WO2018190493A1 - Method for synthesizing sucralfate and sucralfate thereby - Google Patents

Abstract

The present invention relates to a method for synthesizing sucralfate and sucralfate thereby. More specifically, sucralfate is obtained through: a first step for sulfating sucrose to prepare sucrose polysulfate; a second step for neutralizing the sucrose polysulfate with an alkali metal aqueous solution to prepare a sucrose polysulfate alkali metal salt; a third step for replacing an alkali metal salt with an aluminum salt in the sucrose polysulfate alkali metal salt to prepare a sucrose polysulfate aluminum salt; and a fourth step for neutralizing the sucrose polysulfate aluminum salt.

Description

Sucralate synthesis method and thereby sucralate

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

Sucralate is the basic aluminum sucrose sulfate. The compound is used as a human medicine to remove symptoms of gastric and duodenal ulcers and to promote healing of ulcers.

The action of sucralate is characterized by exhibiting pepsin-binding and antacid effects. Sucralate is also very resistant and works in acidic media of the digestive tract, in particular at pH below 4, lining the mucosa of the stomach and duodenum with a protective coating. Excellent affinity to bind damaged mucous membranes, thereby increasing the protection of the ulcers, promotes healing of the ulcers and regeneration of the mucous membranes, as well as exerts its effect.

Korean Patent No. 10-0453179 discloses that the sucralate is changed from an acidic gastric fluid to a viscous substance and then applied to the gastric wall to protect the gastric wall from attacking the gastric wall. Also available is Alvis Tablet ™, a combination tablet containing ranitidine hydrochloride, potassium bismuth citrate, and sucralate.

[Preceding technical literature]

[Patent Documents]

(Patent Document 1) Domestic Registered Patent No. 10-0453179 B1 (2004.10.15.)

Providing a novel method for producing sucralate that satisfies the Sucralfate assay item of the USP, and the sucralate dissolution rate of the formulation containing the sucralate may exhibit the same level as the sucralate dissolution rate of Alvis tablet ™ in the market. It provides a good solubility of sucralate.

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

A first step of sucrose sucrose to produce sucrose polysulfate; Neutralizing the sucrose polysulfate with an aqueous alkali metal solution to prepare a sucrose polysulfate alkali metal salt; 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 addition, in the method for producing sucralate of the present invention, the fourth step provides a method for producing sucralate, which comprises neutralizing a sucrose polysulfate aluminum salt using an alkaline hydroxide aqueous solution having a normal concentration of 0.6 to 1.5. .

In addition, in the method for producing sucralate of the present invention, the fourth step is the addition of an aqueous alkaline hydroxide solution at a rate of less than 20000ml / min by the addition of a sucralate polysulfate, characterized in that to neutralize the sucrose polysulfate aluminum salt It provides a manufacturing method.

In the method for producing sucralate of the present invention, the third step is performed in an aqueous solution in the presence of aluminum chloride, wherein the aluminum chloride has a molar ratio of 1: 15 to 18 molar ratio of sucrose polysulfate alkali metal salt to aluminum chloride. It provides a method for producing sucralate, characterized in that the ratio.

In the method for producing sucralate of the present invention, the first step is a method for producing sucralate, characterized in that it is made under one or more solvents selected from the group consisting of pyridine, pyridine-sulfur trioxide complex, and chlorosulfonic acid. to provide.

In the method for producing sucralate of the present invention, the second step provides a method for producing sucralate, characterized in that the pH concentration adjusted to the aqueous alkali metal solution is in the range of pH 5.6 to 6.8.

Also provided is a sucralate prepared by the method for producing sucralate of the present invention.

The production method of the present invention enables to obtain a high yield of the sucralate satisfying the Sucralfate assay item of the USP, and the resulting sucralate can be obtained even if the size of the sucralate of the commercially available Albis tablet ™ is different from each other. Nevertheless, it exhibits excellent solubility that can be formulated to satisfy an equivalent dissolution rate.

