CN114605563B - Preparation method of icodextrin raw material medicine single enzyme system for peritoneal dialysis solution - Google Patents
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Abstract
The invention belongs to the technical field of medicine preparation, and particularly relates to a preparation method of a single enzyme system of icodextrin raw material medicines for peritoneal dialysis solution. The method sequentially comprises the working procedures of enzymolysis, ultrafiltration and spray drying; the proportion of alpha-1, 6 glucosidic bonds in the starch raw material is controlled, only alpha-high temperature amylase is used for enzymolysis reaction without debranching enzyme for debranching branched chains, ultrafiltration membranes with different pore diameters are used for screening molecular weights, and finally spray drying operation is carried out to obtain the icodextrin with the weight average molecular weight and the number average molecular weight which simultaneously meet the requirements of the proportion of the alpha-1, 6 glucosidic bonds and the proportion of the alpha-1, 4 glucosidic bonds. The invention develops a method for preparing icodextrin by using an alpha-high temperature amylase single enzyme system, has simple process and high preparation efficiency, and is more suitable for industrial amplification.
Description
Technical Field
The invention belongs to the technical field of medicine preparation, and particularly relates to a preparation method of a single enzyme system of icodextrin raw material medicines for peritoneal dialysis solution.
Background
Peritoneal Dialysis (PD) is a home-based renal replacement therapy that is cost effective and achieves similar therapeutic effects to hemodialysis in end-stage renal disease patients (ESRD). Icodextrin (Icodextrin) is a water-soluble glucose polymer, and metabolites are not easily absorbed into the body through the peritoneum. Icodextrin is formed by connecting glucose through alpha-1, 4 and less than 10 percent of alpha-1, 6 glycosidic bonds, has the weight-average molecular weight of 13000Da to 19000Da and the number-average molecular weight of 5000Da to 6500Da, and can reduce the generation of vascular endothelial growth factors and advanced glycosylation end products (AGEs) compared with glucose peritoneal dialysis solution.
At present, the preparation modes of icodextrin are mainly divided into two types, namely acid method preparation and enzyme method preparation.
Chinese patent CN 103467608B discloses a method for preparing icodextrin by acid hydrolysis of starch, which comprises hydrolyzing a starch slurry solution prepared in advance with acid of a certain concentration at a certain temperature to obtain an acidolysis solution, then screening molecular weights by ultrafiltration membranes with different pore diameters, and finally drying to obtain a finished product of icodextrin. Chinese patent CN 105131135B adjusts the feeding sequence, firstly prepares low-concentration acid solution, and then adds corn starch, thus the molecular weight of the prepared hydrolysate is more concentrated; and the icodextrin with qualified molecular weight distribution can be obtained only by one 1000Da ultrafiltration membrane. Chinese patent CN 106755199A mainly improves the decolorization process when preparing icodextrin by acid method, and improves the reaction efficiency by adding activated carbon and chitosan to decolorize once or twice at pH 3-4.
However, the main problems of the acid method for preparing icodextrin are that the conditions for acid hydrolysis of starch are severe, the selectivity is poor, the reaction degree is difficult to control, the molecular weight distribution is wide, and the loss is large when the ultrafiltration process is subsequently used for molecular weight screening, thereby reducing the final yield. Compared with an acid method, the molecular weight distribution of the product obtained by preparing the icodextrin by enzymolysis of the starch is more concentrated, and the consistency of the hydrolyzed product and the original research is better.
