A preparation method of hydrocortisone sodium succinate lyophilized powder injection for injection

Abstract

The invention discloses a method for preparing hydrocortisone sodium succinate lyophilized powder injection for injection, first hydrocortisone succinate, graphene carbon nanotube composite material and acetone ultrasonic oscillation are uniform, and suspension is obtained; sodium bicarbonate, disodium hydrogen phosphate, sodium dihydrogen phosphate and water for injection are stirred and mixed to obtain saline solution; then the saline solution is slowly added to the suspension at a uniform speed while stirring, the reaction is stirred under electric field conditions, and the supernatant is taken by centrifugation; finally chitosan modified activated carbon is added to the supernatant, and decolorization is stirred, chitosan modified activated carbon is removed by filtration, sterilization, microwave pretreatment, vacuum freeze drying, aseptic subpackaging, and the preparation method of the present invention has a short drying time, greatly reduces production cost, and the obtained products have high quality and short redissolution time.

Description

Technical Field

[0001] The present invention relates to a preparation method of hydrocortisone sodium succinate preparation, in particular to a preparation method of hydrocortisone sodium succinate freeze-dried powder injection for injection, belonging to the technical field of pharmaceutical preparation processing. Background Art

[0002] Hydrocortisone sodium succinate is a salt compound of hydrocortisone, chemical name 11β,17-dihydroxy-21-(3-carboxy-1-hydroxypropoxy)pregnane-4-ene-3,20-dione-sodium salt, molecular formula C 25 H 33 O8Na, molecular weight 484.52.

[0003] Hydrocortisone sodium succinate has multiple pharmacological effects such as anti-inflammatory, anti-allergic and immunosuppressive, and belongs to the adrenal cortex hormone class of drugs. The specific pharmacological effects are as follows:

[0004] 1. Anti-inflammatory effect: reduce and prevent tissue response to inflammation and alleviate inflammatory manifestations;

[0005] 2. Immunosuppressive effect: prevent or inhibit cell-mediated immune responses, delay allergic reactions, and reduce the expansion of primary immune responses;

[0006] 3. Anti-toxic and anti-shock effects: counteract the stimulating response of bacterial endotoxins to the body, reduce cell damage, and play a role in protecting the body.

[0007] Hydrocortisone sodium succinate is rapidly absorbed after oral administration. max For 1 hour, T 1 / 2 The drug is absorbed by the skin and mainly metabolized by the liver. A very small amount of hydrocortisone sodium succinate is excreted in the urine in its original form. In clinical practice, hydrocortisone sodium succinate is widely used in the treatment of acute allergic diseases, status asthmaticus, adrenal crisis, infectious toxic shock, etc. It is also commonly used in the treatment of malignant lymphoma.

[0008] Hydrocortisone sodium succinate for injection is usually a sterile powder injection prepared with hydrocortisone succinate as raw material under the action of a suitable base.

[0009] The traditional production process of hydrocortisone sodium succinate for injection has the following problems:

[0010] 1. Hydrocortisone succinate is almost insoluble in water and difficult to be neutralized by sodium alkali (sodium hydroxide, sodium carbonate, sodium bicarbonate) in pure water. It needs to be stirred for a long time or heated to above 40°C for a period of time to dissolve and neutralize, which in turn causes hydrolysis, turbidity, and high impurity content. Using sodium hydroxide or sodium carbonate for hydrolysis produces more serious impurities.

[0011] 2. The method of neutralizing in an acetone aqueous solution and then directly distilling to dryness results in a high impurity content and unsatisfactory clarity after re-dissolution.

[0012] 3. The method of carrying out neutralization reaction in an acetone aqueous solution and then adding a large amount of acetone for crystallization, the obtained product is severely solvated, difficult to filter and separate, and difficult to dry, and is not suitable for industrialization.

[0013] 4. Since the preparation of hydrocortisone sodium succinate is carried out in a solution, the wet material needs to be dried to obtain the finished product. Usually, freeze drying is used, which takes a long time and is prone to deterioration during the drying process.

[0014] 5. Hydrocortisone sodium succinate is highly hygroscopic and easily soluble in water. It is unstable in solution and even more unstable when heated, and is prone to ester hydrolysis.

[0015] In general, the traditional production process has disadvantages such as small production scale, low yield, high drying cost, difficulty in drying, and product impurity content that does not meet the standards.

[0016] Patent application CN116407508A discloses a method for preparing hydrocortisone sodium succinate for injection, comprising the following steps: dissolving hydrocortisone sodium succinate and buffer salt in water for injection to form a liquid medicine, adjusting the pH to 7.5-7.9, filtering the liquid medicine, filling it into a bottle, and freeze-drying it. The patented technology has a long freeze-drying time, a long re-dissolution time, and a high impurity content, and there is still a lot of room for improvement in product quality. Summary of the invention

[0017] The purpose of the present invention is to overcome the deficiencies of the prior art and provide a method for preparing hydrocortisone sodium succinate lyophilized powder injection for injection, which has short drying time, high product quality and short reconstitution time.

[0018] To achieve the above object, the present invention adopts the following technical solutions:

[0019] A method for preparing hydrocortisone sodium succinate lyophilized powder injection for injection, the specific steps are as follows:

[0020] (1) firstly ultrasonically oscillate hydrocortisone succinate, graphene-carbon nanotube composite material and acetone to obtain a suspension;

[0021] (2) stirring and mixing sodium bicarbonate, disodium hydrogen phosphate, sodium dihydrogen phosphate and water for injection to obtain a saline solution;

[0022] (3) Then, the salt solution is slowly added to the suspension at a uniform speed while stirring, the reaction is stirred under electric field conditions, and the supernatant is collected by centrifugation;

[0023] (4) Finally, chitosan-modified activated carbon is added to the supernatant, stirred for decolorization, filtered to remove the chitosan-modified activated carbon, sterilized, microwave pre-treated, vacuum freeze-dried, and aseptically packaged.

[0024] Preferably, in step (1), the graphene-carbon nanotube composite material is obtained by the following preparation method, in parts by weight: first, 10 parts of graphene oxide, 0.1-0.2 parts of carbon nanotubes, and 0.01-0.02 parts of sodium dodecyl sulfate are added to 45-55 parts of deionized water, and ultrasonically dispersed at 100-200W for 30-40 minutes to obtain a suspension, and spray-dried to obtain a powder, and then the powder is placed in a tube furnace, reduced, and washed alternately with distilled water and anhydrous ethanol for 3-4 times to obtain the obtained product.

