JP3182404B2 - Orally disintegrating tablet and method for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing a tablet which is easily disintegrated in the oral cavity (hereinafter referred to as "orally disintegrating tablet") and an orally disintegrating tablet produced by the above-mentioned method.

[0002]

2. Description of the Related Art In an aging society, there is a demand for a formulation in a form that is easy for the elderly to take. However, at present, most oral preparations are ordinary tablets and capsules, and it is not always possible for the elderly to take them. It's not easy. In addition, these conventional preparations are often difficult to take for children and patients who have difficulty swallowing. Furthermore, in powders and granules,
There are problems such as handling at the time of opening and adhesion to the oral cavity, which are not satisfactory for the elderly, children and patients who have difficulty swallowing. For the purpose of solving such problems, some preparations have already been attempted for tablets that can be taken without water and that are easy to handle.

[0003] Japanese Patent Publication No. 62-50445 discloses a PT
A method of injecting a suspension of a drug, a saccharide and a gelling agent into a P (press-through package) blister, removing water by freeze-drying, and forming a tablet in the blister is described, and WO93-12767. The publication describes a method of injecting a suspension of a drug, mannitol and agar into a blister of PTP, removing water by vacuum drying, and forming a tablet in the blister.

[0004] Japanese Patent No. 2650493 (WO93-)
No. 15724) describes a fast-dissolving tablet which dissolves rapidly in the oral cavity, produced by compressing and drying wet granules mainly composed of saccharides granulated with water.
No. 054 describes a method for producing an orally disintegrating tablet in which a mixture containing water to such an extent that the surface of the particles is wetted is tableted, and these production methods are generally known as a wet production method.

[0005] JP-A-8-291051 and JP-A-9-48726 disclose that a tablet containing a saccharide as a main component and a water-soluble binder added thereto is subjected to compression molding at a low pressure and then placed under humidification. A method for producing an orally disintegrating tablet by wetting and drying the same is described (hereinafter sometimes referred to as "humidifying method").

[0006] Japanese Patent No. 2640570 (WO93-
13758), after low-pressure compression molding of a powder to which a water-soluble melting binder such as polyerylene glycol is added,
A method for producing a tablet having increased strength by melting at a temperature higher than the melting point of the water-soluble fusible binder and then solidifying the water-soluble fusible binder is described (hereinafter referred to as "heat melting method"). Sometimes).

Japanese Patent Application Laid-Open No. 9-316006 describes an orally soluble solid preparation containing erythritol and a small amount of a solid organic acid to improve the cooling sensation.

On the other hand, WO 95-34290 discloses that
As a special method, a production method of preparing a shear foam matrix in a state in which an amorphous cotton candy-like material is cut, making this a granule having good fluidity, and then preparing a tablet is described.
WO95-34293 and JP-A-8-38138
Japanese Patent Application Laid-Open Publication No. HEI 9-203 (1995) describes a tablet manufactured using the above-mentioned shear form matrix.

[0009]

The tablets described above are all porous and fast disintegrating tablets obtained by pursuing how to increase the strength of the tablet while maintaining its porosity while maintaining a high porosity. However, there are problems in terms of production complexity and cost, and there is a demand for a comprehensively superior production method for orally disintegrating tablets.

For example, a tablet obtained by the method described in JP-B-62-50445 has low tablet strength,
There is a disadvantage that trouble occurs when pushing out from the TP.
Furthermore, the manufacturing process is complicated and a new machine is required, which is not advantageous in terms of cost. On the other hand, in the method described in WO93-12770, although the tablet strength is improved,
As in Japanese Patent Publication No. Sho 62-50445, the manufacturing process is complicated and the cost is not advantageous.

Further, in the method by the wet manufacturing method, the wet powder easily adheres to the mortar or punch at the time of tableting, and furthermore, some measure is required to supply the wet powder to the mortar quantitatively. Not suitable for tableting. Therefore, in order to solve these problems, it may be necessary to improve the tableting machine itself (JP-A-8-19589 and JP-A-8-1989).
-19590).

In addition, the humidification method requires a step of humidifying the tablet in addition to the usual step of manufacturing a tablet. In addition, the humidification method is not suitable for a drug unstable in humidity or a drug showing deliquescence at high humidity. Absent. Furthermore, the above-mentioned heat melting method has a problem that it is not suitable for a drug unstable to heat or a drug having poor compoundability with a water-soluble fusible binder.

[0013]

Means for Solving the Problems As a result of studying to solve such a conventional problem, the present inventors dissolved saccharides having high solubility in water and a water-soluble binder in water, Economical method of manufacturing an orally disintegrating tablet that can be easily removed from PTP by wet granulation, has strength that does not cause a problem in handling, and disintegrates quickly in the oral cavity. And found a superior manufacturing method.

