JP2001328948A - Solid preparation containing hydroxypropyl cellulose having low substitution degree and method for producing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an easily producible solid preparation quickly disintegrating in the mouth by swallowing together with the saliva in the mouth or a small amount of water and having a moderate strength to keep the form during the production and distribution stages and provide a method for the production of the solid preparation. SOLUTION: The solid preparation contains a sugar or a sugar alcohol and a hydroxypropyl cellulose having low substitution degree, a loose bulk density of >=0.40 g/ml and a tight bulk density of >=0.60 g/ml. The present invention further provides a method for the production of the solid preparation. More particularly, the present invention provides a solid preparation containing a sugar or a sugar alcohol and a hydroxypropyl cellulose having low substitution degree and a volume-average particle diameter of <=25 μm measured by dry laser diffraction method and produced by crushing a hydroxypropyl cellulose having low substitution degree, a loose bulk density of >=0.40 g/ml, a tight bulk density of >=0.60 g/ml and a volume-average particle diameter of >=30 μm and a method for the production of the solid preparation.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a solid preparation which is rapidly disintegrated in the oral cavity by saliva or a small amount of water in the oral cavity.

[0002]

2. Description of the Related Art In recent years, a solid preparation that can be easily taken and administered has been desired for patients such as the elderly and children having a low swallowing ability. Specifically, orally disintegrating preparations, jelly-like preparations,
Examples include paste-form preparations. Particularly, orally disintegrating tablets can be taken without water or with a small amount of water, and can be taken easily and relatively easily, and are suitable for elderly people and children. Dosage form.

[0003] Various orally disintegrating preparations have been proposed so far. For example, Japanese Patent Publication No. Sho 62-50445 discloses that an aqueous solution of a polymer such as a drug or gelatin is prepared using PTP (Pr).
An orally disintegrating tablet produced by filling a essThrough Package) pocket and freeze-drying, and a method for producing the same have been proposed. However, this method requires a special production process, and the strength of the obtained tablet is small, and there is a problem in handling.

Japanese Patent Application Laid-Open No. Hei 5-27054 proposes an orally disintegrating tablet which is obtained by compressing a kneaded product containing a drug, a saccharide and an appropriate water at a low pressure, and then drying the tablet. At the time of tableting, there is a problem that the kneaded material easily adheres to a mortar, a punch, and the like, and it is difficult to control the moisture in the manufacturing process, so that it is not suitable for mass production.

[0005] On the other hand, JP-A-8-291051 and JP-A-9-48726 disclose that a saccharide / sugar alcohol, a water-soluble binder and a drug are mixed and tableted at a low pressure, and the tablet strength is reduced. Wet the tablet under humidification for growth,
Then, a dry orally disintegrating tablet and a method for producing the same have been proposed. However, the manufacturing process is multi-stage, the appearance of the tablet is changed in the humidification process, and the commercial value is impaired. There is a problem that it is not suitable for drugs that show deliquescence.

[0006] Several methods have been proposed for preparing orally disintegrating preparations using general equipment without the need for such special preparation techniques. Japanese Patent Application Laid-Open No. 9-71523 proposes an orally disintegrating tablet prepared by tableting a mixture of a drug, a low-substituted hydroxypropylcellulose as a disintegrant, a crystalline cellulose as an excipient and a lubricant at a low pressure. However, since a large amount of cellulose-based or polyvinylpyrrolidone-based additives are used, there is a drawback that the tablet is practically inferior in disintegration, solubility, texture, and taste.

JP-A-11-43429 proposes an orally disintegrating tablet comprising a drug, a sugar and a low-substituted hydroxypropylcellulose having a limited degree of substitution. However, the tablet has improved tongue and taste. It was not enough.

[0008]

DISCLOSURE OF THE INVENTION The present invention is intended to disintegrate quickly in the oral cavity by taking it with saliva or a small amount of water in the oral cavity, to facilitate the production process, and to improve the moldability during production and distribution. It is an object of the present invention to provide a solid preparation having an appropriate strength capable of retaining a solid preparation and a method for producing the same.

