KR101837104B1 - Method for the synthesis of sucralfate and sucralfate synthesized by the same - Google Patents

Abstract

The present invention relates to a synthesis method of sucralfate and to the sucralfate synthesized by the method, and more particularly, to a synthesis method for obtaining sucralfate through the following steps: a first step for producing sucrose polysulfate by sulfating the sucrose; a second step for producing a sucrose polysulfate alkali metal salt by neutralizing the sucrose polysulfate with an alkali metal aqueous solution; a third step for producing the sucrose polysulfate aluminum salt by replacing the alkali metal salt with the aluminum salt in the sucrose polysulfate alkali metal salt; and a fourth step for neutralizing the sucrose polysulfate aluminum salt. The production method of the present invention enables a user to obtain sucralfate satisfying the USP Sucralfate assay article at a high yield.

Description

METHOD FOR THE SYNTHESIS OF SUCRALFATE AND SUCRALFATE SYNTHESIZED BY THE SAME < RTI ID = 0.0 >

The present invention relates to a process for synthesizing sucralate and to sucralate produced thereby.

Sucralate is a basic aluminum sucrose sulfate. These compounds have been used as human medicines to eliminate the symptoms of stomach and duodenal ulcers and promote healing of ulcers.

The action of sucralfate is characterized by a pepsin-binding and dissociation effect. Sucralate is also very resistant and lyses the mucous membranes of the stomach and duodenum with a protective coating, exerting its action at the acidic medium of the digestive tract, especially at a pH below 4. The excellent affinity for binding the damaged mucosal sites increases the protection of the ulcer, promotes the healing of the ulcer and the regeneration of the mucous membrane, as well as its action effect.

Korean Patent No. 10-0453179 discloses that the sucralfate is changed from an acidic stomach fluid to a viscous substance and then applied to the stomach wall to protect the stomach wall from the attacking factors such as gastric acid attacking the stomach wall. In addition, the complex tablet, which contains ranitidine hydrochloride, potassium bismuth citrate, and sucralfate, is commercially available.

Domestic Registration No. 10-0453179 B1 (Oct. 15, 2004)

The present invention provides a novel preparation method of sucralfate that satisfies the USP's Sucralfate assay item and that the sucralfate dissolution rate of the formulation containing the sucralfate is equivalent to the sucralfate dissolution rate of commercially available ≪ RTI ID = 0.0 > sucralfate < / RTI >

The present invention has been made to provide a novel method for producing sucralfate,

A first step of producing sucrose polysulfate by sulfating the sucrose; A second step of preparing a sucrose polysulfate alkali metal salt by neutralizing the sucrose polysulfate with an alkali metal aqueous solution; A third step of preparing a sucrose polysulfate aluminum salt by replacing an alkali metal salt with an aluminum salt in the sucrose polysulfate alkali metal salt; And a fourth step of neutralizing the sucrose polysulfate aluminum salt.

Also, in the method for producing sucralate of the present invention, the fourth step provides a method for producing sucralfate, wherein the sucralose polysulfate aluminum salt is neutralized using an alkaline hydroxide aqueous solution having a normal concentration of 0.6 to 1.5 .

Further, in the sucralate production method of the present invention, the fourth step is a step of neutralizing the sucrose polysulfate aluminum salt by charging at a rate of less than 20000 ml / min without simultaneously supplying the alkaline hydroxide aqueous solution. And a manufacturing method thereof.

In the method for preparing sucralate of the present invention, the third step is carried out in an aqueous solution in the presence of aluminum chloride, and the aluminum chloride is used in a molar ratio of alkali metal salt of sucrose polysulfate to aluminum chloride of 1:15 to 18 By weight based on the total weight of the sucralate.

In the method for preparing sucralate of the present invention, the first step is performed in at least one solvent selected from the group consisting of pyridine, pyridine-sulfur trioxide complex, and chlorosulfonic acid. to provide.

Also, in the sucralate production method of the present invention, the second step is a method for producing sucralfate, wherein the pH concentration of the alkali metal solution is within a range of pH 5.6 to 6.8.

In addition, sucralfate prepared by the sucralfate production method of the present invention is provided.

