JPH08310969A - Solid pharmaceutical composition and method for producing the same - Google Patents

Abstract

(57) [Summary] [Structure] A water-swellable shape is formed on a granulated product containing two or more water-insoluble drugs or a granulated product containing two or more water-insoluble drugs, respectively. A solid chemical composition comprising an agent and one or more sugar components selected from sugars and sugar alcohols. [Effect] Even with a solid chemical composition containing two or more drugs that are poorly soluble in water, a formulation with good disintegration can be obtained by adding a small amount of additives.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a solid chemical composition and a method for producing the same, more specifically, a solid chemical composition which exhibits excellent disintegration property even if it contains two or more kinds of water-insoluble chemicals. The present invention relates to a composition and a method for producing the composition.

[0002]

2. Description of the Related Art When preparing a solid pharmaceutical composition, generally, a solid drug composition is used as a means for improving the absorbability in the body and a pharmaceutical composition aiming at improving the ingestability. Often devised. These solid pharmaceutical compositions may be used as they are by mixing all the components of the composition, or may be used as tablets, capsules or granules depending on the purpose of use. For example, in the case of a granule, a suitable granule is added together with an active ingredient, and a dry granulation method using a roll compactor (Japanese Patent Publication No. 45-15755) and a wet granulation method using an extrusion granulator (Japanese Patent Laid-Open No. Hei 5) -2
No. 29936) and a method of treating an active ingredient with a water-soluble polymer compound into a granule by using a fluidized granulator. The granules or granule-like composition obtained in this way are sized to a certain particle size, and then additives are further added, and the resulting tablets are used as tablets or filled with a certain amount thereof. It is used as hard capsules and sachets.

However, when the target drug has low solubility in water, the solid drug composition containing the drug granulated by the above-mentioned granulation method is unlikely to disintegrate in the body and, in particular, is crystallized. If the active drug or drug has a large particle size, a large amount of excipient is required for the drug in order to ensure good disintegration in the body, which increases the dose or the drug itself. There is a problem that the absorbability of is affected. As a countermeasure in this case, for example, a method in which a poorly water-soluble drug is sufficiently finely powdered to increase the surface area of the drug as an active ingredient, and further mixed with a binder to improve the absorbability, or a suitable surface active agent is used. Methods such as improving the affinity with water by adding agents such as sucrose fatty acid ester and polyoxyethylene sorbitan fatty acid ester are used.

However, in a solid pharmaceutical composition in which two or more kinds of poorly water-soluble drugs are mixed, an attempt is made to solve the problem by mixing the finely divided drug with a binder as in the above-mentioned former method. In this case, since the binder is directly applied to the surface of the poorly water-soluble drug (the infiltrating biological fluid does not act efficiently on these binding parts), sufficient disintegration performance for the entire composition is obtained. Can't have On the other hand, when a surfactant is added as in the latter method, the affinity for water is improved, but the physical disintegration performance of the entire composition is drastically affected by the physical inhibition of the binder at the interface between the granules. Can't be solved.

The present invention has been made in view of the above circumstances, and an object thereof is to provide a solid chemical composition containing two or more kinds of poorly water-soluble drugs and having improved disintegration property, and a method for producing the same. To do.

[0006]

Means and Actions for Solving the Problems As a result of intensive studies to achieve the above object, the present inventors have found that in the case of a solid chemical composition containing a plurality of poorly soluble drugs in water, those water It was found that the disintegration property was remarkably improved by adding a sugar component such as sugar or sugar alcohol to a granulated product containing a poorly soluble drug, together with a water-swelling excipient. Invented.

That is, the present invention provides a water-swellable shape-forming agent for a granulated product containing two or more kinds of poorly water-soluble drugs or two or more kinds of granulated products respectively containing poorly water-soluble drugs. There is provided a solid chemical composition characterized by comprising an agent and one or more kinds of sugar components selected from sugars and sugar alcohols, and a method for producing the same. Here, the water-swellable excipient is one or two selected from crystalline cellulose, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose crosslinked body, carboxymethylethyl cellulose and polyvinylpyrrolidone crosslinked body.
It is preferable to use at least one kind.

