JPH09278661A - Suspension formulation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To prepare a readily drinkable suspension formulation, soft and pleasant to the palate, having masked strong bitterness of a digestive agent and stable and good in uniformity even when preserved for a long period. SOLUTION: This suspension formulation comprises 0.01-0.05wt./vol.% digestive agent (e.g. ursodeoxycholic acid), 2-20wt./vol.% inorganic antacid (e.g. magnesium metasilicate aluminate), 0.01-5wt./vol.% xanthan gum and 0.1-20wt./vol.% modified starch (e.g. hydroxypropyl starch) as active ingredients. Furthermore, usual ingredients are suitably blended therewith and the resultant blend as converted into a uniform suspension by using a homogenizer, etc., according to a conventional method and, as necessary, sterilized by heating, etc., to afford the objective substance. The suspension formulation is capable of maintaining a stable suspended state even when preserved for a long period and the redispersion thereof can readily by carried out in a short time even in the case of performing the sedimenting and separating. Furthermore, the suspension formulation is effective in promoting digestion and reducing symptoms such as gastric and abdominal inflations, gastralgia or gastric hyperacidity caused by dyspepsia, anorexia, excessive eating, a dull feeling in the stomach or lying of foods heavy in the stomach.

Description

Detailed Description of the Invention

[0001]

The present invention relates to a digestive agent, an inorganic antacid,
It relates to a suspension agent comprising xanthan gum and modified starch.

[0002]

2. Description of the Related Art Preparations such as digestive agents and antacids are used for promoting digestion, dyspepsia, loss of appetite, overeating, stomach upset, chest tightness, bloating due to indigestion, gastric pain, hypergastric acid, etc. Used to improve symptoms. The above-mentioned preparations were usually used as solid preparations such as granules or tablets. The bitterness of digestive choleretic agents is so strong that they cannot be accepted by users, so in order to alleviate this, solid coatings can be done by film coating or inclusion compounding means. This is because it is easy. However, the solid preparation has a problem that it takes time to disintegrate or disperse in the stomach after taking the drug, resulting in delaying the onset of the medicinal effect and not rapidly improving the symptoms.
As a method for solving this problem, the emergence of a liquid agent in which the active ingredient in the preparation can be easily dispersed in the stomach has been desired. In addition, liquids using such digestive agents and antacids are uniformly suspended and dispersed in order to improve the texture of the tongue and make it easy to drink, and from the aspect of taste, the strong bitterness of the digestive agent is sufficient. Must be masked by. However, it is not easy to uniformly suspend a liquid agent containing an inorganic antacid, and to mask the bitterness of the digestive agent. Even if it can be done, the masking of bitterness becomes incomplete, and a suspension agent that makes them compatible has not been reported yet. Further, even if the stability of the liquid agent is good, it deteriorates after being stored for a long period of time, and there is a problem that a great deal of labor is required when it is once separated by sedimentation and then dispersed again.

[0003]

DISCLOSURE OF THE INVENTION The present invention has a good texture on the tongue and is easy to drink, masks the strong bitterness of the digestive agent, and has stable ingredients such as an inorganic antacid even after long-term storage. An object of the present invention is to provide a suspension agent which can maintain a turbid state and can be easily redispersed even if it is once separated by sedimentation.

[0004]

Means for Solving the Problems As a result of intensive studies to solve the above-mentioned problems, the present inventors used xanthan gum and modified starch in combination as a dispersant to mask the bitterness of the digestive agent. It has been found that a stable suspended state can be maintained even after long-term storage. The present invention has been made based on such findings. That is, the present invention is 0.01 to 0.05 W
/ V% digestive agent, 2-20 W / V% inorganic antacid, 0.
01-5 W / V% xanthan gum, 0.1-5 W /
It is a suspension agent characterized by comprising V% of modified starch.

The digestive agents used in the present invention include choleretic agents such as ursodesoxycholic acid, oxycholanic acid, dehydrocholic acid, cholic acid, bile powder,
Bile extract, animal gall, etc. can be mentioned. In the present invention, one type or two or more types of the above-mentioned choleretic agents can be used in combination. The compounding amount of the above-mentioned bile agent is 0.01 to 0.05 W / V%, preferably 0.01 to 0.025 W / V% with respect to the total amount of the suspension.

