A preparation process of icodextrin raw material medicine and icodextrin raw material medicine

Abstract

The invention discloses a preparation process of an icodextrin bulk drug, comprising the following steps: S1 subjecting a starch raw material to high-temperature gelatinization treatment to obtain a gelatinized liquid; S2 subjecting the gelatinized liquid to hydrolysis treatment, then using a debranching enzyme to cut branches, and then subjecting the liquid to enzyme inactivation treatment to obtain an icodextrin hydrolyzed liquid; S3 subjecting the hydrolyzed liquid to ultrafiltration membrane concentration to obtain an icodextrin ultrafiltration membrane concentrated liquid; S4 adding sodium hypochlorite to the icodextrin ultrafiltration membrane concentrated liquid for decolorization; then adding activated carbon for decolorization, and simultaneously removing residual endotoxins and peptidoglycan by adsorption to obtain an icodextrin decolorized refined filtrate; S5 using an ultrafiltration membrane combination to remove impurities and screen the molecular weight of the icodextrin decolorized refined filtrate to obtain an icodextrin ultrafiltration membrane separated liquid; and S6 finally subjecting the liquid to reduced pressure concentration and drying to obtain an icodextrin finished product. The present invention also discloses a corresponding product, which has a bacterial endotoxin content of less than 0.33 EU / g, a peptidoglycan content of not more than 2 ng / g, a 5-hydroxymethylfurfural content of not more than 0.25, a magnesium salt content of not more than 0.8 ppm, and an aluminum salt content of not more than 0.1 ppm.

Description

Technical Field

[0001] The invention belongs to the technical field of medicines, and particularly relates to a preparation process of an icodextrin bulk drug and the icodextrin bulk drug. Background Art

[0002] Icodextrin is a colloidal osmotic agent derived from maltodextrin. It is used in the form of an aqueous solution for peritoneal dialysis or to reduce adhesions (fibrous bands that form between tissues and organs) after laparoscopic gynecological surgery. When used for peritoneal dialysis, the icodextrin solution absorbs waste products from the blood and is removed from the peritoneum along with the waste products after 8 to 16 hours. When used for postoperative adhesion prevention, icodextrin's osmotic activity allows the solution to remain within the peritoneum for three to four days, separating the tissues and thus reducing adhesions when fibrin is formed after surgery.

[0003] Icodextrin is produced from starch hydrolyzates of a specific molecular weight obtained through acid or enzymatic hydrolysis. Microbial contamination in the starting materials used in icodextrin production is difficult to control, often containing large amounts of bacterial endotoxins and peptidoglycan. Endotoxins are components of the cell walls of many Gram-negative bacteria, released upon bacterial lysis. They can cause fever, microcirculatory impairment, endotoxic shock, and disseminated intravascular coagulation. Peritoneal dialysis fluid prepared using APIs with substandard endotoxin levels is highly susceptible to peritonitis. Peptidoglycan, primarily found in the cell walls of Gram-positive bacteria, has been documented as a potential cause of sterile peritonitis. Therefore, the levels of endotoxins and peptidoglycan in icodextrin APIs must be strictly controlled.

[0004] At the same time, starch, the starting material for producing icodextrin, contains large amounts of aluminum and magnesium salts. Existing icodextrin API preparation processes often use activated carbon for decolorization. Activated carbon contains a large amount of metal ions, such as magnesium ions exceeding 100 μg / g and aluminum ions exceeding 50 μg / g, as well as zinc ions and other heavy metal ions, significantly increasing the risk of metal contamination in the feed solution. If the dialysate contains a large amount of aluminum salts, dialysis patients will ingest excessive aluminum through peritoneal dialysis therapy. Long-term, high-volume dialysate use can lead to aluminum salt accumulation in the body, resulting in a certain degree of toxicity. High aluminum concentrations in the dialysate are the cause of dialysis-related dementia. The presence of magnesium salts in the icodextrin API directly affects the quality of the icodextrin peritoneal dialysis fluid. Conventional methods for removing magnesium and aluminum salts include ion exchange resins and crystallization precipitation to purify icodextrin. Ion exchange resins can process relatively small amounts of sample at a time, making them unsuitable for large-scale production. Crystallization precipitation methods often fail to achieve a complete precipitate, failing to reduce metal impurities to the required minimum limits.

[0005] In addition, the production process of icodextrin reported in existing literature is relatively complicated, the purity of the obtained product is low, the molecular weight of the product is uncontrollable, and the production efficiency is low.

[0006] In summary, designing a preparation process for icodextrin API that can remove aluminum salts, magnesium salts, endotoxins, and peptidoglycan from icodextrin while ensuring that the molecular weight meets the requirements, so as to meet the hygienic indicators required by the quality standards for icodextrin finished products, is a technical problem that needs to be urgently solved in this field. Summary of the Invention

[0007] In response to one or more of the above-mentioned deficiencies or improvement needs in the prior art, the present invention provides a process for preparing an icodextrin API and an icodextrin API, which can ensure that the aluminum salt, magnesium salt, endotoxin, and peptidoglycan in the icodextrin meet the hygienic index requirements of the icodextrin finished product quality standards while ensuring that the molecular weight meets the requirements, thereby effectively ensuring the quality reliability and safety of the product.

[0008] To achieve the above object, according to one aspect of the present invention, a process for preparing an icodextrin bulk drug is provided, comprising the following steps:

[0009] S1: gelatinizing the starch raw material at high temperature to obtain a gelatinized liquid;

[0010] S2: adding acid to the gelatinized liquid for hydrolysis, then using a debranching enzyme to cut branches, and then inactivating the enzyme to obtain an icodextrin hydrolyzate;

[0011] S3: performing ultrafiltration membrane concentration on the icodextrin hydrolyzate to remove part of the endotoxin and macromolecular dextrin to obtain an icodextrin ultrafiltration membrane concentrate;

[0012] S4: adding sodium hypochlorite to the icodextrin ultrafiltration membrane concentrate for decolorization; then adding activated carbon for decolorization and simultaneously removing the remaining endotoxins and peptidoglycan by adsorption to obtain an icodextrin decolorized filtrate;

[0013] S5 uses an ultrafiltration membrane combination to remove impurities and screen the molecular weight of the icodextrin decolorized filtrate to obtain an icodextrin ultrafiltration membrane separated liquid;

[0014] S6 is finally concentrated under reduced pressure and dried to obtain the finished product of icodextrin.

[0015] As a further improvement of the present invention, the gelatinization process is as follows: the starch raw material is mixed with water to form a 20-30 w / v% suspension, and the suspension is kept at 95-100° C. for 1-2 hours.