The present invention will be described in more detail below. The solid pharmaceutical composition of the present invention comprises a granulated product containing two or more kinds of poorly water-soluble drugs, a water-swellable excipient, and a saccharide. And a sugar component consisting of sugar alcohols as essential components.

Although the solubility of the poorly water-soluble drug of the present invention is not particularly limited, a drug having a solubility in water at 30 to 40 ° C. of 1 (g / 100 g water) or less is used as an active ingredient. In this case, the present invention is particularly useful. Such active ingredients include, for example, etenzamid, ibuprofen, tolfenamic acid, phenacetin, mefenamic acid, flufenamic acid, floctafenin, sazapyrine,
Ketophenylbutazone, phenylbutazone, alclofenac, fenbufen, methiazinate, ketoprofen, naproxen, flurbiprofen, pranoprofen, antipyretic and analgesic agents such as tinoridine hydrochloride, as well as noscapine and allylisopropylacetylurea And two or more of them are combined and compounded. Here, the combination of these drugs is not particularly limited as long as they can be combined and formulated in an ordinary preparation.

Regarding the particle size of these drugs, it is desirable to adjust the particle size distribution and apparent specific gravity in consideration of the compatibility with other drugs to be combined, but generally, the particle size is 1 to 500 μm, especially The thickness is preferably 10 to 80 μm. If it is less than 1 μm, it may be difficult to uniformly disperse it in the excipient or other active ingredient, and if it exceeds 500 μm, the active ingredient may be easily separated and segregated.
Here, in order to obtain a particularly uniform preparation, the particle size of each drug is most preferably 10 to 80 μm as described above.

The solid drug composition of the present invention comprises the above drug.
Use as a single granulated product that combines two or more kinds or 2 of the above drugs
A mixture of two or more kinds of granules, each containing one or more kinds, is used, and a known method can be adopted as the granulation method, for example, a fluidized granulation method or a roll compression method. The extrusion granulation method, the stirring granulation method and the like can be appropriately selected and granulated according to the purpose of the formulation. For example, when the dosage form of the solid drug composition of the present invention is a tablet, a capsule, or the like, it is flowable. The effect of the present invention is particularly remarkable when the granulated product is produced by the granulation method or the roll compression method. On the other hand, when the main purpose is to rapidly disintegrate the solid drug composition, if the granulation product is formed by the fluidized granulation method, the contact between the granulation product and the excipient and the sugar component of sugar or sugar alcohol is more reliable. And is most suitable. When granulating the drug, an excipient, a binder, and a disintegrant can be appropriately added within the range that does not impair the effects of the present invention, if necessary.

The particle size of the above granulated product is 100 to 2000 μm.
m is preferable, and more preferably 350 to 1000.
μm, particularly preferably 350 to 800 μm. 10
If it is less than 0 μm, the fluidity of the particles becomes insufficient, which may hinder the processes such as transfer, mixing, and tableting in the subsequent steps, and if it exceeds 2000 μm, the variation in the content of the drug per single dose may occur. May increase, and problems such as granule separation and segregation may occur.

The above-mentioned drugs may be mixed in various amounts depending on the types of drugs, their combination, dosage form, purpose of application, etc., but in the usual preparations, the total amount of one-time use of these drugs is 50 mg or more. The effect of the present invention is particularly large for the combination of. In addition, generally 95% (% by weight, the same applies below) or less, especially 90% of the total composition.
The following is preferable. If it exceeds 95%, it may be difficult to obtain sufficient disintegration.

The water-swellable excipient of the present invention is not particularly limited in kind as long as it is a polymeric substance which is insoluble or swellable in water and is porous, but it has the above-mentioned physical properties. A cellulose derivative or a cross-linked water-soluble polymer compound that is used as an excipient in ordinary preparations is preferably used. Examples of such excipients include crystalline cellulose, low-substituted hydroxypropyl cellulose (substitution degree 5.0 to 16.0), carboxymethyl cellulose (eg carmellose), carboxymethyl cellulose calcium (eg carmellose calcium), sodium carboxymethyl cellulose. Examples thereof include crosslinked products (eg, croscarmellose sodium), carboxymethylethyl cellulose, polyvinylpyrrolidone crosslinked products (eg, crospovidone), and among these, carboxymethylcellulose sodium crosslinked products such as croscarmellose sodium and crospovidone, etc. Particularly preferred is a polyvinylpyrrolidone crosslinked product.