The inorganic antacid is not particularly limited, but a water-insoluble antacid is more preferable in the present invention. Examples of the water-insoluble inorganic antacid include water-insoluble metal oxides, metal hydroxides, metal acid salts and complex metal compounds. More specifically,
For example, metal oxides such as magnesium oxide, aluminum hydroxide, metal hydroxides such as magnesium hydroxide,
Metal carbonates such as calcium carbonate and magnesium carbonate,
Alternatively, it is possible to use one kind or two or more kinds appropriately selected from composite metal compounds such as magnesium aluminate metasilicate, magnesium aluminate silicate, alumina magnesia hydroxide, and synthetic hydroxytalcite.
A more preferable combination of the present invention is the case where aluminum hydroxide, magnesium hydroxide, magnesium aluminometasilicate, magnesium aluminate silicate, or synthetic hydroxytalcite is used alone or in combination of two or more kinds. The compounding amount of these antacids is usually 2 to 20 W / V%, preferably 5 to 15 W / V% as a solid matter with respect to the total amount of the suspension agent. The above-mentioned inorganic antacid may be derived from a natural product or a synthetic product and is not particularly limited. However, when a powdered product is used, it is preferable to use it by pulverizing it into a fine powder as much as possible. Further, when the synthetic product is used, a paste-like product before drying the synthetic product can be used if necessary. The particle size of the inorganic antacid is preferably 0.1 to 10 μm, particularly preferably 0.1 to 5 μm. In the present invention, in addition to the above antacid, a water-soluble inorganic antacid such as sodium hydrogen carbonate can be added if necessary. The amount of these water-soluble inorganic antacids to be used can be freely used as long as it does not affect the suspension uniformity and redispersibility of the suspension of the present invention.

Examples of the xanthan gum include natural gums obtained by refining fermented polysaccharides, those that are clear and soluble in water and those that are opaque and dispersed. In the present invention, any of these may be used or they may be used in combination. More specific examples include commercially available products such as Echo Gum (trade name, manufactured by Dainippon Pharmaceutical), Neosoft (trade name, manufactured by Kojin), and Rodingel (trade name, manufactured by Ron Poulenc Japan). The blending amount of these xanthan gum is 0.01 to 5 W / V%, preferably 0.05 to 1 W / V% with respect to the total amount of the suspension agent.

Examples of the modified starch include hydroxypropyl starch, which is a starch derivative, and partially pregelatinized starch which is partially pregelatinized by heat-treating starch.
And dextrin obtained by hydrolysis with acid and the like. More specifically, commercially available products such as hydroxypropyl starch such as HPS (trade name, manufactured by Freund Sangyo); PCS (trade name, manufactured by Asahi Kasei Kogyo)
And partially pregelatinized starch such as Starch 1500 (trade name, manufactured by Nippon Colorcon); dextrin (trade name,
Examples thereof include dextrin such as Nitto Kagaku) or Paindex (trade name, manufactured by Matsutani Chemical Co., Ltd.).
The blending ratio of the modified starch is preferably 0.1 to 20 W / V%, and more preferably 1 to 5 W / V% with respect to the total amount of the suspension agent.

In addition to the above components, the suspension of the present invention comprises
Polyhydric alcohols such as D-sorbitol, concentrated glycerin or mannitol, crude drugs such as cinnamon bark, clove, red bud, licorice, antifoaming agents such as dimethylpolysiloxane or silicone resin, preservatives such as methyl paraoxybenzoate and sodium benzoate. If desired, flavoring agents such as peppermint oil, menthol, and lemon oil, and sweetening agents such as sodium saccharin or glycyrrhizic acid can be added. These ingredients are used in the production of pharmaceuticals and foods,
Those generally used can be used alone or in combination, and are not particularly limited.

The suspension of the present invention can be produced by a conventional method for producing an aqueous suspension. That is, the above-mentioned components may be added to a container containing an appropriate amount of purified water as it is or after being dissolved in purified water in advance, and a homogenizer or the like may prepare a uniform suspension for sterilization by heating if necessary.
As a suitable combination of the suspension agent of the present invention, for example, a combination of D-sorbitol, xanthan gum, hydroxypropyl starch, magnesium aluminometasilicate and ursodesoxycholic acid can be mentioned.

