JP6688819B2 - Easy-to-dose solid formulation - Google Patents

Description

TECHNICAL FIELD The present invention relates to a coating composition for use in an easy-to-dose oral preparation with improved dosing properties and / or an easy-to-dose preparation with improved dissolution properties.

Currently, oral preparations account for a large proportion of pharmaceuticals, and solid preparations are the mainstream among them, but there are many preparations with large doses, and these preparations become large when made into single-unit tablets. The powders and granules are bulky because of their low density, which is often difficult for children and elderly people with low swallowing function to take.
A technique for rapidly disintegrating buccal tablets has been developed in order to improve the ingestability of tablets. However, since the content of the main drug in the whole tablet is small, it is not suitable for a preparation having a large content of the main drug. When the rapidly disintegrating tablet in the oral cavity is made large, the feeling of foreign matter in the oral cavity after disintegration becomes large. Further, when the main drug has an unpleasant taste such as bitterness, there are many problems such as difficulty in masking.
In addition, preparations such as liquids and jellies have been proposed as dosage forms with good dosing properties, but even with these dosage forms, it is difficult to mask the taste when the content of the main drug is high, and further, in water. It has a problem of ensuring stability.
An example of a high-dose formulation is a cholesterol-lowering agent containing cholestimide, which is an anion exchange resin, as the active ingredient, and a multi-unit formulation (mini-tablet package) is used to make the formulation compact and easy to take. Developed and sold. Patent No. 38835
In No. 05 (Patent Document 1), a mini-tablet disintegrates in the oral cavity by coating with a water-soluble polymer cellulose and then with ethyl cellulose in order to improve the ingestability of a multi-unit preparation of colestimide (mini tablet). It is described that it is possible to prevent aggregation and deterioration of ingestability. However, there is no description of a technique for improving the slipperiness of tablets to facilitate swallowing.

In recent years, as a method for facilitating swallowing of a solid agent, a technique using a gelling agent with good mucosal slippage is being developed. For example, in Japanese Patent Publication No. 2000-516222 (Patent Document 2), in granules, pellets and minitablets, a high-viscosity gelling agent is coated on the inner layer and a low-viscosity gelling agent is coated on the outer layer, so that the oral cavity is unified and bitterness masked. And formulations with improved swallowability are described. However, the method disclosed herein has a drawback in that it takes a long time to form a gel, and the formed gel has high adhesion to mucous membranes.
JP 2002-275054 (Patent Document 3) describes a swallowable tablet coated with a coating liquid containing 40 parts or more of sugar alcohol when xanthan gum is used as a gelling agent and the coating solid composition is 100 parts. There is. When this coating is used in the oral cavity, it does not give a slimy feeling or a sticky feeling and the mucous membrane has a good slippery feel, but xanthan gum alone makes the gel formed in the oral cavity too soft and bitterness masking is insufficient and the mucous membrane is insufficient. Further improvement is required in terms of the slipperiness.
Japanese Patent No. 4267926 (Patent Document 4) discloses a film agent that gels.
This film agent is a sheet-like preparation in which a drug layer is sandwiched between carboxyvinyl polymer layers cross-linked with a polyvalent metal salt, which rapidly gels in the oral cavity, is less likely to be caught in the throat, etc. and bitterness is masked. Is described. However, it does not disclose coating of tablets or granules. Since the carboxyvinyl polymer of the present technology is subjected to a manufacturing process as a solution having a very high viscosity cross-linked with a polyvalent metal ion, it is considered that spray coating on tablets or granules is difficult (see Reference Example 1 described later). ). Therefore, it is a film agent that can be produced by the present technology, which requires a special process and apparatus of application, and the production cost tends to be higher than that of coating of tablets and granules. Furthermore, as described in Reference Example 2 described below, the coated minitablet manufactured by improving the present technology so that spray coating was possible could not obtain practically satisfactory swallowability.
On the other hand, in the case of coating with a gelling agent, if a gel is formed in the digestive tract, diffusion of the drug is suppressed, and elution delay may occur. JP-A-11-60472 (Patent Document 5)
) Discloses that in a swallow-coated tablet coated with methylcellulose, dissolution delay can be prevented by adding a saccharide. However, this coated tablet cannot be expected to have a cohesive feeling in the oral cavity when it is made into a mini tablet.
As described above, it is a great problem to prevent delay of drug elution in a preparation coated with a gelling agent.

Patent No. 3883505 Tokuyo 2000-516222 JP-A-2002-275054 Patent No. 4267926 Japanese Patent Laid-Open No. 11-60472

As described above, it is desired to provide a coating preparation which has an effect of masking unpleasant taste such as bitterness, good swallowability, and is easy to manufacture in the preparations for oral administration, particularly tablets with a large dose. It is rare. It is also desired to provide a coating preparation having improved dissolution properties. It is an object to provide a coating preparation having any one or more of these properties, preferably all, and a coating composition for producing the same.

In view of the above problems, the inventors of the present invention have conducted extensive studies to improve the ingestability of oral preparations, and as a result, the first thickener such as carboxyvinyl polymer as a thickener and the second thickener such as xanthan gum. In combination with the thickener of the above, and by coating a solid composition for oral use such as tablets with a coating composition containing a small amount of a polyvalent metal compound as a viscosity modifier, the unpleasant taste is masked and the mucous membrane is slippery more easily. Therefore, it has been found that it becomes easier to swallow and the production becomes easier. The present inventors have also found that the addition of sucralose to the coating composition further improves the unpleasant taste masking effect. Furthermore, the inventors of the present invention added hydroxypropylmethylcellulose (hereinafter sometimes referred to as HPMC) and sugar or sugar alcohol having specific properties to the coating composition to rapidly disintegrate the film after swallowing and delay dissolution. They have found that they can be prevented, and have completed the present invention.

That is, the first aspect of the present invention is the following coating composition.
[1-1] A first thickener which is a metal crosslinking thickener, preferably a first thickener selected from the group consisting of carboxyvinyl polymer and sodium alginate;
A polyvalent metal compound; and
At least one second thickener selected from the group consisting of xanthan gum, guar gum and sodium alginate (provided that when the first thickener is sodium alginate, the second thickener is sodium alginate; Not included).
[1-1a] A coating composition containing a carboxyvinyl polymer, a polyvalent metal compound, and xanthan gum.
[1-2] The coating composition according to the above [1-1], wherein the first thickener is a carboxyvinyl polymer or sodium alginate that is not substantially crosslinked by a polyvalent metal ion.
[1-2a] The coating composition as described in [1-1a] above, wherein the carboxyvinyl polymer is not substantially crosslinked.
[1-3] The above-mentioned [1-1] further containing a sugar or sugar alcohol having a solubility at 20 ° C. of 30 or more.
, [1-2], [1-1a], and the composition for coating according to any one of [1-2a].
[1-4] The coating composition according to any one of [1-1] to [1-3], [1-1a], and [1-2a], further containing HPMC.
[1-5] The content of the first thickener is 3 to 15% by mass or 3 to 20% by mass (mass% in all components excluding the solvent, the same applies hereinafter), and the second thickener Is 10 to 40% by mass, the content of HPMC is 5 to 35% by mass, and the content of the sugar or sugar alcohol is 10 to 50% by mass. 1-4] The coating composition according to [1-4].
The content of [1-5a] carboxyvinyl polymer is 3 to 15% by mass or 3 to 20% by mass (mass% in all components excluding the solvent, the same applies hereinafter), and the content of xanthan gum is 10%.
To 40% by mass, the content of HPMC is 5 to 35% by mass, and the content of the sugar or sugar alcohol is 10 to 50% by mass. The coating composition described.
[1-6] The content of the polyvalent metal compound is 2 to 15% by mass with respect to the content of the first thickener, and the content of the above-mentioned [1-1] to [1-5] The coating composition according to any one of claims.
[1-6a] The content of the polyvalent metal compound is 2 to the content of the carboxyvinyl polymer.
It is 15% by mass, [1-1a], [1-2a], [1-3], [1]
-4] and the coating composition according to any one of [1-5a].
[1-7] [1-1] to [1-6], characterized by containing alcohol as a solvent,
1-1a], [1-2a], [1-5a], and [1-6a].
[1-8] [1-1] to [1-7], further including sucralose, [1-1a],
The coating composition according to any one of [1-2a], [1-5a], and [1-6a].
[1-9] The content of the first thickener is 3 to 20% by mass (mass% of all components except the solvent, the same applies hereinafter), and the content of the second thickener is 10 to 10. 40% by mass, the content of sucralose is 0.01 to 5% by mass, the content of HPMC is 5 to 35% by mass, and the content of the sugar or sugar alcohol is 10 to 50% by mass. % In the above [1-8
] The coating composition according to.
The content of [1-9a] carboxyvinyl polymer is 3 to 20 mass% (mass% in all components except the solvent, the same applies hereinafter), and the content of xanthan gum is 10 to 40 mass%,
The content of sucralose is 0.01 to 5% by mass, the content of HPMC is 5 to 35% by mass, and the content of the sugar or sugar alcohol is 10 to 50% by mass. The coating composition according to the above [1-8].
The oral composition coated with the coating composition according to the first aspect of the present invention is
It has a good slippery property and has good swallowability without adhesion to mucous membranes. Alternatively, a sufficient unpleasant taste masking effect can be obtained. It preferably has both effects. In the coating composition of a more preferable embodiment, the drug dissolution property is also improved. In another preferred embodiment of the coating composition, the drug core can be easily spray-coated and dried easily.

The second aspect of the present invention is the following oral composition.
[2-1] A drug core containing an active ingredient;
In the drug core,
A first thickener which is a metal cross-linking thickener, preferably a first thickener selected from the group consisting of carboxyvinyl polymers and sodium alginate,
A polyvalent metal compound and at least one or more second thickeners selected from the group consisting of xanthan gum, guar gum and sodium alginate (provided that when the first thickener is sodium alginate, Oral composition having a coating comprising a thickener is not sodium alginate).
[2-1a] An oral composition comprising a drug core containing an active ingredient and a coating containing a carboxyvinyl polymer, a polyvalent metal compound and xanthan gum in the drug core.
[2-2] The oral composition according to the above [2-1], wherein the first thickener is a carboxyvinyl polymer or sodium alginate that is not substantially crosslinked by a polyvalent metal ion.
[2-2a] The oral composition according to the above [2-1a], wherein the carboxyvinyl polymer is not substantially crosslinked.
[2-3] Any of [2-1], [2-2], [2-1a], and [2-2a], wherein the coating further contains a sugar or sugar alcohol having a solubility at 20 ° C. of 30 or more. Or 1
The oral composition according to the item.
[2-4] [2-1] to [2-3], wherein the coating further contains HPMC,
2-1a] and the composition for oral administration according to any one of [2-2a].
[2-5] The content of the first thickener is 3 to 15% by mass or 3 to 20% by mass (mass% to all components in the coating, the same applies hereinafter), and the content of the second thickener is Content is 10-4
0% by mass, the content of HPMC is 5 to 35% by mass, and the content of the sugar or sugar alcohol is 10 to 50% by mass, [2-4]. Oral composition.
The content of [2-5a] carboxyvinyl polymer is 3 to 15% by mass or 3 to 20% by mass (% by mass relative to all components in the coating, the same applies hereinafter), and the content of xanthan gum is 10 to 40% by mass. And the content of HPMC is 5 to 35% by mass, and the content of the sugar or sugar alcohol is 10 to 50% by mass, for oral use according to the above [2-4] Composition.
[2-6] The content of the polyvalent metal compound is 2 to 15 mass% with respect to the content of the first thickener, and the content of the above-mentioned [2-1] to [2-5] The oral composition according to any one of claims.
[2-6a] The content of the polyvalent metal compound is 2 to the content of the carboxyvinyl polymer.
15% by mass of the above [2-1a], [2-2a], [2-3], [2]
-4], and the oral composition according to any one of [2-5a].
[2-7] The drug core is a tablet core containing an active ingredient, [2-1]
~ The oral composition according to any one of [2-6], [2-1a], [2-2a], [2-5a], and [2-6a].
[2-8] The second thickener is at least one or more thickeners selected from the group consisting of xanthan gum, guar gum, and sodium alginate that is not substantially crosslinked by polyvalent metal ions. The composition for oral administration according to any one of [2-1] to [2-7].
[2-9] A seal coating is further provided between the drug core and the coating.
2-1] to [2-8], [2-1a], [2-2a], [2-5a], and [2-6a].
] The oral composition according to any one of [1].
[2-10] The above-mentioned [2-1] to [2-], wherein the coating further contains sucralose.
9], [2-1a], [2-2a], [2-5a], and the oral composition according to any one of [2-6a].
[2-11] The content of the first thickener is 3 to 20% by mass (mass% with respect to all components in the coating, the same applies hereinafter), and the content of the second thickener is 10 to 40. % By mass, the content of sucralose is 0.01 to 5% by mass, the content of HPMC is 5 to 35% by mass, and the content of the sugar or sugar alcohol is 10 to 50% by mass. The oral composition according to the above [2-10].
The content of the [2-11a] carboxyvinyl polymer is 3 to 20% by mass (mass% based on all components in the coating, the same applies hereinafter), and the content of xanthan gum is 10 to 40% by mass. The content is 0.01 to 5% by mass, the content of HPMC is 5 to 35% by mass, and the content of the sugar or sugar alcohol is 10 to 50% by mass. The oral composition according to [2-10].
[2-12] The oral composition according to any one of [2-9] to [2-11] and [2-11a], which further has a middle coating between the seal coating and the coating.
The oral composition of the second aspect of the present invention has good slipperiness and has good swallowability without adhesion to mucous membranes. Alternatively, an unpleasant taste masking effect can be obtained. It preferably has both effects. In a more preferable embodiment of the oral composition, the drug dissolution property is also improved.

A third aspect of the present invention is the following oral composition.
[3-1] A first thickening agent which is a metal crosslinking thickening agent in an alcohol solution in which a polyvalent metal compound is dissolved, preferably a first thickening agent selected from the group consisting of carboxyvinyl polymer or sodium alginate. And at least one second thickener selected from the group consisting of xanthan gum, guar gum and sodium alginate (provided that the second thickener is sodium alginate when the first thickener is sodium alginate). Is not sodium alginate)
An oral composition obtained by spray-coating a liquid in which is dispersed onto a drug core containing an active ingredient.
[3-1a] An oral composition obtained by spray-coating a liquid in which a carboxyvinyl polymer and xanthan gum are dispersed in an alcohol solution in which a polyvalent metal compound is dissolved, onto a drug core containing an active ingredient.
[3-2] The oral composition according to the above [3-1], wherein the first thickener is a carboxyvinyl polymer or sodium alginate that is not substantially crosslinked by a polyvalent metal ion.
[3-2a] The oral composition according to [3-1a] above, wherein the carboxyvinyl polymer is not substantially crosslinked.
[3-3] The above-mentioned [3-1], [3-2], [3], wherein a sugar or a sugar alcohol having a solubility of 20 ° C. of 30 or more is further dispersed in the liquid for spray coating.
-1a] and [3-2a], the oral composition.
[3-4] The liquid for spray coating further contains HPMC, [3-1] to [3-1]
3-3], [3-1a], and the oral composition according to any one of [3-2a].
[3-5] The content of the first thickening agent in the liquid to be spray-coated is 3 to 15% by mass or 3 to 20% by mass (% by mass in all components except the solvent, the same applies hereinafter), and The content of the thickener of No. 2 is 10 to 40% by mass, the content of HPMC is 5 to 35% by mass, and the content of the sugar or sugar alcohol is 10 to 50% by mass. [3-4]
] Oral composition of these.
[3-5a] The content of carboxyvinyl polymer in the liquid for spray coating is 3 to 1
5% by mass or 3 to 20% by mass (mass% in all components except the solvent, the same applies hereinafter),
The content of xanthan gum is 10 to 40% by mass, the content of HPMC is 5 to 35% by mass, and the content of the sugar or sugar alcohol is 10 to 50% by mass. The oral composition according to [3-4].
[3-6] The content of the polyvalent metal compound is 2 to 15% by mass with respect to the content of the first thickener, [3-1] to [3-5] The oral composition according to any one of claims.
[3-6a] The content of the polyvalent metal compound is 2 to the content of the carboxyvinyl polymer.
15% by mass of the above [3-1a], [3-2a], [3-3], [3]
-4], and the oral composition according to any one of [3-5a].
[3-7] The above-mentioned [3-1], wherein the drug core is a tablet core containing an active ingredient.
~ The oral composition according to any one of [3-6], [3-1a], [3-2a], [3-5a], and [3-6a].
[3-8] The second thickener is at least one or more thickeners selected from the group consisting of xanthan gum, guar gum, and sodium alginate that is not substantially crosslinked with a polyvalent metal ion. The oral composition according to any one of 3-1] to [3-7].
[3-9] The above-mentioned [3-1] to [3-8], [3-1a], [3-2a], and [3-2] in which the drug core to be spray-coated is a seal-coat drug core having a seal coating. Three
-5a], and the oral composition according to any one of [3-6a].
[3-10] The above [3-1, wherein the liquid for spray coating further contains sucralose.
]-[3-9], [3-1a], [3-2a], [3-5a], and the oral composition according to any one of [3-6a].
[3-11] The content of the first thickener in the liquid to be spray-coated is 3 to 20% by mass (
Mass% in all components excluding the solvent, the same applies hereinafter), and the content of the second thickener is 10 to 40.
% By mass, the content of sucralose is 0.01 to 5% by mass, the content of HPMC is 5 to 35% by mass, and the content of the sugar or sugar alcohol is 10 to 50% by mass. The oral composition according to the above [3-10].
[3-11a] The content of carboxyvinyl polymer in the liquid for spray coating is 3
To 20% by mass (% by mass in all components except the solvent, the same applies hereinafter), the content of xanthan gum is 10 to 40% by mass, and the content of sucralose is 0.01 to 5% by mass. And the content of HPMC is 5 to 35% by mass, and the content of the sugar or sugar alcohol is 10
The composition for oral administration according to the above [3-10], which is -50% by mass.
[3-12] Oral according to any one of [3-9] to [3-11] and [3-11a], wherein the seal coat drug core further has a middle coating on the seal coating. Composition.
The oral composition according to the third aspect of the present invention has good slipperiness and has good swallowability without adhesion to mucous membranes. Alternatively, a sufficient unpleasant taste masking effect can be obtained. It preferably has both effects. In a more preferable embodiment of the oral composition, the drug dissolution property is also improved.

