WO2007111375A1

WO2007111375A1 - Intraorally rapidly disintegrating tablet

Info

Publication number: WO2007111375A1
Application number: PCT/JP2007/057007
Authority: WO
Inventors: Masatsugu Nozaki; Sachio Motegi; Kana Matsumoto
Original assignee: Kowa Company, Ltd.
Priority date: 2006-03-24
Filing date: 2007-03-23
Publication date: 2007-10-04
Also published as: KR20080111014A; KR101470483B1; CN101410127B; SG170766A1; CN101410127A; JP5100634B2; MY149923A; JPWO2007111375A1

Abstract

An intraorally rapidly disintegrating tablet of useful bacteria, such as bifidobacteria and lactic bacteria, excelling in tableting stability and storage stability is obtained by compression molding of a powdery mixture of useful bacteria, crystalline cellulose/light anhydrous silicic acid (vehicle produced by mixing crystalline cellulose with a small amount of light anhydrous silicic acid in slurry form and spray drying of the mixture) and starch-containing sugars (starch powder, granulated starch, granulated starch/lactose mixture, etc.) in the dry state into a tablet of about 30 to 60 N tablet hardness and 3.2 wt.% or less water content.

Description

Oral rapidly disintegrating tablets

The present invention relates to a rapidly disintegrating tablet in the oral cavity that rapidly disintegrates in the presence of saliva in the oral cavity or in the presence of a small amount of water. More specifically, the present invention contains useful bacteria and is excellent in long-term storage stability. Orally disintegrating tablets. Background art

Intestinal bacteria are present in the intestines of baboons.

It is said that there are 100 trillion intestinal bacteria, forming the intestinal flora

. Enterobacteriaceae include useful bacteria such as bifidobacteria lactic acid bacteria or good bacteria and bad bacteria such as large intestinal bacteria welsh bacteria. Yes. It has been known in recent years that disturbance of this balance affects the breakdown, digestion, absorption, immunity, infection defense, aging, etc. of the nutrients, and maintaining the balance of the gut microbiota is deeply related to the health of chicks. Yes. Disturbances of the intestinal flora are not only caused by the situation that modern people often fall into, such as stress, disorder of eating habits, fatigue, lack of sleep, etc.Aging also causes disturbance of the intestinal flora etc. It is a symptom that can happen to anyone.

To improve the roses _v of the intestinal flora, viable cell preparations such as bifidobacteria is provided powder as ethical drugs, generally pharmaceuticals or supplements, tablets agent, to a patient in the form of a force capsule agents I.

Orally disintegrating tablets should not be taken anywhere, even in patients with low swallowing ability, such as elderly people, children, or general adults. The development of these products is desired, and several such preparations have already been developed. Known literatures disclosing such preparations include: (1) a method of tableting and drying a drug, a saccharide, and a mixture containing moisture to such an extent that the particle surface of the saccharide is wet (see JP-A-5-27 1054). (2) A tablet produced by a method in which a drug, a water-soluble excipient and an amorphous saccharide are compressed and then aged (see JP-A-11-12161), 3) A tablet (see Japanese Patent Laid-Open No. 2000-273038) characterized by containing a certain ratio of drug, lactose, crystalline cellulose, and light anhydrous key acid, and further containing a disintegrating agent such as crospopidone. It has been.

Furthermore, in (4) The 124th Annual Meeting of the Pharmaceutical Society of Japan, “Crystalline Cellulose / Light Caustic Anhydride (Product Name: Prosolve) (2)” An application formulation for glycerin and light anhydrous caylic acid can be formulated at low tableting pressure, and the loss of viable cell count during tableting can be reduced. And it was shown that the disintegration time of the tablet at this time was about 1.5 to 2 minutes.

However, these known literatures do not clearly disclose orally disintegrating tablets containing useful bacteria. In other words, the tablet (1) compresses the wet mixture, and it is difficult to apply it to useful bacteria that are unstable to moisture, and the tablet (2) is bare under conditions of constant temperature and humidity. The tablets need to be aged, which has the disadvantage of increasing the loss on drying of the tablets and reducing the storage stability of useful bacteria. The tablet of (3) has a different tablet composition from that of the present invention, the crystalline cellulose and light anhydrous anhydrous used in the present invention are not used, and any useful bacterial preparation and its storage stability are described. Not. In addition, (4) shows an example in which crystalline cellulose and light anhydrous carboxylic acid are applied to useful bacteria such as bifidobacteria, and it is possible to reduce the loss of the number of viable bacteria during tableting. Is also shown. However, (4) does not describe the storage stability and rapid disintegration property of the obtained viable bacterial preparation. Disclosure of the invention

Therefore, the object of the present invention is to break down rapidly in the oral cavity of useful bacteria, have an appropriate strength, can be produced by a very simple method using a normal compression molding machine, and contain useful bacteria The purpose of this study is to develop an orally rapidly disintegrating tablet with excellent long-term storage stability.