Chinese patent CN 10639616A discloses a method for preparing icodextrin raw material by enzyme method, which uses starch as raw material, firstly uses alpha-amylase to make enzymolysis, then uses debranching enzyme to make debranching, finally makes alcohol precipitation, ultrafiltration and chromatographic separation so as to obtain the icodextrin whose weight-average molecular weight, number-average molecular weight and alpha-1, 6 glycosidic bond are in accordance with the requirements. Chinese patent CN 106755199A uses lysozyme to break the cell wall of bacteria and release peptidoglycan, so that the peptidoglycan can be better removed by activated carbon adsorption and ultrafiltration. And in order to facilitate the heating process, debranching by using debranching enzyme with lower proper temperature (40-80 ℃), heating to the proper temperature (80-100 ℃) of alpha-amylase, adding the alpha-amylase for enzymolysis, and finally sequentially carrying out ultrafiltration, decoloration, filtration and spray drying to obtain the icodextrin. However, the two enzymatic processes use various enzymes such as lysozyme, alpha-amylase, debranching enzyme and the like for reaction, the operation is complex, the reaction process is difficult to control, and the two enzymatic processes are not suitable for industrial amplification.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a preparation method of a single enzyme system of an icodextrin raw material medicine for peritoneal dialysis solution, which only uses alpha-high temperature amylase and then combines ultrafiltration and spray drying operations to obtain the icodextrin, and has the advantages of simple and convenient process, simple operation, high preparation efficiency and suitability for industrial amplification.
The invention adopts a gel exclusion chromatography-multi-angle laser scattering method to determine the weight-average molecular weight and the number-average molecular weight of the obtained icodextrin product; by means of H 1 -NMR to determine the hydrogen spectrum of the product; the icodextrin product prepared by the method is found to meet the requirements on the weight-average molecular weight, the number-average molecular weight and the proportion of alpha-1, 4 glycosidic bonds and alpha-1, 6 glycosidic bonds.
In order to achieve the purpose, the invention is realized by the following technical scheme:
the preparation method of the icodextrin bulk drug single enzyme system for the peritoneal dialysis solution comprises the following steps:
(1) Enzymolysis: adding starch into water of 10-40 ℃ to prepare a starch slurry solution with the mass concentration of 5-40%, adding 5-100ppm calcium chloride relative to the starch slurry, adding an alkali aqueous solution to adjust the pH value to 5.0-7.0, stirring and heating to 80-100 ℃, keeping the temperature in the temperature interval and stirring for 30-60min, adding alpha-high temperature amylase to carry out enzymolysis for 60-90min, then adjusting the pH value to 2.0-4.0 by using acid, keeping the temperature at high temperature for 20-30min to inactivate the enzyme, and filtering the enzymolysis liquid with diatomite while the liquid is hot to obtain a filtrate A;
(2) And (3) ultrafiltration: screening the molecular weight of the filtrate A by using a large-aperture ultrafiltration membrane and a small-aperture ultrafiltration membrane in sequence to obtain a feed liquid B of a component with the weight-average molecular weight of 13000Da-19000Da, the number-average molecular weight of 5000Da-6500Da and the mole ratio of alpha-1, 6 glucosidic bonds in starch of less than 10%;
(3) And (3) spray drying: and (3) spraying the material liquid B obtained by ultrafiltration to obtain the icodextrin for the peritoneal dialysis solution.
Wherein:
preferably, in step (1), the starch requires a ratio of alpha-1, 6 glucosidic bonds of not more than 5% (H) 1 NMR determination of the proportion of alpha-1, 6 glycosidic bonds).
Preferably, in the step (1), the starch is selected from one of corn starch, waxy corn starch, wheat starch, sweet potato starch or potato starch. More preferably, the starch is selected from corn starch.
Preferably, in step (1), the α -high temperature amylase is selected from the group consisting of novacin and jerincke high temperature amylases.
Preferably, in the step (1), the mass concentration of the starch slurry is 5-15%.
Preferably, in step (1), the amount of the anhydrous calcium chloride is 10-100ppm per gram of starch slurry, more preferably 10-20ppm.
Preferably, in step (1), the alkali is selected from sodium hydroxide or potassium hydroxide, and the concentration is 0.1-1M.
Preferably, in step (1), the acid is selected from hydrochloric acid, sulfuric acid or acetic acid, and the concentration is 0.1-1M.
Preferably, in the step (2), the ultrafiltration pressure is 0.2-0.6MPa.
Preferably, in the step (2), the pore diameter of the macromolecular ultrafiltration membrane ranges from 50KD to 60KD.
Preferably, in the step (2), the pore size of the small-molecule ultrafiltration membrane is in the range of 1000Da to 2000Da.
