KR20210018030A - Enteric coated tablet containing lactoferrin and manufacturing method thereof - Google Patents

Abstract

The present invention relates to an improved means for maintaining dissolution of lactoferrin in the intestine with time, particularly at a high temperature. The present invention provides an enteric coated tablet including: (A) lactoferrin; and (B) crystalline cellulose, wherein the crystalline cellulose has a bulk density of 0.23 g/cm^3 or more. Preferably, the crystalline cellulose has a bulk density of 0.25 g/cm^3. In addition, the weight ratio (B/A) of the crystalline cellulose to lactoferrin is preferably 0.09 or more. Preferably, the weight ratio (B/A) is 60 or less. The present invention also provides a method for preparing an enteric coated tablet, including a step of forming tablets from mixed powder containing (A) lactoferrin and (B) crystalline cellulose having a bulk density of 0.23 g/cm^3 or more by using a tablet machine to obtain tablets and coating the tablets.

Description

Enteric tablet containing lactoferrin and its manufacturing method {ENTERIC COATED TABLET CONTAINING LACTOFERRIN AND MANUFACTURING METHOD THEREOF}

The present invention relates to an enteric tablet containing lactoferrin and a method for producing the same.

Patent Documents 1 to 3 disclose enteric tablets containing lactoferrin. These enteric tablets are coated with a predetermined (素錠) containing lactoferrin. As the coating inhibits the elution of lactoferrin in the stomach, lactoferrin is mainly eluted from the intestine.

Patent Documents 1 and 2 disclose that the elution of lactoferrin in the intestine is satisfactorily maintained even after long-term storage of enteric tablets by adding stearate as a lubricant. Patent Document 3 discloses that the inhibition of lactoferrin elution in the stomach is maintained satisfactorily even after long-term storage of enteric tablets by performing precoating between a predetermined and a coating.

International Publication No. 2016/163460 International Publication No. 2016/163463 International Publication No. 2016/035756

The present invention provides an enteric tablet containing lactoferrin and a method for producing the same. In the enteric tablet, stearate is added as a lubricant in a predetermined amount. For this reason, lactoferrin can be efficiently eluted in the intestine even after long-term storage of the enteric tablet. Here, in particular, improvement in the dissolution properties of lactoferrin after long-term storage under high temperature has been desired. An object of the present invention is to provide an improvement means for maintaining lactoferrin dissolution properties in the intestine over time, particularly under high temperature.

<1> Sojeong contains (A) lactoferrin and (B) crystalline cellulose,

The (B) crystalline cellulose has a bulk density of 0.23 g/cm 3 or more.

<2> the bulk density of the (B) crystalline cellulose is 0.25 g/cm 3 or more,

The enteric tablet of <1>, wherein the weight ratio (B/A) of the (B) crystalline cellulose and the (A) lactoferrin is 0.09 or more.

<3> The enteric tablet according to <2>, wherein the weight ratio (B/A) is 60 or less.

<4> The enteric tablet according to <3>, wherein the weight ratio (B/A) of the (B) crystalline cellulose and the (A) lactoferrin is 0.65 or more and 2.60 or less.

<5> The enteric tablet according to any one of <2> to <4>, further containing another crystalline cellulose having a bulk density smaller than 0.25 g/cm 3 in the predetermined amount.

<6> The enteric tablet according to any one of <1> to <5>, wherein the average particle diameter of the crystalline cellulose (B) is 20 μm or more.

<7> Sojeong contains (A) lactoferrin and (B) crystalline cellulose,

The weight ratio (B/A) of the (B) crystalline cellulose and the (A) lactoferrin is 0.65 or more and 2.60 or less,

The predetermined hardness is 7kgf or more,

Jang Yongjeong with a dissolution retention rate of 70% or more.

<8> The enteric tablet according to any one of <1> to <7>, wherein the predetermined amount further contains (C) stearate.

<9> The enteric tablet according to any one of <1> to <8>, wherein the predetermined is coated with a protective film component of any one of a methacrylic acid-based polymer compound, shellac, zein, alginic acid, and alginate.

<10> The enteric tablet according to <9>, in which a pre-coating that does not contain the protective film component is applied between the predetermined and the coating.

<11> Any of the above (A) lactoferrin activation of lipid metabolism, treatment or prevention of constipation, activation of intestinal flora, promotion of secretion of face, growth hormone, dry eye and corneal epithelial detachment, and ocular diseases derived from these Among <1> to <10> contained as a physiologically active ingredient for any one of treatment or prevention, lowering blood pressure, treatment or prevention of allergies, activation of immunity, treatment or prevention of menopausal disorder, and activation of liver function The enteric tablet described in any one.

<12> As a manufacturing method of enteric tablet,

(A) A method of obtaining a predetermined by tableting a mixture powder containing the powder of lactoferrin and the powder of (B) crystalline cellulose having a bulk density of 0.23 g/cm 3 or more with a tablet press to obtain a predetermined value, and coating the powder.

According to the present invention, in an enteric tablet containing lactoferrin and a method for producing the same, it is possible to provide an improvement means for maintaining the lactoferrin dissolution property in the intestine over time, particularly under high temperature.

1 is a photograph showing the adhesion state (***) of raw materials.
2 is a photograph showing the adhesion state (**) of raw materials.
3 is a photograph showing the adhesion state (*) of raw materials.

<1. Composition of Jang Yongjeong>

The enteric tablet of this embodiment has been coated with a protective film component. The predetermined contains (A) lactoferrin and (B) crystalline cellulose. In one embodiment, enteric tablet (A) lactoferrin is sent to the intestine as a physiologically active ingredient. In one embodiment, enteric tablet (A) lactoferrin is sent to the intestine as a component other than the physiologically active component.

The protective film component in the coating interferes with the elution of (A) lactoferrin in the gastric juice, but does not interfere with the elution in the intestinal fluid. A pre-coating that does not contain a protective film component may be further applied between the predetermined and the coating. An additional coating that does not contain a protective film component may be further applied to the outside of the coating.

