JPH0233012B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for producing amfenac formulations that are stable over time. Amfenac sodium (sodium 2-amino-3-benzoyl benzene acetate) was published in the Journal of Medicinal Chemistry by WJ Welstead et al.
It is a nonsteroidal anti-inflammatory analgesic classified as an allylcarboxylic acid and is described in many papers such as 22(9) 1074-1079 (1779)}. Amfenac sodium and amfenac calcium are highly evaluated for their effectiveness as anti-inflammatory analgesics. Possible formulations of amfenac sodium and amfenac calcium include capsules, tablets, granules, fine granules, and powders. To manufacture these preparations, for example, according to the ``Preparation Guidelines Commentary'' (published by Yakuji Nipposha), capsules and tablets are generally formulated with lactose, starch, or crystalline cellulose as excipients, and are lubricated. As a drug,
Manufactured by adding magnesium stearate or calcium stearate. In granules and fine granules, binders such as starch, gelatin, gum arabic, cellulose ethers, polyvinylpyrrolidone, etc., and a small amount of flavoring agents may be added. In addition to excipients, flavoring agents may also be added to powders as flavoring agents. However, if these Amfenac formulations are manufactured by such known methods, i.e. capsules with the formulation shown in Table 1 of Example 1, tablets, granules, fine granules and powders with the formulation shown in Example 3. .6th
When the capsules were manufactured using the formulations shown in formulations 1 to 4 in the table and stored for one year at room temperature, the yellow content derived from amfenac sodium turned pale red, and the tablets In the case of , the yellow surface turned red, and in the case of powder, the yellow powder turned pale red. Furthermore, analysis by thin layer chromatography confirmed that 7-benzoyl-2-oxindole, which is the main decomposition product of amfenac sodium and amfenac calcium, was produced in each formulation. As described above, when Amfenac preparations were manufactured by conventional known methods, it was thought that it would be difficult to formulate formulations due to the formation of decomposition products and changes in appearance due to discoloration. Therefore, as a result of repeated research in order to produce a formulation that is stable over time, the present inventors have found that amounts of magnesium oxide, basic magnesium carbonate, and calcium carbonate that do not show medicinal efficacy for amfenac sodium or amfenac calcium. It has been found that by adding one or more selected types, a stable preparation that does not change color over time can be produced. The present invention was completed based on this knowledge. These additives are usually added to Amfenac sodium or Amfenac calcium from 0.1 to
It is desirable to add 1 times the amount. These additives are defined by the Japanese Pharmacopoeia as follows:
Its safety has been confirmed. Next, Examples will be shown to concretely demonstrate the method of the present invention and its effects. Example 1 The additives shown in Column 1 of Table 3 were mixed in the amounts shown in Column 2 of the additives shown in Column 1 of Table 3 as various stabilizers to the formulation of capsules shown in Table 1, and the mixture was filled into gelatin capsules using a Xanasi type capsule filling machine. After leaving the capsule under airtight conditions at 60℃ for one month, the discoloration of the capsule contents is recorded in column 3.
Furthermore, using a silica gel plate, thin layer chromatography was performed using ethyl acetate: ethanol: 10% aqueous ammonia = 3:1:1 as a developing solvent, and the presence or absence of the decomposition product 7-benzoyl-2-oxindole was detected in the fourth column. Shown in the column. From the results in Table 3, it is clear that magnesium oxide, basic magnesium carbonate, and calcium carbonate have a stabilizing effect.
No effect was observed with sodium carbonate and potassium carbonate. Similarly, for Amfenac calcium, the second
Similar tests were conducted using the capsule formulations shown in Table 4. As shown in Table 4, similar to amfenac sodium, magnesium oxide, basic magnesium carbonate, and calcium carbonate had stabilizing effects. Since this stabilizing effect is observed only in oxides and carbonates of divalent alkaline earth metals, it is presumed that the effect is due to a weak chelate.

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[Table] Example 2 Next, regarding magnesium oxide, which has a strong stabilizing effect, the amount added was examined in detail using amfenac sodium. For the capsule formulation in Table 1, the second formulation in Table 5
After adding the amount of magnesium oxide shown in the column and mixing well, fill it into gelatin capsules using a Xanasy filling machine, and store it at 60℃ in an airtight environment for 1 month, and at 40℃ with 81% RH open.
Storage tests were carried out for 1 month and 1 year under airtight conditions at room temperature, and the results are shown in Table 5, column 3 shows changes in the appearance of the capsule contents, and column 4 shows the presence or absence of decomposed products by thin layer chromatography. From the results in Table 5, Amfenac sodium 50
It has been found that capsules that are completely stable over time can be produced when 5 mg or more of magnesium oxide is added per mg of magnesium oxide.

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[Table] Example 3 Next, the present invention was applied to formulations other than capsules.
A formulation was prepared by adding 20 mg of magnesium oxide to the formulations of tablets, granules, fine granules, and powders (containing 50 mg of amfenac sodium) shown in Formulation 1 to 4 in Table 6, and was kept under airtight conditions at room temperature for 1 year. A storage test was conducted, and the results are shown in the third column of Table 7 for changes in appearance, and in the fourth column for the presence or absence of decomposed products by thin layer chromatography. From the results in Table 7, it was clear that the stabilizing effect of magnesium oxide addition was observed in tablets, granules, fine granules, and powders as well.

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[Table] Example 4 Next, regarding the stabilizing effect when two or more types of stabilizers are added, the combination of capsules in Table 1 and the fine granule formulation of Formulation 3 in Table 6, as shown in Table 8. Capsules and fine granules were prepared by adding the stabilizer shown in Column 2 in the amount shown in Column 3, and a storage test was conducted for 1 year under airtight conditions at room temperature. The change in appearance and the change in the appearance of fine granules are shown, and the fifth
The column indicates the presence or absence of decomposed products by thin layer chromatography. From the results in Table 8, a stabilizing effect was observed by the combined use of magnesium oxide, basic magnesium carbonate, and calcium carbonate. From the results of Examples 1 to 4, at least one of magnesium oxide, basic magnesium carbonate, and calcium carbonate was added to oral preparations (capsules, tablets, granules, fine granules, powders, etc.) of amfenac salt. It has become clear that by adding these compounds, it is possible to produce a formulation that is stable over time.

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Claims (1)

[Claims] 1. A method for producing a stable Amfenac preparation, which comprises adding at least one member selected from magnesium oxide, basic magnesium carbonate, and calcium carbonate in an amount that does not exhibit medicinal efficacy to Amfenac sodium and Amfenac calcium. .