JP2001181212A - Heat-resistant gel-like oral composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a medicine-containing oral gel-like composition which has good heat resistance against thermal sterilization and good strength stability for a long period and does not cause syneresis. SOLUTION: Agar, xanthan gum and/or galactomannan are used as a gelling agent.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a gel oral composition having heat resistance and excellent storage stability, and more particularly to a gel oral pharmaceutical composition.

[0002]

2. Description of the Related Art Conventionally, powdery ion exchange resin drugs, such as cholestyramine, which are hardly soluble in water, have a large dose and have a strong discomfort in the oral cavity of patients when taken orally. Poor compliance. In order to solve such a problem, there is a report (for example, Japanese Patent Application No. 63-230636) that improves the compliance by gelling a resin drug.

[0003] However, the gel oral pharmaceutical compositions reported so far have not yet been satisfactory in heat resistance, storage stability and gel stability.

[0004] For example, a lactulose-containing jelly-like intestinal function improving preparation (JP-A-5-163151) is disclosed in
When stored at 0 ° C., the gel strength is reduced.

[0005] In consideration of its pharmaceutical properties, oral gel-form pharmaceuticals are not suitable for other oral solid pharmaceuticals (tablets, powders, granules,
Capsules) and must be sterile. For this reason, heat sterilization at 121 ° C. or higher where almost all microorganisms are killed is desirable. However, when a drug-containing gel composition is heat-sterilized at 121 ° C., a change in the bioavailability of the drug contained due to a decrease in gel strength, a change in physical properties such as a change in texture, etc. often occur, and the quality as a drug -Brings fatal flaws in effectiveness and safety.

As described above, in the prior art, although an oral gel pharmaceutical composition having improved drug compliance has been provided, stability such as gel physical properties which can be sterilized by heating and which is important as the quality of the pharmaceutical is provided. There is no report on a gel-type oral pharmaceutical composition which is guaranteed.

[0007]

Accordingly, an object of the present invention is to provide a gel oral composition having heat resistance against heat sterilization, storage stability and long-term gel stability.

[0008]

Means for Solving the Problems The present inventors have made intensive studies to solve the above-mentioned problems, and as a result, agar, xanthan gum and / or xanthan gum have been used as gelling agents for gel compositions containing drug resins. Alternatively, by blending galactomannan in a specific ratio, a gel having heat resistance (gelling again after sterilization and having a certain strength) against heat sterilization at 121 ° C. and excellent gel stability. It has been found that an oral composition can be obtained, and the present invention has been completed.

That is, the present invention provides (1) a heat-resistant oral gel composition having the following properties: (a) As a gelling agent, 0.20 to 1.00% (weight) of agar based on the total weight of the gel composition. ), Xanthan gum 0.10 ~
0.70% (weight), and / or galactomannan 0.10-0.
(B) 0.005 as measured by a texture analyzer
0.040 N / mm ² , preferably 0.010 to 0.030
(2) a heat-resistant gel-like oral composition according to (1), which has a gel strength of N / mm ² and contains an effective amount of a pharmaceutical;
The heat-resistant gel-form oral composition according to (2), wherein the effective amount of the drug is calcium polystyrene sulfonate.

Hereinafter, the present invention will be described in detail.

[0011]

BEST MODE FOR CARRYING OUT THE INVENTION The gel composition of the present invention specifies the gel strength in order to prevent sedimentation and segregation of the contained drug. Specifically, for example, the measured value of a texture analyzer (a device that quantifies and measures changes in physical properties caused by applying operations such as compression and tension to an object) and is 0.005 to 0.040 N / mm ² , preferably Is 0.010 to 0.030
Setting the gel strength to fall in the range of N / mm ^2. For that purpose, agar, xanthan gum and / or galactomannan are blended in a specific ratio as a gelling agent.

When agar and xanthan gum are used as gelling agents, agar is 0.20-1.00% and xanthan gum is 0.10-0.1% based on the total weight of the gel oral composition.
70%, preferably 0.30 to 0.70% agar and 0.18 to 0.40% xanthan gum.

