KR101739818B1 - Pharmaceutical composition for oral administration in form of suspension comprising revaprazan or its salt - Google Patents

Abstract

The present invention provides a pharmaceutical composition in the form of a suspension containing levaprazan or its salt for oral administration having excellent dispersion stability and high bioavailability. More particularly, the present invention relates to a pharmaceutical composition comprising revaprazan or a salt thereof; A dispersion stabilizer selected from the group consisting of polyethylene glycol and glycerin; And a pH adjusting agent, in the form of a suspension having a pH of 7 to a pH of 13.

Description

[0001] The present invention relates to a pharmaceutical composition for oral administration in the form of a suspension containing revaprazan or a salt thereof,

The present invention relates to a pharmaceutical composition in the form of a suspension containing levaprazan or its salt for oral administration having excellent dispersion stability and high bioavailability.

Revaprazan is a compound of formula (I) wherein the chemical name is 5,6-dimethyl-2- (4-fluorophenylamino) -4- (1 -methyl-1,2,3,4-tetrahydroisoquinolin- (1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl) pyrimidine) represented by the following formula , Hydrochloric acid, and the like (International Patent Publication Nos. WO96 / 05177, WO97 / 42186, WO98 / 18784, etc.).

Rebaprazan or its salt reversibly binds to the H ⁺ / K ⁺ exchange site of the proton pump (H ⁺ / K ⁺ ATPase) present in the gastric wall cells and competitively inhibits the secretion of H ⁺ into the gastric canal. Rebaprazan or its salt binds to a specific site of the H ⁺ / K ⁺ ATPase, thereby blocking the transport of H ⁺ and increasing the intragastric pH by inhibiting acid secretion into the gut duct. Unlike irreversible proton pump inhibitors such as omeprazole, revaprazan or its salts do not depend on the acid activation of the drug in the stomach or the secretion state of the proton pump. Therefore, based on a different mechanism from irreversible proton pump inhibitors such as omeprazole, revaprazan or its salts are classified as Acid Pump Antagonist (APA).

Rebaprazan has a very low solubility in water with a solubility of less than 0.2 mg / mL and a solubility lower than that of water in a pH 1-12 buffer. Its inherent dissolution rate is also as low as 0.0086 mg / min / cm ² . Because of this low solubility and slow inherent dissolution rate, the elution in the gastrointestinal tract is poor and the oral absorption rate is relatively low. In addition, revaprazan has strong adhesive cohesiveness, and when it is formulated with tablets, capsules, etc., there is a problem that it is adhered to punches, dies, and the like, resulting in poor formulation stability. In order to solve the problem of revaprazan, International Patent Publication No. WO08 / 078922 discloses an oral preparation prepared by solid-dispersing the surface of levaprazan with a water-soluble polymer, a water-soluble saccharide, a surfactant, etc. There is one.

On the other hand, in the case of elderly people, especially elderly people, it is difficult to take a solid preparation such as tablets or capsules, and therefore, a liquid pharmaceutical formulation is required to improve the compliance with the medicines. However, when formulating levaprazan or its salt having a low water-solubility in a liquid form preparation such as a suspension or the like, layer separation and precipitation phenomenon occur.

The present inventors conducted various studies to develop a suspension containing levaprazan or its salt as a suspension having a dispersion stability without causing layer separation phenomenon. As a result, it has been found that when the formulation is formulated to have a certain range of pH using a particular dispersion stabilizer, the resulting suspension remains stable without layer separation and precipitation. It has also been found that such formulated suspensions exhibit good bioavailability.

Accordingly, it is an object of the present invention to provide a pharmaceutical composition in the form of a suspension containing levaprazan or its salt for oral administration having excellent dispersion stability and high bioavailability.

According to one aspect of the present invention, levaprazan or a salt thereof; A dispersion-stabilizing agent selected from the group consisting of polyethylene glycol and glycerin; And a pH adjusting agent, in the form of a suspension having a pH of 7 to a pH of 13.

The pharmaceutical composition in the form of a suspension according to the present invention may further comprise a thickener which provides a viscosity of from 400 cP to 3000 cP, wherein the thickener is polyvinylpyrrolidone; Xanthan gum; Sodium carboxymethylcellulose; And a mixture of microcrystalline cellulose and sodium carboxymethylcellulose.

In addition, the content of the dispersion stabilizer may be in the range of 50 to 2000 parts by weight based on 100 parts by weight of levaprazan or its salt, and the pH adjusting agent may be sodium carbonate, sodium bicarbonate, sodium hydroxide, or a mixture thereof.