[0025] Further preferably, the graphene oxide is prepared by an improved Hummers method using 50 mesh graphite powder as a raw material; in parts by weight, the specific method is as follows: first, 20 parts of graphite powder, 10 parts of potassium persulfate and 10 parts of phosphorus pentoxide are added to 150-160 parts of 98% concentrated sulfuric acid at 80°C, stirred evenly, cooled naturally to room temperature, washed with distilled water until neutral, and dried to obtain a solid; then the solid is added to 150-160 parts of 98% concentrated sulfuric acid at 0°C, and then 60 parts of potassium permanganate are added, and the mixture is stirred at 30-35°C for 2 hours, and 950-970 parts of deionized water are slowly added at a uniform speed for 40-50 minutes, and then 25-30 parts of 5-6% hydrogen peroxide solution are added, stirred and mixed, and the residue is filtered out by suction, and the residue is washed 3-4 times with a 10% hydrochloric acid solution by mass, and vacuum dried at 50-60°C for 45-48 hours to obtain the obtained product.

[0026] Further preferably, the process conditions for spray drying are: pressure 3-4 MPa, air inlet temperature 110-120°C, and air outlet temperature 70-80°C.

[0027] Further preferably, the process conditions for the reduction treatment are: first, heat to 500-520°C in a nitrogen atmosphere, keep warm for 5-6 hours, cool to room temperature with the furnace, pass hydrogen into the tubular furnace at 60-70 mL / min for 5-7 minutes, discharge the nitrogen atmosphere in the tubular furnace, heat to 750-780°C, keep warm for 5-6 hours, and naturally cool to room temperature in a hydrogen atmosphere.

[0028] Preferably, in step (1), the mass ratio of hydrocortisone succinate, graphene-carbon nanotube composite material and acetone is 1:0.1-0.2:1.5-2.

[0029] Preferably, in step (1), the process conditions of ultrasonic oscillation are: 400-500W ultrasonic oscillation treatment for 30-40 minutes.

[0030] Preferably, in step (2), the mass ratio of sodium bicarbonate, disodium hydrogen phosphate, sodium dihydrogen phosphate and water for injection is 0.2-0.22:0.08-0.1:0.02-0.03:6-8.

[0031] Preferably, in step (3), the mass ratio of the sodium bicarbonate contained in the salt solution to the hydrocortisone succinate contained in the suspension is 0.2-0.22:1.

[0032] Preferably, in step (3), the electric field conditions are: electric field strength 15-20 kV / cm, pulse frequency 200-300 Hz, pulse width 30-40 μs.

[0033] Preferably, in step (3), the stirring reaction process conditions are: stirring reaction at 300-400 r / min for 2-3 hours.

[0034] Preferably, in step (4), the chitosan-modified activated carbon is prepared by the following method, in parts by weight: first dissolving 8 to 10 parts of chitosan in 100 parts of 0.5% acetic acid solution, then adding 30 to 40 parts of medicinal activated carbon, stirring at 300 to 400 r / min for 1 to 2 hours to obtain a suspension; then pouring the suspension into 500 to 520 parts of 45 to 55% sodium carbonate solution, stirring at 300 to 400 r / min for 3 to 4 hours, standing for 30 to 40 minutes under an electric field of 2 to 3 V / cm, separating the layers, and obtaining a precipitate; washing the precipitate with distilled water until it is neutral, and vacuum drying at 60 to 70° C. for 45 to 48 hours to obtain the obtained product.

[0035] Preferably, in step (4), the mass ratio of the supernatant to the chitosan-modified activated carbon is 100:1-2.

[0036] Preferably, in step (4), the stirring decolorization process conditions are: stirring at 300-400 r / min for 30-40 minutes.

[0037] Preferably, in step (4), a 0.22 μm microporous filter is used for filtration and sterilization.

[0038] Preferably, in step (4), the process conditions of microwave pretreatment are: 300-400W microwave treatment for 30-40s, stop for 10s, and repeat this cycle 3-4 times.

[0039] Preferably, in step (4), the process conditions for vacuum freeze drying are: first cool to -40 to -50°C at 0.6 to 0.7°C / min, keep warm for 3 to 4 hours, evacuate to 10 to 12 Pa, then heat to 33 to 35°C at 0.6 to 0.7°C / min, and keep warm for 3 to 4 hours.

[0040] Beneficial effects of the present invention:

[0041] The present invention firstly ultrasonically oscillates hydrocortisone succinate, graphene-carbon nanotube composite material and acetone uniformly to obtain a suspension; then stir and mix sodium bicarbonate, disodium hydrogen phosphate, sodium dihydrogen phosphate and water for injection to obtain a saline solution; then slowly add the saline solution to the suspension at a uniform speed while stirring, stir and react under electric field conditions, centrifuge and take the supernatant; finally, add chitosan-modified activated carbon to the supernatant, stir and decolorize, filter and remove the chitosan-modified activated carbon, sterilize, microwave pretreatment, vacuum freeze drying, and aseptic packaging to obtain a hydrocortisone sodium succinate lyophilized powder injection for injection. The preparation method of the present invention has a short drying time, greatly reduces the production cost, and the obtained product has high quality and a short re-dissolution time.

[0042] Hydrocortisone succinate has poor hydrophilicity and poor dispersibility in the reaction system, which affects the salt-forming effect. The present invention adds a graphene-carbon nanotube composite material, which has good adsorption, increases the contact area between hydrocortisone succinate and sodium bicarbonate, and promotes the salt-forming reaction.

[0043] The salt-forming reaction of the present invention is carried out under electric field conditions. Through the synergistic effect of the graphene-carbon nanotube composite material (with certain conductivity) and the electric field conditions, the difficulty of the salt-forming reaction is greatly reduced, and no heating is required, and salt formation can be achieved in a relatively short time.

[0044] The present invention utilizes chitosan modified activated carbon to achieve decolorization. When preparing chitosan modified activated carbon, the chitosan molecules are oriented and arranged by electric field, and loaded on the surface and pores of the medicinal activated carbon, so that the decolorization effect is good. In addition, the hydrophilicity of chitosan modified activated carbon inhibits product solvation, which helps to improve the subsequent separation effect, shorten the subsequent drying time, and improve the product quality.

