JP7718672B2 - Enteric-coated tablets - Google Patents

Description

The present invention relates to enteric coated tablets .

Lactoferrin has various physiological functions, and a variety of functional food and health food products are already commercially available. In the food industry, many solid formulations, such as tablets, are commercially available due to their ease of administration and excellent storage stability. Furthermore, the lactic acid bacterium Lactobacillus casei is known to have an intestinal regulating effect that improves constipation, as well as the ability to prevent and alleviate allergic symptoms such as atopic dermatitis and hay fever, and, like lactoferrin, a variety of products are commercially available.

Because the binding strength between lactoferrin powder particles is weak, in order to produce tablets containing high concentrations of lactoferrin, they must be compressed at high pressure to reduce tablet friability. However, tablets compressed at high pressure inevitably have the problem of poor disintegration in the body.

Solid formulations containing such high concentrations of lactoferrin contain sugar alcohols and crystalline cellulose as excipients to improve the dissolution and disintegration properties of lactoferrin (see Patent Document 1).

Lactoferrin is known to have functions such as improving constipation and intestinal flora, and when combined with the lactic acid bacteria Lactobacillus casei, its function of improving bowel movements is further enhanced, while its function of maintaining skin moisture is also exerted. However, solid preparations containing lactoferrin and Lactobacillus casei cells have issues with moldability and disintegration, and there has been a strong desire to resolve these issues.

International Publication No. 2016/163460

The present invention aims to solve the above-mentioned problems of the prior art and achieve the following objectives. Specifically, the present invention aims to provide a solid preparation that has excellent moldability and does not lose its disintegration properties, even when it contains lactoferrin and Lacticaseibacillus casei lactic acid bacteria cells.

As a means for solving the above problems, the solid preparation of the present invention comprises: (A) lactoferrin;
(B) Lactobacillus casei cells;
(C) an excipient; and
A solid dosage form having the formula:
The (C) excipient contains one or more of (C1) cellulose or a derivative of the cellulose, and (C2) sugar alcohol.

The present invention solves the above-mentioned problems of the prior art and achieves the following objectives. Specifically, the present invention provides a solid preparation that has excellent moldability and does not lose its disintegration properties, even though it contains lactoferrin and Lacticaseibacillus casei lactic acid bacteria cells.

[Solid preparations]
The solid preparation of the present invention comprises (A) lactoferrin, (B) Lactobacillus casei cells, and (C) an excipient, wherein the excipient (C) comprises one or more of (C1) cellulose or a derivative of the cellulose and (C2) a sugar alcohol, and optionally contains other ingredients.

<(A) Lactoferrin>
The lactoferrin (A) is contained to exert the functions of improving lipid metabolism, improving constipation, improving intestinal flora, improving sleep, promoting growth hormone secretion, improving dry eye, corneal epithelial abrasion and the resulting eye disorders, lowering blood pressure, alleviating allergies, maintaining, improving and enhancing immune function, and improving liver function. In particular, as a function of improving lipid metabolism, it is useful for reducing visceral fat and BMI, and for exerting the functions of maintaining, improving and enhancing immune function.

The lactoferrin (A) is not particularly limited and can be appropriately selected depending on the purpose, but examples include lactoferrin isolated from mammalian colostrum, transitional milk, normal milk, terminal milk, etc., or processed products of mammalian milk such as skim milk and whey, lactoferrin produced from plants, lactoferrin obtained by genetic recombination, etc. Among these, lactoferrin concentrates containing 50% by mass or more of lactoferrin monomer are preferred.
The mammal is not particularly limited and can be appropriately selected depending on the purpose, and examples thereof include humans, cows, sheep, goats, and horses.
The plant is not particularly limited and can be appropriately selected depending on the purpose, and examples thereof include tomato, rice, and tobacco.
The method for separating lactoferrin is not particularly limited and can be appropriately selected depending on the purpose, and examples thereof include ion exchange chromatography.
The lactoferrin used may be a commercially available product or may be prepared by a known method. Lactoferrin produced by a conventional method may also be used.

From the viewpoint of the expression of physiological functions, the daily intake of (A) lactoferrin is preferably 50 mg or more and 1000 mg or less, more preferably 100 mg or more and 500 mg or less, and particularly preferably 200 mg or more and 400 mg or less.

From the viewpoint of the expression of physiological functions, the content of (A) lactoferrin is preferably 4% by mass or more and 50% by mass or less, more preferably 10% by mass or more and 40% by mass or less, and particularly preferably 20% by mass or more and 35% by mass or less, relative to the total mass of the uncoated tablet.

When the content of (A) lactoferrin is 4% by mass or more relative to the total mass of the uncoated tablet, the physiological functions are exerted and the number of tablets to be taken can be kept within an appropriate range, improving ease of administration.
When the content of (A) lactoferrin is 50% by mass or less relative to the total mass of the uncoated tablet, the initial dissolution and disintegration of the lactoferrin, the disintegration retention rate, and the moldability of the uncoated tablet can be improved. Note that the "disintegration retention rate" in the present invention indicates the degree to which the disintegration of a tablet is maintained over time compared to that of the tablet immediately after production.