According to the present invention, the following steps (a) and (b)
And (c) wherein the drug is mixed in step (b) before granulation or tableting: (a) at least one saccharide having high solubility in water and water-soluble (B) mixing at least one excipient into the solution obtained in the above step (a), granulating and drying, and then subjecting the solution to low pressure. (C) aging the tablet obtained in the step (b), and an orally disintegrating tablet produced by the production method.

Hereinafter, terms used in the present specification will be described.

As used herein, the term "sugar having high solubility in water" means a saccharide having such properties relatively among saccharides, and 100 ml of purified water at about 25 ° C. Solubility (hereinafter sometimes simply referred to as “solubility”, and the measurement of the solubility will be described later)
From about 40 g to about 250 g. Specific examples of these saccharides (hereinafter, also referred to as “saccharides used in the present invention”) include the monosaccharides glucose and xylose [solubility of about 125 g; Merck Index 12th edition,
10220 (1996)], sugar alcohols such as xylitol, sorbitol, erythritol, and disaccharide sucrose (sucrose).
Xylitol and sucrose are preferred. These saccharides can be used alone or in combination of two or more,
The tablet usually contains about 0.1 to about 20% by weight, preferably about 0.5 to about 10% by weight.

Accordingly, in the present specification, for example, mannitol and lactose have low solubility as shown in the examples described below, and do not fall under the category of “saccharides having high solubility in water” in the present invention. Is treated as a non-saccharide.

The water-soluble binder is one that can be dissolved in water alone or in water and an alcohol (eg, ethanol) together with the saccharide used in the present invention, and as a result, exhibits a desired binding property. Meaning includes, for example, polyvinylpyrrolidone, pullulan, hydroxypropylcellulose, hydroxypropylmethylcellulose, gum arabic, water-soluble gelatin and the like, with polyvinylpyrrolidone being preferred. These water-soluble binders can be used alone or in combination of two or more. The compounding amount of these water-soluble binders is usually selected from the range of about 0.1 to about 20% by weight, preferably the range of about 0.5 to about 5% by weight in the tablet.

Although corn starch is generally used as a binder, its dissolution rate in water is slow, so that the disintegration delay of the formed tablet is so remarkable that it cannot be used as the water-soluble binder in the present invention.

As the excipient, saccharides other than those used in the present invention, for example, mannitol, lactose and mannose can be used, but the saccharides used in the present invention can also be used.

As the orally disintegrating tablet of the present invention, any drug which can be formulated by ordinary wet granulation or fluidized bed granulation can be used. For example, mosapride citrate, alacepril , Brotizolam, berberine hydrochloride or tannate, loperamide hydrochloride. The drug can be mixed at any time before granulation or tableting in step (b), but is preferably mixed before granulation. The content of drug per tablet is usually
About 0.01 to about 20% by weight, preferably about 0.1 to about 20% by weight.
About 10% by weight.

The orally disintegrating tablet of the present invention may optionally contain a sweetener or a fragrance for improving the feeling of taking. Further, a lubricant and a disintegrant necessary for a usual preparation process may be added.

The tableting at a low pressure in the step (b) is as follows:
Usually about 20 to about 300 kg / cm ^TwoDone in, preferred
About 50 to about 200 kg / cm^TwoDone in

The tablet obtained in the step (b) is subjected to ordinary aging, ie, disintegration in the oral cavity having a desired strength by leaving it at room temperature (preferably room temperature of about 15 ° C. or more) for several hours to about several days. Although a tablet is obtained, a step of heating the tablet obtained in the above step (b) at a temperature higher than room temperature and aging for several tens seconds to several days may be positively added.

"Aging" means that the physical properties of the preparation such as a tablet are brought to a steady state, and the aging is usually left at room temperature or heated at a temperature exceeding room temperature, preferably about 30 ° C. or more. It is performed at a temperature lower than the softening point of the water-soluble binder used in the present invention, and more preferably at a temperature of about 40 ° C. or higher,
More preferably, it is performed at about 40C to about 80C. Also,
The aging in the present specification is not limited to the method described in the present specification, but also includes a process of bringing the physical properties of the preparation such as tablets into a steady state by other methods.

The term "softening point" means a temperature at which a solid substance is heated to be softened and easily deformed. Specifically, polyvinylpyrrolidone is about 150 ° C and hydroxypropylcellulose is about 130 ° C.

[0027]

BEST MODE FOR CARRYING OUT THE INVENTION Preferred methods for producing an orally disintegrating tablet of the present invention include, for example, the following forms.

The following steps (a '), (b') and (c ')
A method for producing an orally disintegrating tablet, which comprises mixing a drug before granulation or tableting in step (b ′): (a ′) at least one of erythritol, xylitol, sorbitol, glucose and sucrose About 0.5 to about 10% by weight of a saccharide selected from the group consisting of polyvinylpyrrolidone, pullulan, hydroxypropylcellulose,
About 0.5 water-soluble binder selected from at least one of hydroxypropyl methylcellulose and water-soluble gelatin
(B ′) at least one excipient is mixed with the solution obtained in the above step (a ′), and the mixture is granulated and dried. Tableting at a low pressure of 50 to about 200 kg / cm ² ,
(C ′) The tablet obtained in the step (b ′) is further treated at a temperature lower than the softening point of the water-soluble binder used in the step (a ′) and at a temperature of about 40 ° C. or more for about 1 minute to about 24
Time aging process.

