CN112336850A

CN112336850A - Enteric coated tablet containing lactoferritin and its preparation method

Info

Publication number: CN112336850A
Application number: CN202010759471.6A
Authority: CN
Inventors: 松本夏季; 森部光俊; 满留卓实
Original assignee: Lion Corp
Current assignee: Nisshin Foods Inc
Priority date: 2019-08-06
Filing date: 2020-07-31
Publication date: 2021-02-09
Anticipated expiration: 2040-07-31
Also published as: KR20210018030A; JP2021024821A; CN112336850B; JP7339057B2

Abstract

The present invention addresses the problem of providing means for improving the lactoferrin elution property of an enteric tablet in the intestine over time, particularly at high temperatures. One embodiment of the present invention is an enteric coated tablet comprising (A) lactoferrin and (B) crystalline cellulose, the bulk density of (B) crystalline cellulose being 0.23g/cm³The above. In one embodiment, the bulk density of the crystalline cellulose (B) is preferably 0.25g/cm³The above. Further, the weight ratio (B/a) of (B) crystalline cellulose and (a) lactoferrin is preferably 0.09 or more. In one embodiment, the weight ratio (B/a) is preferably 60 or less. Another embodiment of the present invention is a process for producing enteric-coated tablets, wherein (A) lactoferrin is incorporated and the bulk density is 0.23g/cm by a tableting machine³Tabletting the mixed powder of the crystalline cellulose (B) to obtain a plain tablet, and coating the plain tablet.

Description

Enteric coated tablet containing lactoferritin and its preparation method

Technical Field

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

Background

Patent documents 1 to 3 disclose enteric coated tablets containing lactoferrin. These enteric coated tablets are tablets coated with plain tablets containing lactoferrin. The coating inhibits the dissolution of lactoferrin in the stomach, so that lactoferrin is mainly dissolved from the plain tablets in the intestine.

Patent documents 1 and 2 disclose: stearate is added to the plain tablet as a lubricant, whereby lactoferrin dissolution in the intestine can be well maintained even after the enteric tablet is stored for a long period of time. Patent document 3 discloses: by applying a precoating layer between the plain tablet and the coating, the dissolution of lactoferrin in the stomach can be well suppressed even after the enteric tablet is stored for a long period of time.

[ Prior art documents ]

[ patent document ]

[ patent document 1 ] WO2016/163460

[ patent document 2] WO2016/163463

[ patent document 3 ] WO2016/035756

Disclosure of Invention

[ problem to be solved by the invention ]

The present invention provides an enteric coated tablet containing lactoferrin and a method for producing the same. In the enteric coated tablet, stearate is added as a lubricant to the plain tablet. Therefore, even after the enteric coated tablet is stored for a long period of time, lactoferrin can be efficiently dissolved in the intestine. Here, it is particularly required to improve the elution property of lactoferrin after long-term storage at high temperature. The present invention addresses the problem of providing means for improving the retention of the elution of lactoferrin in the intestine over time, particularly at high temperatures.

[ MEANS FOR solving PROBLEMS ] to solve the problems

<1>An enteric coated tablet comprising (A) lactoferrin and (B) crystalline cellulose, wherein the bulk density of the crystalline cellulose is 0.23g/cm³The above.

<2> the enteric coated tablet according to <1>, wherein,

the bulk density of the crystalline cellulose (B) is 0.25g/cm³In the above-mentioned manner,

the weight ratio (B/A) of the crystalline cellulose (B) to the lactoferrin (A) is 0.09 or more.

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

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

<5>According to<2>～<4>The enteric coated tablet according to any one of the above, wherein the plain tablet further comprises a bulk density of less than 0.25g/cm³Other crystalline cellulose.

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

<7> an enteric coated tablet, wherein the plain tablet comprises (A) lactoferrin and (B) crystalline cellulose,

the weight ratio (B/A) of the crystalline cellulose (B) to the lactoferrin (A) is 0.65 to 2.60,

the hardness of the base sheet is 7kgf or more,

the enteric-coated tablet has a dissolution maintenance rate of 70% or more.

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

<9> the enteric coated tablet according to any one of <1> to <8>, wherein the plain tablet is coated with a protective film component selected from the group consisting of a methacrylic polymer compound, shellac, zein, alginic acid and alginate.

<10> the enteric coated tablet according to <9>, wherein a precoat layer containing no said protective film component is applied between said plain tablet and said coating layer.

<11> the enteric coated tablet according to any one of <1> to <10>, which comprises the lactoferrin (A) as a physiologically active ingredient for use in activation of lipid metabolism, treatment or prevention of constipation, activation of intestinal flora, sleep improvement, promotion of growth hormone secretion, treatment or prevention of dry eye and corneal epithelial exfoliation, and of eye diseases caused by them, reduction of blood pressure, treatment or prevention of allergy, activation of immunity, treatment or prevention of climacteric disorder, and activation of liver function.

<12> a method for producing an enteric coated tablet, wherein,

the powder containing (A) lactoferrin and the bulk density of the powder were adjusted to 0.23g/cm by using a tableting machine³Tabletting the mixed powder of the crystalline cellulose powder (B) to obtain a plain tablet, and coating the plain tablet.

[ Effect of the invention ]

The present invention can provide: disclosed are a lactoferrin-containing enteric tablet and a method for producing the same, which are intended to improve the dissolution property of lactoferrin that can be maintained in the intestine over time, particularly at high temperatures.

Drawings

Fig. 1 is a photograph showing the adhesion state (×) of the raw material.

Fig. 2 is a photograph showing the adhesion state (×) of the raw material.

Fig. 3 is a photograph showing the adhesion state (#) of the raw material.