The predetermined|prescribed may contain a physiologically active component other than (A) lactoferrin. In one embodiment, (A) lactoferrin is a physiologically active component having the highest content among physiologically active components in a predetermined. (A) Lactoferrin may be the only physiologically active ingredient in a given period.

In this embodiment, the bulk density of crystalline cellulose is 0.23 g/cm 3 or more. For this reason, enteric tablets can maintain the elution of lactoferrin in the intestine over time, particularly under high temperatures. Next, each ingredient required for Jangyongjeong and its amount will be explained.

<2-1.(A) Lactoferrin>

Lactoferrin is an iron-binding glycoprotein with a molecular weight of about 80,000, and binds two irons to one molecule. In one embodiment, lactoferrin is bound to iron. In one embodiment, lactoferrin is not bound to iron. Lactoferrin in the experimental examples described later has an iron content of 0.05% or less and is a composition that does not substantially bind iron.

Lactoferrin has the ability to improve lipid metabolism, improve constipation, improve intestinal flora, improve sleep, promote the secretion of growth hormone, dry eye and corneal epithelial detachment, and eye disorders resulting from these It is a physiologically active ingredient having a function of improving blood pressure, a function of lowering blood pressure, a function of improving allergy, a function of improving immunity, a function of improving menopausal disorder, a function of improving liver function, and other functions.

When lactoferrin is digested with pepsin, a peptide with stronger antibacterial activity, lactofericin, is produced. In one embodiment the lactoferrin is a composition comprising lactofericin. In one embodiment, the lactoferrin is a composition that does not contain lactofericin. In the experimental examples described later, lactoferrin is a composition that does not contain lactofericin.

In one embodiment, the content of lactoferrin for the predetermined is 1% by weight or more and 60% by weight, preferably 4% by weight or more and 60% by weight or less, more preferably 15% by weight or more and 56% by weight or less, more preferably It is 18% by weight or more and 50% by weight or less.

By setting the content to 4% by weight or more, it is suppressed that the mixed powder containing lactoferrin adheres to the tablet press during tableting. Attaching is further suppressed by making the content 15% by weight or more, preferably 17.2% by weight or more. The initial dissolution rate is improved by adjusting the content to 18% by weight or more, preferably 18.5% by weight or more.

By setting the content to 50% by weight or less, preferably 48.2% by weight or less, the predetermined moldability at the time of tableting is improved. By adjusting the content to 45% by weight or less, preferably 41.5% by weight or less, the initial dissolution rate and the dissolution retention rate are improved. By setting the content to 36.3% by weight or less, the predetermined moldability at the time of tableting is further improved. In addition, the elution retention rate is further improved. By setting the content to 35% by weight or less, preferably 30.8% by weight or less, the elution retention rate is further improved.

Here, the dissolution retention rate refers to a measure of which only the dissolution rate is maintained by resisting the deterioration of dissolution property through the storage period of the enteric tablet. In addition, in this embodiment, the dissolution retention rate means the dissolution retention rate in storage under a high temperature exceeding 40°C. In addition, in one embodiment, the dissolution retention rate refers to the dissolution retention rate in storage at a high temperature exceeding 50°C. In addition, in one embodiment, the dissolution retention rate refers to the dissolution retention rate in storage under high temperature reaching 60°C.

Lactoferrin is, for example, isolated from milk obtained from useful livestock. Examples of useful livestock include cattle, sheep, goats, and horses, but are not limited thereto. Milk is classified as colostrum, transitional milk, stag milk, and terminal oil at each harvesting period. You can use milk at any time. You may separate lactoferrin from what is obtained by treating milk, for example, skim milk or whey. All lactoferrins in the experimental examples are derived from cattle.

Lactoferrin may be produced by recombinant organisms. The host organism may be an animal, a plant, or a microorganism. Further, the host may be a cultured cell. Host plants include tomatoes, rice and tobacco. The lactoferrin gene to be introduced may be one of humans and useful livestock. A lactoferrin derivative may be produced by mutating the introduced lactoferrin gene. Such lactoferrin derivatives are contained in the lactoferrin of this embodiment. In one embodiment, the lactoferrin is lactoferrin without mutation as it is cloned.

The isolated or produced lactoferrin may be chemically treated to produce a lactoferrin derivative. Such lactoferrin derivatives are contained in the lactoferrin of this embodiment. In one embodiment the lactoferrin is a non-derivative of lactoferrin.

Lactoferrin can be purified and concentrated using a conventional method called ion exchange chromatography. Drying of the concentrated lactoferrin may be performed by either freeze drying or spray drying.

Before mixing lactoferrin with other raw material powders, processing such as granulation of lactoferrin and pulverization of lactoferrin may be performed. It is preferable to mix lactoferrin particles having a predetermined particle diameter distribution or average particle diameter obtained by these processes with other raw material powders. You may coat lactoferrin particles.

The average particle diameter of the lactoferrin particles is preferably 20 µm to 300 µm, more preferably 20 µm to 200 µm, and still more preferably 20 µm to 100 µm. In the following experimental examples, the average particle diameter was set to 80 µm.

The average particle diameter of the lactoferrin particles can be measured by a low tap method or a laser diffraction scattering method. The average particle diameter measured by the low tap method corresponds to the particle diameter at which the cumulative frequency is 50% by weight on a weight basis. In addition, in this Example, the bulk density of lactoferrin is not particularly limited. Here, the bulk density is the density when a container of a certain volume is filled with powder and the internal volume is made into a volume.

In this example, lactoferrin may or may not be aggregated. The apparent molecular weight of lactoferrin in the aggregate is not particularly limited. Lactoferrin may be scattered per molecule. Another protein may be contained in the lactoferrin aggregate. Other proteins or peptide fragments of lactoferrin may be contained in the lactoferrin aggregate.

