CN1027180C - Process of the preparation crystalline glucose for medicine - Google Patents
Process of the preparation crystalline glucose for medicine Download PDFInfo
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- CN1027180C CN1027180C CN86106624A CN86106624A CN1027180C CN 1027180 C CN1027180 C CN 1027180C CN 86106624 A CN86106624 A CN 86106624A CN 86106624 A CN86106624 A CN 86106624A CN 1027180 C CN1027180 C CN 1027180C
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- glucose
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- resin
- saccharification
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
- C12N1/10—Protozoa; Culture media therefor
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- C—CHEMISTRY; METALLURGY
- C13—SUGAR INDUSTRY
- C13K—SACCHARIDES OBTAINED FROM NATURAL SOURCES OR BY HYDROLYSIS OF NATURALLY OCCURRING DISACCHARIDES, OLIGOSACCHARIDES OR POLYSACCHARIDES
- C13K1/00—Glucose; Glucose-containing syrups
- C13K1/10—Crystallisation
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Abstract
The invention relates to a novel method for crystalline glucose for injection. Starch is liquefied and saccharified with a debranching enzyme and glucoamylase to obtain a high-purity sugar syrup having a glucose content of >=97.0% in solid component, then treat a hydrolyzed starch with a debranching enzyme and glycoamylase and purify and concentrate can obtain crystalline glucose without using recrystallization process. Though this process can obtain high- purity crystalline glucose without pyrotoxin in low cost.
Description
The invention relates to crystalline glucose for medicine, particularly as the manufacture method of the crystalline dextrose of injection raw material, this method technological process is simple, energy-conservation and cost is low.
Specification about glucose injection, have as the Japanese Pharmacopoeia of drug standard in Japan and to be stipulated that also all there is regulation other various countries, but when business transaction, requirement just should meet medicine quality standard, the prerequisite when this is business transaction in this step of crystalline dextrose as raw material.In order to reach this standard, the point of particularly important is: first is the purity of glucose, i.e. specific rotatory power [α]
2D
0Answer conformance with standard; Second must not contain impurity such as pyrotoxin.
All there is regulation standard various countries about specific rotatory power, are [α] in the tenth revised edition of Japanese Pharmacopoeia
2D
0+ 52.2 °～53.2 °, in the American Pharmacopeias in 1985 be+52.6 °～53.2 °, Britain's pharmacopeia in 1980 is defined as 52.5 °～53.0 °, and Chinese Pharmacopoeia (Guangdong is provisional) is+52.5 °～53.0 ° etc.But in order to meet these regulations,, need once more it to be used water dissolution to acquired crystalline dextrose, further recrystallize, this method is called the recrystallize method.The recrystallize method adopted the starch hydrolysis process that uses α-Dian Fenmei and glucoamylase in the past, aspect industrial production, can only reach DE97, glucose content is a 95%(weight) (for solids), [α] of the crystalline dextrose that obtains by refining, concentrated solution
2D
0Only be+53.2 °～53.5 °, thus just acquired crystalline dextrose must be dissolved once more, make high purity stoste after, carry out recrystallize.Its result makes process become very complicated, consumes a large amount of energy, and product yield is reduced to below 50%, causes cost to raise, and is disadvantageous economically.
So-called heating is former to be had at human body when being injection and causes fever or the dangerous material that feels cold, and its representative is the intracellular toxin of microorganisms.This endogenous toxic material have from the raw starch person, have in saccharification, in the refining step because of microbial contamination person of causing or the like; But particularly in utilizing the ion exchange resin treatment operation, because of the microbial contamination causer a lot.Utilize the TREATMENT OF ION EXCHANGE RESINS operation to form: at first to use Zeo-karb usually by following several steps, handle (double bed operation) respectively afterwards with anionite-exchange resin again, further use the mixture bed (mixing bed) of two kinds of resins to handle.If making ion exchange treatment at high temperature carries out.The danger that produces Dian Fentang isomerization reaction and decomposition reaction is arranged, so always ion exchange treatment is being carried out below 40 ℃ usually.The result who under this temperature, carries out, be easy to generate microorganism in exchange resin tower, even with resin regeneration, this microorganism also is difficult to knock out, after circulation, accumulate gradually, not only become the cause of the former generation of heating, and because processed liquid glucose fermentation, the tower internal pressure is risen, cause liquid to circulate, moreover, also make problems such as washing draining increase.