Detailed Description

<1> construction of enteric coated tablet

The enteric coated tablet of the present embodiment is a tablet in which a plain tablet is coated with a protective film component. The plain tablet contains (A) lactoferrin and (B) crystalline cellulose. In one embodiment, the enteric tablet delivers (a) lactoferrin as the physiologically active ingredient to the intestine. In one embodiment, the enteric tablet delivers (a) lactoferrin to the intestine as an additional ingredient other than the physiologically active ingredient.

The protective film component in the coating hinders the dissolution of (a) lactoferrin in gastric juice, but does not hinder its dissolution in intestinal juice. A precoating layer containing no protective film component may be further applied between the plain tablet and the coating. An additional coating containing no protective film component may be further applied to the outside of the coating.

The plain tablet may contain (a) a physiologically active ingredient other than lactoferrin. In one embodiment, (a) lactoferrin is the most abundant physiologically active ingredient within the physiologically active ingredients in the plain tablet. (A) Lactoferrin may be the only physiologically active ingredient in the plain tablet.

In the present embodiment, the bulk density of the crystalline cellulose is 0.23g/cm³The above. Therefore, the lactoferrin dissolution property of the enteric tablet in the intestine can be maintained over time especially at high temperature. Hereinafter, each component required in the enteric-coated tablet and its amount are explained.

<2-1.(A) Lactoferrin >

Lactoferrin is an iron-binding glycoprotein with a molecular weight of about 80,000, and binds 2 irons on 1 molecule. In one embodiment, lactoferrin is bound to iron. In one embodiment, the lactoferrin is not bound to iron. The iron content of lactoferrin in the experimental examples described hereinafter was 0.05% or less, and it was a composition that did not substantially bind iron.

Lactoferrin is a physiologically active ingredient having a function of improving lipid metabolism, a function of improving constipation, a function of improving intestinal flora, a function of improving sleep, a function of promoting secretion of growth hormone, a function of improving dry eye and corneal epithelial exfoliation and ocular disorders caused by them, a function of lowering blood pressure, a function of improving allergy, a function of improving immunity, a function of improving climacteric disorders, a function of improving liver functions, and other functions.

When lactoferrin is digested by pepsin, a peptide having a stronger antibacterial activity, lactoferricin, is produced. In one embodiment, the lactoferrin is a lactoferrin peptide-containing composition. In one embodiment, the lactoferrin is a composition free of lactoferricin. The lactoferrin in the experimental examples described hereinafter is a composition containing no lactoferricin.

In one embodiment, the content of lactoferrin is 1 wt% or more and 60 wt% or less, preferably 4 wt% or more and 60 wt% or less, more preferably 15 wt% or more and 56 wt% or less, and further preferably 18 wt% or more and 50 wt% or less, relative to the plain tablets.

When the content is 4 wt% or more, the mixed powder containing lactoferrin can be inhibited from adhering to the tableting machine during tableting. By setting the content to 15% by weight or more, preferably 17.2% by weight or more, adhesion can be further suppressed. The initial dissolution rate is improved by setting the content to 18% by weight or more, preferably 18.5% by weight or more.

By setting the content to 50 wt% or less, preferably 48.2 wt% or less, the moldability of the plain sheet during tableting is improved. By setting the content to 45 wt% or less, preferably 41.5 wt% or less, the initial dissolution rate and the dissolution property maintenance rate are improved. By setting the content to 36.3 wt% or less, the moldability of the plain tablet during tableting is further improved. In addition, the dissolution maintaining rate is further improved. The dissolution property maintenance rate is further improved by setting the content to 35 wt% or less, preferably 30.8 wt% or less.

Here, the dissolution property maintenance rate refers to a measure of how much the dissolution rate is maintained against the degradation of dissolution property during storage of the enteric tablet. In the present embodiment, the dissolution property maintenance rate refers to the dissolution property maintenance rate during storage at a high temperature of more than 40 ℃. In one embodiment, the dissolution property maintenance rate refers to a dissolution property maintenance rate during storage at a high temperature of more than 50 ℃. In one embodiment, the dissolution property maintenance rate refers to a dissolution property maintenance rate during storage at a high temperature of up to 60 ℃.

Lactoferrin may be isolated, for example, from milk obtained from dairy livestock. Examples of the dairy livestock include cattle, sheep, goats, horses, and the like, but are not limited thereto. Milk can be classified into colostrum, transitional milk, mature milk, and late milk according to each sampling period. Milk of any period can be used. Lactoferrin can also be isolated from substances obtained by treating milk, such as skim milk or whey. The lactoferrin in the experimental examples was obtained from cattle.

Lactoferrin can be produced by transgenic organisms. The host organism may be an animal, a plant, or a microorganism. In addition, the host may be a cultured cell. As host plants, tomato, rice and tobacco are exemplified. The lactoferrin gene to be introduced may be a lactoferrin gene of any one of human and dairy livestock. The lactoferrin derivative can be produced by mutating the introduced lactoferrin gene. Such a lactoferrin derivative is included in the lactoferrin of the present embodiment. In one embodiment, the lactoferrin is directly cloned unmutated lactoferrin.

The isolated or produced lactoferrin may be chemically treated to produce a lactoferrin derivative. Such a lactoferrin derivative is included in the lactoferrin of the present embodiment. In one embodiment, the lactoferrin is a non-derivative of lactoferrin.

Lactoferrin can be purified and concentrated using a common method such as ion exchange chromatography. The drying of the concentrated lactoferrin may be performed by any one of freeze drying and spray drying.

The lactoferrin can be processed such as granulation of lactoferrin and pulverization of lactoferrin before mixing with other raw material powder. It is preferable to mix the lactoferrin particles having a predetermined particle size distribution or average particle size obtained by the processing with other raw material powder. The lactoferrin particles may be coated.

