CN113786793B - Heparin sodium crude product extraction device and extraction method - Google Patents
Heparin sodium crude product extraction device and extraction method Download PDFInfo
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- B01D21/02—Settling tanks with single outlets for the separated liquid
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- B01D21/26—Separation of sediment aided by centrifugal force or centripetal force
- B01D21/262—Separation of sediment aided by centrifugal force or centripetal force by using a centrifuge
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- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/0003—General processes for their isolation or fractionation, e.g. purification or extraction from biomass
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- C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
- C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
- C08B37/0075—Heparin; Heparan sulfate; Derivatives thereof, e.g. heparosan; Purification or extraction methods thereof
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- C12M41/00—Means for regulation, monitoring, measurement or control, e.g. flow regulation
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- F26B15/14—Machines or apparatus for drying objects with progressive movement; Machines or apparatus with progressive movement for drying batches of material in compact form with movement in a path composed of one or more straight lines, e.g. compound, the movement being in alternate horizontal and vertical directions the lines being all horizontal or slightly inclined the objects or batches of materials being carried by trays or racks or receptacles, which may be connected to endless chains or belts
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- F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
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- F26B23/00—Heating arrangements
- F26B23/04—Heating arrangements using electric heating
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Abstract
The invention relates to the field of heparin sodium preparation methods, in particular to a heparin sodium crude product extraction device and an extraction method.
Description
Technical Field
The invention relates to the field of heparin sodium preparation methods, in particular to a heparin sodium crude product extraction device and an extraction method.
Background
The cardiovascular and cerebrovascular diseases are killers of the first disease of human beings, the morbidity and the mortality of the cardiovascular and cerebrovascular diseases are gradually increased along with the increase of the living standard of people, the occurrence rate and the mortality of the cardiovascular and cerebrovascular diseases are gradually increased, the appearance of heparin creates the wonderful life for a plurality of patients with the cardiovascular and cerebrovascular diseases, the heparin is the most effective anticoagulant medicament in the world at present and is the most clinically used, and is mainly applied to the treatment of the cardiovascular and cerebrovascular diseases and hemodialysis, wherein, the heparin is the only effective specific medicament in the hemodialysis treatment, the clinical application and research show that the heparin has various biological activities and clinical applications besides the anticoagulant effect, including the blood fat reducing effect, the anti-mesoderm Smooth Muscle Cell (SMC) proliferation, the promotion of the fibrinolysis and the like, in addition, the low molecular heparin is a large group of anti-blood medicaments which are further processed by taking heparin as a raw material, has wider clinical medical application and becomes a first choice medicine for treating diseases such as acute venous thrombosis, acute coronary syndrome (angina, myocardial infarction) and the like.
Heparin sodium is a glycosaminoglycan compound with the most complex molecular structure known to date, products for clinical application at present comprise heparin sodium, series of low-molecular heparin and the like, required raw materials can only be extracted from small intestine mucosa of pigs, raw materials of heparin raw material medicines are heparin crude products, the extraction can only be derived from small intestine mucosa of healthy pigs, and heparin raw material medicines are prepared by directionally obtaining heparin with complete natural structural groups through physical and chemical extraction and separation processes due to the fact that the heparin raw material medicines contain a large amount of impurities such as impurity proteins, impurity nucleic acids, microorganisms and the like.
Disclosure of Invention
The invention aims to overcome the defects in the prior art and provides a heparin sodium crude product extraction device and an extraction method capable of purifying crude heparin sodium.
The invention is realized by the following technical scheme: a heparin sodium crude product extraction device, which comprises a dissolution treatment device, an enzymolysis treatment device, a first precipitation and impurity removal device, an oxidation treatment device, a second precipitation and impurity removal device, a precipitation collection device, a refining device and a purification water bin which are arranged in sequence,
the dissolution treatment device is connected with a raw material bin and comprises a first reaction tank;
the enzymolysis device comprises a reaction tank II, the reaction tank II is connected with a temperature control device I, and the reaction tank II is also connected with a pH adjusting device I;
the first precipitation and impurity removal device comprises a first centrifugal machine, a slag outlet of the first centrifugal machine is connected with a first slag receiving tank, a liquid outlet of the first centrifugal machine is connected with a first liquid receiving tank, and the first centrifugal machine is connected with a second pH adjusting device;
the oxidation treatment device comprises a third reaction tank, the third reaction tank is connected with a second temperature control device, the third reaction tank is also connected with a third pH adjusting device, and the third reaction tank is connected with a first liquid collecting tank;
the second precipitation and impurity removal device comprises a second centrifugal machine, a slag outlet of the second centrifugal machine is connected with a second slag receiving tank, a liquid outlet of the second centrifugal machine is connected with a second liquid receiving tank, the second slag receiving tank is connected to a purified water bin, and the second centrifugal machine is connected with a fourth pH adjusting device;
the sediment collecting device comprises a reaction tank IV, the reaction tank IV is connected with a temperature control device III, and the reaction tank IV is also connected with a sodium chloride filling device, an ethanol filling device and a waste liquid collecting device;
the refining device comprises a grinding device, the grinding device is connected with the four lower ends of the reaction tank, and a discharge port of the grinding device is connected with a drying device.