In the concentrate of lactoferrin used as a raw material, the purity of lactoferrin is not particularly limited. The purity is preferably 50% by weight or more, and more preferably 85% by weight or more based on weight. The purity of the concentrate of lactoferrin may not necessarily be 100% by weight. In one embodiment, (A) lactoferrin is mixed in a predetermined amount as a raw material, for example, lactoferrin concentrate purified from whey.

When determining the lactoferrin content, the purity or net content, ie weight, of lactoferrin in the lactoferrin concentrate may be considered. In the following experimental examples, the content of lactoferrin is specified as the net amount of lactoferrin. In one embodiment, iron to which lactoferrin is bound is included in the net amount. In one embodiment, the iron to which lactoferrin is bound is not included in the net amount.

<2-2.(B) Crystal cellulose>

In one embodiment, crystalline cellulose is obtained by partially depolymerizing and purifying α-cellulose obtained from fibrous plants with an acid. Cellulose in the crystalline cellulose is not provided with a functional group or the like. Cellulose in crystalline cellulose is non-derived cellulose.

Crystalline cellulose improves the bonding strength between particles in the mixed powder provided for tableting. Crystalline cellulose also improves the dissolution properties of lactoferrin. The content of the crystalline cellulose relative to the predetermined amount is preferably 5% by weight or more and 70% by weight or less, more preferably 15% by weight or more and 60% by weight or less, and still more preferably 27% by weight or more and 57% by weight or less.

When the content is 5% by weight or more, preferably 12% by weight or more, the predetermined moldability at the time of tableting is improved. By setting the content to 15% by weight or more, preferably 18.7% by weight, the initial dissolution rate and the dissolution retention rate are improved. When the content is 23.8% by weight or more, the predetermined moldability at the time of tableting is further improved. In addition, the elution retention rate is further improved. By setting it as 27% by weight or more, preferably 29.3% by weight or more, the elution retention rate is further improved.

By setting the content to 57% or less, preferably 56.2% or less, the adhering of the mixed powder containing lactoferrin to the tableting machine at the time of tableting is suppressed. When the content is 45% or less, preferably 43.0% or less, adhesion is further suppressed. By setting the content to 42% or less, preferably 41.7% or less, the initial dissolution rate is improved.

Crystalline cellulose is particulate. It is preferable that the bulk density of crystalline cellulose is 0.23 g/cm 3 or more. The bulk density is preferably 0.40 g/cm 3 or less. The bulk density is preferably 0.25 g/cm 3 or more and 0.35 g/cm 3 or less. The bulk density is preferably 0.28 g/cm 3 or more and 0.31 g/cm 3 or less.

By setting the bulk density to 0.23 g/cm 3 or more, the elution retention rate is improved. By setting the bulk density to 0.25 g/cm 3 or more, the elution retention rate is further improved. By setting the bulk density to 0.35 g/cm 3 or less, preferably 0.31 g/cm 3 or less, the predetermined moldability at the time of tableting is improved.

In addition, as described above, the bulk density is the density when a container of a certain volume is filled with powder and the internal volume is made into a volume. Since the crystalline cellulose powder in the tablet is compressed, it may have a bulk density different from the bulk density before tableting. When the bulk density is changed by tableting, the bulk density may be specified based on the raw material stage immediately before preparing the mixed powder.

The measurement of the bulk density may be performed by the method described in "Crystal cellulose" of the 17th Revised Japanese Pharmacy Store. Bulk density can be measured with a Japanese pharmacy-designated instrument, here a Scott volume meter. Unless otherwise specified, the bulk density refers to the bulk density measured according to the method of a Japanese pharmacy.

Crystalline cellulose has a predetermined particle size distribution. The average particle diameter is preferably 20 µm or more and 180 µm or less, and more preferably 40 µm or more and 150 µm or less. The average particle diameter can be measured by a low tap method or a laser diffraction scattering method. The average particle diameter measured by the low tap method corresponds to the particle diameter at which the cumulative frequency is 50% by weight on a weight basis.

The following is exemplified as a method for measuring the particle size of crystalline cellulose dispersed in a predetermined or enteric tablet. First, after disintegrating the tablet with a medium for dissolving components other than crystalline cellulose, such as water or ethanol, the powder of crystalline cellulose in the solvent is collected. Next, the particle diameter distribution of the collected powder is measured by the above method. Alternatively, the particle diameter distribution is measured with a particle image analysis device. Examples of the particle image analysis device include particle image analysis "Mophorogi 4" and particle image analysis and Raman spectroscopy analysis device "Mophorogi 4-ID", all manufactured by Spectris Co., Ltd.

By setting the average particle diameter to 20 µm or more, preferably 40 µm or more, and more preferably 50 µm or more, the elution retention rate is improved. By setting the average particle diameter to 180 µm or less, preferably 150 µm or less, the predetermined moldability at the time of tableting is improved, and the adhering of the mixed powder containing lactoferrin to the tableting machine is suppressed.

In the preparation of crystalline cellulose, pay attention to the bulk density. The bulk density can be adjusted according to a general method. In the preparation of crystalline cellulose, attention is also paid to the particle diameter distribution. In order to obtain crystalline cellulose having a desired average particle diameter or particle diameter distribution, a general method may be used.

As a method for preparing crystalline cellulose, the description of [0024] from paragraph [0022] of Japanese Patent Laid-Open No. 2019-026558 can be mentioned, for example. For example, large particles may be obtained by subjecting the cellulose dispersion to dehydration purification. Further, it may be sorted by sieving, and the particle diameter distribution may be biased toward the large particle side. Further, smaller particles may be obtained by increasing the primary particle ratio by pulverization. Other general methods can also be used to adjust the average particle diameter or particle diameter distribution.