Former in order to remove this heating, in the refining step of Glucose Liquid, adopted a large amount of gac or ultra-filtration membrane and accurate filter membrane etc. in the past.Therefore, cost is risen.
Purpose of the present invention provides a kind of pharmaceutical, method of glucose for injection particularly of making, and this glucose meets Japan and various countries' pharmacopeia specified standards.A kind of high purity saccharification liquid that makes in the starch hydrolyzing process promptly is provided, this high purity saccharification liquid is after refining concentrating, can save the recrystallize operation, the while can make and not contain the former crystalline dextrose that waits impurity of heating, and low, the energy-conservation industrial process of cost.
The inventor finds, in the starch hydrolyzing process, adopt debranching factor and glucoamylase simultaneously, it is heavy to utilize this method can obtain containing glucose 97.0%() (for solids) above liquid glucose [oligosaccharide contg 3%(is heavy) following], this liquid glucose is refining in processing more than 55 ℃, below 80 ℃ in dual bed Zeo-karb tower, utilize the primary crystallization operation just to have and meet specific rotatory power Japanese and various countries' pharmacopeia regulation, can make to very economical highly purified injection material crystal glucose.
In the present invention, at first with starch in DE6～15, be preferably in 8～12, after the liquefaction, adjusting pH with hydrochloric acid or oxalic acid is 4～5, is keeping making the Ye Huamei inactivation more than 10 minutes more than 90 ℃.Be cooled to 60 ℃ again, make debranching factor and glucoamylase effect, carry out saccharification.Debranching factor is a kind of enzyme of α-1,6 key that can disconnect starch, any enzyme with this effect all can, for example Pu Luomozhamu (グ Le コ ァ ミ ラ ゼ) the 200L debranching factor produced of fertile (ノ ボ) company of Denmark's promise etc. is all very suitable.Moreover as glucoamylase, the AMG300L that produces with same company etc. are just very suitable, but are not limited to these zymins.About the consumption of these enzymes,,, be preferably in more than the 0.5PUN for every gram solids as above-mentioned Pu Luomozhamu 200L; AMG300L for every gram solids, is preferably in below the 0.3AGU.About the saccharification condition, when concentration is that 30%(is heavy) when following, saccharification time was preferably in more than 45 hours, so just can make the saccharification liquid of high DE value, high glucose content, and wherein DE can reach more than 98.0, and glucose content can reach 97.0%.
Moreover, the every 1PUN of debranching factor Pu Luomozhamu represents a kind of unit of enzyme, its expression this kind of enzyme is under 5.0 the condition after the effect in 40 ℃, pH in 0.2% starch polymer, can produce to have the reducing sugar that is equivalent to 1 μ mol glucose reducing power in one minute.Moreover, about the represented unit of enzyme of the 1AGU of glucoamylase AMG, be to be matrix with every liter of 10g maltose of 0.1M acetate buffer solution, therein, be to do the time spent under 4.3 the condition in 25 ℃ of pH, in one minute, can decompose 1 μ mol maltose.
The saccharification liquid that makes like this adopts traditional method to filter, and after measures such as activated carbon decolorizing, it is refining to carry out ion-exchange.
Ion-exchange is refining, is made up of following several steps: at first with Zeo-karb handle, secondly with double bed operation of anion exchange process, and then with the mixed bed processing of the mixture process of two kinds of resins.But in above-mentioned dual bed operation of the present invention,, make saccharification liquid below 80 ℃, so just can prevent to produce pyrotoxin because of microbial contamination by the resin cation (R.C.) tower more than 55 ℃; And improve the clarity of liquid, when 55 ℃ of temperature less thaies by the Zeo-karb liquid glucose, just can not prevent the former generation of generating heat fully.Moreover, if surpass 80 ℃, can cause saccharic decomposition and other side reaction, this is undesirable.After the anion exchange process of double bed operation, preferably make liquid 40 ℃ of circulations down.
