CN117050201B - Method for removing aluminum salt and magnesium salt in icodextrin bulk drug - Google Patents
Method for removing aluminum salt and magnesium salt in icodextrin bulk drug Download PDFInfo
- Publication number
- CN117050201B CN117050201B CN202310944864.8A CN202310944864A CN117050201B CN 117050201 B CN117050201 B CN 117050201B CN 202310944864 A CN202310944864 A CN 202310944864A CN 117050201 B CN117050201 B CN 117050201B
- Authority
- CN
- China
- Prior art keywords
- icodextrin
- molecular weight
- magnesium salt
- aluminum salt
- salt
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 229920002177 Icodextrin Polymers 0.000 title claims abstract description 147
- 229940016836 icodextrin Drugs 0.000 title claims abstract description 147
- 159000000003 magnesium salts Chemical class 0.000 title claims abstract description 69
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 title claims abstract description 67
- 238000000034 method Methods 0.000 title claims abstract description 62
- 239000003814 drug Substances 0.000 title claims abstract description 33
- 229940079593 drug Drugs 0.000 title claims abstract description 33
- 239000012528 membrane Substances 0.000 claims abstract description 73
- 239000000047 product Substances 0.000 claims abstract description 60
- 238000009826 distribution Methods 0.000 claims abstract description 56
- 238000000108 ultra-filtration Methods 0.000 claims abstract description 47
- 239000007788 liquid Substances 0.000 claims abstract description 42
- 238000001728 nano-filtration Methods 0.000 claims abstract description 31
- 229920002472 Starch Polymers 0.000 claims abstract description 28
- 235000019698 starch Nutrition 0.000 claims abstract description 28
- 239000008107 starch Substances 0.000 claims abstract description 28
- 239000012141 concentrate Substances 0.000 claims abstract description 19
- 239000012466 permeate Substances 0.000 claims abstract description 18
- 108010009736 Protein Hydrolysates Proteins 0.000 claims abstract description 9
- 238000001035 drying Methods 0.000 claims abstract description 7
- 229920002261 Corn starch Polymers 0.000 claims description 20
- 239000008120 corn starch Substances 0.000 claims description 20
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 18
- 239000000413 hydrolysate Substances 0.000 claims description 18
- 229910052782 aluminium Inorganic materials 0.000 claims description 15
- 238000001694 spray drying Methods 0.000 claims description 14
- 238000012544 monitoring process Methods 0.000 claims description 13
- 238000005227 gel permeation chromatography Methods 0.000 claims description 12
- 230000003301 hydrolyzing effect Effects 0.000 claims description 9
- 239000004382 Amylase Substances 0.000 claims description 5
- 102000013142 Amylases Human genes 0.000 claims description 5
- 108010065511 Amylases Proteins 0.000 claims description 5
- 235000019418 amylase Nutrition 0.000 claims description 5
- 238000000149 argon plasma sintering Methods 0.000 claims description 5
- 238000010998 test method Methods 0.000 claims description 5
- 229940099112 cornstarch Drugs 0.000 description 18
- 102000004139 alpha-Amylases Human genes 0.000 description 15
- 108090000637 alpha-Amylases Proteins 0.000 description 15
- 229940024171 alpha-amylase Drugs 0.000 description 15
- 230000006872 improvement Effects 0.000 description 12
- 230000008569 process Effects 0.000 description 9
- 230000000052 comparative effect Effects 0.000 description 8
- 230000001105 regulatory effect Effects 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 230000007062 hydrolysis Effects 0.000 description 7
- 238000006460 hydrolysis reaction Methods 0.000 description 7
- 239000012535 impurity Substances 0.000 description 7
- 238000005070 sampling Methods 0.000 description 7
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 6
- 229910052749 magnesium Inorganic materials 0.000 description 6
- 239000011777 magnesium Substances 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 238000000502 dialysis Methods 0.000 description 3
- 239000011148 porous material Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 2
- NOEGNKMFWQHSLB-UHFFFAOYSA-N 5-hydroxymethylfurfural Chemical compound OCC1=CC=C(C=O)O1 NOEGNKMFWQHSLB-UHFFFAOYSA-N 0.000 description 2
- 208000024827 Alzheimer disease Diseases 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- 208000001647 Renal Insufficiency Diseases 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 239000000385 dialysis solution Substances 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- RJGBSYZFOCAGQY-UHFFFAOYSA-N hydroxymethylfurfural Natural products COC1=CC=C(C=O)O1 RJGBSYZFOCAGQY-UHFFFAOYSA-N 0.000 description 2
- 238000001095 inductively coupled plasma mass spectrometry Methods 0.000 description 2
- 239000003456 ion exchange resin Substances 0.000 description 2
- 229920003303 ion-exchange polymer Polymers 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 201000006370 kidney failure Diseases 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000011574 phosphorus Substances 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 208000000044 Amnesia Diseases 0.000 description 1
- 208000020084 Bone disease Diseases 0.000 description 1
- 208000014644 Brain disease Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 208000032274 Encephalopathy Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 208000015710 Iron-Deficiency Anemia Diseases 0.000 description 1
- 208000026139 Memory disease Diseases 0.000 description 1
- 102000057297 Pepsin A Human genes 0.000 description 1
- 108090000284 Pepsin A Proteins 0.000 description 1
- 206010039966 Senile dementia Diseases 0.000 description 1
- 231100000076 Toxic encephalopathy Toxicity 0.000 description 1
- 206010044221 Toxic encephalopathy Diseases 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000004411 aluminium Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000006931 brain damage Effects 0.000 description 1
- 231100000874 brain damage Toxicity 0.000 description 1
- 208000029028 brain injury Diseases 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 206010061428 decreased appetite Diseases 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 210000002249 digestive system Anatomy 0.000 description 1
- 231100000676 disease causative agent Toxicity 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 201000006549 dyspepsia Diseases 0.000 description 1
- 230000007071 enzymatic hydrolysis Effects 0.000 description 1
- 238000006047 enzymatic hydrolysis reaction Methods 0.000 description 1
- 239000012527 feed solution Substances 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000006984 memory degeneration Effects 0.000 description 1
