JP2928261B2 - Method for producing stable polyprenyl compound-containing composition - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a method for producing a stable composition containing a polyprenyl compound, and more particularly to a composition containing a stable polyprenyl compound by adding citric acid or tartaric acid. And a method for producing the same.

[Problems to be solved by the prior art and the invention] General formula (1) (Wherein n represents an integer of 1 to 3) The polyprenyl compound represented by the formula is developed as a prodrug of indomethacin, and is a compound having low toxicity and remarkable anti-inflammatory action.

Many steroid hormones, non-steroid drugs, and anti-inflammatory enzymes have been developed as anti-inflammatory drugs, and in recent years, non-steroidal anti-inflammatory drugs have been actively developed. In particular, there are indoleacetic acid compounds such as indomethacin, phenylacetic acid compounds such as ibuprofen, and acidic compounds such as salicylic acid compounds such as aspirin and salicylic acid.

However, many side effects of nonsteroidal compounds such as gastrointestinal disorders and renal disorders have been reported clinically.

Indomethacin, a representative of indoleacetic acid compounds, which is said to have a strong action among nonsteroidal anti-inflammatory drugs, is widely used as a therapeutic agent for rheumatism in clinical settings and is considered to be therapeutically effective. However, since diseases such as rheumatism require long-term continuous administration, they have side effects such as severe stomach disorder, central action, and renal disorder, and are hampered in use.

As a prodrug of indomethacin, a compound represented by the above general formula (1) has already been developed as a long-lasting anti-inflammatory agent (JP-A-58-15940). Show action. However, this compound has a drawback that the residual ratio decreases with time due to oxidation, which is a bottleneck for practical use.

In particular, since many polyprenyl compounds are fat-soluble substances, they are adsorbed on a powder having a large surface area so as to be suitable for a solid preparation for internal use, so that they are more susceptible to oxidation and it is difficult to ensure quality.

[Means for solving the problem]

In view of such circumstances, the present inventors have studied various stabilization methods in order to find a method that can store the polyprenyl compound represented by the general formula (1) as a stable composition for a long period of time.

It has been reported that indomethacin, which is an indoleacetic acid-based compound, is relatively stable in the neutral region, but the N-amide bond is easily decomposed in the basic region (Shigeru Goto et al .; Pharmacology, 33 (3), 139). (1973), A. Cipiciani et a
l., J. Pharm. Sciences, 72 (9), 1975 (1983)).

On the other hand, it is well known that side chains having a double bond are susceptible to oxidation, so that a stable composition can be obtained by blending citric acid or tartaric acid with the polyprenyl compound. And completed the present invention.

That is, in the present invention, citric acid or tartaric acid is added to 0.1 part by weight of the polyprenyl compound represented by the general formula (1).
It is an object of the present invention to provide a method for producing a stable composition containing a polyprenyl compound, wherein the composition is added in an amount of from 0005 to 0.004 parts by weight.

Among the compounds represented by the general formula (1), which are objects of the present invention, compounds having a remarkable pharmacological action are represented by the following formula (2)
1- (p-chlorobenzoyl) -2-methyl-5-methoxy-3-indolylacetic acid-3,7,11,15-tetramethyl-2,6,10,14 hexadecatetraenyl ester represented by (Hereinafter abbreviated as indomethacin farnesyl).

The amount of citric acid or tartaric acid used in the present invention may be 0.0005 to 0.004 parts by weight, preferably 0.001 part by weight, based on 1 part by weight of the polyprenyl compound represented by the general formula (1). Parts by weight to 0.002 parts by weight.

Further, in the present invention, a mixture of citric acid or tartaric acid and tocopherols may be added. The tocopherols are free tocopherols or tocopherol derivatives, which may be any homologs such as α, β, γ, δ, and particularly preferred examples are dl-α-tocopherol, d-δ
-Tocopherol, natural tocopherol. The addition amount of tocopherols is preferably 0.001 part by weight or more, more preferably 0.001 part by weight to 0.01 part by weight, based on 1 part by weight of the polyprenyl compound represented by the general formula (1). 1: 1 weight ratio
In the case of, a particularly excellent stabilizing effect is exhibited.

〔The invention's effect〕

Hereinafter, the effects of the present invention will be described in detail with reference to experimental examples.
The percentages in the examples are on a weight basis unless otherwise specified.