The preparation method of the present invention makes it possible to obtain sucralate satisfying the US Sucralfate assay item with a high yield, and the sucralfate obtained by this method can be used in a wide range of sizes, such as sucralfate, But also exhibits excellent solubility such that it can be formulated so as to satisfy an equivalent dissolution rate.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a block diagram showing an embodiment where the solvent is a pyridine and a pyridine-sulfur trioxide complex in the method of synthesizing sucralate according to the present invention. FIG.
Fig. 2 is a block diagram showing the case where the solvent is 2-methylpyridine and chlorosulfonic acid in the method of synthesizing sucralate according to the present invention.
FIG. 3 is a block diagram showing the case where the solvent is pyridine and chlorosulfonic acid in the method of synthesizing sucralate according to the present invention.
4 is a photograph showing the dissolution rate of sucralate according to the ultrasonic impact time (in the order of the control group, Examples 1 to 6 from the left side).
5 shows the results of particle size distribution and average particle size measurement of sucralate obtained according to Example 4 of the present invention.
6 shows the particle size distribution and average particle size distribution of sucralfate, a raw material of the manufacturer (BK Giulini, Germany) included in the comparative drug Albisuite ™ in the Drug Equivalence Test vs. Treaty Selection Notice (No. 2017-80) .
Figure 7 shows the results of a comparison of sucralfate dissolution rate at pH 1.2 with a film coating formulation comprising sucralate obtained according to the example of the present invention.
Figures 8 and 10 are graphs of comparative dissolution rates of sucralate at pH 6.8 in a film coating formulation containing sucralate obtained according to the present invention.
Figure 9 is a graph of comparative dissolution rate of sucralfate at pH 6.8 in a film coating formulation containing sucralate obtained according to the present invention.

Hereinafter, the present invention will be described more specifically.

According to an aspect of the present invention,

A first step of producing sucrose polysulfate by sulfating the sucrose; A second step of preparing a sucrose polysulfate alkali metal salt by neutralizing the sucrose polysulfate with an alkali metal aqueous solution; A third step of preparing a sucrose polysulfate aluminum salt by replacing an alkali metal salt with an aluminum salt in the sucrose polysulfate alkali metal salt; And a fourth step of neutralizing the sucrose polysulfate aluminum salt.

In preparing sucralate according to the present invention, it may be synthesized through a sulfation step of the first step sucrose, a second step neutralization step, a third step aluminum substitution step and a fourth step neutralization step, 3 shows an exemplary block diagram for synthesizing 70 kg of sucralfate according to the present invention.

The first step may be carried out in one or more solvents selected from the group consisting of pyridine, pyridine-sulfur trioxide complex, and chlorosulfonic acid. For example, the solvent may be selected from the group consisting of pyridine and a pyridine-sulfur trioxide complex, a chlorosulfonic acid-pyridine complex formed from chlorosulfonic acid and pyridine at low temperature, or a chlorosulfonic acid-pyridine complex formed from chlorosulfonic acid- Pyridine complex. The pyridine-sulfur trioxide complex, the chlorosulfonic acid-pyridine complex, and the chlorosulfonic acid-2-methylpyridine complex produced at a low temperature can be obtained by a combination of a non-covalent electron pair of nitrogen present in pyridine and 2- , Which can act as a catalyst in reacting sucrose with sulfur trioxide.

In the second step, an alkali metal aqueous solution which can be used by a person skilled in the art can be used. As a non-limiting example, the alkali metal aqueous solution may be an aqueous solution of sodium hydroxide or an aqueous solution of potassium hydroxide .

In the second step, in neutralizing sucrose polysulfate with an alkali metal aqueous solution, the pH concentration of the sucrose polysulfate aqueous solution may be in the range of 5.6 to 6.8, preferably in the range of 5.8 to 6.5.

Wherein the third step is carried out in an aqueous solution in the presence of aluminum chloride, wherein the molar ratio of the alkali metal polysulfate to the aluminum chloride is in the molar ratio of 1:15 to 18, preferably 1:16 . The above molar ratio range does not have a comparatively large influence on the elution or solubility in the acidic range but may have a relatively large influence on the elution or solubility in the neutral or basic range such as pH 6.8. A more detailed understanding of this may be made through Examples and Experimental Examples to be described later.

The fourth step is preferably neutralization of the sucrose polysulfate aluminum salt with an alkaline hydroxide aqueous solution having a normal concentration of 0.6 to 1.5, preferably an alkaline hydroxide aqueous solution having a normal concentration of 0.7 to 1.2. More particularly, the neutralization reaction may be by an aluminum hydroxidation reaction of an aluminum salt.

As the alkaline hydroxide aqueous solution, a general alkaline aqueous hydroxide solution which can be used by a person skilled in the art may be used. As a non-limiting example, the alkaline aqueous hydroxide solution may be an aqueous solution of sodium hydroxide, an aqueous solution of potassium hydroxide, Or aqueous calcium hydroxide solution.

Particularly, in the fourth step, the alkaline hydroxide aqueous solution is injected at a rate of not more than 800 ml / min, preferably not more than 800 ml / min, most preferably not more than 500 ml / Min to relatively neutralize the sucrose polysulfate aluminum salt.

Another aspect of the present invention relates to sucralfate prepared by the sucralfate production method of the present invention,

Wherein the content of sucrose octasulfate defined by the following formula (1) is at least 30%

The average particle size is within the range of 30 to 300 mu m,

wherein the solubility of sucrose octasulfate defined by the following formula (2) is 5 to 15% or more at pH 6.8.