[0045] The present invention performs microwave pretreatment before vacuum freeze drying, and determines appropriate microwave power and time through screening. Too high power and too long time affect product purity. Appropriate microwave pretreatment helps to regulate water content and microstructure. Subsequently, a shorter vacuum freeze drying time can be used for effective drying, thereby ensuring that the product has a lower water content. DETAILED DESCRIPTION

[0046] The present invention is further described below in conjunction with embodiments. It should be noted that the following description is only for explaining the present invention and does not limit its contents.

[0047] Embodiment 1:

[0048] A method for preparing hydrocortisone sodium succinate lyophilized powder injection for injection, the specific steps are as follows:

[0049] (1) firstly ultrasonically oscillate 1 kg of hydrocortisone succinate, 0.1 kg of graphene-carbon nanotube composite material and 1.5 kg of acetone to obtain a suspension;

[0050] (2) 0.2 kg of sodium bicarbonate, 0.08 kg of disodium hydrogen phosphate, 0.02 kg of sodium dihydrogen phosphate and 6 kg of water for injection were stirred and mixed to obtain a saline solution;

[0051] (3) Then, the salt solution is slowly added to the suspension at a uniform speed while stirring, the reaction is stirred under electric field conditions, and the supernatant is collected by centrifugation;

[0052] (4) Finally, chitosan-modified activated carbon is added to the supernatant, stirred for decolorization, filtered to remove the chitosan-modified activated carbon, sterilized, microwave pre-treated, vacuum freeze-dried, and aseptically packaged.

[0053] Wherein, in step (1), the graphene-carbon nanotube composite material is obtained by the following preparation method: first, 0.2 kg of graphene oxide, 0.002 kg of carbon nanotubes, and 0.0002 kg of sodium dodecyl sulfate are added to 0.9 kg of deionized water, and ultrasonically dispersed at 100 W for 30 minutes to obtain a suspension, and spray-dried to obtain a powder, and then the powder is placed in a tube furnace, reduced, and washed alternately with distilled water and anhydrous ethanol for 3 times to obtain the obtained product.

[0054] The graphene oxide is prepared by using 50-mesh graphite powder as a raw material through an improved Hummers method; the specific method is as follows: first, 0.2 kg of graphite powder, 0.1 kg of potassium persulfate and 0.1 kg of phosphorus pentoxide are added to 1.5 kg of 98% concentrated sulfuric acid at 80°C, stirred evenly, cooled naturally to room temperature, washed with distilled water until neutral, and dried to obtain a solid; then the solid is added to 1.5 kg of 98% concentrated sulfuric acid at 0°C, and then 0.6 kg of potassium permanganate is added, and the mixture is stirred at 30°C for 2 hours, 9.5 kg of deionized water is added slowly at a uniform speed for 40 minutes, and then 0.25 kg of 5% hydrogen peroxide solution is added, stirred and mixed, and the residue is filtered out by suction, and the residue is washed 3 times with a 10% hydrochloric acid solution, and vacuum dried at 50°C for 45 hours to obtain the obtained product.

[0055] The process conditions of spray drying are: pressure 3MPa, air inlet temperature 110℃, and air outlet temperature 70℃.

[0056] The process conditions of the reduction treatment are as follows: first, heat to 500°C in a nitrogen atmosphere, keep warm for 5 hours, cool to room temperature with the furnace, pass hydrogen into the tubular furnace at 60 mL / min for 5 minutes, exhaust the nitrogen atmosphere in the tubular furnace, heat to 750°C, keep warm for 5 hours, and naturally cool to room temperature in a hydrogen atmosphere.

[0057] In step (1), the process conditions of ultrasonic oscillation are: 400W ultrasonic oscillation treatment for 30 minutes.

[0058] In step (3), the electric field conditions are: electric field intensity 15 kV / cm, pulse frequency 200 Hz, pulse width 30 μs.

[0059] In step (3), the process conditions for the stirring reaction are: stirring the reaction at 300 r / min for 2 hours.

[0060] In step (4), the chitosan modified activated carbon is prepared by the following method: first, 0.8 kg of chitosan is dissolved in 10 kg of 0.5% acetic acid solution, then 3 kg of medicinal activated carbon is added, and the mixture is stirred at 300 r / min for 1 hour to obtain a suspension; then the suspension is poured into 50 kg of 45% sodium carbonate solution, stirred at 300 r / min for 3 hours, and allowed to stand for 30 minutes under an electric field of 2 V / cm, separated into layers, and a precipitate is obtained; the precipitate is washed with distilled water until it is neutral, and vacuum dried at 60° C. for 45 hours to obtain the obtained product.

[0061] In step (4), the mass ratio of the supernatant to the chitosan-modified activated carbon is 100:1.

[0062] In step (4), the stirring decolorization process conditions are: stirring at 300 r / min for 30 minutes.

[0063] In step (4), a 0.22 μm microporous filter is used for filtration and sterilization.

[0064] In step (4), the process conditions of microwave pretreatment are: 300 W microwave treatment for 30 seconds, stop for 10 seconds, and repeat this cycle 3 times.

[0065] In step (4), the process conditions for vacuum freeze drying are: first cool to -40°C at 0.6°C / min, keep warm for 3 hours, evacuate to 10Pa, then heat to 33°C at 0.6°C / min, and keep warm for 3 hours.

[0066] Embodiment 2:

[0067] A method for preparing hydrocortisone sodium succinate lyophilized powder injection for injection, the specific steps are as follows:

[0068] (1) firstly ultrasonically oscillate 1 kg of hydrocortisone succinate, 0.2 kg of graphene-carbon nanotube composite material and 2 kg of acetone to obtain a suspension;

[0069] (2) 0.2 kg of sodium bicarbonate, 0.1 kg of disodium hydrogen phosphate, 0.03 kg of sodium dihydrogen phosphate and 8 kg of water for injection were stirred and mixed to obtain a saline solution;

[0070] (3) Then, the salt solution is slowly added to the suspension at a uniform speed while stirring, the reaction is stirred under electric field conditions, and the supernatant is collected by centrifugation;

[0071] (4) Finally, chitosan-modified activated carbon is added to the supernatant, stirred for decolorization, filtered to remove the chitosan-modified activated carbon, sterilized, microwave pre-treated, vacuum freeze-dried, and aseptically packaged.

