JP6907160B2 - Method for manufacturing easily dispersible compression molded product - Google Patents

Description

The present invention relates to a method for producing an easily dispersible compression molded product that can be quickly dispersed in a hydrophilic solvent containing water while maintaining a hardness of a certain level or higher.

It is widely known that the hardness of a molded product obtained by compressing an organic powder containing chitin and chitosan depends on the pressure applied during compression. On the other hand, there is a need for a compression molded product (so-called easily dispersible compression molded product) that has contradictory characteristics such as rapid disintegration or dispersion under specific conditions while maintaining the hardness of the molded product above a certain level. There are also fields.

Tablets can be mentioned as a form in which the characteristics of the easily dispersible compression molded product can be utilized. Tablets obtained by molding powder containing an active ingredient into tablets are required to have a certain hardness or higher so as not to cause problems such as cracking, chipping, and abrasion in the packaging during transportation and storage. .. Furthermore, tablets are also required to have a disintegrating property that disintegrates in the digestive tract within an appropriate time after ingestion.

When the active ingredient having low moldability is tablet-molded, for example, an excipient is blended. Further, when the persistently disintegrating active ingredient is tablet-molded, for example, a disintegrant is blended. Further, in order to prevent locking obstacles such as binding and capping, a lubricant having an effect of reducing friction between particles may be blended. That is, tablets, which are easily dispersible compression molded products, are often produced by optimizing the compounding composition according to the characteristics of the active ingredient and the like. In other words, it is rare that only the active ingredient can be tableted to meet various required characteristics. As described above, the process of blending various kinds of raw materials and the granulation process lead to an increase in the number of manufacturing processes and an increase in cost. Therefore, it is necessary to develop a method for producing tablets satisfying various required characteristics by a simple process. Is requested.

Since the shape of many dietary fibers such as chitosan is fibrous, the powder fluidity is poor, and it is difficult to make tablets as they are. Further, since chitosan has a small bulk specific density, the filling amount of chitosan is limited, and the obtained tablets tend to be easily worn. Therefore, in order to mold tablets containing dietary fiber such as chitosan, a lubricant such as talc, magnesium stearate, sucrose fatty acid ester is usually added, or fluidity such as crystalline lactose and crystalline cellulose is added. Mix with a good mold release agent and tablet. However, when molded by mixing with other ingredients such as a lubricant, the content of dietary fiber is reduced, and it is necessary to enlarge the tablet in order to sufficiently ingest the active ingredient. However, since it may lead to a decrease in adherence of the person taking the drug, it is desired to develop a tablet capable of increasing the amount of dietary fiber in the tablet while increasing the fluidity.

Conventionally, it has been studied to produce tablets having a certain degree of hardness and disintegration property by adjusting the blending balance between the active ingredient and an auxiliary ingredient such as a binder, a disintegrant, and an excipient. .. For example, a tablet in which a calcium material is blended as a molding aid to increase the hardness has been proposed (Patent Document 1). Further, a chitosan-containing tablet having improved hardness and disintegration, which is obtained by blending a calcium powder material and crystalline cellulose and tableting, has been proposed (Patent Document 2). Further, a chitosan-containing tablet having excellent disintegration property, which contains calcium carbonate, cellulose, and saponin in a predetermined ratio, has been proposed (Patent Document 3). Further, an orally disintegrating type tablet containing 30 to 90% by mass of N-acetylglucosamine (Patent Document 4) and a tablet containing chitosan, a calcium material, and an organic acid (Patent Document 5) have been proposed. Further, a tablet capable of disintegrating in the stomach, which is obtained by tableting chitosan powder with a large pressing force, has been proposed (Patent Document 6).

Japanese Patent No. 4132870 Japanese Unexamined Patent Publication No. 2004-262860 Japanese Patent No. 4824213 Japanese Patent No. 4403182 Japanese Patent No. 3737881 Japanese Patent No. 5969680

However, although the tablets proposed in Patent Documents 1 and 2 all have a certain degree of hardness, their disintegration property is still insufficient, and there is room for further improvement. Further, in order to produce these tablets, it is necessary to blend a specific ingredient other than the active ingredient as a molding aid, so that there is also a problem that the content of the active ingredient tends to decrease relatively. Further, in Patent Document 3, the hardness of the obtained tablet is not examined at all. Further, in Patent Document 4, the disintegration time of the tablet at the time of chewing is examined, but the disintegration property in water is not examined at all. Further, since the tablet proposed in Patent Document 5 contains an organic acid and a calcium material as components other than chitosan, the content of chitosan is low. Furthermore, the tablets proposed in Patent Document 6 are still insufficient in hardness and dispersibility in water, and there is room for further improvement.