[0009]

Means for Solving the Problems The present inventors have found that the loose bulk density is 0.40 g / ml or more and the hardened bulk density is 0.4 g / ml.
By using a solid preparation containing a low-substituted hydroxypropylcellulose of 60 g / ml or more and a sugar / sugar alcohol, the solid preparation is given an appropriate strength, and at the same time, without feeling unpleasant taste in the oral cavity, It has been found that the drug disintegrates in the present invention, and the present invention has been accomplished. That is, the loose bulk density is 0.40 g / ml or more,
A solid preparation comprising low-substituted hydroxypropylcellulose having a bulk density of 0.60 g / ml or more and sugar / sugar alcohol, and a method for producing the same. A low-substituted hydroxypropylcellulose having a loose bulk density of 0.40 g / ml or more, a hardened bulk density of 0.60 g / ml or more, and a volume average particle diameter of 30 μm or more measured by a dry laser diffraction method is used. Provided is a solid preparation characterized by containing a low-substituted hydroxypropylcellulose having a volume average particle diameter of 25 μm or less obtained by pulverization and sugar / sugar alcohol, and a method for producing the same.

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION "Loose bulk density" in the present invention
Means the bulk density in a loosely packed state, having a diameter of 5.03c.
m, a sample is uniformly supplied from above (23 cm) through a JIS 24-mesh sieve into a cylindrical container (material: stainless steel) having a height of 5.03 cm (volume: 100 ml), and is measured by wiping the upper surface and weighing. Is done. on the other hand,
The term “solid bulk density” refers to the bulk density when the material is densely packed by tapping. Here, tapping is
This refers to the operation of repeatedly dropping a container filled with a sample from a certain height to give a light impact to the bottom and to tightly fill the sample. In practice, when measuring the loose bulk density, after weighing the top of the container, put a cap (supplied by Hosokawa Micron's powder tester) on this container, and add powder to the upper edge. Tapping is performed 180 times with a tap height of 1.8 cm. After completion, the cap is removed and the powder is ground and weighed on the upper surface of the container, and the bulk density in this state is hardened to obtain the bulk density. These operations can be measured by using a powder tester (PT-D) manufactured by Hosokawa Micron Corporation.

The low-substituted hydroxypropylcellulose of the present invention has a low-substituted hydroxypropylcellulose having a loose bulk density of at least 0.40 g / ml and a hardened bulk density of at least 0.60 g / ml. It is obtained by pulverizing a low-substituted hydroxypropylcellulose having an average volume particle diameter of 30 μm or more by a dry laser diffraction method. In addition, the grinding process
It is performed according to a conventional method, and for example, a pulverizer such as a ball mill, a hammer mill, a knife mill, and a jet mill can be used. The dry laser diffraction method referred to in the present invention is, for example, a method using a HELOS device manufactured by Sympatec of Germany. A method for measuring the diameter. The volume average particle size can be calculated by the formula {(volume average particle size) as described in, for example, "Revised Augmented Powder Physical Properties Illustration", edited by Japan Society of Powder Technology and Japan Powder Industry Technical Association, Nikkei Technical Book, 1985, page 88. nD ³ ) / {n} ^1/3 .
In the formula, D is the diameter of the particle, n is the number of particles of that diameter, and Δn is the total number of particles.

The low-substituted hydroxypropylcellulose used in the present invention is a kind of cellulose ether and is similar to hydroxypropylcellulose generally used as a binder, but has different properties. The essential difference between the former and the latter lies in the content of hydroxypropoxyl groups,
The value of the former is 5 to 16.0% by weight,
The latter is 53.4 to 77.5% by weight. This value is measured by the method described in the Japanese Pharmacopoeia, and its range is clearly defined in the monograph of Japanese Pharmacopoeia "Low-substituted hydroxypropylcellulose". That is, the content of the hydroxypropoxyl group in the low-substituted hydroxypropylcellulose is 5.0 to 16.0% by weight.

The low-substituted hydroxypropylcellulose having a loose bulk density of 0.40 g / ml or more and a hardened bulk density of 0.60 g / ml or more can be produced by the following method. That is, the pulp is immersed in an alkaline solution to form alkali cellulose, which is reacted with propylene oxide. In the subsequent step, the product is put into water or water adjusted to alkaline, completely dissolved, and turned into an almost uniform transparent slurry, and then neutralized with hydrochloric acid to precipitate a low-substituted hydroxypropyl. After collecting the cellulose, it is washed with water, dried and pulverized. The term "completely dissolved state" as used herein means a state in which the product almost completely loses its shape. That is, it includes not only complete transparency but also an opaque slurry state and the degree to which 5 to 10 small product lumps remain in a 3 liter slurry. The state after dissolution is a slurry of high viscosity and requires a kneading machine such as a kneader with a strong stirring power. Thereafter, the mixture is neutralized with an acid such as hydrochloric acid to precipitate hydroxypropylcellulose having a low degree of substitution, which is collected, washed, dried and pulverized to obtain a product.