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

The average particle size of the lactoferrin particles can be measured using the Ro-Tap method or the laser diffraction scattering method. The average particle diameter measured by the Ro-Tap method corresponds to a particle diameter having a cumulative frequency of 50 wt% on a weight basis. In the present example, the bulk density of lactoferrin is not particularly limited. The bulk density here refers to a density when a container having a certain volume is filled with the powder to the maximum extent, and the internal volume is taken as a volume.

In this example, lactoferrin may or may not be aggregated. The apparent molecular weight of lactoferrin of the aggregate is not particularly limited. Lactoferrin may be mutually dispersed per molecule. The lactoferrin aggregate may further comprise other proteins. Other proteins or peptide fragments of lactoferrin may be included in the aggregate of lactoferrin.

In the lactoferrin concentrate used as a raw material, the purity of lactoferrin is not particularly limited. The purity is preferably 50% by weight or more, more preferably 85% by weight or more. The purity of the lactoferrin concentrate does not have to be 100% by weight. In one embodiment, (a) lactoferrin is mixed in the plain tablets as a lactoferrin concentrate purified from the starting material, e.g. whey.

The purity, the amount of pure components, i.e. the weight, of the lactoferrin in the lactoferrin concentrate may be taken into account when determining the content of lactoferrin. In the following experimental examples, the content of lactoferrin was determined by the amount of the pure component of lactoferrin. In one embodiment, the pure component amounts comprise lactoferrin-bound iron. In one embodiment, the amount of pure ingredients does not comprise lactoferrin bound iron.

<2-2.(B) crystalline cellulose >

In one embodiment, the crystalline cellulose may be obtained by partially depolymerizing alpha-cellulose obtained from fibrous plants with an acid, purifying. The cellulose in the crystalline cellulose does not have a functional group or the like. The cellulose in the crystalline cellulose is a non-derivative cellulose.

Crystalline cellulose improves the bonding force between particles in the mixed powder for tableting. Crystalline cellulose further improves the dissolution of lactoferrin. The content of the crystalline cellulose in the plain sheet is preferably 5 wt% or more and 70 wt% or less, more preferably 15 wt% or more and 60 wt% or less, and still more preferably 27 wt% or more and 57 wt% or less.

By setting the content to 5% by weight or more, preferably 12% by weight or more, the moldability of the plain sheet 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 property maintenance rate can be improved. By setting the content to 23.8 wt% or more, the moldability of the plain tablet during tableting is further improved. In addition, the dissolution maintaining rate is further improved. The dissolution property maintenance rate is further improved by setting the content to 27% by weight or more, preferably 29.3% by weight or more.

By setting the content to 57% by weight or less, preferably 56.2% by weight or less, the lactoferrin-containing mixed powder can be inhibited from adhering to the tableting machine during tableting. By setting the content to 45 wt% or less, preferably 43.0 wt% or less, adhesion can be further suppressed. The initial dissolution rate is improved by setting the content to 42 wt% or less, preferably 41.7 wt% or less.

The crystalline cellulose is in the form of granules. The bulk density of the crystalline cellulose is preferably 0.23g/cm³The above. The bulk density is preferably 0.40g/cm³The following. Preferably, the bulk density is 0.25g/cm³Above, 0.35g/cm³The following. Preferably, the bulk density is 0.28g/cm³Above, 0.31g/cm³The following.

By making the bulk density 0.23g/cm³This improves the dissolution property maintenance rate. By making the bulk density 0.25g/cm³As described above, the dissolution property maintenance rate is further improved. By making the bulk density 0.35g/cm³Below, 0.31g/cm is preferable³The moldability of the plain tablet during tableting is improved as follows.

As described above, the bulk density refers to a density when a container having a certain volume is filled with the powder to the maximum extent, and the internal volume is taken as a volume. Since the crystalline cellulose powder in the tablet is compressed, the crystalline cellulose powder may have a bulk density different from that before tableting. When the bulk density is changed by tableting, the bulk density can be determined based on the stage of the raw material immediately before the preparation of the mixed powder.

The measurement of the bulk density can be carried out by the method described in "crystalline cellulose" of the seventeenth revised Japanese pharmacopoeia. The bulk density can be measured here using Scott volumetric meters using equipment specified in japanese pharmacopoeia. Hereinafter, unless otherwise specified, the bulk density refers to the bulk density measured according to the method of the japanese pharmacopoeia.

The crystalline cellulose has a predetermined particle size distribution. The average particle diameter is preferably 20 to 180 μm, more preferably 40 to 150 μm. The average particle diameter can be measured by the Ro-Tap method or the laser diffraction scattering method. The average particle diameter measured by the Ro-Tap method corresponds to a particle diameter having a cumulative frequency of 50 wt% on a weight basis.

Examples of a method for measuring the particle diameter of crystalline cellulose dispersed in a plain tablet or an enteric tablet include the following. First, the tablet is disintegrated with a medium such as water or ethanol in which components other than crystalline cellulose are dissolved, and then the crystalline cellulose powder in the solvent is collected. Next, the particle size distribution of the collected powder was measured by the above-described method. Alternatively, the particle size distribution is measured using a particle image analysis apparatus. Examples of the particle image analyzing apparatus include a particle image analyzing apparatus "Morphologi 4" and a particle image analyzing and raman spectroscopy apparatus "Morphologi 4-ID", both manufactured by Spectris corporation.

The retention rate of elution property is improved by setting the average particle diameter to 20 μm or more, preferably 40 μm or more, and more preferably 50 μm or more. By setting the average particle diameter to 180 μm or less, preferably 150 μm or less, the moldability of the plain tablet during tableting can be improved and the adhesion of the lactoferrin-containing mixed powder to the tableting machine can be suppressed.

When preparing crystalline cellulose, attention is paid to the bulk density. The bulk density can be adjusted in accordance with a conventional method. When preparing crystalline cellulose, attention is also paid to the particle size distribution. In order to obtain crystalline cellulose having a desired average particle diameter or particle diameter distribution, a general method can be used.

