JPH09241169A - Gel state composition having compound releasing and adsorbing property - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a gel state composition having properties of adsorbing bile acids and long chain fatty acids, and releasing a substance taken up in gel matrix thereof, the useful for the treatment of hyperlipemia, especially for removing the bile acids in a gastrointestinal tract. SOLUTION: This gel state composition in obtained byincluding a salt consisting of a high molecular material having primary, secondary, tertiary and/or quaternary amino groups (e.g.; chitoxan) and a material having carboxyl group (e.g. lactic acid) into a gel matrix (e.g.; alginic acid gel). Especially, the alginic acid gel including a chitoxan-lactic acid salt has a function of distributing in humane small intestine in a state of maintaining shape thereof and taking up bile acids to prohibit reabsorption of the acids after oral intake of the gel, and useful as a specific health food or a food containing limited cholesterol, etc. Also, the alginic acid gel beads including the chitoxan-nicotinic acid salt, is useful as a multi-functional anti-hyperlipemic agent by preventing an adverse effect due to the sustained release of the nicotinic acid and taking up the bile acids in the gastrointestinal tract.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention includes in a gel matrix a salt formed of a polymer substance having a primary, secondary, tertiary and / or quaternary amino group and a substance having a carboxyl group. The present invention relates to a gel composition having a property of releasing a substance having the carboxyl group and adsorbing bile acids and long chain fatty acids.

The gel composition of the present invention can be used in a wide variety of industrial fields.

When the gel composition of the present invention is used for medicinal purposes, for example, when it is orally administered, it absorbs bile acid and blocks its reabsorption, so that it has preventive and therapeutic effects on hyperlipidemia. , Exerts the function of gradually releasing the drug contained in the gel.

When the gel composition of the present invention is used for foods, it absorbs saturated long-chain fatty acids and unsaturated long-chain fatty acids contained in foods, so that the fat composition ratio of the foods is reduced and low. Can be converted into calories. It is also possible to adsorb and remove the unsaturated unsaturated long-chain fatty acid.

Furthermore, by adsorbing and removing long-chain fatty acids contained in the environment of seawater or fresh water, it is useful for purification of the environment.

[0006]

2. Description of the Related Art The recent increase in arteriosclerotic diseases is largely associated with the increase in hyperlipidemia associated with changes in dietary habits. Therefore, it is considered necessary to recognize as Western countries. Food is a very important factor for the treatment and prevention of hyperlipidemia, and in particular, in hyperlipidemic patients, daily intake of cholesterol is restricted in order to prevent the progression of the disease. It is said that good eating habits are important.

Most of the cholesterol in the body is catabolized by the liver to bile acids. Bile acid biosynthesized from cholesterol is secreted into the intestinal tract through the bile duct to help digestion and absorption of fat in the small intestine. More than 95% of the secreted bile acid is reabsorbed from the intestinal tract to perform enterohepatic circulation, and less than 5% is excreted outside the body as feces (Makino et al., Metabolism, 24 (8), 685, 1987).

[0008] Therefore, as one method for lowering the cholesterol level in blood, by absorbing and removing bile acid in the intestinal tract, the enterohepatic circulation of bile acid is suppressed, and the catabolic action of cholesterol to bile acid is achieved. Various methods have been tried to promote the above.

[0009] One of the drugs marketed as a drug based on this mechanism of action is cholestyramine, which is an anion exchange resin, and its efficacy and safety in long-term use have been confirmed, and has been widely clinically applied. However, the daily dose of cholestyramine is as high as 8 to 12 g, and it has to be suspended in water or juice to be taken. As a side effect, gastrointestinal symptoms such as abdominal bloating and constipation often occur. Therefore, compliance has become a major issue.

Therefore, a synthetic anion exchange resin having a better ability to adsorb bile acids and being easy to take is being actively developed (JP-A-3-35005, JP-A-2-21250).
No. 5, JP-A No. 6-321786, etc.). However, a substance having a property of adsorbing bile acid and releasing a drug has not been known so far.