[0072] Wherein, in step (1), the graphene-carbon nanotube composite material is obtained by the following preparation method: first, 0.2 kg of graphene oxide, 0.004 kg of carbon nanotubes, and 0.0004 kg of sodium dodecyl sulfate are added to 1.1 kg of deionized water, and ultrasonically dispersed at 200 W for 40 minutes to obtain a suspension, and spray-dried to obtain a powder, and then the powder is placed in a tube furnace, reduced, and washed alternately with distilled water and anhydrous ethanol for 4 times to obtain the obtained product.

[0073] The graphene oxide is prepared by using 50-mesh graphite powder as a raw material through an improved Hummers method; the specific method is as follows: first, 0.2 kg of graphite powder, 0.1 kg of potassium persulfate and 0.1 kg of phosphorus pentoxide are added to 1.6 kg of 98% concentrated sulfuric acid at 80°C, stirred evenly, cooled naturally to room temperature, washed with distilled water until neutral, and dried to obtain a solid; then the solid is added to 1.6 kg of 98% concentrated sulfuric acid at 0°C, and then 0.6 kg of potassium permanganate is added, and the mixture is stirred at 35°C for 2 hours, 9.7 kg of deionized water is slowly added at a uniform speed for 50 minutes, and then 0.3 kg of 6% hydrogen peroxide solution is added, stirred and mixed, and the residue is filtered out, and the residue is washed 4 times with a 10% hydrochloric acid solution, and vacuum dried at 60°C for 48 hours to obtain the obtained product.

[0074] The process conditions of spray drying are: pressure 4MPa, air inlet temperature 120℃, and air outlet temperature 80℃.

[0075] The process conditions of the reduction treatment are as follows: first, heat to 520°C in a nitrogen atmosphere, keep warm for 6 hours, cool to room temperature with the furnace, pass hydrogen into the tubular furnace at 70 mL / min for 7 minutes, exhaust the nitrogen atmosphere in the tubular furnace, heat to 780°C, keep warm for 6 hours, and naturally cool to room temperature in a hydrogen atmosphere.

[0076] In step (1), the process conditions of ultrasonic oscillation are: 500W ultrasonic oscillation treatment for 40 minutes.

[0077] In step (3), the electric field conditions are: electric field intensity 20 kV / cm, pulse frequency 300 Hz, pulse width 40 μs.

[0078] In step (3), the process conditions for the stirring reaction are: stirring the reaction at 400 r / min for 3 hours.

[0079] In step (4), the chitosan modified activated carbon is prepared by the following method: first dissolving 1 kg of chitosan in 10 kg of 0.5% acetic acid solution, then adding 4 kg of medicinal activated carbon, stirring at 400 r / min for 2 hours to obtain a suspension; then pouring the suspension into 52 kg of 55% sodium carbonate solution, stirring at 400 r / min for 4 hours, standing for 40 minutes under 3 V / cm electric field conditions, separating the layers, and taking the precipitate; washing the precipitate with distilled water until neutral, and vacuum drying at 70° C. for 48 hours to obtain the obtained product.

[0080] In step (4), the mass ratio of the supernatant to the chitosan-modified activated carbon is 100:2.

[0081] In step (4), the stirring decolorization process conditions are: stirring at 400 r / min for 40 minutes.

[0082] In step (4), a 0.22 μm microporous filter is used for filtration and sterilization.

[0083] In step (4), the process conditions of microwave pretreatment are: 400 W microwave treatment for 40 seconds, stop for 10 seconds, and repeat this cycle 4 times.

[0084] In step (4), the process conditions for vacuum freeze drying are: first cool to -50°C at 0.7°C / min, keep warm for 4 hours, evacuate to 12 Pa, then heat to 35°C at 0.7°C / min, and keep warm for 4 hours.

[0085] Embodiment 3:

[0086] A method for preparing hydrocortisone sodium succinate lyophilized powder injection for injection, the specific steps are as follows:

[0087] (1) firstly ultrasonically oscillate 1 kg of hydrocortisone succinate, 0.1 kg of graphene-carbon nanotube composite material and 2 kg of acetone to obtain a suspension;

[0088] (2) 0.2 kg of sodium bicarbonate, 0.08 kg of disodium hydrogen phosphate, 0.03 kg of sodium dihydrogen phosphate and 6 kg of water for injection were stirred and mixed to obtain a saline solution;

[0089] (3) Then, the salt solution is slowly added to the suspension at a uniform speed while stirring, the reaction is stirred under electric field conditions, and the supernatant is collected by centrifugation;

[0090] (4) Finally, chitosan-modified activated carbon is added to the supernatant, stirred for decolorization, filtered to remove the chitosan-modified activated carbon, sterilized, microwave pre-treated, vacuum freeze-dried, and aseptically packaged.

[0091] Wherein, in step (1), the graphene-carbon nanotube composite material is obtained by the following preparation method: first, 0.2 kg of graphene oxide, 0.004 kg of carbon nanotubes, and 0.0002 kg of sodium dodecyl sulfate are added to 1.1 kg of deionized water, and ultrasonically dispersed at 100 W for 40 minutes to obtain a suspension, and spray-dried to obtain a powder, and then the powder is placed in a tube furnace, reduced, and washed alternately with distilled water and anhydrous ethanol for 3 times to obtain the obtained product.

[0092] The graphene oxide is prepared by using 50-mesh graphite powder as a raw material through an improved Hummers method; the specific method is as follows: first, 0.2 kg of graphite powder, 0.1 kg of potassium persulfate and 0.1 kg of phosphorus pentoxide are added to 1.6 kg of 98% concentrated sulfuric acid at 80°C, stirred evenly, cooled naturally to room temperature, washed with distilled water until neutral, and dried to obtain a solid; then the solid is added to 1.5 kg of 98% concentrated sulfuric acid at 0°C, and then 0.6 kg of potassium permanganate is added, and the mixture is stirred at 35°C for 2 hours, 9.7 kg of deionized water is slowly added at a uniform speed for 40 minutes, and then 0.25 kg of 6% hydrogen peroxide solution is added, stirred and mixed, and the residue is filtered out, and the residue is washed 3 times with a 10% hydrochloric acid solution, and vacuum dried at 60°C for 45 hours to obtain the obtained product.

