KR0135736B1 - A stable omeprazole resin salt - Google Patents

Abstract

The present invention relates to a salt of an omeprazole and an anion exchange resin, and more particularly to an omeprazole resin salt in which an anion exchange resin selected from the group consisting of omeprazole and cholestyramine resin and a Dowex resin is ion-bonded. Omeprazole resin salt according to the present invention is not only stable to acid, but also provides a variety of release rates according to the type of resin, there is an advantage that can simplify the formulation process of omeprazole and achieve a variety of formulations.

Description

Stable Omeprazole Resin Salt

1 is the IR spectrum of omeprazole cholestyramine salt.

2 is the IR spectrum of the omeprazole Dowex 1 × 8-400 salt.

3 is the IR spectrum of the omeprazole Dowex 1 × 2-400 salt.

4 is the IR spectrum of omeprazole Dowex 1 × 4-400 salt.

5 is the IR spectrum of omeprazole (A) itself.

6 is an IR spectrum of cholestyramine resin.

7 is the IR spectrum of Dow X 1 × 8-400 resin.

8 is a graph showing a comparison of the release pattern of omeprazole resin salts.

The present invention relates to a stable novel omeprazole resin salt, a preparation method thereof and a pharmaceutical preparation containing the same.

Omeprazole, or 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole, has strong gastric acid secretion and is therefore And known compounds having the structure of formula (A), useful for the treatment of duodenal ulcers.

Despite the clinical utility of omeprazole's potent gastric acid secretion, omeprazole is highly unstable under acidic to neutral conditions, which imposes significant constraints on its formulation. Indeed, omeprazole has a half-life of less than 10 minutes under acidic conditions of pH 4 or less, and the decomposition products also exhibit acidity, so the decomposition of omeprazole under acidic conditions accelerates rapidly over time. On the other hand, under neutral conditions of about pH 7.0, the half-life of omeprazole is increased to about 14 hours, its half-life is longer as the pH increases, the half-life is reported to be about 300 days at pH 11. In addition, omeprazole is rarely soluble in water and has been reported to be well soluble in alkaline solutions (Pilbrant and Cedergerg, Scand, J. Gastroenterology, 1985, 20 (Suppl. 108), p113-120). The degradation of omeprazole by acid is explained by acid-catalytic potential reaction [G. Rackur et al., Biochem, Biophys, Res, Commun, 1985; 128 (1), p466-484].

As a means for improving the stability of the omeprazole, various methods have been proposed. For example, Korean Patent Publication Nos. 91-4579 and 87-718 disclose a method of using an inorganic alkalizing agent as a stabilizer for omeprazole. According to these methods, omeprazole was made into a core with an inorganic alkalizing agent, the core was coated with a water-soluble endothelial layer, and finally an enteric coating was applied to prepare an enteric preparation of omeprazole. However, since this method requires a two-stage coating process, the formulation process is very complicated, and since the enteric coating is usually an acidic substance, there is a high possibility of damage of the enteric coating by the inorganic alkalizing agent, which may cause problems in storage stability.

Therefore, the stabilization method using an alkalizing agent is the most basic and conventional stabilization method of omeprazole in view of the instability of the omeprazole, but did not provide satisfactory results in terms of long-term storage stability.

In addition, there have been attempts to improve the stability by converting omeprazole itself into an alkali salt, but such an omeprazole could not obtain satisfactory improvement of the alkali salt. For example, Korean Patent Publication No. 87-1005 discloses that alkali salts of omeprazole, i.e. lithium, sodium, potassium, magnesium, calcium or titanium salts, quaternary alkylammonium salts or guanidine salts have better storage stability than neutral omeprazole. Reported. However, no pH-stability in vivo of the alkali salts of omeprazole has been reported.

Therefore, the present inventors have conducted extensive research to develop a new type of omeprazole derivative which can improve the stability of omeprazole to acid and can freely control the release at a desired site. As a result, when omeprazole is reacted with a specific ion exchange resin to form a resin salt of omeprazole, the fundamental acid-catalytic potential reaction is inhibited to provide an effect of improving the stability of omeprazole as well as appropriately selecting the type and particle size of the ion exchange resin. It was found that the release mode of omeprazole can be freely controlled to complete the present invention.

Accordingly, the present invention relates to an omeprazole resin salt formed by the anion exchange resin of omeprazole combined.

More specifically, the present invention relates to an omeprazole resin salt in which an anion exchange resin selected from the group consisting of omeprazole, cholestyramine resin and Dowex resin is ion-bonded.