[Equation 1]

Where C is the mg / ml concentration of anhydrous potassium sucrose octasulfate in the standard solution, R _u is the peak response of sucrose octasulfate determined from the test solution, and R _s is the peak response of sucrose octasulfate determined from the standard solution.

&Quot; (2) "

Here, the standard product is potassium sucrose octasulfate defined according to USP, and 11.4 mg of the standard product is precisely weighed into a 10 ml volumetric flask. 1 ml of the standard stock solution obtained by adding water is placed in a 10 ml volumetric flask, The test solution is prepared by precisely weighing 33.4 mg of sucralfate to be measured, placing it in a 100 ml volumetric flask, circulating it in 100 ml of diluent, stirring at 38 ° C for 30 minutes, and then taking the supernatant.

The sucralate may have an average particle size of 30 to 300 탆, for example, 50 to 250 탆, 100 to 200 탆, or 110 to 170 탆.

In the present specification, the average particle size means the volume weighted mean D [4,3] value as the center of gravity of the distribution as the average of the volume or mass, respectively.

The average particle size and particle size distribution of sucralate particles can be measured using a commercially available apparatus based on the laser diffraction / scattering method based on the Mie theory. For example, a commercially available device such as a Mastersizer laser diffraction device manufactured by Malvern Instruments. In this device, scattering occurs when a helium-neon laser beam and a blue light emitting diode are irradiated to a particle, a light scattering pattern appears on the detector, and the light scattering pattern is analyzed according to the Mie theory to obtain a particle diameter distribution. The measurement method can be either dry or wet method.

Also, the sucralfate of the present invention can be used to produce tablets satisfying the same level of solubility of sucralfate as that of Alvise ^TM and having excellent solubility. In particular, sucralfate according to the present invention, an average particle size in spite of a relatively large, and the average particle size indicates the dissolution no less than the material sucralfate small Albis information ^TM, is also excellent in solubility. The solubility is preferably within a range of 5 to 15%, and if it is outside this range, it becomes very difficult to control the dissolution rate at pH 6.8 to an equivalent level. More details of this will be understood through the following examples and experimental examples.

Hereinafter, the present invention will be described in more detail by way of examples. It is to be understood that the following embodiments are for the purpose of illustration only, and are not intended to limit the scope of the invention.

Example

Example  One

33.6 L of pyridine was added to the reaction tank, and 42.7 kg of pyridine-sulfur trioxide complex was added thereto and stirred. To this was added 11.5 kg of white sugar, and the mixture was thoroughly stirred and reacted at 65 to 70 ° C for 6 hours. An aqueous solution of sodium hydroxide prepared by stirring 101.8 L of purified water and 10.7 kg of sodium hydroxide was added to the above reactant and neutralized by stirring. When layer separation occurred, the lower layer was recovered and diluted to 101.8 L of purified water. 712.7 L of purified water and 71.6 kg of aluminum chloride were added to the diluted neutralized water, and the reaction was carried out by adjusting the molar ratio of sucrose octasulfate to aluminum chloride to 1: 8. The sucrose octasulfate aluminum salt, which is the reactant, was neutralized by the addition of 0.7N aqueous sodium hydroxide solution at a rate of 500ml / min to adjust the pH to 4.5. The reaction product was washed with water, filtered under reduced pressure, and dried to obtain sucralfate .

Example 2

Sucralate was obtained under the same conditions as in Example 1 except that the sucrose octasulfate aluminum salt was neutralized by the addition of a 2N aqueous sodium hydroxide solution while stirring.

Example 3

33.6 L of pyridine was added to the reaction tank, and 42.7 kg of pyridine-sulfur trioxide complex was added thereto and stirred. To this was added 11.5 kg of white sugar, and the mixture was thoroughly stirred and reacted at 65 to 70 ° C for 6 hours. Sodium hydroxide aqueous solution prepared by stirring 101.8 L of purified water and 10.7 kg of sodium hydroxide was added to sucrose octasulfate as the above reactant, and the mixture was stirred to neutralize to pH 6.2. When layer separation occurred, the lower layer was recovered and diluted to 101.8 L of purified water. 712.7 L of purified water and 71.6 kg of aluminum chloride were added to the diluted neutralized water and the reaction was carried out by adjusting the molar ratio of sucrose octasulfate to aluminum chloride to 1:16. Sodium sucrose octasulfate as the reactant was neutralized by adding 0.5 N sodium hydroxide aqueous solution at a rate of 500 ml / min to adjust the pH to 4.5. The reaction product was washed with water, filtered under reduced pressure, and dried to obtain sucralfate .

Example  4

Sucralate was obtained under the same conditions as in Example 3, except that the sucrose octasulfate aluminum salt was neutralized by the addition of a 0.7 N aqueous sodium hydroxide solution while stirring.