Adopt method provided by the invention, used ion exchange resin, employee in the double bed operation, the グ ィ ャ ィ ォ Application SKIB that can adopt Mitsubishi Chemical Industries Limited's preparation are as resin cation (R.C.), and resin anion(R.A) adopts the グ ィ ャ ィ ォ Application WA30 of same company preparation; The グ ィ ャ ィ ォ Application PK218 that the used resin cation (R.C.) of mixed bed operation can be produced with the said firm, the グ ィ ャ ィ ォ Application PA408 that used resin anion(R.A) can adopt the said firm to produce; But be not limited to above-mentioned resin, as long as any resin identical with above-mentioned resin property all can.
After ion exchange resin is refining, saccharification liquid is concentrated, as crystalline dextrose stoste.About crystallization, can adopt the traditional method of the method for intermittently stirring off, infusion under 60 °～70 ℃, the condition of degree of supersaturation 1.03～1.04.It is former that employed sugar cook water wishes not contain heating in this process.
After the person of enduring, the converted mash after the infusion is contained on the separating centrifuge, makes honey and Crystallization Separation.The bath water of separating centrifuge, it is former also to wish not contain heating.The crystallization of separating, drying machine, water cooler etc. are finished product after sieving.
About the concrete trade(brand)name of used enzyme of the present invention and resin, that puts down in writing in this explanation only gives an example, and the present invention is not restricted to these examples, but can adopt the enzyme and the resin of similar properties fully.
Embodiment
With oxalic acid the pH value of liquefied starch (ED11.0) is adjusted to 4.5, kept 20 minutes, make the Ye Huamei inactivation at 95 ± 3 ℃.Be quickly cooled to 60 ℃ then, concentration transferred to 25%(weigh), pH transfers to 4.5.AMG300L with the production of saccharifying enzyme (Denmark's promise is fertile) company) adds 0.15AGU, debranching factor (the Pu Luomozhamu 200L that same company produces) by the every gram interpolation of solid ingredient 0.6PUN by the every gram of solid ingredient, be added in the liquefied starch respectively, 60 ℃ carry out saccharification after (intermittent type, 500l).Its result as the 1st the table shown in, the saccharification through 48 hours, reaction solution is 97.8% for the glucose containing ratio (DX) of solids, the saccharification through 60 hours, DX is 98.1%.(table 1 is seen the literary composition back)
Then, making this saccharification liquid decolour, filter, carry out ion exchange resin makes with extra care.
Refining about ion, in the double bed operation, at first utilize heat exchanger to make saccharification liquid temp temperature be raised to 60 ℃, and by resin cation (R.C.) tower (the グ ィ ャ ィ ォ Application SKIB2.51 that interior dress Mitsubishi Chemical Industries Limited produces), after utilizing heat exchanger to make this liquid glucose temperature reduce to 40 ℃ again, by resin anion(R.A) tower (the グ ィ ャ ィ ォ Application WA30 3.51 that interior dress Mitsubishi Chemical Industries Limited produces).Continue to make liquid glucose to pass through the mixing bed tower of being formed by resin cation (R.C.) (above-mentioned ダ ィ ャ ィ ォ Application PK 218 11) and resin anion(R.A) (above-mentioned ダ ィ ャ ィ ォ Application PA408 21) with company with company.Liquid glucose is 151/ hour by the speed of ion exchange resin dual bed, mixing bed, liquid reduces to 4.5 by proceeding in the pH value of the outlet of dual bed resin anion(R.A) tower, the outlet of mixing bed tower, or the resistivity of dual bed anionite-exchange resin tower outlet reduce to 100,000 Europe/centimetre, the resistivity of mixing the bed outlet reduce to 500,000 Europe/centimetre, when being lower than above-mentioned value when the pH value or than resistance value, resin just should be regenerated.
Behind the logical liquid of the 2nd table expression ion exchange resin, the former mensuration situation of each tower exit heating and the result of general aerobic plate count after 5,10,15 hours.Moreover this result carries out the situation of six regeneration backs (being the period 6) for resin.(table 2 is seen the literary composition back)
The above-mentioned ion purified Glucose Liquid that carried out then is concentrated into 60% concentration, and concentrated solution is stirred off under 60 ℃, degree of supersaturation are 1.032 condition in 20 liters sugar boiling pot.The water and the purging bath water of stirring off and to be added are the water of acomia pyrogen.After the sugar cook, carry out purging, drying, can obtain the injection raw materials of glucose with 40% yield.The specific rotatory power of this product is+52.8 °, generate heat former according to defined in Limulus HS Single Test experiment and the Japanese Pharmacopoeia with the experiment of rabbit fever property, all negative, so be very suitable injection raw materials of glucose product.