Further, raw materials storehouse passes through the inlet pipe intercommunication of auger one and retort one, be provided with anti-clogging device between the inlet pipe of auger one and retort, anti-clogging device is including setting up the gas tube at auger one discharge end, the gas tube communicates to dry air supply, anti-clogging device is still including setting up the anti-clogging takeover on the inlet pipe of auger one, anti-clogging takeover cross section is oval, the discharging pipe of auger one is through takeover and anti-clogging takeover intercommunication, the takeover is close to the one end of preventing stifled takeover and is described for loudspeaker.
Furthermore, the first temperature control device, the second temperature control device and the third temperature control device all comprise jacket sleeves sleeved outside the corresponding reaction tanks, refrigerant pipes are arranged in the jacket sleeves, three-way reversing valves are arranged at inlet ends and outlet ends of the refrigerant pipes, and the refrigerant pipes are connected to high-temperature refrigerants and low-temperature refrigerants through the three-way reversing valves.
Further, the pH adjusting device I, the pH adjusting device II, the pH adjusting device III and the pH adjusting device IV all comprise an adjusting agent storage tank, and a discharge pipe of the adjusting agent storage tank is provided with a metering pump.
Furthermore, the first slag collecting tank and the second slag collecting tank comprise tank bodies, the upper end of the tank body is connected with a cleaning pipe, the upper end of the tank body of the second slag collecting tank is provided with a water supplementing pipe, the water supplementing pipe is communicated with the purification water tank, the lower end of the tank body of the second slag collecting tank is provided with a water return pipe, and the water return pipe is communicated with an inlet pipe of the second centrifugal machine.
Further, the colloid mill is selected for use by the grinding device, the drying device comprises a drying cover, a dust collecting cover is arranged at the upper end of the drying cover, a heating device is arranged in the drying cover, a track is further arranged in the drying cover, a drying tray is arranged on the track, and the drying tray is connected with a mobile driving device.
A method for extracting a crude heparin sodium product comprises the following steps:
dissolving, namely putting a heparin sodium crude product into a dissolving treatment device, adding purified water to dissolve the heparin sodium crude product into the solution to obtain a concentration, wherein the weight ratio of the heparin sodium crude product to the purified water is 1:10, and stirring the solution until the heparin sodium crude product and the purified water are completely dissolved to obtain a crude product solution;
step two, enzymolysis, namely transferring the crude product solution into an enzymolysis treatment device, adjusting the pH to 6.0-8.0, heating to 50-60 ℃, adding proteolytic enzyme, and preserving heat for 2 hours to obtain an enzymolysis solution;
thirdly, removing impurities by primary precipitation, heating the enzymolysis solution to boiling, cooling to 0-10 ℃ after 5min, transferring into a centrifuge, adjusting the pH to 1.2-1.5, standing for 3min, starting the centrifuge, and collecting a liquid phase to obtain a primary impurity-removed solution;
step four, oxidizing, namely transferring the primary impurity removal solution into an oxidation treatment device, adjusting the pH to 9.0-10.0 by using a sodium hydroxide solution, heating to 28-32 ℃, adding hydrogen peroxide with the volume of 1.0% of the feed liquid, and oxidizing for 8-12 hours to obtain an oxidized solution;
fifthly, removing impurities by secondary precipitation, transferring the oxidation solution into a centrifuge, centrifuging for 10min, collecting a liquid phase, adding purified water to dilute the solid phase, centrifuging for 10min again, collecting the liquid phase, and combining the two liquid phases to obtain a secondary impurity-removed solution;
sixthly, collecting the precipitate, transferring the secondary impurity removal solution into a precipitation collection device, adjusting the pH value to be neutral, diluting, adding sodium chloride in the weight of the material liquid, heating to 50-60 ℃, adding medicinal ethanol with the volume of 0.46 times that of the material liquid, stirring, cooling to 0-5 ℃, precipitating for 8-10h, and collecting the precipitate;
and seventhly, refining, grinding the precipitate by adding ethanol, filtering, drying for 3-6 hours at 60 ℃, collecting, packaging and weighing.