The method for producing the lactoferrin is not particularly limited, and lactoferrin produced by a conventional method can be used, which may include a drying step, for example.
The drying step in the lactoferrin production method includes freeze-drying and spray-drying. The lactoferrin obtained by the drying step is preferably contained in the dried product at a purity of 85% or more. Furthermore, the loss on drying in the drying step is preferably 6% by mass or less.
The method for producing lactoferrin may include processing steps such as granulation, particle coating, and pulverization.

The average particle size of the lactoferrin (A) is preferably 20 μm or more and 300 μm or less, and more preferably 20 μm or more and 100 μm or less.
In the present invention, the average particle size refers to the 50% diameter (median diameter, volume basis) in the particle size distribution by laser diffraction scattering.

<(B) Lactobacillus casei cells>
The (B) Lactobacillus casei fungus is contained to exhibit the following functions: improving bowel movements, improving intestinal flora, maintaining skin moisture, protecting skin from dryness, maintaining skin barrier function, improving skin texture, preventing rough skin, tightening skin, maintaining skin flexibility, protecting skin from UV rays, softening skin, giving skin firmness, giving skin luster, smoothing skin, improving sleep quality, improving immunity, preventing and alleviating allergic symptoms such as atopic dermatitis and hay fever, improving blood flow, lowering blood pressure, preventing periodontal disease, and preventing bad breath.In particular, it is useful for improving bowel movements and preventing skin moisture from escaping, thereby protecting skin from dryness and maintaining skin barrier function.

The (B) Lactobacillus casei bacteria were classified as Lactobacillus casei, but in 2020, Zheng et al. reclassified the Lactobacillus genus into a total of 25 genera, and the classification name was changed to Lacticaseibacillus casei (Int. J. Sys. Evol. Microbiol., 2020; 70: 2782-2858).
The (B) Lactobacillus casei cells are not particularly limited and can be appropriately selected depending on the purpose, and examples thereof include those derived from the human intestinal tract, dairy products, and plants (plant-derived products including processed foods such as miso, soy sauce, pickles, bran, grass, rice, wheat, and malt). Among these, those isolated from rice or processed rice foods are preferred.
The (B) Lactobacillus casei cells may be live cells or sterilized cells that have been subjected to a sterilization process.

The (B) Lactobacillus casei cells are not particularly limited and can be selected appropriately depending on the purpose, but are preferably a dispersion with an excipient, and more preferably a dispersion with dextrin.
The bacterial cell content of the dispersion with the excipient is preferably 10% by mass to 90% by mass, more preferably 40% by mass to 60% by mass. By making the bacterial cell content in the dispersion 40% by mass or more, physiological functions are more easily expressed. By making the bacterial cell content in the dispersion 60% by mass or less, sufficient hardness is obtained, resulting in good disintegrability.

The average particle size of the (B) Lactobacillus casei cells is preferably 20 μm or more and 100 μm or less, and more preferably 40 μm or more and 80 μm or less. The average particle size can be determined in the same manner as for (A) lactoferrin.

The daily intake of the (B) Lactobacillus casei cells is preferably 5 billion to 1 trillion cells, more preferably 10 billion to 800 billion cells, and particularly preferably 30 billion to 700 billion cells.
The number of Lactobacillus casei cells contained in the raw material powder or solid preparation can be measured by a hemocytometer measurement method or a DAPI staining method, and measurement by a DAPI staining method is preferred. Examples of measuring the number of cells by the DAPI staining method include the following methods.
0.1 g of sample was weighed into a 15 ml centrifuge tube and phosphate buffered saline (34 g of anhydrous potassium dihydrogen phosphate was dissolved in purified water, and then 1 M sodium hydroxide was added to adjust the pH to 7.2, bringing the total volume to 1000 mL) was added and mixed to achieve a 100-fold dilution. The mixture was homogenized using a vortex mixer and ultrasonic treatment to obtain a stock sample solution. The stock sample solution was further diluted appropriately to obtain a measurement sample solution.
The sample solution for measurement was filtered through a membrane filter with a pore size of 0.20 μm, then reacted with DAPI solution (reagent) for about 1 minute, and filtered. The cells captured on the membrane filter were photographed using an epifluorescence microscope. The number of cells in the photographed image was counted, the average number of cells per image was calculated, and the total number of bacteria per gram of sample was calculated using the following formula:
Total number of bacteria (cells/g) = average number of cells per image x effective filtration area / area of one image / filtration volume. For the effective filtration area, check the specifications of the filtration device to be used.