Moreover, the 4th aspect of this invention is a manufacturing method of the following oral compositions.
[4-1] A method for producing an oral composition, comprising a first thickener which is a metal crosslinking thickener, preferably a carboxyvinyl polymer and sodium alginate, in an alcohol solution in which a polyvalent metal compound is dissolved. A first thickener selected from the group consisting of: and xanthan gum,
At least one or more second thickeners selected from the group consisting of guar gum and sodium alginate (provided that when the first thickener is sodium alginate, the second thickener is not sodium alginate; A method for producing an oral composition, which comprises spray-coating a liquid containing the active ingredient) on a drug core containing an active ingredient.
[4-1a] A method for producing an oral composition, which comprises spray-coating a liquid in which a carboxyvinyl polymer and xanthan gum are dispersed in an alcohol solution containing a polyvalent metal compound, on a drug core containing an active ingredient. A method for producing an oral composition comprising:
[4-2] The method for producing the oral composition according to the above [4-1], wherein the first thickener is a carboxyvinyl polymer or sodium alginate that is not substantially crosslinked by a polyvalent metal ion.
[4-2a] The method for producing the oral composition according to the above [4-1a], wherein the carboxyvinyl polymer is not substantially crosslinked.
[4-3] The above-mentioned [4-1], [4-2], [4], wherein a sugar or sugar alcohol having a solubility of 20 ° C. of 30 or more is further dispersed in the liquid for spray coating.
-1a] and [4-2a].
[4-4] The above-mentioned [4-1]-[wherein the liquid for spray coating further contains HPMC.
4-3], [4-1a], and the method for producing the oral composition according to any one of [4-2a].
[4-5] The content of the first thickening agent in the liquid to be spray-coated is 3 to 15% by mass or 3 to 20% by mass (mass% in all components except the solvent, the same applies hereinafter), The content of the thickener of No. 2 is 10 to 40% by mass, the content of HPMC is 5 to 35% by mass, and the content of the sugar or sugar alcohol is 10 to 50% by mass. [4-4]
] The manufacturing method of the composition for oral use of description.
[4-5a] The content of carboxyvinyl polymer in the liquid for spray coating is 3 to 1
5% by mass or 3 to 20% by mass (mass% in all components except the solvent, the same applies hereinafter),
The content of xanthan gum is 10 to 40% by mass, the content of HPMC is 5 to 35% by mass, and the content of the sugar or sugar alcohol is 10 to 50% by mass. The method for producing the oral composition according to [4-4].
[4-6] The content of the polyvalent metal compound is 2 to 15 mass% with respect to the content of the first thickener, and the content of the above [4-1] to [4-5] A method for producing the oral composition according to any one of items.
[4-6a] The content of the polyvalent metal compound is 2 to the content of the carboxyvinyl polymer.
15% by mass of the above [4-1a], [4-2a], [4-3], [4]
-4], and the method for producing the oral composition according to any one of [4-5a].
[4-7] The drug core is a tablet core containing an active ingredient, and the above-mentioned [4-1]
To [4-6], [4-1a], [4-2a], [4-5a], and [4-6a].
[4-8] The above-mentioned [wherein the second thickener is at least one or more thickeners selected from the group consisting of xanthan gum, guar gum, and sodium alginate that is not substantially crosslinked by polyvalent metal ions. 4-1] to the method for manufacturing the oral composition according to any one of [4-7].
[4-9] The above-mentioned [4-1] to [4-8], [4-1a], [4-2a], and [4-1], wherein the spray-coated drug nucleus is a seal-coated drug nucleus having a seal coating. Four
-5a], and a method for producing the oral composition according to any one of [4-6a].
[4-10] The above-mentioned [4-1], wherein the liquid for spray coating further contains sucralose.
]-[4-9], [4-1a], [4-2a], [4-5a], and the manufacturing method of the composition for oral use of any one of [4-6a].
[4-11] The content of the first thickener in the liquid for spray coating is 3 to 20% by mass (% by mass in all components excluding the solvent, the same applies hereinafter), and the second thickener Content of 10
40% by mass, the content of sucralose is 0.01 to 5% by mass, the content of HPMC is 5 to 35% by mass, and the content of the sugar or sugar alcohol is 10 to 50% by mass. %
The method for producing an oral composition according to the above [4-10].
[4-11a] The content of the carboxyvinyl polymer in the liquid for spray coating is 3 to 20 mass% (mass% in all components except the solvent, the same applies hereinafter), and the content of xanthan gum is 10 to 40 mass. %, The sucralose content is 0.01 to 5% by mass, the HPMC content is 5 to 35% by mass, and the sugar or sugar alcohol content is 1%.
It is 0 to 50 mass%, The manufacturing method of the oral composition as described in said [4-10].
[4-12] Oral according to any one of [4-9] to [4-11] and [4-11a], wherein the seal coat drug core further has a middle coating on the seal coating. For producing a composition for use.
In the method for producing the oral composition according to the fourth aspect of the present invention, the drug core can be easily spray-coated and dried easily. Further, the oral composition obtained by this production method has good slipperiness, has no adhesion to mucous membranes, and has good swallowability. Alternatively, a sufficient unpleasant taste masking effect can be obtained. It preferably has both effects. In the oral composition obtained by the production method of a more preferable embodiment, the drug dissolution property is also improved.

A fifth aspect of the present invention is the following coating composition.
[5-1] A coating composition containing a thickener that gels when contacted with water, a sugar or sugar alcohol having a solubility at 20 ° C. of 30 or more, and HPMC.
[5-2] The coating composition according to the above [5-1], wherein the thickener is at least one selected from the group consisting of xanthan gum, guar gum, and sodium alginate.
[5-2a] The coating composition according to the above [5-1], wherein the thickener contains xanthan gum.
[5-3] The coating composition according to the above [5-1], wherein the thickener is selected from the group consisting of carboxyvinyl polymer and sodium alginate.
[5-3a] The coating composition according to the above [5-1], wherein the thickener contains a carboxyvinyl polymer.
[5-4] One of the thickeners selected from the group consisting of carboxyvinyl polymer and sodium alginate, and at least one or more selected from the group consisting of xanthan gum, guar gum and sodium alginate (however, a combination of the same substances). And the above [5-
1] The coating composition according to [1].
[5-4a] The above-mentioned [5-1, wherein the thickener contains a carboxyvinyl polymer and xanthan gum.
] The coating composition according to.
[5-5] The coating composition according to the above [5-3], [5-4], [5-3a] or [5-4a], further containing a polyvalent metal compound.
[5-6] HPMC and the mixing ratio of the sugar or sugar alcohol are 1: 1 to 1: 4, and the above-mentioned [5-1] to [5-5] and [5-2a] to The coating composition according to any one of [5-4a].
[5-7] The content of HPMC is 5 to 35% by mass (% by mass in all components except the solvent, the same applies hereinafter), and the content of the sugar or sugar alcohol is 10 to 50% by mass. The content of carboxyvinyl polymer is 3 to 15% by mass or 3 to 20% by mass, and the content of at least one selected from the group consisting of xanthan gum, guar gum and sodium alginate is 10 to 40% by mass. [5-4] to [5-6]
] The coating composition according to any one of [1].
[5-7a] The content of HPMC is 5 to 35% by mass (mass% of all components except the solvent, the same applies hereinafter), and the content of the sugar or sugar alcohol is 10 to 50% by mass. The content of the carboxyvinyl polymer is 3 to 15% by mass or 3 to 20% by mass, and the content of the xanthan gum is 10 to 40% by mass, [5-4a], [5-
5] and the composition for coating according to any one of [5-6].
[5-8] The above-mentioned [5-1] to [5-7], which contains alcohol as a solvent.
The coating composition according to any one of [5-2a] to [5-4a], and [5-7a].
[5-9] The sugar or sugar alcohol is selected from the group consisting of erythritol, reduced maltose starch syrup and trehalose, and the above [5-1] to [5-8] and [5-2a] to [5-4a.
], And the coating composition according to any one of [5-7a].
[5-10] The coating composition according to the above [5-9], wherein the sugar or sugar alcohol is erythritol.
[5-11] [5-1] to [5-10] and [5-2a] further containing sucralose
]-[5-4a], and the composition for coating of any one of [5-7a].
[5-12] The content of HPMC is 5 to 35 mass% (mass% of all components except the solvent, the same applies hereinafter), and the content of the sugar or sugar alcohol is 10 to 50 mass%. The content of carboxyvinyl polymer is 3 to 20% by mass, and the content of at least one selected from the group consisting of xanthan gum, guar gum and sodium alginate is 1
It is 0-40 mass%, and the content of sucralose is 0.01-5 mass%. The coating composition as described in [5-11] above.
[5-12a] The content of HPMC is 5 to 35% by mass (mass% of all components except the solvent, the same applies hereinafter), and the content of the sugar or sugar alcohol is 10 to 50% by mass. , The content of carboxyvinyl polymer is 3 to 20% by mass, and the content of xanthan gum is 1
It is 0-40 mass%, and the content of sucralose is 0.01-5 mass%. The coating composition as described in [5-11] above.
The oral composition coated with the coating composition according to the fifth aspect of the present invention exhibits substantially the same drug dissolution properties as the uncoated oral composition. Further, the coating composition of the preferred embodiment has good slipperiness, no adhesion to mucous membranes, and good swallowability. Alternatively, an unpleasant taste masking effect can be obtained. It preferably has both effects. In another preferred embodiment of the coating composition, the drug core can be easily spray-coated and dried easily.

The sixth aspect of the present invention is the following oral composition.
[6-1] A drug core containing an active ingredient, and a thickener that gels when contacted with water, 2
An oral composition having a coating comprising a sugar or sugar alcohol having a solubility at 0 ° C. of 30 or more and HPMC.
[6-2] The oral composition according to the above [6-1], wherein the thickener is at least one selected from the group consisting of xanthan gum, guar gum, and sodium alginate.
[6-2a] The oral composition according to the above [6-1], wherein the thickener contains xanthan gum.
[6-3] The oral composition according to the above [6-1], wherein the thickener is selected from the group consisting of carboxyvinyl polymer and sodium alginate.
[6-3a] The oral composition according to the above [6-1], wherein the thickener contains a carboxyvinyl polymer.
[6-4] One thickener is selected from the group consisting of carboxyvinyl polymer and sodium alginate, and at least one or more species selected from the group consisting of xanthan gum, guar gum and sodium alginate (provided that the combination of the same substances is used. [6]
-1] The oral composition according to [1].
[6-4a] The above-mentioned [6-1] in which the thickener contains a carboxyvinyl polymer and xanthan gum.
] Oral composition of these.
[6-5] [6-3] and [6-4] wherein the coating further contains a polyvalent metal compound.
], [6-3a], and the oral composition according to any one of [6-4a].
[6-6] The mixing ratio of HPMC to the sugar or sugar alcohol is 1: 1 to 1: 4, and the above [6-1] to [6-5] and [6-2a] to Any one of [6-4a]
The oral composition according to the item.
[6-7] The content of HPMC is 5 to 35% by mass (% by mass based on all components in the coating, the same applies hereinafter), and the content of the sugar or sugar alcohol is 10 to 50% by mass, The content of one kind selected from the group consisting of carboxyvinyl polymer and sodium alginate is 3 to 15% by mass or 3 to 20% by mass, and at least 1 selected from the group consisting of xanthan gum, guar gum and sodium alginate. Content of 1 or more types is 10-40 mass%, The oral composition as described in any one of said [6-4]-[6-6].
[6-7a] HPMC content is 5 to 35 mass% (mass% based on all components in the coating, the same applies hereinafter), and the sugar or sugar alcohol content is 10 to 50 mass%, [6-4a], wherein the content of the carboxyvinyl polymer is 3 to 15% by mass or 3 to 20% by mass, and the content of the xanthan gum is 10 to 40% by mass.
, [6-5], and the oral composition according to any one of [6-6].
[6-8] The above-mentioned [6], wherein the drug core is a seal coat drug core having a seal coating.
-1]-[6-7], [6-2a]-[6-4a], and the oral composition according to any one of [6-7a].
[6-9] The sugar or sugar alcohol is selected from the group consisting of erythritol, reduced maltose starch syrup and trehalose, [6-1] to [6-8], [6-2a] to [6-4a.
], And the oral composition according to any one of [6-7a].
[6-10] The oral composition according to the above [6-9], wherein the sugar or sugar alcohol is erythritol.
[6-11] The above-mentioned [6-1] to [6-, wherein the coating further contains sucralose.
10], [6-2a] to [6-4a], and the oral composition according to any one of [6-7a].
[6-12] The content of HPMC is 5 to 35% by mass (% by mass relative to all components in the coating, the same applies hereinafter), and the content of the sugar or sugar alcohol is 10 to 50% by mass, 1 selected from the group consisting of carboxyvinyl polymer and sodium alginate
The content of the seed is 3 to 20% by mass, the content of at least one kind selected from the group consisting of xanthan gum, guar gum and sodium alginate is 10 to 40% by mass, and the content of sucralose is [6-
[11] The oral composition according to [11].
[6-12a] HPMC content is 5 to 35 mass% (mass% of all components in the coating, the same applies below), and the sugar or sugar alcohol content is 10 to 50 mass%, The content of carboxyvinyl polymer is 3 to 20% by mass, the content of xanthan gum is 10 to 40% by mass, and the content of sucralose is 0.01 to 5% by mass. The oral composition according to [6-11].
[6-13] The oral according to any one of [6-8] to [6-12] and [6-12a], wherein the seal coat drug core further has a middle coating on the seal coating. Composition.
Although the oral composition of the sixth aspect of the present invention is coated with a thickener, it exhibits substantially the same drug dissolution properties as an uncoated oral composition. The oral composition of the preferred embodiment has good slipperiness, no adhesion to mucous membranes, and good swallowability. Alternatively, a sufficient unpleasant taste masking effect can be obtained. It preferably has both effects.