According to the present invention, there is provided an orally rapidly disintegrating tablet containing useful bacteria, crystalline cellulose, light anhydrous anhydrous caustic acid and starch-containing saccharide, and having a moisture content of 3.2% by weight or less.

Embodiments of the present invention are described below.

(1) The intraorally rapidly disintegrating tablet, wherein the useful bacteria are bifidobacteria or lactic acid bacteria.

(2) The intraorally rapidly disintegrating tablet, wherein the useful bacteria are bifidobacteria.

(3) The above-mentioned intraoral rapidly disintegrating tablet containing 35 to 70 parts by weight of crystalline cellulose and light galeic anhydride with respect to 100 parts by weight of the tablet.

(4) The intraorally rapidly disintegrating tablet containing 25 to 60 parts by weight of starch-containing saccharide with respect to 100 parts by weight of the tablet.

(5) The aforementioned intraoral rapidly disintegrating tablet containing crystalline cellulose, 40 to 70 parts by weight of light anhydrous caustic acid, and 30 to 60 parts by weight of starch-containing saccharide with respect to 100 parts by weight of the tablet.

(6) The intraorally rapidly disintegrating tablet having a tablet hardness of 30N to 60N.

(7) Useful bacteria, crystalline cellulose · Lightly mixed with anhydrous caustic acid and starch-containing saccharides Compressed in a dry state to produce tablets with a moisture content of 3.2 wt% or less. Method. BEST MODE FOR CARRYING OUT THE INVENTION

As a result of repeated studies to solve the above-mentioned problems, the inventors of the present invention use a combination of crystalline cellulose, light anhydrous keyic acid and starch-containing saccharides in a useful bacterium. By tableting with pressure, it rapidly disintegrates in the oral cavity, has an appropriate strength, has a low kill rate when tableting useful bacteria, and has excellent long-term storage stability. It was found that an internal fast disintegrating tablet was obtained. The present invention was completed by further research based on such knowledge.

Any useful bacteria can be used in the present invention as long as they are useful for human digestive activity. Bifidobacterium (Bifidobacterium longum, Bifidobacterium infant is, Bifidobacterium bifidunu Bif idobacterium breve, etc.), Lactobacillus (Lactobacillus casei, Lactobac i 1 lus gasseri, Lactobacillus acidophilus, Streptococcus faecal is, ept be able to. Preferable examples include bifidobacteria such as Bifidobacterium longum, Bifidobacterium longum, and Bifidobacterium infantis. Two or more useful bacteria can be used in combination as appropriate.

Useful bacteria used in the present invention may be in the form of, for example, viable powder or lyophilized product. The blending amount can be 0.03 to 30 parts by weight with respect to 100 parts by weight of the tablet, and 0.1 to 20 parts by weight, particularly 0.5 to 10 parts by weight, in order to obtain better moldability. I like it. The number of mixed bacteria is not particularly limited, but considering its effectiveness, the number of viable bacteria is 10 ⁵ to 10 ^ια / tablet, preferably 10 ⁶ to 10 ⁹ / tablet.

The useful bacteria used in the present invention can also be used in combination with other active ingredients such as pharmaceuticals and health foods that do not adversely affect the useful bacteria. Crystalline cellulose used in the present invention, light anhydrous key acid, is an excipient manufactured by spray drying after mixing crystalline cellulose and a small amount of light anhydrous key acid in a slurry state. The method is shown. This can be used as: "Prosolv (PR0S0LV)" (registered trademark) from TRS PHARMA. The crystalline cellulose / light anhydrous caustic anhydride is used in an amount of about 35 to 70 parts by weight, preferably 40 to 70 parts by weight, based on 100 parts by weight of the tablet.

The starch-containing saccharides used in the present invention may be those containing at least starch, may be starch alone, or may be a mixture of starch and one or more other saccharides in an appropriate ratio. Or they may be granulated. In the present invention, the starch-containing sugar is usually one containing 40 parts by weight or more, preferably 70 parts by weight or more of starch. The method for granulating the starch-containing saccharide is not particularly limited, and examples thereof include spray drying, stirring granulation, fluidized bed granulation, and extrusion granulation. The origin of starch is not particularly limited. Examples include corn starch, wheat starch, and potato starch. Examples of other saccharides include lactose, lactulose, sucrose, maltose, flour, glucose, fructose, maltitol, mannitol, sorbitol, xylitol, and erythritol.