Example  5

Sucralate was obtained under the same conditions as in Example 3, except that the sucrose octasulfate aluminum salt was neutralized by the addition of a 1N aqueous sodium hydroxide solution while stirring.

Example 6

Sucralate was obtained under the same conditions as in Example 3 except that the sucrose octasulfate aluminum salt was neutralized by the addition of a 2N aqueous sodium hydroxide solution while stirring.

Example  7

Sucralate was obtained under the same conditions as in Example 4, except that a sucrose octasulfate aluminum salt was neutralized by the addition of an aqueous 0.7 N sodium hydroxide solution at a time with impulse injection and neutralization (at a rate of about 20000 ml / min) while stirring.

Example 8

To the reaction tank, 108.5 L of 2-methylpyridine was added, and 19.1 L of chlorosulfonic acid was slowly added while maintaining the temperature at 10 to 20 ° C. 11.6 kg of white flakes were added thereto and stirred at 60 to 65 ° C for 3 hours. After the reaction was completed, the mixture was allowed to cool to room temperature, and the supernatant was removed. To this was added 4.0 M sodium hydroxide aqueous solution (about 150 L) to neutralize pH 6.2. To this was added 95.2 kg of charcoal activated, and the mixture was stirred for 1 hour while being kept at 80 캜 and bleached. Cooled at room temperature, filtered under reduced pressure, and then diluted with 1,021 L of purified water. Then, an aqueous aluminum solution (72.5 kg of aluminum chloride, 721 L of purified water) was added thereto so that the molar ratio of sucrose octasulfate to aluminum chloride was 1: 16, stirred for 1 hour, and then 0.7N sodium hydroxide aqueous solution 2,600 L) was added to adjust the pH to 4.5. The reaction was then washed with water, filtered under reduced pressure and then dried to obtain sucralfate.

Example 9

68.0 L of pyridine was added to the reaction vessel, and 19.1 L of chlorosulfonic acid was slowly added thereto while maintaining the temperature at 5 to 10 ° C. 11.6 kg of white flakes were added thereto and stirred at 65 to 70 ° C for 3 hours. After the reaction was completed, the reaction mixture was allowed to cool to room temperature. To this was added 4.0 M sodium hydroxide aqueous solution (about 150 L) to neutralize pH 6.2. When layer separation occurred, the lower layer was recovered and diluted to 1,020 L of purified water. Then, an aqueous aluminum solution (72.5 kg of aluminum chloride, 721 L of purified water) was added thereto so that the molar ratio of sucrose octasulfate to aluminum chloride was 1: 16, stirred for 1 hour, and then 0.7N sodium hydroxide aqueous solution 2,000 L) was added to adjust pH to 4.5. The reaction was then washed with water, filtered under reduced pressure and then dried to obtain sucralfate.

Example  10

Sucralate was obtained under the same conditions as in Example 4, except that sucrose octasulfate was added with an aqueous solution of sodium hydroxide and stirred to neutralize the solution to pH 5.2.

Example  11

Sucralate was obtained under the same conditions as in Example 4, except that sucrose octasulfate was added to an aqueous solution of sodium hydroxide to stir to neutralize the solution to pH 5.8.

Example  12

Sucralate was obtained under the same conditions as in Example 4, except that sodium hydroxide aqueous solution was added to sucrose octasulfate and stirred to neutralize to pH 6.5.

Example  13

Sucralate was obtained under the same conditions as in Example 4, except that sucrose octasulfate was added to an aqueous sodium hydroxide solution and stirred to neutralize to pH 7.0.

Example  14

To 100 mg of sucralfate obtained in Example 1, 100 mg of potassium bismuth citrate and 84 mg of ranitidine hydrochloride as active ingredients, 97 mg of microcrystalline cellulose, 45 mg of croscarmellose sodium and 15 mg of a lubricant (colloidal silicon dioxide 15 mg, magnesium stearate 25 mg ), And the mixture was directly coated and kneaded with a coating agent (Opadry 88A610005 32 mg) to prepare a film-coated tablet.

Example  15

A film-coated tablet was prepared under the same conditions as in Example 14, except that a film-coated tablet containing sucralfate obtained by Example 3 was prepared.

Example  16

A film-coated tablet was prepared under the same conditions as in Example 14, except that a film-coated tablet containing sucralfate obtained by Example 4 was prepared.

Example  17

A film-coated tablet was prepared under the same conditions as in Example 14, except that a film-coated tablet containing sucralfate obtained by Example 5 was prepared.

Example  18

A film-coated tablet was prepared under the same conditions as in Example 14, except that a film-coated tablet containing sucralfate obtained by Example 8 was prepared.