Comparative example
With oxalic acid liquefied starch (DE 11.0) being adjusted to pH is 4.5, keeps 20 minutes at 95 ± 3 ℃, carries out the inactivation of Ye Huamei.Make liquid be cooled to 60 ℃ rapidly then, adjusting concentration is that 30%(is heavy), pH is 4.5, (corporate system is irrigated in promise, AMG300L), carries out saccharification with 500 liters batches at 60 ℃ to add saccharifying enzyme by every gram solids 0.21AGU.DX, DE and sugar in corresponding saccharification time are formed as shown in table 3.For example, saccharification 48 hours, DX was 94.4; Saccharification 60 hours, DX is 94.9, and can not get very pure glucose.(table 3 is seen the literary composition back)
Then, carry out ion and make with extra care after this saccharification liquid decolouring, filtering.Refining about ion, all 40 ℃ were carried out, all the method with previous examples was identical for all the other by dual bed, mixing bed operation except that liquid.
Table 4 is depicted as the circulating liquid of period 6, after the 5th, 10,15 hour, and the mensuration that each ion exchange tower exit heating is former and the measurement result of general aerobic plate count.(table 4 is seen the literary composition back)
Utilize aforesaid method to carry out the Glucose Liquid of ion-exchange after refining, it is heavy to be concentrated into 65%(), then by the method identical with previous embodiment stir off, purging and drying etc., can obtain the crystalline dextrose product with 38% yield.The specific rotatory power of this product is+53.5 °, and it is former positive to measure heating according to Limulus HS Single test, can not satisfy the standard of Japan and other various countries' injection crystallization glucose sugar.
Moreover, pass through multiple about liquid in the ion treating process, this comparative example is shown in table 5 with the comparative result of previous embodiment, adopt method of the present invention (embodiment) because the not pollution that causes because of microorganism, so compare with method (comparing embodiment) in the past, the pressure reduction of double bed ion exchange tower is little, so liquid passes through multiple, increase is about 18% in double bed resin anion(R.A) tower, mixes to increase in the bed tower to be about 37%.(table 5 is seen the literary composition back)
In the saccharification operation of starch of the present invention, owing to adopted debranching factor and glucoamylase simultaneously, can obtain glucose content and be the high-purity Glucose Liquid more than 97%, so, can make as pharmaceutical, injection crystalline dextrose particularly, this product satisfies the desired specific rotatory power standard in various countries, and needn't adopt numerous and diverse and uneconomic method of the sort of so-called recrystallize in the past again.
Moreover, about method of the present invention, because handling, the Zeo-karb in the double bed operation carrying out below 80 ℃ more than 55 ℃, can prevent the pollution that this operation causes because of microorganism, reduced the pyrotoxin in the product significantly, therefore, can make the product that satisfies injection crystalline dextrose standard.Simultaneously,, eliminated the liquid communication difficulty that produces because of microbial fermentation because adopted the double bed operation, thus the treatment capacity of refining step can be increased, owing to saved aforesaid recrystallize operation, and the corresponding wastewater flow rate that reduced, thus reach tangible reduction effect.
Description of drawings
The 1st figure represents respectively as pH, resistivity and the chromatic number of dual bed resin anion(R.A) tower liquid by the multiple function.
The 2nd figure represents as mixing pH, resistivity and the chromatic number of bed tower liquid by multiple (corresponding to the resin anion(R.A) amount) function.
In the 1st and the 2nd figure, solid line is represented treatment process of the present invention, and dotted line is represented former treatment process, and the X-coordinate express liquid is by multiple, and ordinate zou is represented pH, resistivity and chromatic number respectively.
Table 1
Saccharificatinn period sugar forms and DE
(time) the above DE of DX G2 G3 G4
24 96.8 1.6 0.6 1.0 98.0
48 97.8 1.4 0.4 0.4 98.8
60 98.1 1.3 0.4 0.2 99.0
Annotate: G2, G3, G3 represent respectively 2 carbohydrates, 3 carbohydrates, 4 carbohydrates.