The particle size of the water-swellable excipient is not particularly limited, but is preferably 1 to 100 μm, particularly 5 to 30 μm. If it is less than 1 μm, the effect of excipient blending may be reduced due to aggregation of excipient particles, and if it exceeds 100 μm, it may be difficult to obtain sufficient disintegration. In addition, the shape of the water-swellable excipient is preferably such that it has pores large enough to contain particles of sugars and sugar alcohols, and the larger the number of pores, the more preferable.

[0016] The amount of the water-swellable excipient to be blended depends on the dosage form,
Although it varies depending on the purpose of application, etc., generally, 1 to 50% of the total compounding amount of the above-mentioned two or more water-insoluble drugs
It is particularly preferably set to 3 to 45%. If it is less than 1%, it may be difficult to sufficiently improve the disintegration property of the solid drug composition, and if it exceeds 50%, the dose is increased, which is not desirable. In addition, for the same reason as above, the compounding amount relative to the entire composition is generally 0.5 to 0.5 of the entire composition.
It is preferably 40%, particularly preferably 1 to 30%.

The solid pharmaceutical composition of the present invention comprises one or more sugar components selected from sugars and sugar alcohols, together with the above-mentioned excipient. Here, as the saccharide of the present invention, known saccharides that are usually added to medicines can be used, and examples of such saccharides include lactose, anhydrous lactose, sucrose, fructose, and dextrose. These may be used alone or in combination of two or more, and among these, lactose and anhydrous lactose are particularly preferable because they have little influence under humidification. Further, the sugar alcohols of the present invention may be known ones which are usually added to chemicals, and examples of such sugar alcohols include mannitol, sorbitol, xylitol and the like. They may be used alone or in combination of two or more.

The particle size of the sugar component is not particularly limited, but is generally 1 to 800 μm, particularly 10 to 1
Those having a diameter of 00 μm are preferably used. Outside the above range, it may be difficult to add a sugar component to form a solid preparation.

The blending amount of the above sugar component varies depending on the dosage form, the purpose of application, etc., but is generally 0.5 to 40% of the total blending amount of the above-mentioned two or more poorly water-soluble drugs. , Especially 1
It is preferably set to -30%. If it is less than 0.5%, it may be difficult to sufficiently improve the disintegration property of the solid drug composition, and if it exceeds 50%, the dose is increased, which is not desirable. In addition, the compounding amount with respect to the entire composition is generally 0.1 to 3 of the entire composition for the same reason as above.
It is preferably 5%, particularly preferably 1 to 20%. The total content of the water-swellable excipient and the sugar component is preferably 1.5 to 90%, and particularly preferably 3 to 80% of the total content of the poorly water-soluble drug. Moreover, it is preferable to be 0.6 to 75%, especially 2 to 50% of the whole composition. By setting the total amount of the water-swellable excipient and the sugar component to be in the above range, the effect of the present invention becomes particularly remarkable.

When producing the solid chemical composition of the present invention,
First, a single granule containing two or more water-insoluble drugs or a mixture of two or more granules each containing one or more water-insoluble drug is prepared. A water-swellable excipient and a sugar component are mixed, and then granulation, tableting and the like are performed depending on the final dosage form.

When granulating or tableting, if necessary, a disintegrating agent such as starch, hydroxypropyl cellulose (substitution degree 53.4 to 77.5%), methyl cellulose, gelatin, vinylpyrrolidone, partial Binders such as pregelatinized starch, various flavoring agents, pigments and the like can be appropriately added within a range that does not impair the effects of the present invention.

[0022]

INDUSTRIAL APPLICABILITY According to the present invention, even a solid chemical composition containing two or more kinds of drugs which are poorly soluble in water, a formulation having good disintegration can be obtained by adding a small amount of additives. be able to.

