CN105524181A - Novel synthesis technology for icodextrin bulk drug - Google Patents
Novel synthesis technology for icodextrin bulk drug Download PDFInfo
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- CN105524181A CN105524181A CN201410567567.7A CN201410567567A CN105524181A CN 105524181 A CN105524181 A CN 105524181A CN 201410567567 A CN201410567567 A CN 201410567567A CN 105524181 A CN105524181 A CN 105524181A
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Abstract
The invention relates to the field of medicine preparation, and especially relates to a novel synthesis technology for icodextrin bulk drug. The technology comprises the following steps: employing starch maize as an initial raw material, adding hydrochloric acid for hydrolysis to certain degree, performing ultrafiltration by an ultrafilter membrane with molecular weight cut-off of 5000; adding active carbon, adjusting the pH value and controlling temperature, and performing spray drying to obtain the product with qualified quality control index. The product can control endotoxin. The raw material has the advantages of low cost and easy acquisition, the technology has the advantages of simple process and easy operation, by controlling an addition method of the active carbon and a decarburization process, and the product with endotoxin controlled to less than 1.2 EU/g can be obtained by adjusting the temperature and the pH value.
Description
Technical field
The present invention relates to medicine preparation field, particularly the brand-new synthesis technique of a kind of icodextrin bulk drug.
Background technology
Icodextrin is starch derivative by α (1-4) and the Water-Soluble Glucose polymkeric substance being less than 10% α (1-6) glycosidic link and being connected, and weight-average molecular weight is 13000 ~ 19000 dalton.
Icodextrin and other ionogen share clinically for peritoneal dialysis, are developed the earliest by ATTELION company of the U.S., and obtain FDA approval by hundred special medical company in 2002.The new peritoneal dialysis solution icodextrin (Icodextrin) of hundred spies (Baxter) company gets permission listing on July 18th, 2003 in Japan, trade(brand)name: Extraneal.Extraneal is the first dialyzate for peritoneal dialysis patient new class permeate agent, gets permission listing in 36 countries at present, and the domestic icodextrin peritoneal dialysis solution that there is no at present is produced and listing.
Production technique external is at present take maltodextrin solution as starting raw material, with the ultra-filtration membrane ultrafiltration of molecular weight cut-off 45000, then with the ultra-filtration membrane ultrafiltration of molecular weight cut-off 1638; Add activated carbon treatment, spraying dry obtains finished product.Adopt the indexs such as temperature, specific rotation, osmotic pressure to carry out Quality Control, regularly adopt NMR method to investigate the amount that α-1,6 connects.Domestic only have one section of patent CN201310453098 to report the synthetic method of icodextrin, but only compare from the scope of molecular weight and reference preparation, do not study from other quality control indexs, particularly induced by endotoxin controls, do not relate in patent, and the difficult point of icodextrin bulk drug is produced in endotoxic control exactly.In addition, the technique that external production technique and domestic patent CN201310453098 report all needs employing two to overlap ultra-filtration membrane bag and ultrafiltration apparatus, ultra-filtration membrane bag and equipment price costliness, and two cover ultrafiltration technologies are very loaded down with trivial details in actual production operation simultaneously.
Summary of the invention
For the deficiencies in the prior art, the invention provides a kind of raw material cheap and easy to get, technical process is simple to operation and very stable, the brand-new synthesis technique of icodextrin bulk drug that quality control index is all qualified.