[0093] The process conditions of spray drying are: pressure 4MPa, air inlet temperature 110℃, and air outlet temperature 80℃.

[0094] The process conditions of the reduction treatment are as follows: first, heat to 500°C in a nitrogen atmosphere, keep warm for 6 hours, cool to room temperature with the furnace, pass hydrogen into the tubular furnace at 60 mL / min for 7 minutes, exhaust the nitrogen atmosphere in the tubular furnace, heat to 750°C, keep warm for 6 hours, and naturally cool to room temperature in a hydrogen atmosphere.

[0095] In step (1), the process conditions of ultrasonic oscillation are: 400W ultrasonic oscillation treatment for 40 minutes.

[0096] In step (3), the electric field conditions are: electric field strength 15 kV / cm, pulse frequency 300 Hz, pulse width 30 μs.

[0097] In step (3), the process conditions for the stirring reaction are: stirring the reaction at 400 r / min for 2 hours.

[0098] In step (4), the chitosan modified activated carbon is prepared by the following method: first dissolving 1 kg of chitosan in 10 kg of 0.5% acetic acid solution, then adding 3 kg of medicinal activated carbon, stirring at 400 r / min for 1 hour to obtain a suspension; then pouring the suspension into 52 kg of 45% sodium carbonate solution, stirring at 400 r / min for 3 hours, standing for 30 minutes under 3 V / cm electric field conditions, separating the layers, and taking the precipitate; washing the precipitate with distilled water until neutral, and vacuum drying at 70° C. for 45 hours to obtain the obtained product.

[0099] In step (4), the mass ratio of the supernatant to the chitosan-modified activated carbon is 100:2.

[0100] In step (4), the stirring decolorization process conditions are: stirring at 300 r / min for 40 minutes.

[0101] In step (4), a 0.22 μm microporous filter is used for filtration and sterilization.

[0102] In step (4), the process conditions of microwave pretreatment are: 300 W microwave treatment for 40 seconds, stop for 10 seconds, and repeat this cycle 3 times.

[0103] In step (4), the process conditions for vacuum freeze drying are: first cool to -40°C at 0.7°C / min, keep warm for 4 hours, evacuate to 10Pa, then heat to 33°C at 0.7°C / min, and keep warm for 4 hours.

[0104] Embodiment 4:

[0105] A method for preparing hydrocortisone sodium succinate lyophilized powder injection for injection, the specific steps are as follows:

[0106] (1) firstly ultrasonically oscillate 1 kg of hydrocortisone succinate, 0.15 kg of graphene-carbon nanotube composite material and 1.8 kg of acetone to obtain a suspension;

[0107] (2) 0.2 kg of sodium bicarbonate, 0.09 kg of disodium hydrogen phosphate, 0.025 kg of sodium dihydrogen phosphate and 7 kg of water for injection were stirred and mixed to obtain a saline solution;

[0108] (3) Then, the salt solution is slowly added to the suspension at a uniform speed while stirring, the reaction is stirred under electric field conditions, and the supernatant is collected by centrifugation;

[0109] (4) Finally, chitosan-modified activated carbon is added to the supernatant, stirred for decolorization, filtered to remove the chitosan-modified activated carbon, sterilized, microwave pre-treated, vacuum freeze-dried, and aseptically packaged.

[0110] Wherein, in step (1), the graphene-carbon nanotube composite material is obtained by the following preparation method: first, 0.2 kg of graphene oxide, 0.003 kg of carbon nanotubes, and 0.0003 kg of sodium dodecyl sulfate are added to 1 kg of deionized water, and ultrasonically dispersed at 150 W for 35 minutes to obtain a suspension, and spray-dried to obtain a powder, and then the powder is placed in a tubular furnace, reduced, and washed alternately with distilled water and anhydrous ethanol for 3 times to obtain the obtained product.

[0111] The graphene oxide is prepared by using 50-mesh graphite powder as a raw material through an improved Hummers method; the specific method is as follows: first, 0.2 kg of graphite powder, 0.1 kg of potassium persulfate and 0.1 kg of phosphorus pentoxide are added to 1.6 kg of 98% concentrated sulfuric acid at 80°C, stirred evenly, cooled naturally to room temperature, washed with distilled water until neutral, and dried to obtain a solid; then the solid is added to 1.6 kg of 98% concentrated sulfuric acid at 0°C, and then 0.6 kg of potassium permanganate is added, and the mixture is stirred at 33°C for 2 hours, 9.6 kg of deionized water is slowly added at a uniform speed for 45 minutes, and then 0.28 kg of 5.5% hydrogen peroxide solution is added, stirred and mixed, and the residue is filtered out by suction, and the residue is washed 3 times with a 10% hydrochloric acid solution, and vacuum dried at 55°C for 47 hours to obtain the obtained product.

[0112] The process conditions of spray drying are: pressure 4MPa, air inlet temperature 115℃, and air outlet temperature 75℃.

[0113] The process conditions of the reduction treatment are as follows: first, heat to 510°C in a nitrogen atmosphere, keep warm for 6 hours, cool to room temperature with the furnace, pass hydrogen into the tubular furnace at 65 mL / min for 6 minutes, exhaust the nitrogen atmosphere in the tubular furnace, heat to 7700°C, keep warm for 5 hours, and naturally cool to room temperature in a hydrogen atmosphere.

[0114] In step (1), the process conditions of ultrasonic oscillation are: 450W ultrasonic oscillation treatment for 35 minutes.

[0115] In step (3), the electric field conditions are: electric field intensity 18 kV / cm, pulse frequency 300 Hz, pulse width 35 μs.

[0116] In step (3), the process conditions for the stirring reaction are: stirring the reaction at 350 r / min for 2.5 hours.

[0117] In step (4), the chitosan modified activated carbon is prepared by the following method: first, 0.9 kg of chitosan is dissolved in 10 kg of 0.5% acetic acid solution, then 3.5 kg of medicinal activated carbon is added, and the mixture is stirred at 350 r / min for 1.5 hours to obtain a suspension; then the suspension is poured into 51 kg of 50% sodium carbonate solution, stirred at 350 r / min for 3.5 hours, and allowed to stand for 35 minutes under an electric field of 3 V / cm, separated into layers, and a precipitate is obtained; the precipitate is washed with distilled water until it is neutral, and vacuum dried at 65° C. for 46 hours to obtain the obtained product.

