TWI543780B - Capsule for delivering bifidobacteria to the colon, and method for producing the same - Google Patents

Description

Biloba lactobacillus large intestine delivery capsule and preparation method thereof

The present invention relates to a Bifidobacterium large intestine delivery capsule and a method for producing the same, which are on the surface of a hard capsule filled with Lactobacillus bifidum, have a layer containing chitosan, and contain an intestine A layer of a soluble substrate.

A pharmaceutical preparation, a health food, a health supplement, and the like which have been obtained by taking, ingesting a probiotic agent, and a probiotics as a medicine or a food. As a kind of Bifidobacterium breve which is such a probiotic, it is known that it has an effect of suppressing the proliferation of harmful bacteria in the intestine and improving the intestinal environment, thereby improving the bowel movement and the like. For this reason, attempts have been made to obtain a medical effect or a health care effect such as an enteral action by ingesting various types of pharmaceuticals and foods containing live bacteria of Lactobacillus bifidum.

However, the Lactobacillus bifidum has to pass through a stomach acid having a strong bactericidal action when it reaches the lower part of the digestive tract, especially to the large intestine, and the known lactic acid bacillus cannot survive in a low pH environment such as gastric acid. Therefore, in the case of directly taking the lactic acid bacillus, it is difficult to reach the large intestine which can react with the living bacteria, and there is a problem that sufficient medical effects or health effects cannot be obtained.

As a means for solving this problem, a large intestine drug delivery system which is used in the large intestine to be specifically decomposed to dissolve contents has been considered.

In the case of a large intestine drug delivery system, for example, a solid preparation in which a physiologically active substance (active ingredient) is formed together with an excipient is known as a coating for a large intestine drug delivery system using a chitosan coating liquid (for example, a reference patent) Documents 1 to 2). However, the chitosan coating layer of the solid preparation has fine pores in the coating layer, and the intestinal juice intrudes therefrom, and a part of the active ingredient is dissolved therefrom, which can be rapidly dissolved only in the large intestine. The effect cannot be said to be sufficient. Further, the intestinal juice and water invaded by the pores of the chitosan coating film have a problem of being inactivated before reaching the large intestine.

Therefore, it is considered that a solid capsule is used without using a hard capsule, and a bifidobacterium is encapsulated in a capsule which is a large intestine delivery capsule which does not inactivate before it reaches the large intestine.

For the hard capsule, for example, a hard capsule containing chitosan has been proposed (refer to Patent Document 3). When the hard capsule is used, compared with the case of the solid preparation, the blending ratio of the active ingredient can be increased by reducing the additive other than the active ingredient, and heating, pressurization, drying, etc. are not required in the production step. Since there is a step, there is an advantage that the active ingredient does not deteriorate in the production step.

However, with this method, since the chitosan capsule is fragile, there is a problem that the capsule is broken when it is taken out by a press through package (PTP). In order to solve this problem, it has been considered to thicken the capsule film, but the manufacturing is complicated and the cost is also disadvantageous. Further, since the thickness of the capsule is increased, the step difference of the fitting portion becomes large, and it becomes difficult to embed the step in the coating layer of the enteric substrate. Further, when the capsule film becomes thick, there is a problem that the collapse time in the large intestine increases.

Moreover, for other solutions, coatings have been considered to increase the strength of chitosan capsules. However, this method has a problem that the coating layer is thickened, the manufacturing steps are complicated, and the cost is unfavorable.

Therefore, the development of a Bifidobacterium breve large intestine delivery capsule, which is a bifidobacterium lactobacillus large intestine delivery capsule containing Bifidobacterium breve in a hard capsule, is not strongly sought in the stomach and small intestine. Dissolve, quickly dissolve in the large intestine, and inhibit the invasion of water into the hard capsule in the stomach and small intestine, inhibit the inactivation of the bifidobacteria, and the capsule has sufficient strength, no need to increase the strength of the coating The cloth, which in turn suppresses the amount of coating, can be manufactured at an advantageous manufacturing cost.

[Previous Technical Literature] [Patent Literature]

[Patent Document 1] Japanese Patent Publication No. 08-013748

[Patent Document 2] International Publication No. 2008/075448

[Patent Document 3] Japanese Patent No. 2555520

The present invention addresses various conventional problems to achieve the following objectives. That is, the object of the present invention is to provide a Bifidobacterium Lactobacillus large intestine delivery capsule and a method for producing the same, which is a Bifidobacterium breve large intestine delivery capsule containing Bifidobacterium breve in a hard capsule, which is not in the stomach and Dissolved in the small intestine, rapidly dissolving in the large intestine, and inhibiting the invasion of the stomach and the small intestine into the hard capsule, inhibiting the inactivation of the bifidobacteria, and the capsule has sufficient strength and does not need to be used to increase the strength. Coating, thereby suppressing the amount of coating, and manufacturing the capsule at an advantageous manufacturing cost;

In order to solve this problem, the inventors have focused on the results of the review to obtain the following findings. That is, the large intestine delivery capsule applies a band sealing to a fitting portion of a capsule filled with a gelatin or a cellulose derivative as a base material of Lactobacillus bifidum, and secondly, the surface of the capsule is sequentially coated. The layer containing chitosan and the layer containing the enteric substrate have an effective dissolution property in the large intestine by a thin film containing chitosan.