For achieving the above object, the technical solution used in the present invention is as follows:
Step 1: hydrolysis
W-Gum and water being configured to concentration of substrate is after the solution of 25wt%, adding concentrated hydrochloric acid formation final concentration is the solution of 0.51%v/v, be hydrolyzed reaction under temperature 75 DEG C of-83 DEG C of conditions, weight-average molecular weight is measured when reaching 1.0 ten thousand ~ 1.25 ten thousand Da after hydrolysis 5h, add alkaline solution and regulate pH to 2-3, be cooled to 60 DEG C, obtain product 1;
Step 2: once decolour:
Decolouring still is evacuated to below-0.08Mpa, product 1 is drawn to decolouring still, be warming up to 60 DEG C, add the craboraffin of the 0.5%w/v of product 1,60 ± 2 DEG C of insulation 2h, take off charcoal through plate filter, are delivered in ultrafiltration storage tank, sheet frame pressure <0.2MPa, obtains product 2;
Step 3: essence filter:
By product 2 in ultrafiltration storage tank through 0.2 μm of filtering with microporous membrane to ultrafiltration tank, sheet frame pressure <0.2MPa;
Step 4: ultrafiltration:
Purified water is added to about 1500L in ultrafiltration tank, regulate pH between 3.5-4.5, feed temperature is 30-50 DEG C, ejector priming, start ultrafiltration, make inlet hydraulic maintain 0.2-0.5MPa, fluid pressure at 0.1-0.3MPa, when during ultrafiltration, in ultrafiltration tank, 500L feed liquid is fallen in every ultrafiltration, add purified water again to 1500L, shut down after ultrafiltration the 5th time, molecular weight detection confirms that qualified rear ultrafiltration is complete, obtains product 3;
Step 5: secondary decolourization:
Decolouring still is evacuated to below-0.08Mpa, product 3 is drawn to decolouring still, stir, regulate pH4-5, be warming up to 80 ± 2 DEG C, add the 0.25w/v needle-use activated carbon of product 3,80 ± 2 DEG C of insulation 1h; Take off charcoal through plate filter, de-charcoal feed liquid cycles back to decolouring still, de-charcoal backflow 1h; In decolouring still feed liquid, again add the 0.25w/v needle-use activated carbon of product 3,80 ± 2 DEG C of insulation 1h; Take off charcoal through plate filter, decarburization feed liquid is cycled back to decolouring still, feed liquid is delivered in treatment tank by decarburization backflow 1h, and sheet frame pressure <0.2MPa, obtains product 4;
Step 6 is refined:
By product 4 through 0.1 μm of filtering with microporous membrane, backflow 10-20min, after feed liquid is delivered to receiver; Stir, regulate pH4-6,75 DEG C-85 DEG C insulations, obtain product 5;
Step 7: spraying dry:
By product 5 dry solidification, packaging warehouse-in.
Preferably, the alkaline solution described in step 1 is one or more in sodium hydroxide solution, potassium hydroxide solution, carbonate solution.
Preferably, the spray drying condition described in step 7 is inlet temperature 180 DEG C-190 DEG C, air outlet temperature 100 DEG C-110 DEG C and material pump rotational frequency 0-50HZ.
Beneficial effect of the present invention: patent of the present invention adopts W-Gum to be starting raw material, adds hydrochloric acid hydrolysis to after to a certain degree, with the ultra-filtration membrane ultrafiltration of molecular weight cut-off 5000, add gac, by adjust ph and control temperature, spraying dry obtains all qualified product of every quality control index, especially induced by endotoxin controls, raw material of the present invention is cheap and easy to get, technical process is simple to operation and very stable, by controlling Adding Way and the decarburization program of gac, and control be less than the product of 1.2EU/g by regulating temperature and pH value to obtain intracellular toxin, meet icodextrin peritoneal dialysis solution completely to the endotoxic requirement of bulk drug, gained finished product molecular weight distributing index more concentrated (2.3 ~ 2.8), weight-average molecular weight controls at 1.5 ten thousand ~ 1.8 ten thousand Da, meet the requirement of icodextrin and be better than domestic and international technique products obtained therefrom, other quality control indexs are as specific optical rotation, side chain degree, heavy metal, muriate, microbial limits etc. all meet the requirements compared with hundred special reference preparations, what is more important the present invention only needs a set of ultrafiltration apparatus and ultra-filtration membrane bag to obtain qualified product, required equipment cost reduces greatly, be beneficial to suitability for industrialized production.
Embodiment
The present invention is set forth further below in conjunction with embodiment
W-Gum used in embodiment, purchased from: Dezhou great achievement Food Co., Ltd;
Hydrochloric acid, sodium hydroxide are purchased from traditional Chinese medicines group chemical reagent limited-liability company;
Millipore filtration is purchased from upper Haixing County sub-scavenging material factory;
Needle-use activated carbon is purchased from Ningguo City Heng Da gac company limited;
Craboraffin is purchased from Ningguo City Heng Da gac company limited;
Ultra-filtration membrane bag is purchased from Shanghai Fu Lite Industrial Co., Ltd.;
Embodiment 1:
The brand-new synthesis technique of a kind of icodextrin bulk drug, specifically comprises the steps:
1. be hydrolyzed:
A, add purified water 1000L at hydrolysis kettle, open and stir, add W-Gum 250kg, stir 30min.
B, add 5.1L concentrated hydrochloric acid, be warmed up to about 75 DEG C, adjustment steam valve open degree, makes temperature slowly rise to 82 DEG C, 82 DEG C-83 DEG C insulations.
C, insulation are recorded temperature after 5 hours and are sampled the weight-average molecular weight of HPLC working sample.
D, when weight-average molecular weight reaches 1.0 ten thousand-1.25 ten thousand, in hydrolysis kettle, add sodium hydroxide (2.1kg) solution, regulate pH to 2.0-3.0, be cooled to about 60 DEG C.
2. once decolour:
A, sealing decolouring still tank mouth, decolouring still is evacuated to below-0.08Mpa, and feed liquid in hydrolysis kettle is drawn to decolouring still, and suction is complete, injects and is about 100L brush tank with water, opens and stirs.