The seventh aspect of the present invention is the following oral composition.
[7-1] A thickener that gels when exposed to water, a sugar or sugar alcohol having a solubility of 30 or more at 20 ° C., and HPMC dispersed in an alcohol solution is used as a drug core containing an active ingredient. An oral composition obtained by spray coating.
[7-2] The oral composition according to the above [7-1], wherein the thickener is at least one selected from the group consisting of xanthan gum, guar gum, and sodium alginate.
[7-2a] The oral composition according to the above [7-1], wherein the thickener contains xanthan gum.
[7-3] The oral composition according to the above [7-1], wherein the thickener is selected from the group consisting of carboxyvinyl polymer and sodium alginate.
[7-3a] The oral composition according to the above [7-1], wherein the thickener contains a carboxyvinyl polymer.
[7-4] One thickener is selected from the group consisting of carboxyvinyl polymer and sodium alginate, and at least one or more species selected from the group consisting of xanthan gum, guar gum and sodium alginate (provided that the combination of the same substances is used. And [7-
The composition for oral administration according to 1].
[7-4a] The thickener includes a carboxyvinyl polymer and xanthan gum.
] Oral composition of these.
[7-5] The solution for spray coating further contains a polyvalent metal compound [7-3].
, [7-4], [7-3a] or [7-4a].
[7-6] The above-mentioned [7-1] to [7-5], wherein the compounding ratio of HPMC of the liquid for spray coating and the sugar or sugar alcohol is 1: 1 to 1: 4, and [ 7-2a
]-[7-4a] The oral composition according to any one of [1].
[7-7] The content of HPMC in the liquid for spray coating is 5 to 35% by mass (% by mass in all components except the solvent, the same applies hereinafter), and the content of the sugar or sugar alcohol is 10 to 10%.
50% by mass, and the content of carboxyvinyl polymer is 3 to 15% by mass or 3 to
20% by mass, and the content of at least one selected from the group consisting of xanthan gum, guar gum and sodium alginate is 10 to 40% by mass, [7-4] to [7] -6] An oral composition according to any one of [6].
[7-7a] The content of HPMC in the liquid for spray coating is 5 to 35% by mass (% by mass in all components except the solvent, the same applies hereinafter), and the content of the sugar or sugar alcohol is 10
To 50% by mass, and the content of the carboxyvinyl polymer is 3 to 15% by mass or 3
To 20% by mass, and the content of xanthan gum is 10 to 40% by mass, in any one of [7-4a], [7-5], and [7-6] above. The oral composition described.
[7-8] The above-mentioned [7-1] to [7-7], [7-2a] to [7-4a], and the drug core to which the spray coating is applied is a seal coat drug core having a seal coating. The oral composition according to any one of [7-7a].
[7-9] The sugar or sugar alcohol is selected from the group consisting of erythritol, reduced maltose starch syrup and trehalose, [7-1] to [7-8], [7-2a] to [7-4a.
], And the oral composition according to any one of [7-7a].
[7-10] The oral composition according to the above [7-9], wherein the sugar or sugar alcohol is erythritol.
[7-11] The liquid for spray coating further contains sucralose.
]-[7-10], [7-2a]-[7-4a], and the composition for oral use in any one of [7-7a].
[7-12] The content of HPMC in the liquid for spray coating is 5 to 35 mass% (mass% in all components excluding the solvent, the same applies hereinafter), and the content of the sugar or sugar alcohol is 10
˜50% by mass, the content of carboxyvinyl polymer is 3 to 20% by mass,
The content of at least one selected from the group consisting of xanthan gum, guar gum and sodium alginate is 10 to 40% by mass, and the content of sucralose is 0.0.
The oral composition according to the above [7-11], which is 1 to 5% by mass.
[7-12a] The content of HPMC in the liquid to be spray-coated is 5 to 35% by mass (% by mass in all components excluding the solvent, the same applies hereinafter), and the content of the sugar or sugar alcohol is 1
0 to 50% by mass, the content of carboxyvinyl polymer is 3 to 20% by mass, the content of xanthan gum is 10 to 40% by mass, and the content of sucralose is 0.0.
The oral composition according to the above [7-11], which is 1 to 5% by mass.
[7-13] Oral according to any one of [7-8] to [7-12] and [7-12a], wherein the seal coat drug core further has a middle coating on the seal coating. Composition.
The oral composition of the seventh aspect of the present invention is obtained by spray-coating a drug core with an alcohol solution and drying the composition, and is easy to manufacture. In addition, although it is coated with a thickener, it exhibits almost the same drug dissolution properties as an oral composition without coating. The oral composition of the preferred embodiment has good slipperiness, no adhesion to mucous membranes, and good swallowability. Alternatively, a sufficient unpleasant taste masking effect can be obtained. It preferably has both effects.

The eighth aspect of the present invention is a method for producing the oral composition described below.
[8-1] A method for producing an oral composition, comprising a thickener that gels when an alcohol solution in which a polyvalent metal compound is dissolved is brought into contact with water, a sugar or a sugar alcohol having a solubility at 20 ° C of 30 or more. A method for producing an oral composition, which comprises spray-coating a liquid containing HPMC dispersed therein on a drug core containing an active ingredient.
[8-2] The method for producing the oral composition according to [8-1], wherein the thickener is at least one selected from the group consisting of xanthan gum, guar gum and sodium alginate.
[8-2a] The method for producing the oral composition according to the above [8-1], wherein the thickener contains xanthan gum.
[8-3] The method for producing the oral composition according to the above [8-1], wherein the thickener is selected from the group consisting of carboxyvinyl polymer and sodium alginate.
[8-3a] The method for producing the oral composition according to the above [8-1], wherein the thickener contains a carboxyvinyl polymer.
[8-4] The thickener is one selected from the group consisting of carboxyvinyl polymer and sodium alginate, and at least one or more selected from the group consisting of xanthan gum, guar gum and sodium alginate (however, a combination of the same substances. And [8-
[1] The method for producing the oral composition according to [1].
[8-4a] The thickening agent contains a carboxyvinyl polymer and xanthan gum.
] The manufacturing method of the composition for oral use of description.
[8-5] The above-mentioned [8-1] to [8-4], wherein the compounding ratio of HPMC of the liquid for spray coating and the sugar or sugar alcohol is 1: 1 to 1: 4, and [8]. 8-2a
]-[8-4a] or any one of the manufacturing methods of the composition for oral administration of.
[8-6] The content of HPMC in the liquid to be spray-coated is 5 to 35 mass% (mass% of all components excluding the solvent, the same applies hereinafter), and the content of the sugar or sugar alcohol is 10 to 10.
50% by mass, the content of one kind selected from the group consisting of carboxyvinyl polymer and sodium alginate is 3 to 15% by mass or 3 to 20% by mass, and consists of xanthan gum, guar gum and sodium alginate. [8-4] or [wherein at least one selected from the group has a content of 10 to 40% by mass.
8-5] is a method for producing the oral composition.
[8-6a] The content of HPMC in the liquid for spray coating is 5 to 35% by mass (% by mass in all components excluding the solvent, the same applies hereinafter), and the content of the sugar or sugar alcohol is 10
To 50% by mass, and the content of the carboxyvinyl polymer is 3 to 15% by mass or 3
It is -20 mass%, and the content of xanthan gum is 10-40 mass%, The manufacturing method of the oral composition as described in said [8-4a] or [8-5].
[8-7] The above-mentioned [8-1], wherein the drug core is a tablet core containing an active ingredient.
To [8-6], [8-2a] to [8-4a], and the method for producing the oral composition according to any one of [8-6a].
[8-8] The above-mentioned [8-1] to [8-7], [8-2a] to [8-4a], and the drug core to which the spray coating is applied is a seal coat drug core having a seal coating. The method for producing the oral composition according to any one of [8-6a].
[8-9] The sugar or sugar alcohol is selected from the group consisting of erythritol, reduced maltose syrup and trehalose, [8-1] to [8-8], [8-2a] to [8-4a.
], And the manufacturing method of the composition for oral use of any one of [8-6a].
[8-10] The method for producing the oral composition according to the above [8-9], wherein the sugar or sugar alcohol is erythritol.
[8-11] The above-mentioned [8-1], wherein the liquid for spray coating further contains sucralose.
]-[8-10], [8-2a]-[8-4a], and the manufacturing method of the oral composition as described in any one of [8-6a].
[8-12] The content of HPMC in the liquid for spray coating is 5 to 35% by mass (% by mass in all components excluding the solvent, the same applies hereinafter), and the content of the sugar or sugar alcohol is 10
˜50% by mass, the content of carboxyvinyl polymer is 3 to 20% by mass,
The content of at least one selected from the group consisting of xanthan gum, guar gum and sodium alginate is 10 to 40% by mass, and the content of sucralose is 0.0.
It is 1-5 mass%, The manufacturing method of the oral composition as described in said [8-11] characterized by the above-mentioned.
[8-12a] The content of HPMC in the liquid for spray coating is 5 to 35% by mass (% by mass in all components except the solvent, the same applies hereinafter), and the content of the sugar or sugar alcohol is 1
0 to 50% by mass, the content of carboxyvinyl polymer is 3 to 20% by mass, the content of xanthan gum is 10 to 40% by mass, and the content of sucralose is 0.0.
It is 1-5 mass%, The manufacturing method of the oral composition as described in said [8-11] characterized by the above-mentioned.
[8-13] Oral according to any one of [8-8] to [8-12] and [8-12a], wherein the seal coat drug core further has a middle coating on the seal coating. For producing a composition for use.
In the method for producing an oral composition according to the eighth aspect of the present invention, the drug core can be easily spray-coated and dried easily. Further, the oral composition obtained by the present production method exhibits substantially the same drug dissolution properties as the oral composition not coated, although it is coated with the thickener. In addition, the coating composition obtained by the production method of the preferred embodiment has good slipperiness, no adhesion to mucous membranes, and good swallowability. Alternatively, a sufficient unpleasant taste masking effect can be obtained. It preferably has both effects.

The ninth aspect of the present invention is the following oral composition.
[9-1] A drug core containing an active ingredient;
In the drug core,
A gelled material selected from the group consisting of carboxyvinyl polymers crosslinked with polyvalent metal ions in the presence of water and sodium alginate crosslinked with polyvalent metal ions, and at least selected from the group consisting of xanthan gum and guar gum. An oral composition having a coating comprising one or more thickening agents.
[9-2] The oral composition according to the above [9-1], wherein the coating further contains a sugar or a sugar alcohol having a solubility at 20 ° C of 30 or more.
[9-3] [9-1] or [9-2], wherein the coating further contains HPMC.
The oral composition according to.
[9-4] The content of the gel-like substance is 3 to 15% by mass or 3 to 20% by mass (% by mass based on all components in the coating, the same applies hereinafter), and the content of the thickener is 10 to 40%. mass%
And the content of HPMC is 5 to 35% by mass, and the content of the sugar or sugar alcohol is 10 to 50% by mass, for oral use according to [9-3] above. Composition.
[9-5] [9-1] to [9-, wherein the coating further contains sucralose.
[4] The oral composition according to any one of [4].
[9-6] The content of the gel-like substance is 3 to 20% by mass (% by mass based on all components in the coating, the same applies hereinafter), and the content of the thickener is 10 to 40% by mass, The content of HPMC is 5 to 35% by mass, the content of the sugar or sugar alcohol is 10 to 50% by mass, and the content of sucralose is 0.01 to 5% by mass. [9-
The oral composition according to [5].
[9-7] The oral composition according to any one of [9-1] to [9-6], which further has a seal coating between the drug core and the coating.
[9-8] The oral composition according to [9-7], which further has a middle coating between the seal coating and the coating.
The oral composition of the ninth aspect of the present invention is equivalent to the oral composition of the second aspect of the present invention produced by water such as saliva in the oral cavity. That is, the oral composition according to the ninth aspect of the present invention has good slipperiness, good adhesion to mucous membranes, and good swallowability. Alternatively, an unpleasant taste masking effect can be obtained. It preferably has both effects. In a more preferable embodiment of the oral composition, the drug dissolution property is also improved.

The tenth aspect of the present invention is the following oral composition.
[10-1] Contains levofloxacin hydrate as an active ingredient, and further contains crystalline cellulose, sodium carboxymethyl starch, pregelatinized starch (eg, SWELSTAR WB-1
(Trade name)) and a tablet core (preferably a mini tablet) containing sodium stearyl fumarate;
A seal coating containing HPMC (eg, TC-5R (trade name)) and Macrogol 6000 (trade name) on the tablet core;
A carboxyvinyl polymer (eg, Carbopol 974P (
(Trade name)), calcium chloride, xanthan gum, sucralose, HPMC (eg, TC-5
E (trade name)), erythritol, and a coating containing HPC (eg, HPC-L (trade name));
[10-2] The content of levofloxacin hydrate in the tablet core (mass of all components excluding the solvent in the tablet core, the same applies hereinafter) is 69.7% by mass, and the content of crystalline cellulose is 6. 2% by weight, the content of sodium carboxymethyl starch is 17.7% by weight, the content of pregelatinized starch is 2.7% by weight, and the content of sodium stearyl fumarate is 3%.
． 7% by mass,
The content of HPMC in the seal coating (mass of all components excluding the solvent of the seal coating, the same hereinafter) is 95.2 mass%, and Macrogol 6000 (trade name)
Content of 4.8% by mass,
The content of carboxyvinyl polymer in the coating (mass in all components except the solvent of the coating, the same applies hereinafter) was 12.7% by mass, and the content of calcium chloride was 0.5.
The content of xanthan gum is 25.3% by mass, the content of sucralose is 0.8% by mass, the content of HPMC is 15.2% by mass, and the content of erythritol is 35% by mass. 0.4% by mass, and the content of HPC is 10.1% by mass.
0-1] The composition for oral administration according to [1].
[10-3] The content of levofloxacin hydrate in the tablet core (mass in all components excluding the solvent of the tablet core, the same applies hereinafter) is 69.7% by mass, and the content of crystalline cellulose is 6. 2% by weight, the content of sodium carboxymethyl starch is 17.7% by weight, the content of pregelatinized starch is 2.7% by weight, and the content of sodium stearyl fumarate is 3%.
． 7% by mass,
The content of HPMC in the seal coating (mass of all components excluding the solvent of the seal coating, the same hereinafter) is 95.2 mass%, and Macrogol 6000 (trade name)
Content of 4.8% by mass,
The content of carboxyvinyl polymer in the coating (mass in all components except the solvent of the coating, the same hereinafter) was 9.4% by mass, the content of calcium chloride was 0.4% by mass, and the content of xanthan gum was The content is 26.3% by mass, the content of sucralose is 0.9% by mass, the content of HPMC is 15.8% by mass, the content of erythritol is 36.8% by mass, And the content of HPC is 10.5% by mass. [10]
-1].
The oral composition according to the tenth aspect of the present invention has good slipperiness, has no adhesion to mucous membranes, and has good swallowability. Alternatively, a masking effect on the unpleasant taste resulting from the active ingredient levofloxacin hydrate can be obtained. It preferably has both effects. In a more preferable embodiment of the oral composition, the drug dissolution property is also improved.

The eleventh aspect of the present invention is the following oral composition.
[11-1] Contains valacyclovir hydrochloride as an active ingredient, and further includes (i) partially pregelatinized starch (eg, PCS (trade name)), sodium carboxymethyl starch, pregelatinized starch (eg, SWELSTAR WB-1 (commodity). Name)), talc and sodium stearyl fumarate, or (ii) partially pregelatinized starch (eg, PCS (trade name)), pregelatinized starch (
Example, SWELSTAR WB-1 (trade name)), a tablet core (preferably a mini tablet) containing talc and sodium stearyl fumarate;
On the tablet core, (iii) pregelatinized starch (eg, SWELSTAR WB-1 (trade name))
And a seal coating comprising erythritol or (iv) HPMC (eg TC-5E (trade name)) and erythritol;
A carboxyvinyl polymer (eg, Carbopol 974P (
(Trade name)), calcium chloride, xanthan gum, sucralose, HPMC (eg, TC-5
E (trade name)), erythritol, and a coating containing HPC (eg, HPC-L (trade name));
[11-2] The content of valacyclovir hydrochloride in the tablet core (mass of all components excluding the solvent of the tablet core, the same hereinafter) is 75.6% by mass, and the content of partially pregelatinized starch is 4 0.6% by mass, the content of sodium carboxymethyl starch is 13.6% by mass, the content of pregelatinized starch is 2.0% by mass, the content of talc is 2.7% by mass. , And the content of sodium stearyl fumarate is 1.4% by mass,
The erythritol content of the seal coating (mass of all components excluding the solvent of the seal coating, the same hereinafter) was 90% by mass, and the pregelatinized starch content was 10%.
Mass%,
The content of carboxyvinyl polymer in the coating (mass in all components except the solvent of the coating, the same applies hereinafter) was 16.7% by mass, and the content of calcium chloride was 0.6.
The content of xanthan gum is 23.4% by mass, the content of sucralose is 0.8% by mass, the content of HPMC is 13.9% by mass, and the content of erythritol is 33% by mass. 0.4% by mass, and the HPC content is 11.1% by mass.
1-1] The composition for oral administration according to [1].
[11-3] The content of valacyclovir hydrochloride in the tablet core (mass of all components excluding the solvent of the tablet core, the same applies hereinafter) is 75.6% by mass, and the content of partially pregelatinized starch is 18 0.7% by mass
And the content of pregelatinized starch is 1.5% by weight, the content of talc is 2.7% by weight, and the content of sodium stearyl fumarate is 1.4% by weight,
The HPMC content of the seal coating (mass of all components excluding the solvent of the seal coating, the same hereinafter) was 29.4% by mass, and the erythritol content was 70.
． 6% by mass,
Content of carboxyvinyl polymer in the coating (mass in all components except solvent,
The same shall apply hereinafter) is 9.3% by mass, the content of calcium chloride is 0.2% by mass, the content of xanthan gum is 26.1% by mass, and the content of sucralose is 0.9% by mass. The content of HPMC is 15.5% by mass, the content of erythritol is 37.3% by mass, and the content of HPC is 10.6% by mass. [11-1] above Oral composition.
The oral composition according to the eleventh aspect of the present invention has good slipperiness, has no adhesion to mucous membranes, and has good swallowability. Alternatively, a masking effect on the unpleasant taste resulting from the active ingredient valacyclovir hydrochloride can be obtained. It preferably has both effects. In a more preferable embodiment of the oral composition, the drug dissolution property is also improved.