[0016] As a further improvement of the present invention, the starch raw material includes one or more of corn starch, potato starch, pea starch or tapioca starch.

[0017] As a further improvement of the present invention, the process of the hydrolysis treatment is:

[0018] The gelatinized liquid obtained in step S1 is added with acid to a final concentration of 0.25 to 0.35 mol / L, and a hydrolysis reaction is carried out at a temperature of 55 to 65° C., and the reaction progress is monitored in a timely manner using a GPC method; the acid comprises one or more of acetic acid, citric acid, sulfuric acid, and hydrochloric acid;

[0019] When the retention time of starch hydrolysate in the reaction solution is measured to be within the range of 13.5 to 14.5 minutes, an alkali solution is used to adjust the pH to 4.5 to 5.5 to terminate the hydrolysis reaction; and / or,

[0020] The branch cutting process comprises: adding a debranching enzyme so that the final concentration of the debranching enzyme relative to the reaction solution after hydrolysis treatment is 1:400000±10 W / V, and reacting under this condition for 3.5 to 4.5 hours; and / or,

[0021] The process of the enzyme inactivation treatment is: high temperature boiling for 10 to 20 minutes.

[0022] As a further improvement of the present invention, the process of ultrafiltration membrane concentration is specifically as follows:

[0023] The supernatant of the icodextrin hydrolyzate obtained in step S2 was coarsely filtered and then concentrated using an ultrafiltration membrane with a nominal molecular weight cutoff of 50,000 Da and a membrane inlet pressure of -0.6 MPa;

[0024] When the volume of the concentrate is 80L to 120L, add purified water to make up to the set volume and continue membrane concentration. Repeat this operation several times and collect the permeate.

[0025] Then, an ultrafiltration membrane with a nominal molecular weight cutoff of 1500 Da was used and the membrane inlet pressure was set to -0.4 MPa to concentrate the permeate until the concentration of the concentrate reached 10% to 15%. The concentrate was the icodextrin ultrafiltration membrane concentrate.

[0026] As a further improvement of the present invention, the decolorization process is specifically as follows:

[0027] The icodextrin ultrafiltration membrane concentrate obtained in step S3 was taken, the temperature was adjusted to 45-55° C., sodium hypochlorite was added to make the final concentration of sodium hypochlorite 0.013-0.019 V / V%, and the decolorization was performed for 1 hour;

[0028] Adjust the liquid temperature to 60-70°C, add 8% to 10% by weight of activated carbon relative to the starch feed amount, and perform secondary decolorization for 1 to 2 hours;

[0029] After decolorization, the product is filtered to remove the activated carbon, thereby obtaining the decolorized icodextrin filtrate.

[0030] As a further improvement of the present invention, the process of ultrafiltration membrane separation is:

[0031] S51 takes the decolorized icodextrin filtrate obtained in step S4 and uses the first set of ultrafiltration membranes to filter at equal volume; stops when the molecular weight of icodextrin in the feed liquid reaches the finished product quality standard under the control state;

[0032] The quality standards of the finished product are: weight average molecular weight Mw: 13000-19000Da; number average molecular weight Mn: 5000-6500Da; molecular weight and molecular weight distribution Mw accounts for not less than 85.0% in the range of 1638-45000Da;

[0033] S52: continue to use the second set of nanofiltration membranes to maintain constant volume until the conductivity of the permeate is lower than 5 μs / cm, and then stop to obtain the icodextrin ultrafiltration membrane separated liquid;

[0034] The nominal molecular weight cut-off of the first set of ultrafiltration membranes is preferably 1000Da to 3000Da;

[0035] The nominal molecular weight cut-off of the second group of nanofiltration membranes is 100Da to 300Da.

[0036] As a further improvement of the present invention,

[0037] In S51, the isochoric pressure is -0.1 MPa to -0.6 MPa, and the isochoric time is 360 min to 480 min;

[0038] In S52, the isochoric pressure is -0.3 MPa to -0.9 MPa.

[0039] As a further improvement of the present invention, the drying is spray drying, and the conditions of the spray drying are: inlet air temperature 190°C to 200°C, high-speed centrifugal atomizer speed 8064±50r / min, and outlet air temperature above 92°C.

[0040] According to another aspect of the present invention, there is provided an icodextrin bulk drug, which is obtained by the preparation process of the icodextrin bulk drug.

[0041] The icodextrin API is a water-soluble glucose polymer composed of starch derivatives linked by α(1-4) and less than 10% α(1-6) glycosidic bonds; its weight-average molecular weight (Mw) is 13,000 to 19,000, its number-average molecular weight (Mn) is 5,000 to 6,500, and its molecular weight and molecular weight distribution (Mw) are not less than 85.0% in the range of 1,638 to 45,000 Da.

[0042] The bacterial endotoxin content of the icodextrin raw material is less than 0.33EU / g, the peptidoglycan content is not more than 2ng / g, the 5-hydroxymethylfurfural content is not more than 0.25, the magnesium salt content is not more than 0.8ppm, and the aluminum salt content is not more than 0.1ppm.

[0043] In general, the above technical solutions conceived by the present invention have the following beneficial effects compared with the prior art:

[0044] (1) The preparation process of the icodextrin API of the present invention utilizes multiple endotoxin removal steps. The use of continuous automated production and a combined membrane separation system significantly reduces the risk of microbial contamination during production. Combined with reliable central control measures such as GPC and online conductivity monitoring, product quality can be effectively controlled, ensuring product quality reliability and safety. The icodextrin product produced by the present invention is consistent with the original product.

[0045] (2) The preparation process of the icodextrin raw material of the present invention kills the microorganisms in the starting material and releases bacterial endotoxins and peptidoglycan by high temperature in the gelatinization step and strong acid in the hydrolysis step, and then removes bacterial endotoxins and peptidoglycan in the product by ultrafiltration membrane concentration combined with activated carbon adsorption, so as to meet the requirements of the hygienic indicators in the finished product quality standard, so that the bacterial endotoxin is less than 0.33EU / g and the peptidoglycan is not more than 2ng / g.

[0046] (3) The preparation process of the icodextrin bulk drug of the present invention combines ultrafiltration membrane and nanofiltration membrane. After the quality standard of the icodextrin finished product is met and a large amount of magnesium salts and aluminum salts are initially removed by ultrafiltration membrane, the magnesium salts and aluminum salts are further removed by nanofiltration membrane, thereby ensuring that the magnesium salts and aluminum salts in the product are completely removed without affecting the molecular weight and molecular weight distribution of icodextrin, so that the aluminum salt content in the icodextrin finished product is less than 0.1 ppm and the magnesium salt content is less than 0.8 ppm.