Example  19

A film-coated tablet was prepared under the same conditions as in Example 14, except that a film-coated tablet containing sucralfate obtained by Example 9 was prepared.

Example  20

A film-coated tablet was prepared under the same conditions as in Example 14, except that a film-coated tablet containing sucralfate obtained by Example 7 was prepared.

Comparative Example

Comparative Example  One

In the Drug Equivalence Test vs. Treaty Selection Notice (No. 2017-80), the source of sucralfate, a raw material of the manufacturer (BK Giulini, Germany) included in the comparative drug,

Comparative Example  2

Albisung ™ (Manufacturing and sales: Daewoong Pharmaceutical)

Experimental Example

Experimental Example  1. sucrose Octasulfate  Content test

The following experiment was conducted to confirm that sucralfate obtained through Examples 1 to 9 satisfied sucrose octasulfate content (30 to 38%) through USP's sucralfate assay item.

Mobile phase: 132 g of ammonium sulfate was dissolved in 900 ml of water, diluted to 1000 ml with water, and mixed. After that, the pH of the solution was adjusted to pH 3.5 ± 0.1 with phosphoric acid, followed by vacuum filtration.

Standard solution: sucrose octasulfate potassium standard foam was prepared and dissolved in a mobile phase to give a concentration of 10 mg / ml.

Test solution: 450 mg of sucralfate obtained in Examples 1 to 9 and Comparative Example 1 (control) was placed in a 35 ml centrifuge tube, and 10 ml of a solution prepared by mixing 4 N sulfuric acid and 2.2 N sodium hydroxide in the same ratio was added thereto. Lt; / RTI > After stirring, the solution was ultrasonicated for 5 minutes while keeping the temperature below 30 캜. The solution was adjusted to pH 2 with 0.1 N sodium hydroxide while stirring. This amount was called V (ml), and this solution was diluted with (15.0-V) ml of water. The mixture was mixed for 1 minute and centrifuged for 5 minutes. The pH of the clear supernatant was measured by standing at room temperature. If the pH is not between 2.3 and 3.5, adjust to 0.1 N sodium hydroxide.

HPLC operating conditions

Column: Aminopropylsilyl silica gel (4.6 x 250 mm, 5 탆)

- Column temperature: 30 ° C

- Flow rate: 1 ml / min

- Detector: Differential refractometer (RID)

- Injection amount: 50 μl

The sucrose octasulfate content (%) was calculated from the following equations (1) (a) and (b), and the results are shown in Table 1. (In the following formula 1, 974.75 represents the molecular weight of sucrose octasulfate, 1287.53 is the molecular weight of anhydrous potassium sucrose octasulfate, C is mg / ml concentration of anhydrous potassium sucrose octasulfate in the standard solution, R _u is the peak response of sucrose octasulfate obtained from the test solution, R _s is the concentration of sucrose octasulfate peak response).

Sucrose octasulfate content (%) Comparative Example 1 (control group) 33.00 Example 1 31.53 Example 2 30.62 Example 3 35.96 Example 4 35.47 Example 5 35.06 Example 6 33.24 Example 7 34.64 Example 8 34.73 Example 9 31.04 Example 10 27.62 Example 11 31.43 Example 12 36.84 Example 13 28.92

As a result, the content of sucralate octasulfate in sucralfate obtained through Examples 1 to 9 was found to be higher than that of sucrose octasulfate in sucralfate, 30 to 38%, it was confirmed that the Sucralfate assay item of USP was satisfied.

In preparing sucralate according to the present invention, the sucrose octasulfate content of sucralfate as a final product increases as the pH concentration of sucrose octasulfate neutralized with an aqueous solution of sodium hydroxide increases within a certain range .

Experimental Example  2. Identification of particle size distribution and average particle size

The particle size distribution and average particle size of sucralate prepared in Example 4 according to the present invention and Comparative Example 1 (control group) were measured using a Mastersizer 2000 laser diffractometer manufactured by Malvern Instruments. The results of particle size measurement of sucralate prepared in Example 4 are shown in FIG. 5, and the results of particle size measurement of the control group are shown in FIG.

5, the average particle size of sucralate prepared in Example 4 of the present invention is 221.616 탆, the particle size distribution is d (10) is 34.072 탆, d (50) is 187.251 탆, and d (90) Was 458.612 占 퐉.

6, the average particle size of the control group was 3.016 μm, and the particle size distribution was found to be 0.630 μm for d (10), 2.357 μm for d (50), and 6.426 μm for d (90).

Experimental Example  3. Solubility test

(1) Ultrasonic impact test

In confirming the dissolution rate of sucralate prepared according to the example of the present invention, 450 mg of sucralate obtained through Examples 1 to 6 and Comparative Example 1 (control group) was sampled, and a 35 ml centrifuge tube , 10 ml of a solution prepared by mixing 4 N sulfuric acid and 2.2 N sodium hydroxide in the same ratio, stirring for 1 minute, ultrasound shock for 5 minutes while maintaining the solution below 30 ° C, and clarification of the solution after 10 minutes of ultrasonic impact, Table 2 and Fig.