The content of the (B) Lactobacillus casei cells is preferably 0.5% by mass or more and 50% by mass or less, more preferably 1% by mass or more and 40% by mass or less, and particularly preferably 1.5% by mass or more and 25% by mass or less, relative to the total mass of the uncoated tablet.
When compounded into a solid preparation, it is preferable to compound it so that 5 billion to 1 trillion particles can be ingested per day, more preferably 10 billion to 800 billion particles can be ingested, and particularly preferably 30 billion to 700 billion particles can be ingested.

It is preferable that the content of the (B) Lactobacillus casei cells is 0.5% by mass or more relative to the total mass of the uncoated tablet, since this allows physiological functions to be expressed.
When the content of the (B) Lactobacillus casei cells is 50% by mass or less relative to the total mass of the uncoated tablet, sufficient hardness and good disintegrability can be obtained.

The (B) Lactobacillus casei bacterial cells can be produced by culturing them in an MRS medium or the like according to a conventional method, recovering the bacterial cells from the resulting culture, washing them with water, adding an excipient as necessary, and spray-drying or freeze-drying them.
The method for recovering the bacterial cells is not particularly limited and can be appropriately selected depending on the purpose. Examples thereof include filtration and centrifugation.

<(C) Excipient>
The (C) excipient contains one or more of (C1) cellulose or a derivative of the cellulose and (C2) sugar alcohol.

((C1) Cellulose or a derivative thereof)
The (C1) cellulose or the cellulose derivative is contained to exhibit functions such as improving tablet physical properties (moldability, disintegrability) immediately after production, promoting dissolution of functional ingredients, improving the dissolution retention rate of functional ingredients, storage stability, and suppressing tableting problems. It is particularly useful for improving tablet physical properties (moldability, disintegrability, dissolution) immediately after production, storage stability, improving the dissolution retention rate of functional ingredients, and suppressing tableting problems.

The (C1) cellulose or cellulose derivative is not particularly limited and can be selected appropriately depending on the purpose, but examples include crystalline cellulose, methyl cellulose, microfibrous cellulose, hydroxypropyl cellulose, and ethyl cellulose. Among these, crystalline cellulose is preferred because of its excellent moldability and disintegrability.

When the (C1) cellulose or the cellulose derivative is crystalline cellulose, the bulk density of the crystalline cellulose is preferably 0.15 g/cm ^{or more} and 0.40 g/cm ^{or less} , and more preferably 0.20 g/cm or ^more and 0.35 g/cm or ^less . The bulk density can be measured by the method described in "Crystalline Cellulose" in the 17th Edition of the Japanese Pharmacopoeia using a Scott volume meter.
The average particle size of the cellulose or cellulose derivative (C1) is preferably 20 μm or more and 180 μm or less, more preferably 40 μm or more and 150 μm or less. The average particle size can be determined in the same manner as for the lactoferrin (A).

The content of the (C1) cellulose or the cellulose derivative is preferably 15% by mass or more and 80% by mass or less, more preferably 20% by mass or more and 65% by mass or less, and particularly preferably 25% by mass or more and 45% by mass or less, relative to the total mass of the uncoated tablet.
When the content of the (C1) cellulose or the cellulose derivative is 15% by mass or more relative to the total mass of the uncoated tablet, moldability, tablet disintegration property, dissolution property of the functional ingredient, and maintenance rate of disintegration property and dissolution property are improved, and tableting problems are less likely to occur, which is preferable.
When the content of the cellulose or cellulose derivative (C1) is 80% by mass or less relative to the total mass of the uncoated tablet, sufficient hardness and good disintegrability can be obtained. In addition, the thickness can be reduced, which is preferable because it improves ease of administration and makes it difficult for the mixed powder to adhere to the tablet press.

((C2) Sugar Alcohol)
The (C2) sugar alcohol is contained to exhibit functions such as tablet moldability, tablet physical properties (moldability, disintegrability) immediately after production, storage stability, promotion of dissolution of functional ingredients, improvement of dissolution maintenance rate of functional ingredients, etc. It is particularly useful for improving tablet physical properties (disintegrability) immediately after production, storage stability, promotion of dissolution of functional ingredients, and improvement of dissolution maintenance rate of functional ingredients.

The (C2) sugar alcohol is not particularly limited and can be selected appropriately depending on the purpose. Examples include maltitol, erythritol, xylitol, fructose, sucrose, glucose, sorbitol, and lactitol.

The average particle size of the (C2) sugar alcohol is preferably 50 μm or more and 400 μm or less, and more preferably 200 μm or more and 300 μm or less. The average particle size can be determined in the same manner as for (A) lactoferrin.

The content of the (C2) sugar alcohol is preferably 5% by mass or more and 50% by mass or less, more preferably 10% by mass or more and 40% by mass or less, and particularly preferably 12% by mass or more and 30% by mass or less, relative to the total mass of the uncoated tablet.
If the content of the (C2) sugar alcohol is 5% by mass or more relative to the total mass of the uncoated tablet, moldability, tablet disintegration property, dissolution property of the functional ingredient, and maintenance rate of disintegration property and dissolution property are improved, which is preferable.
When the content of the sugar alcohol (C2) is 50% by mass or less relative to the total mass of the uncoated tablet, sufficient hardness and good disintegrability can be obtained, and resistance to gastric juice can be ensured, which is preferable.