In a preferred embodiment of the present invention, the loose bulk density is 0.40 g / ml or more (more preferably 0.40 g / ml).
/ Ml or more and less than 0.60 g / ml) and a consolidated bulk density of 0.60 g / ml or more (more preferably 0.60 g / m
1 to less than 0.85 g / ml) and a low-substituted hydroxypropylcellulose having an average volume particle size of 30 μm or more (more preferably 30 μm or more and 200 μm or less) determined by dry laser diffraction. Low-substituted hydroxypropylcellulose having a volume average particle size of 25 microns or less. The low-substituted hydroxypropylcellulose thus obtained has a loose bulk density of 0.29 g / ml or more (more preferably 0.29 g / ml or more and less than 0.55 g / ml) and a hardened bulk density of 0.55 g. / Ml or more (more preferably 0.
55 g / ml or more and less than 0.85 g / ml).

The amount of the low-substituted hydroxypropylcellulose used in the present invention is 1 per 100 parts by weight of the solid preparation.
-99 parts by weight, preferably 5-50 parts by weight. If the amount of low-substituted hydroxypropylcellulose is less than 1 part by weight, tablet strength is insufficient and handling becomes difficult. If it exceeds 99 parts by weight, tablet strength is obtained, but disintegration in the oral cavity is delayed. There is a risk.

In the present invention, the sugar / sugar alcohol is
It is a sugar in a broad sense, including sugar alcohols. Sugar is a general term for water-soluble and sweet saccharides, and includes monosaccharides and most oligosaccharides. Polysaccharides are also included in saccharides because they are converted into sugars by hydrolysis. Sugar alcohol refers to a polyhydric alcohol on the chain in which the carbonyl group of the sugar has been reduced, and also includes cyclic sugar alcohols (cyclitols) having similar properties. In the present invention, the sugar / sugar alcohol is preferably erythritol, sorbitol, trehalose, xylitol, mannitol, glucose,
Sucrose and the like are particularly preferred, and erythritol or sorbitol, trehalose, and xylitol are particularly preferred. These can be used alone or in combination of two or more. These sugars / sugar alcohols are used in the form of crystals or powders. When the sugars / sugar alcohols have an average particle diameter of 500 μm or less, they exhibit excellent properties in terms of moldability, disintegration, and texture.

The amount of the sugar / sugar alcohol to be added is as follows:
1 to 99 parts by weight, preferably 10 to 90 parts by weight in 00 parts by weight
Parts by weight. If the amount of the sugar or sugar alcohol is less than 1 part by weight, it takes time to disintegrate in the oral cavity, and if it exceeds 99 parts by weight, sufficient strength of the preparation may not be obtained.

The main components to be added to the solid preparation of the present invention are antipyretic analgesics, antibiotics, anti-inflammatory agents, and pharmaceuticals.
There is no particular limitation on vitamins and nutrition. Further, as other components, for example, a lubricant, a binder, a stabilizer, a coloring agent, a flavoring agent, and the like may be added.

Regarding the method for producing the solid preparation of the present invention,
Any method such as mixing the above composition and directly tableting or dry tableting, dry granulation, fluidized bed granulation or wet granulation can be applied. A tableting method for producing tablets is generally performed using a device for forming or granulating tablets, and examples thereof include a single-shot tableting machine, a rotary tableting machine, and a tableting tester. The molding pressure during tableting is usually 50 to 300 MPa, preferably 80 to 300 MPa.
It is 200 MPa. If the molding pressure is lower than 50 MPa, tablet hardness becomes insufficient and handling becomes difficult, and 300 MPa
Higher values may delay disintegration.

The solid preparation of the present invention, particularly an orally disintegrating tablet produced as described above, has excellent disintegration in the oral cavity,
In addition, it maintains an appropriate formability (strength). That is, the oral disintegration time of the solid preparation of the present invention (the time required for the tablet to completely disintegrate in the oral cavity of a healthy adult) is usually 1 to 1.
60 seconds, preferably 1 to 40 seconds, more preferably 1 to
It is about 30 seconds. The tablet hardness (based on a tablet hardness tester) is usually 2 to 15 kgf, preferably 3 to 10 kgf.
It is about.

