WO1998024410A2

WO1998024410A2 - Controlled release matrix tablet and method for its preparation

Info

Publication number: WO1998024410A2
Application number: PCT/JP1997/004385
Authority: WO
Inventors: Yoshinobu Fukumori; Hideki Ichikawa; Yoshitaka Mikami
Original assignee: Schering-Plough Kabushiki Kaisha
Priority date: 1996-12-03
Filing date: 1997-12-02
Publication date: 1998-06-11
Also published as: AU5135898A; WO1998024410A3

Abstract

A controlled release matrix tablet comprising agglomerates of raw pharmaceutical particles, wherein said agglomerates are formed by coating said raw pharmaceutical particles with a binder and have an average particle diameter of not less than 25 νm but less than 200 νm, and a method for preparing such tablets. The tablet has a higher content of an active ingredient, can be produced by handling the active ingredient-containing particles in a tableting step in essentially the same manner irrespective of the differences in the physical properties of raw pharmaceutical particles, and exhibits a moderate sustained release property of the active ingredient after tableting.

Description

DESCRIPTION Controlled Release Matrix Tablet and Method for Its Preparation Technical Field

The present invention relates to a controlled release matrix tablet and a method for preparing it, more particularly to a controlled release matrix tablet comprising agglomerates of raw pharmaceutical particles, wherein said agglomerates are formed by coating said raw pharmaceutical particles with a binder and have an average particle diameter of not less than 25 β m but less than 200 β m, as well as a method for preparing such tablets.

Background Art

Controlled release tablets can stably and continuously release an active ingredient over a long period of time and thus reduce the dosing frequency, thereby reducing the burden on the part of patients and achieving the maximum effect of the pharmaceuticals administered.

Among these controlled release tablets, a matrix type of tablets is generally produced by forming raw pharmaceutical particles into controlled release-type agglomerates by a suitable process, mixing the agglomerates with auxiliary additives, and then compressing the mixture into a tablet having a desired shape, size and weight.

Japanese Patent Laid-Open Publication No. Sho 63-39811 discloses a sustained release granules-containing tablet which is formed from active ingredient-containing sustained release granules and auxiliary additives by compression tableting, characterized in that the auxiliary additives and/or a mixture thereof with an active ingredient is preliminarily coated on the granules in layers. This design is intended to maintain the integrity of the individual granules by forming a protective film of the layers of the auxiliary additives, such as excipient, binder and disintegrator, on the external surfaces of the sustained release granules, thereby avoiding a fusion, deformation or destruction of the granules which may occur when they are being compressed into a tablet.

Japanese Patent Laid-Open Publication No. Hei 8-40905 merely discloses a sustained release pharmaceutical composition which is formed by mixing diamorphine with a mixture of release-improving components such as hydrophobic carriers or diluents under mechanical agitation in a high shear mixer to form a matrix comprised of the hydrophobic and meltable carrier or diluent in which diamorphine is dispersed.

However, Japanese Patent Laid-Open Publication No. Sho 63-39811 merely discloses use of sustained release granules prepared by a cylindrical granulator with a 0.5 mm screen, while Japanese Patent Laid-Open Publication No. Hei 8-40905 discloses use of granules passing through a mesh with a size of 0.1-3.0 mm. Such relatively large particles experience a high pressure at the time of compression tableting and the coating thereon is damaged so that a sufficiently sustained release property cannot be achieved.

Japanese Patent Laid-Open Publication No. Sho 62-70322 discloses a tablet comprising an active ingredient and a carrier and exhibiting a controlled delayed release of the active ingredient, said tablet being formed by compressing the active ingredient-containing particles having a particle size of 10-500 micron.