The present inventors have based on the above-described knowledge as a means for solving the problem, and the present invention is as follows. which is,

<1> A bifidobacteria large intestine delivery capsule, characterized in that the capsule is a hard capsule containing gelatin or a cellulose derivative as a base material, and contains Lactobacillus bifidum, and the fitting portion of the capsule has a belt The sealing layer has a layer containing chitosan and a layer containing an enteric substrate on the surface of the capsule.

<2> The Bifidobacterium breve large intestine delivery capsule according to <1>, wherein the cellulose derivative is hydroxypropylmethylcellulose.

The Bifidobacterium breve large intestine delivery capsule according to any one of <1> to <2> wherein the layer containing chitosan coats a coating solution containing chitosan Formed on the surface of the capsule.

<4> The Bifidobacterium breve large intestine delivery capsule according to <3>, wherein the coating liquid containing chitosan is formed by dissolving chitosan in a volatile organic acid aqueous solution.

<5> A method for producing a bifidobacterium lactobacillus large intestine delivery capsule, characterized in that the capsule is a hard capsule containing gelatin or a cellulose derivative as a base material, and the body is filled with a bifidobacteria, the body of the capsule The portion and the cap portion are fitted, and the fitting portion is sealed by a tape seal, and a coating liquid containing chitosan is applied or sprayed on the surface of the capsule to form a layer containing chitosan. A coating liquid containing an enteric substrate is coated or sprayed on the layer containing chitosan to form a layer containing an enteric substrate.

According to the present invention, various problems can be solved, and to achieve the object, a Bifidobacterium lactiformum large intestine delivery capsule and a method for producing the same can be provided, which is a Bifidobacterium breve which comprises Bifidobacterium breve in a hard capsule. The large intestine delivery capsule, which does not dissolve in the stomach and small intestine, dissolves rapidly in the large intestine, and inhibits the intrusion of moisture in the stomach and small intestine into the hard capsule, inhibits inactivation of the bifidobacteria, and the capsule It has sufficient strength, does not require coating for increasing strength, and thus suppresses the amount of coating, and can be manufactured at an advantageous manufacturing cost.

(Bifidobacterium lactis large intestine delivery capsule and method for producing the same)

The Bifidobacterium breve large intestine delivery capsule of the present invention contains at least a Lactobacillus bifidum in a hard capsule containing gelatin or a cellulose derivative as a substrate, and has a band seal on the fitting portion of the capsule on the surface of the capsule It has a layer containing chitosan and a layer containing an enteric substrate in sequence, and has other layers as necessary.

The method for producing a Bifidobacterium breve large intestine delivery capsule of the present invention comprises at least the steps of: filling a hard capsule of gelatin or a cellulose derivative as a base material with a bifidobacterium, and embedding the body portion and the cap portion of the capsule The fitting portion is sealed by a tape seal, and a coating liquid containing chitosan is applied onto the surface of the capsule to form a layer containing chitosan, and the layer containing the chitosan is coated. The cloth contains a coating liquid of an enteric substrate to form a layer containing an enteric substrate, and further includes other steps appropriately selected as necessary.

<hard capsule>

The hard capsule used in the present invention is a cellulose derivative which denatures cellulose derived from gelatin or a plant as a substrate.

Further, the hard capsule is formed by the main body portion and the cap portion, and the main body portion covers the cap portion to fit the two to be encapsulated.

The gelatin is not particularly limited and may be appropriately selected depending on the intended purpose, and examples thereof include animal collagen (collagen) contained in cowhide, pig skin, bovine bone, and the like, and gelatin derived from fish. Among these examples, it is preferred to use gelatin from animals other than cattle, and there is no risk of infection with mad cow disease.

The cellulose derivative may, for example, be an alkyl cellulose (for example, methyl cellulose or the like), a hydroxyalkyl cellulose (for example, hydroxyethyl cellulose, hydroxypropyl cellulose, or the like), A hydroxyalkylalkylcellulose (for example, hydroxypropylmethylcellulose (HPMC), hydroxyethylmethylcellulose, hydroxyethylethylcellulose, etc.) or the like. These may be used alone or in combination of two or more. In the above, hydroxyalkylalkylcellulose is preferred, and in particular, HPMC is used as a viewpoint that the strength of the capsule is excellent and that the layer containing chitosan is dissolved and rapidly dissolved in the large intestine. optimal.

The hard capsule can be produced by, for example, using the gelatin or the cellulose derivative as an aqueous solution, impregnating the metal plug in the solution, pulling the plug, ensuring the shape, and drying it.

Generally, the cellulose derivative may be prepared in an amount of from about 5% by mass to 25% by mass, from about 74% by mass to 94% by mass of water, from about 0.01% by mass to about 0.5% by mass of the gelling agent, and from about 0.01% by mass to about 0.5% by mass of the gelling aid. The aqueous solution of the cellulose derivative is appropriately blended with a coloring agent (for example, titanium oxide, rouge, blue No. 2, yellow No. 5, etc.), an opaque agent (for example, titanium oxide, etc.) as needed. , spices, etc.

As for the size of the hard capsule, there are No. 00, No. 0, No. 1, No. 2, No. 3, No. 4, No. 5, etc., but any of the hard capsules of any size may be used in the present invention.