The present invention has been made in view of the problems of the prior art, and the subject thereof is chitosan, which quickly disperses in a hydrophilic solvent containing water while maintaining a certain hardness or higher. It is an object of the present invention to provide a method for producing an easily dispersible compression molded product containing insoluble dietary fiber as a main component.

That is, according to the present invention, the following method for producing an easily dispersible compression molded product is provided.
[1] A method for producing an easily dispersible compression molded product that is dispersed in a hydrophilic solvent containing water (excluding an acidic aqueous solution), and contains a crude product containing at least one of chitin and chitosan, and water. A step of pulverizing a crude raw material having a water content (1) of 15% by mass or more represented by the following formula (1) to obtain a powder component, and mixing the obtained powder component with water. After adjusting the water content of the powder component, it is stirred under heating conditions to impart kinetic energy to obtain a water-containing raw material having a water content (2) represented by the following formula (2) of 50% by mass or less. A step of drying the obtained water-containing raw material to obtain a dry powder having a water content (2) represented by the following formula (2) of 15% by mass or less, and 10 of the obtained dry powder. A method for producing an easily dispersible compression molded product, comprising a step of compression molding a molding material containing a mass% or more.
Moisture content (1) (%) = {W ₁ / (P ₁ + W ₁ )} x 100 ... (1)
P ₁ : Amount of crude material (g)
W ₁ : Amount of water (g)
Moisture content (2) (%) = {W ₂ / (P ₂ + W ₂ )} x 100 ... (2)
P ₂ : Amount of powder component (g)
W ₂ : Amount of water (g )
[2 ] The method for producing an easily dispersible compression molded product according to the above [1], wherein the crude raw material is pulverized to obtain the powder component having a particle size that passes through a mesh having a mesh size of 180 μm.
[ 3 ] The method for producing an easily dispersible compression molded product according to the above [1] or [2] , wherein the crude raw material is pulverized by using a shearing force.
[ 4 ] The method for producing an easily dispersible compression molded product according to any one of [1] to [3 ], wherein the crude product has a weight average molecular weight of 500,000 or more.

According to the present invention, it is possible to provide a method for producing an easily dispersible compression molded product containing insoluble dietary fiber such as chitosan as a main component, which quickly disperses in water while maintaining a certain hardness or higher.

<Manufacturing method of easily dispersible compression molded product>
Hereinafter, embodiments of the present invention will be described, but the present invention is not limited to the following embodiments. The method for producing an easily dispersible compression molded product (hereinafter, also simply referred to as “compression molded product”) of the present invention has a water content (1) containing a crude material containing at least one of chitin and chitosan, and water. A step (step (1)) of crushing a crude raw material having an amount of 15% by mass or more to obtain a powder component, and adjusting the water content of the obtained powder component and imparting kinetic energy to the water content (step (1)). A step of obtaining a water-containing raw material having a water content of 50% by mass or less (step (2)) and a step of drying the obtained water-containing raw material to obtain a dry powder having a water content of 15% by mass or less (2) (step (2)). It has a step (3)) and a step (step (4)) of compression molding a molding raw material containing 10% by mass or more of the obtained dry powder. The details will be described below.