Preferably, the weight average molecular weight and the number average molecular weight in step (2) are measured by a method of Gel Permeation Chromatography (GPC) -laser Light Scattering (LS) -differential detection (RI) detection, and the proportion of α -1,6 glycosidic bonds is measured by nuclear magnetic hydrogen spectroscopy.
Preferably, in step (3), the spray drying operation: the feeding temperature is 90-100 ℃, the air inlet temperature is 180-220 ℃, and the air outlet temperature is 110-130 ℃.
Compared with the prior art, the invention has the following beneficial effects:
1. compared with the acid method for preparing the icodextrin, the method for preparing the icodextrin by the enzyme method has the advantages that the enzyme method is adopted, certain selectivity is realized when the glycosidic bond in the starch is hydrolyzed, the reaction is milder, and the hydrolysis degree of the reaction is easier to control, so that the preparation efficiency of the icodextrin can be improved.
2. Compared with the reported enzyme method for preparing icodextrin, the method controls the proportion of alpha-1, 6 glycosidic bonds to meet the requirement through the source of starch, only uses alpha-high temperature amylase to carry out enzymolysis to cut off the main chain of the starch, and achieves the control of molecular weight distribution by combining the optimization of parameters such as temperature, enzyme adding quantity, pH value, starch slurry concentration and the like. The invention uses the alpha-high temperature amylase single enzyme system to prepare the icodextrin, has mild condition, simple process and high preparation efficiency, and is more suitable for industrial amplification.
Drawings
FIG. 1 is H of corn starch 1 of examples 1 and 2 1 -an NMR spectrum;
FIG. 2 is H of corn starch 2 of example 3 1 -an NMR spectrum;
FIG. 3 is H of icodextrin C1 in example 1 1 -an NMR spectrum;
FIG. 4 is H of icodextrin C2 in example 2 1 -NMR spectrum;
FIG. 5 is H of icodextrin C3 in example 3 1 -NMR spectrum;
FIG. 6 is a molecular weight distribution diagram of icodextrin C3 in example 3;
FIG. 7 is a molecular weight distribution diagram of icodextrin C1 in example 1;
FIG. 8 is a molecular weight distribution diagram of icodextrin C2 in example 2.
Detailed Description
In order to better understand the present invention, the following examples are given to further illustrate the present invention. While the invention has been described with respect to a number of successful embodiments, specific embodiments are set forth below, but the scope of the invention as claimed is not limited to the embodiments set forth herein.
The molecular weight and molecular weight distribution range of icodextrin in the product were determined by Gel Permeation Chromatography (GPC), laser Light Scattering (LS), differential detection (RI) (FIG. 3). The specific parameters are as follows: TSKguandcolumn-PWH is taken as a protective column, a Gel permeation chromatography column TSK Gel G2000PW and TSK Gel 52000PW are connected in series, ultrapure water is taken as a mobile phase, the column temperature is 35 ℃, the flow rate is 0.6mL/min, and the detector temperature is 35 ℃.
Measuring the H of the corn starch raw material at the temperature of 70 ℃ by using deuterated DMSO as a solvent 1 NMR, at which the chemical shift of the hydrogen in position 1 corresponding to the alpha-1, 4 glycosidic linkage is 5.15ppm and the chemical shift of the hydrogen in position 1 corresponding to the alpha-1, 6 glycosidic linkage is 4.80ppm (FIG. 1);
with deuterium substituted H 2 O is solvent, the measuring temperature is 25 ℃, and H of the icodextrin product is measured 1 NMR, when the chemical shift of the hydrogen in position 1 corresponding to the α -1,4 glycosidic linkage is 5.41 and the chemical shift of the hydrogen in position 1 corresponding to the α -1,6 glycosidic linkage is 4.98 (see FIG. 2).