When agar and galactomannan (for example, locust bean gum) are used as the gelling agent, the amount of agar is 0.20 to 0.20% based on the total weight of the gel oral composition.
1.00%, locust bean gum 0.10-0.70%, preferably agar 0.25-0.50%, locust bean gum 0.
It mixes so that it may become 10-0.30%.

As a gelling agent, agar, xanthan gum,
And galactomannan (eg locust bean gum)
When used, agar is 0.20-1.00%, xanthan gum is 0.10-0.1% based on the total weight of the gel oral composition.
0.70%, locust bean gum 0.10-0.70%, preferably agar 0.20-0.50%, xanthan gum 0.10-0.
30%, locust bean gum is blended to be 0.10 ~ 0.30%.

Agar for use in the gel oral composition of the present invention;
Xanthan gum and galactomannan can be used as long as they are usually used as a gelling agent for jelly, but agar is preferably used because of its high gel strength in terms of gel stability (for example, Ina Food Industry Co., Ltd.). Company, Japanese Pharmacopoeia product PS-9, etc.). Examples of the galactomannan include locust bean gum, guar gum, tara gum, glucomannan and the like.

In the present invention, starch can be added for the purpose of preventing syneresis. The starches used for the purpose of preventing syneresis in the gel oral composition of the present invention are a single composition or a mixture of waxy corn starch, pregelatinized starch, partially pregelatinized starch, hydroxypropyl starch, carboxymethyl starch and the like. Yes, starches used in ordinary pharmaceutical compositions or foods can be used without particular limitation. Further, the content of starches in the gel composition of the present invention is preferably 0.1 to 5.0% by weight, more preferably 1.0 to 2.0% by weight, based on the total amount of the composition.

Further, as the above-mentioned optional ingredients, saccharides, sweeteners, organic acids, organic acid salts, fruit juices, flavors, and other coloring agents commonly used in food jelly may be added as necessary. it can. As carbohydrates, purified sucrose,
Glucose, D-sorbitol, D-mannitol, xylitol, maltitol and the like can be exemplified. Examples of the sweetener include saccharin sodium, aspartame, stevia, glycyrrutin and the like. In addition, in addition to fruit juice, fruit flavor, coffee flavor,
Flavors such as spearmint taste can also be added. Examples of the stabilizer include ascorbic acid, sodium edetate, and tocopherol. As a buffer,
Examples include potassium chloride, sodium chloride, citric acid, sodium citrate, dipotassium phosphate, sodium phosphate, and the like. As preservatives, for example,
Examples thereof include ethyl paraoxybenzoate (ethylparaben), methyl paraoxybenzoate (methylparaben), and sorbic acid. Examples of the fragrance include flavors such as menthol and fruit juice, essential oils and the like.

The gel oral composition of the present invention contains, in addition to the above components, substances conventionally known as jelly bases and various optional components which are acceptable as additives for pharmaceuticals and foods and which can be orally administered. It is possible.

Drugs to be contained in the gel oral composition include not only non-absorbable drugs represented by resin drugs (for example, ion exchange resins such as cation exchange resins and anion exchange resins), but also Drugs can also be used. Examples of such non-absorbable drugs include cholestyramine, calcium polystyrene sulfonate, sodium polystyrene sulfonate, spherical adsorbed carbon, lactulose (JP-A-5-163151) and the like. Further, the absorbable drug, for example, terfenadine (JP-A-10-7565), ibuprofen (JP-A-10-18244)
9), domperidone (JP-A-10-7561), acetaminophen, loperamide hydrochloride, sodium picosulfate, bromhexine hydrochloride, theophylline, chromium pheniramine maleate, indomethacin, vitamins, cimetidine, ranitidine hydrochloride, clarithromycin ( Above JP 1
0-236983).

The oral gel composition of the present invention can be prepared according to the same method as that for preparing a conventionally known gel composition. For example, a gelling agent is dispersed in a dispersion medium at an appropriate temperature, and then a drug or food is added and dispersed.
It can be prepared by cooling and gelling. The optional component can be added at the same time as the gelling agent when the gelling agent is dispersed in a dispersion medium such as hot water, provided that the gelled oral composition of the present invention is not gelled. It can be added as needed.