The composition having a preferable coating of the present invention is a metal cross-linking thickener which is a metal cross-linking thickener due to a polyvalent metal ion produced from a polyvalent metal compound at the same time as a tablet surface layer is rapidly gelated by a small amount of water or saliva. The agent, preferably a carboxyvinyl polymer and / or a first thickening agent such as sodium alginate, is crosslinked to increase viscosity and form a jelly-like relatively stiff gel, making it slippery on mucous membranes. It improves the swallowability. In addition, the gelled coating film can be expected to exhibit an unpleasant taste masking effect by suppressing drug elution for a short time before swallowing. Furthermore, the composition having the preferable coating of the present invention can be expected to improve the dissolution property that the film is not rapidly disintegrated after swallowing and the drug dissolution is not affected. The coating composition of the present invention has at least one, and preferably all, of the above preferred properties. The more preferable coating composition of the present invention can be made into a formulation having improved dosing properties without affecting drug elution when a drug with a large dose is formulated. The particularly preferred coating composition of the present invention further improves the unpleasant taste masking effect.
In addition, with the preferred coating composition of the present invention, a coating preparation can be easily obtained using a conventional coating technique.

Hereinafter, the present invention will be described in detail.
The first thickener used in the present invention is a metal crosslinking thickener. The metal cross-linking thickener is cross-linked by a polyvalent metal ion generated from a polyvalent metal compound with a small amount of water, and in the absence of water (
In the presence of an alcohol solvent or the like) means a substance that is not crosslinked because a polyvalent metal ion is not generated from the polyvalent metal compound, and is not particularly limited as long as it is a substance showing such properties,
Specifically, carboxyvinyl polymer, sodium alginate, polyacrylic acid, polymethacrylic acid, pectin, carboxymethyl cellulose, glucomannan, carmellose nalorium and the like, preferably, carboxyvinyl polymer and sodium alginate, More preferably, carboxyvinyl polymer is used. By this cross-linking, the viscosity is increased, and by forming a gel that is relatively hard like a jelly, as described below,
It can be expected to exhibit an unpleasant taste masking effect by suppressing drug elution for a short time before swallowing, which causes slippery slippage on the mucous membrane during administration and improves swallowability.
The carboxyvinyl polymer used in the present invention is not particularly limited, but has a displayed viscosity of 4
000 to 60,000 mPa · s (0.5%, 25 ° C., 20 rpm) can be preferably used. Those having a display viscosity of 4000 to 40,000 mPa · s are more preferable because they are unlikely to cause elution delay. More specifically, as a carboxyvinyl polymer, a commercially available product,
For example, Carbopol 971P (trade name) (Lubrizol AdvancedMat)
initial Inc. , Display viscosity: 6420 mPa · s), Carbopol 974P (trade name)
(Lubrizol Advance Material Inc., indicated viscosity: 3285
0 mPa · s), Hibiswako 103 (trade name) (Wako Pure Chemical Industries, indicated viscosity: 15000
mPa · s), Hibiswako 104 (trade name) (Wako Pure Chemical Industries, indicated viscosity: 26000
mPa · s), Hibiswako 105 (trade name) (Wako Pure Chemical Industries, indicated viscosity: 4000 mP
a * s) etc. can be used.
The sodium alginate used in the present invention is not particularly limited, but has a displayed viscosity of 600.
Those having a mPa · s or more (1% / 1% KCl solution, 25 ° C.) can be preferably used. It is preferable that the display viscosity is further 800 to 1600 mPa · s. More specifically, as sodium alginate, a commercially available product, for example, Kimika Algin I-8 (Kimika Co., indicated viscosity,
800 to 900 mPa · s (1%, 20 ° C.), Duck Algin (trade name) (Kibun Food Chemifa, displayed viscosity: 850 mPa · s) and the like can be used.
The first thickening agent such as carboxyvinyl polymer and sodium alginate increases the viscosity in the presence of water by being cross-linked by the polyvalent metal ion generated from the polyvalent metal compound described later, and the gel-like comparison It is a metal cross-linking thickener that forms a relatively hard gel. The carboxyvinyl polymer and the sodium alginate in the composition of the present invention are preferably those which are not substantially crosslinked by polyvalent metal ions. The content of the carboxyvinyl polymer or sodium alginate is preferably 3 to 15% by mass, and more preferably 10 to 13% by mass as the mass% of all components excluding the solvent in the coating composition of the present invention. Alternatively,
The content of the carboxyvinyl polymer or sodium alginate is preferably 3 to 20% by mass, and preferably 3 to 15% by mass, based on the total mass of all components excluding the solvent in the coating composition of the present invention.
Mass% or 8-18 mass% is more preferable, and 9-17 mass% is still more preferable. The same applies to the ratio of the oral composition of the present invention to all components in the coating (hereinafter sometimes referred to as a coating film).
In the present specification, the polyvalent metal compound includes calcium, magnesium, aluminum,
It means a pharmaceutically acceptable water-soluble salt of a polyvalent metal such as zinc. Specifically, calcium chloride, magnesium chloride, aluminum chloride, aluminum sulfate, potassium alum, iron alum, ammonium alum, ferric sulfate, aluminum hydroxide, aluminum silicate, aluminum phosphate, iron citrate, magnesium oxide. , Calcium oxide, zinc oxide, zinc sulfate, or hydrates thereof. Calcium chloride or its hydrate is preferable, and calcium chloride dihydrate is more preferable. The polyvalent metal ion generated from the polyvalent metal compound, specifically, calcium ion, magnesium ion,
Examples thereof include aluminum ions, divalent or trivalent iron ions, zinc ions and the like. Preferred is calcium ion.
The amount of the polyvalent metal compound used in the present invention is preferably 2 to 15 mass% with respect to the first thickener selected from the group consisting of carboxyvinyl polymer and sodium alginate. More preferably, it is 2 to 11 mass%. Alternatively, the blending amount of the polyvalent metal compound used in the present invention is preferably 0.1 to 1% by mass, more preferably 0, as mass% in all components excluding the solvent in the coating composition of the present invention. 0.2 to 0.7% by mass.
The xanthan gum used in the present invention is not particularly limited, but has a displayed viscosity of 600 mPa.
Those of s or more (1% / 1% KCl solution, 25 ° C.) can be preferably used. Further, those having a display viscosity of 800 to 1600 mPa · s are preferable. More specifically, the xanthan gum is a commercially available product, for example, Keltrol CG-T (trade name) (tri-crystal, labeled viscosity: 1555).
mPa ・ s), San Ace (trade name) (San-ei Gen F ・ F ・ I, displayed viscosity: 1600 m
Pa · s) or the like can be used.
The guar gum used in the present invention is not particularly limited, but those having a display viscosity of 600 mPa · s or more (1% / 1% KCl solution, 25 ° C.) can be preferably used. Furthermore, the displayed viscosity is 80
It is preferably 0 to 1600 mPa · s (1% / 1% KCl solution, 25 ° C). More specifically, as the guar gum, a commercially available product, for example, guar gum RG100 (trade name) (MRC Polysaccharide, displayed viscosity: 1100 mPa · s) can be used. Also, Bistop D-2029 (trade name) (San-Ei Gen F / F / I, display viscosity: about 450 m
Pa · s (0.5%) can also be used.
Xanthan gum, guar gum, and sodium alginate are the second thickeners, and the addition of the second thickener causes appropriate adhesion between the tablets, which improves the cohesion of the tablets in the oral cavity and facilitates swallowing. Become. The content of at least one or more second thickeners selected from the group consisting of xanthan gum, guar gum and sodium alginate in the coating film can be appropriately adjusted according to other component composition, The content is preferably 10 to 40% by mass, more preferably 20 to 30% by mass, in order to bring about the drugability.

A combination of a first thickener and a second thickener in a coating composition and an oral composition of the present invention (provided that the second thickener is the second thickener when the first thickener is sodium alginate). The agent is not sodium alginate), and the following combinations can be exemplified.
(1) A first thickener: a combination of carboxyvinyl polymer and a second thickener: xanthan gum;
(2) A first thickener: a combination of carboxyvinyl polymer and a second thickener: guar gum;
(3) First thickener: a combination of carboxyvinyl polymer and second thickener: sodium alginate;
(4) First thickener: a combination of carboxyvinyl polymer and second thickener: xanthan gum and guar gum;
(5) First thickener: carboxyvinyl polymer and second thickener: xanthan gum and sodium alginate in combination:
(6) First thickener: a combination of carboxyvinyl polymer and second thickener: guar gum and sodium alginate;
(7) First thickener: a combination of carboxyvinyl polymer and second thickener: xanthan gum, guar gum and sodium alginate;
(8) A first thickener: a combination of sodium alginate and a second thickener: xanthan gum;
(9) A first thickener: a combination of sodium alginate and a second thickener: guar gum; and
(10) A first thickener: sodium alginate in combination with a second thickener: xanthan gum and guar gum.

As the combination of the first thickener and the second thickener in the preferred embodiment of the present invention, the following combinations can be exemplified.
(1) A first thickener: a combination of carboxyvinyl polymer and a second thickener: xanthan gum;
(2) A first thickener: a combination of carboxyvinyl polymer and a second thickener: guar gum;
(3) First thickener: a combination of carboxyvinyl polymer and second thickener: sodium alginate;
(4) A first thickener: a combination of sodium alginate and a second thickener: xanthan gum; and
(5) A first thickener: a combination of sodium alginate and a second thickener: guar gum.

In a further preferred embodiment of the present invention, the combination of the first thickener and the second thickener is (1)
A first thickener: a combination of carboxyvinyl polymer and a second thickener: xanthan gum.

First selected from the group consisting of carboxyvinyl polymer and sodium alginate
Composition coated with a thickener, a polyvalent metal compound, and at least one second thickener selected from the group consisting of xanthan gum, guar gum and sodium alginate. The surface layer of (eg, tablets, etc.) is rapidly gelled with a small amount of water or saliva, and at the same time, the polyvalent metal ion produced from the polyvalent metal compound crosslinks the carboxyvinyl polymer and / or sodium alginate to increase the viscosity. By increasing and forming a gel that is relatively stiff, it becomes slippery on the mucous membrane and improves swallowability. At the same time, the gelled film exhibits an unpleasant taste masking effect by suppressing drug elution for a short time until swallowing. When used in a multi-unit described below, the tablets are better cohesive in the oral cavity, and swallowability is further improved.

Sucralose that can be used in the present invention is a sweetener that is widely used as a substitute for sucrose. The content of sucralose in the coating film (mass% with respect to all components except the solvent in the coating film) is preferably 0.01 to 5 mass%, 0.5 to 1 mass%
Or 0.1-2 mass% is more preferable. Sucralose that can be used in the present invention is
It is considered to exhibit the effect of further improving the unpleasant taste masking effect.

The sugar or sugar alcohol that can be used in the present invention has a solubility at 20 ° C. of 30 or more. It is preferably 50 or more. Solubility means the maximum mass (g) of a solute that dissolves in 100 g of water. Preferred sugars or sugar alcohols that can be used in the present invention include trehalose, maltose, erythritol, maltitol (reduced maltose syrup).
Etc. Erythritol and maltitol, which have a moderate sweetness when placed in the mouth, are preferable from the viewpoint of taking sensation. In addition, erythritol, maltitol, and trehalose have low hygroscopicity and are particularly preferable in terms of storage stability of the preparation. The content of sugar or sugar alcohol in the coating film (% by mass relative to all components excluding the solvent in the coating film) is preferably 10 to 50% by mass, more preferably 30 to 40% by mass.
The sugar or sugar alcohol having a solubility of 30 or more at 20 ° C. that can be used in the present invention accelerates the swelling of the gel by the thickener. Furthermore, it is considered that this also has the effect of promoting the disintegration of the gel and improving the drug dissolution property.
The HPMC used in the present invention is not particularly limited, but preferably has a viscosity of 100 mPa · s or less, more preferably 10 mPa · s or less. More specifically, the HPMC is more commercially available, for example, TC-5E (trade name) (Shin-Etsu Chemical, indicated viscosity: 3 mPa ·
s), TC-5R (trade name) (Shin-Etsu Chemical, displayed viscosity: 6 mPa · s) and the like can be used.
The content of HPMC in the coating film (% by mass relative to all components in the coating film excluding the solvent) is preferably 5 to 35% by mass, and more preferably 10 to 30% by mass. More preferably, it is 10 to 20 mass% or 13 to 25 mass%.
HPMC, when combined with a sugar or sugar alcohol having a solubility in the oral cavity of 20 ° C. of 30 or more, promotes gel disintegration as compared with the case of using the sugar or sugar alcohol alone. This can prevent a simple increase in the amount of the sugar or sugar alcohol when it is necessary to disintegrate the gel at an early stage.
As described above, HPMC and sugar or sugar alcohol having a solubility at 20 ° C. of 30 or more show a synergistic effect when used in combination, and accelerate the gel disintegration. As a result, when the gel is coated on the drug core, the drug dissolution property is effectively improved. The compounding ratio (mass ratio) of HPMC and the sugar or sugar alcohol is preferably 1: 1 to 1: 4, more preferably 1: 2 to 1: 3.

The thickener used in the fifth to eighth aspects of the present invention means a substance that gels when contacted with water, and is not particularly limited as long as it exhibits such properties, The metal cross-linking thickener and the second thickener described in the description of the first to fourth aspects are included. More specifically, carboxyvinyl polymer, xanthan gum, starch and its derivatives, agar, sodium alginate, arabinogalactan, galactomannan, cellulose and its derivatives, carrageen, dextran, tragacanth, gelatin, pectin, hyaluronic acid, guar gum, gellan gum. , Collagen, casein and the like.
The thickeners may be used alone or in combination of several kinds, and a combination of two or more kinds containing a metal crosslinking thickener is preferable. As a preferred example, a combination of one or more selected from carboxyvinyl polymers and sodium alginate as a metal cross-linking thickener and one or more selected from xanthan gum, guar gum and sodium alginate (however, the combination of the same substances is excluded) Can be mentioned.
The coating composition of the present invention and the oral composition having the coating of the present invention may further contain hydroxypropyl cellulose (hereinafter sometimes referred to as HPC) and the like. Since HPC can be dissolved in alcohol to obtain an appropriate viscosity, it is possible to suppress rapid sedimentation of particles when spray coating by dispersing the coating composition in ethanol, which is advantageous in maintaining uniformity. Is. Further, as a binder, it can help the particles adhere to the tablet surface, enhance the coating efficiency, and form a smooth film. For this reason, the addition of a fixed amount of HPC to the coating composition is advantageous for the production of oral compositions having a coating.
The HPC which can be used in the present invention is not particularly limited, but one having a low viscosity is preferable, and one having 10 mPa · s (2%, 20 ° C.) or less is preferable. More specifically, HPC is more commercially available, for example, HPC-L (trade name) (Nippon Soda, displayed viscosity: 6.0-1).
0 mPa · s), HPC-SL (trade name) (Nippon Soda, displayed viscosity: 3.0 to 5.9 mPas)
-S) etc. can be used. The content of HPC in the coating film (mass in all components excluding the solvent in the coating film) is preferably 0.1 to 15% by mass, and 5 to 15% by mass.
% Or 0.1 to 12 mass% is more preferable. The content of HPC in the coating composition (coating liquid) of the present invention used for spray coating is 0.1 to 5% by mass, preferably 0.2 to 3% by mass, based on the total mass of the coating liquid. Preferably 0.5 to 1
． It is 8% by mass.

As the solvent that can be used for preparing the coating composition of the present invention, water, alcohol, a mixed solvent of water and alcohol, or the like can be used. Of these, alcohol is preferable. Ethanol or absolute ethanol is preferable as the alcohol. Here, ethanol, ethanol _(C 2 _{H 6} O) contained more than 95.1～96.9Vol%, absolute ethanol refers to those containing more ethanol 99.5 vol%. It is preferably 95.1 to 96.9 vol% or more ethanol.
Glycerin may be included in the preparation of the coating composition of the present invention. Glycerin
It is considered that it acts as a plasticizer in the coating composition and has an effect of promoting the swelling of the gel when the coating film comes into contact with water. The glycerin used in the composition of the present invention is not particularly limited, but in the case of quantification, glycerin 98.0 is calculated based on the converted dehydrated product.
Concentrated glycerin, containing at least%, is preferred. When glycerin is included, its content is 0.1 to 5% by mass, preferably 0.5 to 3% by mass, and more preferably 0.5 to 1% by mass based on the total mass of the coating composition containing a solvent. %.
For the preparation of the coating composition, water or an aqueous solvent such as a water / alcohol mixed solvent can be used depending on the type or amount of the thickener used. When an aqueous solvent is used as the coating composition of the present invention, if the concentration of the coating composition is increased, the viscosity may be increased and the operability may be deteriorated. Must be selected.