This tablet is produced by a process comprising dissolving an emulsion polymer having a certain particle size together with the active ingredient in an appropriate organic solvent, forming a thin layer with the resulting solution, removing the solvent to form a film, and then pulverizing the film into particles having a desired size. Therefore, the tablet is not such that it is formed by applying a coating solution to raw pharmaceutical particles as they remain in the solid state. In the particles prepared in such a manner, the active ingredient is not necessarily embedded in the film and thus the physical properties of the active ingredient may not only directly affect the preparation processes such as tableting but also cause such a problem that an unfavorable solvent has to be used depending on the solubility of the active ingredient.

In the "Symposium on Pharmaceutical Preparation and Particle Design" held by the Pharmaceutical Preparation and Particle Design Section of the Particle Technology Society at Nagaragawa International Convention Hall, Gifu, November 6 to 7, 1996, Tsujimoto et al have reported in the panel discussion titled "12 Preparation of Micronuclear Particles by means of a Fluidized Bed Agglomerating Processor 'Agromasta' Equipped with a Countercurrent Type Pulse Jet Dispersion System and Limitations of Microagglomeration by Coating" that agglomerates having the average particle diameter of 33.7 were formed by spraying an aqueous hydroxypropyl cellulose solution onto finely divided core pharmaceutical particles having an average particle diameter of 5 /m or less using a fluidized bed agglomeration coating processor to agglomerate the particles.

However, neither the availability of these agglomerates for producing a controlled release matrix tablet nor the concrete means for producing the controlled release matrix tablet in practice have been reported.

Further, in the same symposium, Naka et al have reported in the discussion titled "3 Design of Core Pharmaceutical Powder-Based Nuclear Particles" that agglomerates having an average particle diameter of about 110 to 180 m were formed by spraying hydroxypropyl cellulose or Aquacoat® as a binder onto finely divided core pharmaceutical particles having an average particle diameter of 5 β m or less using a rolling fluidized bed agglomerating processor. They suggested that this technique may be a useful means in designing functional particles for controlled release preparation. However, they taught no concrete means for producing the controlled release matrix tablet in practice.

Disclosure of the Invention

An object of the present invention is to provide a controlled release matrix tablet which has a higher content of an active ingredient, which can be produced by handling the active ingredient- containing particles in a tableting step in essentially the same manner irrespective of the differencies in the physical properties of raw pharmaceutical particles, and that exhibits a moderate sustained release property of the active ingredient after tableting. Another object of the present invention is to provide a method for preparing such a controlled release matrix tablet.

The present invention relates to a controlled release matrix tablet and a method for preparing it, more particularly to a controlled release matrix tablet comprising agglomerates of raw pharmaceutical particles, wherein said agglomerates are formed by coating said raw pharmaceutical particles with a binder and have an average particle diameter of not less than 25 m but less than 200 μ m, and a method for preparing such tablets. Brief Description of the Drawings

Fig. 1 is a schematic view of the spouted bed coating processor equipped with a draft tube which was used in the Examples of the present invention. Fig. 2 is a graph showing the effect of binder level on Cumulative undersize distributions of the microagglomerates (MG-4) which were used in Example 6. Binder applied (% by weight): O. 0; • • 12.5; Δ, 25; A, 37.5; Q. 50.

Fig. 3 is a graph showing the effect of the amount of plasticizer on the change of average particle diameter of microagglomerates. Plasticizer applied (% by weight): O, 0; •, 8; Δ, 10.5; A, 13.

Fig. 4 is a graph showing the elution of acetaminophen from tablets composed of microagglomerates prepared with a binder but without a plasticizer (MG-1). Tablet Hardness (kg): O. 4; Δ, 6; □. 8.

Fig. 5 is a graph showing the effect of the amount of plasticizer on acetaminophen release from tablets composed of microagglomerates. Plasticizer applied (% by weight): O. 0; •, 8; Δ, 10.5; A, 13.

Fig. 6 is a graph showing the effect of pH of elution fluid on acetaminophen release from tablets composed of microagglomerates (MG-

2). Tablet hardness (kg): O Φ , 4; ΔA . 6; □■ , 8. Open symbols, disintegration 1st fluid (pH 1.2), closed, disintegration 2nd fluid

(pH 6.8).

