Contrast agent powder injection, preparation method therefor, and use thereof

Abstract

A contrast agent powder injection capable of forming a supersaturated solution in absolute ethanol, comprising a contrast agent and a crystallization inhibitor. The contrast agent powder injection is an amorphous product, and can significantly increase the solubility of the contrast agent in absolute ethanol. In the contrast agent powder injection, the crystallization inhibitor can increase the stability of the supersaturated solution, change the viscosity of the supersaturated ethanol solution, and prolong the retention time in the blood vessel. Further provided are a preparation method for and use of the contrast agent powder injection. The contrast agent powder injection can achieve real-time and dynamic monitoring of the flowing direction of absolute ethanol and prevent ethanol from overflowing into normal tissues with the help of digital subtraction angiography and other instruments in the sclerotherapy process, thereby achieving the effects of precise and visualized treatment and reduction of treatment risks and complications. Meanwhile, the viscosity of the ethanol solution can be increased, prolonging the contact time with the blood vessel wall and the acting time and enhancing the efficacy of ethanol sclerotherapy.

Description

A developer powder injection and its preparation method and use Technical Field

[0001] The present disclosure relates to the technical field of developer powder injections, and in particular to a developer powder injection capable of forming a supersaturated solution in anhydrous ethanol, and a preparation method and application thereof. Background Art

[0002] Hemangiomas and vascular malformations are common clinical diseases. Current clinical treatment methods mainly include surgical resection, electrochemical therapy, cryotherapy, laser therapy, and sclerotherapy intervention. Among them, sclerotherapy is the most effective means of treating vascular malformations. Sclerotherapy refers to the injection of certain drugs into the lumen of the blood vessels to destroy the endothelial cells of the lumen, thereby causing fibrosis of the lumen wall and achieving the effect of completely blocking the lumen. With the development of imaging technology, more and more scholars recommend the use of ultrasound-guided sclerosant injection for patients with head and neck vascular malformations. This can not only accurately locate the lesion, but also improve the accuracy of puncture and reduce the incidence of postoperative complications.

[0003] Anhydrous ethanol is recognized as the most effective chemical sclerosant. It is often used as a liquid embolic agent in clinical practice. It can diffuse fully within abnormal vascular masses, has significant effects in treating venous malformations and arteriovenous malformations, has a low recurrence rate, and can quickly destroy vascular endothelial cells. Although anhydrous ethanol has the strongest therapeutic effect, it also has the most serious side effects. Common complications of anhydrous ethanol embolization for arteriovenous malformations include local and systemic symptoms or damage. Considering the problem that anhydrous ethanol cannot be monitored during use, clinical studies have shown that anhydrous ethanol can be mixed with a certain proportion of iodized oil for embolization, which can be traced during use and also has a hardening effect. The preparation method of iodized oil-ethanol emulsifier requires repeated aspiration or placement in a medical vortex oscillator to ensure sufficient emulsification, and it is prepared before clinical use.

[0004] The embolic effect of ethanol is related to its concentration. The results of the examples in CN 111840265 A show that the embolic effect increases with the volume fraction of anhydrous ethanol. When the volume fraction of anhydrous ethanol is 70% and the volume fraction of water is 30%, the embolic effect (embolization rate) is only 25%. However, when the volume fraction of anhydrous ethanol reaches 90% and the volume fraction of water is 10%, the embolic effect reaches 90%. This shows that the hardening and embolic ability of ethanol is related to its purity (water content), and the introduction of water greatly affects the hardening ability of ethanol. Summary of the Invention

[0005] In one aspect, the present disclosure provides a pharmaceutical composition comprising a contrast agent, a crystallization inhibitor, and the like. Upon dissolution of the composition by adding a desired amount of anhydrous ethanol, a supersaturated solution can be formed. By varying the amount of anhydrous ethanol added and adjusting the solution concentration and viscosity, the retention time of the agent in malformed blood vessels can be prolonged, extending the duration of ethanol embolization. This pharmaceutical composition can be clinically applied to visualize anhydrous ethanol embolization therapy for vascular abnormalities. This composition is amorphous.

[0006] In another aspect, the present disclosure provides a developing powder injection capable of forming a supersaturated solution in anhydrous ethanol, comprising a contrast agent, a crystallization inhibitor, and the like. In the pharmaceutical composition, the crystallization inhibitor is a physiologically inert, non-toxic, and chemically stable material acceptable to the human body, such as polyethylene glycols (PEG), polyvinylpyrrolidone (PVP), surfactants (e.g., poloxamers), cellulose derivatives (e.g., HPC, HPMC), sugars (e.g., chitosan, sucrose), and organic acids (e.g., citric acid, succinic acid). Furthermore, the crystallization inhibitor can be selected from one or more of polyethylene glycol, poloxamer, and povidone.

[0007] Furthermore, in the pharmaceutical composition, the crystallization inhibitor is an excipient that is readily soluble in both water and anhydrous ethanol. This allows for the elimination of large particles during the preparation of lyophilized solutions and injection of supersaturated ethanol solutions, does not affect the filtration and sterilization of aqueous solutions, and prevents the inhibitor from becoming difficult to dissolve or causing damage and clogging of normal capillaries after entering the human body. Examples include polyethylene glycols (PEG), polyvidones (PVP), and surfactants (such as poloxamer), with polyvidone (PVP) being preferred.

[0008] Furthermore, the crystallization inhibitor is preferably povidone PVP. Furthermore, among various types of PVP, PVP K12 is preferred.

[0009] The contrast agent powder injection can significantly increase the solubility of the contrast agent in anhydrous ethanol, increase the viscosity of the anhydrous ethanol solution, prolong the residence time in the diseased blood vessels, enhance the hardening effect, and monitor the movement of ethanol in real time while exerting the embolization effect, achieving the purpose of visualization, enabling precise treatment, enhancing drug efficacy, and improving the safety during the use of anhydrous ethanol.

[0010] Furthermore, in the pharmaceutical composition, the ratio of the developer to the crystallization inhibitor is in the range of 3:1 to 1:5. Furthermore, the ratio of the developer to the crystallization inhibitor is in the range of 2.5:1 to 1:3, 2:1 to 1:2, 2:1 to 1:1, 1.5:1 to 1:0.5, etc. Furthermore, the ratio of the developer to the crystallization inhibitor is preferably 2:1, 1:1, or 1:2.

[0011] The pharmaceutical composition or developing powder injection provided by the present disclosure contains 0.5-1.5g, preferably 0.5-1g, of the developing agent API, such as iopromide, per unit of product; and 1-3g, more preferably 1-2g, of the crystallization inhibitor povidone per unit of product.

[0012] The pharmaceutical composition or developing powder injection provided herein can be packaged in conventional containers, such as vials. If packaged in vials, the drug content per unit of product referred to herein refers to the drug content per vial. The packaging container can be a conventional glass vial in the art, preferably a 20 ml vial, and the pharmaceutical composition can be packaged in any quantity.

[0013] On the other hand, the present disclosure also provides a method for preparing the pharmaceutical composition or developing powder injection.

[0014] The composition or developer powder injection can be prepared by freeze-drying. Specifically, a certain proportion of the crystallization inhibitor and developer is dissolved in water for injection, filtered through a microporous filter membrane or other sterilizing particulate filter, and then packaged into vials. The vials are freeze-dried and sealed with a rubber stopper to control the residual moisture content to less than 5%.

[0015] The composition or developer powder injection can be prepared using a spray drying method. Specifically, a certain proportion of a crystallization inhibitor and a developer are dissolved in water for injection to prepare a solution with a concentration of 5% to 50% by weight. After filtration and sterilization, the solution is spray-dried in a sterile workshop using a spray dryer to obtain a solid powder with a residual moisture content of less than 5%. The powder is then packaged into vials, sealed with rubber stoppers, and capped with aluminum caps.

[0016] The preparation method of the pharmaceutical composition is preferably freeze-drying.

[0017] In the freeze-drying method for the pharmaceutical composition, a preferred freeze-drying curve is: the sample is pre-frozen to -35±5°C and held for 4 hours, evacuated to a vacuum of 350 mTorr and maintained at -35±5°C for 1 hour, heated to -20°C within 2.5 hours and maintained for 4 hours, heated to -10°C within 2.5 hours and maintained for 4.5 hours, heated to 0°C within 2.5 hours and maintained for 4.5 hours, heated to 20°C within 2 hours and maintained for 3 hours, heated to 30°C within 2 hours and maintained for 2 hours, heated to 45°C within 2 hours and maintained for 3 hours, and maintained at a vacuum of 350 mTorr during this process. The product is then plugged, removed, and covered with an aluminum cap to obtain a product with a moisture content of <5%.

[0018] In the preparation method provided by the present disclosure, the sterilization requirements are as follows: the sterile raw materials and auxiliary materials are dissolved in injection water, filtered through a filter membrane and then filled, and freeze-dried or spray-dried under sterile production conditions. The sterile raw materials and auxiliary materials are preferably injection-grade developer raw materials, BASF injection-grade povidone K12.

[0019] The present disclosure also provides uses of the pharmaceutical composition or developer powder injection, including as an anhydrous ethanol developer hardener. Specifically, the pharmaceutical composition or developer powder injection disclosed herein can be applied to the improvement of traditional DSA-guided sclerotherapy, thereby overcoming the shortcomings of traditional methods that cannot accurately reflect the volume of the lesion, the hardener cannot completely replace the contrast agent, or the hardener overflows the lesion cavity into the normal tissue site. Without affecting the development effect, the purpose of more accurate filling of the lesion, improving the treatment effect, reducing the occurrence of complications, and being convenient and fast is achieved. At room temperature (25°C), the solubility of developers such as iopromide in anhydrous ethanol is only 10 mg / ml. Under DSA, the minimum concentration for clear imaging needs to reach 68 mg / ml. The developer powder injection disclosed herein is an amorphous product with a maximum solubility of 1 g / ml in anhydrous ethanol, forming a supersaturated solution. Because it is unstable in anhydrous ethanol and precipitates in about 5-10 minutes, the stability of the supersaturated solution is increased by adding a certain amount of crystallization inhibitor.

