JP2001342127A - Intestinally absorbable antiinflmmatory factor- containing immunological substance and application thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an enteric antiinflammatory factor-containing immunological substance absorbable in the intestines and capable of sufficiently exhibiting effects thereof without deteriorating the effects of the antiinflammatory factor-containing immunological substance in the stomach and a healthy food as utilization thereof. SOLUTION: This intestinally absorbable antiinflammatory factor-containing immunological substance is coated with a substance slightly soluble in the gastric juice or a substance gradually dissolving in the gastric juice or contained in the substance as a matrix. The antiinflammatory factor-containing immunological substance may directly be coated with the substance slightly soluble in the gastric juice or the substance gradually dissolved in the gastric juice or contained in the substance as the matrix or a capsule or a microcapule comprising the antiinflammatory factor-containing immunological substance sealed therein may be coated with the substance slightly soluble in the gastric juice or the substance gradually dissolved in the gastric juice. The antiinflammatory factor-containing immunological substance can be added and utilized in an ice cream, a candy, a baked confectionery, a bread, a cake, a custard pudding, a mousse, a jelly, a frozen sweet, a tastily seasoned dried food for sprinkling over rice, a gummy candy, a chocolate, a caramel, a jam, a chewing gum or a curry.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to an intestinal-absorbable anti-inflammatory factor-containing immunological substance and its application. In particular, it is intended to increase the absorption in the intestine of an immunological substance containing an anti-inflammatory factor, which is weak against heat, acid or organic solvent, without impairing its effect in the stomach as much as possible.

[0002]

2. Description of the Related Art Inflammation is a "local reaction such as destroying, diluting or isolating both the cause of the injury and the injured tissue when the tissue is injured or destroyed." It is accompanied by signs such as "redness, swelling, and loss of function" (Roland Medical Dictionary). When inflammation occurs,
Generally, an anti-inflammatory drug is administered. As anti-inflammatory drugs,
Antihistamines, steroidal and nonsteroidal anti-inflammatory drugs, anti-inflammatory enzyme agents, immunosuppressants and the like are known.

[0003] However, each of these anti-inflammatory drugs has a problem of causing side effects and adverse reactions. For example, salicylates, one of the most common anti-inflammatory drugs, aspirin is well known, but at high doses can cause central respiratory paralysis and circulatory collapse, epigastric pain, nausea, vomiting and digestion. It is said to cause duct bleeding.

[0004] From such a viewpoint, the appearance of an anti-inflammatory agent which does not cause side effects or adverse reactions is desired. An anti-inflammatory drug composition derived from milk has been proposed as an anti-inflammatory agent having no such side effects or adverse reactions (JP-A-57-188523, JP-A-59-161316). The use as an anti-inflammatory drug has been proposed (Japanese Patent Publication No. 2-503802, Publication No. 8-502515, Publication No. 8).
-502718, Publication No. 10-509420).

An object of the present invention is to provide a technique for utilizing an anti-inflammatory factor-containing immunological substance containing an anti-inflammatory factor derived from milk as a so-called health food. Here, the anti-inflammatory factor-containing immunological substance refers to attenuated or killed microorganisms, an attenuated virus or an inactivated virus, and a female milk of a mammal which has been hyperimmunized with an adjuvant mixed vaccine using a toxoid. Is an immunological substance obtained by mixing a milk protein fraction and a low molecular weight fraction having a molecular weight of 10,000 or less, separated from whey obtained after delipidation and decasein as a raw material. The milk protein fraction and each fraction of the low molecular weight fraction having a molecular weight of 10,000 or less can be obtained from whey by, for example, separation by chromatography, separation by gel filtration, or separation by ultrafiltration. Further, the methods described in JP-T2-503802, JP-T-8-502515, JP-T-8-502718, JP-T-10-509420 and the like can also be used.