The coating composition of some embodiments of the present invention comprises:
Carboxyvinyl polymer as the first thickener (eg Carbopol 974P (trade name))
;
Calcium chloride as a polyvalent metal compound;
Xanthan gum as a second thickener;
Sucralose;
HPMC (eg, TC-5E (trade name));
Erythritol as a sugar or sugar alcohol having a solubility at 20 ° C of 30 or more;
HPC (eg, HPC-L (trade name)); and ethanol as a solvent.
Preferably, in the above coating composition, the content of carboxyvinyl polymer (mass in all components excluding the solvent, the same applies hereinafter) is 3 to 20% by mass, more preferably 9 to 17% by mass.
% By mass, and the content of calcium chloride is 0.1 to 1% by mass, more preferably 0.2 to 0.
． 7% by mass, the content of xanthan gum is 10 to 40% by mass, and more preferably 20 to
30% by mass, and the content of sucralose is 0.01 to 5% by mass, more preferably 0.5 to
1 mass%, the content of HPMC is 5 to 35 mass%, more preferably 10 to 20 mass%, the content of erythritol is 10 to 50 mass%, more preferably 30 to 40 mass%, The content of HPC is 0.1 to 15% by mass, more preferably 5 to 15% by mass.
More preferably, in the above coating composition, the content of carboxyvinyl polymer (mass in all components excluding the solvent, the same applies hereinafter) is 12.7 mass%, and the content of calcium chloride is 0.5 mass. %, The xanthan gum content is 25.3% by mass,
The content of sucralose is 0.8% by mass, the content of HPMC is 15.2% by mass, the content of erythritol is 35.4% by mass, the content of HPC is 10.1% by mass. is there.
In another more preferred embodiment, in the coating composition, the content of carboxyvinyl polymer (mass in all components except solvent, the same applies hereinafter) is 9.4% by mass, and the content of calcium chloride is 0. The content of xanthan gum is 26.3% by mass.
, The content of sucralose is 0.9% by mass, the content of HPMC is 15.8% by mass, the content of erythritol is 36.8% by mass, and the content of HPC is 10.5.
It is% by mass.
In another more preferable aspect, in the coating composition, the content of the carboxyvinyl polymer (mass in all components except the solvent, the same applies hereinafter) is 16.7% by mass,
The content of calcium chloride is 0.6% by mass, the content of xanthan gum is 23.4% by mass, the content of sucralose is 0.8% by mass, the content of HPMC is 13.9% by mass. And the content of erythritol is 33.4% by mass, and the content of HPC is 11.
It is 1% by mass.
In another more preferred embodiment, in the coating composition, the content of carboxyvinyl polymer (mass in all components except solvent, the same applies hereinafter) is 9.3% by mass, and the content of calcium chloride is 0. The content of xanthan gum is 26.1% by mass.
The content of sucralose is 0.9% by mass, the content of HPMC is 15.5% by mass, the content of erythritol is 37.3% by mass, and the content of HPC is 10.6.
It is% by mass.

The method for preparing the coating composition of the first aspect of the present invention includes dissolving or uniformly dispersing the components of the coating composition of the present invention in water, alcohol, a mixed solvent of water and alcohol, or the like. Good. Preferably, a method of uniformly dispersing other constituent components in an alcohol solution in which a polyvalent metal compound is dissolved is preferable. Specifically, in an alcohol solution in which a polyvalent metal compound is dissolved, at least one second thickener (preferably xanthan gum) selected from the group consisting of xanthan gum, guar gum and sodium alginate, and a carboxyvinyl polymer and First selected from the group consisting of sodium alginate
A thickener (preferably carboxyvinyl polymer) (provided that the first thickener is sodium alginate, the second thickener is not sodium alginate), preferably (i) HPMC and / or sugar or sugar alcohol having a solubility of 30 or more at 20 ° C., or (ii) at least one selected from the group consisting of sucralose, HPMC, and sugar or sugar alcohol having a solubility of 20 or more at 30 ° C. It may be prepared by uniformly dispersing fine powder containing the above. More preferably, ethanol is used as the solvent.
More preferably, at least one second thickener (more preferably xanthan gum) selected from the group consisting of xanthan gum, guar gum and sodium alginate, the first thickener which is a metal crosslinking thickener (more preferably Is a thickening agent selected from the group consisting of carboxyvinyl polymer and sodium alginate, even more preferably carboxyvinyl polymer), provided that the second thickening agent is sodium alginate. The agent is not sodium alginate), HPMC, and a fine powder of sugar or sugar alcohol having a solubility of 30 or more at 20 ° C uniformly dispersed in a mixed solution of ethanol and glycerin is separately prepared, and then polyvalent To prepare a coating solution by adding a solution of a metal compound in ethanol. .
More preferably, at least one second thickener (more preferably xanthan gum) selected from the group consisting of xanthan gum, guar gum and sodium alginate, the first thickener which is a metal crosslinking thickener (more preferably Is a thickener selected from the group consisting of carboxyvinyl polymers and sodium alginate, and even more preferably carboxyvinyl polymers), provided that the second thickener is sodium alginate.
The thickener is not sodium alginate), sucralose, HPMC, and a fine powder of sugar or sugar alcohol having a solubility of 30 or more at 20 ° C uniformly dispersed in a mixed solution of ethanol and glycerin. That is, a coating solution is prepared by adding a solution of a polyvalent metal compound dissolved in ethanol thereto.

As a method for preparing the coating composition of the fifth aspect of the present invention, HPMC and a sugar or sugar alcohol having a solubility at 20 ° C. of 30 or more are contained in a suspension or a solution in which a thickener is dispersed. It is prepared by dissolving or evenly dispersing fine powder. Similar to the above, it is preferable to use alcohol as the solvent. More preferably, it is ethanol.
It is preferable to make the particle diameter of the constituents fine by using a pulverizer such as a jet mill so that a suspension in which the coating composition of the present invention is uniformly dispersed is obtained. The particle diameter is preferably 35 μm or less, more preferably 25 μm or less, and further preferably 10 μm or less when the median diameter (D50: the diameter at which the larger side and the smaller side are equal when the powder is divided into two from a certain particle diameter) preferable.
As a method of coating the coating composition of the present invention on the drug core or the oral solid substance, a known coating technique can be used and is not particularly limited. For example, a pan coating device, a fluidized bed coating device, an aeration type rotary drum coating device and the like can be used. A ventilated rotary drum coating device is particularly suitable for the coating of mini-tablets described below. Further, by performing spray coating or powder coating using these devices, it is possible to coat the drug core or the oral solid substance. The preferred coating method is spray coating. In particular, it is preferable to continuously supply using a spray nozzle. The drug core or the solid for oral administration can be coated with a single coating. However, the coating is not limited to a single time, and may be performed a plurality of times.
When alcohol is used as the solvent as in the preferred examples described above, a coating composition having a low viscosity in which the first thickener such as carboxyvinyl polymer and sodium alginate is not substantially crosslinked by the polyvalent metal ion is obtained. Obtainable. Therefore, spray coating can be easily performed. Further, since it is an alcohol solution, it can be dried in a short time after coating, which is advantageous in manufacturing.
The oral composition of the second aspect of the present invention, when obtained by coating with alcohol as a solvent as described above, has a first thickening property such as carboxyvinyl polymer and sodium alginate in the coating film. The agent is in a state in which it is not substantially crosslinked by the polyvalent metal ion as long as the film does not come into contact with water.
Oral compositions can also be prepared using water as the solvent. When water is used as the solvent, the first thickener such as carboxyvinyl polymer and sodium alginate is substantially cross-linked by the polyvalent metal ion to give a coating composition having high viscosity. Therefore, by coating a drug core or an oral solid with this coating composition, it is selected from the group consisting of carboxyvinyl polymers crosslinked with polyvalent metal ions, sodium alginate crosslinked with polyvalent metal ions, and the like. An oral composition of the ninth aspect of the present invention is produced, which comprises a gel substance.
The solid component amount of the coating composition of the present invention is preferably 2 to 30% by mass, more preferably 3 to 15% by mass, based on the drug core or oral solid substance to be coated. The coating film of the coated oral composition thus obtained has a thickness of 10 μm to
It is 100 μm, and preferably 20 to 70 μm.

The content of the first thickening agent selected from the group consisting of carboxyvinyl polymer and sodium alginate of the coating composition (coating solution) of the present invention used for spray coating is such that when it is present in the coating solution. , 0.5 to 5% by mass, preferably 0.5 to 4% by mass, more preferably 0.1 to 5% by mass relative to the total mass of the coating liquid.
It is 5 to 3 mass%.
The content of at least one second thickener selected from the group consisting of xanthan gum, guar gum and sodium alginate, when present in the coating liquid, is for example 1 to 5% by weight of the total weight of the coating liquid. , Preferably 1 to 4% by mass, more preferably
It is 3 to 4 mass%.
When present in the coating liquid, the total content of the thickener is, for example, 1.5 to 10% by mass, preferably 1.5 to 8% by mass, and more preferably 3.5, based on the total mass of the coating liquid.
Is about 7% by mass.
When present in the coating liquid, the content of HPMC is 1 to 10% by mass, preferably 1 to 5% by mass, more preferably 1.5 to 3.5% by mass of the total mass of the coating liquid.
Is.
The sugar or sugar alcohol having a solubility at 20 ° C. of 30 or more in the coating composition (coating liquid) of the present invention used for spray coating, when present in the coating liquid, is 1 to 10% by mass of the total mass. , Preferably 1 to 6% by mass, more preferably 3 to 6
Mass% is included.
When present in the coating liquid, the content of sucralose is 0.001 to 0.7% by mass, preferably 0.01 to 0.3% by mass, and more preferably 0.1% by mass relative to the total mass of the coating liquid. It is 05 to 0.2 mass%.

The coating composition of the present invention also includes a kit in which the components to be included are combined, or a combination or kit of compositions in which the components to be included are divided into two or more. For example, the first thickener and the second thickener, and (i) HPMC and sugar or sugar alcohol having a solubility of 30 or more at 20 ° C., or (ii) sucralose, HPMC and 20 ° C. of solubility as required. Is 3
A combination of a coating composition (A) containing at least one selected from the group consisting of 0 or more sugars or sugar alcohols, and a coating composition (B) containing a polyvalent metal compound. Further, a kit in which the coating composition (A) and the polyvalent metal compound (C) are combined, a combination composition (D) of the first thickener and the second thickener, HPMC and 20 ° C. Kit comprising a coating composition (E) containing a sugar or sugar alcohol having a solubility of 30 or more and a polyvalent metal compound (C), a combination composition of a first thickener and a second thickener (D),
A coating composition (E ′) containing at least one selected from the group consisting of sucralose, HPMC, and sugars or sugar alcohols having a solubility at 20 ° C. of 30 or more was combined with a polyvalent metal compound (C). A kit etc. are illustrated.
The components contained in these combinations or kits may be combined and coated onto the drug core or oral solid as described above. Further, each of the coating compositions dissolved or uniformly dispersed in an alcohol solvent or water may be sequentially coated on the drug core or the oral solid substance. At this time, the solvent may be changed and coating may be performed. In the above example, the composition (A) dissolved or uniformly dispersed in an alcohol solvent may be first coated on the drug core or the oral solid, and the composition (B) dissolved in water may be subsequently coated. it can. In this case, at the interface between composition (A) and composition (B), the oral composition according to the ninth aspect of the invention, wherein the first thickening agent comprises a coating partially crosslinked by polyvalent metal ions. The thing is manufactured.

The oral composition of the second aspect of the present invention can be obtained by coating the drug core with the coating composition of the first aspect of the present invention. However, the method is not limited to this method, and a carboxyvinyl polymer, sodium alginate, or another primary compound may be attached to the surface of the drug core.
Thickener, a polyvalent metal compound, and a second thickener such as xanthan gum, guar gum, and sodium alginate (provided that the second thickener is alginic acid when the first thickener is sodium alginate). Any oral composition having (not sodium) is included in the oral composition of the second aspect of the present invention.
The oral composition according to the sixth aspect of the present invention can be obtained by coating the drug composition with the coating composition according to the fifth aspect of the present invention. However, the present invention is not limited to this method, and any oral composition having a thickener, a sugar or sugar alcohol having a solubility at 20 ° C. of 30 or more and HPMC on the surface of the drug core may be used in the present invention. In the oral composition according to the sixth aspect of the present invention.
In the present invention, examples of the drug core containing the active ingredient used in the oral composition include solid preparations such as tablet core, pill core, capsule core, pellet core and granule core. The oral solid is not particularly limited as long as it contains a solid drug core and is a solid for oral use. In the case of a large-dose formulation, mini-tablets, which are in a form capable of avoiding an increase in the size of the formulation and reducing the drug content per tablet and minimizing the bulk, are preferable as the drug core. Mini tablets can be manufactured with normal equipment.
The mini-tablet used in the present specification is a form of tablet and has a diameter and a thickness of 6 m.
A granular solid preparation of m or less. In the case of an active ingredient with a large dose, if the diameter is 3 to 4 mm, the number of doses per dose is about 20 to 100. In the present specification, a single dose of an oral preparation having a single dose of 10 or more particles is called a multi-unit. It is preferably a granular tablet having a diameter and a thickness of 0.5 to 5 mm, more preferably 2 to 4 mm.

In the oral composition of the present invention, a seal coating may be provided between the drug core or the oral solid substance containing the active ingredient and the coating (which may be referred to as “overcoating” in the present specification). . The oral composition of the present invention having a seal coating,
The coating composition of the present invention can be obtained by coating a seal coat drug core having a seal coating.
The seal coating of the drug core prevents the drug core components from migrating to the coating layer during storage and causing a change in the composition with the coating layer components. Therefore, it is expected that the coating is prevented from reducing the unpleasant taste masking effect at the time of taking, or the coating is enhanced to enhance the unpleasant taste masking effect at the time of taking.
The seal coating is obtained by coating the seal coating composition on the drug core containing the active ingredient using known coating techniques. The seal coating composition may be one that can prevent the components of the drug core from migrating to the coating during storage of the oral composition, and examples thereof include (i) HPMC, HPC, ethyl cellulose, polyvinylpyrrolidone, and pullulan. , At least one selected from the group consisting of acrylic acid ester / methacrylic acid ester copolymers, or (ii) HPMC, HPC,
Ethyl cellulose, polyvinylpyrrolidone, pullulan, copolymer of acrylic acid ester / methacrylic acid ester, pregelatinized starch, erythritol, macrogol 6000 (trade name)
), Talc, light anhydrous silicic acid, and the like.
As the solvent that can be used for preparing the seal coating composition, water, alcohol, a mixed solvent of water and alcohol, or the like can be used.
The solid component amount of the composition for seal coating is preferably 1 to 10% by mass, more preferably 2 to 5% by mass, based on the drug core or oral solid substance to be coated. The thickness of the seal coating film of the oral composition containing the seal coating thus obtained is
It is 10 to 80 μm, and preferably 20 to 40 μm.
The oral composition of some embodiments of the present invention does not have a seal coating.

In the oral composition of the present invention, a middle coating may be further provided between the seal coating and the coating. The oral composition of the present invention having a middle coating,
The coating composition of the present invention can be obtained, for example, by coating a middle coat-seal coat drug core having a seal coating and a middle coating.
By providing the drug core with a middle coating, the dissolution rate of the drug can be increased while maintaining the unpleasant taste masking effect.
The middle coating is obtained by coating the middle coat coating with the middle coating composition using a known coating technique. The middle coating composition may be any one that enhances the disintegration property of the overcoating which is the coating composition of the present invention. A composition containing at least one selected from the group consisting of, preferably, at least one selected from the group consisting of erythritol, TC-5E (Shin-Etsu Chemical) and the like.
As the solvent that can be used for preparing the middle coating composition, water, alcohol, a mixed solvent of water and alcohol, or the like can be used.
The solid component amount of the composition for middle coating is preferably 1 to 10% by mass, more preferably 2 to 5% by mass, based on the drug core or the solid substance for oral administration. The thickness of the middle coating film of the oral composition containing the middle coating thus obtained is
It is 10 to 80 μm, and preferably 20 to 40 μm.
The oral composition of some embodiments of the present invention does not have a middle coating.

Oral composition of the present invention, for example,
(I) drug core / overcoating;
(Iii) drug core / seal coating / overcoating; or (iii) drug core / seal coating / middle coating / overcoating,
Preferably,
(Iii) drug core / seal coating / overcoating; or (iii) drug core / seal coating / middle coating / overcoating,
More preferably,
(Ii) Composed of drug core / seal coating / overcoating.