- 208000023060 memory loss Diseases 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 229940111202 pepsin Drugs 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 229910052712 strontium Inorganic materials 0.000 description 1
- CIOAGBVUUVVLOB-UHFFFAOYSA-N strontium atom Chemical compound [Sr] CIOAGBVUUVVLOB-UHFFFAOYSA-N 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B30/00—Preparation of starch, degraded or non-chemically modified starch, amylose, or amylopectin
- C08B30/12—Degraded, destructured or non-chemically modified starch, e.g. mechanically, enzymatically or by irradiation; Bleaching of starch
- C08B30/18—Dextrin, e.g. yellow canari, white dextrin, amylodextrin or maltodextrin; Methods of depolymerisation, e.g. by irradiation or mechanically
Landscapes
- Chemical & Material Sciences (AREA)
- Crystallography & Structural Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Materials Engineering (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Polymers & Plastics (AREA)
- Organic Chemistry (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
- Separation Using Semi-Permeable Membranes (AREA)
Abstract
The invention discloses a method for removing aluminum salt and magnesium salt in an icodextrin bulk drug, which comprises the following steps: s1, taking starch hydrolysate, and adopting a first group of ultrafiltration membranes to have equal volume; stopping the control after the molecular weight of the icodextrin in the feed liquid reaches the quality standard of the finished product in the central control state to obtain a first icodextrin concentrate; the quality standard of the finished product is as follows: weight average molecular weight Mw: 13000-19000 Da; number average molecular weight Mn: 5000-6500 Da; the ratio of the molecular weight and the molecular weight distribution Mw in 1638-45000 Da is not less than 85.0%; s2, taking the first icodextrin concentrate obtained in the step S1, adopting a second group of nanofiltration membranes to continue isovolumetric treatment until the conductivity of the permeate is lower than 5 mu S/cm, and stopping to obtain a second icodextrin concentrate; s3, continuously concentrating the second icodextrin concentrate under reduced pressure, and drying to obtain an icodextrin product. The invention combines the ultrafiltration membrane and the nanofiltration membrane, and can ensure that the content of aluminum salt in the finished product of the icodextrin is less than 0.1ppm and the content of magnesium salt is less than 0.8ppm under the condition of not influencing the molecular weight and the molecular weight distribution of the icodextrin.
Description
Technical Field
The invention belongs to the technical field of synthesis of chemical bulk drugs, and particularly relates to a method for removing aluminum salt and magnesium salt in an icodextrin bulk drug.
Background
The icodextrin is prepared by taking starch as a starting material, and finally preparing a hydrolysate with a specific molecular weight range through the procedures of hydrolysis, decoloration, ultrafiltration membrane separation, reduced pressure concentration, spray drying and the like. Are often used as key active ingredients in peritoneal dialysis solutions. Peritoneal dialysis is an important treatment for patients with severe renal insufficiency or renal failure.
However, the starting material starch for the production of icodextrin contains a large amount of aluminum and magnesium salts, and normal people have the ability to excrete aluminum through excretory organs such as kidneys. If a large amount of aluminum salt is contained in the dialysate, the dialysis patient can take in excessive aluminum by peritoneal dialysis therapy, and if the dialysate is used for a long period of time, the aluminum salt accumulates in the body, and a certain toxicity is generated. Studies have shown that once in the human body, aluminum salts first deposit in the brain, possibly resulting in brain damage, causing severe memory loss, a symptom characteristic of alzheimer's disease. If aluminum builds up in the brain over time, it kills the neurons, losing memory in humans. In recent years, the occurrence of senile dementia has also been associated with excessive intake of aluminum element at ordinary times. The high concentration of aluminum in the dialysate is the causative agent of DE (dialysis dementia).
At the same time, absorption of aluminum by the digestive system can also lead to encephalopathy, bone disease, kidney disease and non-iron deficiency anemia. The aluminum element is absorbed more and accumulated in the liver, spleen, kidney and other parts, when the accumulated amount exceeds 5-6 times, the aluminum element can inhibit the absorption of phosphorus in the digestive tract, inhibit the activity of pepsin, prevent the digestion and absorption functions of human bodies, influence the absorption of phosphorus, strontium, iron, calcium and other elements in the intestinal tract, and cause inappetence and dyspepsia of the human bodies. Therefore, it is particularly necessary to control the content of aluminum salt in the dialysate.
In addition, the existence of magnesium salt in the icodextrin bulk drug directly affects the quality of the icodextrin peritoneal dialysis solution, so the control of the magnesium salt is one of important contents to be studied in the research process.
Conventional methods for removing magnesium salt and aluminum salt comprise ion exchange resin, crystallization precipitation and the like, and the icodextrin is refined, wherein the ion exchange resin has a small amount of disposable treated samples, and is not suitable for large-scale production, and the crystallization precipitation method often does not build a bottom, so that metal impurities cannot reach lower limit requirements.
Therefore, how to design a method for removing aluminum salt and magnesium salt in icodextrin, so that the aluminum salt content in the finished icodextrin product is less than 0.1ppm and the magnesium salt content is less than 0.8ppm is a technical problem to be solved in the field.
Disclosure of Invention
In order to overcome one or more of the defects or improvement demands of the prior art, the invention provides a method for removing aluminum salt and magnesium salt in an icodextrin bulk drug, which can thoroughly remove the magnesium salt and the aluminum salt in the product under the condition that the molecular weight and the molecular weight distribution of the icodextrin are not influenced, so that the aluminum salt content in the icodextrin finished product is less than 0.1ppm, and the magnesium salt content is less than 0.8ppm.
