JP2002205938A - Sustained release composition and method for controlling sustained release - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a sustained release composition capable of releasing useful bacteria or a useful substance with a requested release pattern. SOLUTION: The sustained release composition comprises a gel bead containing the useful bacteria or the useful substance and a sustained release regulator, and is characterized in that a sustained release regulator contains at least alginic acid or an alginic acid derivative and the sustained releasability of the sustained release composition is controlled by regulating the kind and the content of an ingredient composing the sustained release regulator.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a sustained-release composition capable of releasing useful bacteria or useful substances in a desired release pattern. The present invention also relates to a method for controlling the sustained release of useful bacteria or useful substances.

[0002]

2. Description of the Related Art Hitherto, various systems have been devised in which bacteria useful for humans and medicinal components desirably released slowly in the intestine are transported to the intestine by capsules using edible oil, alginic acid, gelatin and the like.

[0003] Specifically, useful bacteria such as bifidobacteria are described in, for example, Japanese Patent Publication No. 4-7588 and Japanese Patent Publication No.
-101994, JP-B-7-6948,
As described in JP-A-11-302158 and the like, attempts have been made to encapsulate useful bacteria in capsules and deliver them to the intestine while protecting them from strong acids in the stomach. However, there is a problem that the production process of encapsulating useful bacteria in capsules is complicated and costly. Also,
These systems can prevent stomach acid disintegration,
The intestinal release pattern could not be adequately adjusted to the desired one.

Further, a method of preventing disintegration in the stomach and controlling the release pattern in the intestine by combining algin with chitosan, hyaluronic acid or chondroitin sulfate (for example, Japanese Patent No. 2511577, Japanese Patent Application Laid-Open No. Japanese Patent Laid-Open No. 100468/1994, Japanese Patent Application Laid-Open No. 6-256
No. 221 and Japanese Patent No. 2511612) are disclosed, but also in these, the target substance is limited to a medicinal ingredient whose release control is desired in the intestine. It has not been conceived that substances such as insulin, which are often administered by injection because of the inability to maintain the drug, are subject to sustained release.

[0005] In addition, the above-mentioned sustained release in the intestine remains unsatisfactory in terms of preventing disintegration in the stomach, controlling release in the intestine, and maintaining sustainability. Was.

[0006]

In view of the above-mentioned problems of the prior art, the present invention provides a sustained-release composition capable of releasing useful bacteria or useful substances in a desired release pattern. Assigned. Specifically, in the case of useful bacteria, after ingestion by oral administration, they are not released in the mouth, esophagus, and stomach, and are transported to the intestine without being destroyed by strong acids in the stomach. An object of the present invention is to provide a sustained-release composition capable of freely controlling the release within the body and maintaining the sustainability. Another object of the present invention is to provide a sustained-release composition exhibiting a desirable release pattern while controlling whether or not the useful substance is released in the stomach as desired. Another object of the present invention is to provide a method for easily controlling the sustained release of useful bacteria or useful substances.

[0007]

Means for Solving the Problems The present inventors have conducted intensive studies to solve these problems, and as a result, a sustained-release composition containing gel beads containing useful bacteria or useful substances and a sustained-release regulator. The sustained-release regulator comprises at least alginic acid or an alginic acid derivative, and the sustained-release composition has a controlled release property by controlling the type and ratio of components constituting the sustained-release regulator. It has been found that the subject can be effectively solved by the controlled release composition characterized by being controlled.

The gel beads preferably contain alginic acid or an alginic acid derivative, and the sustained-release controlling agent may contain a polysaccharide. The sustained-release composition of the present invention comprises a gel bead-containing layer containing gel beads and a gel bead-free layer not containing the gel beads, and both the gel bead-containing layer and the gel bead-free layer contain a sustained-release controlling agent. May be used. The gel bead-free layer may further contain fibers, and the gel bead-free layer may be formed of two or more layers.

Further, the present invention provides a method of mixing gel beads containing a useful bacterium or a useful substance with a sustained-release regulator containing alginic acid or an alginic acid derivative to form a formulation.
A method for controlling the sustained release of the useful bacterium or useful substance is also provided.

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, a sustained release composition and a method for controlling sustained release of the present invention will be described in detail. In this specification, “to” means a range including the numerical values described before and after it as a minimum value and a maximum value, respectively.

[0011] The sustained-release composition of the present invention comprises a gel bead containing a useful bacterium or a useful substance and a sustained-release regulator. The sustained-release modifier contains at least alginic acid or an alginic acid derivative. The method for producing gel beads used in the present invention is not particularly limited, but a preferred method is to produce gel beads using a sustained-release regulator. According to a preferred method, gel beads can be produced very simply and inexpensively by mixing a sustained-release regulator with a useful bacterium or a useful substance and dropping the mixture into a polyvalent metal salt solution. Therefore, there is an advantage that a complicated and costly manufacturing process is not required unlike the conventional capsule.