Figure 1 is a block diagram showing the implementation when the solvent is pyridine and pyridine-sulfur trioxide complex in one method of synthesizing sucralate according to the present invention.

Figure 2 is a block diagram showing the implementation when the solvent is 2-methylpyridine and chlorosulfonic acid in one method of synthesizing sucralate according to the present invention.

Figure 3 is a block diagram showing the implementation when the solvent is pyridine and chlorosulfonic acid in one method of synthesizing sucralate according to the present invention.

4 is a photograph of the dissolution rate of sucralate according to the ultrasonic impact time (from the left side to the control, in the order of Examples 1 to 6).

5 is a result of the particle size distribution and the average particle size measurement of the sucralate obtained by Example 4 of the present invention.

6 is a particle size distribution and average particle size measurement of sucralate as a raw material of a manufacturer (BK Giulini, Germany) included in the Alvis tablet ™ as a reference drug in the notification of drug selection test (2017-80) The result is about.

7 is a result of comparing the sucralate dissolution rate in the pH 1.2 solution of the film-coated tablets containing the sucralate obtained by the Examples of the present invention.

8 and 10 are graphs of the dissolution rate of sucralate in the pH 6.8 solution of the film-coated tablets containing sucralate obtained by the Examples of the present invention.

9 is a graph showing the dissolution rate of sucralate in the pH 6.8 solution of the film-coated tablets containing sucralate obtained by the Examples of the present invention.

Hereinafter, the present invention will be described in more detail.

One aspect of the invention,

A first step of sucrose sucrose to produce sucrose polysulfate; Neutralizing the sucrose polysulfate with an aqueous alkali metal solution to prepare a sucrose polysulfate alkali metal salt; 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 the sucralate according to the present invention, the first step may be synthesized through the sulfation step of sucrose, the second step of neutralization, the third step of aluminum substitution, and the fourth step of neutralization. 3 shows an exemplary block diagram for synthesizing 70 kg of sucralate according to the present invention, the following description will be understood.

The first step may be performed under one or more solvents selected from the group consisting of pyridine, pyridine-sulfur trioxide complex, and chlorosulfonic acid. For example, the solvent may be pyridine and pyridine-sulfur trioxide complex, chlorosulfonic acid-pyridine complex formed from chlorosulfonic acid and pyridine at low temperature, or chlorosulfonic acid-2-methyl produced from chlorosulfonic acid and 2-methylpyridine at low temperature. Pyridine complex. The pyridine-sulfur trioxide complex, the chlorosulfonic acid-pyridine complex produced at low temperature, and the chlorosulfonic acid-2-methylpyridine complex are weakly bonded as a non-covalent electron pair of sulfur present in pyridine and 2-methylpyridine as a complex. To form a, it can act as a kind of catalyst in the reaction of sucrose and sulfur trioxide.

In the second step, the alkali metal aqueous solution may be a general alkali metal aqueous solution which may be used by those skilled in the art, and as a non-limiting example, the alkali metal aqueous solution may be an aqueous sodium hydroxide solution or potassium hydroxide solution. Can be.

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

The third step is carried out in an aqueous solution in the presence of aluminum chloride, wherein the aluminum chloride has a molar ratio of sucrose polysulfate alkali metal salt to aluminum chloride in a molar ratio of 1: 15 to 18, preferably a molar ratio of 1: 16 Can be. The molar ratio range does not significantly affect the dissolution or solubility in the acidic range, but may have a relatively large effect on the dissolution or solubility in the neutral or basic range such as pH 6.8. A more detailed understanding of this may be made through the following Examples and Experimental Examples.

In the fourth step, it is preferable to neutralize 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. In more detail, the neutralization reaction may be due to the aluminum hydroxylation reaction of the aluminum salt.

The alkaline hydroxide aqueous solution may be used a general alkaline hydroxide aqueous solution that can be used by those skilled in the art, non-limiting examples of the alkaline hydroxide aqueous solution is sodium hydroxide aqueous solution, potassium hydroxide aqueous solution, Or calcium hydroxide aqueous solution.