In order to achieve the above purpose, the invention provides a method for removing aluminum salt and magnesium salt in icodextrin bulk drug, comprising the following steps:
the method for removing the aluminum salt and the magnesium salt in the icodextrin bulk drug is characterized by comprising the following steps:
s1, taking starch hydrolysate, and adopting a first group of ultrafiltration membranes to have equal volume; stopping the control after the molecular weight of the icodextrin in the feed liquid reaches the quality standard of the finished product in the central control state to obtain a first icodextrin concentrate;
The quality standard of the finished product is as follows: weight average molecular weight Mw: 13000-19000 Da; number average molecular weight Mn: 5000-6500 Da; the ratio of the molecular weight and the molecular weight distribution Mw in 1638-45000 Da is not less than 85.0%;
S2, taking the first icodextrin concentrate obtained in the step S1, adopting a second group of nanofiltration membranes to continue isovolumetric treatment until the conductivity of the permeate is lower than 5 mu S/cm, and stopping to obtain a second icodextrin concentrate;
S3, continuously concentrating the second icodextrin concentrate under reduced pressure, and drying to obtain an icodextrin product.
As a further improvement of the invention, the starch hydrolysate is obtained by hydrolyzing corn starch for 3-5 hours by using alpha amylase, and the mass-volume ratio of the corn starch to the alpha amylase is 400000+/-10:1.
As a further improvement of the invention, in step S1, the nominal molecular weight cut-off of the ultrafiltration membranes of the first group is preferably between 1000Da and 3000Da; preferably 1500Da.
As a further improvement of the invention, in the step S1, the isovolumetric pressure is between-0.1 mpa and-0.6 mpa.
As a further improvement of the invention, in the step S1, the constant volume time is 360-480 min.
As a further improvement of the invention, in the step S1, the central control state refers to monitoring the molecular weight and molecular weight distribution of the icodextrin in the feed liquid by adopting a viscosity test method, a light scattering method or a gel chromatography method.
As a further improvement of the invention, in step S2, the nominal molecular weight cut-off of the second set of nanofiltration membranes is 100Da to 300Da; preferably 200Da.
As a further improvement of the invention, in the step S2, the permeate is stopped after the conductivity is lower than 2 mu S/cm.
As a further improvement of the invention, in the step S2, the isovolumetric pressure is between-0.3 mpa and-0.9 mpa.
As a further improvement of the present invention, in step S3, the drying is spray drying, and the conditions of the spray drying are: the air inlet temperature is 190-200 ℃, the rotating speed of the high-speed centrifugal atomizer is 8064+/-50 r/min, and the air outlet temperature is above 92 ℃.
In general, the above technical solutions conceived by the present invention have the following beneficial effects compared with the prior art:
(1) According to the method for removing the aluminum salt and the magnesium salt in the icodextrin bulk drug, the ultrafiltration membrane and the nanofiltration membrane are combined, the quality standard of the icodextrin finished product is met through the ultrafiltration membrane, and after a large amount of magnesium salt and aluminum salt are primarily removed, the nanofiltration membrane is adopted to further remove the magnesium salt and the aluminum salt, so that the magnesium salt and the aluminum salt in the product are thoroughly removed under the condition that the molecular weight and the molecular weight distribution of the icodextrin are not influenced, the aluminum salt content in the icodextrin finished product is less than 0.1ppm, and the magnesium salt content is less than 0.8ppm.
(2) According to the method for removing the aluminum salt and the magnesium salt in the icodextrin bulk drug, macromolecular ends in the molecular weight distribution of the icodextrin can be controlled through improvement of a hydrolysis process, and the molecular weight distribution are controlled to a certain range, so that a hydrolysate is obtained; the small molecular ends in the molecular weight distribution of the icodextrin are mainly removed through a first group of ultrafiltration membrane separation steps.
(3) According to the method for removing the aluminum salt and the magnesium salt in the icodextrin bulk drug, the result of online conductivity monitoring in the feed liquid is used as a central control condition, and the removal effect of the magnesium salt and the aluminum salt in the product is indirectly reacted, so that the end of the nanofiltration process is controlled, and the content of the aluminum salt and the magnesium salt in the icodextrin finished product is below the limit.
(4) According to the method for removing the aluminum salt and the magnesium salt in the icodextrin bulk drug, the time for the molecular weight of the icodextrin in the feed liquid to reach the standard limit can be balanced through the arrangement of the isovolumetric pressure of the first group of ultrafiltration membranes, and the aluminum and the magnesium can be removed quickly through the arrangement of the isovolumetric pressure of the second group of nanofiltration membranes.
Detailed Description
The present invention will be described in further detail with reference to the following examples in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the invention. In addition, the technical features of the embodiments of the present invention described below may be combined with each other as long as they do not collide with each other.
The invention provides a method for removing aluminum salt and magnesium salt in a raw material drug of icodextrin, which comprises the following steps:
s1, taking starch hydrolysate, and adopting a first group of ultrafiltration membranes to have equal volume; stopping the control after the molecular weight of the icodextrin in the feed liquid reaches the quality standard of the finished product in the central control state to obtain a first icodextrin concentrate;
the quality standard of the finished product is as follows: weight average molecular weight (Mw): 13000-19000 Da; number average molecular weight (Mn): 5000-6500 Da; the ratio of the molecular weight and the molecular weight distribution (Mw) in 1638-45000 Da (Mw) is not less than 85.0%.
Preferably, the starch hydrolysate is obtained by hydrolyzing corn starch by alpha amylase for 3-5 hours, and more preferably 4 hours; the ratio of cornstarch to a amylase is 400000+/-10:1 (W: V); the concentration of the starch hydrolysate is 10-20%, namely 1000L of the starch hydrolysate contains 100-200 kg of primary icodextrin. In the hydrolysis process, the molecular weight and the molecular weight distribution can be controlled to a certain range, and a hydrolysis product is obtained. At this time, the chromatographic peak of the starch hydrolysate in the feed liquid in HPLC is consistent with the peak time of the chromatographic peak of the icodextrin working control. The specific operation method of enzymatic hydrolysis is just to adopt the prior art, and is not described in detail herein.