When mixing the sustained release regulator with the useful bacteria or useful substances, the sustained release regulator and the useful bacteria or useful substances may be mixed first and then dissolved in water. The regulator may be mixed with a culture solution of useful bacteria or a solution of useful substances. Further, an aqueous solution of the sustained-release regulator may be mixed with a culture solution of useful bacteria or a solution of useful substances.

The alginic acid or alginic acid derivative contained in the sustained-release regulator may be used singly or in combination of two or more. In addition, components other than alginic acid or alginic acid derivatives may be used in combination as the sustained release regulator. For example, one or more of polysaccharides, acidic mucopolysaccharides, complex acidic mucopolysaccharides, basic polysaccharides, and fibers can be used. These components other than alginic acid or an alginic acid derivative may be previously mixed with alginic acid or an alginic acid derivative and then mixed with water or a useful bacterium or a useful substance, or separately from the alginic acid or an alginic acid derivative. It may be mixed with useful substances. Further, any one of polysaccharides, acidic mucopolysaccharides, complex acidic mucopolysaccharides, basic polysaccharides, and fibers may be used alone or in combination of two or more. Further, in combination with such a sustained release modulator, or in place of the sustained release modulator,
One or more commonly used excipients, binders and disintegrants can be used in combination.

The obtained mixture can be dropped into a polyvalent metal salt solution immediately after mixing to form gel beads. However, when a useful bacterium is used, the mixture is cultured for a while and then dropped into the polyvalent metal salt solution. Gel beads are preferred. That is, it is preferable to form gel beads after culturing the useful bacteria in alginic acid or an alginic acid derivative, since the number of useful bacteria can be efficiently increased and the production efficiency can be increased. As a specific example, there is an example in which after culturing bifidobacteria in a medium containing sodium alginate, the beads are dropped into a calcium chloride solution to produce gel beads. According to this method, there is an advantage that anaerobic is maintained by the viscosity of sodium alginate.

When the mixture is dropped into the polyvalent metal salt solution, the size of the gel beads can be adjusted by appropriately adjusting the rate and amount of dropping. The size of the gel beads varies depending on the intended sustained release property and the type of useful bacteria, but is preferably 0.1 mm to 30 mm, more preferably 0.2 mm to 10 mm.

Although the gel beads produced using the sustained release regulator show sustained release properties as they are, the gel beads are further processed in the present invention in order to adjust the sustained release properties to a desired pattern. In addition, gel beads produced without using a sustained release controlling agent are processed to have a new sustained release property. Specifically, the processing here means that the gel beads are prepared using a sustained-release regulator.

The specific means of processing for imparting sustained release is not particularly limited. For example, gel beads are freeze-dried and dried under reduced pressure, pulverized, and combined with a sustained-release controlling agent to form one layer. Alternatively, it can be a preparation comprising two or more composite layers. The details of the sustained-release controlling agent are as described above, and one or more alginic acid or alginic acid derivative is used as an essential component. In addition, polysaccharides, acidic mucopolysaccharides, complex acidic mucopolysaccharides, basic polysaccharides, and / or fibers may be used in combination with alginic acid or alginic acid derivatives.
Furthermore, one or more commonly used excipients, binders and disintegrants can be used in combination.

The gel beads and the sustained-release controlling agent may be mixed together to form a single preparation as a whole, or a gel bead-containing layer and a gel bead-free layer comprising only the sustained-release controlling agent mixed together may be used. The preparation may have a multilayered structure. The details of the structure of the preparation are appropriately determined depending on the purpose of use of the preparation, a desired release pattern, and the like. The dosage form can be appropriately selected from tablets, pills and the like.

The sustained release composition of the present invention can control the release pattern of useful bacteria and useful substances by selecting a material to be used as a sustained release regulator. Specifically, useful bacteria and useful substances to be released in the intestine are transported to the intestine without being released in the stomach,
In addition, the release pattern there can be controlled, and the sustainability can be maintained. For example, when it is desired to slowly release sustained or useful substances or useful substances, it is particularly effective to combine them with chitosan. Combining it with alginic acid is particularly effective if you want to release it. If the intermediate between them is good, it is effective to combine them with alginic acid ester, microcrystalline cellulose, carrageenan or the like. By accumulating such sustained release patterns for various materials, a sustained release composition having a desired sustained release pattern can be provided by using them in combination.