B, unlatching heating system heat up to feed liquid, are warming up to 60 DEG C, add 6kg craboraffin.60 ± 2 DEG C are incubated two hours, in insulating process, and an every 30 minutes records temperature.
C, feed liquid is taken off charcoal through plate filter, be delivered in ultrafiltration storage tank, sheet frame pressure <0.2MPa, filter before terminating, inject and be about 100L brush tank with water, filter complete termination of pumping.
3. essence filter:
0.2 μm of millipore filtration is arranged on plate filter, the feed liquid of ultrafiltration storage tank is filtered to ultrafiltration tank, sheet frame pressure <0.2MPa, filter before terminating, inject and be about 100L brush tank with water, filter complete termination of pumping.
4. ultrafiltration:
Purified water is added to about 1500L in ultrafiltration tank; regulate pH between 3.5-4.5; feed temperature is 30-50 DEG C, ejector priming, starts ultrafiltration; inlet hydraulic is made to maintain 0.2-0.5MPa; fluid pressure, at 0.1-0.3MPa, when 500L feed liquid is fallen in every ultrafiltration in ultrafiltration tank during ultrafiltration, then adds purified water to 1500L; shut down after ultrafiltration the 5th time, molecular weight detection confirms that qualified rear ultrafiltration is complete.
5. secondary decolourization:
A, sealing decolouring still tank mouth, decolouring still is evacuated to below-0.08Mpa, and feed liquid in ultrafiltration tank is drawn to decolouring still, and suction is complete, open and stir, regulate pH between 4-5, open heating system and feed liquid is heated up, be warming up to about 80 DEG C, add 3kg needle-use activated carbon, 80 ± 2 DEG C are incubated one hour, in insulating process, and an every 30 minutes records temperature.
Feed liquid is taken off charcoal through plate filter, and de-charcoal feed liquid cycles back to decolouring still, and de-charcoal refluxes one hour.
B, again in decolouring still feed liquid, add 3kg needle-use activated carbon, 80 ± 2 DEG C of insulations one hour, in insulating process, an every 30 minutes records temperature.
Feed liquid is taken off charcoal through plate filter, decarburization feed liquid is cycled back to decolouring still, decarburization reflux feed liquid was delivered in one hour refining between in treatment tank, sheet frame pressure <0.2MPa, before filtration terminates, inject and be about 100L brush tank with water, filter complete termination of pumping.
6 refine:
A, be arranged on plate filter by 0.1 μm of millipore filtration, start refining feed pump, backflow 10-20 minute, is then delivered to receiver by feed liquid, and feed liquid injects and is about 60L with water before filtering and terminating, and filters and terminates, termination of pumping.
B, unlatching receiver stir, and regulate pH4-6, heat up, be warming up to 75 DEG C, 75 DEG C-85 DEG C insulations to feed liquid.
7 spraying dry:
Inlet temperature (180 DEG C-190 DEG C) and air outlet temperature (100 DEG C-110 DEG C) and material pump rotational frequency (0-50HZ).Open hopper wall vibrator, rewinding per half an hour.Packaging warehouse-in.
Claims (3)
1. the brand-new synthesis technique of icodextrin bulk drug, is characterized in that, comprise the following steps:
Step 1: hydrolysis
W-Gum and water being configured to concentration of substrate is after the solution of 25wt%, adding concentrated hydrochloric acid formation final concentration is the solution of 0.51%v/v, be hydrolyzed reaction under temperature 75 DEG C of-83 DEG C of conditions, weight-average molecular weight is measured when reaching 1.0 ten thousand ~ 1.25 ten thousand Da after hydrolysis 5h, add alkaline solution and regulate pH to 2-3, be cooled to 60 DEG C, obtain product 1;
Step 2: once decolour:
Decolouring still is evacuated to below-0.08Mpa, product 1 is drawn to decolouring still, be warming up to 60 DEG C, add the craboraffin of the 0.5%w/v of product 1,60 ± 2 DEG C of insulation 2h, take off charcoal through plate filter, are delivered in ultrafiltration storage tank, sheet frame pressure <0.2MPa, obtains product 2;
Step 3: essence filter:
By product 2 in ultrafiltration storage tank through 0.2 μm of filtering with microporous membrane to ultrafiltration tank, sheet frame pressure <0.2MPa;
Step 4: ultrafiltration:
Purified water is added to 1500L in ultrafiltration tank, regulate pH at 3.5-4.5, feed temperature is 30-50 DEG C, ejector priming, start ultrafiltration, make inlet hydraulic maintain 0.2-0.5MPa, fluid pressure at 0.1-0.3MPa, when during ultrafiltration, in ultrafiltration tank, 500L feed liquid is fallen in every ultrafiltration, add purified water again to 1500L, shut down after ultrafiltration the 5th time, molecular weight detection confirms that qualified rear ultrafiltration is complete, obtains product 3;
Step 5: secondary decolourization:
Decolouring still is evacuated to below-0.08Mpa, product 3 is drawn to decolouring still, stir, regulate pH4-5, be warming up to 80 ± 2 DEG C, add the 0.25w/v needle-use activated carbon of product 3,80 ± 2 DEG C of insulation 1h; Take off charcoal through plate filter, de-charcoal feed liquid cycles back to decolouring still, de-charcoal backflow 1h; In decolouring still feed liquid, again add the 0.25w/v needle-use activated carbon of product 3,80 ± 2 DEG C of insulation 1h; Take off charcoal through plate filter, decarburization feed liquid is cycled back to decolouring still, feed liquid is delivered in treatment tank by decarburization backflow 1h, and sheet frame pressure <0.2MPa, obtains product 4;
Step 6 is refined:
By product 4 through 0.1 μm of filtering with microporous membrane, backflow 10-20min, after feed liquid is delivered to receiver; Stir, regulate pH4-6,75 DEG C-85 DEG C insulations, obtain product 5;
Step 7: spraying dry:
By product 5 dry solidification, packaging warehouse-in.