<Bifidobacterium lactis>

The Bifidobacterium breve is not particularly limited as long as it has a useful effect on humans, and can be appropriately selected depending on the purpose. For example, Lonicera genus ( Bifidobacterium ) can be exemplified ( Bifidobacterium longum ), Bifidobacterium bifidum , Bifidobacterium breve , Bifidobacterium adolescentis , Bifidobacterium infantis , Bifidobacterium animalis , Bifidobacterium pseudolongum and the like. These may be used alone or in combination of two or more. Among the above, from the viewpoint of being usable from foods, Bifidobacterium longum , Bifidobacterium bifidum , and Bifidobacterium breve are preferred.

It is preferred that the Bifidobacterium breve is directly filled in the hard capsule in a living state. Further, the Bifidobacterium breve may be further encapsulated in the capsule and further proliferated in the capsule.

The shape of the Bifidobacterium breve is not particularly limited as long as it can be filled in the capsule, and can be appropriately selected depending on the purpose. For example, a liquid substance and a hardened oil suspended in a suitable medium can be exemplified. Such as mixed solids, dry powder, and the like.

In the case where the Bifidobacterium breve is a dry powder, the concentration of the Bifidobacterium breve at the time of filling the capsule is preferably 1 × 10 ⁶ cfu / g or more, more preferably 1 × 10 ⁹ cfu / g or more. In addition, cfu represents a colony forming unit.

When the Bifidobacterium breve is in the form of a liquid, when the concentration of the Bifidobacterium breve in the liquid is too high, the viscosity of the liquid becomes high and it is difficult to be encapsulated, so that it is encapsulated with a suitable medium. After that, further proliferation is preferred. The concentration of the Lactobacillus bifidum in the liquid is preferably 1 × 10 ⁶ cfu / g or more, more preferably 1 × 10 ⁹ cfu / g to 1 × 10 ¹² cfu / g.

The other components which can be filled in the hard capsule together with the Bifidobacterium breve can be exemplified by the fact that the Bifidobacterium lactis is used as a liquid substance, and the suspended medium and the Bifidobacterium breve are solid. The hardened fats and oils used in the case, the lactose used for the case of making the dry powder of Bifidobacterium breve, the diluent of dry potato starch, etc., lactic acid bacteria, powdered sugar, oligosaccharide, cellulose, etc. These may be used alone or in combination of two or more. In the above, it is preferred that the water activity is lowered or the water activity is low. Specifically, the potato starch is preferably dried.

The content of the capsule of the lactic acid bacillus, the shape of the capsule, and the capacity of the capsule cannot be determined in a general manner, but it is 3% by mass to 90% by mass based on the total amount of the composition contained in the capsule. Preferably, it is more preferably 10% by mass to 60% by mass. When the content is less than 3% by mass, in order to obtain the effect of the whole intestine produced by the lactic acid bacillus, it is necessary to take a large amount of capsules, and when it exceeds 90% by mass, there is a concern that the balance of the intestinal flora is affected.

- Filling of hard capsules with Lactobacillus bifidum and fitting of capsules -

The filling of the Bifidobacterium breve is performed by filling the body of the hard capsule with the Bifidobacterium breve, and for example, the method of injecting or dropping the Bifidobacterium breve as a liquid substance can be carried out by the following method: In the case where the Bifidobacterium breve is a dry powder, the filter is swayed while the filter is dropped.

Next, the main body of the capsule of the Bifidobacterium breve is filled by the above method, and the cap portion of the capsule is covered to fit the both, and the capsule containing the Bifidobacterium breve can be produced by joining the body portion and the cap portion.

The Bifidobacterium breve can be used for the filling of the hard capsule and the fitting of the capsule, and a well-known capsule filling machine, for example, a fully automatic capsule filling machine (manufactured by Qualicaps Co., Ltd., LIQFIL super 100 type), a capsule filling seal can be used. It is implemented by a machine (made by Qualicaps Co., Ltd., LIQFIL super FS type).

<band seal>

This tape seal is used as a sealant (sealing agent) for sealing the fitting portion of the main body portion and the cap portion of the capsule after filling the contents in the hard capsule.

When the chitin coating liquid is used to form a layer containing chitosan by the band sealing, the chitosan coating liquid does not intrude into the capsule by the fitting portion, and further, The fitting portion is smoothed to form a thin and uniform layer containing chitosan.

The material to be band-sealed is not particularly limited and may be appropriately selected from those well-known, and examples thereof include gelatin, cellulose derivatives, polyethylene glycol (PEG), and polyvinyl alcohol. (PVA) and so on.

In the case of the gelatin and the cellulose derivative, it is preferred to use the same material as the hard capsule.

In addition, as long as the band seal does not impair the effects of the present invention, in addition to the above components, a colorant (for example, titanium oxide, iron oxide, tar dye, etc.), an opaque agent, a fragrance may be blended as necessary. Additives commonly used in the manufacture of hard capsules. The blending ratio of the additive to the tape seal is usually from 0.1% by mass to 7% by mass, and can be appropriately selected in consideration of the band sealability in this range.

In general, the tape sealing material is used as an aqueous solution (belt sealing liquid), and is applied to a fitting portion of the body portion and the cap portion of the hard capsule, and dried to form the tape sealing. .

The tape sealing composition can be prepared by dissolving the above-mentioned tape sealing material in water, a hydrophilic solvent, or a mixture of water and a hydrophilic solvent at room temperature or under heating.

