JP7259884B2 - solid formulation - Google Patents

Description

TECHNICAL FIELD The present invention relates to solid preparations that can be taken without water, and to preparations that have excellent disintegration properties without using special manufacturing methods, despite containing specific active ingredients that cause delayed disintegration.

Orally disintegrating tablets and chewable tablets that can be taken without water are excellent formulations that are easy to take, especially for people with low swallowing ability such as children and the elderly, and can be taken in any situation without water. There are merits (Non-Patent Document 1).
Conventional orally disintegrating tablets are known to be molded by freeze-drying a substance such as gelatin in a container, or wet tableted from wet powder or granules. However, these tablets often break or chip during transportation, and it is difficult to say that they have sufficient hardness. Despite the desired dosage form, it is hard to say that it has been widely used yet (Non-Patent Document 2).
On the other hand, in the production of orally disintegrating tablets or chewable tablets using ordinary tablet production equipment, it is necessary to devise a method to achieve both excellent disintegration in the oral cavity and tablet hardness that can withstand production and transportation. Furthermore, since it disintegrates in the oral cavity, a design that takes into consideration the ease of administration, such as masking the bitter taste derived from the drug and reducing roughness, is required.

It has been reported that some active ingredients significantly affect and delay the disintegration of tablets (Non-Patent Document 3). For example, it has been reported that pseudoephedrine, loxoprofen or its salts, fexofenadine and the like delay disintegration (Patent Document 1). Therefore, when these medicinal active ingredients are blended, it is necessary to improve the disintegration property even more than usual.
Various studies have been made so far to obtain an orally disintegrating tablet having rapid disintegrability and high hardness. For example, starch powder and gelatinized starch, a water-soluble excipient containing mannitol, an orally disintegrating tablet containing sodium stearyl fumarate and a medicinal ingredient (Patent Document 2), sugars with low moldability and sugars with high moldability. Oral dissolution type compression molding (Patent Document 3) having rapid disintegration and solubility in the oral cavity, mannitol, disintegrants, celluloses, lubricants, and at least starches and lactose A method for producing an orally disintegrating tablet containing one of them has been reported (Patent Document 4).
However, in Patent Document 2, when starch powder and gelatinized starch are used, sticking to the production equipment tends to occur, and handling during production is difficult. In addition, in the method of Patent Document 2, in order to produce an orally disintegrating tablet, moistening and drying steps after tableting at low pressure are essential conditions, so the number of production steps increases and the operation is complicated. Patent Document 3 discloses an orally disintegrating tablet containing mannitol as a base and substantially containing a super disintegrant such as crospovidone and croscarmellose. It is necessary to consider the change in appearance due to

JP-A-9-169641 Japanese Patent No. 4435424 Japanese Patent No. 3122141 JP-A-2000-273039

Japanese Pharmacopoeia 16th Edition Commentary Hirokawa Shoten Co., Ltd. pp. A-33-34 PHARM TECH JAPAN,28(2),197-201,2012 The Society of Powder Technology, Ed., Formulation and Particle Design Subcommittee, Particle Design and Processing Technology that is Useful Immediately, Jiho Co., Ltd. p.p.187-198 2003

In producing a waterless dosage formulation containing a specific active pharmaceutical ingredient that induces disintegration delay, the present inventors mainly used D-mannitol, which is excellent in disintegration and ingestion, and used various supermarkets from the viewpoint of disintegration. In addition to the disintegrant, an attempt was made to blend a high-intensity sweetener with a sweetness of 200 or more from the viewpoint of ease of administration. However, it has been found that the combined use of these components does not sufficiently shorten the disintegration time and causes tableting problems.

An object of the present invention relates to a solid preparation containing a specific active pharmaceutical ingredient that causes delayed disintegration, which quickly disintegrates or crumbles in the oral cavity without using a special manufacturing method, and is excellent without tableting trouble without water. It is to provide a formulation that can be taken.

The present inventors have made various studies to achieve the above objects, and found that the specific pharmaceutical active ingredients that induce delayed disintegration of the present invention, namely pseudoephedrine or its salts, methylephedrine or its salts, tipepidine or its salt, ibuprofen, loxoprofen or its salts, bromovaleryl urea, fexofenadine or its salts, meclizine or its salts, sofalcone, glycyrrhizin or its salts, or guaifenesin, mannitol and a high-intensity sweetener with a sweetness of 200 or more The present inventors have found that, surprisingly, when silicon dioxide and menthol are blended into a waterless dosage formulation containing the formulation, tableting failure does not occur and rapid disintegration is exhibited, leading to the completion of the present invention.

