CN114773499B - Shugeng sodium gluconate for injection and preparation method thereof - Google Patents

Shugeng sodium gluconate for injection and preparation method thereof Download PDF

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CN114773499B
CN114773499B CN202210496568.1A CN202210496568A CN114773499B CN 114773499 B CN114773499 B CN 114773499B CN 202210496568 A CN202210496568 A CN 202210496568A CN 114773499 B CN114773499 B CN 114773499B
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magnetic
sugammadex sodium
solution
layer
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CN114773499A (en
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王静
冯舟
瞿云安
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Sichuan Pharmaceutical Inc
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Abstract

The invention discloses sugammadex sodium for injection and a preparation method thereof, wherein the preparation method comprises the following steps: s1, dissolving a sugammadex sodium crude product in deionized water, and adding a proper amount of alkali liquor to adjust the pH value of the solution to 6.7-6.9; s2, adding the magnetic nanotube into the alkalized solution, and stirring and adsorbing in a vacuum environment; s3, separating the magnetic nanotubes by using a magnetic field, and dispersing the magnetic nanotubes into deionized water for oscillation desorption; wherein the magnetic nanotube comprises a multilayer structure, and the multilayer structure comprises a compact silicon dioxide nanotube layer and Fe from inside to outside in sequence 3 O 4 A layer and a mesoporous silica layer; s4, merging and crystallizing the sugammadex sodium solution obtained by oscillation desorption to obtain refined sugammadexSodium. According to the method, a special structure of the magnetic nano tube is adopted to reversibly adsorb the sugammadex sodium molecules in a weak acid environment, and the inner layer of the silicon dioxide nano tube and the outer layer of the mesoporous silicon dioxide layer can perform physical adsorption reaction with the sugammadex sodium molecules through hydrogen bonds, surface atom coordination and the like.

Description

Shugeng sodium gluconate for injection and preparation method thereof
Technical Field
The invention relates to the technical field of pharmacy, and particularly relates to sugammadex sodium for injection and a preparation method thereof.
Background
The sugammadex sodium (sugammadex sodium, trade name Bridion) belongs to improved gamma cyclodextrin, is a chemical modifier of cyclodextrin, is also an antagonist of steroid non-depolarizing muscle relaxants, can form an inactive inclusion compound with steroid muscle relaxants, and antagonizes neuromuscular blockade at different depths. The sugammadex sodium is obtained by replacing all 6-hydroxyl groups in 8 glucopyranose units of gamma-cyclodextrin by carboxyethylthio. The synthesis method can be used for carrying out nucleophilic substitution reaction on 6-fully-deoxy-6-fully-halogenated-gamma-cyclodextrin and a 3-mercaptopropionic acid derivative under an alkaline condition to obtain the compound.
At present, the purification process of crude sugammadex sodium mostly adopts modes such as activated carbon adsorption or resin adsorption, and the like, and has the problems of high loss rate and low product yield, or an organic acid-organic base-reducing agent mixed system is adopted to dissociate the crude sugammadex sodium into sugammadex acid, and then the sugammadex sodium is obtained through recrystallization purification and salification.
In addition, the sugammadex sodium as a raw material medicine for injection has high solubility in water, but the sugammadex sodium purification process adopts poor solvent crystallization, freeze-drying, spray drying, reduced pressure evaporation to dryness and then crushing and the like, which easily causes the change of the spatial configuration of the sugammadex sodium, generates water-insoluble substances and visible foreign matters, and for the injection, if the water-insoluble substances or the visible foreign matters are injected into the blood of a human body, serious adverse reaction can be caused, and even the life safety of a patient is threatened.
In view of this, the present application is specifically made.
Disclosure of Invention
The invention aims to solve the technical problems that the existing purification method of the crude sugammadex sodium product has high loss rate and low product yield, and aims to provide a preparation method of the sugammadex sodium, which adopts a special-structure nanotube material to adsorb the sugammadex sodium, does not need to use a large amount of organic reagents, and can obviously improve the product yield and the product purity.
The invention further aims to solve the technical problem that sugammadex sodium can generate insoluble substances and visible foreign matters which can cause turbidity due to the crystallization, freeze-drying, spray drying and the like of poor solvents in a purification process, and aims to provide sugammadex sodium for injection.