[0020] Beneficial Effects: The disclosed pharmaceutical composition or developer powder injection can be used with anhydrous ethanol without dilution, without affecting the embolic effect of the anhydrous ethanol. Its stability meets clinical requirements, and after injection, it is evenly distributed within the lumen. Adjusting the viscosity based on the injection site can reduce the degree of dilution of the anhydrous ethanol by the blood, making it less susceptible to erosion by high-velocity blood. This prolongs its residence time and duration of action within the lumen, allowing a lower dose of anhydrous ethanol to achieve a good therapeutic effect.

[0021] The high-viscosity solution disclosed herein can reduce the infiltration of anhydrous ethanol into normal tissue surrounding the lesion, maximally protecting normal tissue function and reducing the occurrence of complications. The X-ray blocking capability of the composite formulation can also be adjusted according to specific clinical requirements by adjusting the content of iopromide in anhydrous ethanol. For oral and maxillofacial arteriovenous malformations, the conventional two-step drug administration is combined into a single step of simultaneous imaging and hardening, making it more economical than previous methods, improving embolization effectiveness, being safer, and having fewer side effects, thus having broad application prospects.

[0022] The disclosed developer powder injection is amorphous and can form a supersaturated solution in anhydrous ethanol. When administered in vitro, the anhydrous ethanol is administered undiluted, resulting in a superior embolic effect. A crystallization inhibitor is used to modify the solution viscosity, prolonging the contact time between the ethanol and the diseased blood vessels and minimizing dilution by the blood upon entry into the body.

[0023] The developer powder injection disclosed herein forms a supersaturated solution in anhydrous ethanol. While having a strong sclerotic and embolic effect, the movement of anhydrous ethanol can be monitored under imaging equipment during use. This prevents the ethanol from accidentally entering normal tissues such as nerves, muscles, or connective tissues during use, especially from accidentally entering blood supply arteries and causing irreversible damage, thereby reducing the difficulty of surgical operations and improving safety.

[0024] The dosage of each component of the preparation disclosed herein can be adjusted as needed to prepare an anhydrous ethanol hardener with a certain viscosity, thereby reducing the degree of dilution of anhydrous ethanol by blood, thereby increasing its retention time in the target blood vessels and enhancing the efficacy.

[0025] The preparation method disclosed herein is simple and highly stable, and is applicable to a series of developer products, facilitating large-scale production and storage. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] In order to more clearly illustrate the technical solutions in the present invention or the prior art, the following briefly introduces the drawings required for use in the embodiments or the description of the prior art. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0027] Figure 1 is a full UV scan of PVPK12 and iopromide APIs.

[0028] FIG2 is the result of visual observation of a supersaturated solution of 0.2 g / ml iopromide lyophilized powder in anhydrous ethanol.

[0029] FIG3 shows the microscopic observation results of a supersaturated solution of 0.2 g / ml iopromide lyophilized powder in anhydrous ethanol.

[0030] FIG4 shows the concentration change of the supernatant after centrifugation of a 0.2 g / ml iopromide anhydrous ethanol supersaturated solution.

[0031] Figure 5 shows the dissolution effect of PVPK12 as a crystallization inhibitor.

[0032] FIG6 shows the variation trend of absorbance under Experimental Example 1.

[0033] FIG7 is a diagram showing the development effect of supersaturated iopromide ethanol solutions of different concentrations under Guangzhou Boluteng small animal imaging X-ray in Experimental Example 3.

[0034] FIG8 is a graph showing the effects of administering 0.2 ml of anhydrous ethanol to the tail in Experimental Example 4 immediately, 3 days, 10 days, and 20 days later.

[0035] FIG9 is a diagram showing the effect of tail administration of 0.2 ml of a supersaturated solution of iopromide in anhydrous ethanol at 40.2 g / ml in Experimental Example.

[0036] FIG10 is a diagram of the interosseous membrane blood vessels of the lower limbs of normal rats in Experimental Example 5 under light illumination.

[0037] FIG11 is a light image of the interosseous membrane blood vessels of the lower limbs of rats in Experimental Example 5 after administration of 0.2 ml of anhydrous ethanol.

[0038] FIG12 is a diagram showing the effect of anhydrous ethanol administration on the interosseous membrane vessels of the lower limbs of rats in Experimental Example 5 after 3 days.

[0039] FIG13 is a light diagram of the administration of 0.2 ml of 0.1 g / ml iopromide ethanol solution to the interosseous membrane of the lower limb of rats in Experimental Example 5.

[0040] FIG14 is a diagram showing the interosseous membrane blood vessels of the lower limbs of rats in Experimental Example 5 3 days after administration of 0.1 g / ml iopromide ethanol solution.

[0041] FIG15 is a light image of the interosseous membrane blood vessels of the lower limbs of rats in Experimental Example 5, in which 0.2 ml of 0.3 g / ml iopromide ethanol solution was administered.

[0042] FIG16 is a diagram showing the interosseous membrane blood vessels of the lower limbs of rats in Experimental Example 5 3 days after administration of 0.3 g / ml iopromide ethanol solution. DETAILED DESCRIPTION

[0043] Based on the above content of the present disclosure, according to the common technical knowledge and customary means in the art, without departing from the above basic technical ideas of the present disclosure, various other forms of modifications, substitutions or changes can be made. It should be noted that the following detailed description is exemplary and is intended to provide further explanation of the present invention. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the present invention belongs.

[0044] It should be noted that the terms used herein are only for describing specific embodiments and are not intended to limit the exemplary embodiments according to the present application. As used herein, unless the context clearly indicates otherwise, the singular form is also intended to include the plural form. In addition, it should be understood that when the terms "comprise" and / or "include" are used in this specification, they indicate the presence of features, steps, operations, devices, components and / or combinations thereof.

[0045] As used herein, “supersaturated” and “supersaturated” have the same meaning and, unless otherwise specified, the two can be used interchangeably throughout the text.

[0046] The “contrast agent” and “developer” used in this disclosure have the same meaning and can be used interchangeably throughout the text unless otherwise specified.

[0047] Unless otherwise stated, all raw materials and reagents used in the present disclosure can be obtained through commercial channels.

[0048] Solubility test of iopromide API and lyophilized powder

[0049] A full UV scan of the iopromide aqueous solution was performed, as shown in Figure 1. In Figure 1, red represents PVP K12, and blue represents the iopromide API. The results show that iopromide has a maximum absorption at λ = 242 nm. Neither PVP K12 nor iopromide exhibits visible absorption at 700 nm, indicating the stability of the supersaturated solution based on the Beer-Lambert law.

[0050] An excess of iopromide API was added to 20 ml of anhydrous ethanol at room temperature and stirred under closed conditions for 24 hours. The mixture was centrifuged at 3000 rpm for 3 minutes, and the supernatant was filtered through a 0.22 μm microporous filter to obtain a filtrate. The filtrate was diluted and the absorbance was measured at 242 nm to calculate the solubility of iopromide API in anhydrous ethanol.

[0051] An excess of iopromide lyophilized powder was added to 5 ml of anhydrous ethanol at room temperature (n=3). Since the lyophilized powder would precipitate quickly in anhydrous ethanol, rapid stirring was performed at 1000 rpm for 3 minutes to promote dissolution. The mixture was centrifuged at 3000 rpm for 3 minutes. The supernatant was filtered through a 0.22 μm microporous membrane to obtain a filtrate. The filtrate was diluted and the absorbance was measured at 242 nm to calculate the solubility of the iopromide lyophilized powder in anhydrous ethanol.

[0052] Experimental results: The solubility of iopromide raw material in anhydrous ethanol is about 10 mg / ml; the solubility of iopromide lyophilized powder in anhydrous ethanol can reach 1 g / ml.

[0053] Stability test of iopromide lyophilized powder solution:

[0054] A 0.2 g / ml supersaturated solution of iopromide lyophilized powder in anhydrous ethanol was prepared. The solution was filtered through a 0.22 μm filter membrane at different time periods. The absorbance of the filtrate was measured after dilution. The amount of iopromide dissolved in anhydrous ethanol at that time point was calculated, and the solution was observed with the naked eye and under a microscope.

[0055] Visual observation of precipitation after complete dissolution of a 0.2 g / ml iopromide supersaturated solution in anhydrous ethanol at 30 minutes, 1 hour, 2 hours, and 4 hours. As shown in Figure 2, the solution turned from clear to turbid, and the amount of precipitated solids increased over time, with sediment forming at the bottom of the vial.

[0056] When crystals precipitate from a supersaturated solution of iopromide in anhydrous ethanol, the solution first becomes turbid and a small amount of solid is deposited at the bottom of the vial. As time goes by, the amount of solid deposited at the bottom increases.

[0057] Figure 3 shows the precipitation of a 0.2 g / ml iopromide-anhydrous ethanol supersaturated solution at 10 min, 15 min, 20 min, 25 min, 30 min, 40 min, 50 min, 60 min, 1.5 h, 2 h, 3 h, and 4 h after complete dissolution. The results show that within the same field of view, the number of solid particles increases over time, the particle size increases, and lumps composed of small crystals appear.

[0058] After the supersaturated solution is dissolved, it precipitates quickly. As time goes by, a large amount of crystals precipitate, and the precipitated crystals accumulate at the bottom of the vial. Under the microscope, with the same lens and magnification, the number of crystals increases, the crystal particle size increases, and aggregation occurs.

[0059] The concentration change of the supernatant after centrifugation of a supersaturated solution of 0.2 g / ml iopromide lyophilized powder in anhydrous ethanol is shown in Figure 4. As can be seen from Figure 4, iopromide precipitates slowly within 0-1 hour, precipitates rapidly within 1-3 hours, and precipitates almost completely within 3-4 hours.

[0060] In summary, iopromide lyophilized powder can form a supersaturated solution with a maximum concentration of about 1 g / ml in anhydrous ethanol, but it precipitates quickly. A crystallization inhibitor needs to be added to stabilize the supersaturated solution and inhibit precipitation.