<Other ingredients>
Examples of the other components include disintegrants other than component (C), fluidizing agents, lubricants, binders other than component (C), coating agents, enteric coating agents, and the like.
The other components may be used alone or in combination of two or more.

(Disintegrants other than component (C))
A disintegrant other than the component (C) (hereinafter, sometimes referred to as "disintegrant") is contained to promote disintegration of the tablet.

The disintegrant is not particularly limited and can be selected appropriately depending on the purpose. Examples include carboxymethylcellulose (CMC) or its alkali metal salts, partially pregelatinized starch, etc. Among these, from the viewpoints of tablet disintegration property and dissolution property of functional ingredients, carboxymethylcellulose (CMC) or its alkali metal salts are preferred, and carboxymethylcellulose calcium is more preferred.

The content of the disintegrant is preferably 0.1% by mass or more and 5% by mass or less, and more preferably 1% by mass or more and 2% by mass or less, based on the total mass of the uncoated tablet.
If the content of the disintegrant is 0.1% by mass or more relative to the total mass of the uncoated tablet, the disintegration property of the tablet and the dissolution property of the functional ingredient are improved, which is preferable.
It is preferable that the content of the disintegrant is 5% by mass or less relative to the total mass of the uncoated tablet, since this reduces delay in disintegration of the tablet during storage.

(Superplasticizer)
The fluidizing agent is added to prevent adhesion between powder particles, thereby promoting fluidity, which reduces variation in tablet weight.

The fluidizing agent is not particularly limited and can be selected appropriately depending on the purpose. Examples include fine silicon dioxide (silica), light anhydrous silicic acid, calcium silicate, hydrous fine silicic acid powder, and talc.

The average particle size of the silicon dioxide is preferably 0.5 μm or more and 10 μm or less. The average particle size can be determined in the same manner as in (A) lactoferrin.
The silicon dioxide is preferably porous fine particle silicon dioxide.

The content of the fluidizing agent is preferably 0.1% by mass or more and 2.0% by mass or less relative to the total mass of the uncoated tablet, from the viewpoint of suppressing variation in tablet mass.
When the content of the fluidizing agent is 0.1% by mass or more relative to the total mass of the uncoated tablet, the fluidity of the mixed powder is improved, and therefore, variation in tablet mass is preferably suppressed.
It is preferable that the content of the fluidizing agent is 2.0% by mass or less relative to the total mass of the uncoated tablet, since this prevents the hardness of the tablet from becoming too high.

(lubricant)
The lubricant is added to prevent metal adhesion by reducing friction between the metal equipment and the powder particles, which is advantageous because reduced friction between the metal equipment and the powder particles suppresses tableting problems.

The lubricant is not particularly limited and can be selected appropriately depending on the purpose. Examples include metal stearates and sucrose fatty acid esters. Of these, calcium stearate and magnesium stearate are preferred from the viewpoint of suppressing tableting problems (binding, sticking, and picking).

From the viewpoint of preventing adhesion to the tablet press and suppressing tableting problems (binding, sticking, and picking), the content of the lubricant is preferably from 0.01% by mass to 10% by mass, more preferably from 0.05% by mass to 5.0% by mass, and particularly preferably from 0.10% by mass to 3.0% by mass, relative to the total mass of the uncoated tablet.
If the content of the lubricant is 0.01% by mass or more relative to the total mass of the uncoated tablet, adhesion to the tablet press is prevented, and tableting problems (binding, sticking, picking) are less likely to occur, which is preferable.
If the content of the lubricant is 10% by mass or less relative to the total mass of the uncoated tablet, the moldability, disintegrability, and dissolution properties of the tablet are improved, which is preferable.

(Binders other than component (C))
The binder other than the component (C) (hereinafter, sometimes referred to as "binder") is contained to control the hardness of the tablet and the disintegration time of the tablet.

The binder is not particularly limited and can be selected appropriately depending on the purpose. From the viewpoints of preventing tableting problems (capping, lamination), tablet physical properties (hardness, disintegration time), and storage stability of tablet physical properties, examples of suitable binders include starch such as corn starch, gum arabic, gelatin, sodium alginate, polyvinylpyrrolidone, polyvinyl alcohol, and hydroxypropyl methylcellulose (hereinafter sometimes referred to as "HPMC").

From the viewpoints of improving tablet formability, suppressing tableting problems, and improving the storage stability of the tablet physical properties, the content of the binder is preferably 0.01% by mass or more and 30% by mass or less, and more preferably 0.1% by mass or more and 10% by mass or less, relative to the total mass of the uncoated tablet.
If the content of the binder is 0.01% by mass or more relative to the total mass of the uncoated tablet, the tablet moldability is improved and tableting problems are less likely to occur, which is preferable.
If the content of the binder is 30% by mass or less relative to the total mass of the uncoated tablet, the mixed powder is less likely to adhere to the tablet press, and the disintegration properties of the tablet are improved, which is preferable.