That is, the present invention
(1) pseudoephedrine or its salts, methylephedrine or its salts, tipepidine or its salts, ibuprofen, loxoprofen or its salts, bromovaleryl urea, fexofenadine or its salts, meclizine or its salts, sofalcon, glycyrrhizin or its salts, and A preparation that can be taken without water, characterized by containing a pharmaceutical active ingredient selected from the group consisting of guaifenesin, mannitol, a high-intensity sweetener having a sweetness of 200 or more, menthol, and silicon dioxide;
(2) The formulation according to (1), wherein the high-intensity sweetener having a sweetness of 200 or more is one or more selected from the group consisting of sucralose, aspartame, and acesulfame potassium;
(3) The formulation according to (1), wherein the silicon dioxide is light anhydrous silicic acid;
(4) the formulation according to any one of (1) to (3), which is an orally disintegrating tablet or a chewable tablet;
is.

INDUSTRIAL APPLICABILITY According to the present invention, it has become possible to produce an excellent formulation that can be taken without water, which quickly disintegrates in the oral cavity despite containing a specific active pharmaceutical ingredient that causes delayed disintegration. In addition, since tableting failure can be prevented, it has become possible to improve the manufacturability of the formulation.

The "specific active pharmaceutical ingredient that delays disintegration" in the present invention refers to an active pharmaceutical ingredient that has physicochemical properties that interfere with the disintegration of a solid preparation. salt, methylephedrine or its salts, tipepidine or its salts, ibuprofen, loxoprofen or its salts, bromovaleryl urea, fexofenadine or its salts, meclizine or its salts, sofalcone, glycyrrhizin or its salts, guaifenesin. Preferred among these is pseudoephedrine or a salt thereof.
The content of the specific pharmaceutical active ingredient that causes the above disintegration delay in the present invention is preferably 0.5% to 80% by mass, more preferably 1.0% to 70% by mass, based on the total mass of the formulation of the present invention. % by mass.

The mannitol content of the present invention is preferably 30% to 95% by mass, more preferably 40% to 85% by mass, based on the total mass of the formulation of the present invention.

The high-intensity sweetener of the present invention is a sweetener having a sweetness of 200 or more (Non-Patent Literature: Catalog of Sweeteners, Sugar Refining Industry Association), examples of which include sucralose, aspartame, acesulfame potassium, and the like. The content of the sweetener having a sweetness of 200 or more of the present invention is preferably 0.5% to 20% by mass, more preferably 1% to 10% by mass, based on the total mass of the preparation of the present invention.

The menthol used in the present invention is described in the Japanese Pharmacopoeia, and commercially available menthol can also be used. Both natural essential oils and synthetic products can be used. The menthol of the present invention may be either l-form or dl-form. good too. Among these, l-menthol and peppermint oil are preferred. Moreover, the content of menthol is preferably 0.01 to 2% by mass, more preferably 0.05 to 1%, based on the total mass of the preparation of the present invention. Further, it is preferably 1% by mass to 15% by mass with respect to 1 part by mass of the specific pharmaceutical active ingredient that causes delayed disintegration of the present invention.

In order to improve disintegration and prevent tableting failure in the preparation for waterless administration containing a specific pharmaceutical active ingredient that causes delayed disintegration, mannitol, and a high-intensity sweetener having a sweetness of 200 or more, , the addition of silicon dioxide is essential. Silicon dioxide of the present invention includes, for example, light anhydrous silicic acid, heavy anhydrous silicic acid, hydrous silicon dioxide, etc. Light anhydrous silicic acid is preferred. In addition, the content of the silicon dioxide of the present invention is preferably 0.1 parts by mass to 100 parts by mass, particularly preferably 1 part by mass to 1 part by mass of the specific pharmaceutical active ingredient that causes delayed disintegration of the present invention. 50 parts by mass. Furthermore, the content of silicon dioxide is preferably 0.01% by mass to 20% by mass, more preferably 0.1% by mass to 10% by mass, relative to the total mass of the formulation of the present invention.

Examples of the formulation of the present invention that can be taken without water include orally disintegrating tablets and chewable tablets. An orally disintegrating tablet means a tablet that disintegrates very quickly in the oral cavity under normal chewing conditions. Moreover, a chewable tablet means a tablet to be chewed and taken. An orally disintegrating tablet or a chewable tablet is easy to take, and is a suitable dosage form for administration to children and the elderly, for example, who find it difficult to take ordinary tablets.