On the other hand, when the drug is dispersed in a matrix of a substance which controls the release and the drug is released in the digestive organs by oral administration, the insoluble base matrix currently used clinically is porous. Known are plastic matrix (Gradumet), wax matrix, gel-forming polymer such as hydroxypropyl cellulose and hydroxypropylmethyl cellulose. However, there is no known insoluble base matrix having a property of adsorbing bile acids.

[0012]

DISCLOSURE OF THE INVENTION The present invention is effective for treating hyperlipidemia, particularly for removing bile acids in the digestive tract,
The main issue is to provide new formulations.

[0013]

The present inventors have a property of adsorbing bile acid and a property of releasing a drug (eg, antihyperlipidemic drug) dispersed in a matrix. It was conceived that the gel composition is particularly effective for the treatment of hyperlipidemia because it exerts two different functions in the body. And, the present inventors have first, second, third and / or
Alternatively, a salt formed of a polymeric substance having a quaternary amino group and a substance having a carboxyl group is included in a gel matrix to release the substance having the carboxyl group and adsorb bile acid and / or long chain fatty acid. The present invention has been completed by finding a gel-like composition having the above property.

That is, the present invention includes (1) a salt formed from a polymer substance having a primary, secondary, tertiary and / or quaternary amino group and a substance having a carboxyl group in a gel matrix. A gel composition having a property of releasing the substance having a carboxyl group and adsorbing bile acid and / or long-chain fatty acid, (2) primary, secondary, tertiary and / or
Alternatively, the polymer substance having a quaternary amino group is chitosan, and the gel composition according to (1), (3)
The gel-like composition according to (1), wherein the substance having a carboxyl group is selected from the group consisting of lactic acid, malic acid, citric acid, benzoic acid, nicotinic acid, and acidic amino acids.
(4) The gel matrix is alginate gel, agar,
The gel composition according to (1), which is selected from the group consisting of pectin, gelatin, collagen, and glycomannan, and (5) the gel composition according to (1), which forms gel beads.

As an example thereof, the present inventors have proposed a gel comprising a seaweed-derived natural polysaccharide alginate gel containing lactate of chitosan (β-1,4-poly-D-glucosamine) which is a basic polysaccharide. It has been found that the composition having a shape has a property of strongly adsorbing bile acid. Chitosan adsorbs various physiologically active substances such as hepatitis virus (JP-A-59-105843), glutathione (JP-A-52-94485), and erythropoietin (JP-A-56-53696). It is known. However, it is completely unknown that the chitosan salt contained in the gel adsorbs bile acid,
This is a new finding. In the present specification, the bile acids mean primary bile acids such as taurocholic acid, glycocholic acid and glycochenodeoxycholic acid, and secondary bile acids such as taurodeoxycholic acid.

[0016]

BEST MODE FOR CARRYING OUT THE INVENTION As the polymer substance having a primary, secondary, tertiary and / or quaternary amino group, for example, one having a polysaccharide skeleton is used. In addition, 1 in the monomer
The number of secondary, secondary, tertiary and / or quaternary amino groups is not particularly limited, but for example, primary, secondary, or tertiary for one sugar molecule
Those containing about one primary and / or quaternary amino group are used. A suitable example is chitosan. Chitosan is a compound harmless to the living body that can be obtained at low cost by deacetylating a large amount of naturally occurring chitin in the form of a major component of the exoskeleton of crustaceans, and has high utility value in the present invention.

Examples of the substance having a carboxyl group include lactic acid, malic acid, citric acid, benzoic acid, nicotinic acid and acidic amino acids (aspartic acid, glutamic acid, etc.).

Examples of the gel matrix include alginic acid gel, agar, pectin, gelatin, collagen and glycomannan.

There is no particular limitation on the method for forming a salt of a polymeric substance having a primary, secondary, tertiary and / or quaternary amino group and a substance having a carboxyl group, and any known means may be used. Good.

There is no particular limitation on the method of incorporating a salt formed from a polymer substance having a primary, secondary, tertiary and / or quaternary amino group and a substance having a carboxyl group into a gel matrix. Any known means may be used.