2. the brand-new synthesis technique of icodextrin bulk drug according to claim 1, is characterized in that, the alkaline solution described in step 1 is one or more in sodium hydroxide solution, potassium hydroxide solution, carbonate solution.
3. the brand-new synthesis technique of icodextrin bulk drug according to claim 1, is characterized in that, the spray drying condition described in step 7 is inlet temperature 180 DEG C-190 DEG C, air outlet temperature 100 DEG C-110 DEG C and material pump rotational frequency 0-50HZ.
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| CN201410567567.7A CN105524181B (en) | 2014-10-23 | 2014-10-23 | The brand-new synthesis technique of Icodextrin bulk drug |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109400722A (en) * | 2018-11-13 | 2019-03-01 | 华仁药业股份有限公司 | A method of for removing peptide glycan in glucidtemns |
| CN114316076A (en) * | 2020-09-29 | 2022-04-12 | 青岛力腾医药科技有限公司 | Preparation method of starch-derived maltodextrin for nephropathy |
| CN117050201A (en) * | 2023-07-31 | 2023-11-14 | 武汉华科大生命科技有限公司 | Method for removing aluminum salt and magnesium salt in icodextrin bulk drug |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102741296A (en) * | 2010-02-02 | 2012-10-17 | 罗盖特公司 | Branched soluble glucose polymers for peritoneal dialysis |
| WO2013015890A1 (en) * | 2011-07-26 | 2013-01-31 | Grain Processing Corporation | Production of resistant dextrins |
| CN103467608A (en) * | 2013-09-27 | 2013-12-25 | 华仁药业股份有限公司 | Icodextrin and preparing method thereof |
-
2014
- 2014-10-23 CN CN201410567567.7A patent/CN105524181B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102741296A (en) * | 2010-02-02 | 2012-10-17 | 罗盖特公司 | Branched soluble glucose polymers for peritoneal dialysis |
| WO2013015890A1 (en) * | 2011-07-26 | 2013-01-31 | Grain Processing Corporation | Production of resistant dextrins |
| CN103467608A (en) * | 2013-09-27 | 2013-12-25 | 华仁药业股份有限公司 | Icodextrin and preparing method thereof |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109400722A (en) * | 2018-11-13 | 2019-03-01 | 华仁药业股份有限公司 | A method of for removing peptide glycan in glucidtemns |
| CN114316076A (en) * | 2020-09-29 | 2022-04-12 | 青岛力腾医药科技有限公司 | Preparation method of starch-derived maltodextrin for nephropathy |
| CN114316076B (en) * | 2020-09-29 | 2023-01-31 | 青岛力腾医药科技有限公司 | Preparation method of starch-derived maltodextrin for nephropathy |
| CN117050201A (en) * | 2023-07-31 | 2023-11-14 | 武汉华科大生命科技有限公司 | Method for removing aluminum salt and magnesium salt in icodextrin bulk drug |
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| CN105524181B (en) | 2017-12-08 |
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Effective date of registration: 20180929 Address after: 266101 No. 187 Zhuzhou Road, Laoshan District, Qingdao, Shandong. Co-patentee after: China Ren Pharmaceutical (Rizhao) Co., Ltd. Patentee after: Huaren Pharmaceutical Co., Ltd. Address before: 266000 No. 187 Zhuzhou Road, Laoshan District, Qingdao, Shandong. Patentee before: Huaren Pharmaceutical Co., Ltd. |