Example 1
(1) At 25 ℃, 600mL of purified water and 60g of corn starch 1 (figure 1, alpha-1, 6 glycosidic bond ratio is 4.74%) are sequentially added into a 1L three-necked bottle, stirred uniformly, and then 18.4mg of anhydrous calcium chloride is added, and the pH value is measured to be 5.460; 0.1M NaOH solution is dripped to adjust the pH value to 5.802; then, transferring the three-necked bottle to a 90 ℃ oil bath pan, slowly raising the temperature, after 30 minutes, displaying the internal temperature of 90 ℃ by a thermometer, keeping the temperature for gelatinization for 30 minutes, adding 24.2mg of alpha-high temperature amylase (Novoxil, diluted and added by using 4mL of purified water), after reacting for 70 minutes, adjusting the pH value to 3.45 by using 1M hydrochloric acid solution, heating to boiling, stirring for 20 minutes to inactivate the enzyme, and then filtering with diatomite while hot to obtain 580mL of filtrate A1;
(2) Firstly, removing macromolecules from the filtrate A1 obtained in the step (1) by using ultrafiltration pressure of 0.3MPa and membrane pores of 50KD, washing and filtering for 5 times by using 500mL of purified water, and combining permeate; then removing small molecules from the permeate under the pressure of 0.3MPa and the membrane pores of 1500Da, continuing to add 200mL of purified water for washing and filtering for 2 times after the volume of the feed liquid is concentrated to 200mL, and stopping ultrafiltration when the volume of the feed liquid is concentrated to 200mL again to obtain the feed liquid B1 (shown in the table 1) with the molecular weight distribution (the content of alpha-1, 6 glycosidic bonds is 8.6 percent and the content of alpha-1, 4 glycosidic bonds is 91.4 percent) meeting the quality requirement;
(3) The parameters are set as follows: the feed liquid B1 is sprayed and dried at the feed temperature of 95 ℃, the air inlet temperature of 200 ℃ and the air outlet temperature of 120 ℃ to obtain the finished product icodextrin C1.2 g (the yield is 57.1%).
TABLE 1 molecular weight distribution results for icodextrin C1
| Retention time (min) | Retention time after calibration (min) | Number average molecular weight (Mn) | Weight average molecular weight (Mw) |
| 32.800 | 32.800 | 5830 | 14368 |
Example 2
(1) 4L of purified water and 400g of corn starch 1 (the proportion of alpha-1, 6 glycosidic bonds is 4.74 percent in the figure 1) are sequentially added into a 10L reaction barrel at the temperature of 10 ℃, the mixture is uniformly stirred, and then 122.4mg of anhydrous calcium chloride is added, and the pH value is measured to be 5.530; 0.1M NaOH solution is dripped to adjust the pH value to 5.605; then, the starch slurry is transferred to a reaction kettle which is preheated to 95 ℃ in advance, the temperature is slowly raised, the rotation speed is adjusted to be 200rpm, after 15 minutes, the thermometer displays that the internal temperature is 80 ℃, the viscosity is increased at the moment, the rotation speed is adjusted to be 400rpm, after 20 minutes, the thermometer displays that the internal temperature is 95 ℃, after the temperature is kept to be gelatinized continuously for 40 minutes, 160.2mg of alpha-high temperature amylase (Novoxil is added by diluting 20mL of purified water), after 65 minutes of reaction, the pH value is adjusted to be 3.45 by using 1M sulfuric acid solution, the mixture is heated to boiling and stirred for 30 minutes to inactivate the enzyme, and then diatomite is filtered to obtain 3900mL of filtrate A2 when the mixture is hot;
(2) Firstly, removing macromolecules from the filtrate A2 obtained in the step (1) by using ultrafiltration pressure of 0.2MPa and membrane pores of 60KD, washing and filtering for 5 times by using 3500mL of purified water, and combining permeate; then removing small molecules from the permeate under the pressure of 0.3MPa and the membrane pores of 2000Da, adding 400mL of purified water after the volume of the feed liquid is concentrated to 400mL, washing and filtering for 2 times to obtain a feed liquid B2 (shown in a table 2) with the molecular weight distribution (shown in a table 2), wherein the alpha-1, 6 glycosidic bond accounts for 5.9%, the alpha-1, 4 glycosidic bond accounts for 94.1%, and the feed liquid meets the quality requirement (shown in a figure 4 and a figure 8);
(3) The parameters are set as follows: the feed temperature is 90 ℃, the air inlet temperature is 195 ℃ and the air outlet temperature is 115 ℃, and the obtained feed liquid B2 is sprayed and dried to obtain the finished product icodextrin C2 263.2g (the yield is 65.8%).