[0047] (4) The preparation process of the icodextrin bulk drug of the present invention can balance the molecular weight of icodextrin in the feed solution and the time required for chloride to reach the standard limit by setting the isochoric pressure of the first set of ultrafiltration membranes, and can achieve a faster removal rate of aluminum and magnesium by setting the isochoric pressure of the second set of nanofiltration membranes. BRIEF DESCRIPTION OF THE DRAWINGS

[0048] Figure 1 This is a flow chart of the preparation process of the icodextrin API according to an embodiment of the present invention;

[0049] Figure 2 This is the GPC spectrum for molecular weight detection of the icodextrin bulk drug product of Example 3 of the present invention;

[0050] Figure 3This is the GPC calculation spectrum for molecular weight detection of the icodextrin bulk drug product of Example 3 of the present invention;

[0051] Figure 4 This is the one-dimensional hydrogen nuclear magnetic resonance spectrum of the icodextrin raw material drug product of Example 3 of the present invention. DETAILED DESCRIPTION

[0052] In order to make the objectives, technical solutions and advantages of the present invention more clearly understood, the present invention is further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are only intended to illustrate the present invention and are not intended to limit the present invention. In addition, the technical features involved in the various embodiments of the present invention described below may be combined with each other as long as they do not conflict with each other.

[0053] like Figure 1 As shown, the preparation process of the icodextrin raw material drug of the embodiment of the present invention includes the following steps:

[0054] (1) The starch raw material is gelatinized at high temperature to obtain a gelatinized liquid.

[0055] The gelatinization process is as follows: the starch raw material is mixed with water to form a 20% to 30% (w / v) suspension, and the suspension is kept at 95 to 100° C. for 1 to 2 hours.

[0056] In a preferred embodiment, the starch raw material includes one or more of corn starch, potato starch, pea starch or tapioca starch, more preferably corn starch.

[0057] In a preferred embodiment, the water is pure water.

[0058] In a specific embodiment of the present invention, the volume of the suspension is 1700L.

[0059] (2) Hydrochloric acid is added to the gelatinized liquid for hydrolysis, and then the branches are cut using a debranching enzyme, and then the enzyme is inactivated to obtain an icodextrin hydrolyzate.

[0060] Specifically, the process of hydrolysis treatment is:

[0061] The gelatinized liquid obtained in step (1) is added with acid solution to a final concentration of 0.25 to 0.35 mol / L (preferably 0.27 to 0.33 mol / L) in the gelatinized liquid, and a hydrolysis reaction is carried out at a temperature of 55 to 65° C. (preferably 57 to 63° C.), and the reaction progress is monitored in a timely manner using a GPC method;

[0062] When the retention time of the starch hydrolyzate in the reaction solution is measured to be within the range of 13.5 to 14.5 minutes, an alkali solution is used to adjust the pH to 4.5 to 5.5 to terminate the hydrolysis reaction.

[0063] The process of branch cutting is as follows: add debranching enzyme to make the final concentration of debranching enzyme relative to the reaction solution after hydrolysis treatment be 1:400000±10 (W / V), and react under this condition for 3.5 to 4.5 hours. The debranching enzyme is preferably Isoamylase, Pullulanase (English alias D2), further preferably D2.

[0064] The process of enzyme inactivation treatment is: boiling at high temperature for 10 to 20 minutes to quickly inactivate the enzyme, preferably 15 minutes.

[0065] In a preferred embodiment, the acid solution includes one or more of acetic acid, citric acid, sulfuric acid, and hydrochloric acid, more preferably hydrochloric acid, and the concentration is preferably 5 mol / L.

[0066] In a preferred embodiment, the alkali solution in the hydrolysis treatment is used for neutralization and pH adjustment. The alkali solution is an alkaline solution that can neutralize with the acid to form a non-toxic and harmless salt. The alkali solution is preferably a 5 mol / L sodium hydroxide solution. In addition, the 5 mol / L acid solution configured in the acid hydrolysis can be used to adjust the pH. After the acid hydrolysis is completed, 5 mol / L sodium hydroxide is used to adjust the pH to 4.5-5.5. If an excess of alkali is added due to operational reasons, 5 mol / L acid solution can be used for adjustment.

[0067] Debranching enzymes are enzymes that hydrolyze the α(1-6) glycosidic bonds at the branching points of starch, dextrin, or glycogen. They can specifically cut the α(1-6) glycosidic bonds at the branching points of amylopectin, thereby cutting off the entire side branch to form amylose. The amylopectin content of corn starch accounts for 70% to 80%, while the structure of icodextrin requires that the α(1-6) glycosidic bonds be less than 10%. The present invention uses corn starch as the starting material, prepares high-amylose icodextrin by hydrolysis, and uses debranching enzymes to cut the α(1-6) glycosidic bonds to achieve the structural requirement that the α(1-6) glycosidic bonds in the finished product are less than 10%.

[0068] (3) The icodextrin hydrolyzate is concentrated by ultrafiltration membrane to remove part of the endotoxin and macromolecular dextrin to obtain an icodextrin ultrafiltration membrane concentrate.

[0069] Specifically, the ultrafiltration membrane concentration process includes:

[0070] The supernatant of the icodextrin hydrolyzate obtained in step (2) was coarsely filtered and then concentrated using an ultrafiltration membrane with a nominal molecular weight cutoff of 50,000 Da and a membrane inlet pressure of -0.6 MPa;

[0071] When the volume of the concentrated liquid remains at 80L to 120L, purified water is added to make up to the set volume, and membrane concentration is continued. This operation is repeated multiple times (preferably three times or more), and the permeate is collected; the set volume is preferably greater than the initial volume, and the initial volume refers to the volume of the suspension in step (1). For example, in a specific embodiment of the present invention, the initial volume is 1700L, and it is preferably made up to 1700 to 2100L with purified water.

[0072] Then, an ultrafiltration membrane with a nominal molecular weight cutoff of 1500 Da was used and the membrane inlet pressure was set to -0.4 MPa to concentrate the permeate until the concentration of the concentrate reached 10% to 15%. The concentrate was the icodextrin ultrafiltration membrane concentrate.

[0073] In a preferred embodiment, the coarse filtration is firstly filtering through a titanium rod and then filtering through a hollow fiber membrane.

[0074] The ultrafiltration membrane used for removing endotoxins and macromolecular dextrins in step (3) is preferably a spiral membrane with a nominal molecular weight cutoff of 50,000 Da.

