JP6801203B2 - pH Response Elution Coated Granules and Foods - Google Patents

Description

The present invention relates to a coated granule having a pH-responsive elution property that can be suitably used for foods and is insoluble in an acidic stomach and elutes in a neutral intestine.

Since physiologically active substances such as enzymes, lactic acid bacteria, and royal jelly are sensitive to acids, it is desirable that they be protected from gastric acid and reach the small intestine. It is desirable that even physiologically active substances such as capsicum, garlic, and iron, which impose a burden on the stomach when ingested in large amounts, reach the intestines in a protected state. In addition, since it is possible to omit the film coating of tablets after tableting and to design dosage forms other than tablets and capsules, which reduces the burden on consumers, it is particularly desirable to impart enteric properties to powders and granules with a small particle size. Is done. As a protective agent for protecting a physiologically active substance in the stomach and reaching the intestine, a component that does not dissolve under acidic conditions but dissolves under neutral conditions is used. For example, methacrylic acid copolymers, zeins, shellac and the like are commonly used.

However, methacrylic acid copolymers are limited to pharmaceutical applications and cannot be used in foods. In addition, although zein and shellac can be used for food, it is common to use an organic solvent because it is insoluble in water. In terms of residual organic solvent, consideration for the environment, and safety measures for the workplace. Therefore, the use of an organic solvent is not preferable. Alginate, pectin, gellan gum, and the like can be considered as substances that are water-soluble but insoluble under acidic conditions and can serve as protective materials. Conventionally, proposals for imparting enteric solubility using the above-mentioned substances have been made.

For example, a method of coating lactic acid bacteria powder with sodium alginate and further coating a sustained-release film (Patent Document 1), a method of coating with hydrogenated oil in which lactoferrin is melted (Patent Document 2), and the like have been proposed. .. However, in the method of Patent Document 1, the amount of sodium alginate used as the primary coat is 1% by weight or less, and the enteric effect is not due to sodium alginate but due to a sustained-release coating such as zein or shellac. In addition, the disintegration time in artificial intestinal juice is slow, and the acid resistance effect is insufficient. In the method of Patent Document 2, it is necessary to raise the product temperature to 70 ° C. in order to dissolve the hydrogenated oil, and heat-sensitive substances such as lactic acid bacteria and enzymes lose their activity during the manufacturing process, and a versatile method is used. Absent.

As described above, there is a demand for coated particles that protect the stomach and reach the intestines without damaging the bioactive substances to be coated while using materials that can be used for food.

International Publication No. 2005/025609 Special Table 2002-505251

An object of the present invention is to provide a coated granulated product in which a physiologically active substance having an average particle size of 10 to 3000 μm is provided with pH-responsive elution property by using alginate and using only a food material.

As a result of intensive research to solve the above problems, the present inventors have unexpectedly found that the above problems can be solved by using alginate having a specific viscosity in combination. The invention was completed.
That is, the present invention is the following [1] to [3].
[1] A pH-responsive elution coated granulated product having a coating layer of alginate (A) composed of the following alginates (A1) and (A2) on the outer periphery of a core material (S) containing a physiologically active substance. A pH-responsive elution-coated granule having a mass ratio of core material (S) / alginate (A) of 50/50 to 97/3 and an average particle size of 10 to 3000 μm.
Alginate (A1): Alginate having a viscosity of 1% by mass aqueous solution at 20 ° C. of 20 to 1000 mPa · s Alginate (A2): Alginate having a viscosity of 1% by mass aqueous solution at 20 ° C. of less than 20 mPa · s [ 2] The pH-responsive elution coated granule according to the above [1], wherein the mass ratio of A1 / A2 of alginate (A) is 10/90 to 90/10.
[3] A food product using the pH-responsive elution-coated granules according to the above [1] or [2].

INDUSTRIAL APPLICABILITY The present invention provides a coated granule that protects the stomach and reaches the intestine without damaging the bioactive substance to be coated while using a material that can be used for food. Further, by using the coated granule of the present invention as a powder raw material for foods such as hard capsules, tablets, and granules to make foods, a formulation that effectively absorbs physiologically active substances in food products into the body. It will be possible to set the amount accurately and provide food products that are attractive to consumers.