(Coating agent)
The solid preparation of the present invention may be a coated tablet provided with a coating layer containing a coating agent in order to improve ease of administration and mask the plain tablet (mainly the bitterness, odor, etc. caused by the functional ingredients).
The coating layer may contain a plasticizer in addition to the coating agent.
When the solid preparation of the present invention is a coated tablet, the above-mentioned coating layer is present on the surface of the uncoated tablet.

The coating agent is not particularly limited and can be appropriately selected depending on the purpose, and examples thereof include cellulose, cellulose derivatives, methacrylic acid-based polymer compounds, shellac, zein, polyuronic acid and its salts, fucoidan and its salts, and carrageenan and its salts. Among these, HPMC, shellac, zein, polyuronic acid and its salts (particularly alginates), and pectin and its salts are preferred. These may be used alone or in combination.
The cellulose derivative is not particularly limited and can be appropriately selected depending on the purpose, and examples thereof include HPMC.
The polyuronic acid is not particularly limited as long as it is a polymer of uronic acid such as guluronic acid, mannuronic acid, galacturonic acid, or glucuronic acid, and can be appropriately selected depending on the purpose. Examples of the polyuronic acid include alginic acid (a polymer of guluronic acid and mannuronic acid) and pectin (a polymer of galacturonic acid).

The plasticizer used in conjunction with the coating agent is not particularly limited and can be selected appropriately depending on the purpose. Examples include glycerin, polyethylene glycol, and sucrose fatty acid esters. Of these, glycerin and sucrose fatty acid esters are preferred.

When the solid preparation of the present invention is a coated tablet, the content of the coating agent is preferably 0.5% by mass or more and 15% by mass or less, and more preferably 1% by mass or more and 10% by mass or less, relative to the total mass of the coated tablet, from the viewpoints of improving the ease of taking the tablet and masking the bitterness and odor derived from the functional ingredient.
If the content of the coating agent is 0.5% by mass or more relative to the total mass of the coated tablet, it is preferable because it improves ease of administration and masks the bitterness and odor derived from the functional ingredients.
When the content of the coating agent is 15% by mass or less based on the total mass of the coated tablet, the disintegration and dissolution properties of the tablet are good.

The content of the coating agent is preferably 0.5% by mass or more and 15% by mass or less, and more preferably 1% by mass or more and 10% by mass or less, based on the total mass of the uncoated tablet.
If the content of the coating agent is 0.5% by mass or more relative to the total mass of the uncoated tablet, it is preferable because the ease of administration is improved and the bitterness and odor derived from the functional ingredients are masked.
When the content of the coating agent is 15% by mass or less relative to the total mass of the uncoated tablet, the disintegration and dissolution properties of the tablet are good.

The content of the plasticizer is not particularly limited, but is preferably 0.05% by mass or more relative to the total mass of the coated tablet, in order to improve the disintegration and dissolution properties of the coated tablet. Furthermore, the content of the plasticizer is preferably 10% by mass or less, and more preferably 0.1% by mass or more and 5% by mass or less, relative to the total mass of the coated tablet, in order to achieve the coating effect.

The content of the plasticizer is preferably 0.05% by mass or more relative to the total mass of the uncoated tablet from the viewpoint of improving disintegration and dissolution. Furthermore, from the viewpoint of achieving a coating effect, the content of the plasticizer is preferably 10% by mass or less relative to the total mass of the uncoated tablet, and more preferably 0.1% by mass or more and 5% by mass or less.

(Enteric coating agent)
The solid preparation of the present invention may be an enteric-coated tablet provided with a coating layer containing an enteric coating agent in order to inhibit the decomposition of ingredients that are susceptible to deterioration by gastric acid.
The enteric coating layer may contain a plasticizer in addition to the enteric coating agent.
When the solid preparation of the present invention is an enteric-coated tablet, the tablet has an enteric coating layer on the surface thereof.

The enteric coating agent is not particularly limited and can be appropriately selected depending on the purpose, and examples thereof include methacrylic acid-based polymer compounds, shellac, zein, polyuronic acid and its salts, fucoidan and its salts, and carrageenan and its salts. Among these, shellac, zein, polyuronic acid and its salts (particularly alginates), and pectin and its salts are preferred. One or more of these may be used.
The polyuronic acid is a polymer of uronic acid such as guluronic acid, mannuronic acid, galacturonic acid, glucuronic acid, etc., and examples thereof include alginic acid (a polymer of guluronic acid and mannuronic acid) and pectin (a polymer of galacturonic acid).
The enteric coating agent may be used in combination with a cellulose derivative (HPMC, etc.) exemplified as the coating agent.
The enteric coating agent may be used in combination with the coating agent.