[0061] Crystallization inhibition effect of povidone in supersaturated ethanol solution

[0062] A lyophilized product of povidone (PVP K12 / K17 / K25 / K30): iopromide (1:1 / 2:1) was dissolved in anhydrous ethanol to form a supersaturated solution of 0.1-0.5 g / ml in anhydrous ethanol. This solution was then dissolved at room temperature and 37°C. The developer powder injection dissolved slowly at room temperature, with no solid precipitation for a period of time. After reaching a clear, transparent state at 37°C, no solid precipitation occurred after cooling to room temperature (Figure 5). Figure 5 shows the dissolution of a 0.2 g / ml supersaturated solution of iopromide in anhydrous ethanol (PVP K12: iopromide = 2:1) at 37°C and room temperature for 10, 15, 20 minutes, 1 hour, 2 hours, and 3 hours (left: 37°C; right: room temperature). The results show that the dissolution rate at 37°C is faster than at room temperature. This suggests that povidone inhibits the crystallization of supersaturated iopromide solutions. PVP effectively inhibits the precipitation of amorphous iopromide in anhydrous ethanol, ensuring the required time for dissolution and clinical injection. Increasing the temperature promotes the dissolution of the amorphous powder injection in anhydrous ethanol. When the ratio of povidone to iopromide is 2:1, the solution remains stable longer than when the ratio of crystallization inhibitor to developer is 1:1.

[0063] The present invention is further described below with reference to the embodiments.

[0064] Example 1

[0065] The ingredients and content of each vial of contrast agent powder injection are as follows: the mass of contrast agent in each vial is 1.5g, and the mass of water for injection is 5ml.

[0066] composition:

[0067] 1.5g developer

[0068] Water for injection 5ml

[0069] Preparation method: Dissolve the developer (iopromide, iohexol, iopamidol, iodixanol, etc.) in water at room temperature to prepare an aqueous solution with a drug concentration of 0.3g / ml, filter through a 0.22μm microporous filter membrane, measure 5ml and dispense it into 20ml penicillin bottles, and freeze-dry.

[0070] Freeze-drying curve: Prefreeze the aliquoted sample to -40±5°C and hold for 4 hours. Evacuate to a vacuum of 350 mTorr and maintain at -40±5°C for 0.5 hours. Raise the temperature to -20°C within 2 hours and hold for 3 hours. Raise the temperature to -10°C within 1 hour and hold for 3 hours. Raise the temperature to 0°C within 2 hours and hold for 3 hours. Raise the temperature to 20°C within 2 hours and hold for 2 hours. Maintain a vacuum of 350 mTorr throughout this process. Press the stopper, remove, and roll the aluminum cap. The moisture content is <5%.

[0071] Example 2

[0072] The ingredients and content of each vial of contrast agent powder injection are as follows: each vial contains 1g of contrast agent, 1g of crystallization inhibitor, and 5ml of water for injection.

[0073] composition:

[0074] Contrast agent (iopromide) 1g

[0075] Crystallization inhibitor (Poloxamer 188) 1g

[0076] Water for injection 5ml

[0077] Preparation method: Poloxamer 188 iodopromide is dissolved in water at room temperature and prepared into an aqueous solution with a drug concentration of 0.2g / ml. It is filtered through a 0.22μm microporous filter membrane, and 5ml is measured and divided into 20ml penicillin bottles and freeze-dried. Freeze-drying curve: The divided samples are pre-frozen to -40±5℃ and maintained for 4h, evacuated to a vacuum degree of 350mTorr and maintained at -40±5℃ for 0.5h, heated to -20℃ within 2h and maintained for 3h, heated to -10℃ within 1h and maintained for 3h, heated to 0℃ within 2h and maintained for 3h, heated to 20℃ within 2h and maintained for 2h. The vacuum is maintained at 350mTorr during this process. Press the plug, take out, and roll the aluminum cover to obtain the product. The water content is <5%

[0078] Example 3

[0079] The ingredients and content of each vial of contrast agent powder injection are as follows: each vial contains 1g of contrast agent, 1g of crystallization inhibitor, and 5ml of water for injection.

[0080] composition:

[0081] Contrast agent (iohexol) 1g

[0082] Crystallization inhibitor (Poloxamer 188) 1g

[0083] Water for injection 5ml

[0084] Preparation method: Poloxamer 188 and iohexol are dissolved in water at room temperature to prepare an aqueous solution with a drug concentration of 0.2 g / ml. The solution is filtered through a 0.22 μm microporous filter membrane, 5 ml of the solution is measured and dispensed into 20 ml vials, and freeze-dried.

[0085] Freeze-drying curve: The packaged samples were pre-frozen to -40±5℃ and maintained for 4 hours, evacuated to a vacuum of 350mTorr and maintained at -40±5℃ for 0.5 hours, heated to -20℃ within 2 hours and maintained for 3 hours, heated to -10℃ within 1 hour and maintained for 3 hours, heated to 0℃ within 2 hours and maintained for 3 hours, heated to 20℃ within 2 hours and maintained for 2 hours. The vacuum was maintained at 350mTorr during this process. The plug was pressed, removed, and the aluminum cover was rolled to obtain the product. The water content was <5%.

[0086] Example 4

[0087] The ingredients and content of each vial of contrast agent powder injection are as follows: each vial contains 1g of contrast agent, 1g of crystallization inhibitor, and 5ml of water for injection.

[0088] composition:

[0089] Contrast agent (iopamidol) 1g

[0090] Crystallization inhibitor (Poloxamer 188) 1g

[0091] Water for injection 5ml

[0092] Preparation method: Poloxamer 188 and iopamidol are dissolved in water at room temperature to prepare an aqueous solution with a drug concentration of 0.2 g / ml. The solution is filtered through a 0.22 μm microporous membrane, 5 ml of the solution is dispensed into 20 ml vials, and freeze-dried.

[0093] Freeze-drying curve: The packaged samples were pre-frozen to -40±5℃ and maintained for 4 hours, evacuated to a vacuum of 350mTorr and maintained at -40±5℃ for 0.5 hours, heated to -20℃ within 2 hours and maintained for 3 hours, heated to -10℃ within 1 hour and maintained for 3 hours, heated to 0℃ within 2 hours and maintained for 3 hours, heated to 20℃ within 2 hours and maintained for 2 hours. The vacuum was maintained at 350mTorr during this process. The plug was pressed, removed, and the aluminum cover was rolled to obtain the product. The water content was <5%.

[0094] Example 5

[0095] The ingredients and content of each vial of contrast agent powder injection are as follows: each vial contains 1g of contrast agent, 1g of crystallization inhibitor, and 5ml of water for injection.

[0096] composition:

[0097] Developer (iodixanol) 1g

[0098] Crystallization inhibitor (Poloxamer 188) 1g

[0099] Water for injection 5ml

[0100] Preparation method: Poloxamer 188 and iodixanol are dissolved in water at room temperature to prepare an aqueous solution with a drug concentration of 0.2 g / ml. The solution is filtered through a 0.22 μm microporous filter membrane, 5 ml of the solution is measured and dispensed into 20 ml vials, and freeze-dried.

[0101] Freeze-drying curve: The packaged samples were pre-frozen to -40±5℃ and maintained for 4 hours, evacuated to a vacuum of 350mTorr and maintained at -40±5℃ for 0.5 hours, heated to -20℃ within 2 hours and maintained for 3 hours, heated to -10℃ within 1 hour and maintained for 3 hours, heated to 0℃ within 2 hours and maintained for 3 hours, heated to 20℃ within 2 hours and maintained for 2 hours. The vacuum was maintained at 350mTorr during this process. The plug was pressed, removed, and the aluminum cover was rolled to obtain the product. The water content was <5%.

[0102] Example 6

[0103] The ingredients and content of each vial of contrast agent powder injection are as follows: 0.75g of contrast agent, 1.5g of crystallization inhibitor, and 5ml of water for injection in each vial.

[0104] composition:

[0105] Developer (iopromide) 0.75g

[0106] Crystallization inhibitor (Poloxamer 188) 1.5g

[0107] Water for injection 5ml

[0108] Preparation method: Poloxamer 188 and iopromide are dissolved in water at room temperature to prepare an aqueous solution with a drug concentration of 0.15g / ml. The solution is filtered through a 0.22μm microporous filter membrane, 5ml of the solution is measured and dispensed into 20ml vials, and freeze-dried.

[0109] Freeze-drying curve: The packaged samples were pre-frozen to -40±5℃ and maintained for 4 hours, evacuated to a vacuum of 350mTorr and maintained at -40±5℃ for 0.5 hours, heated to -20℃ within 2 hours and maintained for 3 hours, heated to -10℃ within 1 hour and maintained for 3 hours, heated to 0℃ within 2 hours and maintained for 3 hours, heated to 20℃ within 2 hours and maintained for 2 hours. The vacuum was maintained at 350mTorr during this process. The plug was pressed, removed, and the aluminum cover was rolled to obtain the product. The water content was <5%.

[0110] Example 7

[0111] The ingredients and content of each vial of contrast agent powder injection are as follows: each vial contains 1g of contrast agent, 1g of crystallization inhibitor, and 5ml of water for injection.

[0112] composition:

[0113] Contrast agent (iopromide) 1g

[0114] Crystallization inhibitor (Poloxamer 407) 1g

[0115] Water for injection 5ml

[0116] Preparation method: Poloxamer 407 and iopromide are dissolved in water at room temperature to prepare an aqueous solution with a drug concentration of 0.2g / ml. The solution is filtered through a 0.22μm microporous membrane, 5ml of the solution is measured and dispensed into 20ml vials, and freeze-dried.

[0117] Freeze-drying curve: Prefreeze the aliquoted sample to -40±5°C and hold for 4 hours. Evacuate to a vacuum of 350 mTorr and maintain at -40±5°C for 0.5 hours. Raise the temperature to -20°C within 2 hours and hold for 3 hours. Raise the temperature to -10°C within 1 hour and hold for 3 hours. Raise the temperature to 0°C within 2 hours and hold for 3 hours. Raise the temperature to 20°C within 2 hours and hold for 2 hours. Maintain a vacuum of 350 mTorr throughout this process. Press the stopper, remove, and roll the aluminum cap. The moisture content is <5%.