The gel composition of the present invention can take any form depending on its application, and can be used, for example, in the form of gel beads. It can also be coated with any compound or reinforced with any polymer complex. Further, it can be mixed in foods or pharmaceutical preparations.

[0022]

EXAMPLES The present invention will be described below in detail with reference to examples, but the present invention is not limited to these examples.

Example 1 Preparation of Alginate Gel-Like Composition Including Chitosan-Lactate A concentration of 0.75 to 2.0% sodium alginate (manufactured by Nacalai Tesque) was added to chitosan (Kimitsu Chemical Industry, Grade F). Was added to the system so as to be 5%, and was uniformly dispersed while stirring. 0.2 g of this solution was dissolved in lactic acid (Wako Pure Chemical Industries, special grade) to a final concentration of 1%.
5M calcium chloride dihydrate (Nacalai Tesque, special grade)
To the solution (20 ml) was added dropwise with a peristaltic pump while stirring. The alginic acid gel beads formed instantly were heated at 37 ° C. for 3 to 4 hours as they were, and then the gel beads were taken out with a sieve, transferred to 500 ml of water, and left at room temperature overnight. The gel beads were taken out, washed with ethanol, dried at 35 ° C., and then dried and stored in a desiccator under reduced pressure to obtain dry gel beads (phosphorus pentoxide was used as a desiccant).

Example 2 In Vitro Measurement of Bile Acid Uptake Sodium taurocholate (Nacalai Tesque, special grade) or sodium glycocholate (Nacalai Tesque, special grade) was used as the bile acid.

Dry gel beads (dry weight: about 50 mg) prepared according to Example 1 were added to an L-shaped tube containing 15 ml of a 2 mM aqueous bile acid solution, and the mixture was shaken at 37 ° C. at 67 times / min.
Aqueous solution samples are taken over time and the amount of bile acid in the system is determined by HPLC.
Was measured by As a negative control, dry gel beads prepared by the same method as in Example 1 except that chitosan was not added were used to examine the uptake of bile acid by the same method as described above.
The HPLC conditions are COSMOSIL PACKED COLUMN 5 column.
C18-MS (4.6 x 150 mm), eluent was methanol: 30 mM phosphate buffer (pH 3.4): acetonitrile = 6: 3: 1, flow rate was 0.
It was 8 ml / min. Detection was performed by absorbance at 240 nm.

FIG. 1 shows the experimental results when sodium taurocholate was used as the bile acid. The bile acid in the system was gradually incorporated into alginate gel beads containing chitosan lactate, and was almost completed in about 1 hour. At this time, swelling of the gel beads in the solution was visually observed. On the other hand, with chitosan non-dispersed gel beads, no bile acid uptake was observed even after shaking for 4 hours.

FIG. 2 compares the amounts of bile acid uptake when the alginate gel beads containing chitosan-lactate of the present invention contained water (hydrogel beads) and did not contain water (dry gel beads). It was done. From this figure it is clear that bile acid uptake occurs with or without water content in the gel.

FIG. 3 compares the amounts of uptake by alginic acid gel beads containing the chitosan lactate of the present invention when sodium taurocholate was used as the bile acid and when sodium glycocholate was used.
It was confirmed that both the glycine conjugate (sodium glycocholate) and the taurine conjugate (sodium taurocholate), which are the main bile acids in humans, were taken up.

FIG. 4 shows the results of examining the uptake amount of bile acid when malic acid or citric acid was used instead of lactic acid as the carboxylic acid forming a salt with chitosan in the preparation of the gel beads of the present invention. Show. From this figure, the chitosan salt in the alginate gel beads for bile acid uptake is
It has been found that not only lactate salts but also other polycarboxylic acid salts recognized as food additives can be used.

In FIG. 5, in the preparation of the gel beads of the present invention, the amount of uptake of bile acid was examined when glutamic acid or aspartic acid which is an acidic amino acid was used instead of lactic acid as the carboxylic acid forming a salt with chitosan. The results are shown below. It has been found that the chitosan salt included in the alginic acid gel beads for bile acid uptake can use acidic amino acids in addition to lactate.