S2, taking the first icodextrin concentrate obtained in the step S1, adopting a second group of nanofiltration membranes to continue isovolumetric treatment until the conductivity of the permeate is lower than 5 mu S/cm, and stopping to obtain a second icodextrin concentrate;
s3, continuously concentrating the second icodextrin concentrate under reduced pressure, and drying to obtain the icodextrin product.
In step S1, the nominal molecular weight cut-off of the ultrafiltration membranes of the first group is preferably between 1000 and 3000Da, more preferably 1500Da. The nominal molecular weight cut-off of the ultrafiltration membrane is selected based on the icodextrin molecular weight and the ratio of the molecular weight distribution (Mw) in 1638 to 45000 (Mw) being not less than 85.0%.
In the isovolumetric process of the first group of ultrafiltration membranes, small-molecular saccharides with molecular weight lower than 1000-3000 Da, sodium chloride, 5-hydroxymethyl furfural, most of aluminum salt, magnesium salt and other impurities can be gradually discharged along with the permeate liquid through the ultrafiltration membranes, and icodextrin with molecular weight higher than 1000-3000 Da is trapped by the ultrafiltration membranes and returned to the raw material liquid together with the concentrated liquid, and the molecular weight and molecular weight distribution of the icodextrin in the material liquid are sampled and monitored at proper time. Therefore, the small molecular end part with the molecular weight smaller than 1638 in the starch hydrolysate is mainly removed through a first group of ultrafiltration membrane separation steps, and the large molecular end part with the molecular weight larger than 45000 is mainly controlled through starch degradation in the icodextrin production process, namely, the corn starch is hydrolyzed for 3-5 hours by alpha amylase to obtain the starch hydrolysate, and at the moment, the chromatographic peak of the starch hydrolysate in the feed liquid in HPLC is consistent with the peak starting time of the chromatographic peak of the icodextrin working reference substance.
Preferably, in step S1, the isovolumetric pressure is-0.1 mpa to-0.6 mpa, more preferably-0.3 mpa, the isovolumetric pressure determines the ultrafiltration speed, and determines the speed of the small molecular sugar permeating through the ultrafiltration membrane, and when the pressure is too high, the small molecular sugar is removed too quickly, and the situation that the main impurities (chlorides) are still not qualified when the molecular weight and molecular weight distribution of icodextrin in the feed liquid are qualified may occur; when the pressure is too small, the effect is opposite, after the main impurities are removed, the molecular weight and the molecular weight distribution of the icodextrin in the feed liquid are unqualified, so that the isovolumetric time is prolonged, and the longer the isovolumetric time is, the higher the risk of unqualified hygiene indexes is. The ideal state is that the molecular weight and the chloride reach the standard limit at the same time, and the ideal state can be approached by setting the isovolumetric pressure.
Preferably, in step S1, the isovolumetric time is 360 min-480 min, so that the molecular weight and molecular weight distribution of the icodextrin in the feed liquid can meet the quality standard of the finished product, and the isovolumetric time is more preferably 420 min-460 min. The isovolumetric time determines the total displacement of the solvent, and most of the small molecular sugar (Mw is less than 1638) is discharged along with the solvent within the isovolumetric time range, and the small molecular sugar is remained in the feed liquid in a small part, so that the molecular weight and molecular weight distribution of the icodextrin in the feed liquid can meet the quality standard specification, and meanwhile, the main impurity chloride can also meet the quality standard requirement. However, it should be noted that stopping the isovolumetric process in step S1 is still determined by whether the molecular weight of icodextrin in the feed liquid reaches the quality standard of the finished product.
Preferably, in step S1, the central control state refers to monitoring the molecular weight and molecular weight distribution of icodextrin in the feed liquid by using a viscosity test method, a light scattering method (LS) or a gel chromatography (GPC) method; GPC is preferably used.
Further, in step S2, the nominal molecular weight cut-off of the nanofiltration membranes of the second group is preferably 100-300 Da, more preferably 200Da. The molecular weight distributions of magnesium and aluminium are 24 and 27 respectively, so in this step nanofiltration membranes (100-300 Da) with a minimum pore size for the nominal molecular weight cut-off greater than 27 are selected. The first group of ultrafiltration membranes can be used for preparing icodextrin samples with qualified indexes except aluminum and magnesium, and the second group of nanofiltration modules can be used for removing magnesium and aluminum in the feed liquid on the premise of not affecting the molecular weight and molecular weight distribution of icodextrin in the feed liquid.
Preferably, in step S2, the permeate is stopped after having a conductivity of less than 5. Mu.s/cm (preferably 2. Mu.s/cm). Conductivity is a parameter used to describe how hard a charge in a substance flows, and therefore the conductivity of a permeate can be used to measure the concentration of charged ions in a feed solution. The conductivity can be realized by an on-line monitoring probe in the prior art. The test result shows that the ultrafiltration is stopped after the conductivity in the feed liquid is less than 5 mu s/cm (preferably 2 mu s/cm), the aluminum salt content in the finished icodextrin product is less than 0.1ppm, and the magnesium salt content is less than 0.8ppm.
Preferably, in step S2, the isovolumetric pressure is from-0.3 mpa to-0.9 mpa, more preferably-0.6 mpa, and the pressure range is such that the removal rate of aluminum and magnesium is relatively high.
Steps S1 and S2 may be performed at normal temperature.
Further, in step S3, the drying is preferably performed by spray drying under the following conditions: the air inlet temperature is 190-200 ℃, the rotating speed of the high-speed centrifugal atomizer is 8064+/-50 r/min, and the air outlet temperature is above 92 ℃.