Hereinafter, the production method of the present invention will be described in more detail.

The saccharides and the water-soluble binder used in the present invention are dissolved by adding water alone or, if necessary, alcohols, and the resulting mixture is added to an excipient, followed by wet kneading granulation and drying. Or, the saccharide and the water-soluble binder used in the present invention are dissolved by adding water alone or an alcohol as needed, and sprayed on a fluidized excipient to perform fluidized bed granulation. By drying, a co-solvent of the saccharide used in the present invention and the water-soluble binder is obtained. The co-dissolved material is uniformly distributed in the granulated material in a semi-solid state, but the granulated surface is in a dry state. The drug may be added at any time before granulation or tableting, and the granules containing the drug or a mixture of the drug and the granules are compressed at a low pressure of about 20 to about 300 kg / cm ² to form a porous material. Into tablets of sexual nature. In this state, the obtained porous tablet disintegrates quickly in the oral cavity, but has insufficient strength and is insufficient. However, the tablet is allowed to stand at room temperature for several hours to several days, or is heated at a temperature above room temperature for several tens seconds to several days, preferably lower than the softening point of the water-soluble binder and about 40 Aging at a temperature higher than about 1 ° C. for about 1 minute to about 24 hours solidifies the co-dissolved material. Tablets solidified by these ordinary standing conditions or active aging have high strength, can achieve sufficient strength for handling, and exhibit properties of rapidly disintegrating in the oral cavity.

[0031]

The following examples and comparative examples show the tablets of the present invention, the method for producing the same, and the excellent features of the tablets of the present invention. However, the present invention is not limited to these examples. Not something. The method for measuring the solubility of saccharides and the like used in the present invention will be described below.

Example 1 :

[Table 1] 成分 Ingredient weight wt% ─────── ──────────────────────────── ・ Sorbitol 4mg 2% ・ Polyvinylpyrrolidone 4mg 2% ・ Mannitol (excipient) qs ・ Citric acid Mosapride 5mg 2.5% ・ Magnesium stearate 1mg ─────────────────────────────────── Total 200mg ── ─────────────────────────────────

Polyvinylpyrrolidone (K30, BASF
4 g) and 4 g of sorbitol (manufactured by Nacalai Tesque, solubility: about 130 g) in a mortar, and then 10 g of water.
Was added, and 15 g of ethanol was further added for dissolution. Appropriate amount of mannitol (Kao, solubility about 18.5
g) and 5 g of mosapride citrate were placed in a plastic bag, mixed, transferred to a mortar, the above solution was added thereto, kneaded, and dried at 50 ° C. for 16 hours using a box drier. After sieving with a 24 mesh sieve, magnesium stearate was added, and the mixture was placed in a plastic bag and mixed to give granules for tableting.
B type, manufactured by Kikusui Seisakusho) with a diameter of 8.0 mm and a hardness of 0.5 k
g tablets. Further, the obtained tablet was added at room temperature for 3 hours.
After aging for days, orally disintegrating tablets of 200 mg per tablet were obtained.

Example 2 : Same formulation as in Example 1 [Table 1]
After tableting in the same manner as described in Example 1,
After aging at 70 ° C. for 6 hours, orally disintegrating tablets of 200 mg per tablet were obtained.

Example 3 :

[Table 2] ─────────────────────────────────── Ingredient weight wt% ─────── ──────────────────────────── ・ Xylitol 4.5mg 1.5% ・ Polyvinylpyrrolidone 4.5mg 1.5% ・ Mannitol ( Excipient) Appropriate amount ・ Alacepril 12.5mg 4.2% ・ L-menthol 1mg ・ Magnesium stearate 1.5mg ───────────────────────合計 Total 300 mg ───────────────────────────────────

Fluid granulator (flow coater: FLO-
Alacepril 125 using 5 type, manufactured by Freund Corporation
g of mannitol (manufactured by Kao, solubility about 18.
5g), and mixed with water-ethanol (1: 1)
Polyvinylpyrrolidone (K3) dissolved in 1000 g
45 g of xylitol (manufactured by Eisai, solubility: about 135 g) was sprayed and granulated, and then dried in a fluidized bed. After sizing with a twin rotor equipped with a 32 mesh screen, L-menthol 10
g and 15 g of magnesium stearate were added and mixed using a V-type mixer to obtain granules for tableting, using a rotary tableting machine (Clean Press C19, manufactured by Kikusui Seisakusho), diameter 9.5 mm, hardness 0.5 kg. Into tablets. Further, the obtained tablets were aged at room temperature for 3 days to obtain orally disintegrating tablets of 300 mg per tablet.