[0075] The molecular weight and molecular weight distribution of the finished product of icodextrin require that the proportion of Mw in the range of 1638 to 45,000 Da is not less than 85.0%. In step (3), an ultrafiltration membrane with a nominal molecular weight cut-off of 50,000 Da is used to intercept dextrin with a macromolecular end molecular weight greater than 50,000 Da in the hydrolyzate, so as to ensure that the proportion of Mw in the range of 1638 to 45,000 Da in the finished product is not less than 85.0%. The molecular weight of the macromolecular end of icodextrin has been well controlled by GPC monitoring during the acid hydrolysis stage. Step (3) can further ensure that the macromolecular end can meet the standard limit requirements while removing some endotoxins.

[0076] (4) adding sodium hypochlorite to the icodextrin ultrafiltration membrane concentrate for decolorization; then adding activated carbon for decolorization and simultaneously removing the remaining endotoxins and peptidoglycan by adsorption to obtain the icodextrin decolorized filtrate.

[0077] Specifically, the decolorization process is:

[0078] The icodextrin ultrafiltration membrane concentrate obtained in step (3) was taken, the temperature was adjusted to 45-55° C., sodium hypochlorite was added to make the final concentration of sodium hypochlorite 0.013%-0.019% (V / V), and decolorization was performed for 1 hour;

[0079] Adjust the liquid temperature to 60-70°C, add 8% to 10% by weight of activated carbon relative to the starch feed amount, and perform secondary decolorization for 1 to 2 hours, preferably 1.5 hours;

[0080] After decolorization, the product is filtered to remove the activated carbon to obtain the decolorized filtrate of icodextrin.

[0081] In a preferred embodiment, the activated carbon is activated carbon for injection.

[0082] In a preferred embodiment, the activated carbon removal filtration method is titanium rod filtration, pleated filter element filtration, titanium rod and plate-frame filtration, or pleated filter element and plate-frame filtration. More preferably, titanium rod and plate-frame filtration is used.

[0083] The quality standard for finished icodextrin products stipulates that the appearance and properties should be a white to off-white amorphous powder. Sodium hypochlorite is a strong oxidant that can oxidize and decompose colored substances, thereby achieving the purpose of decolorization. Activated carbon, on the other hand, is a carbon material with a well-developed internal pore structure, a large specific surface area, and strong adsorption properties. The numerous micropores on the surface of activated carbon provide excellent adsorption, especially for colored macromolecules, which are more easily adsorbed by activated carbon.

[0084] Endotoxins are components of the cell walls of various Gram-negative bacteria, toxins released after bacterial cell lysis. Peptidoglycans are mainly present in the cell walls of Gram-positive bacteria, and both can be removed using activated carbon adsorption. In step (3), membrane concentration and separation have already removed a portion of the bacterial endotoxins with larger molecular weight, greatly reducing the load of activated carbon adsorption. At this time, activated carbon adsorption is used to remove the remaining bacterial endotoxins and peptidoglycans, achieving the bacterial endotoxins specified in the finished product quality standards of less than 0.33EU / g and peptidoglycans less than 2ng / g.

[0085] The quality standard for finished icodextrin products stipulates that the bacterial endotoxin content should be less than 0.33 EU / g. Using only traditional activated carbon adsorption to remove bacterial endotoxins from the product easily leads to adsorption saturation and fails to guarantee removal efficiency, making it difficult to meet the required limits set in the quality standard. Ultrafiltration is a pressure-driven membrane filtration technology that separates bacterial endotoxins based on relative molecular mass. The relative molecular mass of bacterial endotoxins ranges from several thousand to several hundred thousand. The present invention first uses a spiral wound membrane with a nominal molecular weight cutoff of 50,000 Da to remove bacterial endotoxins with a molecular weight greater than 50,000 Da, and then uses a small amount of activated carbon adsorption to remove the remaining small amount of bacterial endotoxins with a molecular weight less than 50,000 Da, ensuring that the bacterial endotoxin content in the finished icodextrin product is less than 0.33 EU / g.

[0086] (5) Using an ultrafiltration membrane combination to remove impurities and screen the molecular weight of the icodextrin decolorized filtrate to obtain an icodextrin ultrafiltration membrane separated liquid.

[0087] Impurity removal and molecular weight screening are performed using membrane separation methods, which use ultrafiltration membranes, nanofiltration membranes, and a combination of ultrafiltration membranes and nanofiltration membranes, preferably a combination of ultrafiltration membranes and nanofiltration membranes.

[0088] Specifically, the process of impurity removal and molecular weight screening is:

[0089] The decolorized filtrate of icodextrin obtained in step (4) is subjected to isotonic treatment using the first set of ultrafiltration membranes; the isotonic treatment is stopped after the molecular weight of icodextrin in the feed liquid reaches the quality standard of the finished product under the intermediate control state; the isotonic pressure is preferably -0.1 MPa to -0.6 MPa, and the isotonic time is preferably 360 min to 480 min;

[0090] Finished product quality standards are: weight average molecular weight (Mw): 13,000-19,000 Da; number average molecular weight (Mn): 5,000-6,500 Da; molecular weight and molecular weight distribution (Mw) of not less than 85.0% in the range of 1,638-45,000 Da; in-process control refers to monitoring the molecular weight and molecular weight distribution of icodextrin in the feed solution using viscosity testing, light scattering, or gel chromatography.

[0091] Then, the second set of nanofiltration membranes is used to continue isochoric treatment. The isochoric pressure is preferably -0.3 MPa to -0.9 MPa. The treatment is stopped when the conductivity of the permeate is lower than 5 μs / cm to obtain the icodextrin ultrafiltration membrane separated liquid.

[0092] The nominal molecular weight cut-off of the first set of ultrafiltration membranes is preferably 1000-3000 Da, more preferably 1500 Da. The nominal molecular weight cut-off of the ultrafiltration membrane is selected based on the molecular weight of icodextrin and the molecular weight distribution (Mw) of 1638-45000 (Mw) accounting for not less than 85.0%.

[0093] During the isochoric separation process on the first set of ultrafiltration membranes, small molecule sugars with molecular weights below 1000-3000 Da, sodium chloride, 5-hydroxymethylfurfural, and most impurities such as aluminum and magnesium salts gradually permeate through the membranes and are discharged with the permeate. Icodextrin with molecular weights greater than 1000-3000 Da is retained by the membranes and returned to the feed solution along with the concentrate. Samples are taken at appropriate times to monitor the molecular weight and molecular weight distribution of icodextrin in the feed solution. Therefore, the small molecule end portion of the starch hydrolyzate with a molecular weight less than 1638 is primarily removed through the first set of ultrafiltration membrane separation steps, while the large molecule end portion with a molecular weight greater than 45,000 is primarily controlled through starch degradation during the icodextrin production process.