The hydrophilic solvent may, for example, be an organic solvent having compatibility with water. Specifically, a lower alcohol having a carbon number of 1 to 6 such as ethanol or isopropyl alcohol may, for example, be mentioned. Among the above, ethanol is preferred. Further, it is preferred that the hydrophilic solvent is a mixture with water.

When the mixture of the water and the hydrophilic solvent is used for the preparation of the band-sealing preparation liquid, the ratio of the hydrophilic solvent in 100% by mass of the mixed liquid is usually 5% by mass to 80% by mass, and 8 masses. From 5% to 65% by mass is more preferably from 10% by mass to 50% by mass.

In the case of the belt-sealing preparation liquid, the final viscosity of the preparation liquid is usually from 100 mPa ‧ to 5,000 mPa ‧ s, preferably from 125 mPa ‧ to 4,700 mPa ‧ , and from 150 mPa ‧ to 4,500 mPa ‧ good. When the viscosity is less than 100 mPa·s, it is difficult to apply the tape-sealing preparation liquid to the surface of the fitting portion of the hard capsule without dripping, and there is a possibility that a band seal excellent in sealing strength cannot be formed. Sex. Further, when the viscosity exceeds 5,000 mPa ‧ s, the viscosity is too high and there is a possibility that the belt cannot be formed by mechanical sealing. On the other hand, when the viscosity is within the preferred range, the fitting portion of the body portion of the hard capsule and the cap portion can form a strong band seal with a large sealing force (sealing force), and is not towed during manufacture. Silk, the handling in manufacturing is also easy. In addition, the viscosity means a viscosity measured under a condition of 20 ° C and a measurement time of 2 minutes using a rotary viscometer (for example, VT550 type manufactured by Hidehiro Seiki Co., Ltd.).

- Sealing via a band-sealed capsule -

This tape seal is used to produce a capsule containing Bifidobacterium breve by the method, and the tape is sealed on the surface of the body portion and the surface of the cap portion with a constant width centering on the edge portion of the cap portion. The preparation liquid is applied once to several times in the circumferential direction of the main body portion and the cap portion, preferably once to twice, to seal the fitting portion. In this case, it is preferred to control the temperature of the sealant to a certain temperature range as will be described later.

When the main body portion and the cap portion of the hard capsule are fitted, the fitting width of the outer circumference of the main body portion and the inner circumference of the cap portion is not particularly limited, and may be appropriately selected depending on the purpose, but the capsule is appropriately selected. The distance in the axial direction is preferably about 4.5 mm to 6.5 mm for the No. 3 capsule and about 4.0 mm to 6.0 mm for the No. 4 capsule. Further, in terms of the sealing width, it is preferable that the No. 3 capsule is about 1.5 mm to 4.0 mm, and the No. 4 capsule is about 1.5 mm to 2.8 mm.

In general, the band seal preparation liquid can be used at room temperature or under heating, and at this temperature, 14 ° C to 28 ° C is preferred, 15 ° C to 25 ° C is more preferred, and 16 ° C to 22 ° C is the most. good. When the temperature is within the preferred range, the content of the hard capsule can be imparted with a leak-proof effect. The temperature adjustment of the preparation liquid is not particularly limited, and can be carried out by a well-known method such as a panel heater or a warm water heater, for example, a circulating type warm water heater, the integral type capsule is filled and sealed. The sealing disc unit of the machine is used in the reformer of the circulating hot water heater, and it is preferable to finely adjust the temperature range. Further, the alcohol (for example, ethanol) in the band-sealing preparation liquid is volatilized depending on temperature conditions, and it is preferable to appropriately supplement the composition of the belt-sealing preparation liquid to a certain amount.

The sealing of the band-sealed hard capsule can be carried out using a well-known capsule filling and sealing machine, for example, the capsule filling and sealing machine (manufactured by Qualicaps Co., Ltd., LIQFIL super FS type), and the capsule sealing machine (Qualicaps shares limited) Company system, HICAPSEAL 100 type) to implement.

<layer containing chitosan (chitosan coating)>

The chitosan-containing layer contains at least chitosan, and further contains other components as necessary.

The chitosan-containing layer is formed by coating or spraying a chitosan coating solution containing at least chitosan on the surface of the hard capsule.

- Chitosan coating solution -

The chitosan coating solution contains at least chitosan, and other components are necessary as necessary.

-- Chitosan --

The deacetylation degree and molecular weight of the chitosan are not particularly limited and may be appropriately selected depending on the purpose.

The degree of deacetylation of the chitosan is preferably 70 mol% or more from the viewpoints of the solubility of the acid and the suitability for the coating method.

The thickness of the layer containing the chitosan may be appropriately selected depending on the shape, size, quality, and the like of the capsule, but the mass of the chitosan is equivalent to 0.5% by mass to 6.0% by mass based on the mass of the capsule. The thickness is preferably from 0.8% by mass to 5.0% by mass, more preferably from 0.8% by mass to 3.0% by mass. When the thickness is less than 0.5% by mass, the layer containing chitosan having a sufficient thickness is not formed, so that the layer containing the enteric substrate in the small intestine collapses, and the Bifidobacterium breve large intestine delivery capsule is Before the large intestine is delivered, the layer containing chitosan may collapse. When the thickness is more than 6.0% by mass, the coating time may be applied in order to form a layer containing chitosan on the surface of the capsule. Will grow. On the other hand, when the thickness is within the above-mentioned preferable range, the delivery of the Bifidobacterium breve large intestine delivery capsule to the large intestine is indeed possible, and it is attempted to obtain a shortening of the coating time which is advantageous for the layer containing the necessary chitosan. the opinion of.