You may combine a plurality of crystalline cellulose raw materials. A group of two or more crystalline celluloses having different bulk density, particle diameter distribution, or average particle diameter may be mixed. Two or more crystalline celluloses having different bulk densities may be combined and adjusted so that the bulk density is within the range of the bulk density of the present embodiment. In one embodiment, the predetermined bulk density may contain crystalline cellulose of 0.25 g/cm 3 or more, preferably 0.28 g/cm 3 or more, and other crystalline cellulose having a bulk density of less than 0.25 g/cm 3. The bulk density of other crystalline cellulose may be, for example, 0.23 g/cm 3. The content of other crystalline cellulose is preferably less than the content of crystalline cellulose having a bulk density of 0.25 g/cm 3 or more.

<2-3.Weight ratio (B/A)>

The weight ratio (B/A) of (B) crystalline cellulose and (A) lactoferrin is preferably 0.09 to 60, more preferably 0.45 to 15, still more preferably 0.9 to 2.3.

By setting the weight ratio (B/A) to 0.25 or more, the predetermined moldability at the time of tableting is improved. When the weight ratio (B/A) is 0.45 or more, the initial dissolution rate is improved, and the dissolution retention rate is improved. When the weight ratio (B/A) is set to more than 0.63, preferably at least 0.64, more preferably at least 0.65, and even more preferably at least 0.66, the predetermined moldability is further improved. In addition, the elution retention rate is improved. By setting the weight ratio (B/A) to 0.8 or more, preferably 0.95, the elution retention rate is further improved.

By setting the weight ratio (B/A) to 15 or less, preferably 14.04 or less, the adhering of the mixed powder containing lactoferrin to the tableting machine at the time of tableting is suppressed. By setting the weight ratio (B/A) to 4 or less, preferably 2.50 or less, adhesion is further suppressed, and the initial dissolution rate of enteric tablets is improved. The weight ratio (B/A) may be interpreted as a ratio of the weight of the crystalline cellulose (B) to the net content of lactoferrin.

<2-4.(C) Stearate and others>

Some may also contain stearate as a lubricant. The stearate may be at least one of calcium stearate and magnesium stearate. The content of the stearate relative to the predetermined amount is preferably 0.01% by weight or more and 10% by weight or less, more preferably 0.05% by weight or more and 5.0% by weight or less, and still more preferably 0.1% by weight or more and 3.0% by weight or less. By setting it as more than the said lower limit, the adhesiveness improves, and by setting it as the said upper limit or less, elution property becomes favorable. Examples of other lubricants other than stearate include sucrose fatty acid esters. Some may also contain binders, excipients, fluidizing agents, disintegrating agents and other lubricants.

Examples of the binder include arabic rubber, gelatin, sodium alginate, methylcellulose, ethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol and hydroxypropylcellulose. By including the binder in the mixed powder before tableting, the moldability at the time of predetermined tableting is improved. The content of the binder relative to the predetermined amount is preferably 0.1% by weight or more and 50% by weight or less.

As excipients, maltitol, dextrin, xylitol, erythritol, kaolin, cacao butter, fructose, stearic acid, dextran, hydroxypropylmethylcellulose, macrogol, calcium hydrogen phosphate, sodium hydrogen phosphate, sucrose, glucose, sorbitol, lactitol , Corn starch and potato starch. By containing a predetermined excipient, a predetermined dissolution property or dosage is improved. The content of the excipient relative to the predetermined amount is preferably 0.1% by weight or more and 50% by weight or less.

Examples of the fluidizing agent include fine-grained silicon dioxide. Examples of the disintegrant include carboxymethyl cellulose (CMC), alkali metal salts of CMC, partially α-formed starch, and low-substituted hydroxypropyl cellulose (HPC). By including a fluidizing agent in the mixed powder before tableting, the fluidity of powders other than the fluidizing agent is improved. The content of the fluidizing agent relative to the predetermined amount is preferably 0.1% by weight or more and 2.0% by weight or less. By containing a disintegrant in the mixed powder before tableting, the disintegration properties of the predetermined and enteric tablets are improved. The content of the disintegrant relative to the predetermined content is preferably 0.01% by weight or more and 30% by weight or less, more preferably 0.1% by mass or more and 15% by mass or less, and even more preferably 0.5% by mass or more and 10% by mass or less.

<2-5. Other physiologically active ingredients>

As other physiologically active ingredients, ingredients such as plant-derived ingredients, vitamins, minerals, plant fibers, fish oil, and lactic acid bacteria may be further added. Plant-derived ingredients are cacao extract, pistil extract, arrowroot extract, devilia extract, grape seed extract, pine bark extract, coreus forscoli extract, white thistle leaf extract, rosemary extract, rooibos extract, tomato extract, olive extract, whole chil Ginseng extract, and other plant extracts. The processed product of plant extract can also be used suitably as a plant-derived component. Purified compounds obtained from plant extracts can also be suitably used as plant-derived ingredients. Examples of the compound include raspberry ketone and isoflavone. In addition, vitamins, minerals, and plant fibers may be plant-derived ingredients or artificially synthesized ones. Vitamins may be fat-soluble vitamins. Lactobacillus may be live or dead.

The content of the other physiologically active ingredient in the predetermined range is preferably 1% by weight or more and 50% by weight or less, more preferably 4% by weight or more and 30% by weight or less, and still more preferably 8% by weight or more and 20% by weight or less. When the content is 1% by weight or more, the dissolution property is improved. By increasing the content further, the elution property can be made better. When the content is 50% by weight or less, the moldability of the mixed powder is improved. By lowering the content, the moldability of the mixed powder can be made better.

By further containing these other physiologically active ingredients, the enteric tablet of the present embodiment contributes to the prevention or improvement of diseases such as hyperglycemia, allergies, and dry syndrome. In addition, the Jang Yongjeong of this embodiment contributes to the improvement of the intestinal environment. In the enteric tablet of this embodiment, the elution of lactoferrin from the stomach is suppressed, and lactoferrin is mainly eluted from a predetermined amount in the intestine. For this reason, the effect of preventing or treating diseases of lactoferrin can be further improved. In this embodiment, these other physiologically active ingredients further enhance the effect of preventing or treating lactoferrin, particularly for metabolic syndrome.