In addition, the first group of ultrafiltration membranes and the second group of nanofiltration membranes in the steps S1 and S2 of the invention adopt the ultrafiltration membranes and the nanofiltration membranes in the prior art, and the nominal molecular weight cut-off of the ultrafiltration membranes and the nanofiltration membranes can be set in the range by changing the mold cores.
According to the method for removing the aluminum salt and the magnesium salt in the icodextrin bulk drug, the molecular weight and the molecular weight distribution (Mw) 1638-45000 (Mw) of the icodextrin bulk drug are required to be not less than 85.0% by mass standard, if only the step S1 is adopted, the magnesium salt and the aluminum salt are thoroughly removed by using an ultrafiltration membrane with larger interception pore diameter (1000-3000 Da), the isovolumetric time is required to be increased, on one hand, the material loss at the small molecular end of the product is possibly caused, so that the key structural index of the icodextrin is influenced, and on the other hand, the longer the isovolumetric time, the higher the risk of disqualification of the hygiene index is. If only the step S2 is adopted, a nanofiltration membrane with smaller interception pore diameter (100-300 Da) is used for removing magnesium salt and aluminum salt, and the content of the magnesium salt and the aluminum salt can be reduced below the standard limit, but the quality standard of the finished product of the icodextrin can not meet the requirement because the small molecular sugar and impurities with Mw less than 1638 are not removed.
Therefore, the invention combines the ultrafiltration membrane and the nanofiltration membrane, meets the requirement on the quality standard of the finished product of the icodextrin through the ultrafiltration membrane, and further removes the magnesium salt and the aluminum salt by adopting the nanofiltration membrane after a large amount of magnesium salt and aluminum salt are primarily removed, thereby ensuring that the magnesium salt and the aluminum salt in the product are thoroughly removed under the condition of not influencing the molecular weight and the molecular weight distribution of the icodextrin.
According to the method for removing the aluminum salt and the magnesium salt in the icodextrin bulk drug, in the hydrolysis process, the molecular weight and the molecular weight distribution are controlled to a certain range, so that a hydrolysate is obtained; and then a multi-layer multi-stage ultrafiltration nanofiltration combined membrane separation system is adopted to accurately intercept degradation products, effectively cut out ultra-range molecular fragments and remove impurities (aluminum, magnesium, 5-hydroxymethylfurfural, sodium chloride and the like) generated in the steps, and finally, hydrolysate-icodextrin with a specific molecular weight range is prepared.
In a specific embodiment, the method for removing aluminum salt and magnesium salt in icodextrin bulk drug comprises the following steps:
(1) Taking starch hydrolysate, opening a first group of ultrafiltration membranes with nominal cut-off molecular weight of 1000-3000 Da to equal the volume, monitoring the molecular weight and molecular weight distribution of the icodextrin in the feed liquid by adopting a viscosity test method, a light scattering method or a gel chromatography method in the process, and stopping when the molecular weight and molecular weight distribution meet the quality standard of a finished product to obtain a first icodextrin concentrate;
The quality standard of the finished product is as follows: the weight average molecular weight (Mw) is 13000-19000 Da; the number average molecular weight (Mn) is 5000-6500 Da; a molecular weight and molecular weight distribution (Mw) of not less than 85.0% in 1638-45000 Da;
(2) Taking a first icodextrin concentrate, closing a first group of ultrafiltration membranes, opening a second group of nanofiltration membranes with nominal cut-off molecular weight of 1000-3000 Da, continuously removing residual aluminum salt and magnesium salt in the feed liquid in an isovolumetric manner until the conductivity of the permeate liquid is lower than 5 mu s/cm, and stopping to obtain a second icodextrin concentrate;
(3) And concentrating under reduced pressure, and spray drying to obtain the icodextrin product.
The content of aluminum salt in the finished icodextrin product is less than 0.1ppm and the content of magnesium salt in the finished icodextrin product is less than 0.8ppm by adopting an inductively coupled plasma mass spectrometry method.
For a better understanding of the technical solutions of the present invention, the following specific examples and comparative examples are provided.