[0023]

EXAMPLES The present invention will be specifically described below by showing Examples and Comparative Examples, but the present invention is not limited to the following Examples.

The poorly water-soluble drugs used in the following Examples and Comparative Examples were used after passing through the following sieves in advance.

Opening of sieve (μm) mefenamic acid through which poorly soluble drug passed 150 allylisopropylacetylurea 180 ibuprofen 180 etenzamid 106 alclofenac 150 ketoprofen 150

[Example 1] Mefenamic acid and allylisopropylacetylurea were used as a poorly water-soluble drug, and these were fluidized and granulated, and mannitol and crystalline cellulose were added to obtain tablets.

That is, 1500 g of mefenamic acid and 150 g of allylisopropylacetylurea were mixed with a fluid granulator (WS).
G-5 type: manufactured by Okawara Co., Ltd., and previously prepared 100 g of hydroxypropyl cellulose (substitution degree 65%) to 2000 g
The binder solution dissolved in water was sprayed so as to give a predetermined amount of the following composition to obtain a granulated product. 343 parts of the above-mentioned granules sieved using a 1400 μm sieve (weight part, the same applies hereinafter)
To 30 parts of crystalline cellulose and 15 parts of mannitol were added, and these were mixed for 10 minutes using a V-type mixer, and 2 parts of magnesium stearate was further added to obtain 3 parts.
The mixture was mixed for a minute, and a rotary type tableting machine (L-41:
The tablets were tableted with a tableting pressure of 1.2 t / cm ² by Hata Tekko Co., Ltd. to obtain tablets having a tablet weight of 390 mg and a diameter of 10 mm and having a Go composition, having the following composition. Composition mefenamic acid 300 parts Allylisopropylacetylurea 30 parts of hydroxyethyl cellulose (degree of substitution 65%) 13 parts of crystalline cellulose and 30 parts of mannitol, 15 parts 2 parts Total 390 parts of magnesium stearate

Example 2 Ibuprofen and allylisopropylacetylurea were used as poorly water-soluble drugs,
These were subjected to fluidized granulation, sorbitol and crystalline cellulose were added thereto, and the mixture was roll-compressed and then sized to obtain granules.

That is, 1000 g of ibuprofen, 200 g of allylisopropylacetylurea and 200 g of partially pregelatinized starch were charged into a fluidized granulator (WSG-5 type), and hydroxypropyl cellulose (substitution degree 65%) 10
A binder solution prepared by dissolving 0 g in 2000 g of water was sprayed so as to give a predetermined amount of the following composition to obtain a granulated product. 1400
To 147.8 parts of the above granules sieved using a sieve of μm, 7 parts of crystalline cellulose, 5 parts of sorbitol and 0.2 part of yellow No. 5 aluminum lake were added, and these were mixed with V
The mixture was mixed for 15 minutes using a mold mixer, and then dry granulated using an Alexander dry granulator (WP50N: manufactured by Matsuzaka Trading Co., Ltd.) and sized to obtain granules having the following composition. The granules conformed to the regulations of granules described in the Japanese Pharmacopoeia. Composition Ibuprofen 100 parts Allylisopropylacetylurea 20 parts partially α-starch, 20 parts hydroxypropyl cellulose (degree of substitution 65%) 7.8 parts of crystalline cellulose 7 parts sorbitol 5 parts Yellow 5 Aluminum Lake 0.2 parts Total 173 parts

[Comparative Example 1] Mefenamic acid and allylisopropylacetylurea were used as a poorly water-soluble drug, and these were fluidized and granulated, and cornstarch was added as a disintegrant and crystalline cellulose was added as an excipient to form tablets. did.