Hereinafter, the present invention will be described in detail.
In the pH-responsive elution coated granule of the present invention, the coating layer of alginate (A) composed of the following alginates (A1) and (A2) is placed on the outer periphery of the core material (S) containing a physiologically active substance. It is a pH-responsive elution coated granulated product having.
Alginate (A1): Alginate having a viscosity of 1% by mass aqueous solution at 20 ° C. of 20 to 1000 mPa · s Alginate (A2): Alginate having a viscosity of 1% by mass aqueous solution at 20 ° C. of less than 20 mPa · s

<Core material (S) containing a physiologically active substance>
In the pH-responsive elution-coated granules of the present invention, the core material (S) is a powdered bioactive substance or a bioactive substance whose concentration is adjusted by mixing the bioactive substance with an inert solid material. The bioactive substances contained in the core material (S) include enzymes, functional peptides, lactic acid bacteria, royal jelly and other bioactive substances that are sensitive to acids, and capsicum, garlic, iron and other bioactive substances that impose a burden on the stomach when ingested in large amounts. Substances are mentioned. Other physiologically active substances that are absorbed in the intestine include water-soluble vitamins such as thiamine, riboflavin, pyridoxine, cyanocobalamin, niacin, folic acid, pantothenic acid, biotin, and ascorbic acid and their derivatives, vitamins A and D, There are fat-soluble vitamins such as E and K, amino acids, collagen, hyaluronic acid, herbs, and natural extract powder.

Cellulose, which is a general excipient, is used as a core material (S) used in the pH-responsive elution coated granules of the present invention as an inert solid material mixed with a physiologically active substance and adjusted in concentration. , Dextrin and the like. In the pH-responsive elution coated granule of the present invention, the concentration of the bioactive substance in the core material (S) may be appropriately adjusted according to the standard intake amount of the bioactive substance to be blended.

<Alginate (A)>
As the alginate, monovalent and water-soluble salts such as sodium alginate, potassium alginate, and ammonium alginate are preferable. The viscosity of the alginic acid aqueous solution in the present invention is a BL type rotational viscometer (“BLII” manufactured by Toki Sangyo Co., Ltd., rotation speed: 60 rpm, 60 seconds, rotor No. 1, 200 mPa · s when the viscosity is less than 200 mPa · s. In the case of s or more, it can be measured using the rotor No. 2).
The viscosity of alginate varies depending on the molecular weight of alginate, and those having a large molecular weight show a high viscosity and those having a low molecular weight show a low viscosity. The weight average molecular weight (Mw) of the alginate (A1) is 50 or more, and the weight average molecular weight of the alginate (A2) is 50 or less.

<Alginate (A1)>
The alginate (A1) used in the present invention has a viscosity of 1% by mass aqueous solution at 20 ° C. of 20 mPa · s to 1000 mPa · s, preferably 20 mPa · s to 400 mPa · s, and more preferably 50 mPa · s to 200 mPa · s. preferable.

<Alginate (A2)>
The alginate (A2) used in the present invention has a viscosity of a 1% by mass aqueous solution at 20 ° C. of less than 20 mPa · s, and is preferably 1 mPa · s to 10 mPa · s.

Alginate (A1) having a viscosity of 1% by mass aqueous solution at 20 ° C. of 20 to 1000 mPa · s can be sufficiently acid resistant, and the viscosity of the 1% by mass aqueous solution at 20 ° C. is less than 20 mPa · s. By using alginate (A2), the flexibility of the film is increased, the film property is improved, the elution of physiologically active substances under acidic conditions can be further suppressed, and the elution under neutral conditions can be further suppressed. Can be accelerated. In addition, the particle size can be easily controlled.
The mass ratio A1 / A2 of alginate (A1) and alginate (A2) is not particularly limited, but is preferably 10/90 to 90/10, more preferably 10/90 to 50/50, and 10/90 to 30. / 70 is particularly preferable. When the mass ratio A1 / A2 is less than 10/90, the acid resistance is lowered, and elution of acidic conditions is likely to occur. On the other hand, if it exceeds 90/10, the flexibility of the coating film is poor and the binding property is enhanced, so that the particles cannot be uniformly coated and the particles are likely to be coarsened, and the elution delay under neutral conditions is delayed. Occurs.