The invention is realized by the following technical scheme:
the preparation method of sugammadex sodium is characterized by comprising the following steps:
s1, dissolving a crude sugammadex sodium product in deionized water, and adding a proper amount of alkali liquor to adjust the pH value of the solution to 6.7-6.9;
s2, adding the magnetic nanotube into the alkalized solution, and stirring and adsorbing under a vacuum environment for reaction;
s3, separating the magnetic nanotubes by using a magnetic field, and dispersing the magnetic nanotubes into deionized water for oscillation desorption;
wherein the magnetic nanotube comprises a multilayer structure, and the multilayer structure comprises a dense silicon dioxide nanotube layer and Fe from inside to outside in sequence 3 O 4 A magnetic material layer and a mesoporous silica layer;
and S4, combining the solution of the sugammadex sodium obtained by oscillating desorption, and crystallizing to obtain the refined sugammadex sodium.
According to the method, a special structure of the magnetic nano tube is adopted to reversibly adsorb the sugammadex sodium molecules in a weak acid environment, and the inner layer of the silicon dioxide nano tube and the outer layer of the mesoporous silicon dioxide layer can perform physical adsorption reaction with the sugammadex sodium molecules through hydrogen bonds, surface atom coordination and the like. Firstly, the nanotube is used as a hollow structure with openings at two ends, the nanotube has larger specific surface area, and the inner wall and the outer wall of the nanotube both adopt silicon dioxide, so that the nanotube can be more fully adsorbed and combined with sugammadex sodium molecules.
Secondly, the invention carries out adsorption in an alkaline environment, can avoid the defects of new byproducts generated by sugar unit degradation of cyclodextrin framework of the sugammadex sodium and easy opening of glycosidic bond, reduces the oxidation of the sugammadex sodium, can inhibit the generation of new impurities, does not need to add reducing agent or oxidation inhibitor, can avoid the introduction of new pollution source, and simultaneously carries out post-treatment.
And the adsorption reaction is carried out in a vacuum environment, so that the sugammadex sodium molecules can enter the inside of the nanotube more favorably, and the adsorption capacity and efficiency are improved.
Finally, the magnetic nanotube used as the adsorption can be reused after desorption, thereby saving the cost and being beneficial to industrialized low-cost production.
In a specific embodiment, in S2, the preparation method of the magnetic nanotube is as follows: 1) Preparing a nanotube layer: coating a uniform nanotube shell layer on the surface of the carbon nanotube template by adopting a microemulsion method to form a carbon nanotube-nanotube layer core-shell structure; 2) Preparing a magnetic material layer: adding a precursor ion solution of a magnetic material into the solution 1), filtering, adding a filter cake into a sodium hydroxide solution, stirring and ultrasonically treating, then reacting for 2-3 h at 110-130 ℃, removing liquid and drying to form a carbon nanotube-nanotube layer-magnetic material layer core-shell structure; 3) Preparation of the mesoporous silica layer: dispersing the nanotubes with the three-layer core-shell structure obtained in the step 2) into deionized water, adding a cationic surfactant, carrying out ultrasonic treatment, then adding ammonia water, heating and stirring, finally slowly dropwise adding a proper amount of ethyl orthosilicate, and washing and drying after the reaction is finished to obtain a carbon nanotube-nanotube layer-magnetic material layer-mesoporous silica layer core-shell structure; 4) Calcining at high temperature, and removing the carbon nanotube template to form the magnetic nanotubes with a structure of nanotube layer-magnetic material layer-mesoporous silica layer; 5) And (3) putting the magnetic nanotube with the structure of the nanotube layer-magnetic material layer-mesoporous silicon dioxide layer into 2% methanesulfonic acid solution at the temperature of 85-95 ℃ for activation for 3.5-4h to obtain the magnetic nanotube with the activated surface.
The magnetic nano tube is activated by adopting a methanesulfonic acid solution, so that silicon dioxide on the inner surface and the outer surface of the magnetic nano tube is rich in a large number of hydroxyl groups, and can generate esterification reaction with carboxyl and the like on the surface of the sugammadex sodium molecule to form chemical adsorption, and the adsorption capacity is further improved.