Examples of the method for producing crystalline cellulose include the descriptions in paragraphs [0022] to [0024] of Japanese patent laid-open publication No. 2019-026558. For example, the cellulose dispersion can be dehydrated and purified at one time to obtain large particles. Further, the particle size distribution can be biased to the large particle side by screening. In addition, smaller particles can also be obtained by increasing the primary particle fraction by pulverization. Other conventional methods may be used for adjusting the average particle size or the particle size distribution.

A variety of crystalline cellulosic feedstocks can be combined. Groups of 2 or more types of crystalline cellulose having different bulk densities, particle size distributions, or average particle sizes may be mixed. 2 or more kinds of crystalline cellulose having different bulk densities may be combined and adjusted so that the bulk density falls within the range of the bulk density of the present embodiment. In one embodiment, the tablet may comprise a bulk density of 0.25g/cm³Above, preferably 0.28g/cm³The above crystalline cellulose and the bulk density of less than 0.25g/cm³Other crystalline cellulose. The bulk density of the other crystalline cellulose may be, for example, 0.23g/cm³. The content of other crystalline cellulose is preferably 0.25g/cm in specific bulk density³The content of the above crystalline cellulose is small.

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

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

The moldability of the plain tablet during tableting is improved by setting the weight ratio (B/A) to 0.25 or more. By setting the weight ratio (B/A) to 0.45 or more, the initial dissolution rate is improved and the dissolution property maintenance rate is improved. The moldability of the plain sheet is further improved by making the weight ratio (B/a) larger than 0.63, preferably 0.64 or more, more preferably 0.65 or more, and further preferably 0.66 or more. In addition, the dissolution maintenance rate is improved. The dissolution property maintenance rate is further improved by setting the weight ratio (B/A) to 0.8 or more, preferably 0.95 or more.

When the weight ratio (B/a) is 15 or less, preferably 14.04 or less, the lactoferrin-containing mixed powder can be inhibited from adhering to the tableting machine during tableting. By setting the weight ratio (B/a) to 4 or less, preferably 2.50 or less, the adhesion is further suppressed, and the initial dissolution rate of the enteric tablet is further improved. The weight ratio (B/a) can be interpreted as the ratio of the weight of the above-mentioned (B) crystalline cellulose to the amount of the pure component of lactoferrin.

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

The tablet may further contain a stearate as a lubricant. The stearate may be at least any one of calcium stearate and magnesium stearate. The content of the stearate is preferably 0.01 to 10 wt%, more preferably 0.05 to 5.0 wt%, and still more preferably 0.1 to 3.0 wt% with respect to the base sheet. The content is not less than the lower limit to improve the adhesiveness, and the content is not more than the upper limit to improve the elution property. Examples of the lubricant other than stearate include sucrose fatty acid esters. The plain tablets may further contain binders, excipients, glidants, disintegrants and other lubricants.

Examples of the binder include gum arabic, gelatin, sodium alginate, methyl cellulose, ethyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol, and hydroxypropyl cellulose. By adding a binder to the mixed powder before tableting, the moldability of the plain tablet at the time of tableting is improved. The content of the binder is preferably 0.1 wt% or more and 50 wt% or less with respect to the base sheet.

Examples of the excipient include: maltitol, dextrin, xylitol, erythritol, kaolin, cocoa butter, fructose, stearic acid, dextran, hydroxypropylmethyl cellulose, polyethylene glycol, calcium hydrogen phosphate, sodium hydrogen phosphate, sucrose, glucose, sorbitol, lactitol, corn starch, and potato starch. The dissolution and the administration of the tablet are improved by the excipient contained in the tablet. The content of the excipient is preferably 0.1 wt% or more and 50 wt% or less with respect to the plain tablet.

As glidant, microsilica can be mentioned. Examples of the disintegrant include carboxymethylcellulose (CMC), alkali metal salts of CMC, partially gelatinized starch, and hydroxypropyl cellulose (HPC) having a low substitution degree. By including a flow aid in the mixed powder before tableting, the fluidity of the powder other than the flow aid is improved. The content of the glidant is preferably 0.1 to 2.0 wt% relative to the plain tablet. By adding a disintegrant to the mixed powder before tableting, the disintegration properties of the plain and enteric tablets are improved. The content of the disintegrant is preferably 0.01 to 30% by weight, more preferably 0.1 to 15% by weight, and still more preferably 0.5 to 10% by weight, based on the base tablet.

<2-5. other physiologically active ingredients >

The vegetarian tablet may further contain other physiologically active ingredients such as plant-derived ingredients, vitamins, minerals, dietary fibers, fish oil, and lactic acid bacteria. Examples of the plant-derived component include cacao extract, piper longum extract, pueraria flower extract, aureobasidium (durvillea) extract, grape seed extract, pine bark extract, coleus forskohlii extract, artichoke leaf extract, rosemary extract, lewis bauhinia (Rooibos) extract, tomato extract, olive extract, panax notoginseng extract, and other plant extracts. The processed product of the plant extract is also suitable as a plant-derived component. Purified compounds obtained from plant extracts are also suitable for use as plant-derived ingredients. Examples of the compound include raspberry copper and isoflavone. In addition, the vitamins, minerals and dietary fibers may be plant derived ingredients or may be artificially synthesized ingredients. The vitamin may be a fat-soluble vitamin. The lactobacillus can be live bacteria or dead bacteria.

The content of the other physiologically active ingredient in the plain sheet is preferably 1 wt% or more and 50 wt% or less, more preferably 4 wt% or more and 30 wt% or less, and further preferably 8 wt% or more and 20 wt% or less. When the content is 1% by weight or more, the elution property is good. By further increasing the content, the elution property can be further improved. By setting the content to 50% by weight or less, the moldability of the mixed powder is improved. By further reducing the content, the moldability of the mixed powder can be further improved.