That is, 1500 g of mefenamic acid and 150 g of allylisopropylacetylurea were mixed with a fluidized granulator (WS).
G-5 type), and previously sprayed with 100 g of hydroxypropylcellulose (substitution degree 65%) in 2000 g of water to obtain a binder solution having a predetermined amount of the following composition,
A granulated product was obtained. 50 parts of crystalline cellulose and 30 parts of corn starch were added to 343 parts of the above granules sieved using a 1400 μm sieve, and these were mixed for 10 minutes using a V-type mixer, and further magnesium stearate 2
Parts were mixed for 3 minutes and tabletted with a rotary tableting machine (L-41) at a tableting pressure of 1.2 t / cm ^{2 to} give a tablet weight of 425 mg and a diameter of 10 mm. To obtain tablets. Composition mefenamic acid 300 parts Allylisopropylacetylurea 30 parts of hydroxyethyl cellulose (degree of substitution 65%) 13 parts of crystalline cellulose 50 parts Corn starch 30 parts 2 parts Total 425 parts of magnesium stearate

[Comparative Example 2] Mefenamic acid and allylisopropylacetylurea were used as poorly water-soluble drugs, and these were fluidized and granulated, and cornstarch was added as a disintegrant and lactose was added as an excipient to form tablets. .

That is, 1500 g of mefenamic acid and 150 g of allyl isopropyl acetylurea were added to a fluid granulator (WS).
G-5 type), and previously sprayed with 100 g of hydroxypropylcellulose (substitution degree 65%) in 2000 g of water to obtain a binder solution having a predetermined amount of the following composition,
A granulated product was obtained. 50 parts of lactose and 30 parts of corn starch were added to 343 parts of the above granules sieved using a 1400 μm sieve, and these were mixed for 10 minutes using a V-type mixer, and further 2 parts of magnesium stearate were added. Mix the mixture for 3 minutes and use a rotary type tablet press (L-4
The tableting pressure was adjusted to 1.2 t / cm ^{2 in} 1) to obtain tablets having a tablet weight of 425 mg and a diameter of 10 mm and having a composition of the following: Composition mefenamic acid 300 parts Allylisopropylacetylurea 30 parts of hydroxyethyl cellulose (degree of substitution 65%) 13 parts of lactose 50 parts Corn starch 30 parts 2 parts Total 425 parts of magnesium stearate

[Comparative Example 3] Ibuprofen and allylisopropylacetylurea were used as the poorly water-soluble drugs.
These were fluidized and granulated, lactose and hydroxypropyl starch were added, and the mixture was roll-compressed and then sized to give granules.

That is, 1000 g of ibuprofen, 200 g of allylisopropylacetylurea and 200 g of partially pregelatinized starch were charged into a fluidized granulator (WSG-5 type), and hydroxypropyl cellulose (substitution degree 65%) 10
A binder solution prepared by dissolving 0 g in 2000 g of water was sprayed so as to give a predetermined amount of the following composition to obtain a granulated product. 1400
Lactose (10 parts), hydroxypropyl starch (15 parts) and yellow No. 5 aluminum lake were added to 147.8 parts of the above-mentioned granules sieved using a μm sieve, and these were mixed for 15 minutes using a V-type mixer, and then mixed. Dry granulation was carried out using an Alexander dry granulator WP50N, and the granules having the following composition were obtained. The granules conformed to the regulations of granules described in the Japanese Pharmacopoeia. Composition Ibuprofen 100 parts Allylisopropylacetylurea 20 parts partially α-starch, 20 parts hydroxypropyl cellulose (degree of substitution 65%) 7.8 parts of lactose, 10 parts hydroxypropyl starch 15 parts Yellow 5 Aluminum Lake 0.2 parts Total 173 parts

Comparative Example 4 Ibuprofen and allylisopropylacetylurea were used as poorly water-soluble drugs.
Partially pregelatinized starch was added, and these were fluidized granulated, carboxymethyl cellulose and yellow No. 5 aluminum lake were added, and the mixture was roll-compressed and then sized to give granules.

That is, 1000 g of ibuprofen, 200 g of allylisopropylacetylurea and 200 g of partially pregelatinized starch were charged into a fluidized granulator (WSG-5 type), and hydroxypropylcellulose (substitution degree 65%) 10
A binder solution prepared by dissolving 0 g in 2000 g of water was sprayed so as to give a predetermined amount of the following composition to obtain a granulated product. 1400
25 parts of partial carboxymethyl cellulose and 0.2 part of yellow No. 5 aluminum lake were added to 147.8 parts of the above granules sieved using a sieve of μm, and these were mixed with V
The mixture was mixed for 15 minutes using a mold mixer, then dry granulated using an Alexander dry granulator WP50N, and granulated to obtain granules having the following composition. The granules were compatible with the granules described in the Japanese Pharmacopoeia. Composition Ibuprofen 100 parts Allylisopropylacetylurea 20 parts partially α-starch, 20 parts hydroxypropyl cellulose (degree of substitution 65%) 7.8 parts carboxymethyl cellulose 25 parts Yellow 5 Aluminum Lake 0.2 parts Total 173 parts

