JPS58144316A - Stable indomethacin tablet - Google Patents

Abstract

PURPOSE:A compressed tablet of indomethacin not to harden during storage, having stability with time, comprising a base for a tablet prepared by covering indomethacin powder useful as an antiphlogistic and anodyne with a specific amount of a film-forming substance of a hydrophilic high polymer. CONSTITUTION:A film-forming substance of hydrophilic high polymer selected from preferably hydroxypropyl cellulose, hydroxymethyl propyl cellulose, polyvinyl pyrrolidone, methyl cellulose, and sodium carboxymethylcellulose is as a stabilizer, and indomethacin powder shown by the formula as an active ingredient is covered with 1-50wt%, especially 5-20wt% stabilizer based on the powder. The covered substance is used as a base and tableted, to give a compressed tablet of indomethacin having stability with time, having no influence on collapsing time, eluation rate, and absorption rate in the blood in its internal use because it does not harden during storage.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to the tabletting of indomethanone, a drug that has hitherto been considered difficult in the field of pharmaceutical science. Relating to providing locks.

Indomethacin is a white to pale yellow crystalline powder with a melting point of 15 and has the chemical structure shown below: 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1-indole-5=acetic acid.
It is a compound with a temperature of 5 to 162°C.

Indomethacin is a drug frequently used as an anti-inflammatory and analgesic that has been newly listed in the Ninth Edition of the Japanese Pharmacopoeia.
Indomethacin compressed tablets become hard during storage, which delays disintegration and reduces absorption when taken internally, so capsules filled with fine powder are used. '' Also, in the explanation in the column ``Indomethacin Capsules'', it is stated that [compressed tablets of indomethacin become hard during storage, making it difficult to disintegrate, dissolve, and absorb when taken orally, but capsules are better absorbed than tablets. It is said that at the same dose, the blood concentration increases higher than that of tablets. '', and indomethacin capsules have been exclusively used for this purpose, and tablets have not been used until now.

However, it is well known that tablets are more advantageous than capsules in terms of production costs and ease of administration, especially for children and the elderly.

In view of this point, the present inventor has conducted intensive research and succeeded in developing an indomethacin tablet that is stable over time without becoming hard during storage and having no effect on disintegration time, dissolution rate, and blood absorption rate.

That is, the present invention uses polymeric film-forming substances that have a strong affinity for water, such as methylcellulose (MC), sodium carboxymethylcellulose (CMC-Na), polyhinylpyrrolidone (PVP), and hydroxypropylene methylcellulose. (HPMC), hydroxypropyl cellulose (RPC) fx, etc. are dissolved in water and/or an organic solvent as a stabilizer, and this is coated on the surface of indomethacin powder, which is then used as a base to form tablets. Ru.

More preferably, a polymeric film-forming substance with strong affinity for both water and organic solvents, such as HPClHPMC,
It is recommended that the compound be dissolved in one or more organic solvents such as methyl alcohol, ethyl alcohol, isopropyl alcohol, and methylene chloride. In this case, 1 to 50% by weight of stabilizer based on the weight of indomethacin
, preferably 5 to 20% by weight, and the stabilizer can be dissolved in the organic solvent to a concentration of 5 to 40% by weight, but in consideration of workability etc., it is in the range of 5 to 20% by weight. It is recommended that the concentration be A plasticizer soluble in both water and the organic solvent, such as propylene glycol or polyethylene glycol, can be added to this organic solvent solution in a proportion of 3 to 20% by weight relative to the stabilizer.

Still, for indomethacin powder, 0 to 2
0 mouth weight, preferably mouth weight or 50 to 100
It is also possible to use one or a mixture of two or more of microcrystalline cellulose, magnesium aluminate metasilicate, magnesium aluminate silicate, etc. in a proportion of ρ by weight, but this is not an essential condition of the present invention.

Fluidized bed dryers, super mixers, kneaders, ribbon mixers, etc. are selected as machines for achieving the above blending purpose.