The 2nd table
Generate heat former general aerobic plate count (individual/ml)
The logical liquid time (time)
5 10 15 5 10 15
Glucose stoste---0 00
Cation tower outlet---0 00
Anion tower outlet---0 57
Mixed bed tower outlet---2 11 17
Annotate: 1. about the former regulation of generating heat, adopt Limulus HS Simgle Test Wako(Wako Pure Chemical Industries, Ltd. system) carry out, this method can be measured the intracellular toxin (according to the standard of FDA, being equivalent to the intracellular toxin that E.Coli EC-2 is produced) of ultramicron (can reach 0.01ng/ml).With removing endotoxic distilled water diluting checking matter, make concentration reach 10%, utilize gelation to measure."+" expression intracellular toxin is positive, "-" expression negative (intracellular toxin 0.01ng/ml is following).
2. about the mensuration of general aerobic plate count, can adopt mTEG Broth substratum (DIFCO Laboratories corporate system), cultivate 2 days at 37 ℃.
Table 3
Sugar is formed and DE
Saccharification time
The above DE of DX G2 G3 G4
24 90.7 1.9 1.6 5.8 94.3
48 94.4 2.0 1.0 2.6 96.8
60 94.9 2.1 0.9 2.1 97.1
Table 4
Generate heat former general aerobic plate count (individual/ml)
The logical liquid time (time)
5 10 15 5 10 15
Glucose stoste---0 00
Positively charged ion tower outlet+++1.8 * 10
34.5 * 10
46.5 * 10
4
Negatively charged ion tower outlet+++2.5 * 10
43.2 * 10
55.3 * 10
5
Mix bed tower outlet+++5.1 * 10
46.7 * 10
58.7 * 10
5
Annotate: the survey of the former mensuration of generating heat, general aerobic plate count is all identical with the previous embodiment method.
Table 5
The inventive method previous method
(embodiment) (comparative example)
Resin anion(R.A) tower liquid is by multiple 85 72
At liquid communication terminal point and positively charged ion 0.5 2.0
Pressure reduction (kg/cm between the tower
3)
Mixed bed liquid is by multiple 260 190
Annotate: so-called liquid is to represent with the amount of liquid (1) that unit volume resin anion(R.A) (1) is passed through by multiple.
Claims (1)
1, crystalline glucose for medicine manufacture method, wherein without the recrystallize method, it is characterized in that: make debranching factor and glucoamylase act on starch hydrolyzate, the high purity liquid glucose that contains glucose 97.0% (weight) above (for solids) that makes is made with extra care as stoste, wherein allow this high purity liquid glucose in 80 ℃ of following temperature ranges, pass through the Zeo-karb tower more than 55 ℃, after making the liquid temperature drop low then, by anionite-exchange resin tower and mixed-cation/anion exchange resin bed tower, and then the concentrated crystalline dextrose that obtains.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP60220227A JPS6279792A (en) | 1985-10-04 | 1985-10-04 | Production of crystalline glucose as raw material for injection |
| JP220228/85 | 1985-10-04 | ||
| JP60220228A JPH0693840B2 (en) | 1985-10-04 | 1985-10-04 | Sugar liquid purification method |
| JP220227/85 | 1985-10-04 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN86106624A CN86106624A (en) | 1987-04-01 |
| CN1027180C true CN1027180C (en) | 1994-12-28 |
Family
ID=26523595
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN86106624A Expired - Fee Related CN1027180C (en) | 1985-10-04 | 1986-09-29 | Process of the preparation crystalline glucose for medicine |
Country Status (2)
| Country | Link |
|---|---|
| KR (1) | KR920009518B1 (en) |
| CN (1) | CN1027180C (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101748220B (en) * | 2010-01-08 | 2012-06-20 | 西王集团有限公司 | Glucose production process for reducing steam consumption |
-
1986
- 1986-02-13 KR KR1019860001002A patent/KR920009518B1/en not_active IP Right Cessation
- 1986-09-29 CN CN86106624A patent/CN1027180C/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CN86106624A (en) | 1987-04-01 |
| KR920009518B1 (en) | 1992-10-17 |
| KR870004131A (en) | 1987-05-07 |
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