Since omeprazole is a positive substance having pKa of 4 and 8.8, any of cation and anion exchange resin can be used as the resin to be combined with omeprazole, but in order to bind omeprazole to cation exchange resin, the reaction must be performed under acidic conditions. Omeprazole is decomposable, which may lower the yield of the resin salt as a product. Therefore, it is preferable to use an anion exchange resin as resin in this invention.

The anion exchange resin preferably used in the present invention is cholestyramine resin (Duolite AP-143), Dowex 1 × 2-400, DowX 1 × 4-400, DowX 1 × 8-400 or DowX 1 × 8-50. For example, when the anion exchange resin used is cholestyramine resin, the omeprazole resin salt according to the present invention can be represented as follows.

Where n corresponds to the degree of polymerization of the resin.

Omeprazole resin salt of the present invention exhibits the desired release properties according to the type of anion exchange resin. For example, when the anion exchange resin is cholestyramine resin, it exhibits rapid release, and when the anion exchange resin is Dow X 1 × 2-400 or Dow X 1 × 4-400, it exhibits normal release properties. In case of Dow X 1 × 8-400 or Dow X 1 × 8-50, it shows sustained release. Thus, the use of the compounds of the present invention provides the advantage of being able to freely control the release rate without the need for a separate means of formulating the active or slow release formulations.

The omeprazole resin salt according to the present invention is prepared by dissolving omeprazole in an aqueous alkali solution to give an anion charge, and then activating an ion exchange resin with an anion exchange resin having a cation charge.

As a method for preparing omeprazole resin salt according to the present invention, omeprazole is first dissolved in an aqueous alkali solution. As the aqueous alkali solution for dissolving omeprazole, any aqueous solution of a conventional water-soluble inorganic or organic base can be used, but an aqueous solution of sodium hydroxide or potassium hydroxide is preferably used in consideration of ease of use and economy.

The anion exchange resin must be activated prior to reacting with omeprazole so that the group -N ⁺ (X) ₃ (where X is H or CH ₃ ) can bind to the anion of the omeprazole. The method for activating the anion exchange resin may use a method conventionally used in the art. For example, the anion exchange resin is washed with alcohol, then filtered and washed again with deionized distilled water, alkali and acid, and finally with deionized water until the washing solution is neutral and warmed to dryness. The method may be used.

The omeprazole resin salt according to the present invention can be obtained by adding and reacting the activated anion exchange resin to an aqueous alkali solution of omeprazole. The coupling reaction of the omeprazole and the resin may be performed for 30 minutes to 10 hours at room temperature to warm.

After the reaction is completed, the product is worked up in a conventional manner to give the desired omeprazole resin salt.

Omeprazole resin salts according to the invention can be used clinically in the same way as omeprazole. However, since the omeprazole resin salt according to the present invention is stable against acidic substances as described above, it is not necessary to mix omeprazole with a stabilizer such as an inorganic alkalizing agent, and before coating an enteric coating composed mostly of acidic substances. This provides an important advantage in formulations that there is no need to coat the omeprazole-containing core with an aqueous endothelium.

In addition, since the omeprazole resin salt of the present invention exhibits various rapid release, sustained release or normal release properties depending on the type of resin used for binding to omeprazole, the omeprazole resin salt exhibits rapid effect with a single dose and is used for a long time. The resin salts with different release forms may be formulated by filling each capsule with enteric pellets in order to sustain the effect.

The dosage of the omeprazole resin salt of the present invention varies depending on the type and severity of the disease, the mode of administration, and the individual conditions of the patient, but generally 1 to 400 mg is administered as omeprazole daily.

The invention is illustrated in more detail by the following examples.

Example 1

Activation of ion exchange resin

a) 5 g of cholestyramine resin is thoroughly washed with 100 ml of ethanol, filtered, and again thoroughly washed with 100 ml of deionized water. The washed cholestyramine resin was washed again in order of 100 ml of 1N-NaOH and 1N-HC1 each, and washed repeatedly with deionized water until the washing solution was neutral. The washed ion exchange resin was filtered and dried at 50 ° C. to obtain an activated cholestyramine resin.

The IR spectrum of the cholestyramine resin is as shown in FIG.

b) 5 g of Dowex 1 × 8-400 resin was washed with 100 ml of ethanol, filtered, and thoroughly washed with 100 ml of deionized water. The washed DowX 1 × 8-400 resin was washed again with 100 ml of 1N-KOH and 1N-H ₂ SO ₄ . Filtration was repeated washing with demineralized water repeatedly until the wash solution was finally neutral, filtered and dried at 50 ° C. to obtain an activated Dowex 1 × 8-400 resin.