Specifically, first, an appropriate amount of warm water at 80 to 95 ° C. is added as a dispersion medium to a base and optional components, and the mixture is stirred with a stirrer to be dispersed, dissolved, suspended, or the like. An appropriate amount of water as a dispersion medium is added to the agent and the optional components at room temperature, and the mixture is heated to 80 to 95 ° C. with stirring to disperse, dissolve, suspend, and the like. Thereafter, it is confirmed that the base and the optional components are sufficiently dissolved, and a drug or food is further added, and the mixture is dispersed, dissolved, suspended, or the like until uniform. The drug or food to be added, as well as the base and optional components, may be pulverized before addition, if necessary, for the purpose of improving texture or assisting dissolution. Thereafter, a predetermined amount such as a cup is filled and sealed, and the liquid is gelled by heating and sterilizing at an optional temperature of 121 ° C. or lower, followed by cooling, to obtain the gel composition of the present invention.

The gel oral composition thus prepared does not affect the gel strength or quality even if it is filled in a predetermined container, for example, a cup made of a polyresin, and sterilized by heating at 121 ° C. As a result, a gel oral composition excellent in storage stability, gel stability and texture can be obtained.

[0023]

EXAMPLES The present invention will be described below with reference to examples, but the present invention is not limited to these examples. In the following Examples 1 to 9 and Comparative Examples 1 to 4, the mixing ratio of each compounding agent for the preparation of the gel composition containing calcium polystyrene sulfonate is as shown in Table 1, except for the gelling agent and water. Are all the same.

[0024]

[Table 1]

[Examples 1 to 3] Agar + xanthan gum As a gelling agent, agar (Ina Food Industry Co., Ltd., product conforming to the Japanese Pharmacopoeia PS-9) and xanthan gum (Dainippon Pharmaceutical Co., Ltd., Echo Gum) were used. 1) 1.10 g: 0.55 g,
(2) 1.80 g: 0.90 g, or (3) 2.00
g: 1.00 g. The gelling agent, sucrose, and potassium sorbate were mixed well, and purified water was added to make a total amount of 300.00 g. The mixture was heated to 95 ° C. and stirred with a magnetic stirrer to dissolve the gelling agent until the mixture became homogeneous (solution of the gelling agent). Thereafter, calcium polystyrene sulfonate (hereinafter, referred to as “resin”), which is a hyperkalemia improving ion exchange resin, was added to the solution of the gelling agent and mixed well. The mixture was dispensed into a glass cup, sealed, cooled at room temperature, and solidified. Then 12
Autoclave sterilization was performed at 1 ° C for 20 minutes. After sterilization, the mixture was cooled to room temperature and solidified to obtain a resin-containing gel composition.

[Examples 4 to 6] Agar + locust bean gum As a gelling agent, agar and locust bean gum (Hercules Japan KK) were used.
40 g, (5) 1.10 g: 0.55 g, or (6)
It was used in a ratio of 1.42 g: 0.71 g. A resin-containing gel composition was obtained in the same manner as in Example 1.

[Examples 7 to 9] Agar + xanthan gum + locust bean gum As a gelling agent, agar, xanthan gum and locust bean gum (7) 0.75 g: 0.38: 0.38
g, (8) 1.25 g: 0.63: 0.63 g, or (9) 1.30 g: 0.65: 0.65.
A resin-containing gel composition was obtained in the same manner as in Example 1.

Comparative Examples 1 to 3 Agar alone Agar was used as a gelling agent, (1) 1.20 g, (2) 1.5.
4 g or (3) 2.00 g was used. A gel composition was obtained in the same manner as in Example 1. Comparative Example 4 Xanthan Gum + Locust Bean Gum As a gelling agent, xanthan gum and locust bean gum were used in a ratio of 1.60: 1.60. A resin-containing gel composition was obtained in the same manner as in Example 1. Examples 1 to 9 above
The resin-containing oral gel composition obtained in Comparative Examples 1 to 4 was subjected to the following (1) gel stability test, (2) evaluation of resin uniformity by visual observation, and (3) sensory test. did.