The content of the chitosan in the chitosan-containing layer is not particularly limited and may be appropriately selected depending on the intended purpose, but it is preferably 30% by mass to 95% by mass. When the content of the chitosan is less than 30% by mass, the strength of the obtained chitosan film is not sufficient, and there is no practicality. When the content exceeds 95% by mass, the decrease in the residual amount of the organic acid is not sufficient. The water resistance of the polysaccharide film is lowered. On the other hand, when the content of the chitosan is within the preferred range, the viewpoint of thinning the thickness of the layer containing chitosan can be favored.

--acid--

Since the chitosan is insoluble in water and an organic solvent, it is dissolved in water by coexisting with an acid.

The acid may, for example, be an inorganic acid or an organic acid. However, since the interaction between the inorganic acid and the chitosan is extremely uncomfortable, an organic acid is preferred.

The organic acid is not particularly limited and may be appropriately selected depending on the intended purpose. From the viewpoint of sufficient volatility at normal pressure, formic acid, acetic acid, propionic acid, and trichloroacetic acid are preferred. Among the above, acetic acid is more preferable because it is inexpensive, easy to handle, and has little effect on the human body even if the layer containing chitosan remains little.

The amount of the organic acid to be used is not particularly limited and may be appropriately selected depending on the intended purpose, but it is preferably from 0.8 mole equivalent to 2.0 mole equivalent per equivalent of the amine group of the chitosan. When the amount of the organic acid used is less than 0.8 mol equivalent, the solubility of chitosan becomes low, and when it exceeds 2.0 mol equivalent, the acid is not efficiently removed, and a chitosan exhibiting water resistance is obtained. The film (layer containing chitosan) has difficulty in becoming difficult.

From the viewpoint of efficiently removing the organic acid, it is preferred that the chitosan coating liquid contains a glycerin fatty acid ester.

The glycerin fatty acid esters include esters of fatty acids with glycerol or polyglycerol and derivatives thereof. Specific examples of the glycerin fatty acid ester include glycerin fatty acid ester, glycerin acetate fatty acid ester, glycerin lactic acid fatty acid ester, glycerin citrate fatty acid ester, glyceryl succinate fatty acid ester, and glycerin acetate. , polyglycerin fatty acid ester, polyglycerol condensed castor bean oleate and the like.

The fatty acid to be used for the glycerin fatty acid ester is not particularly limited, and may be appropriately selected depending on the intended purpose. For example, caprylic acid, capric acid, lauric acid, and the like may be mentioned. Myristic acid, palmitic acid, stearic acid, behenic acid, oleic acid, linolic acid, erucic acid (myristic acid) Erucic acid), isopalmitic acid, isostearic acid, and the like. Among the above, it is preferred to use myristic acid, palmitic acid or stearic acid.

The number of polymerizations of the glycerin in the polyglycerin fatty acid ester is not particularly limited as long as it is in the range of from 20 to 20, and may be appropriately selected depending on the intended purpose. For example, monoglycerin or two may be mentioned. Glycerin, triglycerin, tetraglycerin, pentaglycerin, hexaglycerol, decaglycerin, and the like. It is difficult to dissolve the water by the fatty acid monomer, and the cost required for the production of 21 or more is high.

The degree of substitution of the fatty acid is not particularly limited as long as the glycerin fatty acid ester is soluble or dispersible in water, and may be appropriately selected depending on the intended purpose, but a range of monoester to triester is preferred.

The content of the glycerin fatty acid ester in the chitosan film is not particularly limited, and may be appropriately selected depending on the purpose, but the quality of the chitosan may be lowered from the viewpoint of reducing the residual amount of the organic acid. It is preferably 5 mass% to 200 mass%. When the content of the glycerin fatty acid ester is less than 5% by mass, the decrease in the residual amount of the organic acid is insufficient, and the water resistance of the chitosan film may be lowered. When the content exceeds 200% by mass, the resulting chitosan film may be obtained. The strength is not sufficient and not practical.

--Other ingredients --

The other components are not particularly limited as long as they do not impair the effects of the present invention, and may be appropriately selected depending on the intended purpose. For example, a filler or a plasticizer may, for example, be mentioned.

By using the filler or the plasticizer, it is possible to further prevent moisture from intruding into the capsule, and it is possible to further suppress the collapse of the large intestine before arrival and the dissolution of the Lactobacillus bifidum.

The filler is not particularly limited and may be appropriately selected depending on the intended purpose. For example, talc, bentonite or a metal salt of an organic acid having 10 or more carbon atoms may, for example, be mentioned.

The plasticizer is not particularly limited and may be appropriately selected depending on the intended purpose, and examples thereof include polyols such as glycerin, diglycerin, diethylene glycol, propylene glycol, triethylene glycol, and polyethylene glycol. . Among the above, glycerin, propylene glycol or polyethylene glycol is preferred for use in the pharmaceutical field.