<2-6. Coating and protective film components>

The tablets of this example are enteric tablets. The tablet has a coating on it. The coating has a protective film component. The protective film component imparts enteric properties to the tablet. Since the protective film component does not dissolve in the stomach, the protective film component interferes with the contact of the gastric juice with lactoferrin or other physiologically active components. After that, the protective film component dissolves in the intestine to facilitate a predetermined contact with the intestinal fluid. In one embodiment, the enteric tablet is suitable for the "enteric preparation" described in the 17th revised Japanese pharmacy.

Examples of the protective film component include methacrylic acid polymer compounds, shellac, zein, alginic acid, and alginate. These may be used alone or in combination of two or more. The alginate may be any one or two or more of ammonium alginate, sodium alginate, and potassium alginate. It is preferable to use two or more types of compounds having different molecular weights as the protective film component. For example, two types of alginate may be used in combination. This improves the acid resistance of enteric tablets and the dissolution of lactoferrin and other physiologically active ingredients in the intestine. A pre-coating having no protective film component may be applied to the inside of the coating.

You may add an anti-adhesive agent or a coloring agent to the coating. Silicon dioxide and talc are mentioned as an adhesion inhibitor. The silicon dioxide is preferably fine-grained silicon dioxide. Examples of the coloring agent include caramel, cacao, gardenia yellow, carotene, gardenia red and blush pigments.

<2-7.The shape of the tablet, etc.>

The shape, size, and weight of the tablet are not particularly limited as long as it is easy to take. The shape is preferably R tablet or two-stage R tablet. The size is preferably 5mm or more and less than 15mm in diameter and 3mm or more and less than 10mm in thickness. Further, the predetermined weight is preferably 200 mg or more and 400 mg or less, and more preferably 250 mg or more and 350 mg or less. In addition, in order to prevent a predetermined wear during coating, the predetermined hardness is preferably 7 kgf or more, more preferably 9 kgf or more, and even more preferably 10 kgf or more. The upper limit of the predetermined hardness is preferably 20 kgf or less from the viewpoint of disintegration of the tablet in the intestine. Further, the hardness of the enteric tablet is preferably 20 kgf or more and 40 kgf or less.

(Example)

<3-1.Prescribed production>

All powdery raw materials including (A) lactoferrin, (B) crystalline cellulose, (C) stearate, and (D) plant extract were weighed and mixed. The composition ratio of each component of the raw material is shown in Tables 2 to 5 shown in Experimental Examples. By mixing, a mixed powder having a total weight of 5 kg was obtained. The mixed powder was tableted using a rotary tableting machine to obtain a predetermined value. In the present example, granulation was not performed in the preparation of the mixed powder.

The tablet press is LIBLA 2 manufactured by Kikusui Seisakusho. The setting of LIBLA 2 is shown below.

-Shape of Jeolgut Gongi mold:

9.0mm diameter, two-stage R chamfer for corners

R1=3.6mm, R2=10.5mm, land part=1.5mm

The land portion represents the distance from the side of the tablet to the raised portion of the R face.

-Speed of stirring blade of feed shoe: 60rpm

In each case, tableting was performed at 15 kN to obtain a predetermined value, and a predetermined hardness was measured. This predetermined hardness was used as an index for evaluating formability. Further, after adjusting the tableting pressure so that the predetermined hardness became 10 kgf based on the measurement result, a predetermined evaluation for the initial dissolution rate and the dissolution retention rate was again prepared. The range of the tableting pressure at this time was 10 to 18 kN. After coating predetermined, the dissolution property of lactoferrin was evaluated.

<3-2.Coating>

The prescribed was pre-coated with the first layer coating solution of the following composition.

HPMC (hydroxypropylmethylcellulose): 6%

Glycerin: 2%

Water: 92%

The pre-coated predetermined was coated with a second layer coating solution having the following composition.

HPMC: 2.1%

Glycerin: 1.1%

Sodium alginate: 3.2%

Fine silicon dioxide: 0.5%

Water:93.1%

As a coating device, a fan rotary coating machine manufactured by Freund Sangyo, High Coater FZ-Lab was used. First, pre-coating was performed by spraying 33 g of the first layer coating liquid at 20°C at an average of 2 g/min for 670 tablets. The predetermined temperature was set to about 50°C. In 33 g of the first layer coating liquid, 2640 mg of components other than water are contained. If 2640mg is divided into 670 tablets, it is about 3.9mg/tablet.

Subsequently, 163 g of the second layer coating liquid at 60°C was sprayed at an average of 2 g/min. After spraying, it was dried at about 45° C. for 2 minutes. Jangyongjeong was obtained by the above. The composition of the solid content in the coating per tablet of enteric tablet is shown below.

Composition of solid content of the first layer of coating (mg/tablet)

Hydroxypropylmethylcellulose 2.9

glycerin 1.0

Composition of solid content of the second coating layer (mg/tablet)

Hydroxypropylmethylcellulose 5.1

glycerin 2.7

Sodium alginate 7.8

Particulate silicon dioxide 1.2

<3-3. Lactoferrin dissolution test>

The measurement of the dissolution rate (%) of lactoferrin was tested in accordance with the dissolution test method of tablets available in the 17th Revised Japanese Pharmacy Store. Specifically, lactoferrin was eluted into the test solution at 50 rotations per minute by the Puddle method. As a test solution, 900 mL of the dissolution test second solution having a pH of about 6.8 was used per tablet. Two hours after the start of the test, a test solution was collected. The dissolution rate was calculated by quantifying the lactoferrin eluted in the test solution. The following test was performed three times, and the average value of the dissolution rate was calculated from these measured values. Further, the test was conducted also in the first solution of the dissolution test having a pH of about 1.2, and it was confirmed in advance that the coating was formed normally. Therefore, furthermore, when it is confirmed that the tablets of this example have dissolution properties with respect to the dissolution test solution 2, it is confirmed that the tablets of this example can be used in vivo as enteric tablets.