In particular, the fourth step is not an impulse addition of an aqueous alkaline hydroxide solution (for example, at a very rapid rate of about 20000 ml / min or more), preferably 800 ml / min or less, most preferably 500 ml It is preferable to neutralize the sucrose polysulfate aluminum salt by introducing it relatively slowly at a rate of / min or less.

Another aspect of the present invention relates to a sucralate produced by the sucralate production method of the present invention,

Sucrose octasulfate content is defined by the following formula (1) is at least 30% or more,

Average particle size is within the range of 30 ~ 300㎛,

At pH 6.8, the sucralate is characterized in that the solubility of sucrose octasulfate, defined by Equation 2 below, is at least 5-15%.

[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 obtained from the sample solution, and R _s is the peak response of sucrose octasulfate obtained from the standard solution.

[Equation 2]

Here, the standard is sucrose octasulfate potassium as defined according to USP, and the standard solution is precisely weighed 11.4 mg of the standard, placed in a 10 ml volumetric flask, added 1 ml of the standard stock solution obtained by adding water, and placed in a 10 ml volumetric flask. The test solution is 33.4mg of sucralate to be precisely weighed, placed in a 100ml volumetric flask, labeled with 100ml of diluent, stirred at 38 ° C for 30 minutes, and then taken to the supernatant.

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

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

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

In addition, using the sucralate of the present invention, a tablet that satisfies the level equivalent to the dissolution rate of the sucralate of Albis tablet ^TM and has excellent solubility can be prepared. In particular, although the sucralate of the present invention has a relatively large average particle size, the sucralate of the present invention exhibits a dissolution comparable to that of the raw material sucralate of Alvis tablet ^TM having a smaller average particle size, and also has excellent solubility. It is preferable that the solubility is within the range of 5 to 15%, and when out of this range, it becomes very difficult to adjust the dissolution rate at pH 6.8 to the equivalent level. More details on this will be understood through examples and experimental examples to be described later.

Hereinafter, the present invention will be described in more detail with reference to Examples. The following examples are only for the detailed description of the invention, it is made clear that it is not intended to limit the scope of the rights thereby.

Example

Example 1

33.6 L of pyridine was added to the reactor, and 42.7 kg of pyridine-sulfur trioxide complex was added thereto and stirred. 11.5kg per bag was added thereto and sufficiently stirred, followed by reaction at 65 to 70 ° C for 6 hours. 101.8 L of purified water and 10.7 kg of sodium hydroxide were added to the reaction mixture, followed by neutralization by stirring with an aqueous sodium hydroxide solution. When layer separation occurred, the lower layer was recovered and diluted with 101.8 L of purified water. An aqueous aluminum chloride solution prepared by stirring 712.7 L of purified water and 71.6 kg of aluminum chloride was reacted by adjusting the molar ratio of sucrose octasulfate to aluminum chloride to 1: 8 to the diluted neutralized solution. While stirring the above reacted sucrose octasulfate aluminum salt, neutralizing 0.7N aqueous sodium hydroxide solution at a rate of 500 ml / min to adjust the pH to 4.5, and then washing the reaction with water, filtration under reduced pressure and drying to obtain sucralate. .

Example 2

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

Example 3

33.6 L of pyridine was added to the reactor, and 42.7 kg of pyridine-sulfur trioxide complex was added thereto and stirred. 11.5kg per bag was added thereto and sufficiently stirred, followed by reaction at 65 to 70 ° C for 6 hours. Aqueous sodium hydroxide prepared by stirring 101.8 L of purified water and 10.7 kg of sodium hydroxide was added to the reactant sucrose octasulfate, and the mixture was stirred to neutralize to a pH of 6.2. When layer separation occurred, the lower layer was recovered and diluted with 101.8 L of purified water. An aqueous aluminum chloride solution prepared by stirring 712.7 L of purified water and 71.6 kg of aluminum chloride was reacted by adjusting the molar ratio of sucrose octasulfate to aluminum chloride to 1:16. While stirring the above reacted sucrose octasulfate aluminum salt, neutralizing 0.5N aqueous sodium hydroxide solution at a rate of 500ml / min to adjust the pH to 4.5, and then the reaction was washed with water, filtered under reduced pressure and dried to obtain sucralate. .