Fig. 7 is a graph showing the effect of binder level on acetaminophen release from tablets composed of MG-2A and MG-2B. Tablet hardness (kg): O , 4; ΔA , 6; □■ . 8. Binder applied (% by weight): Open symbols, 25; closed, 50. Description of the Preferred Embodyments

The agglomerates used for the tablets of the present invention may generally have an average particle diameter of not less than 25#m but less than 200, preferably 25 to 100 m, more preferably 30 to 70 β m , and most preferably 30 to 60 β m.

The agglomerates are formed by coating the raw pharmaceutical particles with a binder preferably by wet spraying. The amount of the binder to be applied may range preferably from 25 to 75 % by weight, more preferably from 35 to 65 % by weight and most preferably from 40 to 60 % by weight, based on the weight of the raw pharmaceutical particles .

The coated binder layer may also contain a plasticizer. The amount of the plasticizer to be contained may range preferably from 5 to 15 % by weight and more preferably from 7 to 13 % by weight, based on the weight of the binder.

These agglomerates may be formed into a tablet at such a compression pressure that the formed tablet has a hardness ranging preferably from 4 to 10 kg, more preferably from 5 to 9 kg.

In the present invention, the tablet may be formed from these agglomerates alone, but preferably in combination with a fluidizing agent .

In a preferred embodiment, the tablet of the present invention is formed by compressing the agglomerates in the presence of a fluidizing agent at such a compression pressure that the formed tablet has a hardness of 4 to 10 kg, said agglomerates having an average particle diameter of 25 to 100 m and containing a binder in an amount of 25 to

75 % by weight based on the weight of the raw pharmaceutical particles, as well as a plasticizer in an amount of 5 to 15 % by weight based on the weight of the binder.

In a more preferred embodiment, the tablet of the present invention is formed by compressing the agglomerates in the presence of a fluidizing agent in an amount of 0.1 to 5 % by weight based on the weight of the agglomerates at such a compression pressure that the formed tablet has a hardness of 5 to 9 kg, said agglomerates having an average particle diameter of 30 to 70 m and containing a binder in an amount of 35 to 65 % by weight based on the weight of raw pharmaceutical particles, as well as a plasticizer in an amount of 7 to 13 % by weight based on the weight of the binder.

In the most preferred embodiment, the tablet of the present invention is formed by compressing the agglomerates in the presence of a fluidizing agent in an amount of 0.2 to 3 % by weight based on the weight of the agglomerates at such a compression pressure that the formed tablet has a hardness of 5 to 7 kg, said agglomerates having an average particle diameter of 30 to 60 β m and containing a binder in an amount of 40 to 60 1 by weight based on the weight of raw pharmaceutical particles, as well as a plasticizer in an amount of 6 to 10 % by weight based on the weight of the binder. The raw pharmaceutical particles which may be used in the present invention can be any of solid pharmaceutical particles, so long as they do not melt at the temperature applied during agglomeration and are slightly-soluble in the solvent that is present during the agglomeration. Examples of the raw pharmaceutical particles include central nervous system drugs such as diazepam, aspirin, ibuprofen, paracetamol, naproxen, piroxicam, diclofenac, indometacin, sulindac, lorazepam, nitrazepam, phenytoin, acetaminophen, ethenzamide and ketoprofen; circulatory system drugs such as molsidomine, vinpocetine, propranolol, methyldopa, dipyridamole, furosemide, nifedipine, atenolol, pindolol and captopril; respiratory system drugs such as amlexanox, dextromethorphan, theophylline, pseudoephedrine and salbutamol; digestive system drugs such as cimetidine, ranitidine, pancreatin, 5-amino salicylic acid and prednisolone; antibiotics such as cefalexin, cefaclor, cefradine, amoxicillin, erythromycin, lincomycin and trimethoprim; metabolic system drugs such as serrapeptase and glibenclamide; and vitamin drugs such as vitamin B1, vitamin B2, vitamin B6, vitamin B12, vitamin C and fursultia ine. The average particle diameter of such raw pharmaceutical particles is less than 25 β m, preferably 1 to 20 β m and more preferably 1 to 10 β m. The raw pharmaceutical particles may be obtained by, for example, pulverizing drug crystals with a hammer mill in the usual manner.