(1) The elution amount of lactoferrin was calculated as follows. First, 75 mg of lactoferrin standard was added to a volumetric flask with a specified volume of 50 mL, and then weighed up to the specified volume with a test solution to obtain a 1/1 standard solution. This standard solution was further diluted with the test solution to prepare 1/5, 1/20 and 1/50 standard solutions. Lactoferrin in each standard solution was detected by HPLC. A calibration curve was prepared by determining the peak area of lactoferrin in each standard solution.

As a lactoferrin standard product, "from lactoferrin milk" for biochemistry, manufactured by Fujifilm Wako Junyaku Kogyo, was used. The purity of the lactoferrin standard was based on the numerical value of the content (HPLC) described in the test report issued by Wako Junyaku High School.

Next, lactoferrin in the test solution collected as described above was detected by HPLC to determine the peak area of lactoferrin. The lactoferrin eluted in the test solution was quantified by determining the lactoferrin concentration in each test solution from the peak area based on the calibration curve.

(2) The content of lactoferrin in the tablet was determined as follows. First, 75 mg of a lactoferrin standard was added to a volumetric flask having a specified volume of 50 mL, and then weighed up to a specified volume with a 3% by weight aqueous NaCl solution to obtain a 1/1 standard solution. This standard solution was further diluted with 3 wt% NaCl aqueous solution to prepare 1/2 and 1/20 standard solutions. Lactoferrin in each standard solution was detected by HPLC. A calibration curve was prepared by determining the peak area of lactoferrin in each standard solution. In addition, in the dissolution test of (1) and the quantitative test of (2), it is preferable to prepare a calibration curve individually, taking note of the difference in dilution ratio between the dilution solution, that is, the dissolution test solution and the 3 wt% NaCl aqueous solution.

Next, a tablet and a 3% by weight NaCl solution were added to a 100 ml volumetric flask to completely dissolve the tablets, and then mass-up to the specified volume was performed to obtain a sample solution. The area of the HPLC detection peak of lactoferrin was determined. The test was conducted 3 times. The lactoferrin content in the tablet was quantified by determining the lactoferrin concentration in each sample solution rather than the peak area based on the calibration curve.

(3) The conditions of HPLC are as follows.

-Detector: Ultraviolet absorbance photometer (measurement wavelength: 280 nm)

-Column filler: 5㎛ butylated polyvinyl alcohol polymer gel for liquid chromatography (Shodex Asahipak C4P-50 4D)

-Column tube: Stainless steel tube with inner diameter 4.6mm and length 15cm

-Guard column: Shodex Asahipak C4P-50G 4A

-Column temperature: 35℃

-Mobile phase A: acetonitrile/sodium chloride solution (3→100) containing 0.03 w/v wt% trifluoroacetic acid mixed solution (10:90)

-Mobile phase B: acetonitrile/sodium chloride solution containing 0.03w/v wt% trifluoroacetic acid (3→100) mixed solution (50:50)

-Concentration gradient: A linear concentration gradient from A:B (50:50) to A:B (0:100) is applied over 25 minutes.

-Flow rate: 0.8mL/min

<3-4.List of raw materials used in the experiment>

CMC-Ca: calcium carboxymethylcellulose

<3-5. Evaluation of moldability>

The predetermined hardness compressed with a tableting pressure of 15 kN was measured with a tablet physical property measuring device (Multicheck 6, manufactured by ERWEKA). The measured hardness is the horizontal hardness. The average value of the hardness between predetermined periods was calculated|required (n=10). The criteria are as follows. In this example, the formulations obtained with high hardness tablets were evaluated as having good moldability.

***9kgf or more

**7kgf or more, less than 9kgf

*Less than 7kgf

<3-6. Evaluation of adhesion to tablet press>

When tabletting a predetermined|prescribed tablet repeatedly, the mixed powder of predetermined raw materials may adhere to a tablet press. It was observed that the mixed powder of the raw material adhered to the rotary tablet press. 1 to 3 are photographs showing the adhesion state of raw materials. Fig. 1 illustrates a state in which there is no adhesion of raw materials. 2 and 3 illustrate a state in which adhesion of a predetermined raw material (Ad) is seen.

As shown in Figs. 2 and 3, adhesion (Ad) occurs on the other side of the tablet press. It also occurs on the wall of a mortar. On the other hand, the adhering mixed powder is attached to resist scratching by the scrapers around each. The mixed powder adhering to the wall of the mortar resists scratching by the mortar and adheres to each tablet.

Tableting was performed for 20 minutes with a rotary tablet press. The time when the mixed powder began to adhere to the other side or the wall of the mortar was visually checked. The criteria are as follows.

*** No adhesion was observed (Fig. 1).

** After 20 minutes from the start of tableting, adhesion was confirmed (Fig. 2).

* From immediately after the start of tableting, adhesion was confirmed (Fig. 3).

It is considered that adhesion of the mixed powder affects the bonding property between the powders in addition to the bonding property between the mixed powder and the metal. That is, the more the powder adheres to the powder, the stronger the shear stress is received from the scraper or the mortar, so the more the powder adheres. The adhesion tends to increase over time. Therefore, as described above, evaluation was performed by the time until the powder adhered.

<3-7.Evaluation of initial dissolution rate>

First, as described in the above <3-3. Lactoferrin dissolution test>, the enteric tablet was subjected to a dissolution test, and the content of lactoferrin in the enteric tablet was determined. In addition, in order to obtain the initial dissolution rate before the preservation test, it was tested with tablets within 7 days after tableting. The judgment criteria are as follows.

