KR960004018B1 - Process for stabilizing preparation of l-glutamine and azulene - Google Patents

Abstract

The stabilization method of a composite antiulcer drug of a L-glutamine and a water-soluble azulene is characterized by adding 0.04˜1.5wt% of a clathrate compound i.e. beta-cyclodextrin, alpha-cyclodextrin, gamma-cyclodextrin, maltosyl cyclodextrin, glucocyclodextrin or methyl cyclodextrin and a filler i.e. carboxymethyl cellulose. The stabilization method prevents an oxidation and a photolysis of the drug, and improves a prolonging property of the drug.

Description

Method for stabilizing L-glutamine and water-soluble azulene complex antiulcer preparations

The present invention is a method for improving the stability of a preparation by adding cyclodextrin as a clathrate compound to a drug obtained by combining L-glutamine and water-soluble azulene.

Originally, L-glutamine and water-soluble azulene alone have been widely used as anti-ulcer and anti-inflammatory drugs for gastrointestinal disorders such as wee ulcer, duodenal ulcer and gastritis.

Water-soluble azulene has the effect of inhibiting histamine release, anti-inflammatory activity, and tissue regeneration, and L-glutamine has anti-ulcer properties. By combining these two components, synergistic effects such as tissue regeneration can be obtained. Recently, a lot of research is being conducted on these.

Azulene compounds are easily oxidized due to light or oxygen in the air, and in acidic solutions, the blue color of the substance itself is discolored, which loses its value as a formulation and decomposes well at room temperature during distribution. There was a problem that the cold storage at the temperature of.

In order to make up for these drawbacks, there have been known methods of preserving sealed containers but substituting oxygen in the containers with nitrogen, maintaining the pH above 7.0 with aqueous solutions, but the materials of the containers are limited. It is a situation that has not been put to practical use due to long-term storage stability problems.

In addition, Japanese Patent Application Laid-Open No. 50-196815 discloses a method of stabilizing by adding a surfactant to a solution containing a water-soluble azulene derivative, and Japanese Patent Laid-Open No. 51-125713 uses an aqueous solution containing a water-soluble azulene derivative. A method of adding cationic surfactants such as tetrabutylammonium salts and backwashing soaps is adopted. These methods are for improving the stability of azulene aqueous solution formulations, which are water-soluble azulene and L-glutamine as in the present invention. It is not suitable when taken orally as a powder or granules such as a combination preparation.

In addition, Japanese Laid-Open Patent Publication 58-144365 is a method for adding condensed phosphate, and Japanese Laid-Open Patent Publication No. 1-121216, a method for adding edetic acid or salts thereof, and Japanese Laid-Open Patent Publication 58-154548. Spray drying or lyophilization as described above may be used as a solid preparation.

However, even in the case of such a method, the cause that does not contribute to the maintenance of stability is a situation that has not been put to practical use because it causes moisture absorption over time to damage the shape of the granules, deteriorate with long-term storage accompanied by odor.

On the other hand, the method of adding a weakly basic alkali salt after mixing the water-soluble azulene and the amino acid (Japanese Patent Publication No. 49-11219) was expected to have some effect on the stabilization of the water-soluble azulene in the solution state, but When formulated with powders, there is an unstable problem.

In addition, the stabilizing method includes a method of stabilizing by adding glycols (Japanese Patent Laid-Open No. 58-1351), but there is a drawback that cannot be put to practical use because it is decomposed again due to an electrophilic substitution reaction of water-soluble azulene.

As mentioned above, water-soluble azulene has high volatility and low melting point, so it is easy to prepare granules of L-glutamine and water-soluble azulene due to its unstable property that drops rapidly at room temperature. There was a problem that the fading effect is reduced or the expensive raw medicines are lost.

The present inventors can specifically stabilize and stabilize the active pentagonal ring portion of the water-soluble azulene by adding an appropriate amount of cyclodextrin while studying to improve the stability by inhibiting the decomposition of L-glutamine and the water-soluble azulene. Not only can it be powdered, but also improves the sustainability of the drug was completed the present invention.

Since the change in the physical properties of the drug due to the inclusion of cyclodextrin is closely related to the molar ratio of the complex and the size of the stability constant, the molar ratio of cyclodextrin is directly correlated with the color of the formulation and the decomposition rate of the water-soluble azulene in the formulation design. There was.

In particular, L-glutamine and water-soluble azulene preparations are degraded or metabolized in the digestive organs, so they may be released into the body in a state in which the medicinal effects cannot be sufficiently exerted, thereby reducing the dosage.