[0118] Example 8

[0119] The ingredients and content of each vial of contrast agent powder injection are as follows: each vial contains 1g of contrast agent, 1g of crystallization inhibitor, and 5ml of water for injection.

[0120] composition:

[0121] Contrast agent (iohexol) 1g

[0122] Crystallization inhibitor (Poloxamer 407) 1g

[0123] Water for injection 5ml

[0124] Preparation method: Poloxamer 407 and iohexol are dissolved in water at room temperature to prepare an aqueous solution with a drug concentration of 0.2 g / ml. The solution is filtered through a 0.22 μm microporous membrane, 5 ml of the solution is dispensed into 20 ml vials, and freeze-dried.

[0125] Freeze-drying curve: Prefreeze the aliquoted sample to -40±5°C and hold for 4 hours. Evacuate to a vacuum of 350 mTorr and maintain at -40±5°C for 0.5 hours. Raise the temperature to -20°C within 2 hours and hold for 3 hours. Raise the temperature to -10°C within 1 hour and hold for 3 hours. Raise the temperature to 0°C within 2 hours and hold for 3 hours. Raise the temperature to 20°C within 2 hours and hold for 2 hours. Maintain a vacuum of 350 mTorr throughout this process. Press the stopper, remove, and roll the aluminum cap. The moisture content is <5%.

[0126] Example 9

[0127] The ingredients and content of each vial of contrast agent powder injection are as follows: each vial contains 1g of contrast agent, 1g of crystallization inhibitor, and 5ml of water for injection.

[0128] composition:

[0129] Contrast agent (iopamidol) 1g

[0130] Crystallization inhibitor (Poloxamer 407) 1g

[0131] Water for injection 5ml

[0132] Preparation method: Poloxamer 407 and iopamidol are dissolved in water at room temperature to prepare an aqueous solution with a drug concentration of 0.2 g / ml. The solution is filtered through a 0.22 μm microporous membrane, 5 ml of the solution is dispensed into 20 ml vials, and freeze-dried.

[0133] Freeze-drying curve: Prefreeze the aliquoted sample to -40±5°C and hold for 4 hours. Evacuate to a vacuum of 350 mTorr and maintain at -40±5°C for 0.5 hours. Raise the temperature to -20°C within 2 hours and hold for 3 hours. Raise the temperature to -10°C within 1 hour and hold for 3 hours. Raise the temperature to 0°C within 2 hours and hold for 3 hours. Raise the temperature to 20°C within 2 hours and hold for 2 hours. Maintain a vacuum of 350 mTorr throughout this process. Press the stopper, remove, and roll the aluminum cap. The moisture content is <5%.

[0134] Example 10

[0135] The ingredients and content of each vial of contrast agent powder injection are as follows: each vial contains 1g of contrast agent, 1g of crystallization inhibitor, and 5ml of water for injection.

[0136] composition:

[0137] Developer (iodixanol) 1g

[0138] Crystallization inhibitor (Poloxamer 407) 1g

[0139] Water for injection 5ml

[0140] Preparation method: Poloxamer 407 and iodixanol are dissolved in water at room temperature to prepare an aqueous solution with a drug concentration of 0.2g / ml. The solution is filtered through a 0.22μm microporous membrane, 5ml of the solution is measured and dispensed into 20ml vials, and freeze-dried.

[0141] Freeze-drying curve: Prefreeze the aliquoted sample to -40±5°C and hold for 4 hours. Evacuate to a vacuum of 350 mTorr and maintain at -40±5°C for 0.5 hours. Raise the temperature to -20°C within 2 hours and hold for 3 hours. Raise the temperature to -10°C within 1 hour and hold for 3 hours. Raise the temperature to 0°C within 2 hours and hold for 3 hours. Raise the temperature to 20°C within 2 hours and hold for 2 hours. Maintain a vacuum of 350 mTorr throughout this process. Press the stopper, remove, and roll the aluminum cap. The moisture content is <5%.

[0142] Example 11

[0143] The ingredients and content of each vial of contrast agent powder injection are as follows: 0.75g of contrast agent, 1.5g of crystallization inhibitor, and 5ml of water for injection in each vial.

[0144] composition:

[0145] Developer (iopromide) 0.75g

[0146] Crystallization inhibitor (Poloxamer 407) 1.5g

[0147] Water for injection 5ml

[0148] Preparation method: Poloxamer 407 and iopromide are dissolved in water at room temperature to prepare an aqueous solution with a concentration of 0.15g / ml. The solution is filtered through a 0.22μm microporous membrane, 5ml of the solution is measured and dispensed into 20ml vials, and freeze-dried.

[0149] Freeze-drying curve: The packaged samples were pre-frozen to -40±5℃ and maintained for 4 hours, evacuated to a vacuum of 350mTorr and maintained at -40±5℃ for 0.5 hours, heated to -20℃ within 2 hours and maintained for 3 hours, heated to -10℃ within 1 hour and maintained for 3 hours, heated to 0℃ within 2 hours and maintained for 3 hours, heated to 20℃ within 2 hours and maintained for 2 hours. The vacuum was maintained at 350mTorr during this process. The plug was pressed, removed, and the aluminum cover was rolled to obtain the product. The water content was <5%.

[0150] Example 12

[0151] The ingredients and content of each vial of contrast agent powder injection are as follows: each vial contains 1.5g of contrast agent, 3g of crystallization inhibitor, and 10ml of water for injection.

[0152] composition:

[0153] Developer (iopromide) 1.5g

[0154] Crystallization inhibitor (PEG6000) 3g

[0155] Water for injection 10ml

[0156] Preparation method: PEG6000 and iopromide are dissolved in 10ml of water at room temperature to prepare 10ml of aqueous solution with a drug concentration of 0.15g / ml, filtered through a 0.22μm microporous filter membrane, divided into 20ml penicillin bottles, and freeze-dried. Freeze-drying curve: The divided samples are pre-frozen to -40±5℃ and maintained for 4h, evacuated to a vacuum degree of 350mTorr and maintained at -40±5℃ for 1h, heated to -20℃ within 2h and maintained for 4h, heated to -10℃ within 1h and maintained for 3h, heated to 0℃ within 1h and maintained for 4h, heated to 20℃ within 2h and maintained for 2h, heated to 30℃ within 2h and maintained for 2h, heated to 45℃ within 2h and maintained for 3h. The vacuum is maintained at 350mTorr during this process. Press the plug, remove it, and roll the aluminum cover to obtain the product. The water content is <5%

[0157] Example 13

[0158] The ingredients and content of each vial of contrast agent powder injection are as follows: each vial contains 1.5g of contrast agent, 3g of crystallization inhibitor, and 10ml of water for injection.

[0159] composition:

[0160] Developer (iohexol) 1.5g

[0161] Crystallization inhibitor (PEG6000) 3g

[0162] Water for injection 10ml

[0163] Preparation method: PEG6000 and iohexol are dissolved in 10 ml of water at room temperature to prepare 10 ml of aqueous solution with a drug concentration of 0.15 g / ml. The solution is filtered through a 0.22 μm microporous filter membrane, dispensed into 20 ml vials, and freeze-dried.

[0164] Freeze-drying curve: Prefreeze the aliquoted sample to -40±5°C and hold for 4 hours. Evacuate to a vacuum of 350 mTorr and maintain at -40±5°C for 1 hour. Raise the temperature to -20°C within 2 hours and hold for 4 hours. Raise the temperature to -10°C within 1 hour and hold for 3 hours. Raise the temperature to 0°C within 1 hour and hold for 4 hours. Raise the temperature to 20°C within 2 hours and hold for 2 hours. Raise the temperature to 30°C within 2 hours and hold for 2 hours. Raise the temperature to 45°C within 2 hours and hold for 3 hours. Maintain a vacuum of 350 mTorr throughout this process. Press the stopper, remove, and roll the aluminum cap to obtain the product. The moisture content is <5%.

[0165] Example 14

[0166] The ingredients and content of each vial of contrast agent powder injection are as follows: each vial contains 1.5g of contrast agent, 3g of crystallization inhibitor, and 10ml of water for injection.

[0167] composition:

[0168] Contrast agent (iopamidol) 1.5g

[0169] Crystallization inhibitor (PEG6000) 3g

[0170] Water for injection 10ml

[0171] Preparation method: PEG6000 and iopamidol are dissolved in 10 ml of water at room temperature to prepare 10 ml of an aqueous solution with a drug concentration of 0.15 g / ml. The solution is filtered through a 0.22 μm microporous membrane, dispensed into 20 ml vials, and freeze-dried.

[0172] Freeze-drying curve: Pre-freeze the aliquoted sample to -40±5°C and hold for 4 hours. Evacuate to a vacuum of 350 mTorr and maintain at -40±5°C for 1 hour. Raise the temperature to -20°C within 2 hours and hold for 4 hours. Raise the temperature to -10°C within 1 hour and hold for 3 hours. Raise the temperature to 0°C within 1 hour and hold for 4 hours. Raise the temperature to 20°C within 2 hours and hold for 2 hours. Raise the temperature to 30°C within 2 hours and hold for 2 hours. Raise the temperature to 45°C within 2 hours and hold for 3 hours. Maintain a vacuum of 350 mTorr throughout this process. Press the stopper, remove, and roll the aluminum cap. The moisture content is <5%.

[0173] Example 15

[0174] The ingredients and content of each vial of contrast agent powder injection are as follows: each vial contains 1.5g of contrast agent, 3g of crystallization inhibitor, and 10ml of water for injection.