The pharmaceutical composition for oral administration in the form of a suspension in the form of a suspension according to the present invention can be formulated to contain a specified dispersion stabilizer, namely polyethylene glycol and / or glycerin, and having a specific range of pH, i.e. pH 7 to pH 13, Exhibit excellent dispersion stability. In addition, the pharmaceutical composition according to the present invention exhibits excellent bioavailability. Therefore, the pharmaceutical composition according to the present invention can be useful for the elderly who have difficulty taking a solid preparation such as tablets or capsules.

Fig. 1 shows the result of observing whether or not the layer obtained after the suspension obtained according to the present invention was allowed to stand at room temperature for 24 hours.
2 is a blood concentration profile obtained after oral administration of a suspension (Group 1) obtained by dispersing in an aqueous solution of 0.5% methylcellulose (MC) and a suspension (Group 2) obtained according to the present invention in rats.

The present invention relates to a pharmaceutical composition comprising revaprazan or a salt thereof; A dispersion-stabilizing agent selected from the group consisting of polyethylene glycol and glycerin; And a pH adjusting agent, in the form of a suspension having a pH of 7 to a pH of 13.

In the pharmaceutical composition of the present invention, the levaprazan or its salt may be used in a therapeutically effective amount, for example, in a range of 10 to 500 mg per suspension unit formulation, but is not limited thereto. The pharmaceutically acceptable salt of levaprazan may be in the form of various acid addition salts including hydrochloride, sulfate, phosphate, nitrate, camphorsulfonate, thiocyanate and the like, preferably it may be revaprazan hydrochloride.

When a specific polymer substance, that is, polyethylene glycol and / or glycerin, is used as a dispersion stabilizer, it is possible that revaprazan or a salt thereof maintains a stable phase without separation or precipitation in an aqueous medium and can achieve a high bioavailability Is found by the present invention. The polyethylene glycol may have various weight average molecular weights, for example, a weight average molecular weight of 200 to 8,000. For example, the pharmaceutical composition according to the present invention may preferably use polyethylene glycol 400. The above-mentioned polyethylene glycol or glycerin may be used alone or in combination with each other. The dispersion stabilizer may be used in an amount that can prevent the precipitation / layer separation phenomenon. For example, the dispersion stabilizer may be added in an amount of 50 to 2000 parts by weight, preferably 200 to 1400 parts by weight, based on 100 parts by weight of revaprazan or its salt Can be used in the negative range. If the content of the dispersion stabilizer is less than the above range, a satisfactory stabilizing effect may not be obtained, and if it exceeds the above range, the bitterness may be increased.

It has also been found by the present invention that the dispersion stability of a suspension containing revaprazan or a salt thereof depends on pH. That is, in order to achieve excellent dispersion stability, a suspension containing revaprazan or a salt thereof must have a neutral pH or higher, and when the acidic pH is used, the dispersion stability is remarkably lowered. Thus, the pharmaceutical composition according to the present invention comprises a pH adjusting agent which maintains the pH in the range of pH 7 to pH 13. The pH adjuster may be an alkaline substance such as sodium carbonate, sodium bicarbonate, or sodium hydroxide, more preferably sodium bicarbonate. Alternatively, various materials capable of maintaining the pH within the above range may be used.

The pharmaceutical compositions in suspension form according to the present invention may be formulated to have a high viscosity suspension form. In other words, the pharmaceutical composition of the present invention may further comprise an enhancer which provides a viscosity of 400 cP to 3000 cP. Various viscosity enhancers commonly used in the field of pharmaceuticals can be used as the incremental agent. For example, the thickener may include polyvinylpyrrolidone; Xanthan gum; Sodium carboxymethylcellulose; And a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose (for example, Avicel RC591 and the like). However, the present invention is not limited thereto.

The pharmaceutical composition in the form of a suspension according to the present invention may contain additives conventionally used in pharmaceuticals, for example, a D-sorbitol solution (for example, in the form of a 70% aqueous solution), xylitol, white sugar, sucralose, etc. Sweetener; Preservatives such as chlorhexidine acetate; Flavoring agents such as mint essence, and the like.

Hereinafter, the present invention will be described in more detail with reference to examples. However, these examples are for illustrating the present invention, and the scope of the present invention is not limited to these examples.

