having an average particle size of 1/3 or less of the average particle size of the coarse particles are mixed,
A method for producing granules, wherein the granulating binder is a water-soluble cellulose derivative. The method according to claim 1 , wherein the water-soluble cellulose derivative is at least one selected from the group consisting of hydroxypropylcellulose and hydroxypropylmethylcellulose. The method according to claim 1 or 2, wherein a mixing ratio of the coarse particles and the fine particles is 50 to 500 parts by mass of fine particles with respect to 100 parts by mass of the coarse particles. The method according to claim 1 , wherein the coarse particles have an average particle size of 180 μm or more. The method according to any one of claims 1 to 4 , wherein the granulating binder is used in such an amount that the content in the granule is 10% by mass or less. The granule obtained by the method as described in any one of Claims 1-5 . Filling the tablet with the tablet containing the granule according to claim 6 into a cylindrical mortar; and compressing the granule filled in the mortar with upper and lower punches;
A method for producing a tablet comprising A tablet obtained by the method according to claim 7 . The tablet according to claim 8, wherein the total content of the binder, the excipient, the disintegrant and the lubricant is 10% by mass or less.

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