The binders which may be used in the present invention can be any of the substances that promote the adhesion between the raw pharmaceutical particles and which do not adversely affect the pharmaceutical efficacy of the particles and which also give a controlled release property to the final tablet. Examples of the binder include cellulose derivatives such as ethyl cellulose, shellac, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl cellulose and hydroxyethyl cellulose; and acrylic copolymers. Among these, hydroxypropyl cellulose and hydroxyethyl cellulose are water-soluble binders but they may be used for mixing with water-insoluble or slightly water- soluble binders in an appropriate ratios to obtain a desired controlled release property. The binders are preferably polymeric latexes. The binder is usually sprayed in a liquid form on the surface of the raw pharmaceutical particles. Examples of a solvent for the binding liquid include water and ethanol, but water is especially preferable. A latex type of aqueous dispersion of ethyl cellulose is a particularly preferable binding liquid. Specific examples include Aquacoat® (Asahi Chemical Industry), Eudragit L30D and Eudragit RS30D (Rheme Pharma) .

Concentration of a binder contained in the binding liquid may be

5 to 30 % by weight, preferably 10 to 30 1 by weight, more preferably

15 to 25 % by weight, based on the total weight of the liquid.

The binding liquid may contain a plasticizer. Examples of the plasticizer include triethyl citrate, acetylated monoglyceride, diethyl phthalate and Triacetin (Wako Pure Chemical). Triacetin is especially preferable. Concentration of a plasticizer contained in the binding liquid may be 0.1 to 5 % by weight, preferably 0.5 to 4 % by weight, more preferably 1 to 3 % by weight, based on the total weight of the liquid. Various additives other than binder and plasticizer which are well-known in the art may be contained in the binding liquid. The additives may be contained in one or more separate liquids from the binding liquid to be coated on the raw pharmaceutical particles. A fluidizing agent may be present during agglomerating. Examples of the fluidizing agent include light silicic anhydride, talc and magnesium stearate. Light silicic anhydride is especially preferable.

Specific examples include Aerosil #200 (Japan Aerosil). The amount of the fluidizing agent which is to be added to the raw pharmaceutical particles may be 0.1 to 5 % by weight, preferably 1 to 4 % by weight and more preferably 1.5 to 3 % by weight based on the weight of the raw pharmaceutical particles.

The agglomeration step may be carried out in any manner, so long as the raw pharmaceutical particles can be adhered one to another. However, the agglomeration is generally carried out by means of wet spraying. Exemplary wet spraying methods include fluidized bed, spouted bed, rolling fluidized bed and centrifugal fluidized bed methods. The spouted bed method is preferable and draft tube-equipped spouted bed method (Waster method) is especially preferable.

The agglomeration by means of the draft tube-equipped spouted bed method is carried out as follows, for example:

First, raw pharmaceutical particles are premixed with a fluidizing agent and the resulting mixture is fed into a draft tube- equipped spouted bed coating processor. Air heated to a specified temperature is then introduced into the processor to fluidize the mixture. The inlet air temperature ranges from 30 to 90 °C , preferably from 50 to 80°C and more preferably from 60 to 70 °C . Next, a binding liquid is sprayed onto the fluidized particles. When a polymer is used as the binder, the softening temperature (Ts) of the polymer should not be lower than the inlet air temperature since blocking of the particles may occur at early stage of the operation due to the softening of the polymer which occurs if the softening temperature of the polymer is lower than the inlet air temperature. On the other hand, if the softening temperature of the polymer is considerably higher than the inlet air temperature, the final tablet is apt to disintegrate. Thus, it is also required that the softening temperature of the polymer be close to the inlet air temperature. This requirement can be met by adding the above plasticizer to the binding liquid to lower the softening temperature of the polymer. In this case, it is desirable that the difference between the inlet air temperature and the softening temperature is 5 to 1 0 °C .