The invention has the beneficial effects that: a heparin sodium crude product extraction device comprises a dissolving treatment device, an enzymolysis treatment device, a first precipitation impurity removal device, an oxidation treatment device, a second precipitation impurity removal device, a first refining device and a purification water bin which are sequentially arranged, wherein the dissolving treatment device is connected with a raw material bin, the enzymolysis treatment device comprises a first reaction tank, the heparin sodium crude product in the raw material bin is put into the reaction tank, the heparin sodium crude product is conveniently dissolved, the processing cost is low, the sealing performance is high, the enzymolysis device comprises a second reaction tank, the second reaction tank is connected with a first temperature control device, the second reaction tank is further connected with a first pH adjusting device, the temperature control, pH adjustment and enzymolysis steps are carried out in the second reaction tank, the operation is convenient, the controllability is high, the first precipitation impurity removal device comprises a first centrifuge, a slag outlet of the first centrifuge is connected with a first slag collection tank, a liquid outlet of the centrifuge is connected with a first liquid collection tank, centrifuge one connects with pH adjusting device two, carries out solid-liquid separation through centrifuge, and separation efficiency is high, oxidation treatment device includes retort three, retort three is connected with temperature control device two, retort three still is connected with pH adjusting device three, retort three is connected with receipts fluid reservoir one, carries out oxidation treatment through retort three, conveniently adjusts temperature, pH value, and convenient operation, control stability is high, sediment edulcoration device two includes centrifuge two, centrifuge two's slag notch is connected with receipts slag pot two, centrifuge's liquid outlet is connected with receives fluid reservoir two, it is connected to the purification sump to receive slag pot two, centrifuge two is connected with pH adjusting device four, sediment collection device includes retort four, retort four is connected with temperature control device three, retort four still is connected with sodium chloride filling device, The device comprises an ethanol filling device and a waste liquid collecting device, wherein the refining device comprises a grinding device, the grinding device is connected with the four lower ends of the reaction tank, a discharge port of the grinding device is connected with a drying device, a continuous and stable extraction system is formed, each step is continuously treated, the operation is convenient, and the device is suitable for industrial production.
Drawings
FIG. 1 is a schematic diagram showing the connection relationship of various devices of a crude heparin sodium product extraction device;
FIG. 2 is a schematic cross-sectional view of the anti-clog apparatus;
FIG. 3 is a schematic cross-sectional view of a second reaction tank;
FIG. 4 is a schematic diagram of a pH adjusting apparatus;
FIG. 5 is a schematic cross-sectional view of a second slag collecting tank;
FIG. 6 is a schematic view showing the connection relationship between the two parts of the precipitation and impurity removal device;
FIG. 7 is a schematic cross-sectional view of a reaction tank;
FIG. 8 is a schematic bottom view of the reaction tank;
FIG. 9 is a schematic cross-sectional view of a drying apparatus;
FIG. 10 is a schematic view of a drying tray structure;
wherein: 1-a raw material bin, 3-a first auger, 2-a purified water bin, 4-a first reaction tank, 5-a second reaction tank, 6-a pH adjusting device I, 7-a temperature control device I, 8-a first centrifugal machine, 9-a pH adjusting device II, 10-a first slag collecting tank, 11-a first liquid collecting tank, 12-a third reaction tank, 13-a third pH adjusting device, 14-a second temperature control device, 15-a second centrifugal machine, 16-a fourth pH adjusting device, 17-a second slag collecting tank, 18-a return pipe, 19-a second liquid collecting tank, 20-a fourth reaction tank, 21-a third temperature control device, 22-a second auger, 23-a waste liquid collecting tank, 24-a colloid mill, 25-a drying device, 26-a collecting box, 27-an air charging pipe and 28-a connecting pipe, 29-anti-blocking connecting pipe, 30-jacket, 31-refrigerant pipe, 32-stirring tooth, 33-three-way reversing valve, 35-temperature sensor, 36-regulator storage tank, 37-metering pump, 38-tank body, 39-cleaning pipe, 40-water return pipe, 41-joint, 42-circulating pump, 43-valve, 44-liquid outlet pipe, 45-liquid outlet hole, 46-sodium chloride filling pipe, 47-ethanol filling pipe, 48-header pipe, 49-liquid outlet pipe, 50-drying cover, 51-dust collecting cover, 52-track, 53-drying tray, 54-mobile driving device, 55-walking wheel, 56-slope, 57-proteolytic enzyme filling pipe, 58-hydrogen peroxide filling pipe and 59-electric heating pipe.
Detailed Description
In the description of the present invention, it should also be noted that, unless otherwise explicitly specified or limited, the terms "disposed," "mounted," "connected," and "connected" are to be construed broadly and may, for example, be fixedly connected, detachably connected, or integrally connected; can be mechanically or electrically connected; they may be connected directly or indirectly through intervening media, or they may be interconnected between two elements. The specific meanings of the above terms in the present invention can be understood in specific cases to those skilled in the art.