[0118] In step (4), the mass ratio of the supernatant to the chitosan-modified activated carbon is 100:1.5.

[0119] In step (4), the stirring decolorization process conditions are: stirring at 400 r / min for 35 minutes.

[0120] In step (4), a 0.22 μm microporous filter is used for filtration and sterilization.

[0121] In step (4), the process conditions of microwave pretreatment are: 400 W microwave treatment for 35 seconds, stop for 10 seconds, and repeat this cycle 4 times.

[0122] In step (4), the process conditions for vacuum freeze drying are: first cool to -45°C at 0.6°C / min, keep warm for 3.5 hours, evacuate to 11 Pa, then heat to 34°C at 0.7°C / min, and keep warm for 3.5 hours.

[0123] Comparative Example 1

[0124] A method for preparing hydrocortisone sodium succinate lyophilized powder injection for injection, the specific steps are as follows:

[0125] (1) First, 1 kg of hydrocortisone succinate and 1.5 kg of acetone are uniformly vibrated by ultrasonic wave to obtain a suspension;

[0126] (2) 0.2 kg of sodium bicarbonate, 0.08 kg of disodium hydrogen phosphate, 0.02 kg of sodium dihydrogen phosphate and 6 kg of water for injection were stirred and mixed to obtain a saline solution;

[0127] (3) Then, the salt solution is slowly added to the suspension at a uniform speed while stirring, the reaction is stirred under electric field conditions, and the supernatant is collected by centrifugation;

[0128] (4) Finally, chitosan-modified activated carbon is added to the supernatant, stirred for decolorization, filtered to remove the chitosan-modified activated carbon, sterilized, microwave pre-treated, vacuum freeze-dried, and aseptically packaged.

[0129] Wherein, in step (1), the process conditions of ultrasonic oscillation are: 400W ultrasonic oscillation treatment for 30 minutes.

[0130] In step (3), the electric field conditions are: electric field intensity 15 kV / cm, pulse frequency 200 Hz, pulse width 30 μs.

[0131] In step (3), the process conditions for the stirring reaction are: stirring the reaction at 300 r / min for 2 hours.

[0132] In step (4), the chitosan modified activated carbon is prepared by the following method: first, 0.8 kg of chitosan is dissolved in 10 kg of 0.5% acetic acid solution, then 3 kg of medicinal activated carbon is added, and the mixture is stirred at 300 r / min for 1 hour to obtain a suspension; then the suspension is poured into 50 kg of 45% sodium carbonate solution, stirred at 300 r / min for 3 hours, and allowed to stand for 30 minutes under an electric field of 2 V / cm, separated into layers, and a precipitate is obtained; the precipitate is washed with distilled water until it is neutral, and vacuum dried at 60° C. for 45 hours to obtain the obtained product.

[0133] In step (4), the mass ratio of the supernatant to the chitosan-modified activated carbon is 100:1.

[0134] In step (4), the stirring decolorization process conditions are: stirring at 300 r / min for 30 minutes.

[0135] In step (4), a 0.22 μm microporous filter is used for filtration and sterilization.

[0136] In step (4), the process conditions of microwave pretreatment are: 300 W microwave treatment for 30 seconds, stop for 10 seconds, and repeat this cycle 3 times.

[0137] In step (4), the process conditions for vacuum freeze drying are: first cool to -40°C at 0.6°C / min, keep warm for 3 hours, evacuate to 10Pa, then heat to 33°C at 0.6°C / min, and keep warm for 3 hours.

[0138] Comparative Example 2

[0139] A method for preparing hydrocortisone sodium succinate lyophilized powder injection for injection, the specific steps are as follows:

[0140] (1) firstly ultrasonically oscillate 1 kg of hydrocortisone succinate, 0.1 kg of graphene-carbon nanotube composite material and 1.5 kg of acetone to obtain a suspension;

[0141] (2) 0.2 kg of sodium bicarbonate, 0.08 kg of disodium hydrogen phosphate, 0.02 kg of sodium dihydrogen phosphate and 6 kg of water for injection were stirred and mixed to obtain a saline solution;

[0142] (3) Then, the salt solution is slowly added to the suspension at a uniform rate while stirring, the reaction is stirred at 25°C, and the supernatant is collected by centrifugation;

[0143] (4) Finally, chitosan-modified activated carbon is added to the supernatant, stirred for decolorization, filtered to remove the chitosan-modified activated carbon, sterilized, microwave pre-treated, vacuum freeze-dried, and aseptically packaged.

[0144] Wherein, in step (1), the graphene-carbon nanotube composite material is obtained by the following preparation method: first, 0.2 kg of graphene oxide, 0.002 kg of carbon nanotubes, and 0.0002 kg of sodium dodecyl sulfate are added to 0.9 kg of deionized water, and ultrasonically dispersed at 100 W for 30 minutes to obtain a suspension, and spray-dried to obtain a powder, and then the powder is placed in a tube furnace, reduced, and washed alternately with distilled water and anhydrous ethanol for 3 times to obtain the obtained product.

[0145] The graphene oxide is prepared by using 50-mesh graphite powder as a raw material through an improved Hummers method; the specific method is as follows: first, 0.2 kg of graphite powder, 0.1 kg of potassium persulfate and 0.1 kg of phosphorus pentoxide are added to 1.5 kg of 98% concentrated sulfuric acid at 80°C, stirred evenly, cooled naturally to room temperature, washed with distilled water until neutral, and dried to obtain a solid; then the solid is added to 1.5 kg of 98% concentrated sulfuric acid at 0°C, and then 0.6 kg of potassium permanganate is added, and the mixture is stirred at 30°C for 2 hours, 9.5 kg of deionized water is added slowly at a uniform speed for 40 minutes, and then 0.25 kg of 5% hydrogen peroxide solution is added, stirred and mixed, and the residue is filtered out by suction, and the residue is washed 3 times with a 10% hydrochloric acid solution, and vacuum dried at 50°C for 45 hours to obtain the obtained product.