Example 1
The method for removing aluminum salt and magnesium salt in icodextrin bulk drug in the embodiment comprises the following steps: the starch hydrolysate (15%) is obtained after hydrolyzing the corn starch for 4 hours by the alpha amylase, and the mass-volume ratio of the corn starch to the alpha amylase is 400000:1. And (3) opening a first group of ultrafiltration membranes with nominal molecular weight cut-off of 1500Da, adjusting the pressure to-0.3 mpa under normal temperature, and sampling and monitoring the molecular weight and molecular weight distribution of icodextrin in the feed liquid by adopting a GPC method. And closing the first ultrafiltration membrane group when the molecular weight and molecular weight distribution of the icodextrin in the feed liquid meet the quality standard of the finished product. And opening a second group of nanofiltration membranes with nominal molecular weight cut-off of 200Da, regulating the pressure to-0.6 mpa under normal temperature, continuing to wait until the conductivity of the permeate is less than 4.6 mu s/cm, and stopping waiting. And then concentrating under reduced pressure, and spray drying to obtain the aluminum salt and magnesium salt content, the molecular weight of the icodextrin and the molecular weight distribution result in the solid icodextrin product, wherein the results are shown in the following table:
Example 2
The method for removing aluminum salt and magnesium salt in icodextrin bulk drug in the embodiment comprises the following steps: the starch hydrolysate (15%) is obtained after hydrolyzing the corn starch for 4 hours by the alpha amylase, and the mass-volume ratio of the corn starch to the alpha amylase is 400000:1. And (3) opening a first group of ultrafiltration membranes with nominal molecular weight cut-off of 1500Da, adjusting the pressure to-0.3 mpa under normal temperature, and sampling and monitoring the molecular weight and molecular weight distribution of icodextrin in the feed liquid by adopting a GPC method. And closing the first ultrafiltration membrane group when the molecular weight and molecular weight distribution of the icodextrin in the feed liquid meet the quality standard of the finished product. And opening a second group of nanofiltration membranes with nominal molecular weight cut-off of 200Da, regulating the pressure to-0.6 mpa under normal temperature, continuing to wait until the conductivity of the permeate is less than 1.9 mu s/cm, and stopping waiting. And then concentrating under reduced pressure, and spray drying to obtain the aluminum salt and magnesium salt content, the molecular weight of the icodextrin and the molecular weight distribution result in the solid icodextrin product, wherein the results are shown in the following table:
Example 3
The method for removing aluminum salt and magnesium salt in icodextrin bulk drug in the embodiment comprises the following steps: the corn starch is hydrolyzed by the alpha amylase for 5 hours to obtain starch hydrolysis liquid (18%), and the mass volume ratio of the corn starch to the alpha amylase is 400000:1. And (3) opening a first group of ultrafiltration membranes with nominal cut-off molecular weight of 1000Da, regulating pressure to-0.6 mpa under normal temperature, and sampling and monitoring the molecular weight and molecular weight distribution of icodextrin in the feed liquid by adopting a light scattering method. And closing the first ultrafiltration membrane group when the molecular weight and molecular weight distribution of the icodextrin in the feed liquid meet the quality standard of the finished product. And opening a second group of nanofiltration membranes with nominal molecular weight cut-off of 300Da, regulating the pressure to-0.3 mpa under normal temperature, continuing to wait until the conductivity of the permeate is less than 1.8 mu s/cm, and stopping waiting. And then concentrating under reduced pressure, and spray drying to obtain the aluminum salt and magnesium salt content, the molecular weight of the icodextrin and the molecular weight distribution result in the solid icodextrin product, wherein the results are shown in the following table:
Example 4
The method for removing aluminum salt and magnesium salt in icodextrin bulk drug in the embodiment comprises the following steps: the starch hydrolysate (12%) is obtained after 3h of hydrolysis of corn starch by a amylase, and the mass-volume ratio of the corn starch to the a amylase is 400000:1. And (3) opening a first group of ultrafiltration membranes with nominal cut-off molecular weight of 3000Da, regulating pressure to-0.1 mpa under normal temperature, and sampling and monitoring the molecular weight and molecular weight distribution of icodextrin in the feed liquid by adopting a viscosity test method. And closing the first ultrafiltration membrane group when the molecular weight and molecular weight distribution of the icodextrin in the feed liquid meet the quality standard of the finished product. And opening a second group of nanofiltration membranes with nominal molecular weight cut-off of 100Da, regulating the pressure to-0.9 mpa under normal temperature, continuing to wait until the conductivity of the permeate is less than 2.1 mu s/cm, and stopping waiting. And then concentrating under reduced pressure, and spray drying to obtain the aluminum salt and magnesium salt content, the molecular weight of the icodextrin and the molecular weight distribution result in the solid icodextrin product, wherein the results are shown in the following table:
The molecular weight and molecular weight distribution of the icodextrin products obtained in examples 1 to 4 above were examined by GPC, and the weight average molecular weight (Mw) of the icodextrin products obtained in examples 1 to 4 were each in the range of 13000 to 19000; the number average molecular weight (Mn) is in the range of 5000-6500; the molecular weight and molecular weight distribution (Mw) 1638-45000 (Mw) are greater than 85.0 percent.
The icodextrin products obtained in examples 1 to 4 above were examined for aluminum and magnesium salt content by inductively coupled plasma mass spectrometry, and the icodextrin products obtained in examples 1 to 4 had an aluminum salt content of less than 0.1ppm and a magnesium salt content of less than 0.8ppm.
Comparative example 1
The method for removing aluminum salt and magnesium salt in the icodextrin bulk drug in the comparative example comprises the following steps: the starch hydrolysate (15%) is obtained after hydrolyzing the corn starch for 4 hours by the alpha amylase, and the mass-volume ratio of the corn starch to the alpha amylase is 400000:1. And (3) opening a first group of ultrafiltration membranes with nominal molecular weight cut-off of 1500Da, adjusting the inlet pressure to-0.4 mpa under normal temperature, and sampling and monitoring the molecular weight and molecular weight distribution of icodextrin in the feed liquid by adopting a GPC method. Stopping when the molecular weight and molecular weight distribution of the icodextrin in the feed liquid meet the quality standard of the finished product. And then concentrating under reduced pressure, and spray drying to obtain the aluminum salt and magnesium salt content, the molecular weight of the icodextrin and the molecular weight distribution result in the solid icodextrin product, wherein the results are shown in the following table:
The results show that step S1 determines the molecular weight and molecular weight distribution of the main structural index of the icodextrin product, and the step S1 can be used for preparing the icodextrin product with the molecular weight and molecular weight distribution meeting the standards, but can not remove the aluminum salt and the magnesium salt in the icodextrin well.
Comparative example 2
The method for removing aluminum salt and magnesium salt in the icodextrin bulk drug in the comparative example comprises the following steps: hydrolyzing corn starch by using alpha amylase for 4 hours to obtain starch hydrolysate (15%), taking the starch hydrolysate, opening a second group of ultrafiltration membranes with nominal cut-off molecular weight of 200Da, adjusting the pressure to-0.6 mpa under normal temperature, and stopping waiting until the conductivity of the permeate is 2.0 mu s/cm. And then concentrating under reduced pressure, and spray drying to obtain the aluminum salt and magnesium salt content, the molecular weight of the icodextrin and the molecular weight distribution result in the solid icodextrin product, wherein the results are shown in the following table:
the results show that step S1 is the most critical and necessary process in the icodextrin manufacturing process, and it determines the results of molecular weight and molecular weight distribution of the main structural index of the icodextrin product. Using step S2 alone will not produce an icodextrin product with a qualified primary index.