Because of these characteristics, useful intestinal microorganisms such as lactic acid bacteria, useful substances which are easily decomposed in the stomach,
Useful substance that stimulates the stomach, useful substance that is easily decomposed in the intestine,
The present invention can be effectively applied to useful substances that are to be continuously absorbed in the intestine over a long period of time.

Hereinafter, the materials used in the present invention will be described in detail with reference to specific examples. The kind of useful bacteria used in the present invention is not particularly limited as long as it exhibits some useful action in the body. In the present invention, useful bacteria that are desirably released particularly at a specific site in the body (particularly intestine) can be effectively used. For example, specific examples of useful bacteria desirably released in the intestine include Lactobacillus acidophilus, Lacto
bacillus casei, Lactobacillus bulgaricus, Lactobac
Lactobacillus such as illus lactics, Bifidobacterium brav
e, Bifidobacterium infantis, Bifidobacterium longu
m, Bifidobacterium genus such as Bifidobacterium bifidum, L
Lactococci such as actcoccus lactis and Streptococcus thermophilus can be exemplified. In the present invention, it is preferable to use at least one of these useful bacteria, but useful bacteria that can be used in the present invention are not limited to these specific examples.

Further, the kind of the useful substance used in the present invention is not particularly limited. In the present invention, a medicinal substance which is absorbed in the intestine, a drug which is easily decomposed in the stomach, and a drug which stimulates the stomach can be effectively used. In particular, those which are easily decomposed in the intestine and those which should be continuously absorbed in the intestine over a long period of time can be used effectively. The useful substance used in the present invention does not necessarily need to be a medicinal ingredient, and may be a nutrient ingredient or a functional ingredient, or may be an ingredient belonging to another category. Further, components generally administered by injection can also be used as useful substances of the present invention. Specifically, it is also possible to use insulin, interferon and the like.

In the present invention, alginic acid or an alginic acid derivative (hereinafter referred to as "alginic acids") is used as an essential component. The average molecular weight and the molecular weight distribution of the alginic acids used in the present invention are not particularly limited.
(Measured with a B-type viscometer) is 1 to 1500 mP
s · s can be preferably used, and 10 to 10
Those having a pressure of 00 mPs · s can be more preferably used. The kind, raw material and production method of alginic acids used in the present invention are not particularly limited. Therefore, alginic acids used in the present invention may be derived from natural products,
It may be obtained by synthesis.

High molecular alginic acid is abundantly contained between cells of brown algae. Therefore, high-molecular alginic acid can be obtained by using a method in which brown algae are washed with, for example, diluted sulfuric acid, extracted with a sodium carbonate solution, and precipitated with sulfuric acid. The high molecular alginic acid thus obtained can be easily reduced in molecular weight by using any of known methods. For example, low molecular weight alginic acid can be prepared using a method of reacting an enzyme with high molecular alginic acid, a method of reacting sodium hypochlorite, hydrogen peroxide, or the like, a method of thermal decomposition, a method of pressure decomposition, and the like. it can.

The β constituting the alginic acids used in the present invention
The ratio and sequence order of -D-mannuronic acid and α-L-guluronic acid are not particularly limited. Therefore, a block containing only β-D-mannuronic acid, a block containing only α-L-guluronic acid, or a block containing all blocks in which both are mixed, or any one of them or You may use what consists of two types.

As used herein, the term "alginate derivative" broadly includes compounds derived from alginic acid, and is preferably an alginate or an alginate. Alginate is a compound having a structure in which at least a part of the carboxyl group constituting alginic acid is converted to a salt. Alginate can be easily obtained by allowing a base to act on alginic acid. Preferred alginates include sodium alginate.

The alginic acid ester is a compound having a structure in which at least a part of the carboxyl group constituting alginic acid is converted to an ester. The degree of esterification of the alginic acid ester is not particularly limited. Preferred alginate esters include propylene glycol alginate.

In the present invention, any one of alginic acid, alginic acid salts and alginic acid esters may be used, or two or more of them may be used in combination.
Further, all three types may be used. In addition, salt,
A plurality of alginates or alginates having different types and molecular weights of the esters may be used in combination. The alginic acids used in the present invention may have a functional group or a crosslinked structure as long as the desired effects are not excessively inhibited.

In the present invention, as the polyvalent metal salt solution used for forming the gel beads, a metal calcium salt solution can be preferably used. Specific examples include calcium chloride and calcium lactate, but the polyvalent metal salt solution that can be used in the present invention is not limited to these specific examples.

