2021-08-17
EXAMPLES 3-7
In the same manner as described in Example 2, tablets of Examples 3 to 7 were obtained.
Example 8 | |
Calcium polycarbophil | 625 mg |
Carboxymethylcellulose | 75 mg |
Hydroxypropylcellulose | 10 mg |
Micromicrocrystalline cellulose | a sufficient quantity |
Magnesium stearate | 6 mg |
Film coating | |
Hydroxypropylmethylcellulosc | 20 mg |
Polyethylene glycol 6,000 | 5 mg |
'Titanium oxide | 5 mg |
Total | 1000 mg |
A portion of carboxymethylcellulose (about half of the total carboxymethylcellulose) and hydroxypropyl cellulose were added to calcium polycarbophil and mixed at room temperature. To the mixture obtained, 7% by weight of water based on calcium polycarbophil was added, and then the mixture was granulated and dried at 50° C. for 12 hours. The granules were passed through a 18 mesh screen and the remaining carboxy methylcellulose and microcrystalline cellulose were added to the granules. After magnesium stearate was added to the granules, the resulting mixture was com- 5 pressed to obtain tablets containing 625 mg of calcium polycarbophil per tablet, which were film-coated by using hydroxypropylmethylcellulose, polyethylene gly col 6000, and titanium oxide to afford film-coated tab lets. 10
EXAMPLES 9 TO 14
In the same manner as described in Example 8, tablets of Examples 9 to 14 were obtained.
15
Calcium polycarbophil
Lactose
Low-substituted hydroxypropylcellulose Magnesium stearate .
Total
Calcium polycarbophil, lactose, and low-substituted hydroxypropylcellulose were mixed at room tempera- 25 ture and 20% by weight of ethanol based on calcium polycarbophil was added to the mixture, which was then granulated and dried at 50° C. for 12 hours. After the granules were passed through a 18 mesh screen, magnesium stearate was added to the granules and then 30 the mixture was filled in capsules so that 312.5 mg of calcium polycarbophil was contained in one capsule.
In the same manner as described in Example 15, cap sules of Examples 16 and 17 were obtained.Lactose and com starch were added to calcium poly carbophil and mixed at room temperature. Hydroxy propylcellulose was dissolved in 30% by weight of ethanol based on calcium polycarbophil, and the solu- 60 tion was then added to the above mixture to obtain granules. After being dried at 50° C. for 5 hours, the granules were passed through a 16 mesh screen. Film coating on the granules was carried out by using hy droxypropylmethylcellulose, polyethylene glycol 6,000 and titanium oxide to obtain film-coated granules.In the same manner as described in Example 18, gran ules of Examples 19 to 22 were obtained.To calcium polycarbophil, 4% by weight of water based on calcium polycarbophil was added and mixed at room temperature. The mixture was granulated and dried at 50® C. for 10 hours. After the granules were passed through a 18 mesh screen, microcrystalline cel lulose was added and mixed with the granules. After magnesium stearate was added and mixed, the resulting powder was compressed to obtain tablets containing 625 mg of calcium polycarbophil per one tablet, which were then film-coated to afford film-coated tablets.
-continued
Comparative Example 2
Polyvinyl pyrrolidone ' 25 mg
Anhydrous silicic acid 5 mg
Stearic acid 15 mg
Total • 933.5 mg
Caramel and polyvinyl pyrrolidone were added to calcium polycrobophil and then a portion of crospovi- jq done (about three fifths of the total crospovidone) was added and mixed. The mixture was granulated by using warm water at a temperature of about 50° to 65° C., which was then dried at 50° C. for 6 hours. After the granules were passed through a 18 mesh screen, the 15 remaining amount of crospovidgne, microcrystalline cellulose, and anhydrous silicic acid were addad to the granules. After magnesium stearate and stearic acid were added to the granules, the mixture was com pressed to obtain tablets containing 625 mg of calcium 20 polycarbophil per one tablet.
COMPARATIVE EXAMPLE 3
Film coating was carried out on the tablets obtained by the process described in Comparative Example 2, by 25 using 20 mg of hydroxypropylmethylcellulose, 5 mg of polyethylene glycol 6,000, and 5 mg of titanium oxide per one tablet to obtain film-coated tablets.
The degree of disintegration and the stability of the above-described pharmaceutical compositions were 30 measured. Tables 1 and 2 summarize the ingredients contained in the pharmaceutical compositions tested.
Experiment 1: Disintegration test
Disintegration test was carried out according to the 35 method described in the Japanese Pharmacopoeia, i.e., with sucrose or other suitable coating agents； procedure (4) capsules； and procedure (5) granules, by using the first fluid (artificial gastric juice) described in the Japa nese Pharmacopoeia. The results are summarized in Table 3.