In addition, by further containing these other physiologically active ingredients, the enteric coated tablet of the present embodiment contributes to prevention or improvement of diseases such as hyperglycemia, allergy, and dry syndrome. In addition, the enteric coated tablet of the present embodiment contributes to improvement of the intestinal environment. According to the enteric coated tablet of the present embodiment, elution of lactoferrin in the stomach is suppressed, and lactoferrin is mainly eluted from the plain tablet in the intestine. Therefore, the prophylactic or therapeutic effect of lactoferrin on diseases can be further improved. In the present 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 ingredients >

The tablets of this example are enteric coated tablets. The tablet has a coating on the tablet. The coating has a protective film component. The protective film component imparts enteric solubility to the tablet. The protective film component is insoluble in the stomach, and therefore, the protective film component hinders contact of gastric juice with lactoferrin and other physiologically active ingredients in the plain tablet. Thereafter, the protective film component dissolves in the intestine, facilitating contact between the intestinal juice and the plain film. In one embodiment, the enteric tablet is suitably an "enteric preparation" described in the seventeenth revised japanese pharmacopoeia.

Examples of the protective film component include methacrylic acid-based polymer compounds, shellac, zein, alginic acid, and alginates. These may be used in 1 kind or in combination of 2 or more kinds. The alginate can be 1 or more than 2 of ammonium alginate, sodium alginate and potassium alginate. As the protective film component, 2 or more compounds having different molecular weights are preferably used in combination. For example, 2 kinds of alginate may be used in combination. This improves the acid resistance of the enteric coated tablet and the elution of lactoferrin and other physiologically active ingredients in the intestine. A precoat layer without protective film ingredients may be applied on the inside of the coating.

An adhesion preventing agent, a coloring agent, or the like may be added to the coating. Examples of the adhesion preventing agent include silica and talc. The silica is preferably microsilica. As the coloring agent, caramel, cacao, gardenia yellow pigment, carotene, gardenia red pigment and radish red pigment are exemplified.

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

The shape, size and weight of the tablet are not particularly limited as long as they can be easily taken. The shape is preferably R sheet or two-layer R sheet. The size is preferably 5mm or more and less than 15mm in diameter and 3mm or more and less than 10mm in thickness. The weight of the plain tablet is preferably 200mg to 400mg, more preferably 250mg to 350 mg. In order to prevent abrasion of the plain tablet during coating, the hardness of the plain tablet is preferably 7kgf or more, more preferably 9kgf or more, and still more preferably 10kgf or more. The upper limit of the hardness of the plain tablet is preferably 20kgf or less from the viewpoint of the disintegration of the tablet in the intestine. The hardness of the enteric-coated tablet is preferably 20kgf to 40 kgf.

[ examples ] A method for producing a compound

<3-1. preparation of plain sheet >

Weighing raw materials including (A) lactoferrin, (B) crystalline cellulose, (C) stearate and other raw materials which are powder-shaped and are mixed with (D) plant extracts. The composition ratios of the respective components of the raw materials are shown in tables 2 to 5 in the experimental examples. The mixed powder was obtained by mixing to a total weight of 5 kg. And tabletting the mixed powder by using a rotary tablet machine to obtain plain tablets. In this example, the mixed powder was prepared without granulation.

Tablet press manufactures LIBLA 2 for chrysanthemum water. The setting of LIBLA 2 is as follows.

Shape of the mortar and pestle die:

r chamfer with diameter of 9.0mm and angle of 2 sections

R1-3.6 mm, R2-10.5 mm, and table (land) 1.5mm

The plateau indicates the distance from the side surface of the tablet to the rising portion of the R-surface

-speed of rotation of the mixing blades of the feeding shoe (feed shoe): 60rpm

In each case, a tablet was prepared by compressing at 15kN to give a green tablet, and the hardness of the green tablet was measured. The hardness of the plain sheet was used as an index for evaluation of moldability. Further, the tablet compression pressure was adjusted based on the measurement results so that the hardness of the base tablet became 10kgf, and then base tablets for evaluation of the initial dissolution rate and the dissolution property maintenance rate were prepared. The tabletting pressure is in the range of 10 to 18 kN. After coating the plain tablets, the elution properties of lactoferrin were evaluated.

<3-2. coating >

The plain sheet was precoated with a 1 st coating solution having the following composition.

HPMC (hydroxypropylmethylcellulose): 6 percent of

Glycerol: 2 percent of

Water: 92 percent of

The precoated plain tablets were coated with a layer 2 coating solution having the following composition.

HPMC：2.1％

Glycerol: 1.1 percent

Sodium alginate: 3.2 percent of

Microsilica: 0.5 percent

Water: 93.1 percent

As the coating apparatus, a disc rotary coater manufactured by the FREUND industry, HICOATER FZ-Lab, was used. First, 670 pieces of plain film were precoated by spraying 33g of coating solution for layer 1 at 20 ℃ at an average of 2 g/min. The temperature of the plain film was adjusted to about 50 ℃. The coating solution for layer 1, 33g, contained 2640mg of components other than water. 2640mg was divided by 670 tablets to give about 3.9 mg/tablet.

Then, 163g of coating liquid for layer 2 at 60 ℃ was sprayed at an average of 2 g/min. After spraying, it was dried at about 45 ℃ for 2 minutes. The enteric coated tablet is obtained by the method. The composition of the solid ingredients in the coating of each 1 enteric-coated tablet is shown below.