[0094] Furthermore, the nominal molecular weight cutoff of the second set of nanofiltration membranes is preferably 100-300 Da, more preferably 200 Da. The molecular weight distributions of magnesium and aluminum are 24 and 27, respectively. Therefore, in this step, a nanofiltration membrane with the smallest pore size (100-300 Da) and a nominal molecular weight cutoff greater than 27 is selected. The first set of ultrafiltration membranes can produce icodextrin samples that meet all other criteria except aluminum and magnesium. The second set of nanofiltration modules can remove magnesium and aluminum from the feed solution without affecting the molecular weight and molecular weight distribution of icodextrin in the feed solution.

[0095] Furthermore, in step (5), the ultrafiltration membrane separation process is stopped when the conductivity of the permeate is less than 5 μs / cm, preferably when it is less than 2 μs / cm. Conductivity is a parameter used to describe the ease with which charge flows in a substance. Therefore, the conductivity of the permeate can be used to measure the concentration of charged ions in the feed solution. Conductivity can be achieved using online monitoring probes in the prior art. Test results show that ultrafiltration is stopped when the conductivity of the feed solution is less than 5 μs / cm, and the aluminum salt content in the finished icodextrin product is less than 0.1 ppm, and the magnesium salt content is less than 0.8 ppm.

[0096] The present invention combines an ultrafiltration membrane and a nanofiltration membrane. After the quality standard of the icodextrin finished product is met and a large amount of magnesium salts and aluminum salts are initially removed by the ultrafiltration membrane, the nanofiltration membrane is used to further remove the magnesium salts and aluminum salts, thereby ensuring that the magnesium salts and aluminum salts in the product are completely removed without affecting the molecular weight and molecular weight distribution of the icodextrin.

[0097] (6) Finally, the product of icodextrin is obtained by concentration under reduced pressure and drying.

[0098] In a preferred embodiment, the drying is spray drying, and the spray drying conditions are preferably: inlet air temperature 190°C to 200°C, high-speed centrifugal atomizer speed 8064±50r / min, and outlet air temperature above 92°C.

[0099] The icodextrin API prepared by the present invention is a water-soluble glucose polymer composed of a starch derivative (a modified product obtained by starch hydrolysis) connected by α(1-4) and less than 10% α(1-6) glycosidic bonds. The icodextrin API has a weight-average molecular weight (Mw) of 13,000 to 19,000 and a number-average molecular weight (Mn) of 5,000 to 6,500. The molecular weight and molecular weight distribution (Mw) of 1,638 to 45,000 Da accounts for no less than 85.0%.

[0100] The bacterial endotoxin content of the icodextrin raw material is less than 0.33EU / g, the peptidoglycan content is not more than 2ng / g, the 5-hydroxymethylfurfural content is not more than 0.25, the magnesium salt content is not more than 0.8ppm, and the aluminum salt content is not more than 0.1ppm.

[0101] In order to better understand the preparation process of the present invention, the following specific examples and comparative examples are provided:

[0102] Example 1

[0103] 1700 L of purified water and 400 kg of corn starch were added to the hydrolysis tank, respectively. Agitation was initiated and the jacket steam temperature was raised to 95-100°C. The tank was then held at this temperature for 1.5 hours. 5 mol / L hydrochloric acid was added to a final concentration of 0.25 mol / L. The hydrolysis reaction was carried out at 55.0°C, and the reaction progress was monitored using gel permeation chromatography (GPC). When the retention time of the starch hydrolysate in the reaction solution reached 13.5 minutes, the pH was adjusted to 4.5 using 5 mol / L sodium hydroxide to terminate the hydrolysis reaction. A debranching enzyme was added to a final concentration of 1:400,000 w / v relative to the reaction solution, and the reaction was continued under these conditions for 3.5 hours. The enzyme was inactivated by boiling at high temperature for 10 minutes to obtain the icodextrin hydrolysate.

[0104] The hydrolyzate supernatant was coarsely filtered through a titanium rod and hollow fiber membrane, then concentrated by ultrafiltration using a spiral wound membrane with a nominal molecular weight cutoff of 50,000 Da at an inlet pressure of -0.6 MPa. When the concentrate volume reached approximately 100 L, purified water was added to bring it up to 1700 L, and membrane concentration was continued three times. The permeate was collected and further concentrated using a spiral wound membrane with a nominal molecular weight cutoff of 1500 Da at an inlet pressure of -0.4 MPa until the concentrate concentration reached 10.2%. The concentrate was then collected as the ultrafiltration concentrate.

[0105] Take the ultrafiltration membrane concentrate, adjust the temperature to 45.2°C, add sodium hypochlorite to make its concentration 0.013% (V / V), decolorize for 1 hour, adjust the temperature to 60.0°C, add 32g of activated carbon (for injection), decolorize for a second time for 1 hour, and after decolorization, coarse filter through titanium rod, plate and frame filtration, remove activated carbon, and obtain the decolorized filtrate of icodextrin.

[0106] The decolorized filtrate was taken and subjected to constant volume using an ultrafiltration membrane with a nominal molecular weight of 1500 Da; under the mid-control state, the molecular weight of icodextrin in the feed liquid was stopped after reaching the finished product quality standard, and then the constant volume was continued using a nanofiltration membrane with a nominal molecular weight of 200 Da until the conductivity of the permeate was lower than 4.8 μs / cm, and the concentrated liquid was taken to obtain the icodextrin ultrafiltration membrane separation liquid.

[0107] The ultrafiltration membrane separation liquid is concentrated under reduced pressure and dried to obtain icodextrin.

[0108] The key quality indicators of the icodextrin product obtained in Example 1 were tested and shown in the following table:

[0109]

[0110]

[0111] The icodextrin product obtained in Example 1 had an α(1-6) glycosidic bond content of 7.41%.

[0112] The yield of the icodextrin product obtained in this Example 1 was 60.96%.

[0113] Example 2

[0114] Add 1700 L of purified water and 500 kg of corn starch to the hydrolysis tank, respectively. Stirring was initiated, and the jacket steam temperature was raised to 95-100°C. The tank was then held at this temperature for 1.5 hours. 5 mol / L hydrochloric acid was added to a final concentration of 0.35 mol / L. The hydrolysis reaction was carried out at 65°C, and the progress of the reaction was monitored using gel permeation chromatography (GPC). When the retention time of the starch hydrolysate in the reaction solution reached 14.5 minutes, the pH was adjusted to 5.5 using 5 mol / L sodium hydroxide to terminate the hydrolysis reaction. A debranching enzyme was added to a final concentration of 1:400,000 w / v relative to the reaction solution, and the reaction was allowed to proceed under these conditions for 4.5 hours. The enzyme was inactivated by boiling at high temperature for 20 minutes to obtain the icodextrin hydrolyzate.