Oral compositions of some aspects of the invention include
A drug core (preferably a tablet core, more preferably a minitablet) containing an active ingredient;
In the drug core,
Carboxyvinyl polymer as the first thickener (eg Carbopol 974P (trade name))
,
Calcium chloride as a polyvalent metal compound,
Xanthan gum as the second thickener,
Sucralose,
HPMC (eg, TC-5E (trade name)),
Erythritol as a sugar or sugar alcohol having a solubility of 20 or more at 20 ° C., and HPC (eg, HPC-L (trade name)),
Coating containing;
Have
Having a further seal coating between the drug core and said coating,
There is no middle coating between the seal coating and said coating.
Preferably, in the coating composition, the content of the carboxyvinyl polymer in the overcoating (mass in all components except the solvent, the same applies hereinafter) is 3 to 20% by mass,
It is more preferably 9 to 17% by mass, the content of calcium chloride is 0.1 to 1% by mass, more preferably 0.2 to 0.7% by mass, and the content of xanthan gum is 10 to 40% by mass.
, More preferably 20 to 30% by mass, the content of sucralose is 0.01 to 5% by mass,
More preferably 0.5 to 1 mass%, the content of HPMC is 5 to 35 mass%, more preferably 10 to 20 mass%, the content of erythritol is 10 to 50 mass%, more preferably 30. To 40% by mass, and the content of HPC is 0.1 to 15% by mass, more preferably 5 to
It is 15% by mass.
In some aspects of the invention, the seal coating comprises HPMC and Macrogol 6
000 (brand name) is included. In this case, preferably, the content of HPMC in the seal coating (mass in all components excluding the solvent of the seal coating, hereinafter the same) is 60 to 99 mass%,
More preferably, it is 90 to 98 mass%, and the content of Macrogol 6000 (trade name) is 1 to
It is 40% by mass, more preferably 2 to 10% by mass.
In some other aspects of the invention, the seal coating comprises erythritol and α
Includes modified starch. In this case, preferably, the content of erythritol in the seal coating (mass in all components excluding the solvent of the seal coating, hereinafter the same) is 60 to 99% by mass.
Is more preferably 80 to 95% by mass, and the content of pregelatinized starch is 1 to 40% by mass, more preferably 5 to 20% by mass.
In some other aspects of the invention, the seal coating comprises HPMC and erythritol. In this case, preferably, the content of HPMC in the seal coating (mass in all components excluding the solvent of the seal coating, hereinafter the same) is 5 to 45% by mass, more preferably 20 to 40% by mass. The content is 55 to 95% by mass, more preferably 60 to 80% by mass.

Preferably, in the above oral composition, the seal coating contains HPMC and Macrogol 6000 (trade name).
At this time, in the above oral composition, the content of carboxyvinyl polymer in the overcoating (mass in all components excluding the solvent of the overcoating, the same applies hereinafter) was 12.
7% by mass, the content of calcium chloride is 0.5% by mass, the content of xanthan gum is 25.3% by mass, the content of sucralose is 0.8% by mass, the content of HPMC Is 15.2% by mass, the content of erythritol is 35.4% by mass, HPC
The content of is 10.1 mass%. Further, the content of HPMC in the seal coating (mass in all components excluding the solvent of the seal coating, the same applies hereinafter) is 95.2 mass%, and the content of Macrogol 6000 (trade name) is 4.8 mass. %.

Preferably, in the above oral composition, the seal coating contains HPMC and Macrogol 6000 (trade name).
At this time, in the above oral composition, the content of carboxyvinyl polymer in the overcoating (mass in all components excluding the solvent in the overcoating, the same applies hereinafter) was 9.4.
% By mass, the content of calcium chloride is 0.4% by mass, the content of xanthan gum is 26.3% by mass, the content of sucralose is 0.9% by mass, the content of HPMC is The content of erythritol is 36.8 mass%, and the content of HPC is 10.5 mass%. Further, the content of HPMC in the seal coating (mass in all components excluding the solvent of the seal coating, the same applies hereinafter) is 95.2 mass%, and the content of Macrogol 6000 (trade name) is 4.8 mass. %.

Preferably, in the above oral composition, the seal coating is erythritol,
Includes pregelatinized starch.
At this time, in the above oral composition, the content of carboxyvinyl polymer in the overcoating (mass in all components excluding the solvent of the overcoating, the same applies hereinafter) was 16.
7% by mass, the content of calcium chloride is 0.6% by mass, the content of xanthan gum is 23.4% by mass, the content of sucralose is 0.8% by mass, the content of HPMC Is 13.9% by mass, the content of erythritol is 33.4% by mass, HPC
Is 11.1% by mass. Further, the content of erythritol in the seal coating (mass of all components excluding the solvent of the seal coating, hereinafter the same) is 90 mass%,
The content of pregelatinized starch is 10% by mass.

Preferably, in the above oral composition, the seal coating contains HPMC and erythritol.
At this time, in the above oral composition, the content of carboxyvinyl polymer in the overcoating (mass in all components except the solvent, the same applies hereinafter) was 9.3% by mass, and the content of calcium chloride was 0. 2% by mass, the content of xanthan gum is 26.1% by mass, the content of sucralose is 0.9% by mass, the content of HPMC is 15.5% by mass, and the content of erythritol is 37.3 mass% and HPC content is 10.6 mass%.
Is. Further, the content of HPMC in the seal coating (mass in all components excluding the solvent of the seal coating, the same hereinafter) was 29.4% by mass, and the content of erythritol was 7%.
It is 0.6% by mass.

The drug core or oral solid substance used in the present invention is prepared by blending a drug carrier commonly used in the technical field of drug formulation, in addition to the desired drug as an active ingredient. As the pharmaceutical carrier, those known in the pharmaceutical technical field can be widely used, for example, lactose, sucrose, mannitol, sodium chloride, glucose, starch, calcium carbonate, kaolin, crystalline cellulose, excipients such as silicates, Water, ethanol, simple syrup, glucose solution, starch solution, gelatin solution,
Binders such as carboxymethyl cellulose, carboxymethyl cellulose Na, shellac, methyl cellulose, HPMC, HPC, polyvinyl alcohol, gelatin, dextrin, pullulan; citric acid, anhydrous citric acid, sodium citrate, sodium citrate dihydrate, anhydrous phosphoric acid PH adjusting agents such as sodium monohydrogen, anhydrous sodium dihydrogen phosphate, sodium hydrogen phosphate, and anhydrous sodium dihydrogen phosphate; carmellose calcium, low-substituted hydroxypropicellulose, carmellose, croscarmellose sodium, partially pregelatinized. Starch, dry starch, sodium carboxymethyl starch, crospovidone,
Disintegrants such as polysorbate 80; absorption enhancers such as sodium lauryl sulfate; refined talc,
Lubricants such as stearate, polyethylene glycol and colloidal silicic acid can be exemplified. When carboxymethyl starch sodium is used, disintegration property may be improved. Examples include Primogel (Matsuya Chemical) Explotab (Kimura Sangyo) and Glycolys (Rocket Japan).
When a mini-tablet is used as a coating formulation and administered as a multi-unit, the tablet surface layer gels after contact with water and at the same time the polyvalent metal ion generated from the polyvalent metal compound causes carboxyvinyl polymer and / or alginic acid. First such as sodium
The viscosity is increased by cross-linking the thickener of (1), and a jelly-like relatively hard gel is formed to make it slippery, and the tablet-to-table cohesion is good and swallowing is easy. Further, since the formed gel layer suppresses the release of the drug for a short time, the masking of unpleasant taste is more effective.
In the oral composition of some aspects of the present invention, the drug core (preferably a tablet core, more preferably a minitablet) contains levofloxacin hydrate as an active ingredient, and
Includes crystalline cellulose, sodium carboxymethyl starch, pregelatinized starch and sodium stearyl fumarate. Preferably, the content of levofloxacin hydrate in the tablet core (
The mass of the tablet core in all components excluding the solvent, hereinafter the same) is 7 to 70 mass%, more preferably 35.
To 70% by mass, and the content of crystalline cellulose is 1 to 20% by mass, more preferably 5 to 7% by mass.
The content of sodium carboxymethyl starch is 5 to 30% by mass, more preferably 15 to 20% by mass, and the content of pregelatinized starch is 0.3 to 20% by mass, more preferably 1% by mass. Is about 5% by mass, and the content of sodium stearyl fumarate is about 0.3 to 2
It is 0% by mass, more preferably 1 to 5% by mass. Particularly preferably, the content of levofloxacin hydrate in the tablet core (mass in all components excluding the solvent of the tablet core, the same applies hereinafter) is 69.7% by mass, and the content of crystalline cellulose is 6.2. % By weight, the content of sodium carboxymethyl starch is 17.7% by weight, the content of pregelatinized starch is 2.7% by weight, and the content of sodium stearyl fumarate is 3.7% by weight. Is.
In the oral composition of some other aspects of the present invention, the drug core (preferably a tablet core, more preferably a minitablet) contains valacyclovir hydrochloride as an active ingredient, and further, partially pregelatinized starch, α Starch, talc and sodium stearyl fumarate, and optionally sodium carboxymethyl starch. Preferably, the drug core has a valacyclovir hydrochloride content (mass of all components excluding the solvent of the tablet core, the same applies hereinafter) of 7
To 80% by mass, more preferably 35 to 80% by mass, and the content of partially pregelatinized starch is 2
To 40% by weight, more preferably 5 to 20% by weight, the content of sodium carboxymethyl starch is 0 to 30% by weight, more preferably 0 to 15% by weight, and the content of pregelatinized starch is 0.3. To 30% by mass, more preferably 1 to 20% by mass, and the content of talc is 0.
． It is 3 to 20% by mass, more preferably 1 to 5% by mass, and the content of sodium stearyl fumarate is 0.3 to 20% by mass, more preferably 1 to 5% by mass. Particularly preferably, the drug core has a valacyclovir hydrochloride content (mass of all components excluding the solvent of the tablet core, the same applies hereinafter) of 75.6% by mass, and a partially pregelatinized starch content of 4 0.6% by mass, the content of sodium carboxymethyl starch is 13.6% by mass, the content of pregelatinized starch is 2.0% by mass, the content of talc is 2.7% by mass. , And the content of sodium stearyl fumarate is 1.4% by mass. Further, particularly preferably, the drug core has a content of valacyclovir hydrochloride (mass of all components excluding the solvent of the tablet core, the same applies hereinafter) is 75.6% by mass, and the content of partially pregelatinized starch is Is 18.7% by mass, the content of pregelatinized starch is 1.5% by mass, the content of talc is 2.7% by mass, and the content of sodium stearyl fumarate is 1.4% by mass. %.
The description of the method for producing the oral composition according to the fourth and eighth aspects of the present invention is as described above.
Further, the oral compositions according to the third and seventh aspects of the present invention can be obtained by the production method described above. In addition, the oral composition of the third aspect of the present invention is the first solution of carboxyvinyl polymer, sodium alginate, etc. in an alcohol solution in which a polyvalent metal compound is dissolved.
A thickener (preferably carboxyvinyl polymer) and a second thickener (preferably xanthan gum) such as xanthan gum, guar gum, sodium alginate (provided that when the first thickener is sodium alginate, the second The thickener is not sodium alginate), but is prepared by spray coating a liquid containing the active ingredient on the drug core. Therefore, as described above, the carboxyvinyl polymer, etc. The thickener of No. 1 is in a state where it is not substantially crosslinked by polyvalent metal ions as long as water does not come into contact with the film. Further, the coating composition of the oral composition of the present invention can be easily washed off with the alcohol solvent used. On the other hand, in an oral composition coated with a solution other than alcohol, for example, an aqueous solution as a solvent, the first thickener such as carboxyvinyl polymer in the coating film is substantially crosslinked by polyvalent metal ions. The coating is not easy to wash off as it is in condition.

Regarding the ease of swallowing the oral composition according to the present invention, specifically, Test Example 1 described below is used.
In the test method described in 1., that is, in the evaluation using a vertically fixed silicone tube (8 × 12) having a length of 5 cm, the lower end of which is stoppered with absorbent cotton (25 to 30 mg), the inside of the tube for the filled oral composition was tested. Of the probe (sphere with a diameter of 6 mm) inserted in the
, The maximum stress required for the vertical movement distance of 40 mm). The oral composition of the present invention preferably has a maximum stress of 41 g or less, more preferably 30 g or less, even more preferably 20 g or less. The area under the stress / distance curve is 6
It is preferably 00 g · mm or less, more preferably 400 g · mm or less, still more preferably 200 g · mm or less.
Regarding the unpleasant taste masking effect in the present invention, specifically, the test method described in Test Example 2 described later, that is, an oral composition containing an active ingredient in a vertically standing 2 mL plastic syringe was used as Test Example 2. Similarly, it should be expressed by the concentration of the active ingredient in the liquid flowing out from the mouth of the syringe when water is filled from the top and heated to 37 ° C from the top at a flow rate of 2 mL / min for a certain period of time, for example, 30 seconds or 2 minutes. You can It is judged that the oral composition of the present invention is sufficiently masked for practical use if the oral composition of the present invention has a concentration below the threshold concentration of the unpleasant taste of the active ingredient when water is dropped for 30 seconds in the above test. . For example, in the case of levofloxacin hydrate, when levofloxacin concentration is 1,000 μg / mL or less when water is dropped for 30 seconds,
Good masking of unpleasant taste is preferable. Even in the case of a formulation to be taken without water, if the concentration is below the threshold concentration of the unpleasant taste of the active ingredient in the above test, it is determined that sufficient masking has been made for practical use, for example, levofloxacin hydrate. In the case of, the concentration is 100 μg /
mL or less, preferably 50 μg / mL or less, more preferably 10 μg / mL or less. In the case of valacyclovir hydrochloride, the concentration is, for example, 100 μg / mL or less, preferably 6 μg / mL or less.
It is 0 μg / mL or less, more preferably 20 μg / mL or less.
Regarding the dissolution property in the present invention, specifically, in the test example described in Test Example 3 below, the Japanese Pharmacopoeia Disintegration Test Solution 1 Solution by the Paddle Method of the Japanese Pharmacopoeia and the evaluation at 50 rpm were 30. It can be expressed as the elution rate after the elapse of minutes. The oral composition of the present invention preferably has an elution rate of 60% or more, more preferably 80% or more. More preferably, it is 90% or more, and there is no substantial dissolution delay, which satisfies the dissolution criteria for immediate release tablets.

The active ingredient contained in the drug core used in the oral composition of the present invention is not particularly limited, but a drug with a large single dose is particularly suitable for the purpose of the present invention. For example, the antibiotics amoxicillin, cefuroxime axetil, cephalexin, fosfomycin, ceftazidime, ampicillin, cyclacillin, renampicillin, cefotianum hexetil, sultamicillin, vancomycin, polymyxin B, erythromycin, clarithromycin, terithromycin, azithromycin, josamycin, josamicin. Midecamycin, rokitamycin, roxithromycin, kanamycin, ceftibutene, chloramphenicol, cycloserine, rifabutin, ofloxacin, enoxacin, which are synthetic antibacterial agents,
Levofloxacin, ciprofloxacin, norfloxacin, moxifloxacin, galenoxacin, lomefloxacin, nalidixic acid, linezolid, salfa drug salazosulfapyridine, antifungal drug voriconazole, itraconazole, antiviral drug acyclovir, valacyclovir, fam Cyclovir, valganciclovir, nelfinavir, raltegravir, labivudine, emtricitabine, ritonavir, ribavirin, abacavir, efavirenz, nelfinavir, tenofovir, disoproxil, darunavir,
Atazanavir, hyperlipidemic drug probucol, clofibrate, colestimide, cholestyramine, anthelmintic drug praziquantel, albendazole, antiprotozoal drug tinidazole, metronidazole, branched chain amino acid for liver disease, antidote Activated carbon, 5-aminosalicylic acid as a gastrointestinal agent, calcium polycarbophil, imatinib mesylate as an antineoplastic agent, mycophenolate mofetil as an immunosuppressant, and inosine pranobex as another drug . Furthermore, the coating composition of the present invention is not limited to these drugs and can be applied to Chinese herbs, OTC drugs and health foods.

Next, the present invention will be described more specifically by showing Examples and Comparative Examples, but the present invention is not limited thereto.

(1) Production of placebo mini tablet (plain tablet P):
The following components were weighed, mixed, and then tabletted to obtain 2 kg (about 80,000 tablets) of about 25 mg / tablet mini tablet having a diameter of 3.1 mm and a thickness of 3.1 mm.
Lactose 2.050kg
Crystalline cellulose 0.519kg
Magnesium stearate 0.026kg

(2) Production of Levofloxacin Hydrate Mini Tablets and Valacyclovir Hydrochloride Mini Tablets:
Levofloxacin hydrate or valacyclovir hydrochloride is selected as a model drug having high water solubility and bitterness, and levofloxacin hydrate-containing minitablets A to C (uncoated tablets A to C) and valacyclovir hydrochloride-containing minitablets D to G (plain). Tablets DG) were produced.
(i) Production of Levofloxacin Hydrate-Containing Mini Tablet A (Uncoated Tablet A):
The following components were weighed, charged into a stirring and mixing granulator (Paurec VG-25) and mixed, and 2000 g of an 8 w / w% HPC aqueous solution was added as a binder for granulation.
Levofloxacin hydrate 4.100kg
Crystalline cellulose 0.364kg
Carmellose 0.392kg
Stearyl sodium fumarate 0.108kg
3. The powder obtained by drying the granulated product with a fluidized bed drier (Pawrec MP-01) and sizing.
To 277 kg, 0.087 kg of sodium stearyl fumarate was added, mixed, and then tableted to form a levofloxacin hydrate minitablet with a diameter of 3.1 mm and a thickness of 3.1 mm, about 24 mg / tablet.
． 612 kg (about 150,500 tablets) were obtained.