After spraying, the particles are dried to produce agglomerates which can be shaped to form a tablet.

The tableting step may be carried out by means of compression tableting by, for example, a conventional method using a rotary tableting machine and the like. The compression tableting can be carried out at such a compression pressure that the formed tablet has a hardness of 4 to 10 kg, preferably 5 to 9 kg. In the compression tableting, it is desirable to add a fluidizing agent such as light silicic anhydride to prevent sticking during the tableting. Light silicic anhydride is preferably used as the fluidizing agent.

Examples of the light silicic anhydride include Aerosil. The amount of the fluidizing agent to be added to the agglomerates is 0.2 to 2 % by weight, preferably 0.5 to 1 % by weight based on the weight of the agglomerates.

In the compression tableting, excipients such as lactose, crystalline cellulose and starch, disintegrators such as hydroxypropyl cellulose and carboxymethyl cellulose having a low degree of substitution, lubricants such as talc, absorbefacients such as quaternary ammonium salts and sodium lauryl sulfate, humectants such as glycerin, and other pharmaceutically acceptable additives may be added to the agglomerates to such an extent that they do not adversely affect the controlled release property of the final tablet. Alternatively, these additives may be added to the binding liquid which is used in the agglomeration step such that they are contained in the agglomerates.

The following examples are provided for purposes of illustration only, and are not intended to limit the scope of the invention. Examples 1 to 6 1. Materials

Acetaminophen crystals were pulverized once with a hammer mill to prepare a model pharmaceutical powder. The pulverized particles had an average particle diameter of 7 m. A latex-type aqueous dispersion of ethyl cellulose (Aquacoat® , Asahi Chemical Industry) was used as a binder; Triacetin (Wako Pure Chemical) as a plasticizer; and light silicic anhydride (Aerosil #200, Japan Aerosil) as a fluidizing agent . 2. Preparation of microagglomerates

Preparation of agglomerates was achieved with a 3 inch draft tube-equipped spouted bed coating processor (NQ-GM, Fuji Paudal). 250 g of the pulverized acetaminophen and 5 g of Aerosil were mixed. The resulting mixture was fed into the processor and then sprayed with a binding liquid to effect agglomeration. Sampling was made for each spraying of a divided amount of the binding liquid. The spraying was stopped when the amount of the applied binder of the sample after drying reached 50 % by weight based on acetaminophen. Then the whole product was dried in the product container for 10 minutes. Fig. 1 shows an outline of the draft tube-equipped spouted bed coating processor. The chamber consists of two portions: the lower cylindrical product container (0.14 m diameter, 0.20 m depth) and the upper conical flared chamber (0.43 m height). Both parts are made of stainless steel with a view port made of a transparent acrylic resin. An inner cylindrical draft tube (0.07 m inner diameter, 0.20 m height) was positioned at a height of 0.03 m from an air distributor. A pneumatic spray nozzle with a liquid outlet caliber of 0.6 mm and a laminated bagfilter with about 1 β m openings were set throughout all experiments.

3. Measurement of particle size distribution

Laser light scattering-type particle size distribution measuring apparatus (LDSA-2400A, Tohnichi Computer Applications) was used. Aerosil was added to each sample in an amount of 1 % by weight prior to measurement. The average particle diameter was determined as cumulative undersize 50 % diameter.

4. Measurement of angle of repose

Three-wheel cylinder rotary-type apparatus for measuring the angle of repose (Tsutsui Rikagaku) was used.