TABLE 2 molecular weight distribution results for icodextrin C2
| Retention time (min) | Retention time after calibration (min) | Number averageMolecular weight (Mn) | Weight average molecular weight (Mw) |
| 33.500 | 33.500 | 5438 | 16350 |
Example 3
(1) At 27 ℃, 600mL of purified water and 60g of corn starch 2 (fig. 2, the alpha-1, 6 glycosidic bond proportion is 8.70%) are sequentially added into a 1L three-necked bottle, the mixture is stirred uniformly, and then 18.2mg of anhydrous calcium chloride is added, and the pH value is measured to be 5.458; 0.1M NaOH solution is dripped to adjust the pH value to 5.798; then, the three-necked bottle is transferred to an oil bath kettle at 91 ℃ for slowly raising the temperature, after 30 minutes, the thermometer shows that the internal temperature is 91 ℃, after keeping the temperature for continuously gelatinizing for 30 minutes, 24.6mg of alpha-high temperature amylase (Novitin, diluted and added by using 4mL of purified water) is added, after 70 minutes of reaction, the pH value is adjusted to 3.45 by using 1M hydrochloric acid solution, the mixture is heated to boiling and stirred for 20 minutes to inactivate the enzyme, and then diatomite is filtered while hot to obtain 580mL of filtrate A1;
(2) Firstly, removing macromolecules from the filtrate A1 obtained in the step (1) by using ultrafiltration pressure of 0.3MPa and membrane pores of 50KD, washing and filtering for 5 times by using 500mL of purified water, and combining permeate; then removing small molecules from the permeate under the pressure of 0.3MPa and the membrane pores of 1500Da, continuing to add 200mL of purified water for washing and filtering for 2 times after the volume of the feed liquid is concentrated to 200mL, and stopping ultrafiltration when the volume of the feed liquid is concentrated to 200mL again to obtain a feed liquid B1 (shown in a table 3) with the molecular weight distribution, wherein the alpha-1, 6-glycosidic bond accounts for 15.60 percent and the alpha-1, 4-glycosidic bond accounts for 84.40 percent;
(3) The parameters are set as follows: the feed temperature is 100 ℃, the air inlet temperature is 205 ℃, the air outlet temperature is 125 ℃, and the obtained feed liquid B1 is sprayed and dried to obtain the finished product icodextrin C1.8 g (the yield is 53.0%).
TABLE 3 molecular weight distribution results for icodextrin C2
| Retention time (min) | Retention time after calibration (min) | Number average molecular weight (Mn) | Weight average molecular weight (Mw) |
| 19.300 | 19.300 | 6213 | 19349 |
Claims (9)
1. A preparation method of icodextrin bulk drug single enzyme system for peritoneal dialysis solution is characterized in that: the method comprises the following steps:
(1) Enzymolysis: adding starch into water of 10-40 ℃ to prepare a starch slurry solution with the mass concentration of 5-40%, adding 5-100ppm calcium chloride relative to the starch slurry, adding an alkali aqueous solution to adjust the pH value to 5.0-7.0, stirring and heating to 80-100 ℃, keeping the temperature and stirring for 30-60min in the temperature interval, adding alpha-high temperature amylase to carry out enzymolysis for 60-90min, then adjusting the pH value to 2.0-4.0 by using acid, keeping the temperature at high temperature for 20-30min, and filtering the enzymolysis liquid by using kieselguhr while the liquid is hot to obtain a filtrate A;
(2) And (3) ultrafiltration: screening the molecular weight of the filtrate A by using a large-aperture ultrafiltration membrane and a small-aperture ultrafiltration membrane in sequence to obtain a feed liquid B of a component with the weight-average molecular weight of 13000Da-19000Da, the number-average molecular weight of 5000Da-6500Da and the mole ratio of alpha-1, 6 glycosidic bonds in starch of less than 10%;
(3) And (3) spray drying: spraying the material liquid B obtained by ultrafiltration to obtain icodextrin for peritoneal dialysis solution;
in the step (1), the starch requires that the content of alpha-1, 6 glucosidic bonds is not higher than 5%.