The method for producing the suspension of the present invention and the suspension for comparison and comparison are shown in the following Examples and Reference Examples, and Table 1 shows each component in the suspension.

【Example】

Example 1 620 g of purified water was put in a 1.5 L container, and 200 g of D-sorbitol, 3 g of xanthan gum, 45 g of hydroxypropyl starch, 1 g of methyl paraoxybenzoate, 80 g of magnesium aluminometasilicate, while stirring.
0.2 g of ursodesoxycholic acid was sequentially added to each and uniformly dispersed, and the temperature of the dispersion was further raised to 80 ° C. After cooling, 1 g of L-menthol was added, and the total amount of liquid was adjusted to 1000 ml with purified water. The viscosity of the obtained suspension was 182 cp. The main prescription ingredients are shown in Table 1. Examples 2 to 3 According to the method of Example 1, 1 of the suspension agent having the formulation shown in Table 1 was prepared.
Each 000 ml was manufactured. The viscosities of the obtained suspensions were 98 cp and 220 cp, respectively. Example 4 According to the method of Example 1, 1 suspension liquid was prepared according to the formulation shown in Table 1.
After preparing 000 ml, it was treated with a homogenizer. The viscosity of the obtained suspension was 142 cp.

Reference Examples 1 to 3 Reference Examples 1 to 3 of the formulations shown in Table 1 according to the method of Example 1.
1000 ml of each suspension was prepared. The viscosities of the resulting suspensions were 16 cp, 111 cp and 96, respectively.
cp.

[0013]

[Table 1]

I. Stability test (settling and redispersibility):
Stability tests (sedimentability and redispersibility) were conducted using the suspensions prepared in the above Examples and Reference Examples. The results were as shown in Table 2.

[0015]

[Table 2]

From the results shown in Table 2, the suspensions of the present invention obtained by the formulations of Examples 1 to 4 are resistant to sedimentation and separation even after long-term storage, and have extremely good redispersibility. I understand. On the other hand, the suspension of the formulation of Reference Example 1 is a formulation that is extremely difficult to re-disperse because it undergoes severe sedimentation separation. The suspension agent of Reference Example 2 is unlikely to cause sedimentation and separation and has good dispersibility. Further, the suspension agent of Reference Example 3 has a larger sedimentation separation than that of Reference Example 1, but is still large,
Moreover, the settling rate tends to gradually increase under heating conditions, and it is difficult to redisperse it.

Test method (1) Room temperature static test: 200 ml of the suspension immediately after production was placed in a cylindrical glass bottle,
After standing at room temperature for 3 months, the height of the supernatant was read and the ratio to the total height was calculated. (2) 40 ° C. static test 200 ml of the suspension immediately after production was placed in a glass bottle between columns,
After standing at 40 ° C. for 3 months, the same measurement as above was performed. (3) Static test at 50 ° C. 200 ml of the suspension immediately after production was placed in a glass bottle between columns,
After standing at 50 ° C. for 2 months, the same measurement as above was performed. (4) Centrifugation test 50 ml of the suspension immediately after production was placed in a glass centrifuge tube with a stopper and centrifuged at 2000 rpm for 15 minutes. I calculated. (5) Redispersion test (1) The sample was left standing at room temperature and 40 ° C. for 3 months and at 50 ° C. for 2 months, and the amount of the supernatant was read. The suspension was shaken back and forth to observe the state of the suspension every minute, and the time until uniform dispersion was obtained in minutes. (6) Redispersibility (2) The sample after the centrifugation test is inverted up to 20 minutes per minute.
The state of the suspension was observed every 1 minute by shaking with 0 reciprocations, and the time until uniform dispersion was obtained in minutes.

II. Bitterness Evaluation Test A bitterness evaluation test was carried out using the suspensions prepared in Examples and Reference Examples. The results were as shown in Table 3. (Test method) The bitterness was evaluated by a bitterness sensory test by 10 panelists (8 boys and 2 girls). Each panelist evaluated the degree of bitterness after containing 10 ml of the sample in the mouth for 30 seconds. The bitterness is indicated by a five-point standard score of very bitter (5 points), bitter (4 points), a little bitter (3 points), hardly bitter (2 points) and no bitterness (1 point). The overall evaluation score was obtained by multiplying the number of panelists corresponding to each standard. The higher the overall evaluation score, the stronger the bitterness, and the smaller the score, the weaker the bitterness.