To the powder or granules thus obtained, binders, disintegrants, excipients, lubricants, etc. commonly used in pharmaceutical preparations are added and the powder or granules are formed into compressed tablets by a conventional method.

The embodiments and effects of the present invention will be explained below with reference to Examples and Comparative Examples.

Example 1 6 parts of HI' CJ Q and 5 parts of polyethylene gelcol
Dissolve in a mixture of 0.00 parts of ethanol and 200 parts of methylene chloride. 250 parts of pulverized indomethacin, 150 parts of microcrystalline cellulose, and 50 parts of magnesium aluminate metasilicate are mixed in a fluidized granulation dryer, and the solution is sprayed to form granules and dried. 250 parts of microcrystalline cellulose, 215 parts of lactose, 30 parts of calcium fibrin glycolate, and 10 parts of magnesium stearate are added to the sized product, and the mixture is compressed into tablets with a diameter of 6 mm and a weight of 10 [1q].

Example 2 Dissolve in a mixture of 25 parts of HP0, 5 parts of polyethylene glycol, 300 parts of total ethanol and 50 parts of methylene chloride. 250 parts of pulverized indomethacin are placed in a fluidized granulation dryer, and the solution is sprayed and dried. 350 parts of microcrystalline cellulose, 50 parts of magnesium aluminate metasilicate, 280 parts of lactose, 50 parts of calcium fibrin glycolate, and 10 parts of magnesium stearate were added to the sized granules, which had a diameter of 6 mm and a weight of 100 mm. Compression mold into tablets.

Example 6 25 parts of HPM0 and 5 parts of polyethylene glycol are dissolved in a mixture of 600 parts of ethanol and 50 parts of methylene chloride. 250 parts of pulverized indomethacin are placed in a fluidized granulator, and the solution is sprayed and dried. 650 parts of microcrystalline cellulose, 50 parts of magnesium aluminate metasilicate, 280 parts of lactose, 60 parts of calcium cellulose glycolate, and 10 parts of magnesium stearate were added to the sized granules and mixed. Compression mold into a cape tablet.

Example 4 50 parts of HPC and 5 parts of polyethylene glycol are dissolved in a mixture of 400 parts of ethanol and 50 parts of methylene chloride.

250 parts of crushed indomethacin, 150 parts of magnesium aluminate metasilicate and 150 parts of microcrystalline cellulose
1 part is mixed in a kneading machine, and the above solution is added to this while stirring. The granulated product is passed through a flash mill, dried, and sized. This includes 255 parts of microcrystalline cellulose and 1 part of lactose.
00 parts, 50 parts of carunium fibrin glycolate and 10 parts of magnesium stearate were added and mixed to give a diameter of 6.
Compress and mold into tablets weighing ioo ~.

Control Example 1 250 parts of pulverized indomethacin and 2 parts of microcrystalline cellulose
70 parts of starch, 190 parts of starch, 250 parts of lactose, 6 parts of calcium cellulose glycolate, and 10 parts of magnesium stearate, and after mixing, tablets with a diameter of 6 by direct compression were added.
NM, compression molding into tablets weighing 100~.

Control Example 2 250 parts of pulverized indomethacin and 1 part of microcrystalline cellulose
20 parts, 190 parts of starch and 250 parts of lactose,
After mixing, knead with 5-chi starch paste liquid, granulate, dry, and size. To this, 150 parts of microcrystalline cellulose, 30 parts of cellulose calcium glycolate and 7 parts of magnesium stearate.
After adding 10 parts of aluminum and mixing, the mixture was compressed into tablets with a diameter of 6 mm and a weight of 1 ooq.

The pharmaceutical effect of unexploited tablets was proven by the following comparative experiment: Accelerated tests were conducted for Examples 1 to 4 and Control Examples 1 to 2, and the disintegration rate and dissolution rate of each were measured.