Comparative example 3
The method for removing aluminum salt and magnesium salt in icodextrin bulk drug in the embodiment comprises the following steps: hydrolyzing corn starch by using alpha amylase for 4 hours to obtain starch hydrolysate (15%), taking the starch hydrolysate, opening a first group of ultrafiltration membranes with nominal cut-off molecular weight of 1500Da, adjusting pressure to-0.4 mpa at normal temperature, waiting for volume, and timely sampling and monitoring the molecular weight and molecular weight distribution of icodextrin in the feed liquid by adopting a GPC method. And closing the first ultrafiltration membrane group when the molecular weight and molecular weight distribution of the icodextrin in the feed liquid meet the quality standard of the finished product. And opening a second group of nanofiltration membranes with nominal molecular weight cut-off of 200Da, regulating the pressure to-0.3 mpa under normal temperature, and stopping waiting until the conductivity of the permeate is less than 14.9 mu s/cm. And then concentrating under reduced pressure, and spray drying to obtain the aluminum salt and magnesium salt content, the molecular weight of the icodextrin and the molecular weight distribution result in the solid icodextrin product, wherein the results are shown in the following table:
Comparative example 4
The method for removing aluminum salt and magnesium salt in icodextrin bulk drug in the embodiment comprises the following steps: hydrolyzing corn starch by using alpha amylase for 4 hours to obtain starch hydrolysate (15%), taking the starch hydrolysate, opening a first group of ultrafiltration membranes with nominal cut-off molecular weight of 1500Da, adjusting pressure to-0.3 mpa at normal temperature, waiting for volume, and sampling and monitoring the molecular weight and molecular weight distribution of icodextrin in the feed liquid by adopting a GPC method. And closing the first ultrafiltration membrane group when the molecular weight and molecular weight distribution of the icodextrin in the feed liquid meet the quality standard of the finished product. And opening a second group of nanofiltration membranes with nominal molecular weight cut-off of 200Da, regulating the pressure to-0.6 mpa under normal temperature, continuing to wait until the conductivity of the permeate is less than 9.8 mu s/cm, and stopping waiting. And then concentrating under reduced pressure, and spray drying to obtain the aluminum salt and magnesium salt content, the molecular weight of the icodextrin and the molecular weight distribution result in the solid icodextrin product, wherein the results are shown in the following table:
The results of comparative examples 3 and 4 show that the removal of aluminum and magnesium salts is poor when the conductivity of the permeate is higher than 5. Mu.s/cm.
According to the method for removing the aluminum salt and the magnesium salt in the icodextrin bulk drug, only a group of nanofiltration membranes with the nominal molecular weight cut-off of 100-300 Da are needed to be added in the existing ultrafiltration membrane system in the icodextrin production process, so that the quality of the icodextrin product can be greatly improved. Compared with other methods, the method is convenient to operate, the molecular weight and the molecular weight distribution of the finished icodextrin product are hardly affected after a group of nanofiltration membranes are added, and the effect of removing aluminum salt and magnesium salt is good.
It will be readily appreciated by those skilled in the art that the foregoing description is merely a preferred embodiment of the invention and is not intended to limit the invention, but any modifications, equivalents, improvements or alternatives falling within the spirit and principles of the invention are intended to be included within the scope of the invention.
Claims (8)
1. The method for removing the aluminum salt and the magnesium salt in the icodextrin bulk drug is characterized by comprising the following steps of:
s1, taking starch hydrolysate, and adopting a first group of ultrafiltration membranes to have equal volume; stopping the control after the molecular weight of the icodextrin in the feed liquid reaches the quality standard of the finished product in the central control state to obtain a first icodextrin concentrate;
the nominal cut-off molecular weight of the first group of ultrafiltration membranes is 1500Da to 3000Da;
The quality standard of the finished product is as follows: weight average molecular weight Mw: 13000-19000 Da; number average molecular weight Mn: 5000-6500 Da; the ratio of the molecular weight to the molecular weight distribution Mw in 1638-45000 Da is not less than 85.0%;
S2, taking the first icodextrin concentrate obtained in the step S1, adopting a second group of nanofiltration membranes to continue isovolumetric treatment until the conductivity of the permeate is lower than 5 mu S/cm, and stopping to obtain a second icodextrin concentrate;
the nominal cut-off molecular weight of the second group of nanofiltration membranes is 100 Da-300 Da;
S3, continuously concentrating the second icodextrin concentrate under reduced pressure, and drying to obtain an icodextrin product;
in the step S1, the constant volume pressure is-0.1 mpa to-0.6 mpa; in the step S2, the constant volume pressure is-0.3 mpa to-0.9 mpa;
in the icodextrin product, the aluminum salt content is less than 0.1ppm, and the magnesium salt content is less than 0.8ppm.
2. The method for removing aluminum salt and magnesium salt in icodextrin bulk drug according to claim 1, wherein the starch hydrolysate is obtained by hydrolyzing corn starch for 3-5 hours by a amylase, and the mass-volume ratio of the corn starch to the a amylase is 400000+/-10:1.
3. The method of claim 1, wherein in step S1, the first group of ultrafiltration membranes has a nominal molecular weight cut-off of 1500Da.
4. The method for removing aluminum salt and magnesium salt in icodextrin bulk drug according to claim 1, wherein in step S1, the constant volume time is 360 min-480 min.
5. The method for removing aluminum salt and magnesium salt from a bulk drug of icodextrin according to claim 1, wherein in step S1, the central control state means monitoring the molecular weight and molecular weight distribution of icodextrin in the feed liquid by a viscosity test method, a light scattering method or a gel chromatography method.
6. The method of claim 1, wherein in step S2, the nominal molecular weight cut-off of the second nanofiltration membrane is 200Da.