When the solid preparation of the present invention is an enteric-coated tablet, the content of the enteric coating agent is preferably 1% by mass or more and 30% by mass or less, and more preferably 1% by mass or more and 15% by mass or less, relative to the total mass of the enteric-coated tablet, from the viewpoint of preventing decomposition of the functional ingredient in the stomach.
It is preferable that the content of the enteric coating agent is 1% by mass or more relative to the total mass of the enteric coated tablet, since this can prevent the functional ingredient from being decomposed in the stomach.
When the content of the enteric coating agent is 30% by mass or less based on the total mass of the enteric coated tablet, the dissolution property in the intestinal environment is good.

The content of the enteric coating agent is preferably 0.1% by mass or more and 30% by mass or less, and more preferably 0.1% by mass or more and 15% by mass or less, relative to the total mass of the uncoated tablet.
It is preferable that the content of the enteric coating agent is 0.1% by mass or more relative to the total mass of the uncoated tablet, since this can prevent the degradation of the functional ingredient in the stomach.
When the content of the enteric coating agent is 30% by mass or less relative to the total mass of the uncoated tablet, the dissolution property in the intestinal environment is good.
When the enteric coating agent is used in combination with a cellulose derivative (HPMC, etc.) exemplified as the coating agent, it is preferable that the amount of the coating agent be 0.1 parts by mass or more and 5 parts by mass or less per 1 part by mass of the enteric coating agent.

The plasticizer used in conjunction with the enteric coating agent is not particularly limited and can be selected appropriately depending on the purpose. Examples include glycerin, polyethylene glycol, and sucrose fatty acid esters. Of these, glycerin and sucrose fatty acid esters are preferred.

The content of the plasticizer is not particularly limited, but is preferably 0.05% by mass or more relative to the total mass of the enteric-coated tablet, in order to improve the disintegration and dissolution properties of the enteric-coated tablet. Furthermore, the content of the plasticizer is preferably 10% by mass or less, and more preferably 0.1% by mass or more and 5% by mass or less, relative to the total mass of the enteric-coated tablet, in order to achieve the coating effect.

The content of the plasticizer is preferably 0.05% by mass or more relative to the total mass of the uncoated tablet from the viewpoint of improving disintegration and dissolution. Furthermore, from the viewpoint of achieving a coating effect, the content of the plasticizer is preferably 10% by mass or less relative to the total mass of the uncoated tablet, and more preferably 0.1% by mass or more and 5% by mass or less.

When the solid preparation of the present invention is an enteric-coated tablet, it is preferable to provide a pre-coating layer between the plain tablet and the enteric coating layer from the viewpoint of preventing deterioration of acid resistance over time. Furthermore, an outermost layer may be provided outside the enteric coating layer to improve appearance, mouthfeel, and ease of administration.
The components contained in the pre-coating layer and the outermost layer include the coating agent and the plasticizer, and the same components as those in the coating agent can be suitably contained.
When the solid preparation of the present invention has the pre-coating layer, the content of the coating agent is preferably 0.1% by mass or more and 5% by mass or less relative to the total mass of the uncoated tablet.
When the solid preparation of the present invention has the outermost layer, the content of the coating agent is preferably 0.1% by mass or more and 5% by mass or less relative to the total mass of the uncoated tablet.

The dosage form of the solid preparation of the present invention is not particularly limited and can be selected appropriately depending on the purpose. Examples include tablets (plain tablets, sugar-coated tablets, coated tablets, enteric-coated tablets, orally disintegrating tablets, chewable tablets, effervescent tablets, etc.), pills, and lozenges. Of these, tablets, coated tablets, and enteric-coated tablets are preferred, with coated tablets being more preferred, as they allow for easier enjoyment of the effects of the present invention.

When the solid preparation of the present invention is a tablet, the size of the tablet is not particularly limited, but from the viewpoint of ease of handling and swallowing, the diameter of the tablet is preferably 5 mmφ or more and 15 mmφ or less, and the thickness of the tablet is preferably 3 mmφ or more and 10 mmφ or less.
When the solid preparation of the present invention is a tablet, the tablet mass per tablet is preferably 150 mg or more and 500 mg or less, and more preferably 250 mg or more and 400 mg or less. A tablet mass of 150 mg or more is preferable because the required amount of functional ingredients can be blended. A tablet mass of 500 mg or less is preferable because it improves ease of administration.
When the solid preparation of the present invention is a tablet, the shape of the tablet is not particularly limited, but is preferably a square flat tablet, a round flat tablet, a rounded R tablet or a two-stage R tablet.
When the solid formulation of the present invention is a tablet, the structure of the tablet may be a single-layer structure (single-layer tablet) or a layered structure (layered tablet). From the viewpoint of more easily enjoying the effects of the present invention, it is preferable to have a layer in which the (A), (B), and (C) components are used in combination (i.e., the (A), (B), and (C) components are present in the same layer) (hereinafter, the layer in which the (A), (B), and (C) components are used in combination may be referred to as the "active ingredient-containing layer"). When the solid formulation is a single-layer tablet, the solid formulation is composed of an active ingredient-containing layer. When the solid formulation is a layered tablet, the solid formulation is composed of an active ingredient-containing layer and a layer other than the active ingredient-containing layer (optional layer).