Example 4

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

Example 5

Sucralate was obtained under the same conditions as in Example 3 except that the aqueous 1N sodium hydroxide solution was neutralized with stirring while sucrose octasulfate aluminum salt was stirred.

Example 6

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

Example 7

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

Example 8

108.5 L of 2-methylpyridine was added to the reactor, and 19.1 L of chlorosulfonic acid was slowly added while maintaining the temperature at 10 to 20 ° C. 11.6 kg per bag was added thereto and stirred at 60 to 65 ° C. for 3 hours. After the reaction, the mixture was cooled to room temperature and the supernatant was removed. A 4.0 M aqueous sodium hydroxide solution (about 150 L) was added thereto, followed by neutralization at pH 6.2. 95.2 kg of activated carbon (Charcoal activated) was added thereto, and the mixture was stirred and bleached for 1 hour while maintaining at 80 ° C. After cooling to room temperature, the mixture was filtered under reduced pressure and diluted with 1,021 L of purified water. An aqueous aluminum solution (72.5 kg of aluminum chloride, 721 L of purified water) was added to the mixture so that the molar ratio of sucrose octasulfate to aluminum chloride was 1: 16, and stirred for 1 hour, followed by 0.7 N aqueous sodium hydroxide solution (about 500 ml / min). 2,600 L) was adjusted to pH 4.5. The reaction was then washed with water, filtered under reduced pressure and dried to give sucralate.

Example 9

68.0 L of pyridine was added to the reactor, and 19.1 L of chlorosulfonic acid was slowly added while maintaining the temperature at 5 to 10 ° C. 11.6kg per bag was added thereto and stirred at 65˜70 ° C. for 3 hours. After the reaction was completed, it was allowed to cool to room temperature. A 4.0 M aqueous sodium hydroxide solution (about 150 L) was added thereto, followed by neutralization at pH 6.2. When layer separation occurred, the lower layer was recovered and diluted with 1,020 L of purified water. An aqueous aluminum solution (72.5 kg of aluminum chloride, 721 L of purified water) was added to the mixture so that the molar ratio of sucrose octasulfate to aluminum chloride was 1: 16, and stirred for 1 hour, followed by 0.7 N aqueous sodium hydroxide solution (about 500 ml / min). 2,000 L) was adjusted to pH 4.5. The reaction was then washed with water, filtered under reduced pressure and dried to give sucralate.

Example 10

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

Example 11

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

Example 12

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

Example 13

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

Example 14

To 300 mg of sucralate, 100 mg of bismuth citrate, 84 mg of ranitidine hydrochloride obtained by Example 1 as an active ingredient, 97 mg of microcrystalline cellulose, 45 mg of croscarmellose sodium, and a lubricant (15 mg of colloidal silicon oxide, 25 mg of magnesium stearate) ) Was added and coated and coated with a coating base (Opadry 88A610005 32mg) on uncoated tablets 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 including sucralate obtained in Example 3 was prepared.

Example 16

A film coated tablet was prepared under the same conditions as in Example 14 except that the film coated tablet including the sucralate obtained in Example 4 was prepared.

Example 17

A film coated tablet was prepared under the same conditions as in Example 14 except that the film coated tablet including the sucralate obtained in Example 5 was prepared.

Example 18

A film coated tablet was prepared under the same conditions as in Example 14 except that the film coated tablet including the sucralate obtained in 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 including sucralate obtained in Example 9 was prepared.

Example 20

A film coated tablet was prepared under the same conditions as in Example 14 except that the film coated tablet including the sucralate obtained in Example 7 was prepared.