The pharmaceutical compositions of the present in vention in the form of plain tablets, film-coated tablets, capsules, and granules had excellent degree of disinte gration. The tablet of Comparative Example 2, which is described in JP KOKAI No. 1988 (Sho-63>253027, and its film-coated tablet (Comparative Example 3), as well as Fibercon (trade name) did not disintegrate in 60 min utes because of gel formation in the glass tubes of the test apparatus.
Experiment 2： Stability test
In order to determine stabilities of the pharmaceutical composition under storage, disintegration tests were carried out on the pharmaceutical compositions in the fbnn of film-coated tablet, which had been stored for one month at 40° C. under 75% RH (relative humidity) before disintegration test was carried out. The results obtained are shown in Table 4.
The disintegration time of the pharmaceutical com position of the present invention, which contains 2 to 80% by weight of the cellulose derivative based on calcium polycarbophil, was not prolonged after the storage. On the other hand, the disintegration time of film-coated tablet of Comparative Example 1 was sig nificantly prolonged after storage, which shows the reduced stability of Comparative Example 1.
One of ordinary skill in the art will recognize that improvements and modifications may be made while remaining within the scope of the present invention. The scope and spirit of the present invention is deter mined solely by the appended claims.
TABLE 1
Example No. | Example 1 | Example 2 | Example 3 | Example 4 | Example 5 | Example 6 | Example 7 |
Sort of tablets | plain tablet | film-coated tablet | film-coated tablet | film-coated tablet | film-coated tablet | film-coated tablet | filnj-coatwi tablet |
Content of Cellulose derivatives (weight/weight %) | 8 | 2 | 4 | 8 | 16 | 40 | 80 |
Calcium Polycarbophil | 625 mg | 625 mg | 625 mg | 625 mg | 625 mg | 625 mg | 625 mg |
Cellulose derivatives | CMC 50 mg | CMC 12.5 mg | CMC 25 mg | CMC 50 mg | CMC 100 mg | CMC 250 mg | CMC 500 mg |
Microcrystalline | a sufficient | a sufficient | a sufficient | a sufficient | a sufficient | a sufficient | a sufficient |
Cellulose | quantity | quantity | quantity | quantity | quantity | quantity | quantity |
Magnesium Stearate Film | 6 mg | 6 mg | 6 mg | 6 mg | 6 mg | 6 mg | 6 mg |
Hydroxypropyl Methylcellulose | — | 20 mg | 20 mg | 20 mg | 20 mg | 20 mg | 20 mg |
Polyethylene Glycol 6000 | — | 5 mg | 5 mg | 5 mg | 5 mg | 5 mg | 5 mg |
Titanium Oxide | — | 5 mg | 5 mg | 5 mg | 5 mg | 5 mg | 5 mg |
Total | 970 mg | 1000 mg | 1000 mg | 1000 mg | 1000 mg | 1200 mg | 1500 mg |
CMC； Carboxymethylcellulose
disintegration test procedure (2) preparations coated
TABLE 2
Example No. | Example 8 | Example 9 | Example 10 | Example 11 |
Sort of tablets | film-coated | film-coated | film-coated | Hlm-coated |
tablet | tablet | tablet | tablet | |
Content of Cellulose | 14 | 18 | 18 | 18 |
derivatives | ||||
(weight/weight %) | ||||
Calcium Polycarbophil | 625 mg | 500 mg | 500 mg | 500 mg |
Cellulose derivatives | CMC 75 mg | CMC 75 mg | CMC-Ca 75 mg | L-HPC 75 mg |
HPC 10 mg | HPC 16 mg | HPC 16 mg | HPC 16 mg | |
Microcrystalline | a sufHcient | a sufficient | a sufficient | a suHicient |
Cellulose | quantity | quantity | quantity | quantity |
Magnesium Stearate | 6 mg | 6 mg | 6 mg | 6 mg |
TABLE 2-continued
Film | ||||
Hydroxypropyl | 20 mg | 18 mg | 18 mg | 18 mg |
Methylcellulose Polyethylene | 5 mg | 3 mg | 3 mg | 3 mg |
Glycol 6000 Titanium Oxide | 5 mg | 2 mg | 2 mg | 2 mg |
Total | 1000 mg | 785 mg | 785 mg | .785 mg |
Example No. | Example 12 | Example 13 | Example 14 | Compar. Example 1 |
Sort of tablets | filn)*coated | filin*coated | HIm-coated | film-coated |
Content of Cellulose | tablet 18 | tablet 18 | tablet 18 | tablet 0 |
derivatives (weight/weight %) Calcium Polycarbophil | 500 mg | 500 mg | 500 mg | 625 mg |