Example 4 : Same formulation as in Example 3 [Table 2]
And after tableting in the same manner as described in Example 3,
After aging at 70 ° C. for 3 hours, orally disintegrating tablets of 300 mg per tablet were obtained.

Example 5 :

[Table 3] ─────────────────────────────────── Ingredient weight wt% ─────── ──────────────────────────── ・ Xylitol 4.5mg 1.5% ・ Hydroxypropylcellulose 3mg 1% ・ Mannitol (shaping Agent) suitable amount ・ mosapride citrate 5 mg 1.7% ・ l-menthol 1 mg ・ magnesium stearate 1.5 mg ────────────────────────合計 Total 300 mg ───────────────────────────────────

According to the formulation shown in Table 3, 45 g of xylitol (manufactured by Eisai, solubility: about 135 g) and 30 g of hydroxypropylcellulose (L, manufactured by Nikko) were dissolved in 1500 g of a mixed solution of water and ethanol (1: 1). The tablet was treated in the same manner as described above, pressed into tablets having a hardness of 0.2 kg, and aged at room temperature for 3 days.
Orally disintegrating tablets were obtained.

Example 6 :

[Table 4] 成分 Ingredient weight wt% ─────── ──────────────────────────── ・ Erythritol 6 mg 2% ・ Polyvinylpyrrolidone 9 mg 3% ・ Mannitol (excipient) suitable amount ・Mosapride citrate 5 mg 1.7% L-menthol 1 mg Magnesium stearate 1.5 mg合計 Total 300 mg ───────────────────────────────────

Polyvinylpyrrolidone [PVP (K30,
90 g of erythritol (manufactured by Niken Kagaku, solubility: about 47.5 g) was mixed in a beaker, dissolved in 150 g of water, and further added with 200 g of ethanol. Appropriate amount of mannitol (made by Kao, solubility about 1
8.5 g) and 50 g of mosapride citrate were mixed in a high-speed stirring granulator (vertical granulator: VG25, manufactured by Powrex), and then the above-mentioned PVP-erythritol solution was added, followed by stirring and granulating for 5 minutes. The mixture was granulated with a flash mill and dried with a box-type blast dryer for 16 hours. After drying, 24
After sieving with a mesh sieve, 10 g of L-menthol and 15 g of magnesium stearate are added and mixed using a V-type mixer to obtain granules for tableting, using a rotary tableting machine (Clean Press C19, manufactured by Kikusui Seisakusho). , Hardness 0.5k
g tablets. Further, the obtained tablets were aged at 50 ° C. for 12 hours to obtain orally disintegrating tablets of 300 mg per tablet.

Example 7 :

[Table 5] ─────────────────────────────────── Ingredient weight wt% ─────── ──────────────────────────── ・ Glucose 9mg 3% ・ Pullulan 1.5mg 0.5% ・ Mannitol (excipient) Mosapride citrate 5 mg 1.7% L-menthol 1 mg Magnesium stearate 1.5 mg合計 Total 300 mg ───────────────────────────────────

According to the formulation in Table 5, 90 g of glucose (manufactured by Wako Pure Chemical Industries, solubility: about 75 g) and pullulan (PI-2)
0, manufactured by Hayashibara) 15 g was dissolved in 150 g of water.
And pressed into tablets having a hardness of 0.3 kg, and aged at 70 ° C. for 3 hours.
0 mg of an orally disintegrating tablet was obtained.

Embodiment 8 :

[Table 6] ─────────────────────────────────── Ingredient weight wt% ─────── ──────────────────────────── ・ Erythritol 3 mg 1% ・ Hydroxypropyl methylcellulose 3 mg 1% ・ Erythritol (excipient) -Mosapride citrate 5 mg 1.7%-Magnesium stearate 1.5 mg合計 Total 300 mg ───────────────────────────────────

According to the formulation in Table 6, 30 g of hydroxypropylmethylcellulose [HPMC (TC-5R, manufactured by Shin-Etsu Chemical)] and 30 g of erythritol (manufactured by Niken Chemical, solubility: about 47.5 g) were dissolved in 150 g of water, and 200 g of ethanol was further dissolved. Was added and dissolved.
And processed into tablets with a hardness of 0.3 kg. Further, the obtained tablets were aged at 70 ° C. for 3 hours to obtain orally disintegrating tablets of 300 mg per tablet.

Example 9 :

[Table 7] ─────────────────────────────────── Ingredient weight% by weight ─────── ──────────────────────────── ・ Erythritol 6mg 2% ・ Polyvinylpyrrolidone 15mg 5% ・ Mannitol (excipient) qs ・ Citric acid Mosapride 5mg 1.7% ・ L-menthol 1mg ・ Magnesium stearate 3mg ────────────────────────────────── ３００ Total 300mg ───────────────────────────────────

According to the formulation in Table 7, 60 g of erythritol (manufactured by Niken Kagaku, about 47.5 g of solubility) and 150 g of polyvinylpyrrolidone (K30, manufactured by BASF) were dissolved in 2000 g of a mixture of water and ethanol (1: 1). The same treatment as in Example 3 was performed, and the mixture was compressed into tablets having a hardness of 0.3 kg.
Further, the obtained tablets were aged at 70 ° C. for 4 hours to obtain orally disintegrating tablets of 300 mg per tablet.

