JPH0253721A - Tablet containing coated granule - Google Patents

Abstract

PURPOSE:To obtain the subject tablet resistant to the collapse of the coating film of coated granule in compression-molding by coating a coated granule further with a protecting coating film of a water-soluble or acid soluble polymer. CONSTITUTION:A coated granule, e.g., granule coated with an insoluble polymer, an enteric polymer or wax is coated with a protecting coating film of a water- soluble polymer (e.g., hydroxypropyl methylcellulose, polyvinyl pyrrolidone or gelatin) or an acid-soluble polymer (e.g., polyvinyl acetal diethylaminoacetate) and is compression-molded to obtain the objective tablet. The breakage of the coating film in the compression molding can be avoided and a tablet keeping expected releasing characteristic can be prepared.

Description

Detailed Description of the Invention [Field of Industrial Application] The present invention relates to tablets obtained by coating coated granules in a double layer with a water-soluble polymer or an acid-soluble polymer and then compression-molding the coated granules. , relates to a tablet containing double-coated granules, which prevents the coating of the coated granules from being destroyed when a pharmaceutical composition containing the coated granules is compression molded.

[Conventional technology and its problems]

Applying an enteric, acid-soluble or insoluble coating to the granules,
Adding various functions such as taste/odor concealment and sustained release properties is widely practiced. These coated granules can be provided as they are or filled into hard gelatin capsules or soft gelatin capsules, but when compressed into tablets, the coating is destroyed by the compression force and loses its function. It often changes. For this reason, when preparing a tablet-type sustained release preparation, we predict in advance that the coating will break due to compression, and coat it with an insoluble polymer to further suppress release. It is compressed into tablets. However, the breakage of the coating during compression molding depends on the condition of the coating, the properties of the uncoated area, etc., and is extremely difficult to predict. Therefore, the release characteristics of the resulting tablets cannot be predicted in advance. Often different.

(Means for Solving the Problems) Under these circumstances, the present inventor conducted intensive research regarding the damage to the coating when the coated granules were compression molded, and found that the coated granules were made of water-soluble polymer or acid-soluble polymer. The present invention has been completed based on the discovery that tablets coated and compressed can prevent the coating from breaking without impairing the properties and functions of the coated granules. The present invention provides a tablet containing coated granules obtained by molding, characterized in that the coated granules are further coated with a protective coating of a water-soluble polymer or an acid-soluble polymer.

The water-soluble polymer or acid-soluble polymer used in the present invention can withstand the compressive force during compression processing without substantially changing the function of the coat of the coated granules when administered in vivo. It has the role of protecting the coated granules. Therefore, the protective coating used in the present invention may be any water-soluble polymer or acid-soluble polymer that can fulfill the above role, and is not particularly limited, but as a preferable example, the water-soluble polymer is: Examples include hydroxypropyl methylcellulose, hydroxypropylcellulose, methylcellulose, polyvinylpyrrolidone, polyethylene glycol, gelatin, etc., and examples of the acid-soluble polymer include aminoalkyl methacrylate copolymer E5 polyvinyl acetal diethylaminoacetate. These polymers may be used alone or in combination of two or more, and when administered into a living body, they do not substantially impede the function of the coating of the coated granules and can withstand compressive force during compression processing. If it is possible to protect the coated granules so as to obtain them, they may be used in combination with enteric-coated, water-insoluble polymers or waxes.

The coating amount of the water-soluble polymer or acid-soluble polymer used in the present invention is not particularly limited, and is determined depending on the characteristics of the coated granules and the excipients to be tableted together. It is usually in the range of 5 to 50%.

To manufacture the tablets of the present invention, first, coated granules are coated with a water-soluble polymer or an acid-soluble polymer by a conventional method.
Make heavy coated granules. At that time, appropriate plasticizers, lubricants, colorants, etc. can be added as necessary. Next, the double-coated granules are mixed with a conventionally known tableting composition containing appropriate excipients, binders, disintegrants, lubricants, colorants, flavoring agents, stabilizers, etc., as required. It is manufactured by mixing it with other materials and compression molding it.

Furthermore, the coat of the coated granule is a sustained-release or enteric coat, and in order to obtain a certain level of blood concentration early after administration, the active drug can be incorporated into the protective coat or the uncoated granule.

Furthermore, the tablet of the present invention can be made into a dry-coated tablet, a multilayer tablet, a film-coated tablet, or a sugar-coated tablet by a commonly used method.

(Operation and Effect) The thus obtained tablet containing the coated granules of the present invention does not impair the function of the coating of the coated granules even when subjected to compression molding treatment due to the action of the water-soluble polymer or acid-soluble polymer coating. , it is possible to obtain the desired effect.

(Example) Examples of the present invention will be shown below to provide a detailed explanation of the present invention.