[0146] The process conditions of spray drying are: pressure 3MPa, air inlet temperature 110℃, and air outlet temperature 70℃.

[0147] The process conditions of the reduction treatment are as follows: first, heat to 500°C in a nitrogen atmosphere, keep warm for 5 hours, cool to room temperature with the furnace, pass hydrogen into the tubular furnace at 60 mL / min for 5 minutes, exhaust the nitrogen atmosphere in the tubular furnace, heat to 750°C, keep warm for 5 hours, and naturally cool to room temperature in a hydrogen atmosphere.

[0148] In step (1), the process conditions of ultrasonic oscillation are: 400W ultrasonic oscillation treatment for 30 minutes.

[0149] In step (3), the process conditions for the stirring reaction are: stirring the reaction at 300 r / min for 2 hours.

[0150] In step (4), the chitosan modified activated carbon is prepared by the following method: first, 0.8 kg of chitosan is dissolved in 10 kg of 0.5% acetic acid solution, then 3 kg of medicinal activated carbon is added, and the mixture is stirred at 300 r / min for 1 hour to obtain a suspension; then the suspension is poured into 50 kg of 45% sodium carbonate solution, stirred at 300 r / min for 3 hours, and allowed to stand for 30 minutes under an electric field of 2 V / cm, separated into layers, and a precipitate is obtained; the precipitate is washed with distilled water until it is neutral, and vacuum dried at 60° C. for 45 hours to obtain the obtained product.

[0151] In step (4), the mass ratio of the supernatant to the chitosan-modified activated carbon is 100:1.

[0152] In step (4), the stirring decolorization process conditions are: stirring at 300 r / min for 30 minutes.

[0153] In step (4), a 0.22 μm microporous filter is used for filtration and sterilization.

[0154] In step (4), the process conditions of microwave pretreatment are: 300 W microwave treatment for 30 seconds, stop for 10 seconds, and repeat this cycle 3 times.

[0155] In step (4), the process conditions for vacuum freeze drying are: first cool to -40°C at 0.6°C / min, keep warm for 3 hours, evacuate to 10Pa, then heat to 33°C at 0.6°C / min, and keep warm for 3 hours.

[0156] Comparative Example 3

[0157] A method for preparing hydrocortisone sodium succinate lyophilized powder injection for injection, the specific steps are as follows:

[0158] (1) firstly ultrasonically oscillate 1 kg of hydrocortisone succinate, 0.1 kg of graphene-carbon nanotube composite material and 1.5 kg of acetone to obtain a suspension;

[0159] (2) 0.2 kg of sodium bicarbonate, 0.08 kg of disodium hydrogen phosphate, 0.02 kg of sodium dihydrogen phosphate and 6 kg of water for injection were stirred and mixed to obtain a saline solution;

[0160] (3) Then, the salt solution is slowly added to the suspension at a uniform speed while stirring, the reaction is stirred under electric field conditions, and the supernatant is collected by centrifugation;

[0161] (4) Finally, add medicinal activated carbon (purchased from Xiamen Tongke Activated Carbon Co., Ltd.) to the supernatant, stir to decolorize, filter to remove the chitosan-modified activated carbon, sterilize, microwave pretreatment, vacuum freeze-dry, and aseptically package.

[0162] Wherein, in step (1), the graphene-carbon nanotube composite material is obtained by the following preparation method: first, 0.2 kg of graphene oxide, 0.002 kg of carbon nanotubes, and 0.0002 kg of sodium dodecyl sulfate are added to 0.9 kg of deionized water, and ultrasonically dispersed at 100 W for 30 minutes to obtain a suspension, and spray-dried to obtain a powder, and then the powder is placed in a tube furnace, reduced, and washed alternately with distilled water and anhydrous ethanol for 3 times to obtain the obtained product.

[0163] The graphene oxide is prepared by using 50-mesh graphite powder as a raw material through an improved Hummers method; the specific method is as follows: first, 0.2 kg of graphite powder, 0.1 kg of potassium persulfate and 0.1 kg of phosphorus pentoxide are added to 1.5 kg of 98% concentrated sulfuric acid at 80°C, stirred evenly, cooled naturally to room temperature, washed with distilled water until neutral, and dried to obtain a solid; then the solid is added to 1.5 kg of 98% concentrated sulfuric acid at 0°C, and then 0.6 kg of potassium permanganate is added, and the mixture is stirred at 30°C for 2 hours, 9.5 kg of deionized water is added slowly at a uniform speed for 40 minutes, and then 0.25 kg of 5% hydrogen peroxide solution is added, stirred and mixed, and the residue is filtered out by suction, and the residue is washed 3 times with a 10% hydrochloric acid solution, and vacuum dried at 50°C for 45 hours to obtain the obtained product.

[0164] The process conditions of spray drying are: pressure 3MPa, air inlet temperature 110℃, and air outlet temperature 70℃.

[0165] The process conditions of the reduction treatment are as follows: first, heat to 500°C in a nitrogen atmosphere, keep warm for 5 hours, cool to room temperature with the furnace, pass hydrogen into the tubular furnace at 60 mL / min for 5 minutes, exhaust the nitrogen atmosphere in the tubular furnace, heat to 750°C, keep warm for 5 hours, and naturally cool to room temperature in a hydrogen atmosphere.

[0166] In step (1), the process conditions of ultrasonic oscillation are: 400W ultrasonic oscillation treatment for 30 minutes.

[0167] In step (3), the electric field conditions are: electric field intensity 15 kV / cm, pulse frequency 200 Hz, pulse width 30 μs.

[0168] In step (3), the process conditions for the stirring reaction are: stirring the reaction at 300 r / min for 2 hours.

[0169] In step (4), the mass ratio of the supernatant to the medicinal activated carbon is 100:1.

[0170] In step (4), the stirring decolorization process conditions are: stirring at 300 r / min for 30 minutes.

[0171] In step (4), a 0.22 μm microporous filter is used for filtration and sterilization.

[0172] In step (4), the process conditions of microwave pretreatment are: 300 W microwave treatment for 30 seconds, stop for 10 seconds, and repeat this cycle 3 times.

[0173] In step (4), the process conditions for vacuum freeze drying are: first cool to -40°C at 0.6°C / min, keep warm for 3 hours, evacuate to 10Pa, then heat to 33°C at 0.6°C / min, and keep warm for 3 hours.