Example 10 :

[Table 8] ─────────────────────────────────── Ingredient weight wt% ─────── ──────────────────────────── ・ Sucrose 6mg 2% ・ Polyvinylpyrrolidone 6mg 2% ・ Mannitol (excipient) qs Mosapride acid 5mg 1.7% ・ L-menthol 1mg ・ Magnesium stearate 3mg ───────────────────────────────── ３００ Total 300mg ───────────────────────────────────

According to the formulation shown in Table 8, 60 g of sucrose (manufactured by Dainippon Meiji Sugar Co., Ltd., solubility: about 170 g) and 60 g of polyvinylpyrrolidone (K30, manufactured by BASF) were dissolved in 1500 g of a mixed solution of water and ethanol (1: 1). The same treatment as in Example 3 was performed, and the mixture was compressed into tablets having a hardness of 0.3 kg. Further, the obtained tablets were aged at 70 ° C. for 4 hours to obtain orally disintegrating tablets of 300 mg per tablet.

Example 11 :

[Table 9] ─────────────────────────────────── Ingredient weight% by weight ─────── ──────────────────────────── ・ Erythritol 6mg 2% ・ Polyvinylpyrrolidone 6mg 2% ・ Mannitol (excipient) qs ・ Citric acid Mosapride 5mg 1.7% ・ L-menthol 1mg ・ Magnesium stearate 3mg ────────────────────────────────── ３００ Total 300mg ───────────────────────────────────

According to the formulation in Table 9, 60 g of erythritol (manufactured by Niken Kagaku, about 47.5 g of solubility) and 60 g of polyvinylpyrrolidone (K30, manufactured by BASF) were dissolved in 2000 g of a mixture of water and ethanol (1: 1). Example 3
And processed into tablets with a hardness of 0.3 kg. Further, the obtained tablets were aged at 80 ° C. for 2 minutes to obtain orally disintegrating tablets of 300 mg per tablet.

Embodiment 12 :

[Table 10] 成分 Ingredient weight wt% ─────── ──────────────────────────── ・ Erythritol 30mg 10% ・ Polyvinylpyrrolidone 6mg 2% ・ Mannitol (excipient) suitable amount ・ Tannic acid Berberine 30mg 10% ・ L-menthol 1mg ・ Magnesium stearate 3mg 合計 Total 300mg ───────────────────────────────────

According to the prescription in Table 10, 300 g of erythritol (manufactured by Niken Kagaku, about 47.5 g of solubility) and 60 g of polyvinylpyrrolidone (K30, manufactured by BASF) were dissolved in 1500 g of a mixture of water and ethanol (1: 1). The same treatment as in Example 3 was performed, and the mixture was compressed into tablets having a hardness of 0.5 kg. Further, the obtained tablets were aged at 70 ° C. for 4 hours to obtain orally disintegrating tablets of 300 mg per tablet.

Embodiment 13 :

[Table 11] 成分 Ingredient weight wt% ─────── ──────────────────────────── ・ Sucrose 2 mg 1% ・ Polyvinylpyrrolidone 4 mg 2% ・ Water-soluble gelatin 2 mg 1% -Mannitol (excipient) suitable amount-Brotizolam 0.25 mg 0.13%-L-menthol 1 mg-Magnesium stearate 2 mg ───────────────────── ────────────── Total 200 mg ───────────────────────────────── ──

According to the formulation of Table 11, the treatment was carried out in the same manner as in Example 3 except that brotizolam was dissolved together with the binder in the granulation liquid, and the tableting pressure was 120 kg / cm ² and the diameter was 9.0 mm.
Into tablets having a hardness of 0.1 kg. Further, the obtained tablets were aged at 70 ° C. for 5 minutes to obtain orally disintegrating tablets of 200 mg per tablet.

Example 14 :

[Table 12] 成分 Ingredient weight wt% ─────── ──────────────────────────── ・ Sucrose 1.8 mg 1% ・ Polyvinylpyrrolidone 3.6 mg 2% ・ Neucillin 5 mg 1%-Mannitol (excipient) suitable amount-Erythritol (excipient) 36 mg-Aspartame 0.9 mg-Loperamide hydrochloride 0.25 mg 0.14%-Berberine tannate 37.5 mg-Magnesium stearate 2 mg １８０ Total 180 mg ──────────── ───────────────────────

According to the formulation shown in Table 12, the treatment was carried out in the same manner as in Example 3. The tablets were pressed to a diameter of 8.5 mm and a hardness of 0.2 kg, and then aged at 70 ° C. for 5 minutes.
mg of orally disintegrating tablet was obtained.