The amount of starch-containing saccharide used varies depending on the content of starch contained in the starch-containing saccharide, but is usually 25 to 60 parts by weight per 100 parts by weight of the tablet. For example, when a starch-lactose granulation mixture containing starch and lactose in a ratio of about 7: 3 is used as the starch-containing saccharide, about 25-60 parts by weight, preferably 30 parts per 100 parts by weight of the tablet. ~ 60 parts by weight are used.

If desired, the tablet of the present invention may be blended with various additives commonly used in tablet production. Such additives can be used alone or May be mixed and used at an appropriate ratio. Examples of additives include disintegrants, binders, acidulants, foaming agents, artificial sweeteners, flavoring agents, flavoring agents, fluidizing agents, lubricants, coloring agents, stabilizers, excipients, and the like. .

Generally, in order to give the desired disintegration in the oral disintegrating tablet, a disintegrant is usually added. Examples of these disintegrants include crospovidone, low-substituted hydroxypropylcellulose, carmellose strength, croscarmellose sodium, carboxymethyl sulfate sodium, and the like. Among these, crospopidone is widely used. However, the rapidly disintegrating tablet in the oral cavity of the present invention disintegrates rapidly in the oral cavity without adding a disintegrating agent.

Production of the rapidly disintegrating tablet in the oral cavity according to the present invention is carried out by compressing in a dry state a useful fungus, crystalline cellulose-light anhydrous caustic acid and starch-containing saccharide, and optionally adding other additives. This is done by obtaining a tablet of 2% by weight or less. In the present invention, the particle diameter of the additive such as useful bacteria is not particularly limited, but the use of a particle having a small particle provides an excellent feeling of dosing. If desired, other additives excluding useful bacteria may be used after being subjected to a wet granulation step and then dried. In this case, crystalline cellulose, light anhydrous galeic acid, starch-containing saccharides, and the like are mixed by a conventional method, followed by spray drying, stirring granulation, fluidized bed granulation, extrusion granulation, and the like. For compression molding, an apparatus generally used for tablet formation is used, and for example, a mouth-and-mouth tableting machine can be used.

In the present invention, in order to avoid the killing of useful bacteria at the time of tableting, it is preferable to set the tableting pressure to be relatively low and to perform tableting so as to obtain a hardness that does not damage the tablet. The tableting pressure is usually preferably about 1 ton or less.

The oral disintegrating tablet of the present invention thus obtained is disintegratable in the oral cavity. There is moderate tablet hardness. The disintegration time in the oral cavity is usually 5 to 50 seconds, preferably 5 to 40 seconds, and more preferably 5 to 30 seconds. The tablet hardness is preferably about 30 N to 60 N, and more preferably about 30 N to have a strength that prevents the tablet from being damaged in the distribution process, and a short disintegration time. Has a hardness of 50N.

The water content in the tablet significantly affects the long-term storage stability of useful bacteria. Therefore, in the present invention, it is necessary to reduce the water content of the rapidly disintegrating tablet in the oral cavity as much as possible. In the present invention, the water content is kept at 3.2% by weight or less, preferably at 2.5% by weight or less. In addition, for storage of tablets, it is usually preferable to store the tablets in a glass bottle containing a desiccant, or SP packaging in which the tablets are completely sealed with an aluminum packaging material.

Methods for taking (1) The tablet is contained in the mouth, the tablet is disintegrated in the oral cavity with saliva without water, and taken as it is, (2) The tablet is contained in the mouth, and a smaller amount (3) A method of taking this tablet in the mouth with water and taking it as it is, or (4) A method of taking this tablet after it has been disintegrated with water Can be mentioned. Intraorally rapidly disintegrating tablets of the present invention (a) When there are many opportunities to take without water, (b) When patients who have difficulty swallowing the tablet, (c) Take many drugs at the same time It can be used particularly effectively when needed, or (d) when taken by an elderly person or child who may be clogged in the throat with normal tablets. Example

Hereinafter, the present invention will be described in detail with reference to Examples and Comparative Examples, but the present invention is not limited thereto. The physical properties of the tablets (hardness, disintegration time, and useful bacteria stability test) were measured by the following test methods.

The bifidobacteria powder used in the following examples and comparative examples is A powder obtained by cultivating Idobacteria longum and Bifidobacterium infant is and then freeze-drying it, and having about 1X 10 ^{1 Q} / g of living bacteria It is.

(1) Hardness test

It was measured using a tablet hardness tester (FUJIWARA). The test was performed 10 times and the average value was shown.