As can be seen from Table 2 and FIG. 4, in Examples 1 to 5, it was confirmed that the solution became clear during an ultrasonic shock for 15 minutes. On the other hand, in Example 6, it was confirmed that the solution was opaque even after 15 minutes of ultrasonic impact. It was confirmed that the solubility of sucralate as a final product tends to be increased as the concentration of sodium hydroxide aqueous solution added during the neutralization of the sucrose octasulfate aluminum salt with an aqueous solution of sodium hydroxide was low.

(2) pH In 6.8 liquid  Solubility assessment

A solubility test at pH 6.8 of sucralate prepared according to the present invention and Comparative Example 1 (control) was carried out.

1) Solubility test conditions

The following experiment was conducted to confirm whether the sucralfate prepared according to the present invention satisfied the same level of physical properties as the control.

Mobile phase: buffer: acetonitrile = 9: 1, followed by filtration under reduced pressure.

(Buffer: 79.3 g of ammonium sulfate was dissolved in 900 ml of water, and the pH was adjusted to 3.5 ± 0.1 with phosphoric acid.

Standard solution: 11.4 mg of potassium sucrose octasulfate standard (USP Potassium Sucrose Octasulfate RS, [CAS-73264-44-5]) was precisely weighed and placed in a 10 ml volumetric flask. Take 1 ml of the standard stock solution, place it in a 10 ml volumetric flask and add water to make the standard solution.

Test solution: 33.4 mg of sucralate obtained in Example 4 and Comparative Example 1 (control group) were precisely weighed and placed in a 100 ml volumetric flask, and the mixture was stirred for 30 minutes at 38 ° C. The supernatant was taken and used as the sample solution.

(Diluent: To 250 ml of 0.2 mol / L potassium dihydrogen phosphate solution, add 118 ml of 0.2 mol / L sodium hydroxide solution and water to make 1000 ml.) The solution is colorless transparent and its pH is about 6.8.

Operating condition

- Detector: Differential refractometer (RI Detector)

- Column: Aminopropyl silylated silica gel for a liquid chromatograph having a pore diameter of 5 탆 is filled in a stainless steel pipe having an inner diameter of 4.6 mm and a length of about 25 cm.

- Flow rate: 1.0 ml / min

- Injection amount: 50 μl

- Column temperature: 35 ° C

2) Solubility test results

The solubility test was carried out as described above and the solubility (%) of sucrose octasulfate (C ₁₂ H ₁₄ O ₃₅ S ₈ ) was calculated through the following equation (2).

(3) Generally, the smaller the average particle size, the higher the elution and the solubility. In view of this, the sucralfate of the present invention, which has a much larger average particle size, shows the same or better solubility in comparison with that of the control group It is a very unusual thing to do.

Experimental Example 4: Comparative dissolution test

(1) Elution test conditions

The sucralate dissolution pattern and the final dissolution rate (the final dissolution rate in the pH 1.2 solution and the final dissolution rate in the pH 6.8 solution and the pH 6.8 solution and the final dissolution rate in the solution of Comparative Example 2 (control agent) were 15 to 30%) For confirmation, the film-coated tablets of Examples 14 to 20 containing sucralfate obtained according to the examples of the present invention were subjected to a dissolution test. The comparative dissolution test was carried out in accordance with " Security Notice No. 2014-188, November 24, 2014). The control protocol used was Daewoong's Alvismnet ™, and the experiment was conducted under the following conditions in accordance with Korean Pharmacopoeia Dissolution Test Method (Paddle Method). HPLC was used for the analysis.

- Eluent: pH 1.2 (the first solution of the disintegration test in General Test Methods for Korean Pharmacopoeia)

          pH 6.8 solution (the second solution of the disintegration test in General Korean Pharmacopoeia)

- Leaching temperature: 37 ± 0.5 ℃

- Rotation speed of paddle: 50rpm

Under the above experimental conditions, 6 samples were taken at 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes, 120 minutes and 180 minutes (120 minutes for pH 1.2, . The eluate was collected in 8 volumes of 180 minutes) and filtered to give a sample solution.

HPLC operating conditions

Column: Aminopropylsilyl silica gel (4.6 x 250 mm, 5 탆)

- mobile phase: buffer: acetonitrile = 9: 1

(Buffer: Ammonium sulfate (79.3 g) was added to make 1000 ml and then adjusted to pH 3.5 with phosphoric acid)

- Column temperature: 30 ° C

- Flow rate: 1 ml / min

- Detector: Differential refractometer (RID)

- Injection amount: 50 μl

(2) Experimental results

The dissolution test was carried out as described above, and the results are shown in Tables 4 to 10 below. As can be seen from Tables 4 to 10, it can be seen that the film-coated tablet containing sucralfate according to the present invention not only satisfies the elution pattern of sucralfate at a level equivalent to that of the reference drug, but also shows the same level in the final dissolution rate.