However, since cyclodextrin is hardly absorbed in the digestive organs, cyclodextrin is more effective because only free drug is absorbed after dissolution in the digestive fluid during oral administration.

That is, volatilization, which is a drawback of L-glutamine and a water-soluble azulene complex preparation, was suppressed, and stabilization function was improved by preventing oxidation and photolysis, thereby achieving stability improvement function of an ideal formulation.

In addition to β-cyclodextrin used in the present invention, α-cyclodextrin, γ-citrodextrin or maltosylcyclodextrin, glucocyclodextrin, and methylcyclodextrin can be used.

The amount of cyclodextrin is preferably mixed with an excipient such as carboxymethyl cellulose by adding 0.4 to 15 mg per 1 g of the formulation, in order to prevent chromaticity and decomposition.

As shown in the examples, it was found that in the preparation of L-glutamine and water-soluble azulene preparations, it is possible to improve drug efficacy and stability without being degraded for a long time at room temperature.

As shown in the following Table 1 (Influence of formulation color by the amount of β-cyclodextrin added), when the β-cyclodextrin was added from 2 mg to 15 mg, respectively, the first chromaticity after preparation of the formulation was determined by The absolute value of b was -19 to -20.9 and the value of b was increased to -1.3 as a result of using a color difference meter (Minolta CR-200) based on the color coordinates.

However, at this time, the difference in b value between 0.9 and 1.2 was 0.9 to 1.2, and the difference in b value of the control was 1.0, so that no significant improvement was observed in preventing fading.

In addition, when 30 mg, 45 mg, and 75 mg of β-cyclodextrin were added, respectively, the color was improved from the initial b value of -16.2 without β-cyclodextrin without the addition of 23.3 to -25.5. There was no change.

As can be seen from this, by increasing the amount of β-cyclodextrin added, the value of b was decreased and the difference in b was relatively small over time, indicating that the effect of adding β-cyclodextrin was high.

As a result of measuring the residual azulene in the formulation, the residual ratio of 87% of β-cyclodextrin was added after 3 months in the case of no addition of β-cyclodextrin, but the temperature of the experiment was 25 ° to 40 to 40 mg of β-cyclodextrin. After 3 months at ℃ showed a residual rate of 100% it was found that the stability is significantly improved.

Example 1

500 μl of distilled water and 15 mg of water-soluble azulene were added 4950 mg of L-glutamine, 35 mg of methyl cellulose, and 50 mg of lactose, and 2.0 mg, 3.8 mg, 7.5 mg, 15.0 mg, 30.0 mg, 45.0 without β-cyclodextrin. After the preparation by adding mg, 60mg, 75.0mg, respectively, the discoloration state of the preparation was measured, and the color stability of the preparation was measured after 1 and 2 weeks, thereby obtaining the results shown in Table 1.

In the esophageal measurement test of such a formulation, the absolute value b of the discoloration state of the formulation was measured using a colorimeter (Minolta CR-200) in a constant temperature and humidity chamber with a temperature of 40 ° C and a relative humidity of 80%. .

[Table 1] Effect of formulation color (b value) by the amount of β-cyclodextrin added

Example 2

After dissolving 15 mg of water-soluble azulene and 45 mg of β-cyclodextrin in 500 μ of distilled water, and then adding 4950 mg of 1-glutamine, 35 mg of methyl cellulose, and 50 mg of lactose, the formulation was tested according to the preparation method of Example 1 below. Was carried out.

Stability test of the formulation was stored for 3 months at 25 ° C, 30 ° C, 40 ° C, 50 ° C, respectively to measure the change in the residual rate of water-soluble azulene with time to obtain the results shown in Table 2.

In addition, when the experiment was conducted with no addition of β-cyclodextrin, the residual rate of water-soluble azulene was 87% after 3 months at 25 ° C.

Here, the residual ratio of the water-soluble azulene was accurately taken about 5 g of the formulation in about 100 ml of mesoprask, dissolved in 100 ml of ph 7.0 phosphate buffer solution, stirred for 20 minutes, and the filtrate was measured by absorbance at 570 nm using a spectrophotometer. The residual rate was calculated | required.

Water soluble azulene (mg) = amount of standard product (mg) × absorbance of the sample ÷ absorbance of the standard part

Residual percentage of water-soluble azulene (%) = amount of azulene measured (mg) ÷ amount of first azulene (mg) × 100

[Table 2] Residual rate of water-soluble azulene by storage temperature (unit:%)

Claims (1)

A method for preparing an anti-inflammatory ulcer agent having improved stability by adding 0.04% to 1.5% of cyclodextrin to a combination preparation of L-glutamine and water-soluble azulene.