From the results shown in Table 3 below, it can be seen that the suspensions of the present invention obtained by the formulations of Examples 1 to 4 hardly give the bitterness of ursodesoxycholic acid. On the other hand, the suspension of the formulation of Reference Example 1 had a very strong bitterness. The suspension of Reference Example 2 is one in which the bitterness is not masked. The suspension of Reference Example 3 shows a slight improvement in the suppression of bitterness, but it is found that the suppression is insufficient as compared with the suspension of the present invention. As a result, the suspensions prepared by the production methods of Examples 1 to 4 are considered to have bitterness masked due to the synergistic effect of mixing xanthan gum and hydroxypropyl starch. By the way, Reference Examples 2 and 3 which were independently blended
In the case of, the bitterness masking effect is not seen.

[0020]

[Table 3]

From the above results, the suspensions of the present invention obtained by the formulations of Examples 1 to 4 described above are unlikely to cause sedimentation separation even when stored for a long period of time, and have extremely good redispersibility,
Moreover, it can be seen that the bitterness of ursodesoxycholic acid is hardly felt. On the other hand, the suspension of the formulation of Reference Example 1 was a formulation that was extremely difficult to re-disperse because it had a strong sedimentation separation, and had a very strong bitterness. The suspension agent of Reference Example 2 hardly causes sedimentation and has good dispersibility, but the bitterness is not masked. Also, the suspension agent of Reference Example 3 has a larger sedimentation separation than that of Reference Example 1, but it is still large, and the sedimentation rate tends to gradually increase under heating conditions, and it is difficult to redisperse it. It is accompanied. In this case, the suppression of bitterness was slightly improved, but it was found that the suppression was insufficient as compared with the suspension of the present invention. As a result, the suspensions prepared by the production methods of Examples 1 to 4 are considered to have bitterness masked due to the synergistic effect of mixing xanthan gum and hydroxypropyl starch. By the way, in the case of Reference Examples 2 and 3 which were blended alone, no bitterness masking effect was observed. Further, the suspension of the present invention is not only good in uniformity and has no bitterness, but also has a good texture and is easy to take.

[0022]

EFFECTS OF THE INVENTION According to the present invention, the texture and the like are easy to drink, the strong bitterness of the digestive agent is masked, and the components such as the inorganic antacid maintain a stable suspended state even after long-term storage. Further, it was possible to provide a suspension agent which can be easily redispersed even when it is once separated by sedimentation. The suspension of the present invention has a feature that it can be easily redispersed even when it is precipitated and separated when stored for a long period of time, and that it can be carried out in a short time.
It is extremely useful as a suspension agent for improving symptoms such as anorexia, overeating, stomach upset, chest tightness, bloating due to indigestion, gastric pain, and gastric hyperacidity.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display area A61K 35/413 A61K 35/413 47/36 47/36 H L // (A61K 33/06 31: 575) (A61K 33/06 35: 413) (A61K 33/06 35:37)

Claims (4)

[Claims] 1. A digestive agent of 0.01 to 0.05 W / V%, 2.
-20 W / V% of inorganic antacid, 0.01-5 W / V% of xanthan gum, 0.1-20 W / V% of modified starch. 2. A patent wherein the digestive agent is one or more selected from the group consisting of ursodesoxycholic acid, oxycholanic acid, dehydrocholic acid, cholic acid, bile powder, bile extract and animal gall. The suspension agent according to claim 1. 3. The inorganic antacid selected from the group of water-insoluble inorganic antacids consisting of magnesium aluminometasilicate, magnesium aluminate silicate, synthetic hydrotalcite, aluminum hydroxide gel, magnesium hydroxide. The suspension agent according to claim 1, which is one kind or two or more kinds. 4. The suspension according to claim 1, wherein the modified starch is one kind or two or more kinds selected from hydroxypropyl starch, partially pregelatinized starches and dextrins.