[0115] The hydrolyzate supernatant was coarsely filtered through a titanium rod and hollow fiber membrane, then concentrated by ultrafiltration using a spiral wound membrane with a nominal molecular weight cutoff of 50,000 Da at an inlet pressure of -0.6 MPa. When the concentrate volume reached approximately 100 L, purified water was added to bring it up to 2100 L, and membrane concentration was continued three times. The permeate was collected and further concentrated using a spiral wound membrane with a nominal molecular weight cutoff of 1500 Da at an inlet pressure of -0.4 MPa until the concentrate reached a concentration of 14.9%. The concentrate was then collected as the ultrafiltration concentrate.

[0116] Take the ultrafiltration membrane concentrate, adjust the temperature to 55.0°C, add sodium hypochlorite to make its concentration 0.019% (V / V), decolorize for 1 hour, adjust the temperature to 70.0°C, add 50g of activated carbon (for injection), decolorize for a second time for 2 hours, and after decolorization, coarse filter through titanium rod, plate and frame fine filtration, remove the activated carbon, and obtain the decolorized filtrate of icodextrin.

[0117] The decolorized filtrate was taken and subjected to constant volume using an ultrafiltration membrane with a nominal molecular weight of 3000 Da; under the mid-control state, the molecular weight of icodextrin in the feed liquid was stopped after reaching the finished product quality standard, and then the constant volume was continued using a nanofiltration membrane with a nominal molecular weight of 300 Da until the conductivity of the permeate was lower than 3.2 μs / cm, and the concentrated liquid was taken to obtain the icodextrin ultrafiltration membrane separation liquid.

[0118] The ultrafiltration membrane separation liquid is concentrated under reduced pressure and dried to obtain icodextrin.

[0119] The key quality indicators of the icodextrin product obtained in Example 2 were tested and shown in the following table:

[0120]

[0121] The icodextrin product obtained in Example 2 had an α(1-6) glycosidic bond content of 6.54%.

[0122] The yield of the icodextrin product obtained in this Example 2 was 63.12%.

[0123] Example 3

[0124] Add 1700 L of purified water and 400 kg of corn starch to the hydrolysis tank, respectively. Stirring was initiated, and the jacket steam temperature was raised to 95-100°C. The tank was then held at this temperature for 1.5 hours. 5 mol / L hydrochloric acid was added to a final concentration of 0.30 mol / L. The hydrolysis reaction was carried out at 65°C, and the progress of the reaction was monitored using gel permeation chromatography (GPC). When the retention time of the starch hydrolysate in the reaction solution reached 14.1 minutes, the pH was adjusted to 5.0 using 5 mol / L sodium hydroxide to terminate the hydrolysis reaction. A debranching enzyme was added to a final concentration of 1:400,000 w / v relative to the reaction solution, and the reaction was allowed to proceed for 4.0 hours. The enzyme was inactivated by boiling at high temperature for 20 minutes to obtain the icodextrin hydrolyzate.

[0125] The hydrolyzate supernatant was coarsely filtered through a titanium rod and hollow fiber membrane, then concentrated by ultrafiltration using a spiral wound membrane with a nominal molecular weight cutoff of 50,000 Da at an inlet pressure of -0.6 MPa. When the concentrate volume reached approximately 100 L, purified water was added to bring it up to 1700 L, and membrane concentration was continued three times. The permeate was collected and further concentrated using a spiral wound membrane with a nominal molecular weight cutoff of 1500 Da at an inlet pressure of -0.4 MPa until the concentrate concentration reached 13.2%. The concentrate was then collected as the ultrafiltration concentrate.

[0126] Take the ultrafiltration membrane concentrate, adjust the temperature to 50.0°C, add sodium hypochlorite to make its concentration 0.016% (V / V), decolorize for 1 hour, adjust the temperature to 65.0°C, add 36g of activated carbon (for injection), decolorize for a second time for 1 hour, and after decolorization, coarse filter through titanium rod, plate and frame fine filtration, remove the activated carbon, and obtain the decolorized filtrate of icodextrin.

[0127] The decolorized filtrate was taken and subjected to constant volume using an ultrafiltration membrane with a nominal molecular weight of 1500 Da; under the mid-control state, the molecular weight of icodextrin in the feed liquid was stopped after reaching the finished product quality standard, and then the constant volume was continued using a nanofiltration membrane with a nominal molecular weight of 200 Da until the conductivity of the permeate was lower than 1.9 μs / cm, and the concentrated liquid was taken to obtain the icodextrin ultrafiltration membrane separation liquid.

[0128] The ultrafiltration membrane separation liquid is concentrated under reduced pressure and dried to obtain icodextrin.

[0129] The key quality indicators of the icodextrin product obtained in Example 3 were tested and shown in the following table:

[0130]

[0131] The icodextrin product obtained in Example 3 had an α(1-6) glycosidic bond content of 6.54%.

[0132] The yield of the icodextrin product obtained in Example 3 was 65.32%.

[0133] Comparative Example 1

[0134] 1700 L of purified water and 400 kg of corn starch were added to the hydrolysis tank, respectively. Agitation was initiated and the jacket steam temperature was raised to 95-100°C. The temperature was maintained at this temperature for 1.5 hours. 5 mol / L hydrochloric acid was added to achieve a final concentration of 0.30 mol / L in the feed solution. The hydrolysis reaction was carried out at 60.0°C, and the reaction progress was monitored using GPC. When the retention time of the starch hydrolysate in the reaction solution reached 14.1 minutes, the pH was adjusted to 4.5 using 5 mol / L sodium hydroxide to terminate the hydrolysis reaction. This yielded an icodextrin hydrolyzate.

[0135] The hydrolyzate supernatant was coarsely filtered through a titanium rod and hollow fiber membrane, then concentrated by ultrafiltration using a spiral wound membrane with a nominal molecular weight cutoff of 50,000 Da at an inlet pressure of -0.6 MPa. When the concentrate volume remained at approximately 100 L, purified water was added to 1700 L, and membrane concentration was continued three times. The permeate was collected and further concentrated using a spiral wound membrane with a nominal molecular weight cutoff of 1500 Da at an inlet pressure of -0.4 MPa until the concentrate concentration reached 13.8%. The concentrate was then collected as the ultrafiltration concentrate.

[0136] Take the ultrafiltration membrane concentrate, adjust the temperature to 50.2°C, add sodium hypochlorite to make its concentration 0.016% (V / V), decolorize for 1 hour, adjust the temperature to 60.0°C, add 32g of activated carbon (for injection), decolorize for a second time for 1 hour, and after decolorization, coarse filter through titanium rod, plate and frame fine filtration, remove the activated carbon, and obtain the decolorized filtrate of icodextrin.