5. Tableting

Light silicic anhydride was added to the agglomerates in an amount of 0.5 % by weight and the resulting mixture was formed into tablets each weighing 300 mg using punches with a diameter of 11 mm and flat faces and round edges, using a rotary tableting machine (RT-

S-9, Kikusui Seisakusho).

6. Elution test

Elution test was carried out according to a 12 Paddle method of Japanese Pharmacopoeia (JP). The 1st (pH 1.2) or 2nd (pH 6.8) fluid, jp was used as a test fluid. One tablet was weighed and immersed in 900 ml of the test fluid and the paddle was rotated at 100 rpm. Samples of the fluid were collected for quantitative determination at certain time intervals and absorbance was measured at 242 nm for the samples. Unless otherwise stated, the 2nd fluid was used as the test fluid.

Table 1 shows the formulations of the spray liquid and the operating conditions. Table 1 Formulations and Operating Conditions in the Microagglomeration Process

MG-1 MG-2 MG-3 MG-4

Raw material: acetaminophen (g) 250

Spray dispersion: Aquacoat ® (g) ^a) 125 125 125 125 Triacetin (g) 0 10 13.125 16.25 Water (g) ad. ad. ad. ad. Total (g) 625 625 625 625 Aqu. /Raw mat . (wt%) 50 50 50 50 Tri./Aqu. (wt%) 0 8 10.5 13

Softening temperature 107 80 72 65 of cast f ilm(°C )

Operating conditions:

Inlet air temperature (°C ) 60 60 60 60 Outlet air temperature(°C ) 23-25 23-26 23-24 23-24 Inlet air rate (m³/min) 0.06-0.11 0.06-0.12 0.06-0.12 0.07-0.13 Liquid flow rate (ml/min) 3.4-4.8 3.4-4.8 3.4-4.8 4.8-5.7 Spray air pressure (atm) 3.0 3.0 3.0 3.0 Spray air rate (1/min) 68 69 69 69

Product :

Yield (%) 101 96 101 103

Average particle 57 48 39 36 diameter( β m) Angle of repose (° ) 35 35 35 36 a) dry basis As can be seen from Table 1, the softening temperature of the binder changed to 80, 72 and 65°C when the plasticizer Triacetin was added to the binder Aquacoat, the cast film of which had a softening temperature of 107 °C , in respective amounts of 8, 10.5 and 13 % by weight based on the solid matter of the polymer.

Fig. 2 shows the particle size distribution of the agglomerate

MG-4 which was obtained by using Aquacoat, the softening temperature of which was changed to 65 °C . The average particle diameter of the agglomerates was 36 β m at a 50 wt% coating level of the binder. It can be seen from Fig. 2 that the particle size increases with increasing binder level up to 25 % by weight while the rate of the particle growth slows down after exceeding 25 % by weight. Thus, it is suggested that the binder contributes to the formation of agglomerates at the early stage of the agglomerating process but to the formation of coating rather than agglomeration after the binder level exceeds 25 % by weight. Fig. 3 shows the change of average particle diameter of microagglomerates. It is found from Fig. 3 that agglomeration of the particles had a tendency to proceed even at a binder level higher than 25 % by weight when a polymeric latex binder _Was used alone; when Triacetin was added, the agglomeration proceeded up to a 25 % by weight binder level and coating of the particles with the binder tended to proceed preferentially at a binder level higher than 25 % by weight. It was also found that the average particle diameter was within the range of from 30 to 70 m at the binder level of 50 % by weight.

Table 1 indicates that the microagglomerates of each Example have an angle of repose ranging from 35 to 36° and, hence, a sufficient fluidity for direct tableting. The agglomerate KG-1 which was agglomerated by using the polymeric latex binder alone was formed into three types of tablets having hardnesses of 4, 6 or 8 kg, and the tablets thus formed were subjected to an elution test. The test results are shown in Table 2 and Fig. 4.