In the pH-responsive elution-coated granules of the present invention, the mass ratio S / A of the core material (S) and alginate (A) made of a physiologically active substance is 50/50 to 97/3, preferably 50/50 to 97/3. It is 60/40 to 95/5, more preferably 70/30 to 90/10. If the alginate (A) is less than 3%, sufficient acid resistance cannot be obtained. If the alginate (A) exceeds 50%, elution under neutral conditions may be delayed, the manufacturing process may take a long time, the particle size may be difficult to control, and the particles may become coarse.

<pH-responsive elution coated granules>
The pH-responsive elution coated granule of the present invention has an average particle diameter of 10 to 3000 μm, preferably 50 to 1500 μm, and more preferably 100 to 800 μm. If the average particle size is too small, the surface area of the particles becomes large, and it is difficult to sufficiently suppress elution under acidic conditions. If the average particle size is too large, the particles are chipped due to the load during the process, and good film formation cannot be performed.
The average particle size in the present invention means a volume average diameter, and can be measured by using a laser diffraction type particle size distribution measuring device.

As a method for producing a pH-responsive elution coated granule of the present invention, a known flow granulation coating method can be used. For example, a solution of alginate (A) is sprayed onto a core material (S) that is in a fluid or rolling motion, and the solution is dried on the outer circumference of the core material (S) to obtain alginate (A). Form a coating layer. Specifically, it is carried out by a known method using a fluidized bed granulation coating device (for example, Freund Sangyo Co., Ltd. "FLOW COATER"), a rolling fluidized bed granulator, a centrifugal rolling granulation coating device, or the like. be able to. A device in which a rotating disk is installed at the bottom of the device is preferable, and the centrifugal force of the rotating disk suppresses granulation due to the binding of particles, so that the particle size can be easily controlled. Further, since the film is spread by the rolling of the particles, the film can be uniformly formed on the surface of the core material particles.

The pH-responsive elution coated granules of the present invention are protected without elution under acidic conditions such as stomach, and are rapidly eluted under neutral conditions such as intestines. Foods requiring pH-responsive elution. In, the pH-responsive elution coated granules can be used as they are or after being processed into various preparations.

The present invention will be specifically described below with reference to examples.
The test method and evaluation method used in each of the examples shown below are shown below.

(1) Dissolution test The elution of the physiologically active substance contained in the pH-responsive elution coated granules obtained in Examples and Comparative Examples into the elution test solution was determined by the "Japanese Pharmacopoeia 6.10 Elution Test Method". It was performed according to the prescribed method. As the test solution, 900 mL of a pH 1.2 aqueous solution equivalent to gastric juice or a pH 6.8 aqueous solution equivalent to intestinal juice was used. The enteric property in the present invention means that the elution rate after 1 hour in a pH 1.2 aqueous solution is 50% or less, and the elution rate after 30 minutes in a pH 6.8 aqueous solution is 70% or more.
(2) Average particle size The measurement was performed with a laser diffraction type particle size distribution measuring device "SALD-2100" manufactured by Shimadzu Corporation.