Comparative example

Comparative Example 1

Sucralate, a raw material from a manufacturer (BK Giulini, Germany), included in the Alvis tablet ™, a reference drug, in the notification of selection of a drug-equivalence test (No. 2017-80).

Comparative Example 2

Alvis Tablet ™ (Manufacturing / Sales: Daewoong Pharmaceutical)

Experimental Example

Experimental Example 1. Sucrose octasulfate content test

In order to check whether the sucralate obtained through Examples 1 to 9 satisfies the sucrose octasulfate content (30 to 38%) through the Sucralfate assay item of the USP, the following experiment was performed.

Mobile phase: 132 g of ammonium sulfate was dissolved in 900 ml of water, diluted to 1000 ml with water, and mixed. After calibrating to pH 3.5 ± 0.1 with phosphoric acid and then vacuum filtered.

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

Sample solution: 450 mg of sucralate and Comparative Example 1 (control) obtained through Examples 1 to 9 were added to a 35 ml centrifuge tube, and 10 ml of a mixture of 4N sulfuric acid and 2.2 N sodium hydroxide in the same ratio was added. Stirred for a minute. After stirring, the solution was sonicated for 5 minutes while maintaining the temperature below 30 ° C. While stirring the solution, 0.1N sodium hydroxide was added thereto to adjust the pH to 2. The amount entered at this time was called V (ml), and the solution was diluted with (15.0-V) ml of water. Mix for 1 minute and centrifuge for 5 minutes. The pH of the clear supernatant was measured while standing at room temperature. If the pH was not between 2.3 and 3.5, it was adjusted with 0.1 N sodium hydroxide.

HPLC operating conditions

-Column: Aminopropylsilyl silica gel (4.6 × 250㎜, 5㎛)

-Column temperature: 30 ℃

Flow rate: 1 ml / min

Detector: Differential Refractometer (RID)

Injection volume: 50µl

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

[Equation 1]

The content of sucrose octasulfate in sucralate was calculated through Equation 1, and as a result, as shown in Table 1, the content of sucrose octasulfate in sucralate obtained through Examples 1 to 9 was By satisfying 30 to 38%, it was confirmed that the content of the USP Sucralfate assay.

In the preparation of sucralate according to the present invention, the concentration of sucrose octasulfate in sucralate, which is a final product, increases as the pH concentration adjusted to the aqueous sodium hydroxide solution is increased during neutralization of sucrose octasulfate. Could be confirmed.

Experimental Example 2. Confirmation of Particle Size Distribution and Average Particle Size

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

5, the average particle size of the sucralate prepared according to Example 4 of the present invention is 221.616 μm, and the particle size distribution is 34.072 μm for d (10), 187.251 μm for d (50), and d (90). It could be confirmed that the 458.612㎛.

Referring to FIG. 6, the average particle size of the control group was 3.016 μm, and the particle size distribution was 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 the sucralate prepared according to the embodiment according to the present invention, the sucralate and Comparative Example 1 (control) obtained through the above Examples 1 to 6 to 450mg to 35ml centrifuge tube 10 ml of a mixture of 4N sulfuric acid and 2.2 N sodium hydroxide in the same ratio was added thereto, and after stirring for 1 minute, the solution was kept at 30 ° C. or lower for 5 minutes by ultrasonic shock, and additionally after 10 minutes by ultrasonic shock. Table 2 and FIG. 4.

Looking at the Table 2 and Figure 4, in the case of Examples 1 to 5 it could be confirmed that the solution is clear during the 15 minutes ultrasonic shock. On the other hand, in the case of Example 6, even after 15 minutes ultrasonic shock it was confirmed that the solution is opaque. The lower the normal concentration of the aqueous sodium hydroxide solution when the sucrose octasulfate aluminum salt was neutralized with an aqueous sodium hydroxide solution, the higher the solubility of the final product, sucralate was confirmed.

(2) Solubility evaluation in pH 6.8 liquid

Solubility test in pH 6.8 liquid of the sucralate synthesized by the present invention and Comparative Example 1 (control) was performed.