[0006] The anti-inflammatory factor-containing immunological substance has an effect of improving the intestinal environment as well as an effect of enhancing immunity and an anti-inflammatory effect on humans and animals. A solution, powder,
It can be injected orally or anus into the body in the form of granules or added to food or drink. Specific effects include:
Improve intestinal environment, improve constipation, prevent and treat colorectal cancer, prevent and treat opportunistic infections, prevent and treat neoplastic disease, alleviate immunodeficiency, prevent and treat periodontal disease, prevent and treat gingivitis Prevention and treatment of ulcerative diseases, alleviation of rheumatic symptoms, prevention and treatment of asthma, and the like.

[0007] As described above, an anti-inflammatory factor-containing immunological substance is a useful substance that is effective without causing side effects on anti-inflammatory and immunity. This anti-inflammatory effect can be confirmed, for example, by an air porch method. The principle of the air porch method is to orally administer an anti-inflammatory substance, create an air porch (air cavity) under the mouse, inject carrageenan (a source of inflammation), and measure the number of leukocytes migrating. is there. At this time, when inflammation occurs, leukocytes migrate to the affected area and are infiltrated, so that the greater the number of leukocytes, the stronger the degree of inflammation. Conversely, the stronger the anti-inflammatory action, the smaller the number of leukocytes that migrate and infiltrate.

[0008]

Since the anti-inflammatory factor-containing immunological substance is weak to acid, its effect is impaired in the stomach, and its effect is small at the stage of absorption in the intestine.
The present invention aims to increase the absorption in the intestine of an anti-inflammatory factor-containing immunological substance without significantly impairing its effect in the stomach, and to open the way for the effect of the anti-inflammatory factor-containing immunological substance to be exerted. . At the same time, the intestinal absorbable anti-inflammatory factor-containing immunological substance is to be applied.

[0009]

SUMMARY OF THE INVENTION The present invention relates to an intestinal absorptive anti-inflammatory factor-containing immunity substance coated or matrixed with an anti-inflammatory factor-containing immunity substance with a substance which is hardly soluble in gastric juice or a substance which gradually dissolves in gastric juice. Substance.

[0010] The invention of claim 2 is the intestinal-absorbable anti-inflammatory factor-containing immunological substance according to claim 1, which is in the form of powder, granules, tablets or chewables.

A third aspect of the present invention is characterized in that a powdery or granular anti-inflammatory factor-containing immunological substance coated or matrixed with a substance that is hardly soluble in gastric juice or a substance that gradually dissolves in gastric juice is encapsulated in a capsule. Intestinal absorptive anti-inflammatory factor-containing immunological substance.

The invention of claim 4 is characterized in that the thickness of the coated poorly soluble gastric fluid substance or the substance gradually dissolved in gastric juice or the proportion of the matrix component of the poorly soluble gastric fluid or the substance component gradually dissolved in gastric juice is different. The intestinal absorbable anti-inflammatory factor-containing immunological substance according to any one of claims 1 to 3.

[0013] The invention of claim 5 is directed to a gut-absorbable composition in which a powdery or granular anti-inflammatory factor-containing immunological substance is sealed in a capsule whose surface is coated with a substance that is hardly soluble in gastric juice or a substance that gradually dissolves in gastric juice. It is an anti-inflammatory factor-containing immunological substance.

[0014] The invention of claim 6 relates to intestinal absorption in which a powdered or granular anti-inflammatory factor-containing immunological substance is sealed in a microcapsule coated on its surface with a substance that is poorly soluble in gastric juice or a substance that gradually dissolves in gastric juice. It is an immunogenic substance containing a sex anti-inflammatory factor.

[0015] The invention of claim 7 is characterized in that the substance which is hardly soluble in gastric juice or the substance which gradually dissolves in gastric juice is used for coating, such as hydroxypropylcellulose, methacrylic acid copolymer, hydroxypropylmethylcellulose phthalate, ethyl acrylate and methyl methacrylate. 7. At least one selected from the group consisting of copolymers, aminoalkyl methacrylate copolymers, shellac, hydroxyapatite, twain, dextrin, gelatin, gum arabic and sucrose. The intestinal absorptive anti-inflammatory factor-containing immunological substance described above.