Example  1 to 7

A suspension was prepared according to the ingredients and contents in Table 1 below. That is, the dispersion was prepared by dispersing levasprazan hydrochloride in a dispersion stabilizer. The pH adjusting agent was dissolved in purified water (about half of the amount shown in Table 1), dissolved by adding an aging agent, and then the dispersion was mixed and stirred. D-sorbitol solution (70% aqueous solution) was added to the resulting suspension, and the remaining amount of purified water was added to prepare a suspension. The pH and viscosity of the obtained suspension are shown in Table 1. The obtained suspension was allowed to stand at room temperature for 24 hours, and layer separation and precipitation were observed. As a result, all of the suspensions were stably dispersed without layer separation or precipitation.

ingredient Example One 2 3 4 5 6 7 Levaprazan hydrochloride 100 mg 100 mg 100 mg 100 mg 100 mg 100 mg 100 mg Dispersion
Stabilizer Polyethylene glycol 400 50 mg 400 mg 1000 mg - - - 200 mg glycerin - - - 400 mg 800 mg 2000 mg 400 mg Incrementer Polyvinylpyrrolidone K12 125 mg 125 mg 125 mg 125 mg 125 mg 125 mg 125 mg Xanthan gum 50 mg 50 mg 50 mg 50 mg 50 mg 50 mg 50 mg pH adjusting agent Sodium bicarbonate 80 mg 80 mg 80 mg 80 mg 80 mg 80 mg 80 mg Sweetener D-sorbitol solution (70%) 1000 mg 1000 mg 1000 mg 1000 mg 1000 mg 1000 mg 1000 mg Purified water 7.5 mL 7.5 mL 7.5 mL 7.5 mL 7.5 mL 7.5 mL 7.5 mL Viscosity (cP) 1682 1750 1812 1776 1792 1835 1781 pH 8.4 8.4 8.3 8.4 8.5 8.6 8.4 Layer separation / settling
(Room temperature, 24 hours, fixed) none none none none none none none

Example  8 to 17

As shown in Table 2, a suspension was prepared in the same manner as in Example 1 except that glycerin was used as a dispersion stabilizer and the kind and content of the thickening agent were varied. The pH, viscosity, and standing of the resulting suspension at room temperature for 24 hours were examined for layer separation and precipitation, and the results are shown in Table 2.

ingredient Example 8 9 10 11 12 13 14 15 16 17 Levaprazan hydrochloride 100 mg 100 mg 100 mg 100 mg 100 mg 100 mg 100 mg 100 mg 100 mg 100 mg glycerin 800 mg 800 mg 800 mg 800 mg 800 mg 800 mg 800 mg 800 mg 800 mg 800 mg Incrementer Polyvinylpyrrolidone K12 50 mg 125 mg - - - - - - - 60 mg Xanthan gum 10 mg 50 mg 100 mg - - - - 50 mg 50 mg 25 mg Avicel RC591 - - - 100 mg 200 mg - - 100 mg 50 mg 50 mg Sodium carboxymethylcellulose - - - 150 mg 150 mg 150 mg 250 mg - 75 mg 75 mg Sodium bicarbonate 80 mg 80 mg 80 mg 80 mg 80 mg 80 mg 80 mg 80 mg 80 mg 80 mg D-sorbitol solution
(70%) 1000 mg 1000 mg 1000 mg 1000 mg 1000 mg 1000 mg 1000 mg 1000 mg 1000 mg 1000 mg Purified water 7.5 mL 7.5 mL 7.5 mL 7.5 mL 7.5 mL 7.5 mL 7.5 mL 7.5 mL 7.5 mL 7.5 mL Viscosity (cP) 428 1792 3384 1535 1740 1476 2275 1926 2665 1693 pH 8.4 8.5 8.3 8.4 8.4 8.5 8.5 8.4 8.5 8.4 Layer separation / settling
(Room temperature, 24 hours, fixed) none none none none none none none none none none

Example  18 to 22

As shown in Table 3, a suspension was prepared in the same manner as in Example 1, except that the kind and content of the pH adjusting agent were varied. The pH, viscosity and temperature of the resulting suspension were allowed to stand for 24 hours at room temperature, and then layer separation and precipitation were observed. The results are shown in Table 3.

ingredient Example 18 19 20 21 22 Levaprazan hydrochloride 100 mg 100 mg 100 mg 100 mg 100 mg glycerin 800 mg 800 mg 800 mg 800 mg 800 mg Incrementer Polyvinylpyrrolidone K12 125 mg 125 mg 125 mg 125 mg 125 mg Xanthan gum 50 mg 50 mg 50 mg 50 mg 50 mg pH adjusting agent Sodium bicarbonate 40 mg 120 mg - - - Sodium hydroxide 20 mg 50 mg 100 mg D-sorbitol solution (70%) 1000 mg 1000 mg 1000 mg 1000 mg 1000 mg Purified water 7.5 mL 7.5 mL 7.5 mL 7.5 mL 7.5 mL Viscosity (cP) 1781 1797 1784 1792 1790 pH 8.2 8.9 11.0 11.6 12.9 Layer separation / settling
(Room temperature, 24 hours, fixed) none none none none none

