CN114605563A - 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 an icodextrin raw material medicine single enzyme system 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 carrying out 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 which meets the requirements on the weight average molecular weight, the number average molecular weight, the alpha-1, 6 glucosidic bonds and the proportion of 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 an icodextrin raw material medicine single enzyme system for peritoneal dialysis solution.
Background
Peritoneal Dialysis (PD) is a kidney replacement therapy for home treatment, is cost effective, and can achieve similar therapeutic effects to hemodialysis in end-stage renal patients (ESRD). Icodextrin (Icodextrin) is a water-soluble glucose polymer, and metabolites are not easily absorbed by the human body through the peritoneum. Icodextrin is formed by connecting glucose through alpha-1, 4 and less than 10% 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 the steps of firstly, hydrolyzing a prepared starch slurry solution by using acid with certain concentration at a certain temperature to obtain an acidolysis solution, then, screening molecular weights by using 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 a low-concentration acid solution, and then adds corn starch, thereby leading the molecular weight of the prepared hydrolysate to be more concentrated; and the icodextrin with qualified molecular weight distribution can be obtained only by one-time 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 106397616A discloses a method for preparing an icodextrin raw material by an enzymatic method, which takes starch as a raw material, uses alpha-amylase for enzymolysis, then uses debranching enzyme for debranching, and finally obtains the icodextrin with the weight-average molecular weight, the number-average molecular weight and the alpha-1, 6 glycosidic bond meeting the requirements through alcohol precipitation, ultrafiltration and chromatographic separation. Chinese patent CN 106755199A uses lysozyme to break the cell wall of bacteria and release peptidoglycan, thereby better removing peptidoglycan during 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, then combines the operations of ultrafiltration and spray drying 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 gel exclusion chromatography-multi-angle laser scatteringThe method measures the weight-average molecular weight and the number-average molecular weight of the obtained icodextrin product; by means of H1-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 glycosidic 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 that the ratio of alpha-1, 6 glucosidic bonds is not higher than 5% (H)1NMR 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, more preferably 10-20ppm, per gram of the starch slurry.
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 0.2-0.6 MPa.
Preferably, in the step (2), the pore diameter of the macromolecular ultrafiltration membrane ranges from 50KD to 60 KD.
Preferably, in the step (2), the pore size of the small-molecule ultrafiltration membrane ranges from 1000Da to 2000 Da.
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 ratio 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 21-NMR spectrum;
FIG. 2 is H of corn starch 2 of example 31-NMR spectrum;
FIG. 3 is H of icodextrin C1 in example 11-NMR spectrum;
FIG. 4 is H of icodextrin C2 of example 21-NMR spectrum;
FIG. 5 is H of icodextrin C3 in example 31-NMR spectrum;
FIG. 6 is a molecular weight distribution plot of icodextrin C3 in example 3;
FIG. 7 is a molecular weight distribution plot 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. There are many successful embodiments of the invention, and specific examples are set forth below, but the scope of the invention as claimed is not limited to the scope of the embodiments presented.
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 chromatographic 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 by using deuterated DMSO as a solvent at the measurement temperature of 70 DEG C1-NMR, when the chemical shift of the hydrogen in position 1 corresponding to the α -1,4 glycosidic linkage is 5.15ppm and the chemical shift of the hydrogen in position 1 corresponding to the α -1,6 glycosidic linkage is 4.80ppm (fig. 1);
by deutero-H2O is solvent, the measuring temperature is 25 ℃, and H of the icodextrin product is measured1-NMR, thisWhen the alpha-1, 4 glycosidic bond is connected with the corresponding hydrogen at the position 1, the chemical shift is 5.41, and the alpha-1, 6 glycosidic bond is connected with the corresponding hydrogen at the position 1, the chemical shift is 4.98 (shown in figure 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, the three-necked bottle is transferred to an oil bath kettle at 90 ℃ for slowly raising the temperature, after 30 minutes, the thermometer shows that the internal temperature is 90 ℃, after keeping the temperature for continuously gelatinizing for 30 minutes, 24.2mg 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, continuously adding 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 a table 1) with the molecular weight distribution (the alpha-1, 6-glycosidic bond proportion is 8.6 percent and the alpha-1, 4-glycosidic bond proportion is 91.4 percent) meeting the quality requirement;
(3) the parameters are set as follows: the feed temperature is 95 ℃, the air inlet temperature is 200 ℃, the air outlet temperature is 120 ℃, and the obtained feed liquid B1 is sprayed and dried to obtain the finished product icodextrin C134.2g (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) Sequentially adding 4L of purified water and 400g of corn starch 1 (shown in figure 1, the ratio of alpha-1, 6-glycosidic bonds is 4.74%) into a 10L reaction barrel at 10 ℃, uniformly stirring, then adding 122.4mg of anhydrous calcium chloride, and measuring the pH value to be 5.530; 0.1M NaOH solution is dripped to adjust the pH value to 5.605; then, the starch slurry is transferred into a reaction kettle preheated to 95 ℃ in advance, the temperature is slowly increased, the rotation speed is adjusted to 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 400rpm, after 20 minutes, the thermometer displays that the internal temperature is 95 ℃, after the temperature is kept and gelatinization is continued for 40 minutes, 160.2mg of alpha-high temperature amylase (Novitin is added by using 20mL of purified water for dilution), after 65 minutes of reaction, the pH value is adjusted to 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 when the mixture is hot to obtain 3900mL of filtrate A2;
(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 figure 4 and a figure 8) with the molecular weight distribution (shown in a table 2), wherein the alpha-1, 6-glycosidic bond accounts for 5.9 percent, the alpha-1, 4-glycosidic bond accounts for 94.1 percent and the mass requirement is met;
(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 C2263.2g (the yield is 65.8%).
TABLE 2 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) |
| 33.500 | 33.500 | 5438 | 16350 |
Example 3
(1) 600mL of purified water and 60g of corn starch 2 (FIG. 2, the ratio of alpha-1, 6-glycosidic bonds is 8.70%) are sequentially added into a 1L three-necked bottle at 27 ℃, 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, continuously adding 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% and the alpha-1, 4-glycosidic bond accounts for 84.40%;
(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 C131.8g (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 (10)
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: and (3) spraying the material liquid B obtained by ultrafiltration to obtain the icodextrin for the peritoneal dialysis solution.
2. 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 starch requires that the content of alpha-1, 6 glucosidic bonds is not higher than 5%.
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 starch is selected from corn starch, waxy corn starch, wheat starch, sweet potato starch or potato starch.
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 alpha-high temperature amylase is selected from high temperature amylases of Novoxin or Jenergic families.
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 alkali is selected from sodium hydroxide or potassium hydroxide, and the concentration is 0.1-1M.
6. 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.
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 ultrafiltration pressure is 0.2-0.6 MPa.
8. 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 pore size range of the macromolecular ultrafiltration membrane is 50KD-60 KD.
9. 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 pore diameter range of the small molecular ultrafiltration membrane is 1000Da-2000 Da.
10. 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 (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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| CN114605563B (en) | 2023-02-17 |
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