The solid formulation of the present invention may be a typical oral (i.e., swallowed) tablet, an orally disintegrating tablet, or the like, but is not particularly limited thereto. In the case of a typical swallowed tablet, it is preferable that the formulation be an enteric-coated formulation. To produce an enteric-coated formulation, it is preferable to incorporate enteric ingredients such as shellac, water-soluble shellac, zein, hydroxymethylcellulose phthalate, hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, cellulose acetate phthalate, methacrylic acid copolymer, ethylcellulose, aminoalkyl methacrylate copolymer, brewer's yeast cell wall (e.g., product name: Yeasttrap), tapioca starch, gelatin, pectin, and fats and oils such as hydrogenated oil. Whether or not a formulation is enteric-coated in the present invention is determined by the disintegration test method of the 17th edition of the Japanese Pharmacopoeia.

[Skin moisture evaporation inhibitor, bowel movement improver, fat accumulation inhibitor, immune function maintainer, and immune function improver]
The skin moisture evaporation inhibitor of the present invention contains (A) lactoferrin and (B) Lactobacillus casei cells, and may further contain other components as necessary.
The laxative of the present invention contains (A) lactoferrin and (B) Lactobacillus casei cells, and may further contain other components as required.
The fat accumulation inhibitor of the present invention contains (A) lactoferrin and (B) Lactobacillus casei cells, and may further contain other components as required.
The immune function maintaining agent of the present invention contains (A) lactoferrin and (B) Lactobacillus casei cells, and may further contain other components as necessary.
The immune function improving agent of the present invention contains (A) lactoferrin and (B) Lactobacillus casei cells, and may further contain other components as necessary.
The lactoferrin (A) in the skin moisture evaporation inhibitor, laxative, fat accumulation inhibitor, immune function maintainer, and immune function improver is the same as the lactoferrin (A) in the solid preparation described above.
The (B) Lactobacillus casei bacteria in the skin moisture evaporation inhibitor, laxative, fat accumulation inhibitor, immune function maintainer, and immune function improver are the same as the (B) Lactobacillus casei bacteria in the solid preparation described above.
The other ingredients in the skin moisture evaporation inhibitor, laxative, fat accumulation inhibitor, immune function maintainer, and immune function improver are the same as the other ingredients in the solid preparation described above.

Examples of the present invention will be described below, but the present invention is not limited to these examples. The content of each component described in the examples and comparative examples is shown in "mass %" and is all a value converted into a pure content.
The lactoferrin composition of the uncoated tablets in the examples of the present invention is the content of lactoferrin powder (raw material), and the content in the solid preparation is the content of pure lactoferrin. The pure lactoferrin content in the lactoferrin powder was calculated as follows using the lactoferrin (in a dried substance) quantification method and loss on drying (105°C, 5 hours) in the Japanese Food Additives Standards, 9th Edition, "Lactoferrin Concentrate."
Pure lactoferrin content = lactoferrin content (in dry matter) (%) x (100 - loss on drying (%))/100

(Preparation of uncoated tablets)
Each of the raw tablet ingredients in Tables 1, 2 and 3 was weighed and mixed so that the total mass of the mixed powder was 5 kg, and the mixture was compressed into tablets using a rotary tablet press (LIBLA 2, manufactured by Kikusui Seisakusho) under the following conditions.
- Mortar and pestle: φ8.5 mm, two-stage R shape (R1 = 3 mm, R2 = 1 mm, land part (distance from the side of the tablet to the rising part of the R) = 1.4 mm)
・Feeder agitator blade rotation speed: 60 rpm
・Tablet pressure: 8kN or more and 11kN or less

(Preparation of first layer coating liquid)
The following materials were mixed to obtain a first layer coating liquid.
Hydroxypropyl methylcellulose (HPMC): 6% by mass
Glycerin: 2% by mass
Ion-exchanged water: 92% by mass

(Preparation of second layer coating liquid)
The following materials were mixed to obtain a second layer coating liquid.
Hydroxypropyl methylcellulose (HPMC): 2.1% by mass
Glycerin: 1.1% by mass
Sodium alginate: 3.2% by mass
・Fine silicon dioxide: 0.5% by mass
Ion-exchanged water: 93.1% by mass

(Preparation of coated tablets)
Using a pan rotary coating machine (HiCoater FZ-Lab, manufactured by Freund Corporation), 33 g of the first layer coating solution (20°C) was sprayed onto 670 plain tablets at an average rate of 2 g/min, and coating was performed at a product temperature of approximately 50°C. Subsequently, 165 g of the second layer coating solution (60°C) was sprayed at an average rate of 2 g/min, and after spraying, the tablets were dried at approximately 45°C for 2 minutes to obtain coated tablets (tablets). The solid content per tablet is shown in Tables 1, 2, and 3.