(2) Disintegration test

It evaluated by the disintegration test by the Japanese Pharmacopoeia. The test was carried out using a disintegration tester (Toyama Sangyo Co., Ltd.) without an auxiliary plate. Water (37 ° C) was used as the test solution. The test was conducted on 6 tablets and the average value was shown.

(3) Oral disintegration time measurement

The time until the tablet disintegrates only with the saliva in the oral cavity was measured. The test was performed three times and the average value was shown.

(4) Storage stability test

Each tablet was packaged in aluminum, and stored at 40 ° C (:, 75% relative humidity for 1 week or 2 weeks. During this period, the number of bacteria was reduced using Pifidobacterium differentiation medium (with horse defibrinated blood added). The survival rate of bifidobacteria was determined from the viable cell count before storage and the viable cell count after storage Examples 1-3

Bifidobacteria powder, crystalline cellulose · light anhydrous anhydrous (Prosolv 90, manufactured by JRS PHARMA), starch-containing saccharide (corn starch, corn starch granulated product, corn starch · lactose granulated mixture (corn starch: lactose (weight ratio) = 70: One of 29) was mixed, and then Mg stearate was added and mixed again to obtain a tableting powder. Using a one-piece tableting machine (PICC0M, manufactured by RIVA. SA) Tablets were made with a sugar-coated candy so that one tablet was 280 mg 9 匪 Φ and the hardness was about 40 Ν. The obtained tablets were subjected to a disintegration test and measurement of disintegration time in the oral cavity. The results are shown in Table 1. table 1

From the results in Table 1, the rapidly disintegrating tablet in the oral cavity of the present invention has an appropriate strength.

In addition, it can be seen that the disintegration test and the oral disintegration test show excellent disintegration properties.

Example 4 and Comparative Example 1

Bifidobacteria powder, crystalline cellulose · light anhydrous galeic acid (Prosolv 90; manufactured by RS PHARMA), corn starch · lactose granulation mixture are mixed, and stearate Mg is added and mixed again to obtain a tableting powder. . Using a lipstick type tableting machine (PIC C0RA RI VA. S.A), one tablet 280 mg 9, with hardness of about 40 硬度 was made with a sugar-coated candy. The obtained tablets were subjected to a storage stability test (storage period 2 weeks). The results are shown in Table 2. Table 2

From the results in Table 2, it can be seen that the rapidly disintegrating tablet in the oral cavity of the present invention exhibits excellent disintegration in the disintegration test and also has an excellent survival rate of bifidobacteria. In contrast, tablets that do not contain starch-containing saccharides (corn starch / lactose granulation mixture) have a longer disintegration time due to the fact that small pieces of the tablets remain in the basket, resulting in a lower survival rate. Karu.

Comparative Examples 2 and 3

Bifidobacteria powder, crystalline cellulose (Avicel PH 101, Asahi Kasei Co., Ltd.), mannitol, lactose, light anhydrous kelic acid, crospovidone (Collidon CL, manufactured by BASF) are added, and then stearic acid Mg is added and remixed The powder was used for tableting. Using a one-piece tableting machine (PIC C0RA, manufactured by RI VA. S.A), tableting was performed with a sugar-coated scissors so that 1 tablet 280 mg, 9 mmΦ, and hardness was about 40 N. The obtained tablets were subjected to a disintegration test, an oral disintegration time measurement, and a storage stability test (storage period 1 week). The results are shown in Table 3. Table 3

From the results shown in Table 3, it can be seen that the rapidly disintegrating tablet in the oral cavity of the present invention exhibits an excellent disintegrating property in the oral cavity while having an appropriate strength, and also has an excellent survival rate of bifidobacteria. On the other hand, it can be seen that the tablet produced without blending crystalline cellulose / light anhydrous anhydrous silicic acid and starch has significantly low storage stability.

Example 5 and Comparative Examples 4 and 5

Bifidobacteria powder, crystalline cellulose · light anhydrous galeic acid (Prosol 90, manufactured by JRS PHARMA), corn starch, corn starch and lactose granulation mixture are added, and then stearate Mg is added and remixed for tableting The end. Using a rotary tableting machine (PI CC0M, manufactured by RI VA. S.A), tableting was performed with a sugar-coated scissors so that 1 tablet 280 mg, 9 ππηφ, and the hardness was about 30-40 Ν. Tablets with a loss on drying of 2.2 to 7.3 wt% were produced. The obtained tablets were subjected to a disintegration test, an oral disintegration time measurement, and a storage stability test (storage period 1 week). The results are shown in Table 4. Table 4

