JP3152978B2 - Double-layer tablet and method for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention provides a novel method for producing a compression-molded bilayer tablet which is formulated for the purpose of maintaining and stabilizing the action, and a bilayer tablet obtained by the method. In particular, the present invention is extremely useful when two or more pharmaceutically active ingredients which are liable to change in composition are formed into a single tablet.

[0002]

2. Description of the Related Art In the design of tablets, a method of making a laminated tablet is well known as a means for stabilizing a preparation, controlling dissolution of contained components, etc., but it is easy to reduce the size especially from the aspect of taking. Double layer tablets are preferred. However, since laminated tablets are produced by compression-molding granules, delamination and the like are likely to occur, and it has not been easy to produce a tablet that is satisfactory in terms of quality stability. In addition, combinations of isopropylantipyrine and acetaminophen are known as pharmaceutically active ingredients that are mutually contraindicated and form a complex when the proportion of contact in the formulation is large, which causes moistening. An example of a single tablet is not yet known.

[0003]

Under the circumstances described above, the development of a simple method for producing a compression-molded two-layer tablet which is difficult to peel off has been expected.

[0004]

Means for Solving the Problems In view of the above situation, the present inventors have conducted intensive studies and as a result, in the production of compression-molded two-layer tablets, the dry weight of each granule was included in each of the upper and lower granules. About 3 to about 30% by weight of
Lactose powder having a specific surface area of 5500 cm ² / g is compounded as a binder, and when the lower layer is compressed and compressed, the tableting pressure is 5 to 50 kg / cm ² , and the upper layer is filled and compressed. The present inventors have found that a compression-molded two-layer tablet excellent in disintegration and having little peeling can be obtained by tableting, and completed the present invention. More specifically, the present invention preferably performs compression tableting at the time of forming the lower layer at a tableting pressure of 10 to 40 kg / cm ² , and subsequently performs compression tableting of the upper layer at 500 to 1000 kg / cm ^2.
The purpose of the present invention is to provide an intended compression-molded double-layer tablet by performing the compression at a compression pressure of ² cm ² .

Hereinafter, the method of the present invention will be described in detail. First, granules for the upper layer and the lower layer are granulated and prepared. Granulation may be performed by a wet method known per se, and examples thereof include a tumbling granulation method, a wet granulation method, and a fluidized bed granulation method. Usually, sucrose, glucose, mannitol, crystalline cellulose and the like are commonly used as binders for granulation, but lactose powder has not been used as a binder.

The lactose powder used in the present invention can be used as long as it does not easily cause volume expansion due to moisture absorption. Specifically, lactose or β-lactose is preferably used in Japan.
The amount used ranges from about 5 to about 30% by weight based on the dry weight of each granule. If it is less than about 5% by weight, peeling or the like is likely to occur, which is not preferable. Also, about 30% by weight
A larger value is not preferable because it causes inconvenience such as extremely fast disintegration. The specific surface area is about 3300 to about 5
It is in the range of 500 cm ² / g. If it is less than about 3300 cm ² / g, peeling or the like is likely to occur, which is not preferable. If it is larger than about 5500 cm ² / g, the strength is increased, but the fluidity is reduced and handling becomes difficult, which is inconvenient in industrial production.

Next, any one of the granules obtained by the above method is subjected to compression tableting to form a lower layer. If there is a difference in weight between the granules, use the larger one. Is preferred. The tableting pressure at this time is about 5 to about 50 kg /
cm ² , preferably about 10 to about 40 kg / cm ² . A two-layer tablet performed at less than about 5 kg / cm ² is difficult to peel off, but becomes a tablet having low strength. When the pressure is higher than about 50 kg / cm ² , the strength as a tablet is satisfied, but delamination tends to occur. Therefore, it is not preferable in any case.

After completion of the lower layer molding, the other granules are successively laminated on the lower layer as an upper layer, followed by compression tableting to obtain the two-layer tablet of the present invention. The tableting pressure at this time is not particularly limited, but is usually about 500 to about 1000 kg / cm.
² , preferably about 600 to about 900 kg / cm ² . In addition, compression tableting for molding each layer may be performed using a commonly used laminated tableting machine or the like.