The solid formulations of Examples 1 to 8 and Comparative Examples 1 to 3 were evaluated for "uncoated tablet disintegration time" and "compactability" using the following methods. The results are shown in Tables 4 and 5 below.

<Evaluation of disintegration time of uncoated tablets>
A test was conducted using the second fluid in the dissolution test in accordance with the intestinal fluid dissolution test method for tablets listed in the 17th edition of the Japanese Pharmacopoeia, and the time it took for the tablets to disintegrate was measured. The disintegration time of the uncoated tablets was evaluated according to the following evaluation criteria. A rating of "△" or higher indicates a level suitable for practical use as a solid preparation.
The disintegration time was the average value of 6 tablets, and the hardness of the uncoated tablets was 9.5 kgf.
-Judgment criteria-
Disintegration time is less than 45 minutes;
Disintegration time: 45 minutes or more and less than 50 minutes;
Disintegration time: 50 minutes or more and less than 60 minutes;
Disintegration time is 60 minutes or more; ×

<Evaluation of moldability>
The hardness was measured when tablets were compressed with a compression force of 8 kN. The moldability of the coating agent was evaluated according to the following evaluation criteria. "○" indicates a level that is practically usable as a solid preparation. The tablet hardness was measured by measuring the horizontal hardness using an automatic tablet physical property measurement device (Multicheck 6, manufactured by ERWEKA) (the average value of 10 tablets was calculated).
-Judgment criteria-
Hardness 6kgf or more;○
Hardness less than 6 kgf: ×

The raw materials used in Examples 1 to 8 and Comparative Examples 1 to 3 are as shown in Table 6 below.

The present invention includes, for example, the following aspects.
<1> (A) lactoferrin,
(B) Lactobacillus casei cells;
(C) an excipient; and
A solid dosage form having the formula:
The solid preparation is characterized in that the (C) excipient contains one or more of (C1) cellulose or a derivative of the cellulose, and (C2) sugar alcohol.
<2> The solid formulation according to <1>, wherein the (C1) cellulose and the cellulose derivatives are at least one selected from the group consisting of crystalline cellulose, microfibrous cellulose, methylcellulose, ethylcellulose, and hydroxypropylcellulose.
<3> The solid formulation according to any one of <1> and <2>, wherein the sugar alcohol (C2) is at least one selected from the group consisting of maltitol, erythritol, xylitol, fructose, sucrose, glucose, sorbitol, and lactitol.
<4> The solid preparation according to any one of <1> to <3>, which is a coated tablet.
<5> (A) lactoferrin,
(B) Lactobacillus casei cells;
The present invention relates to an agent for suppressing skin moisture evaporation, an agent for improving bowel movements, an agent for suppressing fat accumulation, an agent for maintaining immune function, and an agent for improving immune function, which are characterized by comprising the above formula:

The solid preparation according to any one of <1> to <4>, and the skin moisture evaporation inhibitor, laxative, fat accumulation inhibitor, immune function maintaining agent, and immune function improving agent according to <5> can solve the conventional problems and achieve the object of the present invention.

Claims (5)

(A) lactoferrin, (B) Lactobacillus casei cells, and (C) an uncoated tablet containing an excipient;
an enteric coating layer on the surface of the uncoated tablet;
An enteric-coated tablet having a pre-coating layer between the plain tablet and the enteric coating layer ,
the content of the lactoferrin (A) is 20.0 % by mass or more and 24.8% by mass or less based on the total mass of the enteric-coated tablet ;
The content of the (B) Lactobacillus casei cells is 2.1 % by mass or more and 6.0 % by mass or less based on the total mass of the enteric-coated tablet ,
The (C) excipient is
(C1) at least one selected from crystalline cellulose, microfibrous cellulose, methyl cellulose, ethyl cellulose, and hydroxypropyl cellulose;
(C2) An enteric coated tablet characterized by containing at least one selected from maltitol, erythritol, xylitol, sorbitol and lactitol. the enteric coating layer and/or the pre-coating layer comprises an enteric coating agent;
2. The enteric coated tablet according to claim 1, wherein the enteric coating agent comprises at least one selected from the group consisting of hydroxypropylmethylcellulose, methacrylic acid-based polymer compounds , shellac, zein, polyuronic acid and its salts, fucoidan and its salts, and carrageenan and its salts. 3. The enteric-coated tablet according to claim 2, wherein the content of the enteric coating agent is from 1% by mass to 30% by mass relative to the total mass of the enteric-coated tablet . the enteric coating layer and/or the pre-coating layer comprises a plasticizer;
4. The enteric coated tablet according to claim 2 or 3, wherein the plasticizer comprises at least one selected from the group consisting of glycerin, polyethylene glycol, and sucrose fatty acid esters. 5. The enteric-coated tablet according to claim 4, wherein the content of the plasticizer is 0.05% by mass or more and 10% by mass or less relative to the total mass of the enteric-coated tablet .