From the results shown in Table 4, in order to obtain an excellent oral disintegration property in the oral cavity, while the oral disintegrating tablet has an adequate strength, the moisture content of the tablet (loss on drying) It is understood that 3.2 wt% or less is preferable. Examples 6-9 and Comparative Example 6

Powdered bifidobacteria, crystalline cellulose · Light anhydrous galeic acid (Prosolv 90, manufactured by iRS PHARMA), corn starch · lactose granulation mixture were added, and then stearic acid Mg was added and mixed again to obtain a tableting powder. . Using a single tablet press (PI CC0RA, manufactured by RIM. S.A), 1 tablet 280 mg, 9 ππιι φ, hardness of about 30, 40, 50, 60 杵Tableted. The obtained tablets were subjected to a disintegration test and an oral disintegration time measurement. The results are shown in Table 5. Table 5

From the results in Table 5, it can be seen that the hardness of the intraoral quick disintegrating tablet of the present invention is preferably about 30 N or more and about 60 N or less in order to make the disintegration time within about 40 seconds.

Example 10 12 and Comparative Example 7 9

Powdered bifidobacteria powder, crystalline cellulose · light anhydrous key acid (Prosolv 90; manufactured by TRS PHARMA), corn starch and lactose granulation mixture were added, and then stearic acid Mg was added and mixed again to obtain a tableting powder. . Using a lipstick type tableting machine (PI CC0RA RIVA. S. A), tableting was performed with a sugar-coated scissors so that 1 tablet was 280 mg 9 匪 Φ and the hardness was 30 40 Ν. A tablet was prepared containing about 987 parts by weight of crystalline cellulose / light anhydrous caustic anhydride and about 987 parts by weight of the corn starch / lactose granulation mixture in the tablet. The obtained tablets were subjected to a disintegration test, an oral disintegration time measurement, a tableting stability test, and a storage stability test. The results are shown in Table 6. Table 6

From the results in Table 6, in order to make the disintegration time and oral disintegration time within 40 seconds, the blending amount of crystalline cellulose · light anhydrous caustic acid is about 35 to 70 parts by weight in the tablet, starch-containing sugar (corn starch · It is found that the blending amount of the lactose granulated mixture) is preferably about 25 to 60 parts by weight in the tablet. Also, the amount of crystalline cellulose / light anhydrous galeic acid is low at 9.6 parts by weight, and the starch-containing saccharide is 87 parts by weight. A large amount of tablets (Comparative Example 7) is not preferable because the disintegration property is remarkably deteriorated. On the other hand, a tablet (Comparative Example 9) containing 87 parts by weight of light anhydrous hydrous carboxylic acid and 9.6 parts by weight of starch-containing saccharide is not preferable because of low storage stability. Industrial applicability

The rapidly disintegrating tablet in the oral cavity of the present invention exhibits an excellent disintegrating property in the oral cavity while having an appropriate strength, and has excellent tableting stability and storage stability of useful bacteria. Therefore, patients with low swallowing ability such as elderly people and children or It can be provided to patients who want to improve the disturbance of the gut microbiota balance or maintain the gut microbiota balance as a tablet that can be taken without water even in general adults regardless of the location.

Five

Claims

The scope of the claims

1. Useful bacteria, crystalline cellulose · Lightly anhydrous caustic acid and starch-containing saccharides, and a moisture content of 3.2% by weight or less.

2. The intraoral rapidly disintegrating tablet according to claim 1, wherein the useful bacteria are bifidobacteria or lactic acid bacteria.

3. The rapidly disintegrating tablet in the oral cavity according to claim 1, wherein the useful bacteria are bifidobacteria.

4. The intraoral quick-disintegrating tablet according to any one of claims 1 to 3, which contains 35 to 70 parts by weight of crystalline cellulose / light anhydrous caustic acid with respect to 100 parts by weight of the tablet.

5. The rapidly disintegrating tablet in the oral cavity according to any one of claims 1 to 3, wherein the starch-containing saccharide is contained in an amount of 25 to 60 parts by weight with respect to 100 parts by weight of the tablet.

6. The composition according to any one of claims 1 to 3, which contains 40 to 70 parts by weight of crystalline cellulose / light anhydrous caustic acid and 30 to 60 parts by weight of starch-containing saccharides per 100 parts by weight of the tablet. The intraoral rapidly disintegrating tablet as described.

7. The tablet according to any one of claims 1 to 6, which has a tablet hardness of 30 to 60N.

8. Production of rapidly disintegrating tablets in the oral cavity by compressing the dry powder of a useful bacterium, microcrystalline cellulose, light anhydrous caustic acid and starch-containing sugar to obtain tablets with a moisture content of 3.2% by weight or less Method.