The IR spectrum of the Dow X 1 × 8-400 resin is as shown in FIG.

c) after treatment with a resin such as Dow X 1 × 2-400, Dow X 1 × 4-400, Dow X 1 × 8-50 and the like in the same manner as in Example 1-b), Used for binding reactions.

Example 2

Preparation of Omeprazole Cholestyramine Salt

1 g of omeprazole (IR spectrum: FIG. 5) is added to a 100 ml volumetric flask, and 100 ml of 0.1 N-NaOH aqueous solution is added to dissolve completely to obtain a clear aqueous alkali solution of omeprazole. To the obtained aqueous alkali solution of omeprazole, 2 g of cholestyramine resin activated in Example 1-a at room temperature is added and stirred. The reaction solution was aliquoted with stirring and the concentration of omeprazole in the solution was quantified by HPLC to determine the reaction amount of omeprazole and the resin. When the omeprazole no longer reacts by HPLC, the reaction mixture is filtered, and the omeprazole cholestyramine salt obtained by filtration is washed thoroughly with deionized water until the washing solution is neutral and dried. The amount of reacted omeprazole is 0.95 g, thereby obtaining 2.15 g (yield 71.7%) of omeprazole cholestyramine salt. The omeprazole cholestyramine salt obtained is characterized as showing a characteristic peak on the IR spectrum as shown in FIG. 1.

Example 3

Preparation of omeprazole Dow X 1 × 8-400 salt

1 g of omeprazole was placed in a 100 ml volumetric flask, and 100 ml of 0.1 N-NaOH aqueous solution was added to completely dissolve to obtain a clear aqueous alkali solution of omeprazole. To the obtained aqueous alkali solution of omeprazole, 2 g of Dow X 1 × 8-400 resin activated in Example 1-b) at room temperature is added and stirred. The reaction solution was aliquoted with stirring and the concentration of omeprazole in the solution was quantified by HPLC to investigate the progress of the reaction of omeprazole and resin. If the omeprazole no longer reacts by HPLC, the reaction mixture is filtered and the resulting omeprazole Dowex 1 × 8-400 salt is washed thoroughly using deionized distilled water until the wash is neutral and dried. The amount of reacted omeprazole is 0.61 g, thereby obtaining 1.92 g of omeprazole Dowex 1 × 8-400 salt (yield 63.9%), and the obtained omeprazole Dowex 1 × 8-400 salt is shown in FIG. 2 on the IR spectrum. It is specified to exhibit characteristic peaks as shown.

Example 4

Preparation of omeprazole Dowex 1 × 2-400 salt

It was prepared according to the same method as in Example 3, except that 2 g of Dow X 1 × 2-400 resin, which was activated instead of Dow X 1 × 8-400 resin, was used as the resin to be combined with omeprazole. The amount of reacted omeprazole was 0.819 g, to obtain 1.80 g (yield 60.1%) of omeprazole Dowex 1 × 2-400 salt.

The obtained omeprazole Dowex 1 × 2-400 salt is characterized as showing a characteristic peak on the IR spectrum as shown in FIG. 3.

Example 5

Preparation of omeprazole Dowex 1 × 4-400 salt

Use 2g of DowX 1 × 4-400 resin activated instead of DowX 1 × 8-400 resin as the resin to be combined with omeprazole, and use 0.1N KOH instead of 0.1N NaOH as an aqueous alkaline solution for dissolving omeprazole. Except for the same method as in Example 3. The amount of reacted omeprazole was 0.813 g, to obtain 1.90 g (yield 63.3%) of omeprazole Dowex 1 × 4-400 salt.

The obtained omeprazole Dowex 1 × 4-400 salt is characterized as showing a characteristic peak on the IR spectrum as shown in FIG. 4.

Example 6

Comparison of Stability between Omeprazole Resin Salt and Omeprazole

Omeprazole, omeprazole cholestyramine salt, omeprazole sodium salt, and omeprazole magnesium salt in an amount corresponding to 20 mg were exposed under severe conditions (40 ° C., relative humidity 80%), respectively. (Column: μ-Bondpack C18, Detection: UV 280 nm, Fluidized bed: CH ₃ CN: Phosphate buffer solution of pH 7.6 = 34: 66, Injection volume: 10 µl, Flow rate: 1.1 ml / min) was measured. the results are as follow.