(1) Gel Stability Test The various gel compositions obtained in Examples 1 to 9 and Comparative Examples 1 to 4 were stored at 40 ° C. and 75% RH for one month.
Thereafter, syneresis of the various gel compositions was visually observed. Gel strength was measured before and after storage. Here, the gel strength is
Texture analyzer (TA-XT2i, Stable Micro Sy
5mm in diameter at a speed of 1mm / sec using stems (made in the UK)
Was applied with a cylindrical plunger, and the stress when the gel was broken was measured, and this was defined as the gel strength. The gel strength was measured for each of the Examples and Comparative Examples. Syneresis was hardly observed in all the gel compositions of Examples 1 to 9 and Comparative Examples 1 to 4. The measurement results before and after storage of the gel strength are shown in FIGS. In the figure, the bar indicates the standard deviation. From the figure, the gel strength of the gel compositions obtained in Examples 1 to 9 and Comparative Examples 1 to 3 was 4
It is clear that it does not decrease even after storage at 0 ° C. for one month. On the other hand, in Comparative Example 4, a decrease in gel strength was observed after storage.

(2) Visual Observation of Resin Dispersion The degree of resin dispersion was visually observed for each of the three gel compositions obtained in Examples 1 to 9 and Comparative Examples 1 to 4. As a result, in all of the gel compositions obtained in Examples 1 to 9 and Comparative Example 4, the resin was uniformly dispersed and was a uniform yellow-white gel. On the other hand, Comparative Example 1
In all of the samples No. to No. 3, sedimentation of the ocher resin was observed at the bottom.

(3) Sensory Test Eight panelists conducted sensory tests on the texture of each of the various gel compositions obtained in Examples 1 to 9 and Comparative Examples 1 to 4. As a result, for all the gel compositions obtained in Examples 1 to 9 and Comparative Example 4, all panelists obtained a good texture, but in all of Comparative Examples 1 to 3, all panelists I strongly felt the unpleasant texture.

From the above results, the resin-containing gel-containing oral composition of the present invention having the composition shown in Examples 1 to 9 can kill almost all microorganisms and can assure sterility. Also showed no syneresis, indicating that the stability of the gel strength and the uniform content of the resin drug were maintained. On the other hand, in Comparative Examples 1 to 3, the stability of the gel strength was maintained, but the uniform content of the resin drug was not maintained. In Comparative Example 4, the stability of the gel strength could not be maintained.

[0033]

The gel composition of the present invention can be heat-sterilized at 121 ° C., has no substantial decrease in gel strength for a long period of time, and has no syneresis. Are better. Therefore, a change in bioavailability due to a change in gel physical properties, an oral gel composition having excellent stability without a decrease in the effect of improving drug compliance,
Suitable for oral drugs and foods. In particular, it is possible to provide a stable oral pharmaceutical preparation that can easily take a certain amount of a resin drug having poor drug administration easily without water, and can be expected to improve compliance.

[Brief description of the drawings]

FIG. 1 is a graph showing the change over time in the gel strength of the gel compositions prepared in Examples 1 to 3.

FIG. 2 is a graph showing the change over time in the gel strength of the gel compositions prepared in Examples 4 to 6.

FIG. 3 is a graph showing the change over time in the gel strength of the gel compositions prepared in Examples 7 to 9.

FIG. 4 is a graph showing the change over time in the gel strength of the gel compositions prepared in Comparative Examples 1 to 3.

FIG. 5 is a graph showing the change over time in the gel strength of the gel composition prepared in Comparative Example 4.

 ──────────────────────────────────────────────────続 き Continued on the front page F term (reference) 4C076 AA49 BB01 CC11 DD41 DD67 EE30P EE58P FF36 4C086 AA01 AA02 FA04 FA07 MA03 MA05 MA35 MA52 NA03 ZA36 ZC33

Claims (3)

[Claims] 1. A heat-resistant gelled oral composition having the following properties: (a) As a gelling agent, agar 0.20 to 1.00% (weight), xanthan gum 0.10 to 0.1% based on the total weight of the gel composition.
0.70% (weight), and / or galactomannan 0.10-0.
(B) 0.005 as measured by a texture analyzer
0.040 N / mm ² , preferably 0.010 to 0.030
It has a gel strength of N / mm ² . 2. The heat-resistant gel-form oral composition according to claim 1, which contains an effective amount of a drug. 3. The heat-resistant gel-form oral composition according to claim 2, wherein the effective amount of the drug is calcium polystyrene sulfonate.