The invention according to claim 8 is characterized in that a substance which is hardly soluble in gastric juice or a substance which gradually dissolves in gastric juice and which is used for the matrix is hydroxypropylcellulose, hydroxypropylmethylcellulose, ethylcellulose, methylcellulose, carboxymethylcellulose, salts of carboxymethylcellulose, Fatty oils such as ethyl acrylate methyl methacrylate copolymer, triglyceride and the like, fatty acid esters of polyglycerin and the like, selected from the group consisting of indigestible polysaccharides such as polyvinylpyrrolidone, gelatin, gum arabic, polyethylene glycol, cyclodextrin and dextrin. The intestinal-absorbable anti-inflammatory factor-containing immunological substance according to any one of claims 1 to 6, which is at least one.

According to the ninth aspect of the present invention, there are provided the first to eighth aspects.
Ice cream, candy, baked confectionery, bread, cake, pudding, mousse, jelly, frozen dessert, sprinkle, gummy, chocolate, caramel, prepared by adding an intestinal absorbable anti-inflammatory factor-containing immunological substance according to any one of Jam, gum or curry.

According to the present invention, an anti-inflammatory factor-containing immunological substance is coated or matrixed with a sparingly soluble substance in gastric juice or a substance which gradually dissolves in gastric juice to reduce the amount of the anti-inflammatory factor-containing immunological substance dissolved in the stomach. Then, as much as possible of the anti-inflammatory factor-containing immunological substance is introduced into the intestine to increase the absorption in the intestine. At this time, the form of the anti-inflammatory factor-containing immunological substance may be any of powder, granules, tablets, chewables and the like. Further, a powdery or granular anti-inflammatory factor-containing immunological substance may be sealed in a capsule coated with an enteric substance on the surface, or an anti-inflammatory factor-containing immunological substance may be sealed in a microcapsule coated with an enteric substance. May be sealed. Further, those having different coating layer thicknesses or those having different component ratios in the matrix may be mixed and used.

Examples of the substance which is poorly soluble in gastric juice or a substance which gradually dissolves in gastric juice and used for coating include hydroxypropylcellulose, methacrylic acid copolymer, hydroxypropylmethylcellulose phthalate, ethyl acrylate methyl methacrylate methyl copolymer, aminoalkyl methacrylate. Copolymers, shellac, hydroxyapatite, twain, dextrin, gelatin, gum arabic and sucrose can be mentioned.

[0020] Examples of the poorly soluble substance in gastric juice or the substance which gradually dissolves in gastric juice and used in the matrix include hydroxypropylcellulose, hydroxypropylmethylcellulose, ethylcellulose, methylcellulose, and the like.
Fatty acids such as carboxymethylcellulose, salts of carboxymethylcellulose, ethyl acrylate methyl methacrylate copolymer, triglyceride, fatty acid esters of polyglycerin, etc .; Sugars and the like can be mentioned.

The thus obtained anti-inflammatory factor-containing immunological substance having enhanced intestinal absorption is added and prepared, and ice cream, candy, baked confectionery, bread, cake, pudding, mousse, jelly, frozen dessert, sprinkle, Gummies, chocolate, caramel, jam, gum or curry can be made.

As described above, the anti-inflammatory factor-containing immunological substance is obtained by mixing a milk protein fraction and a low molecular weight fraction having a molecular weight of 10,000 or less, separated from whey obtained after defatting and decasein. It is a substance that does not contain milk fat, lactose, casein, etc., which are usually contained in milk. The effect of heating when not containing milk fat, lactose, casein, etc., is greater than when containing milk fat, lactose, casein, etc. Therefore, when lactose, casein and the like are not contained, it is needless to say that individual sterilization and sterilization methods are required when they are contained.