Comparative Example 1 : Conditions not satisfying step (a)

[Table 13] 成分 Ingredient weight wt% ─────── ──────────────────────────── ・ Erythritol 4mg 2% ・ Polyvinylpyrrolidone 4mg 2% ・ Mannitol (excipient) qs ・ Citric acid Mosapride 5mg 2.5% ・ Magnesium stearate 1mg ─────────────────────────────────── Total 200mg ── ─────────────────────────────────

Polyvinylpyrrolidone [PVP (K30,
BASF)] 40 g was added to water 10 g and ethanol 15
g of the mixture. On the other hand, 40 g of mannitol (manufactured by Kao, solubility: about 18.5 g) and erythritol (manufactured by Niken Kagaku, solubility: about 47.5 g) and 50 g of mosapride citrate are mixed in a plastic bag, transferred to a mortar, and placed in the mortar. -The ethanol solution was added, the mixture was kneaded with a pestle, and dried at 50 ° C for 16 hours with a box-type blow dryer. After sieving with a 24 mesh sieve, 10 g of magnesium stearate was added, and the mixture was mixed in a plastic bag to obtain granules for tableting.
Using a B-type (manufactured by Kikusui Seisakusho) into tablets having a hardness of 0.5 kg. The obtained tablets were aged at room temperature for 3 days to obtain orally disintegrating tablets of 200 mg per tablet.

Comparative Example 2 : Conditions not satisfying step (a) Single-shot tableting machine (2B) using the tableting granules obtained in Comparative Example 1
Using a mold (manufactured by Kikusui Seisakusho)) into tablets having a hardness of 0.5 kg. Further, the obtained tablets were aged at 70 ° C. for 3 hours to obtain orally disintegrating tablets of 200 mg per tablet.

Comparative Example 3 : Conditions not satisfying step (a)

The test was performed using the same formulation as in Table 13 in Comparative Example 1. That is, 40 g of erythritol (manufactured by Niken Chemical Co., Ltd .: solubility of about 47.5 g) was added to 10 g of water and 15 g of ethanol.
g. Meanwhile, an appropriate amount of mannitol (made by Kao,
Solubility 18.5 g) and polyvinylpyrrolidone [P
VP (K30, manufactured by BASF)] 40 g and mosapride citrate 50 g were put in a plastic bag, mixed, transferred to a mortar, and the above erythritol-ethanol solution was added and kneaded with a pestle. Dried for 16 hours. 24
After sizing with a mesh sieve, magnesium stearate 10 g
Is added to a plastic bag and mixed to obtain granules for tableting. Using a single-shot tableting machine (type 2B, manufactured by Kikusui Seisakusho), hardness is 0.5 k
g tablets. Further, the obtained tablets were aged at 70 ° C. for 3 hours to obtain orally disintegrating tablets of 200 mg per tablet.

Comparative Example 4 : Conditions not satisfying step (a) Single-shot tableting machine (2B) using the tableting granules obtained in Comparative Example 3
Using a mold (manufactured by Kikusui Seisakusho Co., Ltd.) into tablets having a hardness of 3.0 kg. Further, the obtained tablets were aged at 70 ° C. for 3 hours to obtain orally disintegrating tablets of 200 mg per tablet.

Comparative Example 5 : Formulation in which the saccharide used in step (a) is inappropriate

[Table 14] ─────────────────────────────────── Ingredient weight wt% ─────── ──────────────────────────── ・ Lactose 4mg 2% ・ Polyvinylpyrrolidone 4mg 2% ・ Mannitol (excipient) qs ・ Citric acid Mosapride 5mg 2.5% ・ Magnesium stearate 1mg ─────────────────────────────────── Total 200mg ── ─────────────────────────────────

Polyvinylpyrrolidone [PVP (K30,
BASF) 40 g and lactose (DMV,
(Solubility: about 13.5 g) 40 g was dissolved in 10 g of water and 15 g of ethanol. On the other hand, an appropriate amount of mannitol (manufactured by Kao, solubility about 18.5 g) and 50 g of mosapride citrate are put in a plastic bag, mixed, transferred to a mortar, and placed in a mortar.
A P-lactose solution was added, the mixture was kneaded with a pestle, and dried at 50 ° C. for 16 hours using a box-type blow dryer. After sieving with a 24 mesh sieve, 10 g of magnesium stearate was added, and the mixture was placed in a plastic bag and mixed to give granules for tableting.
(Kikusui Seisakusho) was used to make tablets having a hardness of 0.5 kg. Further, the obtained tablets were aged at 70 ° C. for 3 hours to obtain orally disintegrating tablets of 200 mg per tablet.