The solid preparation of the present invention includes tablets, granules, fine granules, capsules and the like.

[0022]

EXAMPLES Examples and comparative examples of the present invention are shown below.
The present invention is not limited only to the contents of these examples. Example 1 Erythritol (manufactured by Niken Kagaku Co., Ltd.) was pulverized in a mortar, and 70 parts by weight of a powder sieved with a sieve having an opening of 355 μm was added to a low-substituted hydroxypropylcellulose of the present invention (volume by dry laser method). Average particle size 47 microns, loose bulk density 0.47 g / ml, hardened bulk density 0.69 g / ml,
(Hydroxypropoxyl group content 11.0% by weight) 30
After mixing the parts by weight, magnesium stearate was blended at a ratio of 0.5% by weight with respect to the mixed powder, and a single-shot tableting machine (Tabletting Tester manufactured by Sankyo Piotech Co., Ltd.) was used to obtain 11 mmφ at a compression pressure of 100 MPa. 480m per tablet
g of a solid preparation were obtained.

Example 2 Erythritol was ground in a mortar, and 70 parts by weight of a powder sieved with a sieve having a mesh size of 355 μm was mixed with 70 parts by weight of the low-substituted hydroxypropylcellulose of the present invention (the low-substituted hydroxypropyl cellulose of Example 1). Cellulose was finely pulverized: volume average particle size by dry laser method was 16 microns) After mixing 30 parts by weight, magnesium stearate was blended at a ratio of 0.5% by weight with respect to the mixed powder, and single-shot tableting was performed. A tableting pressure of 100 MPa was used to obtain a solid preparation of 11 mmφ and 480 mg per tablet using a press.

Example 3 Erythritol was pulverized in a mortar, and 70 parts by weight of a powder sieved with a sieve having an opening of 355 microns was mixed with 30 parts by weight of the low-substituted hydroxypropylcellulose of Example 1 to obtain a fluidized bed. Granulator (Multiplex MP-0 manufactured by Powrex)
Purified water was sprayed using 1) to perform fluidized bed granulation.
Subsequently, magnesium stearate was blended at a ratio of 0.5% by weight with respect to the obtained granulated powder, and a single tableting machine was used to obtain a solid preparation of 11 mmφ at a compression pressure of 100 MPa and 480 mg per tablet. .

Example 4 Erythritol was pulverized in a mortar, and 70 parts by weight of a powder sieved with a sieve having an opening of 355 microns was mixed with 30 parts by weight of the low-substituted hydroxypropylcellulose of Example 2 to obtain a fluidized bed. Granulator (Multiplex MP-0 manufactured by Powrex)
Purified water was sprayed using 1) to perform fluidized bed granulation.
Subsequently, magnesium stearate was blended at a ratio of 0.5% by weight with respect to the obtained granulated powder, and a single tableting machine was used to obtain a solid preparation of 11 mmφ at a compression pressure of 100 MPa and 480 mg per tablet. .

Example 5 An orally disintegrating tablet was obtained in the same manner as in Example 4 except that the tableting pressure was changed to 200 MPa.

Comparative Example 1 Erythritol was pulverized in a mortar, and powder sieved with a sieve having a mesh size of 355 μm was mixed with 0.5% by weight of magnesium stearate.
A solid preparation of 11 mmφ in Pa and 480 mg per tablet was obtained.

Comparative Example 2 Erythritol was crushed in a mortar, and 70 parts by weight of a powder sieved with a sieve having an opening of 355 μm was mixed with low-substituted hydroxypropylcellulose (LH-21 manufactured by Shin-Etsu Chemical Co., Ltd., using a dry laser method). Volume average particle size is 37 microns, loose bulk density 0.335g / ml hardened bulk density 0.597g / m
1, 30 parts by weight of a hydroxypropoxyl group content of 10.9% by weight),
Magnesium stearate was blended at a ratio of 1% by weight, and a tableting pressure of 100 MPa was applied to a tablet of 11 mmφ,
A tablet 480 mg orally disintegrating tablet was obtained.