***Initial dissolution rate of 85% or more

**Initial dissolution rate of 75% or more and less than 85%

*Initial dissolution rate of 65% or more and less than 75%

In addition, in this experimental example, no prescription was found whose initial dissolution rate did not reach 75%.

<3-8. Evaluation of elution retention rate>

As in the above <3-3. Lactoferrin dissolution test>, the enteric tablet after being filled in a plastic bottle and stored at 60°C for 12 days was subjected to a dissolution test, and the content of lactoferrin in the enteric tablet was determined. The elution retention rate (%) was determined according to the following equation. The judgment criteria are as follows.

Elution retention rate (%) = 100 × (dissolution amount after storage (mg))/(initial dissolution amount (mg))

Level 6 90% or higher

Level 5 85% or higher, less than 90%

Level 4 80% or higher, less than 85%

Level 3 above 75%, below 80%

Level 2 above 70%, below 75%

Level 1 below 70%

This test of the dissolution retention rate at 60°C is to place the enteric tablet under harsher conditions than the test of the dissolution retention rate at 40°C as described in Patent Documents 1 and 2. Therefore, for example, it is suitable for evaluating the difficulty in deterioration of the elution properties of enteric tablets at high temperatures in the summer in temperate or subtropical regions, or under high temperatures in the tropics.

<4.Prescription example>

The formulation of the tablet of this example is not limited to the formulation in the experimental examples. For example, the following prescription may be used.

(Prescribed)

(mg/tablet)

Lactoferrin 79.0

Arrowroot extract 43.0

Crystalline cellulose (UF-F702) 167.0

CMC-Ca 6.0

Particulate silicon dioxide 3.0

Stearic acid Ca 2.0

(Coating first layer, pre-coating) (mg/tablet)

HPMC 2.9

glycerin 1.0

caramel 0.5

(Coating second layer, enteric coating) (mg/tablet)

HPMC 4.6

glycerin 2.3

Sodium alginate 7.1

Particulate silicon dioxide 1.1

Talc 1.1

<5. Experimental Example>

Using the raw materials, the prescribed was prepared by various prescriptions. Coating for predetermined was performed as shown in <3-2. Coating>. Each regimen starting from regimen C1 was evaluated. It is any prescription or an illustration, and does not limit this invention.

Table 2 shows experimental examples for the bulk density of crystalline cellulose. The composition is a weight ratio. In the table, the components contained in the predetermined are shown at the top. The column of evaluation shows the results of each of the tests from <3-5. Evaluation of moldability> to <3-8. Evaluation of dissolution retention rate>. The same is true for other tables. Hereinafter, it demonstrates focusing on the evaluation result of the elution retention rate.

In Table 2, the formulations C1 and C2 were the dissolution retention rate level 1. In addition, the prescriptions W1 to W5 had a dissolution retention level of 2 or more. In the formulations W1 to W5, since the bulk density of the excipient (B) crystalline cellulose is 0.23 g/cm 3 or more, the dissolution property after storage is maintained.

In Table 2, prescriptions W2 to W5 are prescriptions of dissolution retention level 3 or higher. In the table, all are at level 4 or higher. (B) Since the bulk density of the crystalline cellulose is 0.25 g/cm 3 or more, the elution retention rate is higher. That the weight ratio (B/A) also affects the dissolution retention rate is explained from Table 3 described later.

In Table 2, prescriptions W3 to W5 are prescriptions of dissolution retention level 5 or higher. In the table, they are all level 6. (B) Since the bulk density of the crystalline cellulose is 0.28 g/cm 3 or more and the average particle diameter is 50 µm or more, the elution retention rate is further increased. That the weight ratio (B/A) also affects the dissolution retention rate is explained from Table 3 described later.

In Table 2, in formulation W5, (B) crystalline cellulose having a bulk density of 0.28 g/cm 3 or more and another crystalline cellulose having a bulk density of less than 0.25 g/cm 3 were used in combination. Even in prescription W5, the dissolution retention rate level is maintained as in prescription W3.

Table 3 shows an experimental example for the weight ratio (B/A). Endurance MCC VE-050, selected as (B) crystalline cellulose common to each formulation, is the same as used for formulation W3. The bulk density was 0.28 g/cm 3 and the average particle diameter was 50 μm. The same is true for Table 4.

In Table 3, prescriptions W6 to W7 are prescriptions for dissolution retention level 2. In Table 3, prescriptions W8 to W15 are prescriptions of dissolution retention level 3 or higher. In formulations W8 to W15, the dissolution retention rate is increased by setting the weight ratio (B/A) to 0.45 or more.

In Table 3, prescriptions W9 to W15 are prescriptions of dissolution retention level 4 or higher. In prescriptions W9 to W15, the dissolution retention rate is further increased by setting the weight ratio (B/A) to 0.66 or more. Formulations W10 to W15 are formulations of dissolution retention level 5 or higher. In formulations W10 to W15, the dissolution retention rate is further increased by setting the weight ratio (B/A) to 0.95 or more.

Table 4 shows experimental examples for other components.

In Table 4, in the prescription W16, unlike the prescription W3 in Table 2, a necessity extract is used instead of cacao extract. While increasing the elution retention rate, other physiologically active ingredients such as plant extracts can be suitably contained in a predetermined amount.

In Table 4, in Formulation W17, unlike Formulation W3 in Table 2, the content of (B) crystalline cellulose is increased instead of omitting maltitol as an additional excipient. Therefore, in prescription W17, the weight ratio (B/A) is 2.01 or more. Even in prescription W17, the dissolution retention rate level is maintained at level 6 as in prescription W3.

In Table 4, prescription W18 contains dextrin instead of maltitol, unlike prescription W3 in Table 2. In prescription W18, the dissolution retention rate is set to level 5. Other formulations contain maltitol as an additional excipient and an alkali metal salt of carboxymethylcellulose as a disintegrant. Thereby, the elution retention rate level is maintained at level 6.