Table 4 shows the sucralfate dissolution rate of Comparative Example 2, which is commercially available as a comparative product.

pH 1.2 pH 6.8 time Dissolution rate Object deviation Dissolution rate Object deviation 0 0 - 0 - 5 0 ± 0 0 - 10 11.2 ± 5.6 0 - 15 26.5 ± 10.6 0 - 30 58.6 ± 14.8 6.2 ± 2.2 45 71 ± 12.5 7.8 ± 3.2 60 78.8 ± 9.8 9.9 ± 5 90 83.1 ± 5.5 13.0 ± 5.7 120 83.3 ± 5.3 14.4 ± 4.7 180 - - 15.0 ± 3.5

Table 5 below shows the film coating-defined sucralfate dissolution rate according to Example 14. < tb > < TABLE >

pH 1.2 pH 6.8 time Dissolution rate Object deviation Dissolution rate Object deviation 0 0 - 0 - 5 7.8 ± 2.4 1.7 ± 2.2 10 21.6 ± 7.9 3.4 ± 4.8 15 42.6 ± 4.6 10.3 ± 4 30 71.2 ± 7.6 29.6 ± 3.1 45 80.5 ± 7.9 46.1 ± 2.2 60 86.4 ± 10.1 63.4 ± 1.8 90 88.6 ± 8.6 73.0 ± 3.6 120 93.2 ± 8.4 78.2 ± 0.9 180 - - 89.1 ± 1.6

Table 6 below shows the film coating-defined sucralfate dissolution rate according to Example 15. < tb > < TABLE >

pH 1.2 pH 6.8 time Dissolution rate Object deviation Dissolution rate Object deviation 0 0 - 0 - 5 13.6 ± 3.2 5.3 - 10 48.2 ± 5.8 10.6 ± 5.5 15 76.3 ± 10.2 13.7 ± 4.7 30 80.4 ± 7.8 14.4 ± 2.1 45 81.6 ± 6.2 14.6 ± 0.9 60 82.6 ± 8.8 15.2 ± 1.5 90 84.2 ± 6.3 15.1 ± 0.6 120 84.3 ± 8.2 15.6 ± 1.3 180 - - 15.7 ± 1.2

Table 7 below shows the film coating-defined sucralfate dissolution rate according to Example 16.

pH 1.2 pH 6.8 time Dissolution rate Object deviation Dissolution rate Object deviation 0 0 - 0 - 5 1.1 ± 1.3 0 ± 0 10 15.2 ± 3.6 0.2 ± 2.7 15 28.4 ± 5 2.1 ± 3.6 30 62.7 ± 6.3 7.6 ± 0.7 45 73.0 ± 12.2 8.1 ± 3.8 60 80.6 ± 7.8 9.6 ± 4.8 90 84.9 ± 6.2 11.7 ± 3.3 120 85.4 ± 2.6 15.4 ± 0.9 180 - - 16.1 ± 0.6

Table 8 below shows the dissolution rate of sucralfate in film coating according to Example 17.

pH 1.2 pH 6.8 time Dissolution rate Object deviation Dissolution rate Object deviation 0 0 - 0 - 5 0 ± 2.2 0 ± 0 10 12.7 ± 4.8 0 ± 1.3 15 29.6 ± 4.5 0 ± 2.2 30 60.7 ± 8.2 8.7 ± 8.6 45 75.4 ± 7.3 9.9 ± 7.2 60 76.8 ± 6.7 11.2 ± 5.4 90 80.1 ± 5.5 13.6 ± 3.3 120 82.8 ± 1.1 14.9 ± 3.2 180 - - 14.7 ± 2.8

Table 9 below shows the film coating-defined sucralfate dissolution rate according to Example 18.

pH 1.2 pH 6.8 time Dissolution rate Object deviation Dissolution rate Object deviation 0 0 - 0 - 5 0.6 ± 5.5 0 ± 2.4 10 10.1 ± 9.8 0 ± 3.2 15 28.6 ± 10.2 0 ± 3.3 30 55.6 ± 6.3 3.3 ± 1.8 45 70.6 ± 7.2 8.2 ± 2.6 60 76.3 ± 5.2 10.4 ± 1.4 90 82.1 ± 3.3 14.6 ± 0.8 120 82.2 ± 1.8 15.3 ± 0.8 180 - - 15.8 ± 1.1

