WO2018190493A1 - Procédé de synthèse de sucralfate et sucralfate ainsi obtenu - Google Patents

Procédé de synthèse de sucralfate et sucralfate ainsi obtenu Download PDF

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WO2018190493A1
WO2018190493A1 PCT/KR2017/015790 KR2017015790W WO2018190493A1 WO 2018190493 A1 WO2018190493 A1 WO 2018190493A1 KR 2017015790 W KR2017015790 W KR 2017015790W WO 2018190493 A1 WO2018190493 A1 WO 2018190493A1
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sucralate
sucrose
solution
polysulfate
alkali metal
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PCT/KR2017/015790
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English (en)
Korean (ko)
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김대익
이광수
신우철
김영찬
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한국프라임제약주식회사
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Priority to CN201780092050.9A priority Critical patent/CN110741012A/zh
Publication of WO2018190493A1 publication Critical patent/WO2018190493A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H23/00—Compounds containing boron, silicon, or a metal, e.g. chelates, vitamin B12

Definitions

  • 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.
  • 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 TM, a combination tablet containing ranitidine hydrochloride, potassium bismuth citrate, and sucralate.
  • Patent Document 1 Domestic Registered Patent No. 10-0453179 B1 (2004.10.15.)
  • sucralate dissolution rate of the formulation containing the sucralate may exhibit the same level as the sucralate dissolution rate of Alvis tablet TM 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 fourth step of neutralizing the sucrose polysulfate aluminum salt is
  • 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. .
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 TM 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.
  • Example 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.
  • FIG 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.
  • 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 fourth step of neutralizing the sucrose polysulfate aluminum salt is
  • 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.
  • 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 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.
  • 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.
  • it can act as a kind of catalyst in the reaction of sucrose and sulfur trioxide.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • an aqueous alkaline hydroxide solution for example, at a very rapid rate of about 20000 ml / min or more
  • 800 ml / min or less most preferably 500 ml
  • 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 ⁇ m
  • sucralate 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%.
  • 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
  • R s is the peak response of sucrose octasulfate obtained from the standard solution.
  • 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 ⁇ m, for example, 50 to 250 ⁇ m, 100 to 200 ⁇ m, or 110 to 170 ⁇ m.
  • 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.
  • 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.
  • 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.
  • 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. .
  • 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.
  • 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. .
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • a coating base Opadry 88A610005 32mg
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • sucralate 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.
  • concentration adjusted to the aqueous sodium hydroxide solution increases during neutralization of sucrose octasulfate.
  • the average particle size of the sucralate prepared according to Example 4 of the present invention is 221.616 ⁇ m, and the particle size distribution is 34.072 ⁇ m for d (10), 187.251 ⁇ m for d (50), and d (90). It could be confirmed that the 458.612 ⁇ m.
  • the average particle size of the control group was 3.016 ⁇ m, and the particle size distribution was 0.630 ⁇ m for d (10), 2.357 ⁇ m for d (50), and 6.426 ⁇ m for d (90).
  • 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.
  • sucralate prepared by the present invention satisfies the same physical properties as the control group.
  • 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.
  • sucrose octasulfate potassium standard USP Potassium Sucrose Octasulfate RS, [CAS-73264-44-5]
  • 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.
  • 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.
  • 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)
  • 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.
  • Daewoong Pharma's Alvis Tablet TM 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.
  • pH6.8 solution (2nd solution of disintegration test method of the Korean Pharmacopoeia General Test Methods)
  • 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.
  • Table 4 below shows the sucralate dissolution rate of Comparative Example 2 which is commercially available Alvis Tablet TM 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.
  • 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 TM and the control drug satisfies the equivalent level, and also satisfies the equivalent level in the final dissolution rate.

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Abstract

La présente invention concerne un procédé de synthèse de sucralfate et le sucralfate ainsi obtenu. Plus spécifiquement, le sucralfate est obtenu par : une première étape destinée à sulfater le saccharose pour préparer du polysulfate de saccharose ; une deuxième étape destinée à neutraliser le polysulfate de saccharose avec une solution aqueuse de métal alcalin pour préparer un sel de métal alcalin de polysulfate de saccharose ; une troisième étape destinée à remplacer le sel de métal alcalin par un sel d'aluminium dans le sel de métal alcalin de polysulfate de saccharose afin de préparer un sel d'aluminium de polysulfate de saccharose ; et une quatrième étape destinée à neutraliser le sel d'aluminium de polysulfate de saccharose.
PCT/KR2017/015790 2017-04-14 2017-12-31 Procédé de synthèse de sucralfate et sucralfate ainsi obtenu WO2018190493A1 (fr)

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CN109431972A (zh) * 2018-11-20 2019-03-08 昆明积大制药股份有限公司 一种粒径为100nm—500nm的硫糖铝凝胶的成胶方法
CN110981922A (zh) * 2019-12-17 2020-04-10 安徽赛诺制药有限公司 一种蔗糖八磺酸酯钾的制备方法

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CN114437149A (zh) * 2020-11-03 2022-05-06 江苏开元药业有限公司 一种药用辅料盐的关键中间体钙盐的制备方法
CN115974938A (zh) * 2022-12-19 2023-04-18 辅必成（上海）医药科技有限公司 一种蔗糖七硫酸酯盐的合成方法

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JPS63107934A (ja) * 1986-05-16 1988-05-12 Chugai Pharmaceut Co Ltd スクラルフェ−ト製剤
WO1990002133A1 (fr) * 1988-08-25 1990-03-08 Formulations Development Laboratories, Inc. Procede de preparation de sucralfate et d'aai-10001
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Publication number Priority date Publication date Assignee Title
US3432489A (en) * 1965-11-05 1969-03-11 Chugai Pharmaceutical Co Ltd Disaccharide polysulfate aluminium compound and method
JPS63107934A (ja) * 1986-05-16 1988-05-12 Chugai Pharmaceut Co Ltd スクラルフェ−ト製剤
WO1990002133A1 (fr) * 1988-08-25 1990-03-08 Formulations Development Laboratories, Inc. Procede de preparation de sucralfate et d'aai-10001
KR100191189B1 (ko) * 1990-08-31 1999-06-15 나가야마 오사무 수크랄페이트 수성 현탁원액의 제조방법
KR100264547B1 (ko) * 1994-04-26 2000-12-01 나가야마 오사무 수크랄페이트의용융조립제제및그의제조방법

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Publication number Priority date Publication date Assignee Title
CN109431972A (zh) * 2018-11-20 2019-03-08 昆明积大制药股份有限公司 一种粒径为100nm—500nm的硫糖铝凝胶的成胶方法
CN109431972B (zh) * 2018-11-20 2022-02-22 昆明积大制药股份有限公司 一种粒径为100nm—500nm的硫糖铝凝胶的成胶方法
CN110981922A (zh) * 2019-12-17 2020-04-10 安徽赛诺制药有限公司 一种蔗糖八磺酸酯钾的制备方法

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