[Comparative Example 5] Mefenamic acid and allylisopropylacetylurea were used as poorly water-soluble agents, mannitol and crystalline cellulose were added to them, and powder-mixed. After fluidizing and granulating these, magnesium stearate was used. Was added and compressed into tablets.

That is, crystalline cellulose 1 was added to mefenamic acid 1500 g and allylisopropylacetylurea 150 g.
50 parts and 75 parts of mannitol were added, and these were mixed for 10 minutes using a V-type mixer, and then a fluidized granulator (WS
G-5 type), and previously sprayed with 100 g of hydroxypropylcellulose (substitution degree 65%) in 2000 g of water to obtain a binder solution having a predetermined amount of the following composition,
A granulated product was obtained. 2 parts of magnesium stearate was added to 388 parts of the above granules sieved using a 1400 μm sieve, and these were mixed for 10 minutes using a V-type mixer, and then a rotary tableting machine (L-41) was used. ) And the tableting pressure was 1.2 t / cm ² , and the tablet weight was 390 m.
A tablet having the following composition, which is a go stone type and has a diameter of 10 mm, was obtained. Composition mefenamic acid 300 parts Allylisopropylacetylurea 30 parts of hydroxyethyl cellulose (degree of substitution 65%) 13 parts of crystalline cellulose and 30 parts of mannitol, 15 parts 2 parts Total 390 parts of magnesium stearate

The disintegration time of each solid chemical composition of Examples 1 and 2 and Comparative Examples 1 to 5 was measured according to the disintegration test method described in the Japanese Pharmacopoeia. The results are shown in Table 1. The test was performed using a disintegration tester (manufactured by Toyama Sangyo Co., Ltd.) according to the Japanese Pharmacopoeia, and the first solution was used as the test solution.

[0041]

[Table 1]

According to the results shown in Table 1, the solid pharmaceutical composition of the present invention, whether the dosage form is tablet or granule,
While the disintegration time was remarkably shortened respectively, when only the water-swellable excipient was added (Comparative Examples 1 and 4),
Regardless of the dosage form, the case where only the sugar component was added (Comparative Examples 2 and 3) and the case where the water-swellable excipient and the sugar component were added without the drug being granulated (Comparative Example 5) In any case, it is recognized that the disintegration time is hardly shortened. Further, the solid chemical composition of the present invention,
It is recognized that the disintegration time is shortened even in the case of tablets and granules even when the amount of the excipient is small.

Therefore, in the case of the solid pharmaceutical composition of the present invention,
When the water-swellable excipient was added alone or the sugar component was added alone, the effect was not observed, and it was confirmed that the coexistence of both has a remarkable synergistic effect.

In order to investigate the influence of the total amount of the water-swellable excipient and the sugar component, tablets were produced by the same production method as in Example 1 with the composition shown in Table 2, and each tablet was prepared. Disintegration time was measured as above. The results are also shown in Table 2.

[0045]

[Table 2]

According to the results of Table 2, in the case of the above test example,
The total amount of the water-swellable excipient and the sugar component is 4% of the total amount of the drug, and the disintegration property is improved by 4% of the total composition, and 7% or more of the total amount of the drug is added. It is recognized that the effect is particularly remarkable when it is 6% or more with respect to the entire composition.

[Example 3] Ethenzamide and allylisopropylacetylurea were used as poorly water-soluble drugs, and they were fluidized and granulated, and mannitol and crospovidone were added to the tablets.