Example 1 Production of bare granules a: 800 g of diclozenaf sodium, 4 cornstarch
00g was mixed and pulverized to obtain a fine powder. Using 600 g of white sugar sized to a size of 28 to 35 mesh as a core, the fine powder was granulated while pouring a solution prepared by dissolving 25 g of hydroxypropyl cellulose in 475 g of ethyl alcohol to produce spherical granules, and dried at 55°C for 3 hours. do. The dry granules that pass through 16 meshes but do not pass through 35 meshes are designated as bare granules a.

Example 2 Manufacture of coated granules: 800 g of bare granules a produced in Example 1 were placed in a fluidized bed coating device, and a coating liquid 274 having the following composition was added.
Spray coating 6 g according to a conventional method to prepare coated granules. The amount of coating of this material is 2 for bare granules.
It was 3%.

Composition
% methacrylic acid copolymer 6
．． 5 talc 0.
2 μm Total 100.0 Example 3 Production of double coated granules C: 500 g of coated granules B produced in Example 2 were placed in a fluidized bed coating device, and coating liquid 13 having the following composition was added.
Spray coating with 89 g according to the usual method,
Heavy coated granules C are prepared.

The coating amount of this material was 20% of the coated granules.

Composition
% hydroxypropyl methylcellulose 6.
5 macrogol 6000 0.5 talc 0.2 ethyl alcohol 66.8 go
Total too.

Example 4 Production of tablets of the present invention 240 g of crystalline cellulose, 25 g of corn starch, 9 g of milk
Add 172.5 g of mixed powder to 10% (w/w) 50% ethyl alcohol solution of hydroxypropyl cellulose 12
5 g was added and kneaded to produce granules by a conventional method. Next, 203.6 g of these granules, 88.4 g of the double-coated granules Cl obtained in Example 3, 20 g of carboxymethyl cellulose calcium, 4 g of magnesium stearate, and 4 g of talc were uniformly mixed and then compression molded to give a weight of 400+ ng per tablet. A tablet of the present invention having a diameter of 10 mm was manufactured.

Example 5 Manufacture of comparative tablets: Mixed powder of 240 g of crystalline cellulose, 25 g of cornstarch, 172.5 g of lactose and 1 part of 50% ethyl alcohol i-solution of 10% (w/w) hydroxypropylcellulose
25 g was added and kneaded to produce granules by a conventional method. Then 203.6 g of this granule, coated granule b of Example 2
140.3 g, milk) 128.1 g, carboxymethylcellulose calcium 20 g, magnesium stearate 4 g, and talc 4 g were uniformly mixed and then compression molded to produce tablets with a weight of 400 mg and a diameter of 10 mm.

Example 6 The tablets of the present invention obtained in Example 4, the comparative tablets obtained in Example 5, and the coated granules were used as the eluate, and test solutions of pH 4 and 5 were used for 30 minutes from the start of the test. After 60 minutes, test solution with pH 6.8 (Japanese Pharmacopoeia - Part 1)
1 revision, 2nd solution) using the rotating paddle method (Japanese Pharmacopoeia -
(11th Amendment) Measured at 100 r, p, m. The results are shown in Table 1. The tablets of the present invention not only show no destruction of the coating unlike the comparative tablets, but also exhibit the same dissolution characteristics as the comparative granules.

Table 1 Example 7 Production of bare granules d: 800 g of theophylline, 375 g of cornstarch, 28
~600 g of white sugar sized to 35 mesh size and 25 g of hydroxypropyl cellulose are mixed with 475 g of ethyl alcohol.
Naked granules d were prepared in the same manner as in Example 1 using a solution dissolved in
I got it.

Example 8 Manufacture of coated granules e: 800 g of bare granules d produced in Example 7 were placed in a fluidized bed coating device, and a coating liquid 168 having the following composition was added.
Spray coating 4 g according to a conventional method to prepare coated granules e. The coating amount of this substance is 8% for bare granules.
%Met.

Composition
% ethyl cellulose
2,7 Borivinylpyrrolidone K2O0,9 Talc 0.2
Total 100
．． Example 9 Production of double-coated granules used in the present invention: 600 g of the coated granules e produced in Example 8 were placed in a fluidized bed coating device, and spray-coated with 2000 g of a coating solution having the following composition according to a conventional method. to produce double coated granules. The coating amount of this material was 20% of the coated granules e.

Composition
% polyvinyl acetal diethylamino acetate 6. 0 Ethyl alcohol 47.08 Total 100.0 Example 10 Production of tablets of the present invention: Double coated granules 147.8g, crystalline cellulose 1
50g, milk) 146.2g, magnesium stearate 3g 1 talc 3g were mixed uniformly, and compression molded.
Tablets of the present invention each having a weight of 350 mg and a diameter of 9 m+n were manufactured.