1) Solubility Test Condition

In order to confirm whether the sucralate prepared by the present invention satisfies the same physical properties as the control group, the following experiment was conducted.

Mobile phase: Buffer: acetonitrile = 9: 1 and filtered under reduced pressure.

(Buffer: 79.3 g of ammonium sulfate was added, dissolved in 900 ml sufficiently with water, and then adjusted to 1000 ml and adjusted to pH 3.5 ± 0.1 with phosphoric acid.)

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

Sample solution: 33.4 mg of the sucralate and Comparative Example 1 (control) obtained through Example 4 were precisely weighed, placed in a 100 ml volumetric flask, labeled with 100 ml of diluted solution, and stirred at 38 ° C. for 30 minutes. The supernatant was taken to be a sample solution.

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

Operation condition

-Detector: RI Detector

Column: Fill a stainless steel pipe with an inner diameter of 4.6 mm and a length of about 25 cm with aminopropylsilylated silica gel for liquid chromatograph with a pore diameter of 5 µm.

-Flow rate: 1.0 ml / min

Injection volume: 50µl

-Column temperature: 35 ℃

2) Solubility test result

The solubility test was conducted as described above, and the solubility (%) of sucrose octasulfate (C ₁₂ H ₁₄ O ₃₅ S ₈ ) was calculated through Equation 2 below, and the results are shown in Table 3 below.

[Equation 2]

(3) In general, the smaller the average particle size, the higher the dissolution and solubility. In light of this, the sucralate of the present invention having a much higher average particle size shows the same or better solubility than that of the control group. Is very unusual.

Experimental Example 4. Comparative Dissolution Test

(1) elution test conditions

Sucralate dissolution pattern and final dissolution rate (final dissolution rate in pH 1.2 solution of 70 to 90%, final dissolution rate in pH6.8 solution of 15 to 30%) equivalent to Comparative Example 2 (control) In order to confirm the elution experiment was carried out after the production of film coated tablets Examples 14 to 20 containing the sucralate obtained by the embodiment of the present invention. The comparative dissolution test was "pharmaceutical product equivalence test criteria" (Food and Drugs) It was carried out according to the Ministry of Safety Notice No. 2014-188, 2014.11.24. As a reference drug, Daewoong Pharma's Alvis Tablet ™ was used, and the experiment was conducted under the following conditions according to the method of eluting drug dissolution test method 2 (paddle method), and the assay was performed by HPLC method.

-Eluent: pH 1.2 solution (1st solution of disintegration test method of the Korean Pharmacopoeia)

          pH6.8 solution (2nd solution of disintegration test method of the Korean Pharmacopoeia General Test Methods)

Elution temperature: 37 ± 0.5 ℃

Paddle rotation speed: 50 rpm

Under the above experimental conditions, each of the six specimens, 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes, 120 minutes, 180 minutes (pH 1.2 liquid 120 minutes, and pH 6 Eluate was collected and filtered to obtain a sample solution.

HPLC operating conditions

-Column: Aminopropylsilyl silica gel (4.6 × 250㎜, 5㎛)

Mobile phase: buffer: acetonitrile = 9: 1

(Buffer: Take 79.3 g of ammonium sulfate, add water to make 1000 ml, and adjust pH to 3.5 with phosphoric acid.)

-Column temperature: 30 ℃

Flow rate: 1 ml / min

Detector: Differential Refractometer (RID)

Injection volume: 50µl

(2) Experiment result

The dissolution test was conducted as described above, and the results are shown in Tables 4 to 10 below. Looking at Tables 4 to 10, it can be seen that the film-coated tablets containing sucralate according to the present invention not only satisfy the dissolution pattern of sucralate at the same level as the reference drug, but also show the same level in the final dissolution rate.

Table 4 below shows the sucralate dissolution rate of Comparative Example 2 which is commercially available Alvis Tablet ™ as a reference.

Table 5 shows the sucralate dissolution rate of the film-coated tablets according to Example 14.