The preparation method of the present invention that can be taken without water is not particularly limited, and in the case of granulation, either wet granulation method or dry granulation method may be used. After the granulation process or granulation production, drying may be carried out as appropriate. Examples of wet granulation methods include fluidized bed granulation, stirring granulation, kneading granulation, tumbling granulation, and molten solvent methods. Dry granulation includes slug method, roller A compactor method can be used, but the fluidized bed granulation method and stirring granulation method are preferable. The preparation of the present invention that can be taken without water can be obtained by appropriately adding post-paste additives to the obtained granules and subjecting them to general compression molding such as tableting.
It may also be produced by a direct compression method that does not require a granulation step. As a tableting machine, an apparatus generally used for molding tablets is used, and for example, a single-shot tableting machine, a rotary tableting machine and the like are used.

The formulation of the present invention may contain various additives commonly used in the manufacture of formulations that can be taken without water, as long as they do not interfere with the effects of the present invention. Examples of such additives include excipients, disintegrants, binders, acidulants, foaming agents, sweeteners, flavoring agents, flavoring agents, lubricants, coloring agents and the like.

The size and shape of the orally disintegrating tablet or chewable tablet of the present invention are not particularly limited, and it may be a split tablet having a score line.

In producing the formulation of the present invention, conventional production methods can be used without particular restrictions. The formulation of the present invention that can be taken without water exhibits excellent disintegration in the oral cavity. The disintegration time of the formulation that can be taken without water of the present invention is 1 to 60 seconds, preferably 1 to 40 seconds, more preferably 1 to 30 seconds in the disintegration test method according to the Japanese Pharmacopoeia. The time is within 60 seconds, preferably within 30 seconds.

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

(Examples 1-4, Comparative Examples 1-3)
Each component was weighed and mixed so that the composition shown in Table 1 was obtained. The whole amount of the mixture was passed through a sieve to obtain granules for tableting. Tableting was performed at 5 kN using a desktop simple tableting machine (trade name: HANDTAB; Ichihashi Seiki) to obtain tablets with a tablet diameter of 11 mm.

(Test example)
<Evaluation method>
The tablets of Examples and Comparative Examples were measured for disintegration time by the following test methods.

(1) Disintegration test Measured according to the disintegration test method described in the Japanese Pharmacopoeia 16th revision. The disintegration time of each tablet was measured three times, and the average value was obtained.
(result)
Table 2 shows the evaluation results.

As shown in Table 2, the tablets of Examples 1-4 had a disintegration time of 60 seconds or less. In particular, Example 2 exhibited an excellent disintegration property with a disintegration time of 30 seconds. On the other hand, Comparative Examples 1 to 3, which did not contain silicon dioxide and menthol in the formulation, had a disintegration time exceeding 60 seconds.
Moreover, although Comparative Examples 1 and 2 caused tableting failure, the tablets of Examples 1 to 4 did not cause tableting failure.

According to the present invention, without the use of special equipment, production methods, or excipients, it rapidly disintegrates or dissolves without water in the oral cavity, and it is possible to take it without water, which suppresses tableting troubles. It becomes possible to provide formulations.

Claims (4)

(a) a pharmaceutical active ingredient selected from the group consisting of pseudoephedrine or its salts, loxoprofen or its salts, bromovaleryl urea, fexofenadine or its salts, meclizine or its salts, sofalcone, glycyrrhizin or its salts, and guaifenesin; ) mannitol, (c) sucralose, (d) menthol, and (e) silicon dioxide, and the content of (c) is 0.5% by mass to 20% by mass, without water A formulation that can be taken with , but does not contain either magnesium aluminum silicate or prolamin . 2. The formulation of claim 1, wherein the silicon dioxide is light silicic anhydride. 3. The formulation according to claim 1 or 2, which is an orally disintegrating tablet or a chewable tablet. (a) a pharmaceutical active ingredient selected from the group consisting of pseudoephedrine or its salts, loxoprofen or its salts, bromovaleryl urea, fexofenadine or its salts, meclizine or its salts, sofalcone, glycyrrhizin or its salts, and guaifenesin; ) mannitol, (c) sucralose, (d) menthol, and (e) silicon dioxide, and the content of (c) is 0.5% by mass to 20% by mass. Tablets whose disintegration time is within 60 seconds according to the disintegration test method of the 16th revision (however, neither magnesium aluminum silicate nor prolamin is included) .