That is, 2500 g of etenzamid and 300 g of allylisopropylacetylurea were charged into a fluidized granulator (spiral flow type), and 120 g of polyvinylpyrrolidone (K30) was dissolved in 2000 g of water in advance to obtain a binder solution having the following composition. To obtain a granulated product. Granules 2 sieved using a 1400 μm sieve
30 parts of anhydrous caffeine, 100 parts of acetaminophen, 20 parts of crospovidone and 10 parts of mannitol are added to 93 parts, and these are mixed for 20 minutes using a V-type mixer, and further 3 parts of magnesium stearate are added. The mixture was mixed for 3 minutes and tabletted with a rotary tableting machine (clean press) to obtain a football-type tablet having a tablet weight of 456 mg, a major axis of 17 mm and a minor axis of 7 mm and having the following composition. When the disintegration time of this tablet was measured in the same manner as above, the disintegration time was 1.7 minutes. Composition ethenzamide 250 parts 30 parts Allylisopropylacetylurea polyvinylpyrrolidone K30 13 parts 100 parts of anhydrous caffeine, 30 parts acetaminophen crospovidone 20 parts of mannitol, 10 parts 3 parts Total 456 parts of magnesium stearate

Example 4 Alclofenac, ethenzamide and allyl isopropyl acetylurea were used as poorly water-soluble drugs, and these were fluidized and granulated, and carboxymethyl cellulose calcium and mannitol were added to the tablets.

That is, 500 g of alclofenac, 500 g of etenzamid and 300 g of allylisopropylacetylurea were charged into a fluidized granulator (spiral flow type),
200 g of polyvinylpyrrolidone (K30) in advance
A binder solution dissolved in 0 g of water was sprayed so as to give a predetermined amount of the following composition to obtain a granulated product. 25 parts of anhydrous caffeine, 20 parts of carboxymethyl cellulose calcium and 20 parts of mannitol were added to 133 parts of the above granules sieved using a 1400 μm sieve, and these were mixed for 20 minutes using a V-type mixer, and further, A mixture was prepared by adding 2 parts of magnesium stearate and mixing for 3 minutes, and the mixture was tableted with a rotary tableting machine (clean press) to give a tablet weight of 190.
mg, a round tablet having a diameter of 7 mm and having the following composition was obtained.
The disintegration time of this tablet was 1.6 minutes. Composition alclofenac 50 parts ethenzamide 50 parts Allylisopropylacetylurea 30 parts of polyvinyl pyrrolidone K30 3 parts of anhydrous caffeine, 25 parts carboxymethylcellulose calcium 20 parts of mannitol, 10 parts 2 parts Total 190 parts of magnesium stearate

Example 5 Ketoprofen and allylisopropylacetylurea were used as two poorly water-soluble drugs, and these were fluidized and granulated, and mannitol, carboxymethylcellulose calcium and crystalline cellulose were added to obtain granules. The capsules were filled to obtain capsules.

That is, 500 g of ketoprofen and 300 g of allylisopropylacetylurea were charged into a fluidized granulator (spiral flow type), and 100 g of polyvinylpyrrolidone (K30) was dissolved in 2000 g of water in advance to obtain a binder solution having a predetermined amount of the following composition. To obtain a granulated product. 20 parts of carboxymethyl cellulose calcium, 10 parts of crystalline cellulose, and 20 parts of mannitol are added to 133 parts of the above granules sieved using a 850 μm sieve.
No. 2 part was added, and these were mixed for 20 minutes using a V-type mixer, then dry granulated by a roll compression method, 2 parts of magnesium stearate was further added and mixed for 3 minutes, and then filled into a No. 2 hard capsule. Then, a hard capsule having the following composition was obtained. The disintegration time of this capsule was 2.8 minutes. Composition Ketoprofen 50 parts Allylisopropylacetylurea 30 parts of polyvinyl pyrrolidone K30 3 parts of carboxymethyl cellulose calcium 20 parts of crystalline cellulose and 10 parts of mannitol, 20 parts of 2 parts Total 135 parts of magnesium stearate

[Embodiment 6] Ethenzamide and allylisopropylacetylurea were selected as the poorly water-soluble drugs,
These were individually fluidized and granulated, and mannitol and crospovidone were added thereto to make tablets.

That is, 2000 g of etenzamid was charged into a fluidized granulator (spiral flow type), and 100 g of polyvinylpyrrolidone (K30) was previously dissolved in 2000 g of water and sprayed with a binder solution to give a predetermined amount of the following composition: A granulated product was obtained. Next, 300 g of allylisopropylacetylurea was granulated in the same manner as above using a table-top fluidized granulator, and each granulated product was sieved using a 1000 μm sieve to give granules, and the mixing ratio of each granule was 20:30. 30 parts of anhydrous caffeine and 10 parts of acetaminophen to 243 parts of the mixed granules mixed by using a V-type mixer so that
0 parts, crospovidone 20 parts and mannitol 10 parts were added, these were mixed for 20 minutes using a V-type mixer, and further 3 parts of magnesium stearate were added and mixed for 3 minutes. Tableted with a clean press), tablet weight 406 mg, major axis 16 mm, minor axis 6 mm
A tablet having the following composition, which is a football type, was obtained. The disintegration time of this tablet was 1.3 minutes. Composition ethenzamide 200 parts of polyvinyl pyrrolidone K30 11.3 parts 30 parts Allylisopropylacetylurea polyvinylpyrrolidone K30 2.7 parts 100 parts of anhydrous caffeine, 30 parts acetaminophen crospovidone 20 parts of mannitol, 10 parts 3 parts Total 406 parts of magnesium stearate

Example 7 Ketoprofen and allylisopropylacetylurea were selected as poorly water-soluble drugs, and these were dry granulated by a roll compression method to obtain mannitol, carboxymethylcellulose calcium and low-substituted hydroxypropylcellulose (substitution 10.5%)
Was added to form granules, which were filled into capsules to obtain capsules.

That is, lactose (50 g) was added to ketoprofen (500 g) and allylisopropylacetylurea (200 g), and these were uniformly mixed with a V-type mixer, and then dry-granulated with a roll-type granulator (roller compactor type) to granulate. I got a thing. To 75 parts of this granulated product, 20 parts of carboxymethyl cellulose calcium, 10 parts of low-substituted hydroxypropyl cellulose (substitution degree 10.5%) and 20 parts of mannitol were added, and 20 parts of these were mixed using a V-type mixer.
The mixture that had been mixed for a minute was dry-granulated by a roll compression method to give a granulated product, and the granulated product was sieved using a 850 μm sieve to give granules. The mixture for 1 minute was filled in a No. 2 hard capsule to obtain a hard capsule having the following composition. The disintegration time of this capsule was 5.5 minutes. 20 parts Composition Ketoprofen 50 parts Allylisopropylacetylurea 20 parts of lactose and 5 parts of carboxymethyl cellulose calcium low-substituted hydroxypropylcellulose 10 parts (degree of substitution 10.5%) 20 parts hydrogenated castor oil 5 parts Total 130 parts of mannitol

Continuation of the front page (51) Int.Cl. ⁶ Identification number Office reference number FI Technical display location A61K 47/26 A61K 47/26 Z 47/32 47/32 B Z 47/38 47/38 B Z (72) Inventor Masayuki Toda 1-3-7 Main Office, Sumida-ku, Tokyo Inside Lion Corporation

Claims (4)

[Claims] 1. A granulated product containing two or more kinds of poorly water-soluble drugs or two or more kinds of granulated products each containing a poorly water-soluble drug. A solid chemical composition characterized by being blended with one or more sugar components selected from sugar alcohols. 2. The solid chemical composition according to claim 1, wherein the poorly water-soluble drug has a solubility in water at 30 to 40 ° C. of 1 (g / 100 g water) or less. 3. A water-swellable excipient selected from the group consisting of crystalline cellulose, low-substituted hydroxypropylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, sodium carboxymethylcellulose crosslinked body, carboxymethylethylcellulose and polyvinylpyrrolidone crosslinked body, or The solid chemical composition according to claim 1, which comprises two or more kinds. 4. A granule containing two or more kinds of water-insoluble drugs or a water-swelling excipient and sugar in two or more kinds of granules each containing a water-insoluble drug, respectively. A method for producing a solid chemical composition, which comprises blending with one or more sugar components selected from sugar alcohols.