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
In the following embodiments, heparin sodium is extracted by a heparin sodium crude product extraction device, which comprises a dissolution treatment device, an enzymolysis treatment device, a first precipitation and impurity removal device, an oxidation treatment device, a second precipitation and impurity removal device, a precipitation collection device, a refining device and a purified water bin 2 which are sequentially communicated as shown in fig. 1-10,
specifically, the dissolution treatment device is connected to a raw material bin 1, the crude heparin sodium raw material is temporarily stored in the raw material bin, the dissolution treatment device comprises a first reaction tank 4, the raw material bin is communicated with a feeding pipe of the first reaction tank through a first auger 3, the crude heparin sodium raw material is a high-molecular organic mixture, the viscosity is high after water absorption, an anti-blocking device is arranged between the first auger and the feeding pipe of the first reaction tank, the anti-blocking device comprises an inflation pipe 27 arranged at the discharging end of the first auger, the inflation pipe is communicated to a drying air source, the drying air source is a drying air source, the pressure is 0.1MPa, air pressure can be provided, the first auger has internal pressure, pressure is released through a discharging port, water vapor is prevented from flowing into the first auger from the discharging port, stable discharging can be further ensured, the crude heparin sodium product is prevented from being adhered to a blade of the auger, the anti-blocking device further comprises an anti-blocking connecting pipe 29 arranged on the feeding pipe of the first reaction tank, the cross section of the anti-blocking connecting pipe is oval, the anti-blocking connecting pipe is convenient to manufacture, one position of a feeding pipe of the first reaction tank is flattened, the anti-blocking connecting pipe is convenient to manufacture, the area of a circle is the largest under the condition of the same circumference, the cross section area is reduced after flattening, the water flow speed is increased, so that the heparin sodium crude product at the position of the connecting pipe opening can be guaranteed to be quickly diluted and brought into the first reaction tank, the discharging pipe of the first auger is communicated with the anti-blocking connecting pipe through the connecting pipe 28, one end, close to the anti-blocking connecting pipe, of the connecting pipe is horn-shaped, a larger space is provided for discharging of the heparin sodium crude product, high-speed water flow circles round at the horn-shaped position, the dilution effect is improved, the anti-blocking connecting pipe is a flat pipe, and a better connection foundation can be provided for connection of the connecting pipe.
The enzymolysis device comprises a reaction tank II 5, the reaction tank II is connected with a temperature control device I, the reaction tank II is further connected with a pH adjusting device I6 and a proteolytic enzyme filling device, the proteolytic enzyme filling device comprises a proteolytic enzyme filling pipe 57 arranged on the reaction tank II, and the proteolytic enzyme filling pipe is communicated to a proteolytic enzyme storage bin.
Deposit edulcoration device one and include centrifuge one 8, and centrifuge one's slag notch is connected with receipts slag pot one 10, and centrifuge's liquid outlet is connected with and receives liquid pot one 11, and centrifuge one is connected with pH adjusting device two 9.
The oxidation treatment device comprises a third reaction tank 12, the third reaction tank is connected with a second temperature control device 14, the third reaction tank is further connected with a third pH adjusting device 13, and the third reaction tank is connected with the first liquid collecting tank.
The second precipitation and impurity removal device comprises a second centrifugal machine 15, a slag outlet of the second centrifugal machine is connected with a second slag receiving tank 17, a liquid outlet of the second centrifugal machine is connected with a second liquid receiving tank 19, the second slag receiving tank is connected to the purification water sump 2, and the second centrifugal machine is connected with a fourth pH adjusting device 16.
The sediment collecting device comprises a reaction tank IV 20, the reaction tank IV is connected with a temperature control device III 21, the reaction tank IV is further connected with a sodium chloride filling device, an ethanol filling device and a waste liquid collecting device, wherein the sodium chloride filling device is a sodium chloride filling pipe 46 arranged on the reaction tank IV, the sodium chloride filling pipe is connected to a sodium chloride storage bin, the ethanol filling device is an ethanol filling pipe 47 arranged on the reaction tank IV, and the ethanol filling pipe is connected to the ethanol storage bin.