Example 11 Manufacture of comparative tablets: coated granules e 123.2 g, crystalline cellulose 150 g
70.8 g of lactose, 3 g of magnesium stearate, and 3 g of talc were uniformly mixed and compression molded to produce tablets each weighing 350 mg and having a diameter of 9 mm.

Example 12 The tablets of the present invention obtained in Example 10, the comparative tablets obtained in Example 11, and the coated granules e were dissolved at pH 1,
Using the solution No. 2, measurement was performed using the rotating paddle method (Japanese Pharmacopoeia - 11th revision), to or, p, m. The results are shown in Table 2. The tablets of the present invention exhibit approximately the same dissolution characteristics as the comparative granules, and the release rate is not altered as in the comparative tablets.

Table 2 Example 13 Production of naked granules g Cephalexin 1400g, milk fi 160g, purified white 9
Add 40 g of hydroxypropyl cellulose to a mixed bundle of 200 g of crystalline cellulose and 76 g of ethyl alcohol.
Add the solution dissolved in 0g and knead. After granulating this mixture using a cylindrical granulator, using a marmerizer,
Spherical granules are prepared and dried at 55°C for 2 hours. Among these dry granules, those that pass through 16 meshes but do not pass through 35 meshes are referred to as bare granules g.

Example 14 Manufacture of coated granules: 800 g of the bare granules prepared in Example 13 were placed in a fluidized bed coating device, and spray coating was performed using 3582 g of the coating liquid having the composition of Example 2 according to a conventional method to form coated granules. make The amount of this material covered is g of bare granules.
It was 30% of the total.

Example 15 Production of double-coated granules i: 400 g of the coated granules h produced in Example 14 were placed in a fluidized bed coating device, and spray-coated with 1111 g of the coating liquid having the composition of Example 3 according to a conventional method. Coated granules i are prepared. The coating amount of this product was 20% of the coated granules.

Example 16 Production of tablets of the present invention: Cephalexin 700 g, milk 990 g% purified white 920
0g of mixed powder, 10g of hydroxypropylcellulose
A solution of 190 g of ethyl alcohol was added and kneaded, and the mixture was dried at 55° C. for 2 hours to produce granules using a conventional method.

Next, 53.6 g of these granules, 1195 g of the double-coated granules of Example 15, 143.4 g of crystalline cellulose, 4 g of magnesium stearate, and 4 g of talc were uniformly mixed and compression molded to form a book with a weight of 800 mg per unit and a diameter of 13 mm. Invention tablets were manufactured.

Example 17 Manufacture of comparative tablets: Cephalexin 700 g, milk 990 g, purified white l!
A solution prepared by dissolving 10 g of hydroxypropyl cellulose in 190 g of ethyl alcohol was added to 1200 g of the mixed powder, kneaded, and dried at 55° C. for 2 hours to produce granules using a conventional method. Next, 53.8 g of this granule, coated granule h of Example 14 162.5 g 1 crystalline cellulose 143.4 g
g, lactose 32.5g, magnesium stearate 4g,
After 4 g of talc was uniformly mixed, compression molding was performed to produce tablets each weighing 800 mg and having a diameter of 13 mm.

Example 18 Manufacture of comparative granules: 7 g of bare granules glO and 32.5 g of coated granules h were mixed and then divided into 432 mg portions to prepare granules.

Example 19 The tablets of the present invention obtained in Example 16, the comparative tablets obtained in Example 17, and the comparative granules obtained in Example 18 were used as eluents at pH 1, 2 from the start of the test until 630 minutes. Using the test solution (Japanese Pharmacopoeia - 11th revision, 1st solution), 30
After 60 minutes, measure using the rotating paddle method (Japanese Pharmacopoeia - 11th revision) 100 r, p, ra using PI (6, 8 test solution (Japanese Pharmacopoeia - 11th revision, 2nd solution)) The results are shown in Table 3. The dissolution characteristics of the tablets according to the present invention did not change much compared to the comparative granules, whereas the dissolution characteristics of the comparative tablets changed significantly.

Table 3 that's all

Claims (1)

[Scope of Claims] 1. A tablet obtained by compression molding a pharmaceutical composition containing coated granules, in which the coated granules are further coated with a protective coating of water-soluble polymer or acid-soluble polymer. A tablet comprising coated granules characterized by: 2. The tablet according to claim 1, wherein the coating of the coated granules is composed of one or more of insoluble polymers, enteric polymers, and waxes. 3. The tablet according to claim 1 or 2, which contains the active drug in the coated granules. 4. The tablet according to any one of claims 1, 2 and 3, wherein the coated granules and the uncoated granules contain an active pharmaceutical agent.