(ii) Preparation of Mini Tablet B (Uncoated Tablet B) Containing Levofloxacin Hydrate:
The following components were weighed, charged into a stirring and mixing granulator (high speed mixer), then mixed, and water was added to perform granulation.
Levofloxacin hydrate 205.0 g
Crystalline cellulose 18.2g
Pregelatinized starch (SWELSTAR PD-1; Asahi Kasei) 19.6 g
Pregelatinized starch (SWELSTAR WB-1; Asahi Kasei) 9.0 g
Stearyl sodium fumarate 5.4g
Powder 23 obtained by drying the granulated product with a fluidized bed drier (Paurec MP-01) and sizing.
To 9.9 g, 4.9 g of sodium stearyl fumarate was added, mixed and tableted to give a diameter of 3.1.
mm Levofloxacin Hydrate Mini Tablet with a thickness of 3.1 mm About 24 mg / Tablet about 220
g (about 9,200 tablets) was obtained.

(iii) Production of Mini Tablet C (Uncoated Tablet C) Containing Levofloxacin Hydrate:
<Manufacture of 3kg scale>
The following components were weighed, charged into a stirring and mixing granulator (Paurec VG-25), and then mixed, and a 5 w / w% pregelatinized starch (SWELSTARB-1; Asahi Kasei) aqueous solution was used as a binder.
Granulation was carried out by adding 93 kg and 1.57 kg of water.
Levofloxacin hydrate 2.471 kg
Crystalline cellulose 0.220kg
Carboxymethyl starch sodium (Primogel) 0.627kg
Stearyl sodium fumarate 0.065kg
2. The powder obtained by drying the granulated product with a fluidized bed drier (Pawrec MP-01) and sizing.
0.058 kg of sodium stearyl fumarate was added to 095 kg, and the mixture was tableted after mixing to give about 3 kg (about 125,000 tablets) of a levofloxacin hydrate minitablet with a diameter of 3.1 mm and a thickness of 3.1 mm. .

<Manufacture of 50 kg scale>
The following components were weighed, put into a stirring and mixing granulator (Paurec VG-100), mixed, and then mixed with 5.36 kg of a 5 w / w% pregelatinized starch (SWELSTAR WB-1; Asahi Kasei) aqueous solution and 7.00 kg of water as a binder. Then granulation was performed.
Levofloxacin hydrate 11.993 kg
Crystalline cellulose 1.065kg
Carboxymethyl starch sodium (Primogel) 3.042kg
Sodium stearyl fumarate 0.316kg
The granulated product was dried with a fluidized bed drier (Pawrec WSG-30). This operation was repeated 3 times, and the sub-batch was put together to obtain a dried product. Powdered sodium stearyl fumarate obtained by sizing the dried product was added in an amount of 1.87 mg per 100 mg of the powder, mixed, and then tableted to give a diameter of 3.1.
About 49 kg of a levofloxacin hydrate mini-tablet having a thickness of 3.1 mm was obtained.

(iv) Production of valacyclovir hydrochloride-containing mini tablet (plain tablet D):
The following components are weighed, put into a stirring and mixing granulator (high speed mixer), and then mixed, and as a binder, 6.4 w / w% pregelatinized starch (SWELSTARB-1; Asahi Kasei) aqueous solution 1
00g was added and granulated.
Valacyclovir hydrochloride 178.0 g
Crystalline cellulose 10.2g
Carboxymethyl starch sodium (Primogel) 32.0g
Stearyl sodium fumarate 4.3g
Powder 19 obtained by drying the granulated product with a fluidized bed drier (Paurec MP-01) and sizing.
3.6 g of sodium stearyl fumarate was added to 7.6 g and the mixture was tableted after mixing to a diameter of 3.1 m.
17 mg of valacyclovir hydrochloride mini-tablet with a thickness of 3.1 mm (about 24 mg / tablet)
(About 7,400 tablets) were obtained.

(v) Production of valacyclovir hydrochloride-containing mini tablet (plain tablet E):
The following components are weighed, charged into a stirring and mixing granulator (Paurec VG-25), mixed and then used as a binder: 6 w / w% pregelatinized starch (SWELSTAR WB-1; Asahi Kasei) aqueous solution 1
000g was added and granulated.
Valacyclovir hydrochloride 2224g
Partially Pregelatinized Starch (PCS) 136g
Carboxymethyl starch sodium (Primogel) 400g
Talc 80g
The granulated product was dried with a fluidized bed drier (Paurec MP-01), and then the powder obtained by sizing was added with 1.38 mg of sodium stearyl fumarate per 100 mg of the powder, mixed and compressed into a tablet having a diameter of 3.1 mm. 2700 g of valacyclovir hydrochloride minitablets having a thickness of 3.1 mm were obtained.

(Vi) Production of valacyclovir hydrochloride-containing mini tablet (plain tablet F):
The following components were weighed, put into a stirring and mixing granulator (Paurec VG-25), mixed and then used as a binder: 6 w / w% pregelatinized starch (SWELSTAR WB-1; Asahi Kasei) aqueous solution 7
50 g was added and granulated.
Valacyclovir hydrochloride 2224g
Partially Pregelatinized Starch (PCS) 536g
Talc 80g
The granulated product was dried with a fluidized bed drier (Paurec MP-01), and then the powder obtained by sizing was added with 1.38 mg of sodium stearyl fumarate per 100 mg of the powder, mixed and compressed into a tablet having a diameter of 3.1 mm. About 2600 g of valacyclovir hydrochloride minitablets having a thickness of 3.1 mm were obtained.

(Vii) Manufacture of valacyclovir hydrochloride-containing mini tablet (plain tablet G):
The following components were weighed, put into a stirring and mixing granulator (Paurec VG-25), mixed and then used as a binder: 6 w / w% pregelatinized starch (SWELSTAR WB-1; Asahi Kasei) aqueous solution 7
50 g was added and granulated.
Valacyclovir hydrochloride 2224g
Partially pregelatinized starch 551g
Talc 80g
The granulated product was dried with a fluidized bed drier (Paurec MP-01), and then the powder obtained by sizing was added with 1.38 mg of sodium stearyl fumarate per 100 mg of the powder, mixed and compressed into a tablet having a diameter of 3.1 mm. About 2700 g of valacyclovir hydrochloride minitablets having a thickness of 3.1 mm were obtained.

Table 1 shows the formulations of plain tablets A to G (contents of each component when the content of the active ingredient is 500 mg).

Examples 1-2
After mixing concentrated glycerin with ethanol, HPC (HPC-L; Nippon Soda, indicated viscosity: 6 to
10 mPa · s) was added and dissolved. HPMC (TC-5E; Shin-Etsu Chemical, indicated viscosity: 3 mP
a) and carboxyvinyl polymer (Carbopol 971P; Lubrizol A
advanced Material Inc. , Indicated viscosity: 6420 mPa · s) were sequentially added and uniformly dispersed. Furthermore, erythritol (Mitsubishi Corporation Food Tech), xanthan gum (K
Eltrol CG-T; tri-crystal, indicated viscosity: 1555 mPa · s) was pulverized with a jet mill (Seishin Enterprise SJ-3), and then sequentially added and uniformly dispersed. Finally, a solution prepared by dissolving calcium chloride dihydrate in ethanol was added and uniformly dispersed to obtain a coating solution. This coating solution was spray-coated on the plain tablet A using a coating device (Powrec Doria Coater 200) to obtain a coated mini tablet (coating ratio: about 10% by mass ratio to the coated mini tablet). 140 g of plain tablets (
(About 5,833 tablets).
Further, as Examples 1-P and 2-P, coated minitablets were obtained by the same preparation method as in Examples 1 and 2 except that the plain tablet P was used instead of the plain tablet A (140 g of plain tablet,
(About 5,833 tablets).

Example 3
HPC-L was not added in the coating liquid preparation method of Example 1, and the coating minitablet was obtained by the preparation method according to Example 1 thereafter.

Example 4
A coating minitablet was obtained by the preparation method according to Example 1 except that Carbopol 974P (Lubrizol Advance Material Inc., indicated viscosity: 32850 mPa · s) was used in place of Carbopol 971P in the coating liquid preparation method of Example 2. It was

Example 1-1
A coating minitablet was obtained by the preparation method according to Example 1 except that mannitol (Mannitol P; Mitsubishi Corporation Foodtech) pulverized with a jet mill was used in place of erythritol in the coating solution preparation method of Example 1.

Example 1-2
HPMC was not added in the coating liquid preparation method of Example 1, and the coating minitablet was obtained by the preparation method according to Example 1 thereafter.

Example 1-3
Coating minitablets were obtained by the preparation method according to Example 1 except that HPMC was not added in the coating liquid preparation method of Example 1 and erythritol was increased.

Example 1-4
A coated minitablet was obtained by the preparation method according to Example 1 except that the amount of Carbopol 971P was increased and the amount of erythritol was decreased in the method for preparing the coating liquid of Example 1.

Example 1-5
A coated minitablet was obtained by the preparation method according to Example 1 except that HPMC was increased without adding erythritol in the coating solution preparation method of Example 1.

Example 2-1
In the coating liquid preparation method of Example 1, Carbopol 971P was not added and the coating mini tablet was obtained by the preparation method according to Example 1 thereafter.

Example 2-2
In the coating liquid preparation method of Example 1, xanthan gum was not added, and the coating mini tablet was obtained by the same preparation method as in Example 1.

Comparative example 1
As Comparative Example 1, plain tablets A obtained by producing the levofloxacin hydrate mini-tablet were used.

Comparative example 2
Normal film-coated mini tablets were prepared for the purpose of shading and masking bitterness. After dissolving HPMC and Macrogol 6000 (Wako Pure Chemical Industries) in water, talc (Matsumura Sangyo),
Titanium oxide (Freund Industries) was uniformly dispersed to obtain a coating liquid. The coating solution was coated on the plain tablet P or the plain tablet A using a coating device (Paurec Doria Coater 200) to obtain a coated minitablet (coating ratio: about 10% by mass ratio to the coated minitablet).

Comparative Example 3
Except that HPMC and calcium chloride dihydrate were not added in the method for preparing the coating solution of Example 1 and jet mill-milled mannitol (Mannit P; Mitsubishi Corporation Foodtec) was used instead of jet-mill-milled erythritol. A coated minitablet was obtained by the preparation method according to Example 1.

Table 2 shows the coating liquid formulations (number of copies) of Examples 1 to 4, 1-1 to 2-2 and Comparative Examples 2 to 3.

Example 5
After dissolving Macrogol 6000 in water, HPMC (TC-5R; Shin-Etsu Chemical Co., Ltd.) coating solution (seal coating solution formulation I) was spray-coated on the plain tablet C140g using a coating device (Paurec Doria Coater 200). A seal-coated mini tablet was obtained (coating ratio: about 4% by mass ratio to the seal-coated mini tablet). Next, HPC (HPC-L; Nippon Soda, indicated viscosity: 6 to 10 mPa · s) was added to ethanol and dissolved, and then HPMC (TC-5E; Shin-Etsu Chemical) and carboxyvinyl polymer (Carbopol 971P; Lubrizol Advanced Mat).
initial Inc. , Indicated viscosity: 6420 mPa · s) were sequentially added and uniformly dispersed. In addition, erythritol (Mitsubishi Foodtec), xanthan gum (KeltrolCG-T
Tricrystal, indicated viscosity: 1555 mPa · s) was pulverized with a jet mill (Seishin Enterprise SJ-3) and then added sequentially and uniformly dispersed. Finally, a solution prepared by dissolving calcium chloride dihydrate in ethanol was added and uniformly dispersed to obtain an overcoating solution. This overcoating liquid was spray-coated on the above seal-coated mini-tablet using a coating device (Pawreck Doria Coater 200) to obtain a coated mini-tablet (coating ratio: mass ratio to coating mini-tablet: about 8%).

Example 6
A coating mini was prepared in the same manner as in Example 5, except that reduced maltose starch syrup (Amarti MR-100; Mitsubishi Foodtec) was used instead of erythritol in the method for preparing the overcoating liquid of Example 5. Got a tablet.

Example 7
A coated minitablet was obtained by the preparation method according to Example 5, except that trehalose crushed by a jet mill (trehalose S; Asahi Kasei Chemicals) was used in place of erythritol in the method for preparing the overcoating liquid of Example 5.

Example 8
A preparation method according to Example 5 except that guar gum (guar gum RG100; MRC Polysaccharide, indicated viscosity: 1100 mPa · s) ground by a jet mill was used instead of xanthan gum in the preparation method of Example 5. A coated mini tablet was obtained.

Example 9-1
A coated minitablet was obtained by the preparation method according to Example 5 except that sodium alginate crushed by a jet mill (Kimika algin I-8; Kimika) was used in place of xanthan gum in the method for preparing the overcoating liquid of Example 5.

Example 9-2
A coated minitablet was obtained by the preparation method according to Example 5, except that sodium alginate crushed by a jet mill (Kimika algin I-8; Kimika) was used in place of the carboxyvinyl polymer in the preparation method of Example 5. It was

Example 10
A coated minitablet was obtained by the preparation method according to Example 5 except that plain tablet A was used instead of plain tablet C in Example 5.

Example 11
A coated minitablet was obtained by the preparation method according to Example 5 except that plain tablet B was used instead of plain tablet C in Example 5.

Example 12
About 2 kg of the same plain tablet C as in Example 5 was spray-coated with the seal coating liquid (seal coating liquid formulation I) having the same composition as in Example 5 by using a coating device (Pawreck coater 7) to obtain a seal coating mini tablet. (Coating rate: about 4% by mass relative to the seal-coated mini tablet). Next, sucralose and HPC (HPC-L; Nippon Soda) were added to ethanol and dissolved, and then HPMC (TC-5E; Shin-Etsu Chemical).
And carboxyvinyl polymer (Carbopol 971P; LubrizolAdvanc
ed Material Inc. , Indicated viscosity: 6420 mPa · s) were sequentially added and uniformly dispersed. Furthermore, erythritol (Mitsubishi Foodtec), xanthan gum (Keltro)
l CG-T; tri-crystal, indicated viscosity: 1555 mPa · s) on a jet mill (Seishin Enterprise
After crushing with SJ-3), they were sequentially added and uniformly dispersed. Finally, a solution prepared by dissolving calcium chloride dihydrate in ethanol was added and uniformly dispersed to obtain an overcoating solution. This overcoating liquid was spray-coated on the above seal-coated minitablet using a coating device (Pawreck Coater 7) to obtain a coated minitablet (coating ratio: 4.5% by mass ratio to the coated minitablet).

Example 13
About 50 kg of the same plain tablet C as in Example 12 was spray-coated with the seal coating solution (seal coating solution formulation I) having the same composition as in Example 12 by using a coating device (Pawreck Coater 150) to obtain a seal coating mini tablet. (Coating rate: about 4% by mass ratio to the seal-coated mini-tablet). Next, an overcoating solution having the same composition as in Example 12 was spray-coated on the above seal-coated minitablet using a coating device (Pawreck Coater 150) to obtain a coated minitablet (coating ratio: mass relative to the coated minitablet). 4.5%).

Comparative Example 4
As Comparative Example 4, the plain tablet C was used.

Comparative Example 5
As Comparative Example 5, the seal-coated mini tablet prepared in Example 5 was used.

Comparative Example 6
As Comparative Example 6, plain tablet D was used.

Table 3 shows the plain tablets, seal coating, and overcoating liquid formulations (number of copies) used in Examples 5-8, 9-1-9-2, 10-13 and Comparative Examples 4-5. Table 4 shows the formulations (number of copies) of the seal coating liquid and the middle coating liquid coated in Examples 5 to 23 and Comparative Examples 5 to 6. The coating rate (%) in Table 3 is obtained as follows.

Coating rate (%) of seal coating = (mass of 100 tablets after seal coating-100 mass of plain tablets) / mass of 100 tablets after seal coating x 100

Coating rate (%) of overcoating = (mass of 100 tablets after overcoating−mass of 100 tablets of seal coating) / mass of 100 tablets after overcoating × 100

(Note that each tablet weight is a moisture correction value)

Example 14
A coated minitablet was obtained by the preparation method according to Example 5 except that plain tablet D was used instead of plain tablet C in Example 5. The coating rate of the overcoating was 5.0% by mass ratio with respect to the coated minitablets.