The refining device comprises a grinding device, the grinding device is connected with four lower ends of a reaction tank, concretely, a discharge pipe 49 with a valve is installed at the four lower ends of the reaction tank, the discharge pipe is connected with the grinding device through a second auger 22, the grinding device selects a colloid mill 24 for wet grinding to disperse heparin sodium, precipitation collection is carried out in the reaction tank four to remove supernatant and upper flocculent precipitate, four upward liquid outlet pipes 44 are evenly installed in the reaction tank four, the upper ends of the liquid outlet pipes are open, the liquid outlet pipes are close to the four edges of the reaction tank, liquid outlet holes are processed at the upper ends of the liquid outlet pipes, the lower ends of the four liquid outlet pipes are communicated through a main pipe 48, the main pipe is communicated to a waste liquid collecting device through a circulating pump, the waste liquid collecting device is a waste liquid collecting tank 23, a discharge port of the grinding device is connected with a drying device 25, the drying device comprises a drying cover 50, the drying cover is a steel cover, and a polystyrene board heat insulation layer is installed on the inner wall of the drying cover, the upper end of the drying cover is provided with a dust collecting cover 51 which is communicated with a fresh air system and can discharge water vapor, a heating device is arranged in the drying cover, the heating device selects an electric heating tube 59 and has high temperature control stability, the drying cover is of a tunnel type, a track 52 is also arranged in the drying cover, two ends of the track extend out of the drying cover, a drying tray 53 is arranged on the track, the lower end of the drying tray is provided with a travelling wheel 55 matched with the track, the feeding end of the drying tray is connected with a mobile driving device 54 which selects a double-stroke cylinder, the tail end of a piston rod of the double-stroke cylinder is hinged with the drying tray, a downward slope 56 is formed at the tail end of the track, the feeding end of the drying tray extends to the discharge port of the colloid mill and is placed downwards under the double-stroke cylinder in an initial state, so that material can be received, the double-stroke cylinder acts to a first stroke after the material is received, and the drying tray is positioned in the drying box, drying, after the stoving was accomplished, the double-stroke cylinder moved to second stroke, and the discharge end of stoving tray removes to slope department, and the stoving tray is made by glass, and stoving tray lateral wall slope, and then conveniently collect heparin sodium finished product to collecting box 26 through instruments such as scraper blade, because stoving tray lateral wall slope, the discharge gate reduces with the contained angle of collecting the box, avoids the loss, can also increase evaporation area, improves drying efficiency.
The first temperature control device, the second temperature control device and the third temperature control device respectively comprise a jacket 30 sleeved outside the corresponding reaction tank, a refrigerant pipe 31 is installed in the jacket, three-way reversing valves 33 are installed at the inlet end and the outlet end of the refrigerant pipe, the refrigerant pipe is connected to corresponding high-temperature refrigerant and low-temperature refrigerant through the three-way reversing valves, temperature control is convenient to carry out, the outlet end of the refrigerant pipe is located above the upper inlet end, and a temperature sensor 35 is installed at the outlet end to detect the temperature of the temperature refrigerant.
The pH adjusting device I, the pH adjusting device II, the pH adjusting device III and the pH adjusting device IV all comprise an adjusting agent storage tank 36, and a metering pump 37 is installed on a discharge pipe of the adjusting agent storage tank, so that the pH adjusting precision can be guaranteed.
Receive sediment jar one, receive sediment jar two all including jar body 38, jar body upper end is connected with scavenge pipe 39, the scavenge pipe communicates to wasing the water source, wash for convenient, install joint 41 at jar body lower extreme, connect detachable and connect valve 43, when needs wash, demolish the valve, the installation has the agitator motor of stirring tooth, wash, the jar body upper end of receiving sediment jar two is connected with the moisturizing pipe, moisturizing pipe and purification water tank intercommunication, wet return 40 is installed to the jar body lower extreme of receiving sediment jar two, wet return and centrifuge two's inlet pipe intercommunication, dilute the internal material of jar through the moisturizing pipe, then get back to centrifuge two through the wet return, carry out the secondary and deposit the edulcoration, the yield is improved.
Agitator motor is all installed to retort one, retort two, retort three, retort four, and agitator motor connects stirring tooth 32, makes the material even through the stirring for efficiency improves stability.
The reaction tanks are communicated with each other through a pipeline with a circulating pump 42.
Because enzymolysis, deposit and collect, dry, the oxidation step needs the time longer, retort two, retort three, retort four, drying device all have the multiunit, and parallelly connected the installation between the multiunit can realize continuous production, improves production efficiency.
Example 1
A method for extracting a crude heparin sodium product comprises the following steps:
dissolving, namely putting 50kg of heparin sodium crude product into a dissolving treatment device, adding 500L of purified water for dissolving, stirring for 5min at the stirring speed of 200rpm until the heparin sodium crude product is completely dissolved to obtain a crude product solution;
step two, enzymolysis, namely transferring the crude product solution into an enzymolysis treatment device, adjusting the pH to 6.0 by 6mol/L hydrochloric acid, heating to 50 ℃, adding 0.4Kg of Novoxil hydrolase, and preserving heat for 2 hours to obtain an enzymolysis solution;
thirdly, removing impurities by primary precipitation, heating the enzymolysis solution to boiling, cooling to 4 ℃ after 5min, transferring into a centrifuge, adjusting the pH to 1.2 by 6mol/L hydrochloric acid, standing for 3min, starting the centrifuge, centrifuging for 5min at the centrifugal speed of 4000rad/min, and collecting a liquid phase to obtain a primary impurity-removed solution;
step four, oxidizing, namely transferring the primary impurity removal solution into an oxidation treatment device, adjusting the pH to 10.0 by 6mol/L sodium hydroxide solution, heating to 28 ℃, adding hydrogen peroxide with the volume of 1.0% of the feed liquid, and oxidizing for 10 hours to obtain an oxidized solution;
fifthly, removing impurities by secondary precipitation, transferring the oxidation solution into a centrifuge, centrifuging for 10min, collecting a liquid phase, adding 100L of purified water into a solid phase for dilution, centrifuging for 10min again, wherein the centrifugal speed is 4000rad/min, collecting the liquid phase, and combining the two liquid phases to obtain a secondary impurity removal solution;
sixthly, collecting the precipitate, transferring the secondary impurity removal solution into a precipitation collection device, adjusting the pH value to be neutral by 6mol/L hydrochloric acid, diluting to 1200L, adding 95kg of sodium chloride, heating to 50 ℃, adding 552L of medicinal ethanol, stirring, cooling to 4 ℃, precipitating for 8h, and collecting the precipitate;
and seventhly, refining, grinding the precipitate by adding 1 time of ethanol by weight, filtering, drying for 3 hours at 60 ℃, collecting, packaging and weighing.