(Step (1))
In the step (1), the water content (1) represented by the following formula (1), which contains water and a crude material containing at least one of chitin and chitosan, is 15% by mass or more, preferably 20% by mass. As described above, the crude material having a content of 25% by mass or more is more preferably pulverized to obtain a powder component. Chitosan is a deacetylated product of chitin and is a basic polysaccharide (β- (1 → 4) -2-amino-2-deoxy-" having 2-amino-2-deoxy-D-glucose (glucosamine) as a constituent unit. β-D-glucose). Chitosan is industrially produced and various grades are available.
Moisture content (1) (%) = {W ₁ / (P ₁ + W ₁ )} x 100 ... (1)
P ₁ : Amount of crude material (g)
W ₁ : Amount of water (g)

Chitin and chitosan are active ingredients capable of exerting functions such as dietary fiber, LDL cholesterol level reduction, and uric acid level reduction, and are so-called insoluble dietary fibers. The weight average molecular weight of the crude bodies (chitin and chitosan) is preferably 500,000 or more, and more preferably 1,000,000 or more. In order to more effectively exert functions such as dietary fiber, LDL cholesterol level reduction, and uric acid level reduction, it is preferable that the molecular weights of chitin and chitosan are large. Further, when the molecular weight is small, chitin and chitosan are likely to have a low molecular weight and are easily colored by the pulverization treatment. Therefore, the obtained compression molded product may be colored and its appearance may be deteriorated. The weight average molecular weight of chitin and chitosan is preferably 5,000,000 or less.

Chitin and chitosan are generally stored and pulverized with a water content of about 10% by mass or less in order to suppress putrefaction and low molecular weight. On the other hand, in the production method of the present invention, the crude raw material in which the water content (1) represented by a predetermined formula is adjusted to 15% by mass or more is pulverized. This makes it possible to produce an easily dispersible compression molded product having high hardness and quickly dispersing in a hydrophilic solvent containing water. From the viewpoint of suppressing the reduction of molecular weight of chitin and chitosan, the water content (1) of the crude raw material is preferably 50% by mass or less.

The particle size of the powder component obtained by pulverizing the crude material is preferably a particle size that passes through a mesh having a mesh size of 180 μm, and more preferably a particle size that passes through a mesh having a mesh size of 150 μm. If a powder component having a particle size that does not pass through a mesh having a mesh size of 180 μm is used, the hardness of the obtained compression molded product may be slightly reduced. The “mesh” of the sieve means the number of sieve meshes per square inch, and is based on the standard sieve specified in JIS Z 8801: 2006.

The pulverization treatment of the crude raw material is preferably carried out by a method of pulverizing using a shearing force. Examples of the method of crushing using the shearing force include a method using a jet mill, a propeller mill, a cutter mill, a roll mill, a stamp mill, a rake machine, a hammer mill and the like.

The degree of deacetylation of chitosan is preferably 70% or more, more preferably 75 to 99%. When chitosan having a deacetylation degree of 70% or more is used, functions such as dietary fiber, LDL cholesterol level reduction, and uric acid level reduction can be more effectively exerted.

The degree of deacetylation of chitosan can be calculated from the titration amount obtained by performing colloidal titration. Specifically, a free amino group in the chitosan molecule is quantified by colloid titration with an aqueous solution of potassium polyvinyl sulfate using a toluidine blue solution as an indicator, and the degree of deacetylation of chitosan is determined. An example of a method for measuring the degree of deacetylation is shown below.

(1) Transcription test Chitosan was added to a 0.5 mass% acetic acid aqueous solution so that the pure chitosan concentration was 0.5 mass%, and the chitosan was stirred and dissolved to make 100 g of 0.5 mass% chitosan / 0. Prepare a 5 mass% acetic acid aqueous solution. Next, 10 g of this solution and 90 g of ion-exchanged water are stirred and mixed to prepare a 0.05 mass% chitosan solution. Further, 50 mL of ion-exchanged water and about 0.2 mL of toluidin blue solution are added to 10 g of this 0.05 mass% chitosan solution to prepare a sample solution, which is titrated with a polyvinyl sulfate potassium solution (N / 400 PVSK). The titration rate is 2 to 5 ml / min, and the point at which the sample solution is held for 30 seconds or longer after the sample solution changes color from blue to purplish red is defined as the titration amount at the end point. The pure chitosan content means the mass of chitosan in the raw material chitosan sample. Specifically, it is the solid content mass obtained by drying the raw material chitosan sample at 105 ° C. for 2 hours.

(2) Blank test Perform the same titration test using ion-exchanged water instead of the 0.5% by mass chitosan / 0.5% by mass acetic acid aqueous solution used in the above titration test.