The preparation method of the magnetic nanotube comprises the steps of firstly adopting the carbon nanotube as a central template of a core-shell structure, coating the silicon dioxide nanotube, the magnetic material and the mesoporous silicon dioxide layer by layer from inside to outside, and finally removing the carbon nanotube template through a calcination mode.
In a specific embodiment, the specific operation of S2 is as follows: 1) Firstly, placing the magnetic nanotube in a container and pumping to a vacuum state; 2) And pouring the solution in the step S1 into a container in a vacuum state, stirring and adsorbing for 30-45min, recovering the normal pressure state, and continuing stirring and adsorbing for 30-45min.
In the adsorption process, the magnetic nano tube is firstly vacuumized, so that the interior of the nano tube is in a negative pressure state, and after the sugammadex solution is poured in, the sugammadex molecules can be further promoted to enter the interior of the nano tube, thereby improving the adsorption efficiency.
The preparation method of sugammadex sodium for injection comprises the following steps: 1) Adding sugammadex sodium into water for injection or purified water to obtain a sugammadex sodium aqueous solution; 2) Adding a proper amount of ammonia water into the solution, heating and stirring, and filtering to obtain a clear sugammadex sodium water solution for injection.
Furthermore, a proper amount of ammonia water is added until the pH value is 9-10.
Further, the heating temperature is firstly heated to 35-40 ℃ and kept for 30min, then continuously heated to 60-65 ℃ and kept for 1-1.5 h, and finally heated to 90-95 ℃ and kept for 2-3 h.
Further, the solution is heated and stirred, and then the temperature is reduced to 30-35 ℃ and then the solution is filtered by a filter membrane.
Because of the existing processes of crystallization of poor solvent (alcohol solvent), freeze-drying, spray-drying, decompression, evaporation to dryness and then crushing, etc., the sugammadex sodium raw material medicine produced by the prior art can generate turbidity and visible foreign matters when being prepared into preparations, such as injections or preparations.
According to the invention, substances causing turbidity and/or substances capable of forming visible foreign matters in the injection solution can be separated out by adding ammonia water and heating and stirring, and the injection solution can be taken out after filtration, so that the clarity of the sugammadex sodium for injection is improved, and the safety of the sugammadex sodium injection solution is improved.
Firstly, the sugammadex sodium solution is heated and stirred to separate out substances and visible foreign matters which cause turbidity, secondly, ammonia water is added into the sugammadex sodium solution, the ammonia water can generate ammonia gas in the heating process, the ammonia gas can be continuously generated in the solution, and the ammonia gas can break the solution and be continuously discharged, namely, the solution is continuously stirred by the gas in the ammonia gas discharging process, so that the separation of insoluble substances and foreign matters in the solution can be promoted; thirdly, the heating and stirring process is divided into three stages of low temperature, medium temperature and high temperature, the decomposition reaction process of slow ammonia water can be slowed down, and the generated ammonia gas is fully stirred in the solution, so that water insoluble substances and visible foreign matters in the solution are fully separated out, and the quality of the sugammadex sodium product for injection is ensured; and finally, the solution is filtered by using a filter membrane at the temperature of 30-35 ℃, so that the problem that partial impurities and foreign matters are difficult to filter after being cooled down are solved into the solution again.