Experimental Example 1 Stabilizing effect of tartaric acid 15 g of indomethacin farnesyl was dissolved at 60 ° C.
A mixture of 8.92 g of silicic anhydride hydrate and 0.5 g of methylcellulose was added, kneaded, and separately Macrogol 6000 1
g and glycine 0.08 g and tartaric acid in an amount of 0.05% to 0.4% based on indomethacin farnesyl, i.e., 0.008 g, 0.015 g, 0.0
3 g, 0.045 g, and 0.06 g are added, respectively, and a solution obtained by adding and dissolving water is added, kneaded, granulated, and dried at 60 ° C. for 10 hours.

After drying, it is sized to a particle size of 1000 microns, and as a lubricant etc., 1.1 g of carplex, 0.25 g of azecel, aerosil
Add 0.1 g and talc 0.5 g and mix. This was filled into hard capsules to obtain hard capsules.

Separately, a tartaric acid-free product was prepared in the same manner as described above.

The obtained hard capsules were stored at 55 ° C for one month, and the stabilizing effect of tartaric acid was examined by measuring the amount of debenzoyl form of indomethacin farnesyl (vs. indomethacin farnesyl).

 The result is shown in FIG.

Fig. 1 shows that tartaric acid was added to indomethacin farnesyl.
When added in an amount of 0.05% or more, the formation of a debenzoyl derivative of the active ingredient is small, and a stabilizing effect is observed.

Experimental Example 2 Stabilizing and synergistic effect of tocopherol and tartaric acid The compounding weight ratio of natural tocopherol and tartaric acid to 15 g of indomethacin farnesyl was as shown in Table 1,
1, 1: 2, 1: 5 and 1:11 were added and dissolved at 60 ° C. respectively, and a mixture of 8.92 g of anhydrous silicic acid hydrate and 0.5 g of methylcellulose was added and kneaded. You.

In addition, add Macrogol 6000 1g and glycine 0.08g,
The mixture dissolved by adding water is added to the above mixture, kneaded, granulated, and dried at 60 ° C. for 10 hours.

After drying, it is sized to a particle size of 1000 microns, and as a lubricant etc., 1.1 g of Carplex, 0.25 g of Avicel, Aerosil
Add 0.1 g and 0.5 g of talc and knead.

 This was filled into hard capsules to obtain hard capsules.

This hard capsule was stored at 55 ° C. for 13 days, and the stabilizing synergistic effect of tocopherol and tartaric acid was examined by measuring the amounts of the debenzoyl derivative and other decomposed products.

 Table 1 shows the results.

From Table 1, the mixing ratio of tocopherol and tartaric acid is 1: 1.
It can be seen that the case of (1) shows a particularly excellent stabilizing effect.

〔Example〕

Hereinafter, examples in which the method of the present invention is applied to the production of hard capsules will be described.

Example 1 0.25 g of natural tocopherol was added to 150 g of indomethacin farnesyl and dissolved at 60 ° C. Separately, a mixture of 89.2 g of anhydrous silicic acid hydrate and 5.0 g of methylcellulose was added and kneaded.

Macrogol 6000 10g, glycine 0.8g and tartaric acid
A solution obtained by adding 0.25 g, adding water and dissolving is added to the above mixture, kneaded, granulated, and dried at 60 ° C. for 10 hours.

After drying, it is sized to a particle diameter of 1000 microns, and 11 g of carplex, 2.5 g of Avicel, 1.0 g of Aerosil as lubricants, etc.
Add 5.0 g of talc and mix.

 This is filled into hard capsules.

[Brief description of the drawings]

 FIG. 1 is a graph showing the results of Experimental Example 1.

──────────────────────────────────────────────────続 き Continuation of the front page (56) References JP-A-58-15940 (JP, A) JP-A-58-172366 (JP, A) JP-A-58-32873 (JP, A) JP-A-48-48 35025 (JP, A) JP-A-63-198656 (JP, A) JP-A-57-188515 (JP, A) JP-A-51-121509 (JP, A) Pharmaceutical additive research group Products ”(1974) Chemical Industry Co. 218- 219 (58) Fields surveyed (Int. Cl. ⁶ , DB name) A61K 31/405 A61K 47/12 CA (STN)

Claims (1)

(57) [Claims] (1) General formula (Wherein n represents an integer of 1 to 3) Stable polyprenyl compound-containing, characterized by adding 0.0005 to 0.004 parts by weight of citric acid or tartaric acid to 1 part by weight of the polyprenyl compound represented by the formula: Preparation of the composition.