7. The method for removing aluminum salt and magnesium salt from icodextrin bulk drug according to claim 1, wherein in step S2, the permeate is stopped after the conductivity is lower than 2 μs/cm.
8. The method for removing aluminum and magnesium salts from an icodextrin bulk drug according to claim 1, wherein in step S3, the drying is spray drying under the following conditions: the air inlet temperature is 190-200 ℃, the rotating speed of the high-speed centrifugal atomizer is 8064+/-50 r/min, and the air outlet temperature is above 92 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310944864.8A CN117050201B (en) | 2023-07-31 | 2023-07-31 | Method for removing aluminum salt and magnesium salt in icodextrin bulk drug |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310944864.8A CN117050201B (en) | 2023-07-31 | 2023-07-31 | Method for removing aluminum salt and magnesium salt in icodextrin bulk drug |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN117050201A CN117050201A (en) | 2023-11-14 |
| CN117050201B true CN117050201B (en) | 2024-06-21 |
Family
ID=88665446
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202310944864.8A Active CN117050201B (en) | 2023-07-31 | 2023-07-31 | Method for removing aluminum salt and magnesium salt in icodextrin bulk drug |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN117050201B (en) |
Citations (2)
| 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 |
| CN114605563A (en) * | 2022-04-08 | 2022-06-10 | 中国海洋大学 | Preparation method of icodextrin raw material medicine single enzyme system for peritoneal dialysis solution |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1847266A (en) * | 2005-04-15 | 2006-10-18 | 三达工业技术（厦门）有限公司 | Girasole synanthrin producing process based on two-stage ultrafiltering technology |
| CN105524181B (en) * | 2014-10-23 | 2017-12-08 | 华仁药业股份有限公司 | The brand-new synthesis technique of Icodextrin bulk drug |
| CN106525819A (en) * | 2015-09-09 | 2017-03-22 | 华仁药业股份有限公司 | Method for measuring content of magnesium salt in icodextrin bulk drug |
| CN112717719B (en) * | 2020-12-25 | 2023-03-17 | 自然资源部天津海水淡化与综合利用研究所 | Method for preparing graphene oxide composite nanofiltration membrane by spraying method |
-
2023
- 2023-07-31 CN CN202310944864.8A patent/CN117050201B/en active Active
Patent Citations (2)
| 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 |
| CN114605563A (en) * | 2022-04-08 | 2022-06-10 | 中国海洋大学 | Preparation method of icodextrin raw material medicine single enzyme system for peritoneal dialysis solution |
Non-Patent Citations (2)
| Title |
|---|
| The use of membrane filtration for removal of aluminum from drinking water sources;Anna Kwiecińska-Mydlaka 等;Desalination and Water Treatment;20211231;第243卷;第75–82页 * |
| 膜分离技术分离纯化朝鲜蓟叶中洋蓟素的工艺研究;张孝友 等;食品工业科技;20111231;第32卷(第第4期期);第255-257页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN117050201A (en) | 2023-11-14 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN111004827B (en) | Preparation method of xylo-oligosaccharide | |
| CN106397630B (en) | A method of Sodium Hyaluronate is extracted using membrane separation technique | |
| CN109438532B (en) | Method for extracting D-glucosamine | |
| CN102838691A (en) | Extracting and purifying method of chondroitin sulfate | |
| CN111978417B (en) | Extraction method of hemp polysaccharide, product and application thereof | |
| CN101089021B (en) | Process of separating and extracting hyaluronic acid from microbial fermented liquid | |
| JP2022180509A (en) | Pentosan polysulfate and method for producing pentosan polysulfate | |
| CN117050201B (en) | Method for removing aluminum salt and magnesium salt in icodextrin bulk drug | |
| CN113248551B (en) | System and method for preparing refined xylose by utilizing xylose mother liquor chromatographic extract | |
| CN106222313A (en) | A kind of method utilizing the waste liquid produced in viscose staple fiber production process to prepare food stage xylose | |
| CN105820271A (en) | Preparation and purification method of scale micromolecular sodium hyaluronate | |
| CN101508707B (en) | Production process for medicinal sucrose | |
| CN102617743B (en) | Preparation method for hydroxyethyl starch | |
| CN104448043A (en) | Method for producing and purifying enoxaparin sodium | |
| CN111996183A (en) | Preparation method of bromelain | |
| CN112521487A (en) | Improved production process of human serum albumin | |
| CN105440163A (en) | Method for preparing and purifying enoxaparin sodium | |
| CN112321751A (en) | Refining method of high-quality enoxaparin sodium | |
| CN110776538B (en) | Preparation method of low-potassium or low-sodium glucosamine sulfate | |
| CN114262387A (en) | Preparation method of resistant dextrin | |
| CN113149987A (en) | Preparation method of injection-grade ganciclovir | |
| CN112029015A (en) | Production and purification process of high-purity low-molecular-weight heparin sodium | |
| CN117384305A (en) | Preparation process of icodextrin bulk drug and icodextrin bulk drug | |
| CN112321752A (en) | Preparation method of high-quality dalteparin sodium | |
| CN101255177B (en) | Preparation of medicament-grade cane sugar by ion-exchange fibre method |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| CB02 | Change of applicant information |
Country or region after: China Address after: Building 1, No. 3 Huagongyuan Fourth Road, Huagongyuan Science and Technology Park, Donghu New Technology Development Zone, Wuhan City, Hubei Province, 430223 Applicant after: Wuhan University of Science and Technology Life Technology Co.,Ltd. Address before: 430223 Building 1, No. 3, Huagong Science Park 4th Road, Donghu New Technology Development Zone, Wuhan, Hubei Applicant before: WUHAN HUST LIFE SCIENCE & TECHNOLOGY Co.,Ltd. Country or region before: China |
|
| CB02 | Change of applicant information | ||
| GR01 | Patent grant |