Compared with the prior art, the invention has the following advantages and beneficial effects:
1. according to the preparation method of sugammadex sodium provided by the embodiment of the invention, a special structure of a magnetic nano tube is adopted to reversibly adsorb sugammadex sodium molecules, and the inner layer and the outer layer of the silicon dioxide nano tube and the mesoporous silicon dioxide layer can perform physical adsorption reaction with the sugammadex sodium molecules through hydrogen bonds, surface atom coordination and the like;
2. according to the preparation method of sugammadex sodium provided by the embodiment of the invention, the nanotube is used as a hollow structure with openings at two ends, the hollow structure has a larger specific surface area, and the inner wall and the outer wall of the nanotube are both made of silicon dioxide, so that the nanotube can be more fully adsorbed and combined with sugammadex sodium molecules;
3. according to the preparation method of sugammadex sodium provided by the embodiment of the invention, the magnetic nano tube is activated by adopting a methanesulfonic acid solution, so that silica on the inner surface and the outer surface of the magnetic nano tube is rich in a large number of hydroxyl groups, and can generate esterification reaction with carboxyl and the like on the surface of a sugammadex sodium molecule to form chemical adsorption, and the adsorption capacity is further improved;
4. according to the preparation method of sugammadex sodium provided by the embodiment of the invention, the magnetic nanotube is vacuumized in the adsorption process, so that the interior of the nanotube is in a negative pressure state, and after the sugammadex sodium solution is poured, the sugammadex sodium molecules can be further promoted to enter the interior of the nanotube, thereby improving the adsorption efficiency;
5. according to the sugammadex sodium for injection provided by the embodiment of the invention, substances causing turbidity and/or substances capable of forming visible foreign matters in an injection solution can be separated out by adding ammonia water and heating and stirring, and the sugammadex sodium for injection can be taken out after filtration, so that the clarity of the sugammadex sodium for injection is improved, and the safety of the sugammadex sodium injection solution is improved;
6. according to the sugammadex sodium for injection provided by the embodiment of the invention, ammonia gas is generated in the heating process by the added ammonia water, the ammonia gas is continuously generated in the solution, and the ammonia gas can break the solution and is continuously discharged, namely the solution is continuously stirred by the gas in the ammonia gas discharging process, so that insoluble substances and foreign matters in the solution can be promoted to be separated out;
7. according to the sugammadex sodium for injection provided by the embodiment of the invention, the heating and stirring process is divided into three stages of low temperature, medium temperature and high temperature, the decomposition reaction process of slow ammonia water can be slowed down, and the generated ammonia gas is fully stirred in the solution, so that water insoluble substances and visible foreign matters in the solution are fully separated out, and the quality of the sugammadex sodium for injection is ensured.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail below with reference to examples, and the exemplary embodiments and descriptions thereof are only used for explaining the present invention and are not used as limiting the present invention.
In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention. However, it will be apparent to one of ordinary skill in the art that: it is not necessary to employ these specific details to practice the present invention. In other instances, well-known methods have not been described in detail in order not to obscure the present invention.
Throughout the specification, reference to "one embodiment," "an embodiment," "one example," or "an example" means: the particular features, structures, or characteristics described in connection with the embodiment or example are included in at least one embodiment of the invention. Thus, the appearances of the phrases "one embodiment," "an embodiment," "one example" or "an example" in various places throughout this specification are not necessarily all referring to the same embodiment or example. Furthermore, the particular features, structures, or characteristics may be combined in any suitable combination and/or sub-combination in one or more embodiments or examples. Further, those of ordinary skill in the art will appreciate that the illustrations provided herein are for illustrative purposes and are not necessarily drawn to scale. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.
In the description of the present invention, the terms "front", "rear", "left", "right", "upper", "lower", "vertical", "horizontal", "upper", "lower", "inner", "outer", etc., indicate an orientation or positional relationship, which is merely for convenience in describing and simplifying the description, and do not indicate or imply that the device or element being referred to must have a particular orientation, be constructed and operated in a particular orientation, and therefore should not be construed as limiting the scope of the invention.
Preparation example
The preparation method of the magnetic nanotube with the structure of the surface-activated nanotube layer-magnetic material layer-mesoporous silicon dioxide layer comprises the following steps:
1) Preparing a nanotube layer: putting 1 g of carbon nano tube into a 200ml flask, sequentially adding 100ml of ethanol, 50ml of water and 6.9 ml of ammonia water (28 wt%), and uniformly stirring; then, 1mL of ethyl orthosilicate is added, and centrifugal separation is carried out after the reaction is finished; washing and centrifuging for many times by using a mixed solvent of ethanol and water, and drying at room temperature for 12 hours to obtain a carbon nanotube-compact silicon dioxide nanotube core-shell structure;
2) Preparing a magnetic material layer: adding FeCl into the solution of 1) 2 And FeCl 3 The mixed solution is treated by ultrasonic for 50min, and the solution is filtered; adding the filter cake into sodium hydroxide solution, stirring and ultrasonically treating, then reacting for 2-3 h at 110-130 ℃, removing liquid and drying to form the carbon nano tube-silicon dioxide nano tube-Fe 3 O 4 A core-shell structure;
3) Preparation of the mesoporous silica layer: dispersing the three-layer core-shell structure nanotube obtained in the step 2) into 400ml of deionized water, adding a cationic surfactant CTAB, carrying out ultrasonic treatment, adding ammonia water to adjust the pH value to 8.0-89.5, heating in a water bath, stirring to 55-60 ℃, finally slowly dropwise adding 60ml of tetraethoxysilane, washing and drying after the reaction is finished, and obtaining the carbon nanotube-silicon dioxide nanotube-Fe 3 O 4 Layer-mesoporous silica core-shell structure;
4) Under the air atmosphere, the carbon nano tube-silicon dioxide nano tube-Fe is added 3 O 4 The core-shell structure of the layer-mesoporous silica layer is burnt for 3 hours at 700 ℃, the carbon nano tube template is removed, and the silica nano tube-Fe is obtained 3 O 4 Magnetic nanotubes of layer-mesoporous silica layer structure;
5) Mixing silica nanotubes-Fe 3 O 4 And (3) putting the layer-mesoporous silica layer magnetic nanotube into 2% methanesulfonic acid solution at the temperature of 85-95 ℃ for activation for 3.5-4h to obtain the surface activated magnetic nanotube.