Table 2 Results of Elution Test

Examples 1 2 3

Agglomerates MG- 1 MG- 1 MG-1

Triacetin (g) 0 0 0

Tablet hardness (kg) 4 6 8

Elution time (h) 2 \ ca.2 10 f

Table 2 and Fig. 4 show that all tablets having hardnesses of 4 and 6 kg disintegrated within two hours from the start of the elution test and that the elution of the acetaminophen in those tablets also completed within two hours. On the other hand, the tablets having a hardness of 8 kg exhibited a sustained acetaminophen release property and did not disintegrate even 10 hours after the start of the elution test. The elution of acetaminophen from the microagglomerates shown in Table 1 completed within several minutes from the start of the elution test in all runs, indicating that they could not exhibit any controlled release property without tableting.

Next, the agglomerates MG-2, 3 and 4 were compressed into tablets having a hardness of 6 kg and subjected to an elution test. Since a sticking tendency was noted when compressing the microagglomerates containing 13 % by weight of Triacetin, 0.5 1 by weight of Aerosil which is a fluidizing agent was added to all of the agglomerates to prevent sticking. The results are shown in Table 3 and Fig. 5.

Table 3 Results of Elution Test

Examples 4 5 6

Agglomerate MG-2 MG-3 MG-4

Tri./Aqu.(%) 8 10.5 13

Tablet hardness (kg) 6 6 6

Elution time (hr) 10 f 10 f 10 t

Table 3 shows that all of the tablets with the plasticizer maintain their shape under the elution test condition. As can be seen from Fig. 5, the inclusion of 13 % by weight of the plasticizer greatly suppressed the release of acetaminophen from the tablets.

Even when containing 8 or 10.5 % by weight of the plasticizer, those tablets exhibited a moderate sustained release property for practical purposes. There was no difference in elution profile between the two cases .

It was found from the above results that softening a binder by adding a plasticizer is effective in suppressing the disintegration of tablets .

Fig. 6 shows the profile of acetaminophen elution from the tablets formed from MG-2 in the 1st (pH 1.2) and 2nd (pH 6.8) fluids,

JP. There is no difference in the profile between the two cases.

Hence, it was found that the sustained release preparation of the present invention is scarcely affected by pH of the test fluid. Examples 7 to 12

In order to investigate the effect of the binder level on the drug release property, microagglomerates were prepared with the amount of the plasticizer fixed but varying the amount of the binder at 12.5, 25 and 50 % by weight .

Table 4 shows the formulations of the spray liquid and the operating conditions.

Table 4 Formulation and Operating Conditions in Microagglomeration Process at Various Binder Levels

MG-2A MG-2B MG-2C

Raw material: acetaminophen (g) 250

Spray dispersion: Aquacoat ® (g) ^a) 125 62.5 31.25 Triacetin (g) 10 5 2.5 Water (g) ad. ad. ad. Total (g) 625 312.5 156.25

Aqu./Raw mat. (wt%) 50 25 12.5 Tri./Aqu. (wt%)

Operating condition:

Inlet air temperature (°C ) 60 60 60 Outlet air temperature(°C ) 23-26 23-25 23-25 Inlet air rate (m³/min) 0.06-0.12 0.06-0.09 0.06-0.08 Liquid flow rate (ml/min) 3.4-4.8 3.4-4.8 4.0-4.8 Spray air pressure (atm) 3.0 3.0 3.0 Spray air rate (1/min) 69 66 65

Product : Yield (%) 96 102 100 Average particle 48 29 20 diameter( β m) Angle of repose (° ) 35 41 46

a) dry basis The agglomerates were compressed into tablets having the hardnesses of 4, 6 and 8 kg. The agglomerates with a binder level of 12.5 % by weight (MG-2C) experienced sticking and/or capping and hence could not be compressed into tablets. This would be because the agglomerates with the binder level of 12.5 % by weight had a poor fluidity in the tableting step due to the small average particle diameter of 20μm and the large repose angle of 46 ° .