Details of the materials used to prepare the pH-responsive elution coated granules in Examples and Comparative Examples are shown below. It is indicated by an abbreviation in the table.
Riboflavin: BASF's "Riboflavin HF100"
Soy Peptide: "High Newt DL" manufactured by Fuji Oil Co., Ltd.
Sodium ferrous citrate: "Sanferol" manufactured by Eisai Food & Chemical Co., Ltd.
Placenta extract powder: Snowden's "Snow Placenta Gold Pure Powder PJ"
Cellulose: "Theoras ST-02" manufactured by Asahi Kasei Chemicals
CA-IL-6: Product name "Kimika Argin IL-6" manufactured by Kimika Co., Ltd. (viscosity 65 mPa · s, weight average molecular weight about 690,000)
TA-NSPHR: Product name "Tuck Argin-NSPHR" manufactured by Kikkoman Biochemifa Co., Ltd. (viscosity 550 mPa · s, weight average molecular weight about 1.88 million)
CA-IL-2: Product name "Kimika Argin IL-2" manufactured by Kimika Co., Ltd. (viscosity 30 mPa · s, weight average molecular weight about 550,000)
CA-I-8: Product name "Kimika Argin I-8" manufactured by Kimika Co., Ltd. (viscosity 850 mPa · s, weight average molecular weight about 2.1 million)
CA-I-1: Product name "Kimika Argin I-1" manufactured by Kimika Co., Ltd. (viscosity 120 mPa · s, weight average molecular weight about 1.07 million)
CA-ULV-1: Product name "Kimika Argin ULV-1" manufactured by Kimika Co., Ltd. (viscosity 10 mPa · s, weight average molecular weight about 180,000)
CA-ULV-L3: Product name "Kimika Argin ULV-L3" manufactured by Kimika Co., Ltd. (viscosity 1 mPa · s, weight average molecular weight about 40,000)

[Example 1]
291 g of riboflavin was mixed with 291 g of cellulose and charged into a rolling fluidized bed granulator, and 360 g of a coating liquid was sprayed and coated. The composition of the spray solution is sodium alginate (Kimika algin IL-6 [viscosity 65 mPa · s] 9%, Kimika algin ULV-1 [viscosity 10 mPa · s] 1%) 5%, water 95%. The compounding composition is shown in Table 1 together with the evaluation results.
The viscosity described above is the viscosity of a 1% by mass aqueous solution at 20 ° C., and is a BL type rotational viscometer (“BLII” manufactured by Toki Sangyo Co., Ltd., rotation speed: 60 rpm, 60 seconds, viscosity less than 200 mPa · s. In this case, the viscosity is measured using rotor No. 1, and in the case of 200 mPa · s or more, the viscosity is measured using rotor No. 2).

[Examples 2 to 8]
The pH-responsive elution coated granules of the present invention were prepared by changing the type or amount of the material in the same operation as in Example 1. The compounding composition is shown in Table 1 together with the evaluation results.

[Comparative Examples 1 to 4]
In the same operation as in Example 1, the type or amount of the material was changed to prepare a pH-responsive elution coated granule not of the present invention. The compounding composition is shown in Table 2 together with the evaluation results.

From the results shown in Examples 1 to 8, it was found that the pH-responsive elution coated granules of the present invention did not elute under acidic conditions, but elute rapidly under neutral conditions.

On the other hand, in Comparative Example 1 in which alginate (A2) was not blended, it was difficult to control the particle size and coarsening occurred. In addition, since the flexibility of alginate was insufficient, the film property was poor and the elution suppression under acidic conditions was insufficient. In Comparative Example 2, since alginate (A1) was not blended, acid resistance was insufficient and elution was observed under acidic conditions. In Comparative Example 3, since the content of alginate was small, the elution control ability was insufficient and the elution control under acidic conditions was insufficient. In Comparative Example 4, the content of alginate was too high, so that the particle size was coarsened and the elution was delayed under neutral conditions.

Claims (2)

A pH-responsive elution coated granule having a coating layer of alginate (A) composed of the following alginate (A1) and (A2) on the outer periphery of the core material (S) containing a physiologically active substance. , The mass ratio of core material (S) / alginate (A) is 50/50 to 90/10 , and the mass ratio of A1 / A2 of alginate (A) is 10/90 to 30/70, which is an average. pH responsive eluting coating granules having a particle diameter of a 10~ 8 00μm.
Alginate (A1): Alginate having a viscosity of 1% by mass aqueous solution at 20 ° C. of 20 to 1000 mPa · s Alginate (A2): Alginate having a viscosity of 1% by mass aqueous solution at 20 ° C. of less than 20 mPa · s A food containing the pH-responsive elution-coated granules according to claim 1 in the state of the pH-responsive-eluting coated granules .