JP5945191B2 - Intraoral quick disintegrating tablet - Google Patents

Description

  The present invention relates to an intraoral rapidly disintegrating tablet.

  In recent years, it has been desired to develop a tablet that can be taken without water as a dosage form taking into account the ease of taking by consumers, infants who have difficulty swallowing, and patients who have difficulty in behavior. Usually, when taking solid preparations such as tablets, water is required, and there is a problem that it is not convenient. In addition, there is a problem that it is difficult to take a large tablet or a tablet with a large dose. In particular, patients who have difficulty swallowing, children, and elderly people may suffocate by using the throat. On the other hand, chewable tablets do not require water, but are not suitable for children and elderly people with weak chewing ability and teeth. In order to solve these problems, there are dosage forms that disintegrate rapidly in the oral cavity.

As the prior art of a rapidly disintegrating preparation, those relating to a rapidly disintegrating preparation containing erythritol or mannitol (Patent Document 1 and Patent Document 2) can be exemplified. Patent Document 1 relates to a compressed composition imparted with fast disintegration by blending erythritol, and Patent Document 2 relates to a preparation imparted with rapid disintegration by blending mannitol. However, erythritol and mannitol have poor moldability, and many excipients are required for formulation, resulting in an increase in the number of grains. Thus, the technique which adds a disintegration promoter is prevailing.
There is also a patent relating to a solid pharmaceutical preparation (Patent Document 3). Patent document 3 gives quick disintegration by blending erythritol, crystalline cellulose, and a disintegrant into a pharmaceutical ingredient, but the disintegrant to be used is crospovidone which is a pharmaceutical additive. I can not use it.
Moreover, there exists a technique (patent document 4) which provides quick disintegration by making a tablet porous. In Patent Document 4, sugar alcohol and starch are kneaded into an infiltrated lump, then rolled and molded, and further dried under reduced pressure to make it porous and impart quick disintegration. However, since the manufacturing method is complicated and a special device is required, it is a technique for versatility.
Further, Patent Document 5 imparts quick disintegration property by adding water to the main ingredient component and saccharide to moisten, imparting the function as a disintegrant to saccharide, and compressing the wet powder, followed by drying. is there. However, it is difficult to use for an active ingredient that deteriorates when coexisting with water, and there is a problem that a special device for drying wet tablets is required.
In order to enhance the disintegration property in the oral cavity, there is a formulation technique that includes a component that reacts with saliva and foams in the oral cavity and imparts quick disintegration more strongly (Patent Document 6). However, preparations prepared by such a technique often have a problem that foaming occurs due to reaction with moisture in the air.
Patent Document 6 discloses a technique in which an alkali metal carbonate or bicarbonate is used as an acid supply source of fiber glycolic acid.
In addition, the quick disintegrating agent is designed to have a low surface hardness for rapid disintegration in the oral cavity, and it has been pointed out that it is generally fragile and easily worn and carried away in the packaging process. .
In this way, in the production of fast disintegrants, it can be applied to any main agent without requiring complicated processes and special production equipment, and it is excellent in disintegration, but is not easily damaged or worn. There is a need to develop formulations.

International Publication No. 98/02185 JP 2001-58944 A Japanese Patent Laid-Open No. 10-182436 JP 2003-137815 A Japanese Patent No. 3069458 JP 2008-127319 A

  Providing a solid preparation that can be prepared without complicated processes or special manufacturing equipment, that disintegrates quickly when placed in the oral cavity, and has sufficient surface hardness that does not cause wear in the carrying or packaging process This is the issue.

The present invention has the following configuration.
1. A fast disintegrating solid tablet containing saccharide or sugar alcohol and crystalline cellulose as an excipient, comprising porous calcium carbonate and sodium hydrogen carbonate as a foaming component, and citric acid as an acid agent Disintegrating tablets.
2. Fast disintegrating solid tablet containing saccharide or sugar alcohol and crystalline cellulose as excipient, containing calcium citric acid and sodium bicarbonate as foaming component, crystalline citric acid coated with sodium citrate as acid agent A rapidly disintegrating tablet characterized by
3. 1. The sugar or sugar alcohol is erythritol or mannitol A rapidly disintegrating tablet according to 1.
4). 1. The sugar or sugar alcohol is erythritol or mannitol A rapidly disintegrating tablet according to 1.