In the present invention, natural gums and processed ones thereof can be widely used as polysaccharides. For example,
Carrageenan, mannan, pectin, pullulan, locust bean gum, xanthan gum, guar gum, agar,
Cassia gum, curdlan, tamarind gum, gum arabic, tragacanth gum, phaseellelan, gellan gum,
One or two or more substances derived from seaweeds such as psyllium gum and karaya gum, seeds, resins and microorganisms, or substances obtained by processing the same can be used.

In the present invention, an acidic mucopolysaccharide, a complex acidic mucopolysaccharide, or a basic polysaccharide may be used as the polysaccharide. Acidic mucopolysaccharides include hyaluronic acid and its derivatives. Also, as complex acidic mucopolysaccharides,
Chondroitin sulfates A, B, C and heparin. Further, examples of the basic polysaccharide include chitosan and polygalactosamine. However, polysaccharides that can be used in the present invention are not limited to these specific examples.

In the present invention, cellulose or a cellulose derivative can be used as the fibers. For example, one or more of crystalline cellulose, microcrystalline cellulose, methylcellulose (MC), carboxymethylcellulose (CMC), hydroxypropylmethylcellulose (HPMC), and hydroxypropylcellulose (HPC) can be used. However, the fibers that can be used in the present invention are not limited to these specific examples.

In the present invention, commonly used excipients include sugars such as lactose, sucrose, glucose, etc., sugar alcohols such as mannitol and sorbitol, starches such as starch, processed starch and starch derivatives; Silicic acids and silicates such as silicic acid, synthetic aluminum silicate and magnesium aluminate metasilicate, inorganic salts such as calcium phosphate, calcium carbonate and calcium sulfate, and dextran can be used. However, the excipient that can be used in the present invention is not limited to these specific examples.

In the present invention, commonly used saccharides, dextrin, polyvinylpyrrolidone, macrogol and the like can be used as the binder, but the binder that can be used in the present invention is limited to these specific examples. Not something.

In the present invention, commonly used unmodified starches, cellulose derivatives, chemically modified starches and the like can be used as the disintegrant. However, the present invention is not limited to the specific example.

[0036]

The features of the present invention will be described more specifically with reference to the following examples. Material, amount used in the following examples,
The ratio, processing content, processing procedure, and the like can be appropriately changed without departing from the spirit of the present invention. Therefore, the scope of the present invention should not be construed as being limited by the specific examples described below.

Example 1 Bifidobacterium longum was cultured for 20 hours in a culture solution containing sodium alginate (2.0% by weight) at 37 ° C.
This culture was adjusted to 0.4 M adjusted to pH 7.5.
The mixture was dropped into a 1: 1 mixture of calcium chloride solution and condensed milk, and left at 4 ° C. for 24 hours to obtain gel beads containing bifidobacteria. This at -80 ° C
After freezing for 4 hours, it was dried under reduced pressure to obtain dried gel beads. Table 1 shows the viable count of bifidobacteria in each step of the production.
Shown in

[0038]

[Table 1]

As is clear from Table 1, it was confirmed that the bifidobacteria survived even after the gel beads mainly composed of sodium alginate were frozen and dried.

Example 2 0.1 g of a mixture having the composition given in Table 2 below
And then compression molded at 400 kgf / cm ² ,
A one-layer tablet was obtained. The starch used here was AMICOL HF manufactured by Nisseki Chemical Co., Ltd., and the alginate ester was manufactured by Kibun Food Chemifa (1% viscosity 116.5 mP).
s · s, esterification degree 42.3%), and sodium alginate manufactured by Kibun Food Chemifa (1% viscosity 1)
74.5 mPs · s), and the chitosan is Koyo Chitosan FM-80 manufactured by Koyo Chemical Co., Ltd.

[0041]

[Table 2]

Each of the manufactured tablets was prepared according to Japanese Pharmacopoeia XI
PH 1.2 and pH 6.0 according to the dissolution test method (paddle method).
8, a dissolution test was performed. The first solution (artificial gastric juice) for the disintegration test of Japanese Pharmacopoeia XI was used for the dissolution test at pH 1.2, and a 1/500 M phosphate buffer (artificial intestinal fluid) was used for the dissolution test at pH 6.8. The release pattern of starch from each tablet was examined using an automatic dissolution test system (manufactured by Toyama Sangyo Co., Ltd.) at 37 ° C. and 150 rpm. The dissolution amount of starch was 30 minutes after the start of the test.
Minutes, 45 minutes, 1 hour, 2 hours, and 3 hours, quantification was performed by a general iodine reaction method. The starch release pattern of each tablet at pH 1.2 is shown in FIG. 1, and the starch release pattern at pH 6.8 is shown in FIG.