[0009] The bilayer tablet of the present invention can contain various pharmaceutically active ingredients as appropriate according to the purpose of administration. In particular, it is very useful when two or more pharmaceutically active ingredients which are liable to change in composition are formed into a single tablet, and these ingredients may be separately blended in the upper layer and the lower layer. A good example is the use of acetaminophen and isopropylantiantipyrine as pharmaceutically active ingredients. Both of these components are frequently used as active ingredients in antipyretic analgesics, but are incompatible with each other, and if a large percentage of contact occurs in a single tablet, it will form a complex and become wet, making tableting difficult. Have been. However, if these components are blended in the upper layer or the lower layer of the two-layer tablet of the present invention, a tablet can be formed without such a problem. In this case, as a matter of course, any other pharmaceutically active ingredient can be used in combination with acetaminophen and / or isopropylantipyrine, if it does not easily cause a change in blending, and, for example, allyl isopropyl acetyl urea , Anhydrous caffeine, para-aminobenzoic acid, papaverine hydrochloride, phenacetin, bromovalerylurea, etensamide and the like can be used.

The ratio of each granule containing isopropylantipyrine and acetaminophen to the dry weight is appropriately determined depending on the size, formulation and the like of the target bilayer tablet, and can be adjusted by the amounts of various additives. However, from the viewpoint of further reducing the change in the composition due to the interaction between the layers, the content is preferably up to about 70%. The content ratio of isopropylantipyrine to acetaminophen may be appropriately determined in consideration of the formulation of the bilayer tablet of the present invention.

[0011] In order to further improve the stability of the bilayer tablet of the present invention, it is preferable to define the particle size of the raw materials to be compounded in addition to lactose powder. When isopropylantipyrine is used, about 9000 to about 12
000 cm ² / g, about 6000 to about 10000 cm ² / g
Are preferred. Above each upper limit and below each lower limit, it is not preferable for the same reason as described above.

At the time of preparing each granule, known additives (eg, excipients, disintegrants, lubricants, coloring agents, etc.) are appropriately compared with the intended efficacy, size, and quality of the target bilayer tablet. Can be used. Examples of the additives include starches (such as corn starch), glucose, sucrose, calcium carbonate, mannitol, dextrin, tragacanth, gelatin, and celluloses (ethylcellulose, carboxymethylcellulose sodium, hydroxypropyl). Cellulose, crystalline cellulose, polyvinylpyrrolidone, talc, metal stearate (such as magnesium stearate), polyethylene glycols, carboxymethyl cellulose calcium, croscarmellose sodium,
Sodium alginate, gelatin, casein and the like are exemplified. EXAMPLES The present invention will be described in more detail with reference to the following Examples and Reference Examples, which do not limit the present invention in any way.

Example 1 17.8 parts by weight of isopropylantipyrine, 7.1 parts by weight of allylisopropylacetylurea, anhydrous caffeine 6
Parts by weight, 2.8 parts by weight of corn starch, 0.5 parts by weight of carboxymethylcellulose calcium and 8 parts by weight of lactose powder;
After uniformly dispersing an aqueous solution having 4 parts by weight dissolved therein, wet granulating and drying, 5 parts by weight of crystalline cellulose, 1.9 parts by weight of croscarmellose sodium and 0.5 parts by weight of magnesium stearate are added. The mixture is mixed to obtain granules (hereinafter, referred to as A granules). Meanwhile, acetaminophen 29.
7 parts by weight, crystalline cellulose 4.7 parts by weight, carboxymethyl cellulose calcium 0.5 parts by weight and lactose powder 1
Add 2 parts by weight of mixed powder to hydroxypropyl cellulose
An aqueous solution in which 0.8 parts by weight of sulphate was dissolved was uniformly dispersed, wet-granulated and dried, and then 1.8 parts by weight of carboxymethylcellulose calcium and 0.8 parts by weight of magnesium stearate.
5 parts by weight are added and mixed to obtain granules (hereinafter, referred to as B granules). A granule 50 parts by weight is first filled and 25.5 kg
/ Cm ² and compression tableting to form a lower layer.
A two-layer tablet was prepared by laminating 0 parts by weight as the upper layer and then compressing and compressing it at 760 kg / cm ² .

For compression tableting, 2L-51k-AWC is used.
(Manufactured by Kikusui Seisakusho) was used. Further, as the main raw materials, those having specified particle sizes as shown in Table 1 were used.

[Table 1]

Example 2 A two-layer tablet was prepared in the same manner as in Example 1, except that the lower layer was compression-molded at a pressure of 12.7 kg / cm ² . Example 3 A two-layer tablet was prepared in the same manner as in Example 1, except that the lower layer was compression-molded at a pressure of 38.2 kg / cm ² . Example 4 A two-layer tablet having the composition shown in Table 2 was prepared in the same manner as in Example 1.