Table 6 shows the sucralate dissolution rate of the film-coated tablets according to Example 15.

Table 7 shows the sucralate dissolution rate of the film-coated tablets according to Example 16.

Table 8 shows the sucralate dissolution rate of the film-coated tablets according to Example 17.

Table 9 shows the sucralate dissolution rate of the film-coated tablets according to Example 18.

Table 10 shows the sucralate dissolution rate of the film-coated tablets according to Example 19.

Table 11 shows the sucralate dissolution rate of the film coated tablet according to Example 20.

Referring to Tables 4 to 11 and FIGS. 7 to 10, which are graphs, the sucralate dissolution patterns of the film-coated tablets of Examples 16 to 19 in the sucralate dissolution rate in the pH 1.2 solution and the pH6.8 solution. It was confirmed that the sucralate dissolution pattern of the Alvis tablet ™ and the control drug satisfies the equivalent level, and also satisfies the equivalent level in the final dissolution rate. On the other hand, the final dissolution rate of the sucralate of the film-coated tablet of Example 15 satisfied the same level as the final dissolution rate of the sucralate of the control drug Alvis tablet ™, but it was confirmed that the dissolution pattern is not equivalent. In addition, in the case of the film-coated tablets of Example 14 or 20 with respect to the dissolution rate in the pH 6.8 solution, the sucralate dissolution rate rapidly increased after 15 minutes, resulting in dissolution patterns, and the final dissolution rate was significantly different. I could confirm it. In addition, the tablets of the Example had smaller individual deviations as compared with Comparative Example 2.

Claims (8)

1. A first step of sucrose sucrose to produce sucrose polysulfate;

   Neutralizing the sucrose polysulfate with an aqueous alkali metal solution to prepare a sucrose polysulfate alkali metal salt;

   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 method for producing sucralate comprising the fourth step of neutralizing the sucrose polysulfate aluminum salt.
2. The method of claim 1, wherein the fourth step is a method for producing sucralate, characterized in that to neutralize the sucrose polysulfate aluminum salt using an aqueous alkaline hydroxide solution of normal concentration 0.6 to 1.5.
3. The method of claim 2, wherein the fourth step is a method of producing sucralate, characterized in that neutralizing the sucrose polysulfate aluminum salt by adding the aqueous solution of alkaline hydroxide at a rate of less than 20000ml / min.
4. The method of claim 3, wherein the third step is performed in an aqueous solution in the presence of aluminum chloride, wherein the aluminum chloride includes a molar ratio of sucrose polysulfate alkali metal salt to aluminum chloride in a molar ratio of 1:15 to 18. Method for producing sucralate.
5. The method of claim 1, wherein the first step is performed under at least one solvent selected from the group consisting of pyridine, pyridine-sulfur trioxide complex, and chlorosulfonic acid.
6. The method of claim 1, wherein the second step is a method for producing sucralate, characterized in that the pH concentration adjusted to the aqueous alkali metal solution is in the range of pH 5.6 to 6.8.
7. Sucralate produced by the method according to any one of claims 1 to 6.
8. The method of claim 7, wherein

   Sucrose octasulfate content is defined by the following formula (1) is at least 30% or more,

   Average particle size is within the range of 30 ~ 300㎛,

   Sucralate at pH 6.8, characterized in that the solubility of sucrose octasulfate as defined by the following formula (2) is within the range of 5-15%.

   [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 obtained from the sample solution, and R _s is the peak response of sucrose octasulfate obtained from the standard solution.

   [Equation 2]

   

   Here, the standard is sucrose octasulfate potassium as defined according to USP, and the standard solution is precisely weighed 11.4 mg of the standard, placed in a 10 ml volumetric flask, added 1 ml of the standard stock solution obtained by adding water, and placed in a 10 ml volumetric flask. The test solution is 33.4mg of sucralate to be precisely weighed, placed in a 100ml volumetric flask, labeled with 100ml of diluent, stirred at 38 ° C for 30 minutes, and then taken to the supernatant.

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