(3) Calculation of degree of acetylation X = 1/400 × 161 × f × (VB) / 1000
= 0.4025 x f x (V-B) / 1000
Y = 0.5 / 100-X
X: Mass of free amino group in chitosan (corresponding to mass of glucosamine residue)
Y: Mass of bound amino group in chitosan (corresponding to mass of N-acetylglucosamine residue)
f: Titer of N / 400 PVSK V: Titration of sample solution (mL)
B: Blank test titration (mL)
Deacetylation degree (%)
= (Free amino group) / {(Free amino group) + (Binding amino group)} × 100
= (X / 161) / (X / 161 + Y / 203) × 100
In addition, "161" is the molecular weight of the glucosamine residue, and "203" is the molecular weight of the N-acetylglucosamine residue.

(Step (2))
In the step (2), the water content of the powder component obtained in the step (1) is adjusted and kinetic energy is applied so that the water content (2) represented by the following formula (2) is 50% by mass or less. Obtain a water-containing raw material. The water content of the powder component can be adjusted by mixing the powder component with water or removing water from the powder component by drying or the like. Further, the particle surface of the powder component (chitosan particles) can be treated by applying kinetic energy to the powder component containing water by stirring or the like. It should be noted that the compression obtained by compression molding using the powder component obtained by pulverizing the crude raw material with a cutter mill, a jet mill or the like without carrying out the step (2) or the step (3) described later is performed as it is. It becomes difficult for the molded product to disperse in water, and the dispersion time becomes long.
Moisture content (2) (%) = {W ₂ / (P ₂ + W ₂ )} x 100 ... (2)
P ₂ : Amount of powder component (g)
W ₂ : Amount of water (g)

When the water content (2) of the water-containing raw material exceeds 50% by mass, the mixture containing the powder component and water tends to be grouped together. Therefore, the proportion of the powder component having a relatively large particle size (for example, the powder component that does not pass through the mesh having a mesh size of 180 μm) increases, and the yield may decrease. Further, it may be difficult to keep the hardness of the obtained compression molded product high.

A mixer can be used to mix the powder components and water. The type of the mixer is not particularly limited, and for example, a kneader, a cylindrical mixer, a V-type mixer, a screw-type mixer, or the like can be used.

After mixing the powder component and water, it is preferable to stir under heating conditions to obtain a water-containing raw material. By stirring the mixture containing the powder component and water under heating conditions, it is possible to shorten the time required for the particle surface of the powder component to be in a better state.

(Step (3))
In the step (3), the hydrous raw material obtained in the step (2) is dried to obtain a dry powder. The water content (2) of the dry powder represented by the above formula (2) is 15% by mass or less, preferably 10% by mass or less. When the water content (2) of the dry powder obtained by drying the water-containing raw material is more than 15% by mass, coloring and a molecular weight reduction reaction due to a Maillard reaction or the like are likely to occur during long-term storage.

The water-containing raw material may be dried under heating conditions or under reduced pressure conditions. When the water-containing raw material is dried under heating conditions, the drying time can be shortened as compared with the case where it is dried under non-heating conditions.

(Step (4))
In the step (4), a molding raw material containing 10% by mass or more of the dry powder obtained in the step (3) is compression molded. Thereby, an easily dispersible compression molded product can be obtained. At the time of compression molding, only the dry powder obtained in the step (3) may be used as a molding raw material, or a molding raw material containing other components other than the dry powder may be used. Other ingredients make up common tablets such as excipients, lubricants, binders, disintegrants, colorants, flavoring agents, flavoring agents, odorants, emulsifiers, dispersants, preservatives and the like. Various components used for this can be mentioned. Further, the compression molded product can be produced by compressing the molding raw material with a general tablet molding machine such as a tablet press.

Excipients include, for example, crystalline cellulose, purulan, glucose, guar gum, xanthan gum, sorbitol, mannitol, starch, dextrin, lactose, reduced maltose, erythritol, xylitol, sodium alginate, methyl cellulose, ethyl cellulose, arabic gum, hydroxypropyl methyl cellulose phthalate. And so on. Further, a crushed chitin product or a crushed chitosan product before being mixed with water can be used as an excipient. When a crushed chitosan product or the like is compression-molded, the hardness becomes very high due to the entanglement of fibers. Therefore, by taking advantage of such characteristics, a crushed chitosan product or the like can be used as an excipient. Specifically, it is possible to control the balance between the hardness of the obtained tablet and the disintegration property in water by mixing a chitosan-treated product or the like that has been mixed with water and then dried and a chitosan pulverized product or the like that has not been mixed with water. can.