  According to the present invention, there is provided a tablet having a fast disintegrating property while maintaining a sufficient tablet hardness with little abrasion.

It is a manufacturing-process figure of the fast disintegrating tablet of this invention. The image which observed the quick disintegration of the tablet of Example 1 of this invention and the tablet of the comparative example 1 is shown.

  In the present invention, the saccharides used as the main excipient are monosaccharides and disaccharides that can be used in the technical fields of medicines and food preparations, and sugar alcohols thereof. Specific examples thereof include mannitol, erythritol, xylitol, lactose and glucose, as well as maltose, sorbitol, trehalose, sucrose and fructose. These may be used alone or in combination of two or more. In particular, erythritol is preferable for imparting disintegration properties. When erythritol is contained in the tablet in an amount of 30 to 50% by mass, particularly preferably 40% by mass, the tablet can be provided with suitable ease of molding and preferable oral disintegration characteristics.

  In general, in order to increase tablet hardness, for example, polyvinylpyrrolidone, hydroxypropylmethylcellulose, methylcellulose, polyvinyl alcohol and the like are used as water-soluble binders. However, tablets obtained in a normal compression molding process are rapidly disintegrating. Not shown. In the present invention, since a suitable amount of modified cellulose is added as crystalline cellulose and a disintegrant without using such a binder, it has an appropriate hardness by a simple direct tableting method that does not require a granulation step. And a tablet with the characteristic of disintegrating rapidly in an oral cavity can be shape | molded. Crystalline cellulose is blended in an amount of 10 to 20% by mass in the tablet. A preferable result can be obtained by containing 2 to 5% of the modified starch in the tablet.

One of the main characteristics of the present invention is to promote the disintegration of a preparation containing a saccharide and a disintegrant by reacting an acid source with one or more foaming sources via water in saliva. Citric acid as the acid source, at least one selected from the group consisting of alkali metals, alkaline earth metal carbonates and bicarbonates as the foaming source, and in one tablet as an adjunct to flavoring or fine foaming as necessary A small amount of other organic acids can be blended with.
In particular, the combined use of sodium bicarbonate and calcium carbonate is preferred as the foaming source. In the present invention, the calcium carbonate is particularly preferably porous calcium carbonate or porous calcium carbonate.

The porous calcium carbonate used in the present invention is a chemically synthesized high-purity light calcium carbonate, and is porous calcium carbonate obtained by performing multi-stage carbonation of chain-like particles in which fine particles are connected. N (manufactured by Shiroishi Calcium Co., Ltd.) and IK-3000 (manufactured by Shiroishi Central Research Laboratory Co., Ltd.). It is a preferred embodiment as a foaming source in the present invention to use an equal amount of porous calcium carbonate and sodium bicarbonate. The compounding quantity of the porous calcium carbonate in this invention is 0.4 to 1.5 weight%, and 0.7 to 10 weight% is especially preferable. If the blending amount is small, disintegration cannot be promoted, and if the blending amount is large, foaming is severe in the oral cavity, making it difficult to ingest. As a result, the collapse is also delayed.
Sodium bicarbonate reacts quickly with citric acid and foams, and calcium carbonate starts foaming later. In this way, the combined use of both increases the foaming time and prevents the foaming feeling from collapsing. It becomes possible to promote. The amount of sodium bicarbonate is 0.4 to 1.5% by weight, particularly preferably 0.8 to 10% by weight. If the blending amount is small, disintegration cannot be promoted, and if the blending amount is large, foaming is severe in the oral cavity, making it difficult to ingest. As a result, the collapse is also delayed.
When sodium bicarbonate and porous sodium carbonate are used in combination, a preferable result can be obtained by setting both to the same amount and 1% by mass or more per preparation.

  When citric acid dissolves in saliva, it reacts with porous calcium carbonate and sodium bicarbonate to cause foaming and disintegrate the tablet with the force from the inside. However, citric acid gradually reacts with the blowing agent via moisture in the air. In order to suppress this, when a raw material in which the surface of citrate granules is coated with sodium citrate is used, such a change with time can be suppressed. CCA (manufactured by San-Ei Gen FFI Co., Ltd.) can be exemplified as the one in which the surface of the citric acid granule is coated with such sodium citrate. The compounding quantity of a citric acid is 0.4 to 1.5 weight%, and 0.8 to 10 weight% is especially preferable. If the blending amount is small, disintegration cannot be promoted, and if the blending amount is large, the sourness felt in the oral cavity is too strong, which makes it difficult to ingest.