Example 15
After dissolving erythritol in water, pregelatinized starch (SWELSTAR WB-1; Asahi Kasei)
About 2 kg of the uncoated tablet E was spray-coated with a coating device (Pawrec coater 7) to obtain a seal coating mini tablet (seal coating liquid formulation IV, coating rate: to seal coating mini tablet). (4.9% by mass ratio). Next, sucralose and HPC (HPC-L; Nippon Soda) were added to ethanol and dissolved, and then HPMC (TC-5E; Shin-Etsu Chemical) and carboxyvinyl polymer (Carbopol 971P; Lubrizol Advanced Material In).
c. , Indicated viscosity: 6420 mPa · s) were sequentially added and uniformly dispersed. Further, erythritol (Mitsubishi Foodtec Co., Ltd.) and xanthan gum (Keltrol CG-T; Sanshin, indicated viscosity: 1555 mPa · s) were pulverized with a jet mill (Seishin Enterprise SJ-3), and then added sequentially and uniformly dispersed. Finally, a solution prepared by dissolving calcium chloride dihydrate in ethanol was added and uniformly dispersed to obtain an overcoating solution. This overcoating liquid was spray-coated on the above seal-coated mini-tablet using a coating device (Pawreck Coater 7) to obtain a coated mini-tablet (coating ratio: about 5% by mass ratio to the coated mini-tablet).

Example 16
A coated minitablet was obtained by the preparation method according to Example 15, except that the amount of pregelatinized starch was reduced and the amount of erythritol was increased (seal coating formulation V) in the method for preparing the seal coating solution of Example 15.

Example 17
In the seal coating liquid preparation method of Example 15, the seal coating liquid preparation I was used instead of the seal coating liquid preparation V, and the addition amounts of carboxyvinyl polymer, calcium chloride and HPC-L were reduced in the overcoating liquid preparation method to obtain sucralose. A coated minitablet was obtained by the same preparation method as in Example 15, except that was added.

Example 18
Example 17 except that light anhydrous silicic acid was added in the method for preparing the seal coating solution of Example 17 (seal coating solution formulation II), and the coating rate was reduced to 3.0% by mass ratio to the coating minitablet in overcoating. A coated minitablet was obtained by the preparation method according to.

Example 19
A preparation method according to Example 18 except that plain tablet F was used instead of plain tablet E of Example 18, and talc was used instead of light anhydrous silicic acid in the seal coating preparation method (seal coating liquid formulation III). A coated mini tablet was obtained.

Example 20
Uncoated tablet F was used instead of uncoated tablet E of Example 18, and the coating rate of the seal coating was increased. A coated tablet was obtained by the preparation method according to Example 18.

Example 21
Using uncoated tablet G instead of uncoated tablet F of Example 18, in the method for preparing a seal coating solution,
Example except that HPMC was changed from TC-5R to TC-5E of lower viscosity, erythritol was added instead of macrogol 6000 and light anhydrous silicic acid, and ethanol was added to the solvent (seal coating formulation VI). A coated minitablet was obtained by a preparation method according to 18.

Example 22
A coated tablet was obtained by the preparation method according to Example 21, except that the coating rate of the seal coating of Example 21 was increased, the amount of carboxyvinyl polymer added was increased in the overcoating liquid preparation method, and the coating rate of the overcoating was increased. It was

Example 23
After dissolving HPMC (TC-5R; Shin-Etsu Chemical) in a mixture of water and ethanol (35:15),
Approximately 5 kg of the uncoated tablet G was spray-coated with a coating liquid in which talc was dispersed (seal coating formulation VIII) by using a coating device (Pawrec coater 7),
A seal-coated mini tablet was obtained (coating ratio: 3.0% by mass ratio to the seal-coated mini tablet). Next, a coating solution (middle coating formulation VIII) in which erythritol was dissolved in water was applied to a coating device (Paurec Coater 7).
) Was used for spray coating to obtain a middle-coated mini tablet (coating ratio: 3.0% by mass ratio to the middle-coated mini tablet). After adding sucralose and HPC (HPC-L; Nippon Soda) to ethanol and dissolving, HPMC (TC-5
E; Shin-Etsu Chemical) and carboxyvinyl polymer (Carbopol 971P; Lubriso
1 Advanced Material Inc. , Indicated viscosity: 6420 mPa · s) were sequentially added and uniformly dispersed. Furthermore, erythritol (Mitsubishi Corporation Food Tech), xanthan gum (Keltrol CG-T; tri-crystal, indicated viscosity: 1555 mPa · s) were jet-milled (
After being crushed by Seishin Enterprise SJ-3), they were sequentially added and uniformly dispersed. Finally, a solution prepared by dissolving calcium chloride dihydrate in ethanol was added and uniformly dispersed to obtain an overcoating solution. This overcoating liquid was spray-coated on the above-mentioned middle coating minitablets using a coating device (Pawreck Coater 7) to obtain coating minitablets (coating ratio: 4.0% by mass ratio to coating minitablets).

Comparative Example 6
The plain tablet D was used as Comparative Example 6.

Table 5 shows the plain tablets, seal coating formulation and overcoating liquid formulation (number of copies) used in Examples 14 to 23 and Comparative Example 6. The coating rate (%) in Table 5 is
It is obtained as follows.

Coating rate (%) of seal coating = (mass of 100 tablets after seal coating-100 mass of plain tablets) / mass of 100 tablets after seal coating x 100

Coating rate (%) of middle coating = (mass of 100 tablets after middle coating-100 mass of seal-coated tablets) / mass of 100 tablets after middle coating x
100

Coating rate (%) of overcoating = (mass of 100 tablets after overcoating-mass of 100 tablets of seal-coated tablet or middle-coated tablet) / mass of 100 tablets after overcoating x 100

(Note that each tablet weight is a moisture correction value)

Reference example 1
A prescription liquid was prepared according to the liquid A described in Production Example 1 of Patent Document 4. That is, purified water 55.
0 g was taken, 3.0 g of a polyvinyl alcohol saponification product (Wako Pure Chemical Industries, Ltd.) was slowly added thereto with stirring, and the mixture was completely stirred by heating at 70 ° C. for about 1 hour. Similarly, 45.0 g of purified water was taken, and 1.0 g of Carbopol 974P was slowly added thereto with stirring, and the mixture was stirred for about 30 minutes to completely dissolve it. The two solutions were combined and stirred thoroughly. The solution obtained at this time had a very high viscosity even though polyacrylic acid was not cross-linked because calcium chloride was not added, and thus cannot be spray-coated using the spray-coating apparatus described in Example 1. It was Therefore, it was presumed that it would be difficult to carry out spray coating using a solution in which polyacrylic acid was cross-linked with calcium ions generated by ionization of calcium chloride by further adding calcium chloride.

Reference example 2
An inner layer coating liquid was prepared according to Reference Example 1 except that 0.33 g of glycerin was added to the formulation of Reference Example 1 to make the total amount of purified water 250 g. 1. Glycerin 1.0 g, polyvinylpyrrolidone (PVPK-90, ISP Japan Ltd.) in 170 g of purified water 3.
5 g of calcium chloride, 0.5 g of calcium chloride and 0.5 g of xanthan gum (Keltrol CG-T; tri-crystal, indicated viscosity: 1555 mPa · s) were slowly added with stirring, and the mixture was stirred with heating at 70 ° C. for about 30 hours to complete the reaction. To prepare an outer layer coating solution.
The inner layer coating solution was spray-coated on the plain tablet P using a coating device (Pawreck Doria Coater 200) and dried, and then the outer layer coating solution was similarly spray-coated to obtain coated minitablets. Even though the coating was performed in two times, the total coating amount of the inner layer coating and the outer layer coating remained at about 4.3% by mass relative to the mini tablet.

Test Example 1 (Evaluation of slipperiness)
A silicon tube (8 × 12: inner diameter 8 mm, outer diameter 12 mm) was cut into a length of 5 cm and fixed vertically to an aluminum block with an adhesive tape. The lower end was stoppered with absorbent cotton (25 to 30 mg), and 20 mini tablets were placed from above and tapped. 5 mL of water is passed through a silicon tube with a syringe, and immediately after the water is drained, a probe (a spherical probe having a diameter of 6 mm) set in a texture analyzer (TA-XT-Plus) manufactured by Stable Micro Systems is inserted into the tube, and the bottom to bottom Was moved 40 mm at a speed of 8 mm / sec and the stress at that time was measured.

Test Example 2 (evaluation of bitterness masking)
A 2.5 mL plastic syringe is placed vertically and packed with about 27 to 30 coated minitablets (500 mg as levofloxacin or valacyclovir) containing levofloxacin hydrate or valacyclovir hydrochloride, and 2 mL of water warmed to 37 ° C from the top. min
At a flow rate of. The solution was added dropwise for 30 seconds or 2 minutes, the liquid flowing out from the mouth of the syringe was collected, and the concentration of levofloxacin hydrate or valacyclovir hydrochloride was measured.

Test Example 3 (evaluation of dissolution)
About 27 to 30 coated minitablets containing levofloxacin hydrate or valacyclovir hydrochloride (500 mg as levofloxacin or valacyclovir) were tested by the Japanese Pharmacopoeia dissolution test paddle method (Test liquid: Japanese Pharmacopoeia disintegration test liquid 1 Liquid, rotation speed: 50 rotations) The elution rate was measured 30 minutes after the start of the test.
The test results are shown in Tables 6-8.

Evaluation results according to Test Example 1 (Evaluation of slipperiness)
The maximum stress and the stress-distance curve of Comparative Example 1 (plain tablet A), Comparative Example 2 (ordinary film coating on the plain tablet A) and Comparative Example 3 containing carboxyvinyl polymer and xanthan gum but not polyvalent metal salt. It was estimated that the lower area showed a large value, the slipperiness on the mucous membrane was poor, and it was difficult to swallow. In Comparative Example 3, it is considered that this is because the polyvalent metal ion is not produced by water and thus the carboxyvinyl polymer is not cross-linked by the polyvalent metal ion. Examples 1-4 and 1-1 containing carboxyvinyl polymer, polyvalent metal salt and xanthan gum
For Nos. 1 to 5, the stress was 41 g or less and the value of the area under the stress-distance curve was 516 g · mm or less, and it was estimated that swallowing was easy.
Further, Examples 6 and 7 containing reduced maltose syrup or trehalose instead of erythritol.
, 9-1 containing guar gum or sodium alginate instead of xanthan gum
Also in Example 9-2 containing sodium alginate instead of carboxyvinyl polymer, the maximum stress and the area under the stress-distance curve were small, and it was speculated that swallowing was easy.
The slipperiness of Examples 1-P and 2-P was the same as that of Examples 1 and 2, respectively. From this, it was confirmed that if the shape of the uncoated tablet and the coating of the present invention were the same, the same effect of slipperiness could be obtained even if the composition of the uncoated tablet was different.
In addition, the coated mini-tablet obtained in Reference Example 2 was observed to gel slightly due to the addition of water. However, the maximum stress is 62.7g, and the area under the stress-distance curve is 786g.
-Mm, which was a large value as compared with the examples of the present invention, it was estimated that slippage on the mucous membrane was poor and swallowing was difficult.
Although the seal coating was applied in the examinations after Example 5, almost no effect of the seal coating on the measured values was observed. Taking the results of plain tablets together, it was estimated that the slipperiness can be improved by applying the coating of the present invention to the outermost layer of tablets having various surface physical properties.
As shown in Examples 12, 13, 15-23, good slipperiness could be achieved even when sucralose was added to the coating solution.
In Tables 7 and 8, ◯ in the maximum stress column indicates a stress of 41 g or less, and ◯ in the stress / distance curve area indicates a stress / distance curve area under 516 g · mm.

Evaluation according to Test Example 2 (evaluation of bitterness masking)
In Comparative Example 1 (plain tablet A) and Comparative Example 2 (ordinary film coating on plain tablet A), the concentration of levofloxacin hydrate in the effluent when water was dripped for 2 minutes was significantly higher than that of other formulations. Showed the value. Although the concentration of Comparative Example 2 was lower than that of Comparative Example 1, it was considered that the masking effect was insufficient. Examples 1 to 4 and 1-1 to 1-5 containing a carboxyvinyl polymer, a polyvalent metal salt and xanthan gum have an eluent concentration of 3 μg / m when water is dropped for 2 minutes.
It is L or less, and is considered to have a good bitterness masking effect. From these results, it was revealed that a high bitterness masking effect can be obtained by combining carboxyvinyl polymer and xanthan gum.
Further, in the studies after Example 5, the coating amount of the overcoating liquid was reduced, but in the case of levofloxacin hydrate, the concentration of the eluent was 50 μg / mL or less when water was dropped for 30 seconds. It was In Examples 5 to 9-2 and Examples 12 and 13 in which the uncoated tablet C containing levofloxacin hydrate was overcoated, the drug concentration in the effluent was higher than that in Comparative Example 5 (only uncoated tablet C was seal-coated). Shows a low value of about 1/180 to 1/3, and in Examples 14 to 23 in which any of uncoated tablets D to G containing valacyclovir hydrochloride was overcoated, Comparative Example 6 (uncoated tablet D was seal-coated). The drug concentration in the effluent is 1/6000 to 1/100 (for example, in Example 14, the drug concentration in the effluent is about 1/360 as compared with Comparative Example 6). In each of the overcoatings, a practically sufficient masking effect was confirmed. Furthermore, in Examples 12 and 13 and Examples 15 to 23 to which sucralose was added, it was expected that the unpleasant taste masking effect would be further improved.
The drug concentrations in the effluents of Comparative Examples 2 and 5 in which only uncoated tablets were provided with a seal coating were as low as about 1/15 and about 1/20 as compared to the uncoated tablets of Comparative Examples 1 and 4, respectively. Indicated. This means that, by combining the overcoating and the seal coating of the present invention, the effect of enhancing the unpleasant taste masking effect at the time of taking and / or the unpleasant taste component of the drug core is added to the overcoating layer during storage. It is considered that the effect of preventing the migration and the effect of preventing the change in the composition of the drug core component and the overcoating layer component and the decrease of the masking effect was exhibited.
In particular, Example 23, which was a combination of the overcoating, middle coating and seal coating of the present invention, had a lower drug concentration in the effluent than the other Examples of the present invention, which combined the overcoating and the middle coating. It was confirmed that a high unpleasant taste masking effect when taken was shown.
In Table 7, ◯ in the effluent concentration column for 30 seconds represents an eluent concentration of 50 μg / mL or less,
In Table 8, ◯ in the effluent concentration column for 30 seconds represents an eluent concentration of 60 μg / mL or less.

Evaluation results according to Test Example 3 In Comparative Examples 1 and 2, the elution rate was extremely fast. Example 1 containing HPMC and sugar alcohol
4. In Example 2-1 containing xanthan gum, HPMC, and erythritol without containing carbopol, the dissolution rate at 30 minutes was 80% or more, and excellent elution properties were exhibited. In Example 2-2 using only Carbopol as the thickener, the elution rate was 70% or more. From the results of Example 1 and Example 1-4, it was found that when the content of carbopol in the coating was 12%, elution delay did not occur, but when it was increased to 16% by mass, it was slightly delayed.
From the results of Examples 5 to 7, it was found that even when erythritol was replaced with maltitol (reduced maltose syrup) or trehalose, similarly excellent elution properties were exhibited.
In the studies after Example 5, the coating amount of the overcoating liquid was reduced, but the practically sufficient dissolution rate was exhibited in all the formulations after Example 5, and the difference in the formulation of the uncoated tablets or the sealing No effect of coating was seen.
In Tables 7 and 8, ⊚ in the 30-minute dissolution rate column indicates that the 30-minute dissolution rate is 80% or more,
O indicates that the elution rate for 30 minutes is 60% or more.

As described above, in the oral composition of the present invention, the tablet surface layer is rapidly gelated by a small amount of water or saliva, the tablets are easily aggregated, slippery on the mucous membrane, and swallowed easily. Also,
The gelled coating film exhibits an unpleasant taste masking effect by suppressing the drug elution for a short time until swallowing, and the film rapidly disintegrates after swallowing and does not affect the drug outflow.

Claims (2)

An oral composition having a drug core containing an active ingredient and a coating on the drug core, comprising:
Coating
A first thickener selected from the group consisting of carboxyvinyl polymer and sodium alginate,
Polyvalent metal compound ,
At least one second thickener selected from the group consisting of xanthan gum, guar gum and sodium alginate (provided that when the first thickener is sodium alginate, the second thickener is sodium alginate; Not) ,
A sugar or sugar alcohol having a solubility of 30 g or more in 100 g of water at 20 ° C., and
Contains hydroxypropyl methylcellulose ,
In the evaluation using a vertically fixed silicone tube (8 × 12) having a length of 5 cm, the lower end of which was stoppered with absorbent cotton (25 to 30 mg), a probe (diameter) inserted into the tube for the filled oral composition was used. A composition for oral administration in which the maximum stress required for movement of 6 mm spherical) (speed 8 mm / sec, vertical movement distance 40 mm) is 41 g or less, or the area under the stress-distance curve is 600 g · mm or less. The content of the first thickener is 3 to 20% by mass (mass% to all components in the coating, the same applies hereinafter), and the content of the second thickener is 10 to 40% by mass. , the content of hydroxypropyl methylcellulose is a 5 to 35 wt%, the content of the sugar or sugar alcohol is 10 to 50 mass%, the oral composition according to claim 1.