[0175] composition:

[0176] Developer (iodixanol) 1.5g

[0177] Crystallization inhibitor (PEG6000) 3g

[0178] Water for injection 10ml

[0179] Preparation: PEG6000 and iopromide were dissolved in 10 ml of water at room temperature to prepare a 10 ml aqueous solution with a drug concentration of 0.15 g / ml. The solution was filtered through a 0.22 μm microporous membrane, aliquoted into 20 ml vials, and freeze-dried. Freeze-drying curve: The aliquoted samples were pre-frozen to -40 ± 5°C for 4 hours, evacuated to a vacuum of 350 mTorr and maintained at -40 ± 5°C for 1 hour, then heated to -20°C within 2 hours and maintained for 4 hours, then to -10°C within 1 hour and maintained for 3 hours, then to 0°C within 1 hour and maintained for 4 hours, then to 20°C within 2 hours and maintained for 2 hours, then to 30°C within 2 hours and maintained for 2 hours, and finally to 45°C within 2 hours and maintained for 3 hours. A vacuum of 350 mTorr was maintained throughout the process. The vials were then plugged, removed, and sealed with aluminum caps to yield a water content of <5%.

[0180] Example 16

[0181] The ingredients and content of each vial of contrast agent powder injection are as follows: each vial contains 1.5g of contrast agent, 3g of crystallization inhibitor, and 10ml of water for injection.

[0182] composition:

[0183] Developer (iopromide) 1.5g

[0184] Crystallization inhibitor (PEG4000) 3g

[0185] Water for injection 10ml

[0186] Preparation method: PEG4000 and iopromide are dissolved in water at room temperature to prepare an aqueous solution with a drug concentration of 0.15g / ml, filtered through a 0.22μm microporous filter membrane, 10ml of the solution is measured and dispensed into 20ml vials, and freeze-dried.

[0187] Freeze-drying curve: Prefreeze the aliquoted sample to -40±5°C and hold for 4 hours. Evacuate to a vacuum of 350 mTorr and maintain at -40±5°C for 0.5 hours. Raise the temperature to -20°C within 2 hours and hold for 3 hours. Raise the temperature to -10°C within 1 hour and hold for 3 hours. Raise the temperature to 0°C within 2 hours and hold for 3 hours. Raise the temperature to 20°C within 2 hours and hold for 2 hours. Maintain a vacuum of 350 mTorr throughout this process. Press the stopper, remove, and roll the aluminum cap. The moisture content is <5%.

[0188] Example 17

[0189] The ingredients and content of each vial of contrast agent powder injection are as follows: each vial contains 1.5g of contrast agent, 3g of crystallization inhibitor, and 5ml of water for injection.

[0190] composition:

[0191] Developer (iopromide) 1.5g

[0192] Crystallization inhibitor (PVP K12) 3g

[0193] Water for injection 5ml

[0194] Preparation method: PVPK12 and iopromide are dissolved in an appropriate amount of water for injection to prepare a mixed solution, and water for injection is added to a total volume of 5 ml to prepare an aqueous solution with a drug concentration of 0.3 g / ml. The solution is filtered through a 0.22 μm microporous filter membrane, filled into a 20 ml vial, and freeze-dried.

[0195] Freeze-drying curve: The sample was pre-frozen to -40±5°C and held for 4 hours. The sample was then evacuated to a vacuum of 350 mTorr and maintained at -40±5°C for 0.5 hours. The temperature was then raised to -20°C within 2 hours and held for 3 hours. The temperature was then raised to -10°C within 1 hour and held for 3 hours. The temperature was then raised to 0°C within 2 hours and held for 3 hours. The temperature was then raised to 20°C within 2 hours and held for 2 hours. The vacuum was maintained at 350 mTorr. The sample was then plugged, removed, and covered with an aluminum cap. The moisture content was <5%.

[0196] Example 18

[0197] The ingredients and content of each vial of contrast agent powder injection are as follows: each vial contains 1.5g of contrast agent, 1.5g of crystallization inhibitor, and 10ml of water for injection.

[0198] composition:

[0199] Developer (iopromide) 1.5g

[0200] Crystallization inhibitor (PVP K12) 1.5g

[0201] Water for injection 10ml

[0202] Preparation method: PVP K12 and iopromide are dissolved in an appropriate amount of water for injection at room temperature, and the water for injection is added to a total volume of 10 ml to prepare an aqueous solution with a drug concentration of 0.15 g / ml. The solution is filtered through a 0.22 μm microporous membrane, filled into a 20 ml vial, and freeze-dried.

[0203] Freeze-drying curve: Prefreeze the aliquoted sample to -40±5°C and hold for 4 hours. Evacuate to a vacuum of 350 mTorr and maintain at -40±5°C for 1 hour. Raise the temperature to -20°C within 2 hours and hold for 4 hours. Raise the temperature to -10°C within 1 hour and hold for 3 hours. Raise the temperature to 0°C within 1 hour and hold for 4 hours. Raise the temperature to 20°C within 2 hours and hold for 2 hours. Raise the temperature to 30°C within 2 hours and hold for 2 hours. Raise the temperature to 45°C within 2 hours and hold for 3 hours. Maintain a vacuum of 350 mTorr throughout this process. Press the stopper, remove, and roll the aluminum cap to obtain the product. The moisture content is <5%.

[0204] Example 19

[0205] The ingredients and content of each vial of contrast agent powder injection are as follows: each vial contains 1.5g of contrast agent, 1.5g of crystallization inhibitor, and 10ml of water for injection.

[0206] composition:

[0207] Developer (iohexol) 1.5g

[0208] Crystallization inhibitor (PVP K12) 1.5g

[0209] Water for injection 10ml

[0210] PVP K12 and iohexol were dissolved in an appropriate amount of water for injection at room temperature. Water for injection was added to a total volume of 10 ml to prepare an aqueous solution with a drug concentration of 0.15 g / ml. The solution was filtered through a 0.22 μm microporous membrane, filled into a 20 ml vial, and freeze-dried.

[0211] Freeze-drying curve: Prefreeze the aliquoted sample to -40±5°C and hold for 4 hours. Evacuate to a vacuum of 350 mTorr and maintain at -40±5°C for 1 hour. Raise the temperature to -20°C within 2 hours and hold for 4 hours. Raise the temperature to -10°C within 1 hour and hold for 3 hours. Raise the temperature to 0°C within 1 hour and hold for 4 hours. Raise the temperature to 20°C within 2 hours and hold for 2 hours. Raise the temperature to 30°C within 2 hours and hold for 2 hours. Raise the temperature to 45°C within 2 hours and hold for 3 hours. Maintain a vacuum of 350 mTorr throughout this process. Press the stopper, remove, and roll the aluminum cap to obtain the product. The moisture content is <5%.

[0212] Example 20

[0213] The ingredients and content of each vial of contrast agent powder injection are as follows: each vial contains 1.5g of contrast agent, 1.5g of crystallization inhibitor, and 10ml of water for injection.

[0214] composition:

[0215] Contrast agent (iopamidol) 1.5g

[0216] Crystallization inhibitor (PVP K12) 1.5g

[0217] Water for injection 10ml

[0218] Preparation method: PVP K12 and iopamidol are dissolved in an appropriate amount of water for injection at room temperature, and the water for injection is added to a total volume of 10 ml to prepare an aqueous solution with a drug concentration of 0.15 g / ml. The solution is filtered through a 0.22 μm microporous membrane, filled into a 20 ml vial, and freeze-dried.

[0219] Freeze drying curve: The packaged samples are pre-frozen to -40±5℃ and maintained for 4 hours, evacuated to a vacuum of 350mTorr and maintained at -40±5℃ for 1 hour, heated to -20℃ within 2 hours and maintained for 4 hours, heated to -10℃ within 1 hour and maintained for 3 hours, heated to 0℃ within 1 hour and maintained for 4 hours, heated to 20℃ within 2 hours and maintained for 2 hours, heated to 30℃ within 2 hours and maintained for 2 hours, heated to 45℃ within 2 hours and maintained for 3 hours. The vacuum is maintained at 350mTorr during this process. Press the plug, remove it, and roll the aluminum cover to obtain the product. The water content is less than 5%.

[0220] Example 21

[0221] The ingredients and content of each vial of contrast agent powder injection are as follows: each vial contains 1.5g of contrast agent, 1.5g of crystallization inhibitor, and 10ml of water for injection.

[0222] composition:

[0223] Developer (iodixanol) 1.5g

[0224] Crystallization inhibitor (PVP K12) 1.5g

[0225] Water for injection 10ml

[0226] Preparation method: PVP K12 and iodixanol are dissolved in an appropriate amount of water for injection at room temperature, and water for injection is added to a total volume of 10 ml to prepare an aqueous solution with a drug concentration of 0.15 g / ml. The solution is filtered through a 0.22 μm microporous membrane, filled into a 20 ml vial, and freeze-dried.

[0227] Freeze-drying curve: Prefreeze the aliquoted sample to -40±5°C and hold for 4 hours. Evacuate to a vacuum of 350 mTorr and maintain at -40±5°C for 1 hour. Raise the temperature to -20°C within 2 hours and hold for 4 hours. Raise the temperature to -10°C within 1 hour and hold for 3 hours. Raise the temperature to 0°C within 1 hour and hold for 4 hours. Raise the temperature to 20°C within 2 hours and hold for 2 hours. Raise the temperature to 30°C within 2 hours and hold for 2 hours. Raise the temperature to 45°C within 2 hours and hold for 3 hours. Maintain a vacuum of 350 mTorr throughout this process. Press the stopper, remove, and roll the aluminum cap to obtain the product. The moisture content is <5%.

[0228] Example 22

[0229] The ingredients and content of each vial of contrast agent powder injection are as follows: each vial contains 1.5g of contrast agent, 3g of crystallization inhibitor, and 10ml of water for injection.

[0230] composition:

[0231] Developer (iopromide) 1.5g

[0232] Crystallization inhibitor (PVP K17) 3g

[0233] Water for injection 10ml

[0234] Preparation method: PVP K17 and iopromide are dissolved in an appropriate amount of water for injection to prepare a mixed solution, and water for injection is added to a total volume of 10 ml to prepare an aqueous solution with a drug concentration of 0.15 g / ml. The solution is filtered through a 0.22 μm microporous membrane, filled into a 20 ml vial, and freeze-dried.