  The tablet of this invention can mix | blend the lubricant and fluidizing agent required for tableting as materials other than the above. Further, by incorporating a component that promotes the secretion of saliva in the oral cavity, more rapid oral disintegration can be brought about. An example of such a saliva secretion promoter is polyglutamic acid.

  The medicinal component (main drug) applicable in the present invention can include any medicinal component that can be taken orally, or a nutritional component and a functional component. Not only water-soluble but also poorly water-soluble medicinal components can be used. In addition, those having little or no bitterness are preferred, but those having bitterness can also be used after coating. These main ingredient components can be used alone or in combination of two or more. The main drug component can be added to the tableting powder prepared in the mixing step of a mixture of sugar, disintegrant and foaming agent. Moreover, after granulating as needed, it can also be tableted. The blending amount of the active ingredient is preferably 50% by mass or less per tablet. When the content is more than this, problems such as capping occur in tableting.

  The powder for tableting may contain various additives generally used for tablet production as long as the effects of the present invention are not adversely affected. Additives other than binders include acidulants such as citric acid, tartaric acid, malic acid, artificial sweeteners such as aspartame, sodium saccharin, stevia, and flavoring agents such as lemon, orange, and menthol. , For example, magnesium stearate, sucrose fatty acid ester, talc, etc., coloring agents such as food color such as food yellow No. 5, food red No. 2 and food blue No. 2, food lake dye, iron oxide, etc. Can do. These additives can be used alone or in combination of two or more.

The manufacturing process of the present invention is shown in FIG. The present invention is excellent in that the desired rapidly disintegrating tablet can be produced by an extremely simple method by simple mixing and tableting. In the tableting process, a tableting machine commonly used for powder compression molding, for example, a single tableting machine or a rotary tableting machine can be used. The tableting pressure is usually set to about 200 to 1500 kg, preferably about 500 to 1000 kg, when, for example, 200 mg of tableting powder is tableted using a punch with a diameter (φ) of 8 mm and a single tableting machine. The temperature at the time of tableting may be usually room temperature (about 20 to 30 ° C.) and does not need to be adjusted. Since the intraoral rapidly disintegrating tablet of the present invention has an appropriate hardness, it can be processed into a desired shape such as a circle, an ellipse, or a capsule. The diameter or major axis of such a tablet is usually 6 to 15 mm, and its weight is usually 80 mg to 1000 mg, but is not limited thereto. Moreover, it is also possible to set it as the split tablet which engraved the dividing line for dividing | segmenting into a tablet.
Usually, the tablet hardness is 3 kg or more, and it can be applied not only to PTP packaging, but also to bottle containers in which tablets are enclosed in containers such as glass and plastic, that is, between tablets or between tablet and container walls. It is believed that it can withstand contact. The tablet according to the present invention has a hardness of more than 10 kg, and hardly breaks in any distribution in the distribution process.

  The intraoral rapidly disintegrating tablet of the present invention has quick disintegration property in the oral cavity, and is easy to drink and easy to handle. Therefore, it is suitable for long-term administration of patients, particularly elderly people, applied according to the medicinal ingredients contained, and can also be used for prevention and treatment of pediatric patients. Furthermore, when taking it to a patient with Sjögren's syndrome or an elderly person with a small amount of saliva, it is convenient because it quickly disintegrates with a minimum amount of water. It is also suitable for patients and children with limited water intake.

  According to the production method of the present invention, since a general-purpose pulverizer, mixer and tablet press can be used, the conventional production apparatus can be used as it is. Furthermore, there is no need to change or add to the manufacturing process depending on the dissolution characteristics of the medicinal ingredients. Therefore, the production method of the present invention is extremely simple without involving complicated steps, and is advantageous in comparison with the conventional method for producing an orally rapidly disintegrating tablet from the viewpoint of production cost, production time, and the like. It is. Moreover, it becomes a useful product not only as a medicine but also as a health food and tablet confectionery.

  Hereinafter, the present invention will be described in more detail with reference to examples and comparative examples, but it goes without saying that the present invention is not limited to such examples.