Cellulose derivatives | CCM-Na 75 mg | CMC 75 mg | CMC 75 mg | — |
Microcrystalline | HPC 16 mg a sufficient | MC 16 mg a sufficient | CMC-Na 16 mg a sufficient | a sufficient |
Cellulose | quantity | quantity | quantity | quantity |
Magnesium Stearate | 6 mg | 6 mg | 6 mg | 6 mg |
Film Hydroxypropyl | 18 mg | 18 mg | 18 mg | 20 mg |
Methylcellulose Polyethylene | 3 mg | 3 mg | 3 mg | 5 mg |
Glycol 6000 Titanium Oxide | 2 mg | 2 mg | 2 mg | 5 mg |
Total | 785 mg | 785 mg | 785 mg | 1000 mg |
CMC： Carboxymethylcellulose, HPMC： Hydroxypropyl Methylcellulose,
HPC： Hydroxypropyl Cellulose, CMC-Ca： Carboxymethylcellulose Calcium,
L-HPC： Low Substituted Hydroxypropyl Cellulose, CCM-Na： Croscannellose Sodium, MC： Methylcellulose, CMC-Na： Carboxymethylccllulose Sodium
TABLE 3
Disintegration Test
Content of Cellulose derivatives (weight/weight %) | Example No. | Sort of Preparations | Disintegration time (min) |
8 | Example 1 | plain tablet | 0.1 ~0.2 |
2 | Example 2 | film-coated | 6.7-15 |
4 | Example 3 | 43-6.8 | |
8 | Bxample 4 | 1.3~2.9 | |
16 | Example 5 | 0.6~1.2 | |
40 | Example 6 | ‘‘ | 1.0-2.1 |
80 | Example 7 | 2.2 ~ 3.1 | |
14 | Example 8 | 25 〜3.1 | |
18 | Example 9 | 2.1-2.4 | |
16 | Example 15 | hard gelatin capsule | 2.3 ~ 3.9 |
2 | Example 16 | ,, | 6.3-13.5 |
40 | Example 17 | 2.5 〜4.6 | |
1 | Example 18 | film-coated granule | 7.4-15 |
3 | Example 19 | 2.1-9.5 | |
5 | Example 20 | 4.7-12 | |
40 | Example 21 | ‘‘ | 3.O-7.6 |
6 | Example 22 | 0.9-2.2 | |
— | Compar. Example 2 | tablet before coating (JP KOKAI 1988/253027) | M60 |
— | Compar. Example 3 | film-coated tablet of Compar. Example 2 | M60 |
— | Fibercon ® | M60 |
.TABLE 4
Stability Test | ||||
Content of Cellulose derivatives (weight/weight %) | Example No. | Sort of Pharmaceutics | Disintegrating time (min) after stored for 1 month | |
at the time of the start | at 40, C. under 75% RH | |||
0 | Compar. Example 1 | film-coated tablet | 13-27 | M60 |
2 | Example 2 | 6.7 〜15 | 17~35 | |
4 | Example 3 | 4.3~6.8 | 9.1-19 | |
8 | Example 4 | 1.3-2.9 | 0.9~2.3 | |
16 | Example 5 | 0.6 〜1.2 | 0.7-1.1 | |
40 | Example 6 | 1.0 〜2.1 | 0.8-2.7 | |
TABLE 4-continued
Content of Cellulose derivatives (weight/weight %) | Example No. | Subility Tesi | ||
Sort of Pharmaceutics | Disintegrating time (min) | |||
at the time of the start | after stored for 1 month at 406 C. under 75% RH | |||
80 | Example 7 | ,, | 2.2-3.1 | 2.O-2.9 |
What is claimed is:
1. A pharmaceutical composition capable of being
disintegrated in an acidic environment, which com prises calcium polycarbophil mixed with 1 to 80% by weight of a cellulose derivative based on the calcium 15 polycarbophil wherein the cellulose derivative is se lected from the group consisting of polycarboxyme thylethers of cellulose, hydroxypropylethers of cellu lose, methyl and hydroxypropyl mixed ethers of cellu lose, and methylethers of cellulose. 2o
2. A pharmaceutical composition capable of being
disintegrated in an acidic environment, which com prises calcium polycarbophil mixed with 1 to 80% by weight of a cellulose derivative based on the calcium polycarbophil. 25
3. The pharmaceutical composition according to claim 2r wherein the cellulose derivative is selected from the group consisting of carboxymethylcellulose, low-substituted hydroxypropylcellulose, carboxy methylcellulose calcium, carboxymethylcellulose so dium, croscarmellose sodium, hydroxypropylcellulose, hydroxypropylmethylcellulose, methycellulose, and mixtures thereof.
4. The pharmaceutical composition according to claim 2, wherein the composition is in the form of a tablet.
5. The pharmaceutical composition according to claim 2, wherein the composition is in the form of a capsule.
6. The pharmaceutical composition according to claim 2t wherein the composition is in the form of gran ules.