Composition of solid component of coating layer 1 (mg/tablet)

Hydroxypropyl methylcellulose 2.9

Glycerol 1.0

Composition of solid component of coating layer 2 (mg/tablet)

<3-3. dissolution test of lactoferrin >

The dissolution rate (%) of lactoferrin was measured according to the dissolution test method for tablets recorded in the seventeenth revised japanese pharmacopoeia. Specifically, lactoferrin was dissolved into the test solution by the paddle method at 50 revolutions per minute. As a test solution, 900mL of the dissolution test solution No. 2 having a pH of about 6.8 was used for 1 tablet. 2 hours after the start of the test, the test solution was collected. The dissolution rate was calculated by quantifying the amount of lactoferrin dissolved into the test solution. The following test was performed 3 times to calculate an average value of the dissolution rate from these measured values. In addition, it was previously confirmed that a coating was normally formed in the test using the dissolution test solution 1 having a pH of about 1.2. Therefore, if it is confirmed that the tablet of the present example has the dissolution property with respect to the dissolution test solution No. 2, it is confirmed that the tablet of the present example can be used in a living body as an enteric coated tablet.

(1) The elution amount of lactoferrin was determined as follows. First, 75mg of a lactoferrin standard was added to a 50mL volumetric flask having a predetermined volume, and then the volume was made up to the predetermined volume with the test solution to obtain 1/1 as a standard solution. The standard solutions were further diluted with test solutions to make 1/5, 1/20, and 1/50 standard solutions. Lactoferrin was detected in each standard solution by HPLC. The peak area of lactoferrin in each standard solution was determined to prepare a calibration curve.

As a standard lactoferrin, a biochemical "lactoferrin derived from cow's milk" produced by fuji film and Wako pure chemical industries was used. The purity of the lactoferrin standard product refers to the content (HPLC) value described in the examination results book issued by the optical pure drug industry.

Next, the peak area of lactoferrin was determined by detecting lactoferrin in the test solution collected as described above by HPLC. The concentration of lactoferrin in each test solution was determined from the peak area based on the calibration curve, and lactoferrin eluted into the test solution was quantified.

(2) The content of lactoferrin in the tablet was determined as follows. First, 75mg of lactoferrin standard was added to a 50mL volumetric flask having a predetermined volume, and then the volume was made up to the predetermined volume with a 3 wt% aqueous NaCl solution to obtain 1/1 as a standard solution. The standard solutions were further diluted with 3 wt% NaCl aqueous solution to make 1/2 and 1/20 standard solutions. Lactoferrin was detected in each standard solution by HPLC. The peak area of lactoferrin in each standard solution was obtained to prepare a calibration curve. Note that it is preferable to prepare calibration curves by taking note of the difference in dilution ratio between the dissolution test solution as a diluent and the 3 wt% NaCl aqueous solution in the dissolution test (1) and the quantitative test (2), respectively.

Then, the tablet and 3 wt% NaCl solution were added to a 100ml volumetric flask having a predetermined volume to completely dissolve the tablet, and then the solution was made up to the predetermined volume to obtain a sample solution. The area of the HPLC detection peak of lactoferrin was determined. 3 trials were performed. The lactoferrin concentration in each sample solution was determined by peak area based on the calibration curve, and the content of lactoferrin in the tablet was quantified.

(3) The HPLC conditions were as follows.

-a detector: ultraviolet absorption photometer (measuring wavelength: 280nm)

-column packing: 5 μm liquid chromatography with butylated polyvinyl alcohol polymer gel (Shodex Asahipak C4P-504D)

-column tube for chromatography: stainless steel pipe with inner diameter of 4.6mm and length of 15cm

-protective chromatography column: shodex Asahipak C4P-50G 4A

-column temperature: 35 deg.C

-mobile phase a: acetonitrile/sodium chloride solution (3 → 100) containing 0.03 w/v% by weight of trifluoroacetic acid in mixed solution (10: 90)

-mobile phase B: acetonitrile/sodium chloride solution (3 → 100) containing 0.03 w/v% by weight of trifluoroacetic acid in mixed solution (50: 50)

-a concentration gradient: for 25 minutes a reaction was carried out from a: b (50: 50) to A: linear concentration gradient of B (0: 100).

-flow rate: 0.8 mL/min

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

[ TABLE 1 ]

CMC-Ca: calcium carboxymethylcellulose

<3-5. evaluation of moldability >

Hardness of the plain sheet compressed at a tablet compression pressure of 15kN was measured by a tablet physical property measuring machine (Multicheck6, manufactured by ERWEKA). The measured hardness is horizontal hardness. The average hardness between the plain sheets was determined (n: 10). The criteria for determination are as follows. In the present example, the formulation for obtaining a tablet with high hardness was evaluated for good moldability.

9kgf or more

7kgf or more and less than 9kgf

Less than 7kgf

<3-6. evaluation of adhesion to tableting machine >

When the plain tablet is repeatedly tabletted in a tablet machine, a mixed powder of the raw materials of the plain tablet may adhere to the tablet machine. The state of the mixed powder of the raw materials attached to the rotary tablet press was observed. FIGS. 1 to 3 are photographs showing the adhesion state of the raw material. Fig. 1 illustrates a state where no raw material is attached. Fig. 2 and 3 illustrate the state in which Ad attachment of the raw material of the plain piece is observed.

As shown in fig. 2 and 3, attachment Ad is produced on the disc surface of the tablet press. In addition, it also occurs on the wall surface of the mortar. The mixed powder adhered to the surface of the disk adheres against the scraping of the scraper blade of each turn. The mixed powder adhered to the wall surface of the mortar adheres against the scraping of the pestle for each tabletting.

Tabletting with a rotary tablet press for 20 minutes. The time at which the mixed powder began to adhere to the disc surface or the wall surface of the mortar was visually confirmed. The criteria for determination are as follows.

No attachment was observed (fig. 1).

Adhesion was observed after 20 minutes from the start of tabletting (figure 2).