Elution tests were carried out. The results are shown in Table 5 and Fig. 7. Table 5

Results of Elution Test

Examples 7 8 9 10 11 12

Agglomerates MG-2A MG-2A MG-2A MG-2B MG-2B MG-2B

Aqu./Raw mat.(wtZ) 50 50 50 25 25 25 Tablet hardness (kg) 4 6 8 4 6 8

Elution time (hr) 10f 10 f 10 f ca.8 10f 10 f

At the binder level of 25 % by weight, only the tablets having hardnesses of 6 and 8 kg exhibited a sustained release property. Thus, it was found that the release property was greatly affected by the hardness at a lower binder level. On the other hand, the tablets with the binder level of 50 1 by weight exhibited a moderate sustained release property, indicating that the drug release rate is less affected by the hardness at the binder level of 25 %. As can been seen from Fig. 3, the surfaces of the agglomerates with the binder level of 50 % by weight were more thickly coated with the binder than those with the binder level of 25 % by weight.

From the above results, it is concluded that in order to obtain a tablets exhibiting a moderate sustained release property at practical levels of hardness, not only it is required to agglomerate pharmaceutical particles but the agglomerates formed must also have a structure in which their surfaces are coated with a binder.

Claims

1. A controlled release matrix tablet comprising agglomerates of raw pharmaceutical particles, wherein said agglomerates are formed by applying a coating comprising a binder to said raw pharmaceutical particles and have an average particle diameter of not less than 25 m but less than 200 m.

2. The controlled release matrix tablet according to Claim 1, wherein the agglomerate has an average particle diameter of 25 to lOO m.

3. The controlled release matrix tablet according to Claim 1, wherein the agglomerate has an average particle diameter of 30 to 70 β m.

4. The controlled release matrix tablet according to Claim 1, wherein the agglomerate has an average particle diameter of 30 to 60 m.

5. The controlled release matrix tablet according to Claim 1, wherein the amount of the binder coated is 25 to 75 % by weight based on the weight of the raw pharmaceutical particles.

6. The controlled release matrix tablet according to Claim 1, wherein the amount of the binder coated is 35 to 65 % by weight based on the weight of the raw pharmaceutical particles.

7. The controlled release matrix tablet according to Claim 1, wherein the amount of the binder is 40 to 60 % by weight based on the weight of the raw pharmaceutical particles.

8. The controlled release matrix tablet according to Claim 1, wherein the coated binder layer further comprises a plasticizer.

9. The controlled release matrix tablet according to Claim 8, wherein the amount of the plasticizer is 5 to 15 % by weight based on the weight of the binder.

10. The controlled release matrix tablet according to Claim 8, wherein the amount of the plasticizer is 7 to 13 % by weight based on the weight of the binder.

11. The controlled release matrix tablet according to Claim 1, wherein the tablet hardness is 4 to 10 kg.

12. The controlled release matrix tablet according to Claim 1, wherein the tablet hardness is 5 to 9 kg.

13. A method for preparing a controlled release matrix tablet, which comprises: applying a coating comprising a binder to raw pharmaceutical particles to form agglomerates having an average particle diameter of not less than 25 μ m but less than 200 μm and compressing the agglomerates into tablets.

14. The method according to Claim 13, wherein the raw pharmaceutical particles are coated with the binder by wet spraying.

15. The method according to Claim 13, wherein the amount of the binder coated is 25 to 75 % by weight based on the weight of the raw pharmaceutical particles.

16. The method according to Claim 13, wherein the coated binder layer further comprises a plasticizer.

17. The method according to Claim 16, wherein the amount of the plasticizer is 5 to 15 % by weight based on the weight of the binder.

18. The method according to Claim 13, wherein the compression is carried out at such a compression pressure that the formed tablet has a hardness of 4 to 10 kg.

19. The method according to Claim 13, wherein the compression is carried out in the presence of a fluidizing agent.