TABLE 1

From the results of the stability test, it can be seen that omeprazole resin salt is much more stable than omeprazole and omeprazole sodium salt, and omeprazole resin salt shows an equivalent degree of stability to omeprazole magnesium salt suitable for oral use.

Example 7

Comparison of Solubility between Omeprazole Resin Salt and Omeprazole

Solubility test of omeprazole, omeprazole cholestyramine salt, omeprazole magnesium salt and omeprazole sodium salt in an amount corresponding to 20 mg as omeprazole was conducted by paddle method at a rate of 100 rpm in phosphate buffer at pH 6.8, respectively. At 10, 30 and 60 minutes after the start of the test, the omeprazole content in the solution was measured by HPLC (conditions are the same as in Example 6), and the results are as follows.

TABLE 2

As can be seen from the results of Table 2, omeprazole cholestyramine salt has a higher solubility than omeprazole or omeprazole magnesium salt, and has a solubility equivalent to that of omeprazole sodium salt. According to the dissolution test regulations for omeprazole oral preparations, more than 85% must be dissolved in 10 minutes, so omeprazole itself or omeprazole magnesium salt is not suitable for oral preparations.

As can be seen from the stability and solubility comparison test of Tables 1 to 2, since the omeprazole resin salt of the present invention shows excellent results in terms of both stability and solubility, both of them have poor results with omeprazole or stability and solubility. It is superior to the alkali salts of omeprazole, ie magnesium salts (tablets) or sodium salts (liquids), which are suitable only in one aspect and are suitable for only one formulation in tablets or solutions.

Example 8

Comparison of Release Patterns of Omeprazole Resin Salts

The release pattern in 0.1N-NaOH aqueous solution of cholestyramine salt, Dowx 1 × 2-400 salt, Dowx 1 × 4-400 salt and DowX 1 × 8-400 salt of omeprazole was investigated at room temperature. The results are shown in FIG.

As can be seen from the results shown in FIG. 8, the cholestyramine salt of omeprazole exhibits rapid release, and the omeprazole Dowex 1 × 8-400 salt has slow release and omeprazole Dowex 1 × 2- It can be seen that 400 and 1 × 4-400 salts exhibit moderate release.

Thus, as described above, the resin salts of omeprazole having different release modes may be microcapsulated to prepare pellets, and the pellets may be filled into hard gelatin capsules to be formulated into a preparation that can express the action rapidly and for a long time.

As described above, the omeprazole resin salt of the present invention is essentially stabilized by converting the omeprazole itself into the salt form, so that no separate stabilization by the inorganic alkalizing agent as in the prior art is required, and thus enteric by the inorganic alkalizing agent Since the water-soluble endothelial layer provided to prevent damage to the blood is not needed, the formulation process can be shortened and the cost can be reduced, and the omeprazole release rate can be controlled according to the type of resin to be combined with omeprazole. The benefits that make it possible are provided. Accordingly, the present invention provides an innovative effect in the field of formulation of omeprazole.

Claims (8)

Omeprazole resin salts ion-bonded by an anion exchange resin selected from the group consisting of omeprazole, cholestyramine resin and Dowex resin. The method of claim 1, wherein the Dowex resin is selected from Dow X 1 × 2-400 resin, Dow X 1 × 4-400 resin, Dow X 1 × 8-400 resin and Dow X 1 × 8-50 resin. Omeprazole resin salt. The omeprazole resin salt according to claim 1, wherein the anion exchange resin is cholestyramine resin. The omeprazole is dissolved in an aqueous alkali solution, and the resulting omeprazole aqueous alkali solution is added with an anion exchange resin selected from the group consisting of separately activated cholestyramine resin and Dowex resin to ionic bond. A method for producing omeprazole resin salt according to the above. The method of claim 4, wherein the aqueous alkali solution is an aqueous solution of sodium or potassium hydroxide. 5. The method according to claim 4, wherein the anion exchange resin is washed successively with alcohol, deionized water, alkali and acid, and then washed with deionized water until the wash solution is neutral. The method of claim 4, wherein the ionic bonding reaction is performed at room temperature to warm for 30 minutes to 10 hours. The method of claim 4, wherein the Dow X resin is selected from Dow X 1 × 2-400 resins, Dow X 1 × 4-400 resins, Dow X 1 × 8-400 resins and Dow X 1 × 8-50 resins.