[0174] The yield and purity of hydrocortisone sodium succinate obtained in Examples 1 to 4 and Comparative Examples 1 to 3 are shown in Table 1.

[0175] Table 1. Comparison of yield and purity

[0176] Yield (%) purity(%) Example 1 99.1 99.8 Example 2 99.2 99.8 Example 3 99.4 ≥99.9 Example 4 99.6 ≥99.9 Comparative Example 1 90.1 99.1 Comparative Example 2 90.8 99.2 Comparative Example 3 99.1 95.1

[0177] It can be seen from Table 1 that the preparation methods of Examples 1 to 4 have high yields and high product purity.

[0178] In Comparative Example 1, the graphene-carbon nanotube composite material was omitted, and in Comparative Example 2, no electric field was applied during the stirring reaction in step (3), and the yield was significantly reduced, indicating that the graphene-carbon nanotube composite material and the electric field synergistically promoted the salt-forming reaction; in Comparative Example 3, medicinal activated carbon was used to replace chitosan-modified activated carbon, and the product purity was significantly deteriorated, indicating that chitosan-modified activated carbon has better decolorization and impurity removal effects.

[0179] Hydrocortisone sodium succinate was obtained in Examples 1 to 4 and Comparative Example 3, and the moisture content was measured according to the first method (Fischer method) recorded in the 2020 edition of the Chinese Pharmacopoeia, and the re-dissolution time was measured. The test results are shown in Table 2.

[0180] Table 2. Water content and solubility test results

[0181] Water content (%) Reconstitution time (s) Example 1 0.3 ＜5 Example 2 0.4 ＜5 Example 3 0.2 ＜5 Example 4 0.2 ＜5 Comparative Example 3 2.2 8

[0182] It can be seen from Table 2 that the hydrocortisone sodium succinate obtained in Examples 1 to 4 has a low water content and a short re-dissolution time.

[0183] In comparative example 3, chitosan-modified activated carbon was replaced with medicinal activated carbon, and the water content was significantly increased and the re-dissolution time was prolonged, indicating that chitosan-modified activated carbon helps to improve the subsequent drying effect and may also improve the microstructure of hydrocortisone sodium succinate and improve its re-dissolution property.

[0184] Although the above describes the specific implementation methods of the present invention, it does not limit the scope of protection of the present invention. Based on the technical solution of the present invention, various modifications or variations that can be made by those skilled in the art without creative work are still within the scope of protection of the present invention.

Claims

1. A method for preparing hydrocortisone sodium succinate lyophilized powder injection for injection, characterized in that: The specific steps are as follows: (1) firstly ultrasonically oscillate hydrocortisone succinate, graphene-carbon nanotube composite material and acetone to obtain a suspension; (2) stirring and mixing sodium bicarbonate, disodium hydrogen phosphate, sodium dihydrogen phosphate and water for injection to obtain a saline solution; (3) Then, the salt solution is slowly added to the suspension at a uniform speed while stirring, the reaction is stirred under electric field conditions, and the supernatant is collected by centrifugation; (4) finally, chitosan-modified activated carbon is added to the supernatant, stirred for decolorization, the chitosan-modified activated carbon is removed by filtration, sterilized, microwave pre-treated, vacuum freeze-dried, and aseptically packaged; In step (1), the graphene-carbon nanotube composite material is obtained by the following preparation method, in parts by weight: first, 10 parts of graphene oxide, 0.1-0.2 parts of carbon nanotubes, and 0.01-0.02 parts of sodium dodecyl sulfate are added to 45-55 parts of deionized water, and ultrasonically dispersed at 100-200W for 30-40 minutes to obtain a suspension, and spray-dried to obtain a powder, and then the powder is placed in a tube furnace, reduced, and washed alternately with distilled water and anhydrous ethanol for 3-4 times to obtain the obtained product; In step (1), the mass ratio of hydrocortisone succinate, graphene-carbon nanotube composite material and acetone is 1:0.1-0.2:1.5-2; In step (2), the mass ratio of sodium bicarbonate, disodium hydrogen phosphate, sodium dihydrogen phosphate and water for injection is 0.2-0.22:0.08-0.1:0.02-0.03:6-8; In step (3), the mass ratio of the sodium bicarbonate contained in the salt solution to the hydrocortisone succinate contained in the suspension is 0.2 to 0.22:1; In step (3), the electric field conditions are: electric field strength 15-20 kV / cm, pulse frequency 200-300 Hz, pulse width 30-40 μs; The process conditions of the stirring reaction are: stirring reaction at 300-400 r / min for 2-3 hours; In step (4), the chitosan-modified activated carbon is prepared by the following method, based on parts by weight: first, 8 to 10 parts of chitosan are dissolved in 100 parts of 0.5% acetic acid solution, then 30 to 40 parts of medicinal activated carbon are added, and stirred at 300 to 400 r / min for 1 to 2 hours to obtain a suspension; then the suspension is poured into 500 to 520 parts of 45 to 55% sodium carbonate solution, stirred at 300 to 400 r / min for 3 to 4 hours, and allowed to stand for 30 to 40 minutes under an electric field of 2 to 3 V / cm, separated into layers, and a precipitate is obtained; the precipitate is washed with distilled water until it is neutral, and vacuum dried at 60 to 70° C. for 45 to 48 hours to obtain the obtained product; The mass ratio of supernatant to chitosan modified activated carbon is 100:1-2.

2. The preparation method according to claim 1, characterized in that: In step (1), the process conditions of ultrasonic oscillation are: 400-500W ultrasonic oscillation treatment for 30-40 minutes.

3. The preparation method according to claim 1, characterized in that: In step (4), the stirring decolorization process conditions are: stirring at 300-400 r / min for 30-40 minutes; Sterilize by filtering with a 0.22 μm micropore filter.

4. The preparation method according to claim 1, characterized in that: In step (4), the process conditions of microwave pretreatment are: 300-400W microwave treatment for 30-40s, stop for 10s, and repeat this cycle 3-4 times; The process conditions of vacuum freeze drying are: first cool down to -40-50°C at 0.6-0.7°C / min, keep warm for 3-4 hours, evacuate to 10-12 Pa, then heat up to 33-35°C at 0.6-0.7°C / min, and keep warm for 3-4 hours.