Alginic acid gel beads containing chitosan-nicotinate were prepared (dry weight: about 50 mg), and the beads were dissolved in 500 ml of Japanese Pharmacopoeia Disintegration Test Method No. 1 solution (about pH 1.2) at 37 ° C. for 2 hours. No change in appearance was observed in the gel beads even after stirring for a long time. Furthermore, it was confirmed that the gel beads treated with this treatment incorporated bile acid. It was also found that the amount of bile acid uptake can be controlled by the amount of chitosan contained in the alginate gel beads.

Further, even when additives such as curdlan were added to alginic acid gel beads containing chitosan-nicotinate and heat-treated at 90 ° C. for 20 minutes, the same uptake of bile acid was observed.

[Example 3] Measurement of bile acid uptake in vivo (in vivo) Lactic acid-added alginate chitosan gel beads and lactic acid-unadded alginate chitosan gel beads were orally administered to rats, respectively, and bile acid and lactic acid incorporated into the gel beads were measured. I checked the quantity. The measuring method is as follows.

The lactic acid-added chitosan alginate gel beads consist of 0.75% sodium alginate, 5% chitosan and 1%.
Prepared according to Example 1 with the addition of lactic acid. Lactic acid-free chitosan alginate gel beads were prepared according to Example 1 by blending 0.75% sodium alginate and 5% chitosan. For SD male rats (body weight 376.0 to 454.4 g) that had been fasted from the day before the experiment, gel beads were packed in a tube, placed on the tip of a stomach probe, and orally administered with water (4 ml) (n = 3). After 90 minutes, particles thought to be alginate chitosan gel beads were taken out from the small intestine of the rat.

Table 1 shows the dose and recovery of chitosan alginate gel beads to rats. Lactic acid was added to Samples 1 to 3 and lactic acid was not added to Samples 4 to 6.

[0036]

[Table 1] ──────────────────────────────────── Sample number Rat weight / g Dose / mg Number of administered particles Number of recovered particles ───────────── From stomach to small intestine ─────────────────────────── ────────── 1 376.0 51.2 − − Approx. 40 2 401.2 49.6 − − Approx. 40 3 * 454.4 50.1 − − 9 ─────────────────── ───────────────── 4 434.3 50.0 29 27 0 5 418.2 49.4 28 19 9 6 413.3 51.5 31 22 7 ──────────────── ───────────────────── * Sample No. 3 was able to administer only about 1/3 of the prescribed dose. The gel beads were washed with water, dried at 40 ° C. for 48 hours and then extracted with water to measure the amounts of bile acid and lactic acid in the gel. Bile acid is measured by "total bile acid-Test Wako"
(Measurement range: 0-200 μmol / l, Wako Pure Chemical Industries), UV-
The absorbance at 560 nm was measured by 1600 (manufactured by Shimadzu Corporation). L-lactic acid is F-kit L-lactic acid (measurement range: 0-200g / l,
The absorbance at 340 nm was measured with UV-1600 (manufactured by Shimadzu Corporation) using Boehringer Mannheim. Table 2 shows the amount of bile acid in the alginate chitosan gel beads.

[0037]

[Table 2] ──────────────────────────────────── Sample number Sample weight in extraction water For extraction Total bile acid concentration per 1 g of beads Volume of water Total bile acid content (μmol / l) (mg) (ml) (μmol / g) ───────────────── ─────────────────── 1 18260.57 43.92 1.0 415.77 2 19218.96 37.71 1.0 509.65 3 5242.16 8.76 1.0 598.42 ──────────────── ──────────────────── 4 619.03 10.35 0.5 29.90 5 (grains) * 2723.40 6.84 0.5 199.08 5 301.84 4.28 0.5 35.26 6 (grains) * 5697.48 7.62 0.5 373.85 6 472.37 11.15 0.5 21.18 ──────────────────────────────────── * Sample number 5 (grain), 6 (grain) ) Indicates that if the gel beads were collected in granular form from the rat body, No. 5 and 6 show the case where gel beads from rat body has not been recovered in particulate form. FIG. 6 shows the amount of bile acid in the alginate chitosan gel beads.