The present invention is not intended to prescribe an anti-inflammatory factor-containing immunological substance as a drug, but is intended for use as a so-called health food adapted to food and drink. As described above, anti-inflammatory factor-containing immunological substances are impaired by acid, heat and organic solvents. Because of the presence of stomach acid in the stomach, eating an anti-inflammatory factor-containing immune substance as it is changes a considerable portion of the stomach and impairs its effect. In order to maintain its effect in the stomach, the stomach should be as unaltered as possible and only dissolved and absorbed until it reaches the intestine.

A poorly soluble substance in gastric juice or a substance that gradually dissolves in gastric juice and coated or matrixed with an anti-inflammatory factor-containing immunological substance can be added to food or drink to produce a health food. This food and drink is useful as a health food having an anti-inflammatory effect and an immune enhancing effect. Add and prepare an anti-inflammatory factor-containing immunological substance with enhanced intestinal absorption, and prepare ice cream, candy, baked goods, bread, cake, pudding,
Mousse, jelly, frozen dessert, sprinkle, gummy, chocolate, caramel, jam, gum or curry can be made.

[0025]

Embodiments of the present invention will be described below. The essence of the present invention suppresses the dissolution of the anti-inflammatory factor-containing immunological substance in the stomach by coating or matrix the anti-inflammatory factor-containing immunological substance with a gastric juice poorly soluble substance or a substance that gradually dissolves in gastric juice, It is intended to increase absorption in the intestine.

In order to coat a poorly soluble substance in gastric juice or a substance which gradually dissolves in gastric juice onto an immunological substance containing an anti-inflammatory factor, a powdery, granular or tablet immunological substance containing an anti-inflammatory factor can be coated with a poorly soluble substance in gastric juice or A method of directly spraying a solution in which a substance gradually dissolved in gastric juice is sprayed, or a solution in which an enteric substance is dissolved is sprayed on the surface of a capsule or microcapsule in which a powdered or granular anti-inflammatory factor-containing immunological substance is sealed. Is adopted. Among them, a method of coating a capsule can be suitably used. The method of coating and the thickness of the coating layer are appropriately selected according to the form of use. For example, when coating shellac, if it is about 13 g / m ² , it will dissolve in gastric juice in about 2 hours, so this thickness should be used as a guide. on the other hand,
Those having different thicknesses of the coating layers may be mixed and used, or the coating may be partial as well as the whole of the anti-inflammatory factor-containing immunological substance.

For the capsules with poor gastric solubility, a method is employed in which the surface of a gelatin capsule film is coated with a substance that is hardly soluble in gastric juice or a substance that gradually dissolves in gastric juice. As the substance to be coated on the capsule film surface, the aforementioned hydroxypropyl cellulose, methacrylic acid copolymer, hydroxypropyl methyl cellulose phthalate,
Examples thereof include ethyl acrylate methyl methacrylate copolymer, aminoalkyl methacrylate copolymer, shellac, hydroxyapatite, twain, dextrin, gelatin, gum arabic, and sucrose.

In order to form the poorly soluble substance in gastric juice or the substance which gradually dissolves in gastric juice into the matrix with the anti-inflammatory factor-containing immunological substance, the powdery anti-inflammatory factor-containing immunological substance and the sparingly soluble substance in gastric juice or gastric juice are gradually added. The substance to be dissolved is mixed well, and the two are fused with a binder such as glucose or viscous cellulose. This is sieved to obtain a powdery matrix.
The powdery matrix is granulated and sieved to obtain granules and further tableted to obtain tablets. The powder or granule matrix thus obtained may be encapsulated in a capsule.

As a substance which is hardly soluble in gastric juice or a substance which gradually dissolves in gastric juice and is used in the matrix, as described above, hydroxypropylcellulose, hydroxypropylmethylcellulose, ethylcellulose, methylcellulose, carboxymethylcellulose, salts of carboxymethylcellulose, acrylic acid Fatty oils such as methyl methacrylate copolymer and triglyceride, fatty acid esters of polyglycerin, etc., indigestible polysaccharides such as polyvinylpyrrolidone, gelatin, gum arabic, polyethylene glycol, cyclodextrin and dextrin can be mentioned.