Examples of the lubricant include eggshell powder, sucrose fatty acid ester, stearic acid, magnesium stearate, aluminum stearate, calcium stearate, talc, polyvinylpyrrolidone, and hydrogenated plant oil.

Furthermore, in addition to the above components, water-soluble vitamins (vitamins B1, B2, B6, B12, C, etc.), fat-soluble vitamins (vitamins A, D, E, etc.), collagen, ginkgo biloba extract, oligosaccharides, if necessary. , Acerola extract, aloe extract, royal jelly, acetaminophen, acetylsalicylic acid, ibuprofen, tramadol, benzbromalon, probenecid, sulfinpyrazone, bucolome, losartan, balsartan, thermisartan, olmesartan, irbesartan, azirsartan, mephenamic acid, candesartan, etc. Can also be blended.

Further, after compression molding, it may be coated with a coating agent such as shellac to obtain a coated tablet. The amount of the coating agent is not particularly limited, but is preferably 0.1 to 2.0% by mass with respect to the compression molded product. Examples of the coating method include a method of spraying a coating agent on a compression molded product and drying it, and a method of using a sugar coating machine or the like.

The ratio of the dry powder to the total solid content contained in the molding raw material (compression molded product) is 10% by mass or more, preferably 30% by mass or more, and more preferably 60% by mass or more. When the ratio of the dry powder to the total solid content is less than 10% by mass, the amount of the active ingredient such as chitosan contained in the compression molded product is small. The upper limit of the ratio of the dry powder to the total solid content in the compression molded product is not particularly limited, and may be 100% by mass (that is, all the solid content is a dry powder such as chitosan).

(Physical characteristics of compression molded products)
The hardness of a cylindrical compression molded product having a diameter of 8 mm and 200 mg obtained by compression molding a molding raw material containing a dry powder at a compression pressure of 2 tf using, for example, a compressor is preferably 8 kgf or more. More preferably, it is 10 kgf or more. That is, since the compression molded product produced by the production method of the present invention has sufficiently high hardness, defects such as cracking, chipping, and abrasion are less likely to occur in the package during transportation and storage. The hardness of the compression-molded article in the present specification is defined when a tablet hardness tester (for example, trade name “Monsanto Tablet Hardness Meter B Type”, manufactured by Fuji Rika Kogyo Co., Ltd.) is used to compress-break the compression-molded article in the horizontal direction. The required load (unit: kgf). The average value measured 5 times for each formulation was taken as the hardness of the compression molded product.

The dispersion time of the compression molded product produced by the production method of the present invention in water at 37 ° C. is preferably 120 seconds or less, more preferably 60 seconds or less, and particularly preferably 30 seconds or less. That is, the compression molded product produced by the production method of the present invention is excellent in dispersibility so that it can be quickly dispersed in water while maintaining a certain hardness or higher. Therefore, the molded product produced by the production method of the present invention is less likely to cause defects such as cracking, chipping, and abrasion in the package during transportation and storage, and has good dispersibility in water, for example. , Oral tablets, orally disintegrating tablets, chewable tablets, dispersed tablets, health foods, agricultural materials, livestock feeds, cosmetics, flocculants and the like. The dispersion time of the compression molded product is a value (unit: seconds) measured according to the procedure shown below.
[Measurement of dispersion time]
Approximately 80 mL of water at 37 ° C. is placed in a 100 mL beaker, and the compression molded product is charged from a height of 2 cm above the water surface while stirring at a rotation speed of 400 rpm with a 2 cm magnetic stirrer. The time from when the compression molded product comes into contact with water until it swells and disperses and the original shape of the compression molded product cannot be visually confirmed is measured 5 times, and the average value is defined as the dispersion time (unit: seconds). Even when a liquid medium other than water (for example, a hydrophilic solvent containing water) is used, the dispersion time can be measured under the same conditions.

Next, the present invention will be described in more detail with reference to Examples and Comparative Examples, but the present invention is not limited to these Examples. Hereinafter, the terms "part" and "%" are based on mass unless otherwise specified.