[0137] The decolorized filtrate was taken and subjected to constant volume using an ultrafiltration membrane with a nominal molecular weight of 1500 Da; under the mid-control state, the molecular weight of icodextrin in the feed liquid was stopped after reaching the finished product quality standard, and then the constant volume was continued using a nanofiltration membrane with a nominal molecular weight of 200 Da until the conductivity of the permeate was lower than 4.7 μs / cm, and the concentrated liquid was taken to obtain the icodextrin ultrafiltration membrane separation liquid.

[0138] The ultrafiltration membrane separation liquid is concentrated under reduced pressure and dried to obtain icodextrin.

[0139] The key quality indicators of the icodextrin product obtained in this comparative example 1 were tested and shown in the following table:

[0140]

[0141] The icodextrin product obtained in Comparative Example 1 had an α(1-6) glycosidic bond content of 13.57%.

[0142] The yield of the icodextrin product obtained in this comparative example 1 was 61.03%.

[0143] Comparative Example 2

[0144] Add 1700 L of purified water and 400 kg of corn starch to the hydrolysis tank, respectively. Stirring was initiated, and the jacket steam temperature was raised to 95-100°C. The tank was then held at this temperature for 1.5 hours. 5 mol / L hydrochloric acid was added to a final concentration of 0.31 mol / L. The hydrolysis reaction was carried out at 63°C, and the progress of the reaction was monitored using gel permeation chromatography (GPC). When the retention time of the starch hydrolysate in the reaction solution reached 14.3 minutes, the pH was adjusted to 4.8 using 5 mol / L sodium hydroxide to terminate the hydrolysis reaction. A debranching enzyme was added to a final concentration of 1:400,000 w / v relative to the reaction solution, and the reaction was continued under these conditions for 4.0 hours. The enzyme was inactivated by boiling at high temperature for 20 minutes to obtain the icodextrin hydrolysate.

[0145] Take the supernatant of the hydrolyzate, adjust the temperature to 50.2°C, add sodium hypochlorite to a concentration of 0.016% (V / V), decolorize for 1 hour, adjust the temperature to 65.0°C, add 36 g of activated carbon (for injection), decolorize for a second time for 1 hour, and after decolorization, coarsely filter through a titanium rod, filter on a plate and frame, remove the activated carbon, and obtain the decolorized filtrate of icodextrin.

[0146] The decolorized filtrate was taken and subjected to constant volume using an ultrafiltration membrane with a nominal molecular weight of 1500 Da; under the mid-control state, the molecular weight of icodextrin in the feed liquid was stopped after reaching the finished product quality standard, and then the constant volume was continued using a nanofiltration membrane with a nominal molecular weight of 200 Da until the conductivity of the permeate was lower than 2.0 μs / cm, and the concentrated liquid was taken to obtain the icodextrin ultrafiltration membrane separation liquid.

[0147] The ultrafiltration membrane separation liquid is concentrated under reduced pressure and dried to obtain icodextrin.

[0148] The key quality indexes of the icodextrin product obtained in this comparative example 2 were tested and shown in the following table:

[0149]

[0150] The icodextrin product obtained in Comparative Example 2 had an α(1-6) glycosidic bond content of 7.41%.

[0151] The yield of the icodextrin product obtained in this comparative example 2 was 64.82%.

[0152] Comparative Example 3

[0153] Add 1700 L of purified water and 400 kg of corn starch to the hydrolysis tank, respectively. Stirring was initiated, and the jacket steam temperature was raised to 95-100°C. The tank was then held at this temperature for 1.5 hours. 5 mol / L hydrochloric acid was added to a final concentration of 0.35 mol / L. The hydrolysis reaction was carried out at 62°C, and the reaction progress was monitored using gel permeation chromatography (GPC). When the retention time of the starch hydrolysate in the reaction solution reached 14.5 minutes, the pH was adjusted to 5.3 using 5 mol / L sodium hydroxide to terminate the hydrolysis reaction. A debranching enzyme was added to a final concentration of 1:400,000 w / v relative to the reaction solution, and the reaction was allowed to proceed under these conditions for 4.5 hours. The enzyme was inactivated by boiling at high temperature for 20 minutes to obtain the icodextrin hydrolyzate.

[0154] The hydrolyzate supernatant was coarsely filtered through a titanium rod and hollow fiber membrane, then concentrated by ultrafiltration using a spiral wound membrane with a nominal molecular weight cutoff of 50,000 Da at an inlet pressure of -0.6 MPa. When the concentrate volume reached approximately 100 L, purified water was added to bring it up to 1700 L, and membrane concentration was continued three times. The permeate was collected and further concentrated using a spiral wound membrane with a nominal molecular weight cutoff of 1500 Da at an inlet pressure of -0.4 MPa until the concentrate concentration reached 12.0%. The concentrate was then collected as the ultrafiltration concentrate.

[0155] Take the ultrafiltration membrane concentrate, adjust the temperature to 55.0°C, add sodium hypochlorite to make its concentration 0.016% (V / V), decolorize for 1 hour, adjust the temperature to 70.0°C, add 40g of activated carbon (for injection), decolorize for a second time for 2 hours, and after decolorization, coarse filter through titanium rod, plate and frame filtration, remove activated carbon, and obtain the decolorized filtrate of icodextrin.

[0156] The decolorized filtrate was taken and subjected to an ultrafiltration membrane with a nominal molecular weight of 1500Da. The filtration was stopped under the control state until the molecular weight of icodextrin in the feed liquid reached the quality standard of the finished product, and the concentrated liquid was taken to obtain the icodextrin ultrafiltration membrane separation liquid.

[0157] The ultrafiltration membrane separation liquid is concentrated under reduced pressure and dried to obtain icodextrin.

[0158] The key quality indicators of the icodextrin product obtained in this comparative example 3 were tested and shown in the following table:

[0159]

[0160] The icodextrin product obtained in Comparative Example 3 had an α(1-6) glycosidic bond content of 6.54%.

[0161] The yield of the icodextrin product obtained in this comparative example 3 was 64.21%.

[0162] It should be noted that the reference preparations in the Examples and Comparative Examples of the present invention were purchased from the original manufacturer's preparation listed in the UK (reference preparation name: Extraneal, batch number: 21A26G41). In addition, the detection results of α(1-6) glycosidic bonds in the finished product were obtained by one-dimensional nuclear magnetic resonance spectroscopy.