Example 1
The preparation method of sugammadex sodium provided by the embodiment of the invention comprises the following steps:
1) Dissolving 10.0g of crude sugammadex sodium in 190mL of deionized water, stirring and dissolving at 50 ℃, and adding a proper amount of alkali liquor to adjust the pH value of the solution to 6.7;
2) Placing 20g of magnetic nanotubes with activated surfaces in a container and pumping to a vacuum state; 2) Pouring the solution into a container in a vacuum state, heating, stirring and adsorbing for 35min, recovering to a normal pressure state, continuously heating, stirring and adsorbing for 35min, and keeping the heating temperature at 45 ℃ to ensure that the sugammadex sodium is fully adsorbed on the inner wall surface and the outer wall surface of the nanotube;
3) After adsorption, cooling the reaction system to room temperature, and introducing a magnetic field to perform solid-liquid separation so as to separate the magnetic nanotubes;
4) Dispersing the separated magnetic nanotubes into 300mL of deionized water at 30 ℃; adjusting pH to 8 with sodium hydroxide solution, oscillating on a shaking table for desorption for 30min, starting an electromagnetic device, and separating magnetic nanotube by magnetic field solid-liquid separation; dispersing the separated magnetic nano-tubes in 200mL of deionized water, adjusting the pH value to 8 by using sodium hydroxide, continuing to vibrate for desorption, and repeatedly desorbing until the mother liquor after the microspheres are separated does not contain the sugammadex sodium molecules basically; ultrasonically washing the magnetic nano tube by using deionized water and absolute ethyl alcohol, and then, reserving for recycling;
5) Combining the sulgammadex sodium solution obtained by shaking desorption to obtain a light yellow transparent sulgammadex sodium solution with the volume of about 660mL;
6) And (3) carrying out vacuum evaporation and concentration on the obtained sugammadex sodium solution to about 100mL, cooling, adding 800mL of methanol at the same time, stirring and crystallizing for 1h, carrying out suction filtration after crystallization is finished, washing the obtained white solid with methanol, and carrying out vacuum drying to obtain 8.92g of refined sugammadex sodium, wherein the purification yield is about 89.2%, the HPLC purity is 99.69%, and the total content of impurities is about 0.3%.