1. Manufacture of tablets Fast disintegrating tablets were prepared with the composition shown in Table 1. In addition, N-acetylglucosamine which is an active ingredient was manufactured by Yaizu Fisheries Chemical Co., Ltd., and porous calcium carbonate was Porecal-N (manufactured by Shiraishi Calcium Co.)

  In the procedure of FIG. 1, the primary mixing is performed for 10 minutes using a micro-type V mixer S-3 manufactured by Tsutsui Rika, and the secondary mixing is performed for 5 minutes using the micro-type V mixer S-3 manufactured by Tsutsui Rika Then, using a single tableting machine (N-30E manufactured by Okada Seiko Co., Ltd.), the tableting pressure was set so that the hardness of the tablet was 10 kgf or more (performed at about 1800 kgf), the diameter was 15 mm, and the weight was 750 mg. Tablets were produced.

2. Evaluation of tablet (1) Hardness The hardness was measured with a Kiyama hardness tester. In general, since hardness of more than half of the diameter (mm) is required (4 kgf or more if φ8 mm), this time, the evaluation condition is that the hardness is at least 8 kgf or more.

(2) Degree of friability The friability of the preparation was measured using a tablet friability tester manufactured according to the specifications of the 14th Pharmacopoeia reference information. Evaluation was based on 3%, which is the friability of a chewable tablet (manufactured by FANCL Corporation) having the same diameter as the present invention product, which is a normal commercial preparation.

(3) Observation of disintegration condition Put 10 g of test solution (colored red by adding vitamin B12 into water) on a petri dish, and immerse the Kimwipe in one fold. Place the tablet lightly on the soaked Kimwipe and measure the time from placement until the test solution penetrates all the way to the top of the tablet. The tablet touches the Kimwipe only at the bottom, and the test solution is transferred to the tablet only through the Kimwipe. The time when the red color was transferred to the top of the tablet was taken as the transfer time to the top of the test solution, and the disintegration state of the preparation at that time was observed. In addition, photographs were taken of the disintegration of the top and side surfaces of the preparation.

(4) Measurement of oral disintegration time and sensory evaluation In 5 healthy adults, the sample tablet was dissolved while rolling with the tongue without chewing in the oral cavity, and the time until the solid matter disappeared was measured to evaluate the feeling of taking. Went. Oral disintegration time was defined as the average disintegration time of 5 persons. The feeling of ingestion was evaluated in consideration of the situation in the oral cavity according to the following criteria based on the discussion of five people. Moreover, it was decided to express the defects of each preparation with appropriate reviews.
×: Texture is unpleasant and not acceptable △: Texture is uncomfortable but acceptable ○: Texture is good ◎: Texture is very good

(5) Storage stability test Stored for 7 days in an environment of 40 ° C and 75% RH, and at the same time also stored an aluminum bag sealed at 5 ° C. The storage stability was evaluated according to the evaluation criteria.
×: Difference is obvious and product is not established △: Quality is impaired and difference can be recognized ○: Difference is hardly recognized

3. Table 2 shows the evaluation results of the tablets. Moreover, the typical image which observed the disintegration condition of a tablet is shown in FIG.

  As is clear from the above evaluation, the tablets of Examples 1, 2, 3, and 4 of the present invention permeated water rapidly, were completely dissolved in the oral cavity, and did not leave a foreign body sensation in the mouth. Moreover, it had a tablet hardness exceeding the hardness of a fast disintegrating tablet, and was a high-level product exceeding the level of friability necessary and sufficient as a tablet.

Claims (4)

A fast disintegrating solid tablet containing saccharide or sugar alcohol and crystalline cellulose as an excipient, comprising porous calcium carbonate and sodium hydrogen carbonate as a foaming component, and citric acid as an acid agent Disintegrating tablets. Fast disintegrating solid tablet containing saccharide or sugar alcohol and crystalline cellulose as excipient, containing calcium citric acid and sodium bicarbonate as foaming component, crystalline citric acid coated with sodium citrate as acid agent A rapidly disintegrating tablet characterized by   The fast disintegrating tablet according to claim 1, wherein the sugar or sugar alcohol is erythritol or mannitol. The rapidly disintegrating tablet according to claim 2, wherein the sugar or sugar alcohol is erythritol or mannitol.