Comparative Example 6 : Formulation in which the saccharide used in step (a) is inappropriate

[Table 15] 成分 Ingredient weight wt% ─────── ──────────────────────────── ・ Mannitol 4mg 2% ・ Polyvinylpyrrolidone 4mg 2% ・ Erythritol (excipient) qs ・ Citric acid Mosapride 5mg 2.5% ・ Magnesium stearate 1mg ─────────────────────────────────── Total 200mg ── ─────────────────────────────────

Polyvinyl pyrrolidone [PVP (K30,
BASF) and 40 g of mannitol (manufactured by Kao, solubility: about 18.5 g) were dissolved in 10 g of water and 15 g of ethanol. On the other hand, an appropriate amount of erythritol (manufactured by Niken Chemical Co., Ltd., solubility: about 47.5 g) and 50 g of mosapride citrate are mixed in a plastic bag, transferred to a mortar, added with the above PVP-mannitol solution, kneaded with a pestle, and mixed with a pestle. It was dried at 50 ° C. for 16 hours with a blow dryer. After sieving with a 24 mesh sieve, 10 g of magnesium stearate was added and mixed in a plastic bag to obtain granules for tableting.
(Kikusui Seisakusho)) and tableted into tablets having a hardness of 3.0 kg. Further, the obtained tablets were aged at 70 ° C. for 3 hours to obtain orally disintegrating tablets of 200 mg per tablet.

Comparative Example 7 : Inappropriate formulation

[Table 16] 成分 Ingredient weight wt% ─────── ──────────────────────────── ・ Erythritol 4mg 2% ・ Corn starch 3mg 1.5% ・ Mannitol (excipient) qs Mosapride acid 5mg 2.5% ・ Magnesium stearate 1mg ２００ Total 200mg ─ ──────────────────────────────────

30 g of corn starch (Nippon Shokuhin Kako)
Was dispersed in a 30 g beaker of water and stirred at 80 ° C. for 15 minutes to prepare a starch paste. 40 g of erythritol (manufactured by Niken Chemical Co., Ltd., solubility: about 47.5 g) was dissolved therein, and then the mixture was heated to 30 ° C. Reduced temperature. Meanwhile, an appropriate amount of mannitol (manufactured by Kao, solubility about 18.5 g) and 50 g of mosapride citrate are mixed in a plastic bag, transferred to a mortar, added with the above erythritol-starch paste solution, kneaded with a pestle, and mixed with a pestle. It was dried at 50 ° C. for 16 hours with a blow dryer. 2
After sizing with a 4 mesh sieve, magnesium stearate 10
g, and put in a plastic bag, mix to give granules for tableting, and use a single-shot tableting machine (type 2B, manufactured by Kikusui Seisakusho) to have a hardness of 0.5.
The tablets were compressed into kg tablets. Further, the obtained tablet was heated at 70 ° C.
For 3 hours to give an orally disintegrating tablet of 200 mg per tablet.

Comparative Example 8 : Conditions for not performing drying in step (b)

[Table 17] 成分 Ingredient weight% by weight ─────── ──────────────────────────── ・ Erythritol 9mg 3% ・ Polyvinylpyrrolidone 6mg 2% ・ Mannitol (excipient) qs ・ Citric acid Mosapride 5mg 1.7% ・ Magnesium stearate 3mg ─────────────────────────────────── Total 300mg ── ─────────────────────────────────

9 g of erythritol (manufactured by Niken Chemical Co., Ltd., solubility: about 47.5 g) and polyvinylpyrrolidone [PVP
(K30, manufactured by BASF) 6 g was dissolved in 10 g of water, and 15 g of ethanol was further added. An appropriate amount of mannitol (manufactured by Kao, solubility: about 18.5 g) and mosapride citrate (5 g) were mixed in a plastic bag, transferred to a mortar, further mixed with the above erythritol-PVP solution, and kneaded with a pestle. An attempt was made to tablet the kneaded product having a wet surface with a single-shot tableting machine (Model 2B, manufactured by Kikusui Seisakusho), but the kneaded material adhered to the punch and continuous tableting was not possible.

The disintegration time and hardness of the tablets of Examples 1 to 14 and the tablets of Comparative Examples 1 to 8 are shown in Tables 18 and 19, respectively. Note that in the following hardness and disintegration experiments, a tablet having a hardness of 2.5 kg or more and a disintegration time of 30 seconds or less under the conditions shown in the footnote of the following table was evaluated as achieving the object of the present invention.

[0073]

[Table 18] ^{* 1} ) Disintegration time: The time it takes for a tablet to disintegrate with five healthy adult males selected as panelists and lightly touching the tongue without biting the tablet in the oral cavity.

[0074]

[Table 19] ^{* 1} ) Disintegration time: The time it takes for a tablet to disintegrate when five healthy adult boys are selected as panelists and lightly touched with the tongue without biting the tablet in the oral cavity. ^{* 2} ) Not measured because the kneaded material adhered to the punch and tableting was not possible. (Underline) Problem part.