[0163] It will be easily understood by those skilled in the art that the above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A process for preparing an icodextrin bulk drug, characterized in that: The steps include: S1: gelatinizing the starch raw material at high temperature to obtain a gelatinized liquid; S2: adding acid to the gelatinized liquid for hydrolysis, then using a debranching enzyme to cut branches, and then inactivating the enzyme to obtain an icodextrin hydrolyzate; S3: performing ultrafiltration membrane concentration on the icodextrin hydrolyzate to remove part of the endotoxin and macromolecular dextrin to obtain an icodextrin ultrafiltration membrane concentrate; S4: adding sodium hypochlorite to the icodextrin ultrafiltration membrane concentrate for decolorization; then adding activated carbon for decolorization and simultaneously removing the remaining endotoxins and peptidoglycan by adsorption to obtain an icodextrin decolorized filtrate; S5 uses an ultrafiltration membrane combination to remove impurities and screen the molecular weight of the icodextrin decolorized filtrate to obtain an icodextrin ultrafiltration membrane separated liquid; The process of ultrafiltration membrane separation is: S51 takes the decolorized icodextrin filtrate obtained in step S4 and uses the first set of ultrafiltration membranes to filter at equal volume; stops when the molecular weight of icodextrin in the feed liquid reaches the finished product quality standard under the control state; The quality standards of the finished product are: weight average molecular weight Mw: 13000~19000Da; number average molecular weight Mn: 5000~6500Da; molecular weight and molecular weight distribution Mw accounts for not less than 85.0% in the range of 1638~45000Da; S52: continue to use the second set of nanofiltration membranes to maintain constant volume until the conductivity of the permeate is lower than 5µs / cm, and then stop to obtain the icodextrin ultrafiltration membrane separated liquid; The nominal molecular weight cut-off of the first set of ultrafiltration membranes is 1000Da~3000Da; The nominal molecular weight cut-off of the second set of nanofiltration membranes is 100Da~300Da; S6 is finally concentrated under reduced pressure and dried to obtain the finished product of icodextrin; The bacterial endotoxin content of the icodextrin raw material is less than 0.33 EU / g, the peptidoglycan content is not more than 2 ng / g, the 5-hydroxymethylfurfural content is not more than 0.25, the magnesium salt content is not more than 0.8 ppm, and the aluminum salt content is not more than 0.1 ppm.

2. The preparation process of the icodextrin bulk drug according to claim 1, wherein In S1, the gelatinization process is as follows: the starch raw material is mixed with water to form a 20-30 w / v % suspension, and the suspension is kept at 95-100° C. for 1-2 hours.

3. The preparation process of the icodextrin bulk drug according to claim 1, wherein In S1, the starch raw material includes one or more of corn starch, potato starch, pea starch or tapioca starch.

4. The preparation process of the icodextrin bulk drug according to claim 1, wherein In S2, the process of the hydrolysis treatment is: The gelatinized liquid obtained in step S1 is added with acid to a final concentration of 0.25 to 0.35 mol / L, and a hydrolysis reaction is performed at a temperature of 55 to 65° C., and the reaction progress is monitored in a timely manner using a GPC method; the acid comprises one or more of acetic acid, citric acid, sulfuric acid, and hydrochloric acid; When the retention time of starch hydrolysate in the reaction solution is measured to be within the range of 13.5 to 14.5 minutes, the pH value is adjusted to 4.5 to 5.5 using alkaline solution to terminate the hydrolysis reaction; and / or, The branch cutting process comprises: adding a debranching enzyme so that the final concentration of the debranching enzyme relative to the reaction solution after hydrolysis treatment is 1: 400000±10 W / V, and reacting under this condition for 3.5 to 4.5 hours; and / or, The process of the enzyme inactivation treatment is: high temperature boiling for 10 to 20 minutes.

5. The preparation process of the icodextrin bulk drug according to claim 1, wherein In S3, the process of ultrafiltration membrane concentration is: The supernatant of the icodextrin hydrolyzate obtained in step S2 was coarsely filtered and then concentrated using an ultrafiltration membrane with a nominal molecular weight cutoff of 50,000 Da and a membrane inlet pressure of -0.6 MPa; When the volume of the concentrate is 80L~120L, add purified water to make up to the set volume and continue membrane concentration. Repeat this operation several times and collect the permeate. Then, an ultrafiltration membrane with a nominal molecular weight cutoff of 1500 Da was used and the membrane inlet pressure was set to -0.4 MPa to concentrate the permeate until the concentration of the concentrate reached 10% to 15%. The concentrate was the icodextrin ultrafiltration membrane concentrate.

6. The process for preparing the icodextrin bulk drug according to any one of claims 1 to 5, wherein: In S4, the decolorization process is specifically as follows: The icodextrin ultrafiltration membrane concentrate obtained in step S3 was taken, the temperature was adjusted to 45-55°C, sodium hypochlorite was added to make the final concentration of sodium hypochlorite 0.013-0.019 V / V%, and the decolorization was performed for 1 hour; Adjust the liquid temperature to 60-70°C, add 8%-10% by weight of activated carbon relative to the starch feed amount, and perform secondary decolorization for 1-2 hours; After decolorization, the product is filtered to remove the activated carbon, thereby obtaining the decolorized icodextrin filtrate.

7. The process for preparing the icodextrin bulk drug according to any one of claims 1 to 5, wherein: In S5, In S51, the isochoric pressure is -0.1 MPa to -0.6 MPa, and the isochoric time is 360 min to 480 min; and / or, In S52, the isochoric pressure is -0.3 MPa to -0.9 MPa.

8. The process for preparing the icodextrin bulk drug according to any one of claims 1 to 5, wherein: In S6, the drying is spray drying, and the conditions of the spray drying are: inlet air temperature 190°C to 200°C, high-speed centrifugal atomizer speed 8064±50r / min, and outlet air temperature above 92°C.

9. An icodextrin bulk drug obtained by the preparation process of the icodextrin bulk drug according to any one of claims 1 to 8, characterized in that: The icodextrin API is a water-soluble glucose polymer composed of starch derivatives linked by α(1-4) and less than 10% α(1-6) glycosidic bonds; its weight-average molecular weight (Mw) is 13,000-19,000, its number-average molecular weight (Mn) is 5,000-6,500, and its molecular weight and molecular weight distribution (Mw) range from 1,638 to 45,000 Da accounts for no less than 85.0%; The bacterial endotoxin content of this icodextrin raw material is less than 0.33 EU / g, the peptidoglycan content is not more than 2ng / g, the 5-hydroxymethylfurfural content is not more than 0.25, the magnesium salt content is not more than 0.8ppm, and the aluminum salt content is not more than 0.1ppm.

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