In Table 4, in Formulation W19, the component of the disintegrant is changed compared to Formulation W3 in Table 2. Formula 19 enteric tablet contains partially α-starch instead of CMC-Ca. In prescription W19, the dissolution retention rate is set to level 5.

Table 5 shows experimental examples for the average particle diameter of crystalline cellulose. The composition is a weight ratio.

In Table 5, in Formulations W20 to 22, (B) crystalline cellulose having a larger average particle diameter than those used in Formulations W3 or W4 in Table 2 is used. While increasing the elution retention rate, any average particle diameter is suitable.

When the evaluation results of the weight ratio (B/A) shown in Table 3 and the evaluation results of the average particle diameter shown in Table 5 are overlapped, it is considered as follows. That is, it is preferable that the weight ratio (B/A) of (B) crystalline cellulose and (A) lactoferrin is 2.50 or less, and then the particle diameter of (B) crystalline cellulose is 150 µm or less. Thereby, it is possible to suppress adhesion of the raw material remaining during the repetitive tableting to the surface of the tableting machine (see Figs. 1 to 3).

When the evaluation results of the bulk density shown in Table 2, the evaluation results of the weight ratio (B/A) shown in Table 3, and the evaluation results of the average particle diameter shown in Table 5 are overlapped, it is considered as follows. That is, the bulk density of (B) crystalline cellulose is 0.31 g/cm 3 or less, and the weight ratio (B/A) of (B) crystalline cellulose and (A) lactoferrin is 0.66 or more and 2.50 or less, and (B) It is preferable that the particle diameter of the crystalline cellulose be 150 µm or less. Accordingly, even when the same tableting pressure is used, the predetermined hardness can be further increased. This indicates that the moldability of the mixed powder is increasing.

When the evaluation results of the bulk density shown in Table 2 and the evaluation results of the weight ratio (B/A) shown in Table 3 are overlapped, it is considered as follows. That is, the bulk density of (B) crystalline cellulose is 0.28 g/cm 3 or more, the particle diameter is 50 µm or more, and the weight ratio (B/A) of (B) crystalline cellulose and (A) lactoferrin is 0.95. It is desirable to say the above. Thereby, a high dissolution retention rate of level 5 or higher is obtained.

Table 6 shows an experimental example confirming the effect of stearate. The composition is a weight ratio.

Formulation C3 has the same composition as Formulation C2 shown in Table 2 except that Ca stearate was not added. Other than that, there was no significant difference in the level of dissolution retention under high temperature between prescription C3 and prescription C2. From the above, it was found that it is difficult to improve the elution retention rate under high temperature simply by mixing (C) stearate at a predetermined time.

In prescription W23, the bulk density of (B) crystalline cellulose is higher than prescription C3. In Formulation W23, although stearate was not mixed, the dissolution retention rate could be improved. Moreover, the dissolution retention rate was equivalent between the prescription W3 and the prescription W23 containing the same crystalline cellulose. From the above, it was found that by mixing the (B) crystalline cellulose having a high bulk density in a predetermined amount, it was possible to improve the elution retention rate under high temperature regardless of the presence or absence of (C) stearate. In addition, the effect was found to be much higher than the effect caused by (C) stearate.

Further, as described in Patent Literature 1, stearate is helpful in improving the elution retention rate at temperatures around 40°C. Therefore, combining (C) stearate and (B) crystalline cellulose having a high bulk density in a predetermined manner is one of effective means while increasing the dissolution retention rate of (A) lactoferrin under various storage temperature environments.

Claims (12)

A predetermined amount contains (A) lactoferrin and (B) crystalline cellulose,
The (B) crystalline cellulose has a bulk density of 0.23 g/cm 3 or more. The method of claim 1,
The bulk density of the (B) crystalline cellulose is 0.25 g/cm 3 or more,
The weight ratio (B/A) of the (B) crystalline cellulose and the (A) lactoferrin is 0.09 or more. The method of claim 2,
The weight ratio (B / A) is 60 or less enteric. The method of claim 3,
The weight ratio (B/A) of the (B) crystalline cellulose and the (A) lactoferrin is 0.65 or more and 2.60 or less. The method according to any one of claims 2 to 4,
The prescribed enteric tablet further contains other crystalline cellulose having a bulk density of less than 0.25 g/cm 3. The method according to any one of claims 1 to 5,
The (B) crystalline cellulose has an average particle diameter of 20 μm or more. A predetermined amount contains (A) lactoferrin and (B) crystalline cellulose,
The weight ratio (B/A) of the (B) crystalline cellulose and the (A) lactoferrin is 0.65 or more and 2.60 or less,
The predetermined hardness is 7kgf or more,
Jang Yongjeong with a dissolution retention rate of 70% or more. The method according to any one of claims 1 to 7,
The enteric tablet further contains (C) stearate. The method according to any one of claims 1 to 8,
The enteric tablet is coated with a protective film component of any one of a methacrylic acid-based polymer compound, shellac, zein, alginic acid, and alginate. The method of claim 9,
A pre-coating that does not include the protective film component is applied between the predetermined and the coating. The method according to any one of claims 1 to 10,
(A) lactoferrin activation of lipid metabolism, treatment or prevention of constipation, activation of intestinal flora, promotion of secretion of facial and growth hormone, treatment of dry eye and corneal epithelial detachment, and eye diseases derived therefrom Or an enteric tablet containing as a physiologically active ingredient for any one of prevention, lowering blood pressure, treating or preventing allergies, activating immunity, treating or preventing menopausal disorders, and activating liver function. As a manufacturing method of enteric tablet,
(A) A method of obtaining a predetermined by tableting a mixture powder containing the powder of lactoferrin and the powder of (B) crystalline cellulose having a bulk density of 0.23 g/cm 3 or more with a tablet press to obtain a predetermined value, and coating the powder.

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