Example  23

12 g of levaprazole hydrochloride was dispersed in 96 g of glycerin to prepare a dispersion. 9.6 g of sodium bicarbonate was dissolved in 400 ml of purified water, 15 g of polyvinylpyrrolidone K12 and 6 g of xanthan gum were added to dissolve, and the dispersion was mixed and stirred. To the resulting suspension was added 120 g of D-sorbitol solution (70% aqueous solution), 144 g of white sugar, 18 g of xylitol and 0.18 g of chlorhexidine acetate, and finally 16 mg of mint essence was added. . The pH and viscosity of the resulting suspension were pH 8.5 and 1800 cP, respectively. The resultant suspension was allowed to stand at room temperature for 24 hours, and the result of the layer separation and precipitation observation was as shown in Fig. As can be seen from Fig. 1, the suspension thus obtained stably dispersed without layer separation or precipitation.

Comparative Examples 1 and 2

A suspension having an acidic pH was prepared according to the ingredients and contents in Table 4 below. A suspension was prepared in the same manner as in Example 1, except that the pH adjuster was used differently. The pH, viscosity and temperature of the obtained suspension were allowed to stand for 24 hours at room temperature, and then layer separation and precipitation were observed. The results are shown in Table 4.

ingredient Comparative Example 1 Comparative Example 2 Levaprazan hydrochloride 100 mg 100 mg glycerin 800 mg 800 mg Polyvinylpyrrolidone K12 125 mg 125 mg Xanthan gum 50 mg 50 mg Citric acid 80 mg 80 mg Sodium citrate 80 mg - D-sorbitol solution (70%) - 80 mg Purified water 7.5 mL 7.5 mL Viscosity (cP) 1452 1475 pH 2.5 6.9 Layer separation / settling
(Room temperature, 24 hours, fixed) Layer separation Layer separation

From the results in Table 4, it can be seen that when the suspension of acidic (pH 2.5) or slightly acidic (pH 6.9) obtained using citric acid or sodium citrate is allowed to stand at room temperature for 24 hours, a distinct layer separation phenomenon occurs. It can be seen that the dispersion stability of the suspension containing revaprazan greatly depends on the pH as well as the kind of the dispersion stabilizer.

Test Example 1. Evaluation of bioavailability of a suspension containing revaprazan hydrochloride

Three groups of Sprague-Dawley rats weighing 200-230 g fasted for 12 hours were divided into two groups. In Group 1, levaspuran hydrochloride was dispersed in an aqueous solution of 0.5% methylcellulose (MC) The obtained suspension was administered, and in the second group, the suspension obtained in Example 23 was orally administered. For oral administration, each suspension was administered at a dose of 40 mg / kg as revaprazan using an oral syringe. After the administration, about 0.3 ml of blood was sampled at 0.25, 0.5, 1, 1.5, 2, 3, 5, and 7 hours with a heparinized syringe. The collected blood was centrifuged at 10,000 rpm for 1 minute, and the plasma was separated and stored frozen at -20 ° C until analysis. The concentration of revaprazan or its salt in plasma was quantified using LC / UV according to the following conditions, and the pharmacokinetic parameters obtained from the blood concentration profile (FIG. 2) are shown in Table 5 below.

<LC / UV condition>

- HPLC system: Accela UPLC system (Thermo scientific, USA)

Analytical column: Hypersil gold (50 x 2.1 mm I.D., 1.9 um)

- Guard cartridge: Phenomenex C18 (4.0 x 2.0 mm I.D)

- Wavelength: 308 nm

- mobile phase: 10 mM ammonium formate (pH 7.4): acetonitrile = 40: 60 (v / v)

- Flow rate: 0.5 mL / min

- Column temperature: 40 ° C

- Autosampler temperature: 10 ° C

- Injection volume: 12.5 uL

- Run time: 2.5 minutes

PK parameters Group 1 Group 2 AUC _0-7 hr (ng · hr / ml) 5712 ± 335 8520 ± 221 Cmax (ng / ml) 1194 ± 70 1752 ± 121 Tmax (hr) 2.0 ± 0.58 2.0 ± 0.58

As can be seen from the results in Table 5 above, the suspensions prepared according to the present invention were both 1.5 times higher in Cmax and AUC _0-7hr values than the suspension in a conventional suspension, i.e., a 0.5% aqueous solution of methylcellulose. From the above results, it can be seen that the suspension according to the present invention not only has excellent dispersion stability, but also exhibits a high bioavailability.

Claims (5)

Levaprazan or a salt thereof; Glycerin as a dispersion-stabilizing agent; Polyvinylpyrrolidone and xanthan gum as thickeners; And a suspension having a viscosity of 1800 cP and a pH of 8.5, comprising sodium carbonate, sodium bicarbonate, sodium hydroxide, or a mixture thereof as a pH controlling agent. delete delete delete delete

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