The accelerated test was conducted for 12 months at 40°C and 75% relative humidity in accordance with the 1981 Pharmaceutical Manufacture Guidelines, and was submerged every 6 months. In addition, regarding disintegration test and dissolution test, please refer to Section 10.
Revised Japanese Pharmacopoeia, General Test Methods, 66 Disintegration Test Methods and 4
Measured according to the 4 dissolution test method.

These results are shown in Tables 1 and 2 below: Table 1 Disintegration test results Table 2 Dissolution test results (3 [1 minute dissolution rate) (Numbers in the column are %) The above results are shown in Figure 1 of the attached drawing. As shown graphically in Figure 2, the control example was unsuitable for the dissolution test of indomethacin capsules in the 10th edition of the Pharmacopoeia, but the tablets of the present invention example showed no change over time in the 12-month accelerated test. It is stable without causing any problems, and the dissolution test is suitable.
The effects of the present invention and the selection and addition of stabilizers are clearly demonstrated.

Furthermore, animal experiments were conducted for Example 1 and Control Example 1 immediately after production and for those subjected to a 12-month accelerated test, and blood concentrations were compared based on differences in absorption. Rabbits were used as experimental animals, and one tablet was forcibly administered to each rabbit. After administration, blood was collected every 1.2.4.6.8 and 12 hours, and quantified by gas chromatography under the following conditions.

Hitachi gas chromatograph type 073 detector; hydrogen flame ionization detector column; 1.5% in a glass tube with a diameter of 3 mm and a length of 2 m.
Filled with OV-10rasthrom Q Measurement temperature: Column 240°C1 Detector 290'C Carrier gas: Nitrogen (90yyl/min) Sensitivity: 8ens 102, Ra
nqe 16 For comparison, similar animal experiments were conducted on commercially available indomethacin capsules manufactured by Company A and Company B, and blood concentrations were measured.

These results are shown in Tables 3.4 and 5 below, and are also shown graphically in the accompanying drawings as FIGS. 6 and 4.

Table 6 Measured blood concentration values immediately after manufacturing (unit μf/ysl) Table 4 Measured blood concentration values after 12 months accelerated test (unit μf/1g1) Table 5 Measured blood concentration values (Company A product, Company B product) (Unit: μf/ll) The results of these animal experiments show that there is no significant difference in blood concentration due to absorption after oral administration between 1 tablet of the example of the present invention and 1 tablet of the control example immediately after manufacture. When a 12-month accelerated test was carried out, the 1 tablet of the control example clearly showed a decrease in absorption compared to the 1 tablet of the example of the present invention. Furthermore, with reference to FIG. 4 of the accompanying drawings, the tablet of Example 1 of the present invention showed superior efficacy in maximum blood concentration compared to commercially available indomethacin capsule products even after the 12-month acceleration test; It was demonstrated that there was no significant difference even 8 hours after administration.

[Brief explanation of the drawing]

Figure 1 shows the fluctuation in blood concentration immediately after preparation according to the 10th revised Japanese Pharmacopoeia, General Test Methods, and Figure 4 shows the fluctuation in blood concentration after the 12-month accelerated test. In all drawings, -m = 1 tablet of the present invention, (---
4 represents the case of 1 tablet of the control example, ←, -. bars represent the case of commercially available capsules manufactured by Company A, and t → represents the case of commercially available capsules manufactured by Company B. (Patent applicant: Choda Pharmaceutical Co., Ltd.)

Claims (1)

[Scope of Claims] 1. A compressed tablet of indomethacin, which is prepared by preparing a hydrophilic polymeric film-forming substance at a ratio of 1 to 50% by weight to the active ingredient indomethacin powder as a tablet base. 2. The hydrophilic polymer film-forming substance is hydroxyglopylcellulose, hydroxymethylglobilcellulose,
The compressed tablet of indomethane 7 according to claim 1, which is one or more selected from the group consisting of polyvinylpyrrolidone, methylcellulose, and sodium carboxymethylcellulose.