Example 2
The preparation method of the sugammadex sodium provided by the embodiment of the invention comprises the following steps:
1) Dissolving 20.0g of crude sugammadex sodium in 380mL of deionized water, stirring and dissolving at 50 ℃, and adding a proper amount of alkali liquor to adjust the pH value of the solution to 6.9;
2) Taking 35g of magnetic nanotubes with activated surfaces, placing the magnetic nanotubes in a container, and pumping the container to a vacuum state; 2) Pouring the solution into a container in a vacuum state, heating, stirring and adsorbing for 40min, recovering to a normal pressure state, continuously heating, stirring and adsorbing for 40min, and keeping the heating temperature at 50 ℃ to ensure that the sugammadex sodium is fully adsorbed on the inner wall surface and the outer wall surface of the nanotube;
3) After adsorption is finished, cooling the reaction system to room temperature, and introducing a magnetic field to carry out solid-liquid separation so as to separate out the magnetic nanotubes;
4) Dispersing the separated magnetic nanotubes into 400mL of deionized water at 30 ℃; adjusting pH to 8 with sodium hydroxide solution, oscillating on a shaking table for desorption for 30min, starting an electromagnetic device, and separating magnetic nanotube by magnetic field solid-liquid separation; dispersing the separated magnetic nano-tubes in 200mL of deionized water, adjusting the pH value to 8 by using sodium hydroxide, continuing to vibrate for desorption, and repeatedly desorbing until the mother liquor after the microspheres are separated does not contain the sugammadex sodium molecules basically; ultrasonically washing the magnetic nano tube by using deionized water and absolute ethyl alcohol, and then reserving for recycling;
5) Combining the solution of the sugammadex sodium obtained by shaking desorption to obtain about 780mL of light yellow transparent solution of the sugammadex sodium;
6) And (3) carrying out vacuum evaporation and concentration on the obtained sugammadex sodium solution to about 110mL, cooling, simultaneously adding 800mL of methanol, stirring and crystallizing for 1h, carrying out suction filtration after crystallization is finished, washing the obtained white solid with methanol, and carrying out vacuum drying to obtain 18.26g of refined sugammadex sodium, wherein the purification yield is about 91.3%, the HPLC purity is 99.74%, and the total content of impurities is less than about 0.3%.
Comparative example 1
1) Taking 10.0g of a prefabricated crude product of sugammadex sodium, and stirring and dissolving the prefabricated crude product of sugammadex sodium at 50 ℃ by using 190mL of deionized water;
2) Adding 20g of activated carbon into the solution, and introducing nitrogen to replace air atmosphere; maintaining the temperature of the water bath at 55 ℃, and slowly stirring for reaction for 2 hours;
3) Filtering, and cooling the filtrate to room temperature;
4) And (3) carrying out vacuum evaporation and concentration on the obtained sugammadex sodium solution to about 100mL, adding 800mL of methanol, stirring and crystallizing for 1h, carrying out suction filtration after crystallization, and carrying out vacuum drying to obtain 7.3g of refined sugammadex sodium, wherein the purification yield is about 73%, the HPLC purity is 99.09%, and the total content of impurities is more than 0.9%.
According to the results of the examples and the comparative examples, the preparation method of the invention can not only ensure that the purification purity reaches more than 99%, but also effectively reduce the loss in the purification process and improve the yield of the product.
Example 3
A method for removing insoluble (turbidity) substances and visible foreign matters of sugammadex sodium for injection comprises the following steps: the method comprises the following steps:
1) Dissolving 10g of sugammadex sodium prepared in example 1 in 90mL of water for injection, and fixing the volume to 100mL to obtain a sugammadex sodium aqueous solution;
2) Adding a proper amount of ammonia water into the solution to adjust the pH value to 9, heating and stirring, wherein the heating temperature is firstly to 35 ℃, keeping the temperature for 30min, then continuously heating to 60 ℃, keeping the temperature for 1h, and finally heating to 90 ℃, and keeping the temperature for 2h; the stirring speed is 80r/min;
3) Cooling to 30 deg.C, and circularly filtering with 0.10 μm filter membrane.
Taking 5mL of the obtained solution into an injection bottle, sterilizing, and detecting the transparency of the solution by using a clarifier, wherein the result shows that the solution is clear and transparent, is equivalent to purified water and has no turbidity opalescence; after the injection is kept stand for 72 hours at room temperature, the solution is still clear and transparent, is equivalent to purified water, and no white-spot visible foreign matters are generated.
Example 4
A method for removing insoluble (turbidity) substances and visible foreign matters of sugammadex sodium for injection comprises the following steps: the method comprises the following steps:
1) 10g of the sugammadex sodium prepared in example 1 is dissolved in 100mL of water for injection to obtain a sugammadex sodium aqueous solution;
2) Adding a proper amount of ammonia water into the solution to adjust the pH value to 9.5, heating and stirring, wherein the heating temperature is firstly to 40 ℃ and is kept for 30min, then continuously heating to 65 ℃ and is kept for 1.5h, and finally heating to 95 ℃ and is kept for 2.5h; the stirring speed is 80r/min;
3) Cooling to 35 deg.C, and circularly filtering with 0.15 μm filter membrane.