The detection results of heparin sodium obtained in example 1 are shown in Table 1.
| Batch number | Crude titer IU | Charging (g) | Output (g) | Yield potency IU | Yield of crude product |
| 20210305 | 98 | 50 | 24.75 | 181.1 | 90.6% |
The results of the molecular weight measurements are shown in Table 2.
| Sample batch number | MW | MW greater than 24000 | Mw8000-16000 | Mw16000-24000 | Mw8000-16000/Mw16000-24000 |
| 20210305 | 18308 | 16.8% | 46.5% | 33.1% | 1.4 |
Example 2
A method for extracting a crude heparin sodium product comprises the following steps:
dissolving, namely putting 50kg of heparin sodium crude product into a dissolving treatment device, adding 500L of purified water for dissolving, stirring for 5min at the stirring speed of 200rpm until the heparin sodium crude product is completely dissolved to obtain a crude product solution;
step two, enzymolysis, namely transferring the crude product solution into an enzymolysis treatment device, adjusting the pH to 7.0 by 6mol/L hydrochloric acid, heating to 50 ℃, adding 0.5Kg of Novixin proteolytic enzyme, and preserving heat for 2 hours to obtain an enzymolysis solution;
thirdly, removing impurities by primary precipitation, heating the enzymolysis solution to boiling, cooling to 5 ℃ after 5min, transferring into a centrifuge, adjusting the pH to 1.5 by 6mol/L hydrochloric acid, standing for 3min, starting the centrifuge, centrifuging for 5min at the centrifugal speed of 4000rad/min, and collecting a liquid phase to obtain a primary impurity-removed solution;
step four, oxidizing, namely transferring the primary impurity removal solution into an oxidation treatment device, adjusting the pH to 9.0 by 6mol/L sodium hydroxide solution, heating to 28 ℃, adding hydrogen peroxide with the volume of 1.0% of the feed liquid, and oxidizing for 10 hours to obtain an oxidized solution;
fifthly, removing impurities by secondary precipitation, transferring the oxidation solution into a centrifuge, centrifuging for 10min, collecting a liquid phase, adding 100L of purified water into a solid phase for dilution, centrifuging for 10min again, wherein the centrifugal speed is 4000rad/min, collecting the liquid phase, and combining the two liquid phases to obtain a secondary impurity removal solution;
sixthly, collecting the precipitate, transferring the secondary impurity removal solution into a precipitation collection device, adjusting the pH value to be neutral by 6mol/L hydrochloric acid, diluting to 1200L, adding 95kg of sodium chloride, heating to 50 ℃, adding 552L of medicinal ethanol, stirring, cooling to 4 ℃, precipitating for 8h, and collecting the precipitate;
and seventhly, refining, grinding the precipitate by adding 1 time of ethanol by weight, filtering, drying for 4 hours at 60 ℃, collecting, packaging and weighing.
The detection results of heparin sodium obtained in example 1 are shown in Table 1.
| Batch number | Crude titer IU | Charging (g) | Output (g) | Yield potency IU | Yield of crude product |
| 20210401 | 95 | 25 | 10.66 | 180.1 | 80.8% |
The results of the molecular weight measurements are shown in Table 2.