[0235] Freeze-drying curve: Prefreeze the aliquoted sample to -40±5°C and hold for 4 hours. Evacuate to a vacuum of 350 mTorr and maintain at -40±5°C for 1 hour. Raise the temperature to -20°C within 2 hours and hold for 4 hours. Raise the temperature to -10°C within 1 hour and hold for 3 hours. Raise the temperature to 0°C within 1 hour and hold for 4 hours. Raise the temperature to 20°C within 2 hours and hold for 2 hours. Raise the temperature to 30°C within 2 hours and hold for 2 hours. Raise the temperature to 45°C within 2 hours and hold for 3 hours. Maintain a vacuum of 350 mTorr throughout this process. Press the stopper, remove, and roll the aluminum cap to obtain the product. The moisture content is <5%.

[0236] Example 23

[0237] The ingredients and content of each vial of contrast agent powder injection are as follows: each vial contains 1.5g of contrast agent, 3g of crystallization inhibitor, and 10ml of water for injection.

[0238] composition:

[0239] Contrast agent (iopamidol) 1.5g

[0240] Crystallization inhibitor (PVP K17) 3g

[0241] Water for injection 10ml

[0242] Preparation method: PVPK17 and iopamidol are dissolved in an appropriate amount of water for injection to prepare a mixed solution, and water for injection is added to a total volume of 10 ml to prepare an aqueous solution with a drug concentration of 0.15 g / ml. The solution is filtered through a 0.22 μm microporous membrane, filled into a 20 ml vial, and freeze-dried.

[0243] Freeze drying curve: The packaged samples are pre-frozen to -40±5℃ and maintained for 4 hours, evacuated to a vacuum of 350mTorr and maintained at -40±5℃ for 1 hour, heated to -20℃ within 2 hours and maintained for 4 hours, heated to -10℃ within 1 hour and maintained for 3 hours, heated to 0℃ within 1 hour and maintained for 4 hours, heated to 20℃ within 2 hours and maintained for 2 hours, heated to 30℃ within 2 hours and maintained for 2 hours, heated to 45℃ within 2 hours and maintained for 3 hours. The vacuum is maintained at 350mTorr during this process. Press the plug, remove it, and roll the aluminum cover to obtain the product. The water content is less than 5%.

[0244] Example 24

[0245] The ingredients and content of each vial of contrast agent powder injection are as follows: each vial contains 1.5g of contrast agent, 3g of crystallization inhibitor, and 10ml of water for injection.

[0246] composition:

[0247] Developer (iohexol) 1.5g

[0248] Crystallization inhibitor (PVP K17) 3g

[0249] Water for injection 10ml

[0250] Preparation method: PVPK17 and iohexol are dissolved in an appropriate amount of water for injection to prepare a mixed solution, and water for injection is added to a total volume of 10 ml to prepare an aqueous solution with a drug concentration of 0.15 g / ml. The solution is filtered through a 0.22 μm microporous filter membrane, filled into a 20 ml vial, and freeze-dried.

[0251] Freeze-drying curve: Prefreeze the aliquoted sample to -40±5°C and hold for 4 hours. Evacuate to a vacuum of 350 mTorr and maintain at -40±5°C for 1 hour. Raise the temperature to -20°C within 2 hours and hold for 4 hours. Raise the temperature to -10°C within 1 hour and hold for 3 hours. Raise the temperature to 0°C within 1 hour and hold for 4 hours. Raise the temperature to 20°C within 2 hours and hold for 2 hours. Raise the temperature to 30°C within 2 hours and hold for 2 hours. Raise the temperature to 45°C within 2 hours and hold for 3 hours. Maintain a vacuum of 350 mTorr throughout this process. Press the stopper, remove, and roll the aluminum cap to obtain the product. The moisture content is <5%.

[0252] Example 25

[0253] The ingredients and content of each vial of contrast agent powder injection are as follows: each vial contains 1.5g of contrast agent, 3g of crystallization inhibitor, and 10ml of water for injection.

[0254] composition:

[0255] Developer (iodixanol) 1.5g

[0256] Crystallization inhibitor (PVP K17) 3g

[0257] Water for injection 10ml

[0258] Preparation method: PVPK17 and iodixanol are dissolved in an appropriate amount of water for injection to prepare a mixed solution, and water for injection is added to a total volume of 10 ml to prepare an aqueous solution with a drug concentration of 0.15 g / ml. The solution is filtered through a 0.22 μm microporous filter membrane, filled into a 20 ml vial, and freeze-dried.

[0259] Freeze-drying curve: Prefreeze the aliquoted sample to -40±5°C and hold for 4 hours. Evacuate to a vacuum of 350 mTorr and maintain at -40±5°C for 1 hour. Raise the temperature to -20°C within 2 hours and hold for 4 hours. Raise the temperature to -10°C within 1 hour and hold for 3 hours. Raise the temperature to 0°C within 1 hour and hold for 4 hours. Raise the temperature to 20°C within 2 hours and hold for 2 hours. Raise the temperature to 30°C within 2 hours and hold for 2 hours. Raise the temperature to 45°C within 2 hours and hold for 3 hours. Maintain a vacuum of 350 mTorr throughout this process. Press the stopper, remove, and roll the aluminum cap to obtain the product. The moisture content is <5%.

[0260] Example 26

[0261] The ingredients and content of each vial of contrast agent powder injection are as follows: each vial contains 1.5g of contrast agent, 3g of crystallization inhibitor, and 10ml of water for injection.

[0262] composition:

[0263] Developer (iopromide) 1.5g

[0264] Crystallization inhibitor (PVP K25) 3g

[0265] Water for injection 10ml

[0266] Preparation method: PVPK25 and iopromide are dissolved in an appropriate amount of water for injection to prepare a mixed solution, and water for injection is added to a total volume of 10 ml to prepare an aqueous solution with a drug concentration of 0.15 g / ml. The solution is filtered through a 0.22 μm microporous membrane, filled into a 20 ml vial, and freeze-dried.

[0267] Freeze-drying curve: Prefreeze the aliquoted sample to -40±5°C and hold for 4 hours. Evacuate to a vacuum of 350 mTorr and maintain at -40±5°C for 1 hour. Raise the temperature to -20°C within 2 hours and hold for 4 hours. Raise the temperature to -10°C within 1 hour and hold for 3 hours. Raise the temperature to 0°C within 1 hour and hold for 4 hours. Raise the temperature to 20°C within 2 hours and hold for 2 hours. Raise the temperature to 30°C within 2 hours and hold for 2 hours. Raise the temperature to 45°C within 2 hours and hold for 3 hours. Maintain a vacuum of 350 mTorr throughout this process. Press the stopper, remove, and roll the aluminum cap to obtain the product. The moisture content is <5%.

[0268] Example 27

[0269] The ingredients and content of each vial of contrast agent powder injection are as follows: each vial contains 1.5g of contrast agent, 3g of crystallization inhibitor, and 10ml of water for injection.

[0270] composition:

[0271] Contrast agent (iopamidol) 1.5g

[0272] Crystallization inhibitor (PVP K25) 3g

[0273] Water for injection 10ml

[0274] Preparation method: PVPK25 and iopamidol are dissolved in an appropriate amount of water for injection to prepare a mixed solution, and water for injection is added to a total volume of 10 ml to prepare an aqueous solution with a drug concentration of 0.15 g / ml. The solution is filtered through a 0.22 μm microporous filter membrane, filled into a 20 ml vial, and freeze-dried.

[0275] Freeze-drying curve: Prefreeze the aliquoted sample to -40±5°C and hold for 4 hours. Evacuate to a vacuum of 350 mTorr and maintain at -40±5°C for 1 hour. Raise the temperature to -20°C within 2 hours and hold for 4 hours. Raise the temperature to -10°C within 1 hour and hold for 3 hours. Raise the temperature to 0°C within 1 hour and hold for 4 hours. Raise the temperature to 20°C within 2 hours and hold for 2 hours. Raise the temperature to 30°C within 2 hours and hold for 2 hours. Raise the temperature to 45°C within 2 hours and hold for 3 hours. Maintain a vacuum of 350 mTorr throughout this process. Press the stopper, remove, and roll the aluminum cap to obtain the product. The moisture content is <5%.

[0276] Example 28

[0277] The ingredients and content of each vial of contrast agent powder injection are as follows: each vial contains 1.5g of contrast agent, 3g of crystallization inhibitor, and 10ml of water for injection.

[0278] composition:

[0279] Developer (iohexol) 1.5g

[0280] Crystallization inhibitor (PVP K25) 3g

[0281] Water for injection 10ml

[0282] Preparation method: PVPK25 and iohexol are dissolved in an appropriate amount of water for injection to prepare a mixed solution, and water for injection is added to a total volume of 10 ml to prepare an aqueous solution with a drug concentration of 0.15 g / ml. The solution is filtered through a 0.22 μm microporous filter membrane, filled into a 20 ml vial, and freeze-dried.

[0283] Freeze-drying curve: Prefreeze the aliquoted sample to -40±5°C and hold for 4 hours. Evacuate to a vacuum of 350 mTorr and maintain at -40±5°C for 1 hour. Raise the temperature to -20°C within 2 hours and hold for 4 hours. Raise the temperature to -10°C within 1 hour and hold for 3 hours. Raise the temperature to 0°C within 1 hour and hold for 4 hours. Raise the temperature to 20°C within 2 hours and hold for 2 hours. Raise the temperature to 30°C within 2 hours and hold for 2 hours. Raise the temperature to 45°C within 2 hours and hold for 3 hours. Maintain a vacuum of 350 mTorr throughout this process. Press the stopper, remove, and roll the aluminum cap to obtain the product. The moisture content is <5%.

[0284] Example 29

[0285] The ingredients and content of each vial of contrast agent powder injection are as follows: each vial contains 1.5g of contrast agent, 3g of crystallization inhibitor, and 10ml of water for injection.

[0286] composition:

[0287] Developer (iodixanol) 1.5g

[0288] Crystallization inhibitor (PVP K25) 3g

[0289] Water for injection 10ml

[0290] Preparation method: PVPK25 and iodixanol are dissolved in an appropriate amount of water for injection to prepare a mixed solution, and water for injection is added to a total volume of 10 ml to prepare an aqueous solution with a drug concentration of 0.15 g / ml. The solution is filtered through a 0.22 μm microporous membrane, filled into a 20 ml vial, and freeze-dried.