As a specific embodiment, a case will be described in which twain, a kind of enteric substance, is coated on a capsule containing a granular anti-inflammatory factor-containing immunological substance. Tween (5 parts by weight) was added to a mixed solution consisting of 80 parts by weight of ethyl alcohol and 15 parts by weight of purified water, and mixed and dissolved at a temperature of 60 ° C. or lower. The solution was filtered to remove insolubles. On the other hand, a seam capsule made of gelatin in which a granular anti-inflammatory factor-containing immunological substance was put in a seam capsule made of gelatin was prepared. This seam capsule 10
The Tween solution was sprayed onto the capsules at a temperature of about 40 ° C. at a rate of 50 g / min, and the Tweens were coated on the capsules containing the granular anti-inflammatory factor-containing immunological substance.

Next, an example in which a cellulose derivative is used as a substance that is hardly soluble in gastric juice or a substance that gradually dissolves in gastric juice will be described. Hydroxypropyl methylcellulose phthalate is added to acetone-ethyl cellosolve mixed solution at 1: 1.
And a solution in which 10-22% by weight of medium-chain fatty acid triglyceride was added as a plasticizer to hydroxypropylmethylcellulose phthalate was prepared. Using a coating pan or the like, this solution is sprayed onto the anti-inflammatory factor-containing immunological substance or a capsule in which the anti-inflammatory factor-containing immunological substance is sealed by a method such as spraying, and the intestinal absorptive anti-inflammatory factor-containing immunological substance is sprayed. Obtained.

[0032]

EXAMPLE An experiment was conducted to confirm the effect of an anti-inflammatory factor-containing immunological substance coated with a substance that is poorly soluble in gastric juice or a substance that gradually dissolves in gastric juice. Three groups of 10 healthy subjects were treated with capsules containing normal whey protein (abbreviated as WP), whey protein made from milk obtained from immunized cows, A capsule (abbreviated as WPI +) enclosing an inflammatory factor-containing immunological substance,
Each capsule was treated with twain to make the capsule enteric-soluble (abbreviated as enteric), and each group was ingested. The total number of bacteria and the number of bifidobacteria in the excreted stool of each person were determined. Measured. The number of bacteria in each group was averaged to calculate the ratio of bifidobacteria to the total number of bacteria. The results are shown in Table 1.

[0033]

[Table 1]

It can be seen that the administration of WPI + capsule increased the occupancy of bifidobacteria in the stool. This increase was confirmed two weeks after the start of administration. However, with the administration of the WP capsule, the proportion of bifidobacteria began to increase at the third week. Enteric capsules were seen earlier in the rise trend than WPI + capsules. Table 1 shows the change of the ratio of bifidobacteria after administration with respect to the ratio of bifidobacteria before administration. The change of the post-administration ratio when the ratio of the bifidobacteria at the start is 1 is indicated by a coefficient. It can be seen that administration of the enteric capsule increased the proportion of bifidobacteria most.

As described above, the ratio of bifidobacteria in stool is determined by WP
It is increased by administration of I +. In addition, it was recognized that the effect was further enhanced by using an enteric capsule.

Hydroxypropyl methylcellulose as the sieved WPI + and the sieved poorly soluble substance in gastric juice or the substance which gradually dissolves in gastric juice, viscous cellulose as the binder,
Talc, a flavor, a sweetener and the like were mixed as a lubricant. The mixture was kneaded, granulated, sized, dried, and tableted to obtain tablet-like WPI +. The surface of the tablet can be coated if necessary.

In the production of granules (fine granules) and microcapsules, known methods can be used. In addition to the method of applying a necessary coat after the production of the microcapsules, a hardly soluble gastric fluid substance or a substance that gradually dissolves in gastric juice can be mixed into the capsule shell. Here, a method of coating after wet granulation will be described. The sieved WPI + and the sieved excipients, binders, sweeteners, flavors, and the like are mixed, kneaded, granulated, sized, dried, and coated. The coating can be applied not only in one layer but also in multiple layers. For example, the first layer is a hydroxypropylmethylcellulose solution, the second layer is an ethylcellulose solution, the third layer is a mixture of hydroxypropylmethylcellulose and triethyl citrate, and the fourth layer is a mixture of hydroxypropylmethylcellulose and titanium oxide. Can be coated.