| Sample batch number | MW | MW greater than 24000 | Mw8000-16000 | Mw16000-24000 | Mw8000-16000/Mw16000-24000 |
| 20210401 | 22372 | 28.0% | 37.9% | 30.6% | 1.2 |
Example 3
A method for extracting a crude heparin sodium product comprises the following steps:
dissolving, namely putting 50kg of heparin sodium crude product into a dissolving treatment device, adding 500L of purified water for dissolving, stirring for 5min at the stirring speed of 200rpm until the heparin sodium crude product is completely dissolved to obtain a crude product solution;
step two, enzymolysis, namely transferring the crude product solution into an enzymolysis treatment device, adjusting the pH to 7.0 by 6mol/L hydrochloric acid, heating to 50 ℃, adding 0.6Kg of Novixin proteolytic enzyme, and preserving heat for 2 hours to obtain an enzymolysis solution;
thirdly, removing impurities by primary precipitation, heating the enzymolysis solution to boiling, cooling to 5 ℃ after 5min, transferring into a centrifuge, adjusting the pH to 1.4 by 6mol/L hydrochloric acid, standing for 3min, starting the centrifuge, centrifuging for 5min at the centrifugal speed of 4000rad/min, and collecting a liquid phase to obtain a primary impurity-removed solution;
step four, oxidizing, namely transferring the primary impurity removal solution into an oxidation treatment device, adjusting the pH to 10.0 by 6mol/L sodium hydroxide solution, heating to 28 ℃, adding hydrogen peroxide with the volume of 1.0% of the feed liquid, and oxidizing for 10 hours to obtain an oxidized solution;
fifthly, removing impurities by secondary precipitation, transferring the oxidation solution into a centrifuge, centrifuging for 10min, collecting a liquid phase, adding 100L of purified water into a solid phase for dilution, centrifuging for 10min again, wherein the centrifugal speed is 4000rad/min, collecting the liquid phase, and combining the two liquid phases to obtain a secondary impurity removal solution;
sixthly, collecting the precipitate, transferring the secondary impurity removal solution into a precipitation collection device, adjusting the pH value to be neutral by 6mol/L hydrochloric acid, diluting to 1200L, adding 95kg of sodium chloride, heating to 50 ℃, adding 552L of medicinal ethanol, stirring, cooling to 4 ℃, precipitating for 8h, and collecting the precipitate;
and seventhly, refining, grinding the precipitate by adding 1 time of ethanol by weight, filtering, drying for 5 hours at 60 ℃, collecting, packaging and weighing.
The detection results of heparin sodium obtained in example 1 are shown in Table 1.
| Batch number | Crude titer IU | Charging (g) | Output (g) | Yield potency IU | Yield of crude product |
| 20210508 | 106 | 50 | 23.07 | 172.5 | 75.1% |
The results of the molecular weight measurements are shown in Table 2.
| Sample batch number | MW | MW greater than 24000 | Mw8000-16000 | Mw16000-24000 | Mw8000-16000/Mw16000-24000 |
| 20210508 | 13469 | 6.6% | 54.3% | 20.8% | 2.6 |
In conclusion, the method can quickly identify crude heparin from different sources for extraction, the molecular weight and the yield of the crude heparin sodium from different sources are remarkably different after the crude heparin sodium from different sources is quickly treated, internal control standards of titer, molecular weight and yield are established based on the method, the heterosource crude heparin can be efficiently identified, the quality of the crude heparin sodium from normal porcine intestinal mucosa is graded, the economic benefit is improved, and the heparin sodium can be efficiently purified.
Finally, it should be noted that: although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that modifications may be made to the embodiments or portions thereof without departing from the spirit and scope of the invention.
Claims (6)
1. A heparin sodium crude product extraction device, which is characterized by comprising a dissolution treatment device, an enzymolysis treatment device, a first precipitation and impurity removal device, an oxidation treatment device, a second precipitation and impurity removal device, a precipitation collection device, a refining device and a purification water bin which are arranged in sequence,
the dissolution treatment device is connected with a raw material bin and comprises a first reaction tank;
the enzymolysis treatment device comprises a reaction tank II, the reaction tank II is connected with a temperature control device I, and the reaction tank II is also connected with a pH adjusting device I;
the first precipitation and impurity removal device comprises a first centrifugal machine, a slag outlet of the first centrifugal machine is connected with a first slag receiving tank, a liquid outlet of the first centrifugal machine is connected with a first liquid receiving tank, and the first centrifugal machine is connected with a second pH adjusting device;
the oxidation treatment device comprises a third reaction tank, the third reaction tank is connected with a second temperature control device, the third reaction tank is also connected with a third pH adjusting device, and the third reaction tank is connected with a first liquid collecting tank;
the second precipitation and impurity removal device comprises a second centrifugal machine, a slag outlet of the second centrifugal machine is connected with a second slag receiving tank, a liquid outlet of the second centrifugal machine is connected with a second liquid receiving tank, the second slag receiving tank is connected to a purified water bin, and the second centrifugal machine is connected with a fourth pH adjusting device;
the sediment collecting device comprises a reaction tank IV, the reaction tank IV is connected with a temperature control device III, and the reaction tank IV is also connected with a sodium chloride filling device, an ethanol filling device and a waste liquid collecting device;
the refining device comprises a grinding device, the grinding device is connected with the four lower ends of the reaction tank, a discharge port of the grinding device is connected with a drying device,
the raw materials storehouse passes through the inlet pipe intercommunication of auger one and retort one, be provided with anti-clogging device between the inlet pipe of auger one and retort, anti-clogging device is including setting up the gas tube at auger one discharge end, the gas tube communicates to dry air supply, and dry air supply is dry air supply, and pressure is 0.1MPa, anti-clogging device is still including setting up the anti-clogging takeover on auger one's inlet pipe, prevent stifled takeover cross section for oval, flatten the inlet pipe of retort one, obtain anti-clogging takeover, auger one's discharging pipe is through takeover and prevent stifled takeover intercommunication, the takeover is close to the one end of preventing stifled takeover and is described for loudspeaker.