- formation of a layer containing chitosan -

The chitosan-containing layer is formed by coating or spraying a chitosan coating solution containing at least chitosan on the surface of the capsule.

For example, a flow layer granulation coating device (Flow coater, manufactured by FREUND Industries Co., Ltd.), a centrifugal tumbling granulation coating device (CF GRANULATOR, GRANUREX, manufactured by FREUND Industries Co., Ltd.), and a composite granulation coating device are used. (Spiraflow, manufactured by FREUND Industries Co., Ltd.), various coating devices such as a sugar coating film coating device (Hicoater, Aqua coater; manufactured by FREUND Industries Co., Ltd.), which allow the capsule to flow in the device and use dry air. A coating method of spraying the chitosan coating liquid on the surface of the capsule by spraying or the like.

The viscosity and the chitosan concentration of the chitosan coating liquid are not particularly limited as long as they are suitable for the coating apparatus, and may be appropriately selected depending on the purpose.

The viscosity of the chitosan coating liquid is preferably from 10 mPa ‧ to 1,000 mPa ‧ at a solution temperature of 23 ° C.

The chitosan concentration of the chitosan coating liquid is preferably 0.1% by mass to 20% by mass.

The intake air temperature in the formation (coating) of the chitin-containing layer is not particularly limited and may be appropriately selected depending on the intended purpose, but 40 to 95 ° C is preferable. When the intake temperature is lower than 40 ° C, the organic acid cannot be sufficiently removed, so that the water resistance of the chitosan film cannot be imparted. When the temperature exceeds 100 ° C, the chitosan film is colored and deformed. The problem is not good. Further, in the case of water application, the intake air temperature exceeding 100 ° C is not an ordinary temperature, and the burden on the coating device is also large, which is not feasible.

The exhaust gas temperature in the formation (coating) of the chitin-containing layer is not particularly limited as long as it is 30° C. to 90° C., and can be appropriately selected depending on the purpose.

<layer containing enteric substrate>

The layer containing the enteric substrate contains at least an enteric substrate, and further contains other components as necessary.

The layer containing the enteric substrate is formed by coating or spraying an enteric substrate coating liquid containing at least an enteric substrate on the surface of the chitosan-containing layer.

- enteric substrate coating solution -

The enteric substrate coating liquid contains at least an enteric substrate and contains other components as necessary.

--Enteric substrate --

The enteric substrate is a component which is formed in the stomach and small intestine and is insoluble in the large intestine.

The enteric substrate is not particularly limited and may be appropriately selected depending on the intended purpose, and examples thereof include carboxymethylethylcellulose (CMEC), methacrylic acid copolymer, and hydroxypropylmethylcellulose. Hypromellose phthalate (HPMCP), shellac (shellac), water-based shellac, and the like. Among the above, CMEC, HPMCP, alcoholic shellac or water-based shellac is preferred from the viewpoint of preventing water from intruding into the inside of the capsule.

--Other ingredients --

The other components are not particularly limited as long as they do not impair the effects of the present invention, and may be appropriately selected depending on the intended purpose, but it is preferable to contain the glycerin fatty acid ester or the water-insoluble additive.

The double-crossed Lactobacillus large intestine delivery capsule of the present invention is obtained by dissolving water in a layer containing an enteric substrate in a large intestine, and immersing the water in a capsule through a layer containing chitosan, but the layer containing the enteric substrate is dissolved. There is also a certain degree of moisture immersed in a layer containing chitosan through a layer containing an enteric substrate. Therefore, by making the layer containing the enteric substrate more hydrophobic and containing a water-insoluble component, the amount of water passing through the layer containing the enteric substrate can be suppressed, so that the layer containing the chitosan can be suppressed. Immerse the water in the large intestine delivery capsule of the Lactobacillus bifidum.

The water-insoluble additive is not particularly limited, and may be appropriately selected depending on the intended purpose. For example, talc, bentonite, or a metal salt of an organic acid having 10 or more carbon atoms may, for example, be mentioned. In the above, in view of the ease of dispersion of the coating liquid, bentonite is preferred.

The thickness of the layer containing the enteric substrate is not particularly limited and may be appropriately selected depending on the purpose, but the mass of the enteric substrate is 0.8% by mass to 9.0% by mass based on the mass of the capsule. The thickness is preferably from 1.0% by mass to 6.0% by mass, more preferably from 1.1% by mass to 3.5% by mass. When the thickness is less than 0.8% by mass, the layer containing the enteric substrate having a sufficient thickness is not formed, and in the small intestine, the layer containing the enteric substrate is rapidly collapsed, and the Bifidobacterium breve is packaged. When the capsule is applied to the large intestine, the layer containing the chitosan may be broken. When the thickness exceeds 9.0 mass%, the coating may be applied to form a layer containing the enteric substrate on the surface of the capsule. Cloth time will increase.

- formation of a layer containing an enteric substrate -

The layer containing the enteric substrate is formed by applying or spraying an enteric substrate coating liquid containing at least an enteric substrate to the surface of the chitosan-containing layer.