2. The preparation method of the icodextrin drug substance single enzyme system for peritoneal dialysis solution as set forth in claim 1, characterized in that: in the step (1), the starch is selected from corn starch, wheat starch, sweet potato starch or potato starch.
3. The method for preparing icodextrin drug substance single enzyme system for peritoneal dialysis solution according to claim 1, which is characterized in that: in the step (1), the alpha-high temperature amylase is selected from high temperature amylases of Novoxin or Jenergic families.
4. The method for preparing icodextrin drug substance single enzyme system for peritoneal dialysis solution according to claim 1, which is characterized in that: in the step (1), the alkali is selected from sodium hydroxide or potassium hydroxide, and the concentration is 0.1-1M.
5. The method for preparing icodextrin drug substance single enzyme system for peritoneal dialysis solution according to claim 1, which is characterized in that: in the step (1), the acid is selected from hydrochloric acid, sulfuric acid or acetic acid, and the concentration is 0.1-1M.
6. The preparation method of the icodextrin drug substance single enzyme system for peritoneal dialysis solution as set forth in claim 1, characterized in that: in the step (2), the ultrafiltration pressure is 0.2-0.6MPa.
7. The method for preparing icodextrin drug substance single enzyme system for peritoneal dialysis solution according to claim 1, which is characterized in that: in the step (2), the aperture range of the large-aperture ultrafiltration membrane is 50KD-60KD.
8. The preparation method of the icodextrin drug substance single enzyme system for peritoneal dialysis solution as set forth in claim 1, characterized in that: in the step (2), the pore diameter range of the small-pore-diameter ultrafiltration membrane is 1000Da-2000Da.
9. The preparation method of the icodextrin drug substance single enzyme system for peritoneal dialysis solution as set forth in claim 1, characterized in that: in the step (3), the spray drying operation: the feeding temperature is 90-100 ℃, the air inlet temperature is 180-220 ℃, and the air outlet temperature is 110-130 ℃.
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| CN105131135A (en) * | 2015-09-17 | 2015-12-09 | 成都博佳制药有限公司 | Industrial production method of icodextrin |
| CN106397616A (en) * | 2016-08-30 | 2017-02-15 | 华南理工大学 | Preparation method of icodextrin for starch-based peritoneal dialysis solution |
| CN106755199A (en) * | 2017-02-14 | 2017-05-31 | 青岛力腾化工医药研究有限公司 | A kind of preparation method of Icodextrin |
| CN106755203A (en) * | 2016-11-28 | 2017-05-31 | 保龄宝生物股份有限公司 | A kind of preparation method of resistant dextrin |
| CN110257455A (en) * | 2019-06-27 | 2019-09-20 | 山东省食品发酵工业研究设计院 | A kind of preparation process of resistant dextrin |
| CN110862461A (en) * | 2019-11-12 | 2020-03-06 | 潍坊盛泰药业有限公司 | Preparation method of resistant dextrin |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105131135A (en) * | 2015-09-17 | 2015-12-09 | 成都博佳制药有限公司 | Industrial production method of icodextrin |
| CN106397616A (en) * | 2016-08-30 | 2017-02-15 | 华南理工大学 | Preparation method of icodextrin for starch-based peritoneal dialysis solution |
| CN106755203A (en) * | 2016-11-28 | 2017-05-31 | 保龄宝生物股份有限公司 | A kind of preparation method of resistant dextrin |
| CN106755199A (en) * | 2017-02-14 | 2017-05-31 | 青岛力腾化工医药研究有限公司 | A kind of preparation method of Icodextrin |
| CN110257455A (en) * | 2019-06-27 | 2019-09-20 | 山东省食品发酵工业研究设计院 | A kind of preparation process of resistant dextrin |
| CN110862461A (en) * | 2019-11-12 | 2020-03-06 | 潍坊盛泰药业有限公司 | Preparation method of resistant dextrin |
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