<Powder preparation>
(Manufacturing Example 1)
A crude chitosan having a weight average molecular weight of 1 million (deacetylation degree 86%, water content (1) 20%) was pulverized with a jet mill to obtain chitosan powder having a particle size passing through a mesh having an opening of 180 μm. After putting the obtained chitosan powder in a kneader, the water content (2) was adjusted to 20%. After heating to 80 ° C. with the lid of the kneader and stirring for 1 hour, the lid is opened, and the mixture is dried while continuing heating and stirring at 80 ° C., and the moisture content (2) is 7%. Chitosan powder (dry powder) was obtained.

(Manufacturing Examples 2 to 10)
Chitosan powder (dry powder) was obtained in the same manner as in Production Example 1 except that the conditions shown in Tables 1-1 and 1-2 were met.

<Manufacturing of compression molded products>
(Example 1)
Using a tableting machine (trade name "HANDTAB-100", manufactured by Ichihashi Seiki Co., Ltd., diameter of mortar: 8 mm), 200 mg of chitosan powder obtained in Production Example 1 was subjected to a compression pressure of 2 tf to obtain a compression molded product. ..

(Examples 2 , 3, 5 to 8, Reference Example 4, Comparative Examples 1 to 4)
A compression molded product was obtained in the same manner as in Example 1 except that the types and amounts of chitosan powder and crystalline cellulose (trade name “Comprecel” (manufactured by Fushimi Pharmaceutical Co., Ltd.) and food additives) shown in Table 2 were used. rice field.

<Evaluation>
(Measurement of hardness)
Using a tablet hardness tester (trade name "Monsanto Tablet Hardness Tester B type", manufactured by Fuji Rika Kogyo Co., Ltd.), the load (unit: kgf) required for compression fracture in the horizontal direction of the compression molded product was measured. The average value of the loads measured 5 times for each formulation was defined as the hardness. The results are shown in Table 2.

(Measurement of dispersion time)
About 80 mL of water at 37 ° C. was placed in a 100 mL beaker, and the mixture was stirred at a rotation speed of 400 rpm using a 2 cm magnetic stirrer. Next, the compression molded product was put in from a height of 2 cm from the water surface, and the time from when the compression molded product came into contact with water until it swelled and dispersed and the original shape of the compression molded product could not be visually confirmed was measured 5 times. Then, the average value was used as the dispersion time (unit: seconds). The results are shown in Table 2.

The easily dispersible compression molded product produced by the production method of the present invention is useful as, for example, an orally disintegrating tablet.

Claims (4)

A method for producing an easily dispersible compression molded product that is dispersed in a hydrophilic solvent containing water (excluding an acidic aqueous solution).
A crude material containing at least one of chitin and chitosan, and a crude material containing water and having a water content (1) represented by the following formula (1) of 15% by mass or more are pulverized to obtain a powder component. The process of obtaining and
The obtained powder component and water are mixed to adjust the water content of the powder component, and then the powder component is stirred under heating conditions to give kinetic energy, and the water content (2) represented by the following formula (2) is applied. ) To obtain a water-containing raw material having a content of 50% by mass or less,
A step of drying the obtained water-containing raw material to obtain a dry powder having a water content (2) represented by the following formula (2) of 15% by mass or less.
A step of compression molding a molding raw material containing 10% by mass or more of the obtained dry powder, and
A method for producing an easily dispersible compression molded product having.
Moisture content (1) (%) = {W ₁ / (P ₁ + W ₁ )} x 100 ... (1)
P ₁ : Amount of crude material (g)
W ₁ : Amount of water (g)
Moisture content (2) (%) = {W ₂ / (P ₂ + W ₂ )} x 100 ... (2)
P ₂ : Amount of powder component (g)
W ₂ : Amount of water (g) The method for producing an easily dispersible compression molded product according to claim 1, wherein the crude raw material is pulverized to obtain the powder component having a particle size that passes through a mesh having a mesh size of 180 μm. The method for producing an easily dispersible compression molded product according to claim 1 or 2 , wherein the crude raw material is pulverized by using a shearing force. The method for producing an easily dispersible compression molded product according to any one of claims 1 to 3 , wherein the crude body has a weight average molecular weight of 500,000 or more.