As is clear from FIGS. 1 and 2, it was confirmed that the release pattern was different depending on the type of the material to be combined with the starch. This indicates that a sustained release composition having various sustained release patterns can be provided by appropriately combining alginic acid, alginic acid derivatives, and polysaccharides. It also shows that a sustained release composition having a desired sustained release pattern can be provided by accumulating sustained release patterns for a wide range of materials.

Example 3 A mixture for the middle layer having the composition shown in Table 3 below was sandwiched between the upper layer and the lower layer shown in Table 3 to obtain a mixture of 400 kg.
The tablet was compression-molded at f / cm ² to obtain a tablet having a three-layer structure shown in FIG. At this time, the weight per tablet was set to 0.1 g. The starch, sodium alginate, alginate and chitosan used here are the same as those used in Example 2. Carrageenan is Lactarin MV406 manufactured by FMC Biopolymer, and microcrystalline cellulose is Avice manufactured by FMC Biopolymer.
1 FD-100, and alginic acid is manufactured by Kibun Food Chemifa (1% solution viscosity 174.5 mPs · s).

[0045]

[Table 3]

A dissolution test was performed on each of the produced tablets at pH 1.2 and pH 6.8 in the same manner as in Example 2. The starch release pattern of each tablet at pH 1.2 is shown in FIG. 4, and the starch release pattern at pH 6.8 is shown in FIG.

As is apparent from FIG. 4, almost no starch was eluted at pH 1.2 in any of the samples. This means that these three-layer tablets are resistant to acids, and are hardly destroyed by exposure to strong acids such as gastric juice. Indicates that it can be done.

On the other hand, as is apparent from FIG.
In No. 8, it was confirmed that the release pattern was different depending on the type of the material to be combined with the starch.
In other words, it is effective to slowly release the useful bacteria and useful substances slowly or to have a sustained effect, and it is effective to combine them with chitosan, and carry the useful bacteria and useful substances intact to the intestine and release them at once in the intestine. When it is desired to combine them, it is effective to combine them with alginic acid. In addition, if the intermediate between them is good, it is also effective to combine with alginic acid ester, microcrystalline cellulose or color ginnan. As for other materials, a sustained release composition having a desired sustained release pattern can be provided by accumulating the sustained release patterns.

[0049]

Industrial Applicability The sustained-release composition of the present invention can release useful bacteria in a desired release pattern. Further, according to the production method of the present invention, it is possible to produce such a sustained-release composition simply and at low cost. The present invention, various useful bacteria including intestinal useful microorganisms such as lactic acid bacteria,
Useful substances that are easily decomposed in the stomach, useful substances that stimulate the stomach,
It can be effectively applied to useful substances that are easily decomposed in the intestine and useful substances that should be continuously absorbed in the intestine over a long period of time, and its application range is expected to be extremely wide.

[Brief description of the drawings]

FIG. 1 is a graph showing a starch release pattern of each sample of Example 2 at pH 1.2.

FIG. 2 is a graph showing a starch release pattern of each sample of Example 2 at pH 6.8.

FIG. 3 is a schematic view showing the structure of a sample of Example 3.

FIG. 4 is a graph showing a starch release pattern of each sample of Example 3 at pH 1.2.

FIG. 5 is a graph showing the starch release pattern of each sample of Example 3 at pH 6.8.

[Explanation of symbols]

 1 Upper layer (sodium alginate) 2 Middle layer (starch and other components) 3 Lower layer (sodium alginate)

Claims (7)

[Claims] 1. A sustained release composition comprising gel beads containing a useful bacterium or a useful substance and a sustained release regulator, wherein the sustained release regulator comprises at least alginic acid or an alginic acid derivative, and The sustained-release composition according to claim 1, wherein the sustained-release property of the sustained-release composition is controlled by adjusting the types and proportions of components constituting the release-controlling agent. 2. The sustained-release composition according to claim 1, wherein the gel beads contain alginic acid or an alginic acid derivative. 3. The sustained-release composition according to claim 1, wherein the sustained-release regulator comprises a polysaccharide. 4. The gel bead-containing layer containing the gel beads and a gel bead-free layer not containing the gel beads, and both the gel bead-containing layer and the gel bead-free layer contain the sustained-release controlling agent. 3. The sustained-release composition according to any one of 3. 5. The sustained-release composition according to claim 4, wherein the gel bead-free layer further contains fibers. 6. The sustained-release composition according to claim 4, which has two or more layers containing no gel beads. 7. A method for controlling the sustained release of a useful bacterium or a useful substance by formulating a combination of gel beads containing a useful bacterium or a useful substance and a sustained-release regulator containing alginic acid or an alginic acid derivative. .