Taking 5mL of the obtained solution into an injection bottle, sterilizing, and detecting the transparency of the solution by using a clarifier, wherein the result shows that the solution is clear and transparent, is equivalent to purified water and has no turbidity opalescence; after the injection is kept stand for 72 hours at room temperature, the solution is still clear and transparent, is equivalent to purified water, and no white-spot visible foreign matters are generated.
Example 5
A method for removing insoluble (turbidity) substances and visible foreign matters of sugammadex sodium for injection comprises the following steps: the method comprises the following steps:
1) 10g of sugammadex sodium prepared in example 1 is dissolved in 100mL of water for injection to obtain a sugammadex sodium aqueous solution;
2) Adding a proper amount of ammonia water into the solution to adjust the pH value to 10, heating and stirring, wherein the heating temperature is firstly to 40 ℃, keeping the temperature for 30min, then continuously heating to 60 ℃, keeping the temperature for 1h, and finally heating to 95 ℃, and keeping the temperature for 3h; the stirring speed is 80r/min;
3) Cooling to 35 deg.C, and circularly filtering with 0.20 μm filter membrane.
Taking 5mL of the obtained solution into an injection bottle, sterilizing, and detecting the transparency of the solution by using a clarifier, wherein the result shows that the solution is clear and transparent, is equivalent to purified water and has no turbidness opalescence; after the injection is kept stand for 72 hours at room temperature, the solution is still clear and transparent, is equivalent to purified water, and no white-spot visible foreign matters are generated.
Comparative example 2
Taking 5g of sugammadex sodium prepared in example 1 (the last step of example 1 adopts a poor solvent crystallization mode), dissolving the sugammadex sodium in 50mL of water for injection, adjusting the pH value to 9, and performing circular filtration by using a filter membrane with the aperture of 0.10 mu m; filling 5mL of the solution into an ampoule bottle, and sterilizing for 30min at 121 ℃; observing with a clarity detector to find a turbidity standard solution with the clarity greater than 0.5; standing the injection at room temperature for 72 hr to obtain a turbidity standard solution with clarity less than 0.5 and no white spots.
Comparative example 3
Crystallizing the crude product of the common sugammadex sodium by adopting a poor solvent to obtain refined sugammadex sodium, dissolving 5g of the refined sugammadex sodium by using 50mL of water for injection, adjusting the pH value to 9, and performing circulating filtration by using a filter membrane with the aperture of 0.10 mu m; filling 5mL of the solution into an ampoule bottle, and sterilizing for 30min at 121 ℃; observing with a clarity detector to find a turbidity standard solution with the clarity greater than 0.5; the injection is kept still for 72 hours at room temperature, the clarity is less than the No. 0.5 turbidity standard solution, but white-spot-shaped visible foreign matters are generated.
Comparative example 4
Taking a crude product of the common sugammadex sodium to obtain refined sugammadex sodium by adopting a spray drying mode, and taking 5g of the refined sugammadex sodium to dissolve in 50mL of water for injection; circularly filtering with a filter membrane with the pore diameter of 0.10 mu m; filling 5mL of solution into an ampoule bottle, sterilizing for 30min at 121 ℃, and detecting generation of opalescence under a clarification instrument, wherein the clarity is more than a No. 0.5 turbidity standard solution.
As can be seen by comparing examples 3-5 with comparative examples 2-4, the clarity of the solution treated by adding ammonia water and heating and stirring in stages in examples 3-5 is qualified and has no opalescence, no opalescence is generated after sterilization, and the solution still keeps clear and transparent after standing for a long time; comparative examples 2-4 are solutions that were not specially heat treated after the preparation, and that had opalescence at the initial clarity or after sterilization.
As can be seen by comparing comparative example 2 with comparative example 3, comparative example 2 employs the refined sugammadex sodium preparation solution of the present invention, while comparative example 3 employs poor solvent crystallization to obtain refined sugammadex sodium, in comparison, comparative examples 2 and 3 have opalescence at the initial clarity, but no foreign matter is visible in comparative example 2 after standing for 72 hours, which indicates that the sugammadex sodium refined in example 1 has higher purity and contains less impurities.
The above-mentioned embodiments are intended to illustrate the objects, technical solutions and advantages of the present invention in further detail, and it should be understood that the above-mentioned embodiments are merely exemplary embodiments of the present invention, and are not intended to limit the scope of the present invention, and any modifications, equivalent substitutions, improvements and the like made within the spirit and principle of the present invention should be included in the scope of the present invention.