When the chitosan alginate gel beads were administered to rats, the amount of bile acid incorporated into the beads was measured. As a result, the amount of bile acid per 1 g of lactic acid-added chitosan alginate beads (Sample Nos. 1 to 3) was about 400 to 600 μm.
In contrast to the mol / g, lactic acid-free chitosan alginate gel beads in which lactic acid was recovered [Sample No. 5 (grain),
6 (grains)] The amount of bile acid per 1 g is about 200 to 400 μmol /
It was as low as g.

From this, it was revealed that alginic acid chitosan gel beads take up bile acid regardless of whether lactic acid is added or not, but lactic acid-added chitosan alginate beads take in more bile acid.

[0040]

The gel composition of the present invention has the property of adsorbing bile acids and long-chain fatty acids and the property of releasing substances taken up in the gel matrix, and can be used in medicine, food, environmental protection, etc. It is useful in a wide range of industries.

In particular, an alginate gel composition containing chitosan-lactate is ingested orally and then enters the human small intestine while maintaining its shape to take up bile acid and prevent its reabsorption. Possibly having a function. Therefore, for example, it can be used as a food for specified health use for hyperlipidemic patients. Further, it can be expected to function as a cholesterol-limited food and a dietary fiber, and it can be a part of effective use of natural product resources in Japan, which is rich in marine resources.

Further, as an example of utilizing the property of adsorbing bile acids and long-chain fatty acids and the property of releasing substances taken up in the gel matrix, alginic acid gel beads containing chitosan-nicotinate are used for oral administration. 1) after ingestion
The slow release of nicotinic acid in the digestive tract (stomach, upper part of the small intestine) prevents the flushing of the skin, which is a side effect of the nicotinic acid. It is thought that it can be used as an antihyperlipidemic preparation.

Further, the alginic acid composition itself can be reinforced with a polymer complex, and it can be a functional food or a formulation in which the shape in the digestive tract can be positively controlled.

[Brief description of drawings]

FIG. 1 shows adsorption of bile acids on alginate chitosan gel beads containing chitosan-lactate when sodium taurocholate is used as the bile acid.

FIG. 2 is a diagram comparing the uptake amount of bile acid when alginic acid gel beads containing chitosan-lactate contain water (hydrogel beads) and when water does not contain (dry gel beads).

FIG. 3 shows the case of using sodium taurocholate as the bile acid and the case of using sodium glycocholate.
It is the figure which compared the uptake amount by the alginic acid gel beads containing chitosan lactate.

FIG. 4 is a diagram showing the results of examining the uptake amount of bile acid when malic acid or citric acid was used instead of lactic acid as the carboxylic acid forming a salt with chitosan in the preparation of gel beads.

FIG. 5 is a graph showing the results of examining the amount of bile acid uptake when glutamic acid or aspartic acid, which is an acidic amino acid, was used instead of lactic acid as the carboxylic acid forming a salt with chitosan in the preparation of gel beads. .

FIG. 6 is a diagram showing the amounts of bile acid and lactic acid incorporated into gel beads when lactic acid-added chitosan alginate gel beads and lactic acid-free chitosan alginate gel beads were orally administered to rats.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display area A61K 47/36 A61K 47/36 F 47/42 47/42 B CF B01J 2/08 B01J 2 / 08 C08B 37/08 C08B 37/08 A

Claims (5)

[Claims] 1. A gel matrix containing a salt formed of a polymer substance having a primary, secondary, tertiary and / or quaternary amino group and a substance having a carboxyl group, and having the carboxyl group. A gel composition having a property of releasing a substance and adsorbing a bile acid and / or a long chain fatty acid. 2. The gel composition according to claim 1, wherein the polymer substance having a primary, secondary, tertiary and / or quaternary amino group is chitosan. 3. The substance having a carboxyl group is lactic acid,
The gel composition according to claim 1, which is selected from the group consisting of malic acid, citric acid, benzoic acid, nicotinic acid, and acidic amino acids. 4. The gel matrix is alginate gel,
The gel composition according to claim 1, which is selected from the group consisting of agar, pectin, gelatin, collagen and glycomannan. 5. The gel composition according to claim 1, which is in the form of gel beads.