For example, a fluidized layer granulation coating apparatus (Flow coater, manufactured by FREUND Industries Co., Ltd.), a centrifugal tumbling granulation coating apparatus (CF GRANULATOR, GRANUREX; manufactured by FREUND Industries Co., Ltd.), and composite granulation can be used. Various coating devices such as a coating device (Spiraflow, manufactured by FREUND Industries Co., Ltd.) and a sugar coating film coating device (Hicoater, Aqua coater; manufactured by FREUND Industries Co., Ltd.), which allow the capsule to flow in the device to give dry air. A method of spraying or coating the enteric substrate coating liquid on the surface of the layer containing chitosan at the same time using a spray or the like.

The viscosity of the enteric substrate coating liquid and the concentration of the enteric substrate are not particularly limited as long as they are suitable for use in a coating apparatus, and may be appropriately selected depending on the purpose.

The viscosity of the enteric substrate coating liquid is preferably from 10 mPa ‧ to 1,000 mPa ‧ at a solution temperature of 23 ° C.

The concentration of the enteric substrate of the enteric substrate coating liquid is preferably 0.1% by mass to 20% by mass.

The temperature of the intake air in the formation (coating) of the layer containing the enteric substrate is not particularly limited and may be appropriately selected depending on the intended purpose, but it is preferably 30 to 95 ° C. When the intake air temperature is lower than 30 ° C, the drying efficiency is low, and the liquid feeding speed must be suppressed, and the coating time may increase.

The temperature of the exhaust gas in the formation (coating) of the layer containing the enteric substrate is not particularly limited as long as it is 30° C. to 90° C., and may be appropriately selected depending on the purpose.

<other layer>

The Bifidobacterium breve large intestine delivery capsule of the present invention may further have honey in addition to the above hard capsule, Bifidobacterium breve, band seal, layer containing chitosan, and layer containing enteric substrate. A coating layer of a substrate such as wax or carnauba wax.

The coating layer is formed, for example, by coating or spraying a coating liquid containing at least beeswax on the surface of the layer containing the enteric substrate.

The preparation of the coating liquid can be carried out, for example, by dissolving beeswax in an organic solvent such as ethanol.

Further, for the application or spraying of the coating liquid, for example, the same apparatus as that of the layer containing the chitosan or the layer containing the enteric substrate can be used.

[Examples]

The invention is specifically illustrated by the following examples and comparative examples, but the invention is not limited by the examples.

(Example 1) <Filling of hard capsules with Lactobacillus bisporus>

100 g of live bacteria powder of Lactobacillus bifidum (manufactured by Morinaga Dairy Co., Ltd., Morinda Bismuth) and 1400 g of dry potato starch were mixed and diluted, and thoroughly stirred at a temperature of 25 ° C and a humidity of 60% to prepare a capsule filling. Powder used. The powder had a concentration of Lactobacillus bifidum of 1 × 10 ¹⁰ cfu/g.

Hydroxypropylmethylcellulose (HPMC) capsule (Qualiaps Co., Ltd., QUALI-V(R)-N, No. 3, capsule mass: 51 mg) was used as a hard capsule for filling the obtained powder in a capsule filling machine (Qualicaps) Co., Ltd., LIQFIL super 100 type), the powder of the Bifidobacterium breve and the hard capsule were placed, and the hard capsule was filled with 220 mg of Bifidobacterium breve powder.

<Block via band seal>

As a preparation liquid used for the band seal, 16 g of hydroxypropylmethylcellulose (HPMC) was dissolved in a mixed liquid of 34 mL of water and 50 mL of absolute ethanol to prepare a band seal preparation liquid. Using the preparation liquid, a band sealer (HICAPSEAL 100 type manufactured by Qualicaps Co., Ltd.) was used to apply a band seal to the fitting portion of the obtained Bifidobacterium breve filled capsule. Further, the conditions for the belt sealing are as follows.

- Belt sealing conditions -

Coating width: 3mm

Coating times: 2 times

Temperature of the preparation liquid: 20 ° C to 22 ° C

<Formation of a layer containing chitosan>

The chitosan (manufactured by Shikarin Chikkarin Co., Ltd.) having a degree of deacetylation of 80 mol% or more is added with 0.9 mol equivalent of acetic acid based on the amine group of chitosan, and further dissolved in water to make a few The chitosan concentration was 2% by mass, and the mixture was sufficiently stirred to prepare a chitosan coating liquid. The prepared chitosan coating liquid was applied to a capsule containing Bifidobacterium breve which was sealed by a band seal using a film coating apparatus Hicoater HC-LABO 20 type disk (manufactured by FREUND Industries Co., Ltd.). A capsule having a thickness equivalent to 1.5% by mass based on the mass of the capsule.

<Formation of a layer containing an enteric substrate>

Next, 10 parts by mass of a psime shell gum (PEARL-N10 manufactured by Gifu Shellac Manufacturing Co.) and 0.5 part by mass of a glycerin fatty acid ester (manufactured by Eastman Chemical Campany, Myvacet 9-45) were dissolved in an aqueous solution of 8 mass% ethanol solution 54 mL. To prepare an enteric substrate coating solution. The enteric substrate coating liquid was applied to the capsule to make the mass of the shellac 1.5% by mass based on the mass of the capsule. Further, as the coating, a film coating apparatus Hicoater HC-LABO 20 type disc (manufactured by FREUND Industries Co., Ltd.) was used.