[0291] Freeze-drying curve: Prefreeze the aliquoted sample to -40±5°C and hold for 4 hours. Evacuate to a vacuum of 350 mTorr and maintain at -40±5°C for 1 hour. Raise the temperature to -20°C within 2 hours and hold for 4 hours. Raise the temperature to -10°C within 1 hour and hold for 3 hours. Raise the temperature to 0°C within 1 hour and hold for 4 hours. Raise the temperature to 20°C within 2 hours and hold for 2 hours. Raise the temperature to 30°C within 2 hours and hold for 2 hours. Raise the temperature to 45°C within 2 hours and hold for 3 hours. Maintain a vacuum of 350 mTorr throughout this process. Press the stopper, remove, and roll the aluminum cap to obtain the product. The moisture content is <5%.

[0292] Example 30

[0293] The ingredients and content of each vial of contrast agent powder injection are as follows: each vial contains 1.5g of contrast agent, 3g of crystallization inhibitor, and 10ml of water for injection.

[0294] composition:

[0295] Developer (iopromide) 1.5g

[0296] Crystallization inhibitor (PVP K30) 3g

[0297] Water for injection 10ml

[0298] Preparation method: PVPK30 and iopromide are dissolved in an appropriate amount of water for injection to prepare a mixed solution, and water for injection is added to a total volume of 10 ml to prepare an aqueous solution with a drug concentration of 0.15 g / ml. The solution is filtered through a 0.22 μm microporous filter membrane, filled into a 20 ml vial, and freeze-dried.

[0299] Freeze-drying curve: Prefreeze the aliquoted sample to -40±5°C and hold for 4 hours. Evacuate to a vacuum of 350 mTorr and maintain at -40±5°C for 1 hour. Raise the temperature to -20°C within 2 hours and hold for 4 hours. Raise the temperature to -10°C within 1 hour and hold for 3 hours. Raise the temperature to 0°C within 1 hour and hold for 4 hours. Raise the temperature to 20°C within 2 hours and hold for 2 hours. Raise the temperature to 30°C within 2 hours and hold for 2 hours. Raise the temperature to 45°C within 2 hours and hold for 3 hours. Maintain a vacuum of 350 mTorr throughout this process. Press the stopper, remove, and roll the aluminum cap to obtain the product. The moisture content is <5%.

[0300] Example 31

[0301] The ingredients and content of each vial of contrast agent powder injection are as follows: each vial contains 1.5g of contrast agent, 3g of crystallization inhibitor, and 10ml of water for injection.

[0302] composition:

[0303] Contrast agent (iopamidol) 1.5g

[0304] Crystallization inhibitor (PVP K30) 3g

[0305] Water for injection 10ml

[0306] Preparation method: PVPK30 and iopamidol are dissolved in an appropriate amount of water for injection to prepare a mixed solution, and water for injection is added to a total volume of 10 ml to prepare an aqueous solution with a drug concentration of 0.15 g / ml. The solution is filtered through a 0.22 μm microporous filter membrane, filled into a 20 ml vial, and freeze-dried.

[0307] Freeze-drying curve: Prefreeze the aliquoted sample to -40±5°C and hold for 4 hours. Evacuate to a vacuum of 350 mTorr and maintain at -40±5°C for 1 hour. Raise the temperature to -20°C within 2 hours and hold for 4 hours. Raise the temperature to -10°C within 1 hour and hold for 3 hours. Raise the temperature to 0°C within 1 hour and hold for 4 hours. Raise the temperature to 20°C within 2 hours and hold for 2 hours. Raise the temperature to 30°C within 2 hours and hold for 2 hours. Raise the temperature to 45°C within 2 hours and hold for 3 hours. Maintain a vacuum of 350 mTorr throughout this process. Press the stopper, remove, and roll the aluminum cap to obtain the product. The moisture content is <5%.

[0308] Example 32

[0309] The ingredients and content of each vial of contrast agent powder injection are as follows: each vial contains 1.5g of contrast agent, 3g of crystallization inhibitor, and 10ml of water for injection.

[0310] composition:

[0311] Developer (iohexol) 1.5g

[0312] Crystallization inhibitor (PVP K30) 3g

[0313] Water for injection 10ml

[0314] Preparation method: PVPK30 and iohexol are dissolved in an appropriate amount of water for injection to prepare a mixed solution, and water for injection is added to a total volume of 10 ml to prepare an aqueous solution with a drug concentration of 0.15 g / ml. The solution is filtered through a 0.22 μm microporous filter membrane, filled into a 20 ml vial, and freeze-dried.

[0315] Freeze-drying curve: Prefreeze the aliquoted sample to -40±5°C and hold for 4 hours. Evacuate to a vacuum of 350 mTorr and maintain at -40±5°C for 1 hour. Raise the temperature to -20°C within 2 hours and hold for 4 hours. Raise the temperature to -10°C within 1 hour and hold for 3 hours. Raise the temperature to 0°C within 1 hour and hold for 4 hours. Raise the temperature to 20°C within 2 hours and hold for 2 hours. Raise the temperature to 30°C within 2 hours and hold for 2 hours. Raise the temperature to 45°C within 2 hours and hold for 3 hours. Maintain a vacuum of 350 mTorr throughout this process. Press the stopper, remove, and roll the aluminum cap to obtain the product. The moisture content is <5%.

[0316] Example 33

[0317] The ingredients and content of each vial of contrast agent powder injection are as follows: each vial contains 1.5g of contrast agent, 3g of crystallization inhibitor, and 10ml of water for injection.

[0318] composition:

[0319] Developer (iodixanol) 1.5g

[0320] Crystallization inhibitor (PVP K30) 3g

[0321] Water for injection 10ml

[0322] Preparation method: PVPK30 and iodixanol are dissolved in an appropriate amount of water for injection to prepare a mixed solution, and water for injection is added to a total volume of 10 ml to prepare an aqueous solution with a drug concentration of 0.15 g / ml. The solution is filtered through a 0.22 μm microporous membrane, filled into a 20 ml vial, and freeze-dried.

[0323] Freeze-drying curve: Prefreeze the aliquoted sample to -40±5°C and hold for 4 hours. Evacuate to a vacuum of 350 mTorr and maintain at -40±5°C for 1 hour. Raise the temperature to -20°C within 2 hours and hold for 4 hours. Raise the temperature to -10°C within 1 hour and hold for 3 hours. Raise the temperature to 0°C within 1 hour and hold for 4 hours. Raise the temperature to 20°C within 2 hours and hold for 2 hours. Raise the temperature to 30°C within 2 hours and hold for 2 hours. Raise the temperature to 45°C within 2 hours and hold for 3 hours. Maintain a vacuum of 350 mTorr throughout this process. Press the stopper, remove, and roll the aluminum cap to obtain the product. The moisture content is <5%.

[0324] Example 34

[0325] 2 parts of PVP K12 and 1 part of iopromide were dissolved in an appropriate amount of water for injection to prepare a mixed solution, which was diluted with water for injection to an aqueous solution with a drug concentration of 0.1 g / ml. The solution was filtered through a 0.22 μm microporous filter membrane and spray-dried under sterile conditions.

[0326] Spray drying conditions: inlet temperature 105°C, outlet temperature 60°C, injection rate 5 ml / min. The dried powder was collected, aseptically crushed, passed through a 150-mesh sieve, weighed, and dispensed into 20 ml vials. The vials were stoppered and capped with aluminum caps. The moisture content was <5%.

[0327] Example 35

[0328] 2 parts of PVP K12 and 1 part of iopamidol were dissolved in an appropriate amount of water for injection to prepare a mixed solution, which was diluted with water for injection to an aqueous solution with a drug concentration of 0.1 g / ml. The solution was filtered through a 0.22 μm microporous membrane and spray-dried under sterile conditions.

[0329] Spray drying conditions: inlet temperature 120°C, outlet temperature 60°C, injection rate 5 ml / min. The dried powder was collected, aseptically crushed, passed through a 150-mesh sieve, weighed, and dispensed into 20 ml vials. The vials were stoppered and capped with aluminum caps. The moisture content was <5%.

[0330] Example 36

[0331] 2 parts of PVP K12 and 1 part of developer iohexol were dissolved in an appropriate amount of water for injection to prepare a mixed solution, which was diluted with water for injection to an aqueous solution with a drug concentration of 0.1 g / ml. The solution was filtered through a 0.22 μm microporous filter membrane and spray-dried under sterile conditions.

[0332] Spray drying conditions: inlet temperature 110°C, outlet temperature 60°C, injection rate 5 ml / min. The dried powder was collected, aseptically crushed, passed through a 150-mesh sieve, weighed, and dispensed into 20 ml vials. The vials were stoppered and capped with aluminum caps. The moisture content was <5%.

[0333] Example 37

[0334] 2 parts of PVP K12 and 1 part of developer iodixanol are dissolved in an appropriate amount of water for injection to prepare a mixed solution, which is diluted with water for injection to an aqueous solution with a drug concentration of 0.1 g / ml. The solution is filtered through a 0.22 μm microporous filter membrane and spray-dried under sterile conditions.

[0335] Spray drying conditions: inlet temperature 110°C, outlet temperature 60°C, injection rate 5 ml / min. The dried powder was collected, aseptically crushed, passed through a 150-mesh sieve, weighed, and dispensed into 20 ml vials. The vials were stoppered and capped with aluminum caps. The moisture content was <5%.

[0336] Example 38

[0337] 2 parts of PVP K17 and 1 part of developer iopromide were dissolved in an appropriate amount of water for injection to prepare a mixed solution, which was diluted with water for injection to an aqueous solution with a drug concentration of 0.1 g / ml. The solution was filtered through a 0.22 μm microporous membrane and spray-dried under sterile conditions.

[0338] Spray drying conditions: inlet temperature 110°C, outlet temperature 60°C, injection rate 5 ml / min. The dried powder was collected, aseptically crushed, passed through a 150-mesh sieve, weighed, and dispensed into 20 ml vials. The vials were stoppered and capped with aluminum caps. The moisture content was <5%.