As shown in Tables 18 and 19, the tablets of Examples 1 to 14 showed satisfactory values for both disintegration time and hardness, but the tablet of Comparative Example 7 had problems in both disintegration time and hardness. The tablet of Comparative Example 2 was unsuitable because it had a problem in either the disintegration time or hardness.

Measurement of Sugar Solubility In a beaker, 20 ml of purified water at 25 ° C. was added, and various sugars were added with stirring. 1 g each of xylitol, sorbitol, glucose and sucrose, 0.5 g of erythritol, lactose and mannitol were added. 0.1g
The amount dissolved by stirring for 1 hour was defined as the solubility of the saccharide in the present specification.

[0077]

As described above, the production method of the present invention can be carried out without using any special equipment, and the desired orally disintegrating tablets can be easily produced in large quantities. Further, the tablet produced by the method of the present invention is an excellent orally disintegrating tablet that exhibits good disintegration in the oral cavity, has sufficient strength, and does not collapse during handling.

──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Yutaka Higashi 3-10-30-707, Tenjinbashi, Kita-ku, Osaka-shi, Osaka (72) Inventor Yasuhiko Nakamura 2-57-7, Nakayama Sakuradai, Takarazuka-shi, Hyogo (56 References JP-A-9-309822 (JP, A) JP-A-9-309821 (JP, A) JP-A-11-43429 (JP, A) JP-A-11-116465 (JP, A) International publication 93 / 15724 (WO, A1) (58) Fields investigated (Int. Cl. ⁷ , DB name) A61K 9/20

Claims (13)

(57) [Claims] 1. From the following steps (a), (b) and (c)
The drug is mixed before granulation or tableting.
Method for producing orally disintegrating tablet to be prepared: (a) saccharide having high solubility in water,That is, 25
Solubility in 100 ml of purified water at 40 ° C. is 40 g to 250 g
Sugars that areAnd at least one water-soluble binder
Also dissolve one kind in water alone or water and alcohol
(B)  Solution obtained in the above step (a)WhenAt least
Also mixes a kind of excipient,  Granulation,  After drying,
20-300kg / cm ^Two of(C) aging the tablet obtained in the above step (b).
Process. 2. The aging in the step (c) is carried out by subjecting the tablet obtained in the step (b) to a temperature exceeding room temperature for 1 minute.
The method according to claim 1, wherein the heating is performed for 3 days . 3. The method according to claim 1, wherein the saccharide used in step (a) is selected from at least one of erythritol, xylitol, sorbitol, glucose and sucrose. 4. The water-soluble binder is polyvinylpyrrolidone,
The method according to any one of claims 1 to 3 , wherein the method is selected from at least one of pullulan, hydroxypropylcellulose, hydroxypropylmethylcellulose, and water-soluble gelatin. Wherein step (a) process according to any one of claims 1-4 solvent is water as used. 6. A process method according to any one of claims 1 to 5 amount of sugars to be used is 0.5 to 10 wt% of the tablet by (a). 7. The compounding amount of the water-soluble binder is from 0.5 to 0.5 of the tablet.
The production method according to any one of claims 1 to 6 , wherein the content is 5% by weight. 8. The aging in step (c) is a heating condition, the heating temperature is lower than the softening point of the water-soluble binder used in step (a), and 40 ° C.
The method according to any one of claims 1 to 7 , wherein the temperature is as described above, and the aging time is 1 minute to 24 hours. 9. Step (b) The process according to any one of claims 1-8, characterized by mixing the drug granulation before or tabletting in. 10. The method according to claim 10, wherein the drying in the step (b) is carried out on a granulated surface.
Is drying until a dry state is obtained.
The production method according to any one of the preceding claims. 11. The following steps (a), (b) and (c)
Characterized by mixing drugs before granulation or tableting
Orally disintegrating tablets produced by the production method described below: (a) saccharides having high solubility in water,That is,
The solubility in 100 ml of purified water at 25 ° C. is 40
g to 250 g of saccharideWater-soluble bond with at least one of
Dissolve at least one of the agents in water alone or water and alcohols
(B)  Solution obtained in the above step (a)WhenAt least
Also mixes a kind of excipient,  Granulation,  After drying,
20-300kg / cm ^Two of(C) aging the tablet obtained in the above step (b).
Process. 12. The following steps (a), (b) and (c)
Characterized by mixing drugs before granulation or tableting
Orally disintegrating tablets produced by the production method described below: (a) saccharides having high solubility in water,That is, 25
Solubility in 100 ml of purified water at 40 ° C. is 40 g to 250 g
Sugars that areAnd at least one water-soluble binder
Also dissolve one kind in water alone or water and alcohol
(B)  Solution obtained in the above step (a)WhenAt least
Also mixes a kind of excipient,  Granulation,  After drying,
20-300kg / cm ^Two of(C) compressing the tablet obtained in the above step (b) further above room temperature
Heated at the temperature1 minute to 3 daysAging work
About. 13. A tablet weighing 180 mg to 300 mg.
The orally disintegrating tablet according to claim 11 or 12, which is: