JPH07316042A - Multiple unit type tablet - Google Patents

Abstract

PURPOSE:To obtain a tablet preparation of multi-unit type which is is composed of a powdery part and granules of indefinite form comprising primary granules including low-melting fat and the major active ingredient and release-controlling membranes wherein there occurs no uneven precipitation, when other units than the gradually releasing part are mixed, thus showing uniform distribution of the active ingredients and reduced damage in the membrane. CONSTITUTION:This tablet preparation is a granule of indefinite form comprising (A) a powdery part, (B) primary granules from a mixture of (i) a wax preferably melting at about 50-100 deg.C (particularly at 70-90 deg.C), fat and oil from triglycerides and higher fatty acid esters and (ii) the active ingredients at a weight ratio of (0.1-1)/1 and the primary granules are coated with (iii) a release- controlling membrane, preferably composed of an aqueous releasing coater such as an ethyl methacrylate and ethyl acrylate copolymer and talc.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to multiple unit tablets containing amorphous granules. More specifically, the multiple unit type tablet comprising a powder part and granules, the granules comprising elementary granules containing a low melting point oil and a main drug and a controlled release membrane, and the granules are amorphous (amorphous granules) Regarding

[0002]

2. Description of the Related Art Methods for controlling the release of sustained-release preparations, which control the drug release by modifying the preparation, include diffusion type, dissolution type, and chemical bond type. . The diffusion type includes a method of dispersing a drug in a wax as a matrix (matrix type) and a method of controlling a drug permeation rate by an insoluble polymer membrane (membrane permeation type). One type of membrane permeation type is a multiple unit formulation (New formulation development system integrated technology-development design edition (1986)).

[0003] The multiple unit preparation includes a controlled release unit (sustained release granule) in which elementary granules (subunits) are coated with a film, and when this is tableted to give tablets, the membrane is broken. Occurs, and the release control function is lost or changed. As a means for preventing this, spherical granules using spherical nuclei for elementary granules are generally used. This is because spherical granules tend to disperse the load against compression during tableting, and the contact area between the particles is minimized, resulting in less membrane breakage. This is because it is easy to coat and the non-uniform part is less likely to break.

Further, as a protective layer for a control film, an example in which a relatively large amount of a wax layer or fine particles of cellulose is coated on the upper layer to prevent contact between granules, or the like (Japanese Patent Laid-Open No. 4-2088)
9, JP-A-3-240724), there is seen a blending of an excessive amount of excipients or the like for imparting a pressure absorbing function to a normal quick release unit (quick release part) for a release control unit.

However, the tablets produced by these methods have various disadvantages in practical use even if the film breakage is small. First of all, in the production method using spherical granules, generally a core consisting of crystalline cellulose or sucrose has to be used, and this part usually reaches about 50% of the whole granules. This, together with providing many protective layers as a controlled release film, has led to an increase in the size of the unit dosage form. In addition, a decrease in the content of the main drug in the unit dosage form causes a problem of increasing the number of doses. Furthermore, when the release control unit is spherical, segregation is likely to occur during mixing with the quick release part, and it is difficult to obtain tablets having a uniform content of ingredients. Therefore, as a result of intensive studies to overcome the above-mentioned drawbacks, the present inventor has completed a multiple unit type tablet having no such drawbacks.

[0006]

DISCLOSURE OF THE INVENTION The present invention eliminates the above-mentioned drawbacks and membrane destruction by controlling the composition of elementary granules in the sustained-release granules, which are release controlling units, to make the granules amorphous. It has been found that tablets of small size can be obtained.

[0007] Elementary granules for producing amorphous granules are obtained by granulating a main drug and a small amount of low melting point oils and fats. The low-melting oils and fats blended during the production of the elementary granules form a matrix in a state of being coated with the main drug by being melted by heat.
The sustained-release granules obtained by coating the thus-obtained elementary granules with a release-controlling membrane have increased compression resistance even if they are of an irregular type, and they freely deform to absorb pressure during tableting. Avoid the destruction of. In addition, since the sustained-release granules are sized irregularly, segregation does not occur during mixing with units other than the sustained-release part, and tablets having a uniform content of components can be obtained.

[0008] Further, it is possible to granulate without using water because of the heat melting, and it is also suitable for a preparation containing a water-labile main drug.

The term "amorphous" as used herein means the shape of particles formed by increasing the surface roughness of particles, that is,
It means a shape having a large number of irregular projections. It may be particles having a large particle surface roughness obtained by crushing spherical particles or columnar particles formed into a regular shape. Atypical granules mean granules with such a surface state, and are characterized by the fact that there is no nucleus inside the granules when compared with spherical granules. The shape of the amorphous granules used in the present invention is not necessarily limited numerically, but if it is expressed using the specific surface area shape factor (φ '), for example, φ'
> 6, preferably in the range of 6.5-8.

As low-melting oils and fats, waxes such as animal, plant, mineral and petroleum natural waxes, synthetic waxes such as beeswax, spermaceti wax, carnauba wax, montan wax, microcrystalline wax, and triglycerides. As, cacao butter or wax of vegetable fats, or fish oil, hydrogenated hydrogenated oils of other animal and vegetable fatty oils, higher fatty acid esters, such as myristic acid, palmitic acid, stearic acid, glyceryl monostearate, monopalmitin Examples of higher fatty acid alcohols such as sorbitan acid include cetanol, stearyl alcohol, and lauryl alcohol. Further, as water-soluble polymers, macrogol, polyoxyethylene / polyoxypropylene glycol, polyoxyethylene lauryl ether, etc. , Shift also fats solids are exemplified at room temperature. The melting point of these fats and oils is 25 ° C. or higher, but from the viewpoint of stability and easy granulation, it is about 50 to 10
It is preferably 0 ° C, more preferably 70 to 90 ° C.

The amount of the active ingredient contained in the elementary granules is about 60% by weight or less in the unit dosage form, preferably 50 to 10% by weight, more preferably 40 to 20% in order to avoid enlargement of the unit dosage form. % By weight. The main drug used is not particularly limited. The amount of the low melting point oils and fats used is about 30 to 2% by weight, preferably 15 to 4% by weight, and more preferably 10 to 5% by weight in the unit dosage form. The ratio of the main drug and the low melting point oils and fats is about 1: 0.1 to 1 part by weight of the main drug.
1, preferably 1: 0.1 to 0.5, more preferably 1:
It is 0.1 to 0.3% by weight.

As the granulation method of elementary granules, a method of directly producing by a hot melt stirring granulation method using a Loedige mixer, a high speed mixer or the like, a wet cylinder granulation using a kneader or a granulator, Examples include a method in which the particles are sized irregularly and heat-melted in the vicinity of the melting point of the mixed fats and oils. In addition,
When granulating, if necessary, a suitable binder such as HP
A suitable lubricant such as C and PVP, magnesium stearate, etc. may be added.

"Amorphous granules" refer to elementary granules coated with a controlled release film. From the viewpoints of safety, residual solvent, etc., water-based sustained-release coating agents are preferable as release-controlling membrane components used as the sustained-release control membrane, such as ethyl cellulose latexes (Aquacoat (Asahi Kasei Co., Ltd.), etc.), ammonia blending type Examples thereof include ethyl celluloses (Suaresu (Colorcon Co., Ltd.)), methyl methacrylate / ethyl acrylate copolymers (Eudragid NE30D, RS30D, RL30D etc. (Rehm Co.)) and the like, with Eudragit NE30D being particularly preferable. is there. When a water-based sustained-release coating agent is used, it is used in combination with talc, and the mixing ratio thereof is 1: 2-4 by weight, preferably 1: 2.5-3.
Is exemplified. That is, for example, Eudragit NE-
30D has a low glass transition point and is a soft polymer even at room temperature, so it can be deformed at the time of compression, but when the film thickness is thin, it cannot withstand film breakage during tableting, and when it has a sufficient film thickness. May have a significantly reduced release rate. Therefore, if a large amount of talc is blended as a more preferable means for controlling release, desired release controllability can be obtained and there is no film breakage during tableting.

The required coating amount varies depending on the particle size of the elementary granules, the solubility of the main drug, the degree of sustained release, etc., but is usually about 15 to 35% by weight, preferably 20 to 3%, based on the elementary granules.
It is 0% by weight. In addition, by blending talc within the exemplified range, it becomes easy to achieve both release controllability and compression resistance, and it becomes possible to uniformly coat irregularly shaped granules.

Further, the blending of talc improves the ease of coating, for example, the well-known cohesiveness of granules during drying and storage stability. The thickness of the controlled release control film is
It is about 10 to 100 μm, preferably 20 to 80 μm, and more preferably 40 to 60 μm. The average particle size of the irregular granules is about 200 to 800 μm, preferably 400 to
It is 600 μm.

As a method for coating the sustained-release control film, no special equipment is required, and a conventional fluidized bed coating machine,
Ventilated pan coating machines can be used.

The "powder part" is composed of the same and / or different main drug component as the main drug contained in the sustained-release part, or a component other than the main drug, and rapidly disintegrates after administration to release the sustained-release unit. , If it contains the active ingredient,
These mean the part where the dissolution starts immediately. The powder part may contain an excipient, a disintegrating agent, a lubricant and the like used in a normal direct compression method, and the components thereof are not particularly limited. The mixing ratio of the sustained release part (amorphous granules) and the powder part is 1:
0.7 or more (weight ratio) is preferable, and the ratio of the powder part is 0.7.
In the following, contact between the sustained release parts occurs, and rapid disintegration and separation into subunits are less likely to occur. There is no particular upper limit to the amount of powder used. Mixing of the sustained release part and the powder part and tableting are not particularly limited, and they are carried out by an ordinary method using a well-known ordinary mixer and tableting machine. The tableting pressure is usually 0.6 to 1.6t, preferably 0.8 to 1.3t.
The target tablet can be obtained within this range. Since the obtained tablets do not change their release characteristics over time, they may be subjected to curing or further colored coating. Curing is preferably 70 ° C
This is done.

[0018]

【Example】

Example 1 A Lodige mixer (Matsuzaka Giken M2
0) and hot melt granulation were performed under the following conditions to obtain amorphous elementary granules having an average particle diameter of 500 μm. Acetaminophen 1050 g Hydrogenated castor oil 265 g Constant temperature bath temperature 100 ° C. Spindle speed 230 rpm Granulation time 20 minutes 1300 g of the obtained elementary granules was charged into a fluidized bed coating machine (Freund Sangyo FLO-1), and the composition shown below was used. The coating liquid (sustained release coating liquid) was sprayed under the following conditions to coat 30% of the elementary granules. Eudragit NE30D (30% dispersion liquid) 400 g Talc 360 g Purified water 1240 g Blower temperature 55 ° C Spray pressure 1.5 kg / cm ² Liquid speed 20 g / min Blower amount 2.5 m ³ / min

1 part by weight of the powder having the following composition was mixed with 1 part by weight of the obtained irregular-shaped granules, and the mixture was mixed with a tableting machine (Kikusui Seisakusho).
LIBRA 836K-AWCZ) was used for compression molding at a tableting pressure of 1.3 t to obtain tablets of φ9 mm, 340 mg / tablet. The dissolution test results of acetaminophen, which is an amorphous granule component before and after tableting, are shown in FIG. 1, and the results of the tablet hardness, disintegration time, weight variation and content uniformity tests are shown below. The test methods were all in accordance with the Japanese Pharmacopoeia general test method except for tablet hardness. Ethenzamide 450 g Anhydrous caffeine 250 Crawl phenylamine maleate 5 Dextromethorphan hydrobromide 80 Cresol potassium sulphate 400 Crystalline cellulose 235 Polyvinyl polypyrrolidone 200 Magnesium stearate 70 Tablet hardness 6.9 kg / tablet (measured by the Elwaker method) Disintegration time 2.5 minutes (37 ° C water) Weight change 1.2% Content uniformity Acetaminophen cv 1.52% Ethenzamide 1.48% Caffeine 1.61%

The elution rate after tableting shown in FIG. 1 shows no difference from the elution rate before tableting, and it can be seen that the sustained release membrane is not broken during compression molding. Further, the tablet strength has such strength that it can withstand ordinary distribution, and the rapid disintegration time indicates that it immediately returns to the original subunit after administration.
The results of weight variation and content uniformity tests were all good, and a clear effect was observed using atypical granules. High plain coater (Freund Sangyo HCT48)
After curing for 1 hour at 70 ° C, use water-soluble film base, Opadry (Colorcon Co.) for 8 m
Film coating of g / tablet was performed. The obtained film-coated tablet was stored at 45 ° C. for 3 months in a glass bottle tightly closed state, but no change was observed in the dissolution rate, and a multi-unit type tablet showing stable release characteristics was obtained.

Example 2 The components of the following composition were kneaded, extruded into a cylinder having a diameter of 0.7 mm, granulated and dried, and then irregularly crushed and granulated with a roll granulator (Nippon Granulator T-15). Particles having an average particle diameter of 500 μm were obtained. The obtained particles are placed in a fluidized bed granulator (Freund Sangyo FLO-1 type) and heat-melted at 85 ° C. for 1 hour to obtain elementary granules. Acetaminophen 1050 g Hydrogenated castor oil 350 HPC 30

Using the sustained-release coating solution and the coating method used in Example 1, the elementary granules were coated with 35% by weight. To 1 part of the obtained irregular-shaped granules, 1 part of a powder quick-release part having the following composition was mixed, and compression molding was carried out in the same manner as in Example 1. Table 1 shows the results of the dissolution test before and after tableting. As with Example 1, no change in the release characteristics due to tableting was observed. Acetaminophen 450 g Anhydrous caffeine 250 Chlorpheniramine maleate 5 Crystalline cellulose 350 CMC-Ca 100 Magnesium stearate 50

[Table 1] Elution rate of acetaminophen Step 15 minutes 1 hour 2 hours 4 hours 6 hours Before tableting 7.2% 37.0% 63.9% 83.1% 95.7% After tableting 9.7% 37 .1% 63.4% 80.4% 95.1%

Example 3 Ingredients having the following composition were charged in a Loedige mixer, and hot melt granulation was performed under the following conditions to obtain amorphous elementary granules having an average particle diameter of 450 μm. Acetaminophen 1200 g Stearyl alcohol 350 Constant temperature bath temperature 55 ° C Spindle speed 230 rpm RPM Granulation time 10 minutes

1500 g of the obtained elementary granules were charged into a FLO-1 type fluidized bed coating machine, and 28% by weight of coating liquid having the following composition was coated under the conditions shown in Example 1. Eudragit NE30D (30% dispersion liquid) 400 g Talc 420 Purified water 1300 To 1 part of the obtained irregular-shaped granules, 1 part of the powder prepared in Example 1 was mixed and tableted in the same manner as in Example 1. Table 2 shows the results of the dissolution test before and after tableting, but as in Examples 1 and 2, no change in the release characteristics due to tableting was observed.

[Table 2] Process 15 minutes 1 hour 2 hours 4 hours 6 hours Before tableting 5.0% 20.0% 34.7% 63.8% 82.0% After tableting 6.5% 22.4% 38. 0% 65.6% 84.8%

Comparative Example Spherical Avicel granules (Celphia, Asahi Kasei) were used as core granules, and a mixed powder having the following composition was coated and granulated with a centrifugal tumbling granulator (CF granulator Freund Sangyo). Nuclear granules Avicel granules 350 g Acetaminophen 600 Manitol 50 HPC 20

The obtained elementary granules were coated with the sustained-release coating solution used in Example 1 under the same conditions, and the powder part used in Example 1 was mixed at a ratio of 1: 1 and tableted. The results of the dissolution test before and after tableting are shown in FIG. 2, and the results of the content segregation test of acetaminophen and caffeine are shown below. Both the change in the content and the change in the elution rate due to the breakage of the release-controlling membrane are significantly larger than those of the examples of the present invention. Content fluctuation Acetaminophen cv 5.11% Caffeine 3.34%

[Brief description of drawings]

FIG. 1 is a graph showing changes in elution before and after compression of the amorphous granules obtained in Example 1.

FIG. 2 is a graph showing changes in elution before and after compression of spherical granules obtained in Comparative Example.

Claims (8)

[Claims] 1. A multiple unit type characterized by comprising a powder part and granules, the granules comprising elementary granules containing a low melting point oil and a main drug and a controlled release membrane, wherein the granules are amorphous (amorphous granules). tablet. 2. The tablet according to claim 1, wherein the weight ratio of the main drug and the low melting point oils and fats in the amorphous granules is in the range of 1: 0.1 to 1. 3. The tablet according to claim 1, wherein the controlled release film is a water-based sustained-release coating agent. 4. The tablet according to claim 1, wherein the controlled release film is composed of a water-based sustained-release coating agent and talc. 5. The tablet according to claim 4, wherein the water-based sustained-release coating agent is a methyl methacrylate / ethyl acrylate copolymer, and the weight ratio with talc is in the range of 1: 2-4. 6. The tablet according to any one of claims 1 to 5, wherein the mixing ratio of the powder part to the amorphous granule is 0.7 or more in weight ratio. 7. The amorphous granules contain one or more active agents and the powder part contains or does not contain one or more identical and / or different active agents.
7. The tablet according to any one of 6 to 6. 8. A multiple unit type tablet obtained by compression-compacting a mixture of low-melting oils and fats and an active ingredient, which is granulated and has an amorphous granule having a controlled release membrane and a powder part.