In addition, 2 g of a solution of the absolute ethanol dissolved in the saturated dissolved amount of the wax (manufactured by Miki Chemical Industry Co., Ltd.) was applied to the capsule to obtain a Bifidobacterium breve large intestine delivery capsule. Further, as the coating, a film coating apparatus Hicoater HC-LABO 20 type disc (manufactured by FREUND Industries Co., Ltd.) was used.

According to this, the obtained Bifidobacterium breve large intestine delivery capsule is sequentially coated on the surface thereof with a layer containing chitosan and a layer containing an enteric substrate.

<Evaluation: collapse test>

The obtained capsule was subjected to a collapse test using a Japanese Pharmacopoeia collapse test device and an oscillator. For the summary of the test procedure, the capsule was immersed in the first liquid of the collapse test for one hour without the auxiliary tray, and secondly, immersed in the second liquid of the collapse test under the condition of no auxiliary tray. After the hour, it was transferred to a 100 mL Erlenmeyer flask in which 50 mL of the large intestine imaginary solution was placed, and the mixture was shaken back and forth for 2 hours at 100 times in reverse/min. This large intestine imaginary liquid system uses an acetic acid buffer (Michaelis's buffer) of pH 3.5. The test was then carried out as a group of six of the aforementioned capsules.

The capsules after treatment with each liquid were visually observed for swelling and deformation, and whether or not the contents were released. The results are shown in Table 1. Further, the capsules treated with the first liquid and the second liquid were determined in four stages in accordance with the following evaluation criteria.

- Evaluation criteria -

◎: All six are kept in shape and are not considered to be swollen or deformed.

○: More than one of the six is considered to have some swelling or deformation.

△: More than one of the six is considered to have significant swelling or deformation, but the contents are retained.

X: One or more of the six contents are dissolved.

(Example 2)

In the same manner as in Example 1, except that the mass of the decolorized shellac was changed from 1.5% by mass to 1.7% by mass in the same manner as in Example 1, the Bifidobacterium breve large intestine delivery capsule was obtained and evaluated. The evaluation results are shown in Table 1.

(Example 3)

In the same manner as in Example 1, except that the hard capsule was changed from a HPMC capsule to a gelatin capsule (manufactured by Qualicaps Co., Ltd., gelatin capsule for food, No. 3, capsule mass: 48 mg), bifurcation was obtained in the same manner as in Example 1. Capsules were delivered to the large intestine and evaluated. The evaluation results are shown in Table 1.

(Comparative Example 1)

In the first embodiment, the hard capsule was changed from a HPMC capsule to a chitosan capsule (manufactured by AICELLO Chemical Co., Ltd.), and the mass of the decolorized shellac was changed from 1.5% by mass to 1.9% by mass based on the mass of the capsule. In the same manner as in Example 1, a Bifidobacterium lactis large intestine delivery capsule was obtained and evaluated. The evaluation results are shown in Table 1.

(Comparative Example 2)

In the same manner as in Example 2 except that the seal by the band seal was not carried out in Example 2, the Bifidobacterium breve large intestine delivery capsule was obtained and evaluated. The evaluation results are shown in Table 1.

[Industry use possibility]

The double-crossed Lactobacillus large intestine delivery capsule of the present invention and the method for producing the same have the advantages that the hard capsule contains the bifidobacteria, so that it does not dissolve in the stomach and the small intestine, dissolves rapidly in the large intestine, and inhibits moisture in the stomach and small intestine. Intrusion in hard capsules, inhibition of inactivation of Bifidobacterium breve, and sufficient strength, no need to increase the strength of the coating, and because of the suppression of the amount of coating, can be manufactured at an advantageous manufacturing cost, so It is preferably used for pharmaceuticals, health foods, health supplement foods, and the like, and the like, which use an enteral preparation such as Bifidobacterium breve.

Claims (5)

A double-crossed Lactobacillus large intestine delivery capsule characterized in that the capsule is a hard capsule containing gelatin or a cellulose derivative as a base material, and contains Lactobacillus bifidum; the fitting portion of the capsule has a band seal The surface of the capsule sequentially has a layer containing chitosan and a layer containing an enteric substrate; wherein the mass of chitosan relative to the capsule is 0.5 to 6.0% by mass; the enteric substrate is relative to the capsule The mass is 0.8% by mass to 9.0% by mass. The Bifidobacterium breve large intestine delivery capsule according to claim 1, wherein the cellulose derivative is hydroxypropylmethylcellulose. The Bifidobacterium breve large intestine delivery capsule according to claim 1, wherein the chitin-containing layer is formed by applying a coating solution containing chitosan to the surface of the capsule. The Bifidobacterium breve large intestine delivery capsule according to claim 3, wherein the coating solution containing chitosan is formed by dissolving chitosan in a volatile organic acid aqueous solution. A method for producing a bifidobacterium lactobacillus large intestine delivery capsule, characterized in that the capsule is a hard capsule containing gelatin or a cellulose derivative as a base material, and filled with a bifidobacterium; and a body portion of the capsule is fitted a cap portion; the fitting portion is sealed by tape sealing; a coating liquid containing chitosan is coated or sprayed on the surface of the capsule to form a layer containing chitosan, Applying or spraying a coating liquid containing an enteric substrate on the chitosan-containing layer to form a layer containing an enteric substrate; wherein the mass of chitosan relative to the capsule is 0.5 to 6.0% by mass The mass of the enteric substrate relative to the capsule is from 0.8% by mass to 9.0% by mass.