[Table 2]

Reference Example 1 A two-layer tablet was prepared in the same manner as in Example 1, except that the lower layer was compression-molded at a pressure of 63.7 kg / cm ² . Reference Example 2 A two-layer tablet was prepared in the same manner as in Example 1, except that the lower layer was compression-molded at a pressure of 127.4 kg / cm ² . Reference Example 3 The composite tablet of the two-layer tablet obtained in Example 4 was used as Example 4
A single-layer tablet having the same composition as the two-layer tablet was prepared. The composition is shown in Table 3.

[Table 3]

Test Example 1 F-type strength test Using each bilayer tablet obtained from Examples 1 to 3 and Reference Examples 1 and 2, the friability described in the general rules for preparation A-108 in the 12th revised Japanese Pharmacopoeia Manual (Hirokawa Shoten) An F-type strength test was performed based on the test. In each test, 30 tablets were used, and 2 tablets were used.
This was performed at 0 rpm × 30 minutes. Table 4 shows the results.

[Table 4] (Results) In the case of the reference example in which the lower layer was molded at a high pressure, peeling occurred even immediately after tableting, and when pressed at 127.4 kg / cm ² , more than half of the peeling occurred after the F-type strength test. . On the other hand, in the case of the example performed at a low pressure of about 50 kg / cm ² or less, no peeling was observed even after the F-type strength test. (Consideration) Therefore, it can be seen that the lower layer should be formed at a low pressure of about 50 kg / cm ² or less in order to prevent the separation on the two layers.

2. Appearance change and disintegration test The bilayer tablet obtained from Example 4 and the single-layer tablet obtained from Reference Example 3 were opened at 40 ° C and 75% ^RH (PTP packaging).
And stored for 3 months under conditions of 45 ° C. and sealed at 45 ° C. (PTP + aluminum package), and the change in appearance and the disintegration time were compared. In addition, the disintegration test was performed based on the disintegration test method of the 12th revised Japanese Pharmacopoeia. Table 5 shows the results.

[Table 5] (Note) ○: No difference from immediately before storage △: Slightly discolored border line ▲: Discolored border line ×: Discolored as a whole (results) Regarding change in appearance Under both humidification and warming conditions, the one-layer tablet showed considerable discoloration even after one month as compared to immediately before storage, whereas the two-layer tablet of the present invention showed only a change under humidification conditions. It only showed partial discoloration. This discoloration is due to the formation of a complex between isopropylantipyrine and acetaminophen, which reduces the light reflection of the tablet. 2. Regarding disintegration test Regarding the disintegration time, the one-layer tablets showed a considerable extension and did not disintegrate at all after storage for 3 months, while the two-layer tablets showed only a slight extension. From the above test results, it can be seen that the two-layer tablet of the present invention is extremely stable in quality as compared with the one-layer tablet of the same composition.

[0019]

According to the present invention, a compression-molded two-layer tablet can be obtained. However, the two-layer tablet hardly causes appearance changes such as peeling and discoloration, and its disintegration slightly decreases even after storage for several months. Therefore, it is extremely stable in quality. Furthermore, the stability is maintained even if pharmaceutically active ingredients such as isopropylantipyrine and acetaminophen, which are liable to change in composition, are contained.

──────────────────────────────────────────────────続 き Continuation of the front page (72) Inventor Shuichi Hatsudai 4-6-14 Magamicho, Takatsuki-shi, Osaka (56) References JP-A-2-235815 (JP, A) JP-A-63-250319 (JP, A) (58) Field surveyed (Int. Cl. ⁷ , DB name) A61K 9/24, 47/26

Claims (5)

(57) [Claims] 1. A method for producing a compression-molded two-layer tablet, comprising:
In each of the granules for the upper layer and the lower layer, 3300 to 5500 c in an amount of 5 to 30% by weight based on the dry weight of each granule.
A lactose powder having a specific surface area of m ² / g is blended as a binder, and the granules for the lower layer are compressed at a tablet compression pressure of 5 to 50 kg / cm ^2.
After forming the lower layer by compressing and compressing with force,
A method for producing a two-layer tablet, comprising laminating the granules for an upper layer onto the mixture and compressing and compressing . 2. The compression and compression pressure of the upper layer to be subsequently performed is 5
00~1000kg / cm ² bilayer tablet manufacturing method according to claim 1, wherein. 3. The compression tableting pressure of the lower layer is 10 to 40 kg /
The method for producing a two-layer tablet according to claim 1, which has a diameter of ² cm2. 4. The method for producing a two-layer tablet according to claim 1, wherein acetaminophen and isopropylantipyrine are compounded as an active ingredient in an upper layer or a lower layer, respectively. 5. A two-layer compression-molded tablet obtained by the production method according to claim 1, 2, 3 or 4.