[0038]

The surface of a capsule or microcapsule enclosing the anti-inflammatory factor-containing immunological substance by coating or matrixing the anti-inflammatory factor-containing immunological substance with a poorly soluble substance in gastric juice or a substance that gradually dissolves in gastric juice. Is coated with a substance that is hardly soluble in gastric juice or a substance that gradually dissolves in gastric juice. This effect is much more remarkable than when conventionally taken in the form of a powder, granule, tablet or capsule of an anti-inflammatory factor-containing immunological substance.

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Claims (9)

[Claims] 1. An intestinal absorbable anti-inflammatory factor-containing immunological substance which is matrix or coated with an anti-inflammatory factor-containing immunological substance or a substance which is sparingly soluble in gastric juice or a substance which gradually dissolves in gastric juice. 2. The intestinal-absorbable anti-inflammatory factor-containing immunological substance according to claim 1, which is in the form of powder, granules, tablets or chewables. 3. An intestinal absorptive anti-inflammatory agent characterized by encapsulating a powdery or granular anti-inflammatory factor-containing immunological substance coated or matrixed with a substance which is hardly soluble in gastric juice or a substance which gradually dissolves in gastric juice. Immune substance containing inflammatory factor. 4. The method according to claim 1, wherein the thickness of the coated poorly soluble gastric substance or the substance gradually soluble in gastric juice or the proportion of the matrix component of the poorly soluble gastric fluid or the substance gradually soluble in gastric fluid is different. An intestinal absorbable anti-inflammatory factor-containing immunological substance according to any one of claims 1 to 3. 5. An intestinal absorptive anti-inflammatory factor-containing immunity in which a powdery or granular anti-inflammatory factor-containing immunological substance is sealed in a capsule coated on its surface with a substance that is hardly soluble in gastric juice or a substance that gradually dissolves in gastric juice. Substance. 6. An intestinal absorbable anti-inflammatory factor containing a powdered or granular anti-inflammatory factor-containing immunological substance sealed in a microcapsule coated on its surface with a substance that is hardly soluble in gastric juice or a substance that gradually dissolves in gastric juice. Immune substance. 7. A substance which is hardly soluble in gastric juice or a substance which gradually dissolves in gastric juice and which is used for coating is hydroxypropylcellulose, methacrylic acid copolymer, hydroxypropylmethylcellulose phthalate, ethyl acrylate methyl methacrylate methyl copolymer, aminoalkyl methacrylate. The intestinal absorbability according to any one of claims 1 to 6, wherein the at least one is selected from the group consisting of acrylate copolymer, shellac, hydroxyapatite, twain, dextrin, gelatin, gum arabic and sucrose. Immune substance containing anti-inflammatory factor. 8. A substance which is hardly soluble in gastric juice or which is slowly dissolved in gastric juice and which is used as a matrix, is hydroxypropylcellulose, hydroxypropylmethylcellulose, ethylcellulose, methylcellulose, carboxymethylcellulose, salts of carboxymethylcellulose, ethyl methacrylate. Methyl copolymer,
Fatty oils such as triglycerides, fatty acid esters of polyglycerin, etc., characterized by at least one selected from the group consisting of indigestible polysaccharides such as polyvinylpyrrolidone, gelatin, gum arabic, polyethylene glycol, cyclodextrin and dextrin. The intestinal absorbable anti-inflammatory factor-containing immunological substance according to any one of claims 1 to 6. 9. An ice cream, a candy, a baked confectionery, a bread, a cake, a pudding, a mousse to which the intestinal absorptive anti-inflammatory factor-containing immunological substance according to any one of claims 1 to 8 is added and prepared. Jelly, frozen dessert, sprinkle, gummy, chocolate, caramel, jam, gum or curry.