Claims (8)

1. The preparation method of sugammadex sodium is characterized by comprising the following steps:
s1, dissolving a crude sugammadex sodium product in deionized water, and adding a proper amount of alkali liquor to adjust the pH value of the solution to 6.7-6.9;
s2, adding the magnetic nanotube into the alkalized solution, and stirring and adsorbing under a vacuum environment for reaction;
s3, separating the magnetic nanotubes by using a magnetic field, and dispersing the magnetic nanotubes into deionized water for oscillation desorption;
the magnetic nanotube is of a multilayer structure, the multilayer structure is sequentially provided with a compact silicon dioxide nanotube, a magnetic material layer and a mesoporous silicon dioxide layer from inside to outside, and the magnetic nanotube is activated by adopting a methanesulfonic acid solution;
and S4, combining the solution of the sugammadex sodium obtained by oscillating desorption, and crystallizing to obtain the refined sugammadex sodium.
2. The method for preparing sugammadex sodium according to claim 1, wherein in S2, the magnetic nanotubes are prepared as follows: 1) Preparing a nanotube layer: coating a uniform nanotube shell layer on the surface of the carbon nanotube template by adopting a microemulsion method to form a carbon nanotube-nanotube layer core-shell structure; 2) Preparing a magnetic material layer: adding a precursor ionic solution of a magnetic material into the solution 1), filtering, adding a filter cake into a sodium hydroxide solution, stirring and ultrasonically treating, then reacting for 2 to 3h at 110 to 130 ℃, removing liquid and drying to form a carbon nanotube-nanotube layer-magnetic material layer core-shell structure; 3) Preparation of the mesoporous silica layer: dispersing the three-layer core-shell structure nanotube obtained in the step 2) into deionized water, adding a cationic surfactant, carrying out ultrasonic treatment, then adding ammonia water, heating and stirring, finally slowly dropwise adding a proper amount of ethyl orthosilicate, and washing and drying after the reaction is finished to obtain a carbon nanotube-nanotube layer-magnetic material layer-mesoporous silica layer core-shell structure; 4) And (3) high-temperature calcining, and removing the carbon nanotube template to form the magnetic nanotube with a nanotube layer-magnetic material layer-mesoporous silica layer structure.
3. The method for preparing sugammadex sodium according to claim 1, wherein said magnetic material layer is Fe 3 O 4 。
4. The method for preparing sugammadex sodium according to claim 1, wherein the method for preparing magnetic nanotubes further comprises the steps of: 5) And (3) putting the magnetic nanotube with the structure of the nanotube layer-magnetic material layer-mesoporous silicon dioxide layer into 2% methanesulfonic acid solution at the temperature of 85-95 ℃ for activation for 3.5-4h to obtain the magnetic nanotube with the activated surface.
5. A process for the preparation of sugammadex sodium according to claim 1, characterized in that S2 is performed as follows: 1) Firstly, placing the magnetic nano tube in a container and pumping to a vacuum state; 2) And pouring the solution in the S1 into a container in a vacuum state, stirring and adsorbing for 30-45min, recovering to a normal pressure state, and continuously stirring and adsorbing for 30-45min.
6. The sugammadex sodium for injection is characterized in that the preparation method comprises the following steps: 1) Adding sugammadex sodium prepared by the preparation method of any one of claims 1 to 5 into water for injection or purified water to obtain a sugammadex sodium aqueous solution; 2) Adding a proper amount of ammonia water into the solution, heating and stirring, and filtering to obtain a clear sugammadex sodium aqueous solution for injection; the heating temperature is firstly heated to 35 to 40 ℃ and is kept for 30min, then the heating is continuously carried out to 60 to 65 ℃ and is kept for 1 to 1.5h, and finally the heating is carried out to 90 to 95 ℃ and is kept for 2 to 3h.
7. The sugammadex sodium for injection according to claim 6, wherein a proper amount of ammonia water is added to a pH value of 9 to 10.
8. The sugammadex sodium for injection as claimed in claim 6, wherein the solution is heated and stirred, and then filtered by a filter membrane after the temperature is reduced to 30 to 35 ℃.
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