2. The crude heparin sodium extraction device according to claim 1, wherein the first temperature control device, the second temperature control device and the third temperature control device each comprise a jacket sleeved outside the corresponding reaction tank, a refrigerant pipe is arranged in the jacket, three-way reversing valves are arranged at the inlet end and the outlet end of the refrigerant pipe, and the refrigerant pipe is connected to a high-temperature refrigerant and a low-temperature refrigerant through the three-way reversing valves.
3. The crude heparin sodium product extraction device according to claim 1, wherein the pH adjusting device I, the pH adjusting device II, the pH adjusting device III and the pH adjusting device IV respectively comprise an adjusting agent storage tank, and a discharge pipe of the adjusting agent storage tank is provided with a metering pump.
4. The crude heparin sodium product extraction device according to claim 1, wherein the first slag collection tank and the second slag collection tank both comprise tank bodies, a cleaning pipe is connected to the upper ends of the tank bodies, a water replenishing pipe is arranged at the upper ends of the tank bodies of the second slag collection tank and is communicated with a purification water tank, a water return pipe is arranged at the lower end of the tank body of the second slag collection tank and is communicated with a feeding pipe of the second centrifugal machine.
5. The crude heparin sodium extraction device according to claim 1, wherein the grinding device is a colloid mill, the drying device comprises a drying cover, a dust collection cover is arranged at the upper end of the drying cover, a heating device is arranged in the drying cover, a track is further arranged in the drying cover, a drying tray is arranged on the track, and the drying tray is connected with a mobile driving device.
6. A crude heparin sodium extraction method using the crude heparin sodium extraction device according to any one of claims 1 to 5, comprising the steps of:
dissolving, namely putting 50kg of heparin sodium crude product into a dissolving treatment device, adding 500L of purified water for dissolving, stirring for 5min at the stirring speed of 200rpm until the heparin sodium crude product is completely dissolved to obtain a crude product solution;
step two, enzymolysis, namely transferring the crude product solution into an enzymolysis treatment device, adjusting the pH to 6.0 by 6mol/L hydrochloric acid, heating to 50 ℃, adding 0.4Kg of Novoxil hydrolase, and preserving heat for 2 hours to obtain an enzymolysis solution;
thirdly, removing impurities by primary precipitation, heating the enzymolysis solution to boiling, cooling to 4 ℃ after 5min, transferring into a centrifuge, adjusting the pH to 1.2 by 6mol/L hydrochloric acid, standing for 3min, starting the centrifuge, centrifuging for 5min at the centrifugal speed of 4000rad/min, and collecting a liquid phase to obtain a primary impurity-removed solution;
step four, oxidizing, namely transferring the primary impurity removal solution into an oxidation treatment device, adjusting the pH to 10.0 by 6mol/L sodium hydroxide solution, heating to 28 ℃, adding hydrogen peroxide with the volume of 1.0% of the feed liquid, and oxidizing for 10 hours to obtain an oxidized solution;
fifthly, removing impurities by secondary precipitation, transferring the oxidation solution into a centrifuge, centrifuging for 10min, collecting a liquid phase, adding 100L of purified water into a solid phase for dilution, centrifuging for 10min again, wherein the centrifugal speed is 4000rad/min, collecting the liquid phase, and combining the two liquid phases to obtain a secondary impurity removal solution;
sixthly, collecting the precipitate, transferring the secondary impurity removal solution into a precipitation collection device, adjusting the pH value to be neutral by 6mol/L hydrochloric acid, diluting to 1200L, adding 95kg of sodium chloride, heating to 50 ℃, adding 552L of medicinal ethanol, stirring, cooling to 4 ℃, precipitating for 8 hours, and collecting the precipitate;
and seventhly, refining, adding 1 time of ethanol by weight into the precipitate, grinding, filtering, drying for 3 hours at 60 ℃, collecting, packaging and weighing.
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Denomination of invention: Extraction device and method for crude heparin sodium Effective date of registration: 20231129 Granted publication date: 20220802 Pledgee: Bank of China Limited Huangchuan sub branch Pledgor: HUANGCHUAN PENGSHENG LIVESTOCK PRODUCTS CO.,LTD. Registration number: Y2023980068138 |