Adhesion was observed just after the start of tabletting (figure 3).

Consider that: the adhesion of the mixed powder is affected by the bonding between the mixed powder and the metal, and also by the bonding between the powders. That is, the powder adheres more strongly to the scraper and the pestle because the powder is subjected to a stronger shear stress. The adhesion tends to increase with the passage of time. Therefore, the evaluation was performed with the time until the powder was adhered as described above.

<3-7. evaluation of initial dissolution Rate >

First, as described in the above < 3-lactoferrin dissolution test >, the dissolution test was performed on the enteric-coated tablets, and the content of lactoferrin in the enteric-coated tablets was determined. Further, in order to obtain the initial dissolution rate before the storage test, the test was carried out using tablets within 7 days after tabletting. The criteria for determination are as follows.

Initial dissolution rate of 85% or more

The initial dissolution rate is more than 75% and less than 85%

The initial dissolution rate is more than 65% and less than 75%

In addition, in the experimental examples of this time, a formulation having an initial dissolution rate of less than 75% was not found.

<3-8 > evaluation of dissolution Property maintenance >

As described in the above <3-3. lactoferrin dissolution test >, the content of lactoferrin in the enteric coated tablet was determined by performing a dissolution test on the enteric coated tablet after being stored in a plastic bottle at 60 ℃ for 12 days. The dissolution property maintenance rate (%) was determined according to the following formula. The criteria for determination are as follows.

Dissolution maintenance rate (%) < 100 × (amount dissolved after storage (mg))/(amount dissolved at initial stage (mg))

Level 6: over 90 percent

Level 5: more than 85 percent and less than 90 percent

Level 4: more than 80 percent and less than 85 percent

Level 3: more than 75 percent and less than 80 percent

Level 2: more than 70 percent and less than 75 percent

Level 1: less than 70 percent

In the test of the retention rate of dissolution at 60 ℃, the enteric-coated tablet is placed under severer conditions than the test of the retention rate of dissolution at 40 ℃ described in patent documents 1 and 2. Therefore, it is suitable for evaluating the difficulty of deterioration of the dissolution property of the enteric tablet in a temperate zone, a high temperature in the subtropical summer, or a high temperature in the tropical zone, for example.

<4. formulation example >

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

<5. Experimental example >

The raw materials are used to prepare plain tablets according to various formulas. The coating for the plain tablets was performed as shown in <3-2. coating >. Each formulation was evaluated starting from formulation C1. All formulations are exemplary and not intended to limit the invention.

Table 2 shows experimental examples of bulk density of crystalline cellulose. The compositions are in weight ratio. In the table, the components contained in the base sheet are shown in the upper part. The evaluation column shows the results of the tests from <3-5. evaluation of moldability > to <3-8. evaluation of dissolution property retention rate > described above. The same applies to the other tables. Hereinafter, the following description will be made centering on the evaluation result of the dissolution property maintenance rate.

[ TABLE 2]

In table 2, formulations C1 and C2 are dissolution maintenance levels of 1. Further, the formulas W1 to W5 showed a dissolution maintenance rate level of 2 or more. The bulk density of the crystalline cellulose (B) as an excipient in the formulations W1 to W5 was 0.23g/cm³Thus, the dissolution property after storage can be maintained.

In table 2, the formulations W2 to W5 are formulations having a dissolution maintenance rate level of 3 or more. In the table, all levels are 4 or more. (B) The bulk density of the crystalline cellulose was 0.25g/cm³This further improves the dissolution property maintenance rate. The weight ratio (B/A) also affects the dissolution property maintenance ratio, which is shown in Table 3 described later.

In table 2, the formulations W3 to W5 are formulations having a dissolution maintenance rate level of 5 or more. In the table, all are at level 6. (B) The bulk density of the crystalline cellulose was 0.28g/cm³As described above, the average particle diameter is 50 μm or more, and therefore, the dissolution maintaining rate is further improved. The weight ratio (B/A) also affects the dissolution property maintenance ratio, which is shown in Table 3 described later.

In Table 2, in the formulation W5, the bulk density was 0.28g/cm³The above (B) crystalline cellulose and having a bulk density of less than 0.25g/cm³Other crystalline cellulose. The dissolution maintenance level of formulation W5 also remained at the same level as formulation W3.

Table 3 shows examples of experiments on the weight ratio (B/A). Endurance MCC VE-050, which was chosen as the (B) crystalline cellulose common to each formulation, was the same as used in formulation W3. The bulk density was 0.28g/cm³The average particle size was 50 μm. The same is true in Table 4.

[ TABLE 3 ]

In table 3, the recipes W6 to W7 are recipes having the dissolution maintaining rate level 2. In table 3, the formulations W8 to W15 are formulations having a dissolution maintenance rate level of 3 or more. In the formulations W8 to W15, the dissolution property maintenance rate was improved by setting the weight ratio (B/A) to 0.45 or more.

In table 3, the formulations W9 to W15 are formulations having a dissolution maintenance rate level of 4 or more. In the formulations W9 to W15, the dissolution property maintenance rate was further improved by setting the weight ratio (B/A) to 0.66 or more. The formulations W10 to W15 were those with a dissolution maintenance rate level of 5 or more. In the formulations W10 to W15, the dissolution property maintenance rate was further improved by setting the weight ratio (B/A) to 0.95 or more.

Table 4 shows examples of experiments with other components.

[ TABLE 4]

In table 4, unlike formula W3 of table 2, formula W16 used piper longum extract instead of cocoa extract. The tablet can suitably contain other physiologically active ingredients such as plant extract to improve the dissolution maintaining rate.

In table 4, unlike the formula W3 in table 2, the content of (B) crystalline cellulose was increased in the formula W17 instead of omitting maltitol as an additional excipient. Therefore, the weight ratio (B/A) in the formulation W17 is 2.01 or more. The dissolution maintenance level in formulation W17 remained at level 6, as in formulation W3.