Comparative Example 3 Erythritol was pulverized in a mortar, and 70 parts by weight of a powder sieved with a sieve having an opening of 355 μm was mixed with 30 parts by weight of the low-substituted hydroxypropylcellulose of Comparative Example 2 to obtain purified water. The fluidized bed granulation was performed by spraying. Subsequently, after mixing magnesium stearate at a ratio of 0.5% by weight with respect to the obtained granulated powder, a tableting pressure of 100 M was applied by a single tableting machine.
An orally disintegrating tablet of 11 mmφ in Pa and 480 mg per tablet was obtained.

Comparative Example 4 The low-substituted hydroxypropylcellulose of Comparative Example 3 was used (LH-31 manufactured by Shin-Etsu Chemical Co., Ltd., volume average particle diameter by dry laser method: 17 μm, loose bulk density: 0.323)
Orally disintegrating tablets were obtained in the same manner, except that the bulk density was 0.623 g / ml and the hydroxypropoxyl content was 10.9% by weight.

COMPARATIVE EXAMPLE 5 The low-substituted hydroxypropylcellulose of Comparative Example 3 was used (LH-32 manufactured by Shin-Etsu Chemical Co., Ltd., volume average particle diameter by dry laser method: 18 μm, loose bulk density: 0.306)
g / ml consolidated bulk density 0.582 g / ml, with hydroxypropoxyl group content of 8.3% by weight)
An orally disintegrating tablet was obtained in the same manner.

The hardness and disintegration time of the orally disintegrating tablets of Examples 1 to 5 and Comparative Examples 1 to 5 were measured, and the results are shown in Table 1. The hardness of the orally disintegrating tablet was measured using a tablet hardness tester (Elveca hardness tester), and the disintegration time was measured using a Japanese Pharmacopoeia disintegration tester (test solution: water, 37 ° C.), n = 6.
(N represents the number of samples). Oral disintegration time is tested in five healthy adult males and females, and the time taken for the tablet to completely dissolve or disintegrate is measured with the tablet lightly contained in the mouth without chewing in the oral cavity, and the average value is calculated. Calculated. Also,
The feeling of taking at this time was also evaluated. The evaluation was made in four stages: good (◎), slightly good (○), normal (△), and poor (x). From the results shown in Table 1, in the relationship between the hardness and the disintegration time, it was found that the solid preparation of the present invention had a fast disintegration time and a good oral feel.

[0033]

EFFECTS OF THE INVENTION The solid preparation of the present invention has characteristics excellent in moldability and disintegration property, so that it can be easily taken by elderly people and children with weak swallowing power.

[0034]

[Table 1]

Continuation of the front page F term (reference) 4C076 AA37 BB22 CC21 DD38 DD67 EE32B FF04 FF06

Claims (6)

[Claims] 1. A solid containing low-substituted hydroxypropylcellulose having a loose bulk density of at least 0.40 g / ml and a hardened bulk density of at least 0.60 g / ml, and a sugar / sugar alcohol. Formulation. 2. A low-substituted hydroxy resin having a loose bulk density of 0.40 g / ml or more, a hardened bulk density of 0.60 g / ml or more, and a volume average particle diameter of 30 μm or more measured by a dry laser diffraction method. A solid preparation comprising low-substituted hydroxypropylcellulose having a volume average particle size of 25 μm or less obtained by pulverizing propylcellulose and obtained by the diffraction method, and sugar / sugar alcohol. 3. The solid preparation according to claim 1, wherein the sugar or sugar alcohol is at least one selected from the group consisting of erythritol, sorbitol, trehalose, xylitol, mannitol, glucose, and sucrose. . 4. The sugar / sugar alcohol has an average particle diameter of:
The solid preparation according to any one of claims 1 to 3, which has a size of 500 microns or less. 5. The low-substituted hydroxypropylcellulose having a hydroxypropoxyl group content of 5.0-1.
The solid preparation according to any one of claims 1 to 4, which is 6.0% by weight. 6. A method for producing a solid preparation, wherein the loose bulk density is 0.40 g / ml or more, and the loose bulk density is 0.1 g / ml.
A low-substituted hydroxypropylcellulose and sugar / sugar alcohol that are 60 g / ml or more, or the low-substituted hydroxymexylpropylcellulose having a volume average particle diameter of 30 μm or more measured by a dry laser diffraction method is pulverized. A method for producing a solid preparation, comprising mixing the low-substituted hydroxypropylcellulose having a volume average particle diameter of 25 μm or less with the sugar / sugar alcohol.