Table 10 below shows the film coating-defined sucralfate dissolution rate according to Example 19. < tb > < TABLE >

pH 1.2 pH 6.8 time Dissolution rate Object deviation Dissolution rate Object deviation 0 0 - 0 - 5 1.7 ± 6.2 0 ± 4.4 10 10.6 ± 7.1 0 ± 3.2 15 28.2 ± 5.6 0 ± 3.4 30 55.4 ± 8.6 3.3 ± 2.7 45 76.1 ± 10.2 8.2 ± 3.1 60 80.6 ± 8.7 10.4 ± 1.8 90 82.7 ± 5.2 14.6 ± 0.8 120 84.8 ± 5.6 15.3 ± 0.9 180 - - 15.8 ± 0.9

Table 11 below shows the film coating-defined sucralfate dissolution rate according to Example 20. < tb > < TABLE >

pH 1.2 pH 6.8 time Dissolution rate Object deviation Dissolution rate Object deviation 0 0 - 0 - 5 4.7 ± 5.9 0 - 10 8.6 ± 7.9 0.9 ± 3.2 15 26.4 ± 10.5 1.7 ± 3.8 30 58.6 ± 11.3 22.3 ± 2.1 45 77.5 ± 8.2 30.6 ± 2.9 60 84.7 ± 6.6 34.4 ± 3.3 90 85.3 ± 5.2 40.2 ± 1.3 120 86.2 ± 4.3 42.4 ± 1.5 180 - - 48.4 ± 0.9

Referring to Tables 4 to 11 and FIGS. 7 to 10, which are graphical representations thereof, the sucralate dissolution rate at pH 1.2 and pH 6.8, the film coating definition sucralate elution pattern of Examples 16 to 19 And the sucralfate dissolution pattern of the control agent Albisquit ™ were satisfied at the same level, and the final dissolution rate was found to be the same. On the other hand, the film-coated final sucralfate final dissolution rate of Example 15 satisfied the final dissolution rate of sucralfate of the control drug Albispurity, but it was confirmed that the elution pattern was non-dynamic. With respect to the dissolution rate at pH 6.8, the dissolution rate of sucralfate rapidly increased after 15 minutes in the case of the film coating of Example 14 or Example 20, and the elution pattern became non-coincident, and the final dissolution rate was remarkably different I could confirm. In addition, the tablets of the Examples had a smaller overall variation than Comparative Example 2.

Claims (8)

A first step of producing sucrose polysulfate by sulfating the sucrose;
A second step of preparing a sucrose polysulfate alkali metal salt by neutralizing the sucrose polysulfate with an alkali metal aqueous solution;
A third step of preparing a sucrose polysulfate aluminum salt by replacing an alkali metal salt with an aluminum salt in the sucrose polysulfate alkali metal salt; And
And neutralizing the sucrose polysulfate aluminum salt, the method comprising the steps of:
In the second step, the pH adjusted to the alkali metal aqueous solution is within the range of pH 5.6 to 6.8,
Wherein the third step is carried out in an aqueous solution in the presence of aluminum chloride and wherein the aluminum chloride is contained in a molar ratio of alkali metal salt of sucrose polysulfate to aluminum chloride in a molar ratio of 1:15 to 18 Gt; The method for producing sucralfate according to claim 1, wherein the fourth step comprises neutralizing the sucrose polysulfate aluminum salt using an alkaline hydroxide aqueous solution having a normal concentration of 0.6 to 1.5. 3. The method for producing sucralfate according to claim 2, wherein in the fourth step, the alkaline polysulfate aluminum salt is neutralized by adding the alkaline hydroxide aqueous solution at a rate of less than 20000 ml / min. delete The method of claim 1, wherein the first step is performed in at least one solvent selected from the group consisting of pyridine, pyridine-sulfur trioxide complex, and chlorosulfonic acid. delete A sucralate prepared by the process according to any one of claims 1 to 3 and 5. 8. The method of claim 7,
Wherein the content of sucrose octasulfate defined by the following formula (1) is at least 30%
The average particle size is within the range of 30 to 300 mu m,
wherein the solubility of sucrose octasulfate defined by the following formula (2) is within a range of 5 to 15% at pH 6.8.
[Equation 1]

Where C is the mg / ml concentration of anhydrous potassium sucrose octasulfate in the standard solution, R _u is the peak response of sucrose octasulfate determined from the test solution, and R _s is the peak response of sucrose octasulfate determined from the standard solution.
&Quot; (2) "

Here, the standard product is potassium sucrose octasulfate defined according to USP, and 11.4 mg of the standard product is precisely weighed into a 10 ml volumetric flask. 1 ml of the standard stock solution obtained by adding water is placed in a 10 ml volumetric flask, The test solution is prepared by precisely weighing 33.4 mg of sucralfate to be measured, placing it in a 100 ml volumetric flask, circulating it in 100 ml of diluent, stirring at 38 ° C for 30 minutes, and then taking the supernatant.

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