In table 4, unlike the formulation W3 of table 2, the formulation W18 contained dextrin instead of maltitol. In formulation W18, the dissolution maintenance rate was level 5. In other formulations, the plain tablets contain maltitol as an additional excipient and an alkali metal salt of carboxymethylcellulose as a disintegrant. Thereby, the dissolution maintenance rate level was maintained at level 6.

In table 4, the composition of the disintegrant was changed in formulation W19 compared to formulation W3 of table 2. The enteric coated tablets of formulation 19 contained partially pregelatinized starch in place of CMC-Ca. In formulation W19, the dissolution maintenance rate was level 5.

Table 5 shows examples of experiments on the average particle size of crystalline cellulose. The compositions are in weight ratio.

[ TABLE 5 ]

In table 5, the formulas W20 to W22 used crystalline cellulose (B) having a larger average particle diameter than those used in the formulas W3 and W4 of table 2. Any average particle size is suitable for improving the dissolution maintaining rate.

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 were superimposed, they were considered as follows. That is, it is preferable that the weight ratio (B/a) of the (B) crystalline cellulose and the (a) lactoferrin is set to 2.50 or less, and then the particle size of the (B) crystalline cellulose is set to 150 μm or less. Thus, in repeated tableting, the adhesion of the remaining raw material to the tableting machine surface can be suppressed (see fig. 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 were superposed, they were considered as follows. That is, it is preferable that the bulk density of the crystalline cellulose (B) is set to 0.31g/cm³Hereinafter, the weight ratio (B/a) of the crystalline cellulose (B) and the lactoferrin (a) is set to 0.66 or more and 2.50 or less, and the particle size of the crystalline cellulose (B) is set to 150 μm or less. Thus, even when the same tabletting press is used, the hardness of the plain sheet can be further improved. This indicates that the moldability of the mixed powder is improved.

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 were superimposed, they were considered as follows. That is, it is preferable that the bulk density of the crystalline cellulose (B) is set to 0.28g/cm³The particle size is set to 50 μm or more, and the weight ratio (B/a) of the crystalline cellulose (B) and the lactoferrin (a) is set to 0.95 or more. This can provide a high dissolution property maintenance rate of level 5 or more.

Table 6 shows experimental examples for confirming the influence of stearate. The compositions are in weight ratio.

[ TABLE 6 ]

Formulation C3 had the same composition as formulation C2 shown in table 2, except that Ca stearate was not added. Unexpectedly, the dissolution maintenance levels at elevated temperatures did not show significant differences between formulation C3 and formulation C2. From the above, it can be seen that: when the stearate (C) is mixed with the base tablet alone, it is difficult to improve the dissolution maintaining rate at high temperature.

The bulk density of the (B) crystalline cellulose of the formulation W23 was higher than that of the formulation C3. Although the stearate was not added to the formulation W23, the dissolution maintenance rate could be improved. The dissolution rate retention rates of the formulations W3 and W23 containing the same crystalline cellulose were of the same order. From the above, it can be seen that: by mixing (B) crystalline cellulose having a high bulk density into the plain sheet, the retention rate of dissolution at high temperature can be improved regardless of the presence or absence of (C) stearate. Further, it can be seen that: the effect is much higher than that brought by the (C) stearate.

As described in patent document 1, stearate contributes to improvement of the dissolution property maintenance rate at a temperature around 40 ℃. Therefore, combining (C) stearate with (B) crystalline cellulose having a high bulk density in a plain tablet is one of effective means for improving the retention rate of elution of (a) lactoferrin in various storage temperature environments.

Claims

1. An enteric coated tablet characterized in that the plain tablet contains (A) lactoferrin and (B) crystalline cellulose, and the bulk density of the (B) crystalline cellulose is 0.23g/cm³The above.

2. The enteric tablet according to claim 1, wherein the (B) crystalline cellulose has a bulk density of 0.25g/cm³In the above-mentioned manner,

the weight ratio of the crystalline cellulose (B) to the lactoferrin (A), namely B/A, is 0.09 or more.

3. Enteric-coated tablet according to claim 2, wherein the weight ratio B/a is 60 or less.

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

5. Enteric-coated tablet according to any of claims 2 to 4, wherein the plain tablet further comprises a bulk density of less than 0.25g/cm³Other crystalline cellulose.

6. The enteric tablet according to any one of claims 1 to 4, wherein the average particle size of the crystalline cellulose (B) is 20 μm or more.

7. Enteric-coated tablet according to any of claims 1 to 4, wherein the plain tablet further comprises (C) stearate.

8. The enteric tablet according to any one of claims 1 to 4, wherein the plain tablet is coated with a protective film component of any one of methacrylic acid-based high molecular compound, shellac, zein, alginic acid and alginate.

9. An enteric coated tablet characterized in that the plain tablet contains (A) lactoferrin and (B) crystalline cellulose,

wherein the weight ratio of the crystalline cellulose (B) to the lactoferrin (A), namely B/A, is 0.65 to 2.60,

the hardness of the base sheet is 7kgf or more,

the enteric-coated tablet has a dissolution maintenance rate of 70% or more.

10. The enteric tablet of claim 9, wherein the plain tablet further comprises (C) stearate.

11. The enteric tablet according to claim 9 or 10, wherein the plain tablet is coated with any one of a protective film component of methacrylic acid-based high molecular compound, shellac, zein, alginic acid and alginate.

12. A method for producing an enteric coated tablet, characterized in that,

the powder containing (A) lactoferrin and the bulk density of the powder were adjusted to 0.23g/cm by a tablet press³Tabletting the mixed powder of the crystalline cellulose powder (B) to obtain a plain tablet, and coating the plain tablet.