[0339] Example 39

[0340] 2 parts of PVP K17 and 1 part of developer iopamidol are dissolved in an appropriate amount of water for injection to prepare a mixed solution, which is diluted with water for injection to an aqueous solution with a drug concentration of 0.1 g / ml. The solution is filtered through a 0.22 μm microporous filter membrane and spray-dried under sterile conditions.

[0341] Spray drying conditions: inlet temperature 110°C, outlet temperature 60°C, injection rate 5 ml / min. The dried powder was collected, aseptically crushed, passed through a 150-mesh sieve, weighed, and dispensed into 20 ml vials. The vials were stoppered and capped with aluminum caps. The moisture content was <5%.

[0342] Example 40

[0343] 2 parts of PVP K17 and 1 part of developer iohexol were dissolved in an appropriate amount of water for injection to prepare a mixed solution, which was diluted with water for injection to an aqueous solution with a drug concentration of 0.1 g / ml. The solution was filtered through a 0.22 μm microporous filter membrane and spray-dried under sterile conditions.

[0344] Spray drying conditions: inlet temperature 110°C, outlet temperature 60°C, injection rate 5 ml / min. The dried powder was collected, aseptically crushed, passed through a 150-mesh sieve, weighed, and dispensed into 20 ml vials. The vials were stoppered and capped with aluminum caps. The moisture content was <5%.

[0345] Example 41

[0346] 2 parts of PVP K17 and 1 part of developer iodixanol were dissolved in an appropriate amount of water for injection to prepare a mixed solution, which was diluted with water for injection to an aqueous solution with a drug concentration of 0.1 g / ml. The solution was filtered through a 0.22 μm microporous filter membrane and spray-dried under sterile conditions.

[0347] Spray drying conditions: inlet temperature 110°C, outlet temperature 60°C, injection rate 5 ml / min. The dried powder was collected, aseptically crushed, passed through a 150-mesh sieve, weighed, and dispensed into 20 ml vials. The vials were stoppered and capped with aluminum caps. The moisture content was <5%.

[0348] Example 42

[0349] 2 parts of PVP K25 and 1 part of developer iopromide were dissolved in an appropriate amount of water for injection to prepare a mixed solution, which was diluted with water for injection to an aqueous solution with a drug concentration of 0.1 g / ml. The solution was filtered through a 0.22 μm microporous filter membrane and spray-dried under sterile conditions.

[0350] Spray drying conditions: inlet temperature 110°C, outlet temperature 60°C, injection rate 5 ml / min. The dried powder was collected, aseptically crushed, passed through a 150-mesh sieve, weighed, and dispensed into 20 ml vials. The vials were stoppered and capped with aluminum caps. The moisture content was <5%.

[0351] Example 43

[0352] 2 parts of PVP K25 and 1 part of developer iopamidol are dissolved in an appropriate amount of water for injection to prepare a mixed solution, which is diluted with water for injection to an aqueous solution with a drug concentration of 0.1 g / ml. The solution is filtered through a 0.22 μm microporous filter membrane and spray-dried under sterile conditions.

[0353] Spray drying conditions: inlet temperature 110°C, outlet temperature 60°C, injection rate 5 ml / min. The dried powder was collected, aseptically crushed, passed through a 150-mesh sieve, weighed, and dispensed into 20 ml vials. The vials were stoppered and capped with aluminum caps. The moisture content was <5%.

[0354] Example 44

[0355] 2 parts of PVP K25 and 1 part of developer iohexol were dissolved in an appropriate amount of water for injection to prepare a mixed solution, which was diluted with water for injection to an aqueous solution with a drug concentration of 0.1 g / ml. The solution was filtered through a 0.22 μm microporous membrane and spray-dried under sterile conditions.

[0356] Spray drying conditions: inlet temperature 110°C, outlet temperature 60°C, injection rate 5 ml / min. The dried powder was collected, aseptically crushed, passed through a 150-mesh sieve, weighed, and dispensed into 20 ml vials. The vials were stoppered and capped with aluminum caps. The moisture content was <5%.

[0357] Example 45

[0358] 2 parts of PVP K25 and 1 part of developer iodixanol are dissolved in an appropriate amount of water for injection to prepare a mixed solution, which is diluted with water for injection to an aqueous solution with a drug concentration of 0.1 g / ml. The solution is filtered through a 0.22 μm microporous filter membrane and spray-dried under sterile conditions.

[0359] Spray drying conditions: inlet temperature 110°C, outlet temperature 60°C, injection rate 5 ml / min. The dried powder was collected, aseptically crushed, passed through a 150-mesh sieve, weighed, and dispensed into 20 ml vials. The vials were stoppered and capped with aluminum caps. The moisture content was <5%.

[0360] Example 46

[0361] 2 parts of PVP K30 and 1 part of developer iopromide were dissolved in an appropriate amount of water for injection to prepare a mixed solution, which was diluted with water for injection to an aqueous solution with a drug concentration of 0.1 g / ml. The solution was filtered through a 0.22 μm microporous filter membrane and spray-dried under sterile conditions.

[0362] Spray drying conditions: inlet temperature 110°C, outlet temperature 60°C, injection rate 5 ml / min. The dried powder was collected, aseptically crushed, passed through a 150-mesh sieve, weighed, and dispensed into 20 ml vials. The vials were stoppered and capped with aluminum caps. The moisture content was <5%.

[0363] Example 47

[0364] 2 parts of PVP K30 and 1 part of developer iohexol were dissolved in an appropriate amount of water for injection to prepare a mixed solution, which was diluted with water for injection to an aqueous solution with a drug concentration of 0.1 g / ml. The solution was filtered through a 0.22 μm microporous membrane and spray-dried under sterile conditions.

[0365] Spray drying conditions: inlet temperature 110°C, outlet temperature 60°C, injection rate 5 ml / min. The dried powder was collected, aseptically crushed, passed through a 150-mesh sieve, weighed, and dispensed into 20 ml vials. The vials were stoppered and capped with aluminum caps. The moisture content was <5%.

[0366] Example 48

[0367] 2 parts of PVP K30 and 1 part of developer iopamidol were dissolved in an appropriate amount of water for injection to prepare a mixed solution, which was diluted with water for injection to an aqueous solution with a drug concentration of 0.1 g / ml. The solution was filtered through a 0.22 μm microporous filter membrane and spray-dried under sterile conditions.

[0368] Spray drying conditions: inlet temperature 110°C, outlet temperature 60°C, injection rate 5 ml / min. The dried powder was collected, aseptically crushed, passed through a 150-mesh sieve, weighed, and dispensed into 20 ml vials. The vials were stoppered and capped with aluminum caps. The moisture content was <5%.

[0369] Example 49

[0370] 2 parts of PVP K30 and 1 part of developer iodixanol were dissolved in an appropriate amount of water for injection to prepare a mixed solution, which was diluted with water for injection to an aqueous solution with a drug concentration of 0.1 g / ml. The solution was filtered through a 0.22 μm microporous membrane and spray-dried under sterile conditions.

[0371] Spray drying conditions: inlet temperature 110°C, outlet temperature 60°C, injection rate 5 ml / min. The dried powder was collected, aseptically crushed, passed through a 150-mesh sieve, weighed, and dispensed into 20 ml vials. The vials were stoppered and capped with aluminum caps. The moisture content was <5%.

[0372] Experimental Example 1 Stability Determination of PVPK12:Iopromide=2:1 Anhydrous Ethanol Supersaturated Solution

[0373] Test method: UV-visible spectrophotometry was used to measure the absorbance at a wavelength of 700 nm.

[0374] Experimental Principle: The incident light in a UV-visible spectrophotometer is monochromatic. According to the Lambert-Beer law, when a colloidal suspension appears in a solution, larger particles block the passage of light, causing a change in transmittance. Since transmittance and absorbance have the following relationship: A = 1g(1 / T), when precipitation occurs in a supersaturated solution, the absorbance of the solution changes. The more precipitated particles, the lower the transmittance and the greater the absorbance value A. Because neither PVP K12 nor iopromide solutions absorb at a wavelength of 700nm (as shown in Figure 1), the influence of the raw material properties on absorbance can be ruled out. Furthermore, 700nm is within the UV-visible wavelength range, so the absorbance at 700nm was selected to investigate the stability of the supersaturated solution.

[0375] Experimental Method: Prepare a supersaturated solution of a developer (e.g., iopromide) at a concentration of 0.1-0.4 g / ml. Dissolve until clear and transparent. Immediately place the solution in a UV-visible spectrophotometer at 700 nm and measure absorbance at various times. The results are shown in Table 1. Due to the pale yellow color of the PVP K12 raw material, higher concentrations lead to deeper yellow colors and higher initial absorbance. Bubbles are generated during dissolution, increasing absorbance. Therefore, the time it takes for the absorbance to stabilize was determined. This time is used to indicate the stability of the supersaturated solution without precipitation.

[0376] As shown in FIG5 , influenced by the color of PVP K12 itself, PVP K12 and iopromide lyophilized powder were dissolved in anhydrous ethanol to form a yellow transparent supersaturated solution.

[0377] Experimental Results: Based on the absorbance changes in Table 1, the supersaturated solution at 0.1-0.2 g / ml stabilized for approximately 55 minutes, the 0.3 g / ml solution stabilized for approximately 75 minutes, and the 0.4 g / ml solution stabilized for approximately 375 minutes. Under these conditions, the higher the concentration, the slower the precipitation rate of the supersaturated solution. This is because higher concentrations increase the solution's viscosity, slowing molecular thermal motion and slowing precipitation. The results are shown in Figure 6.

[0378] Experimental Example 2 Composition PVP (K12 / 17 / 25 / 30): Iopromide = (2-3): 1 ratio 0.1 ~ 0.3g / ml anhydrous ethanol supersaturated solution viscosity

[0379] Experimental Results: After dissolving the supersaturated solutions at various concentrations, the viscosity values ​​were measured using a rheometer. Table 2 below shows the viscosity values ​​for Experimental Example 2. At room temperature, the viscosity of anhydrous ethanol is 0.6 mPa·s. PVP significantly increases the solution viscosity, and the higher the concentration, the greater the viscosity. A moderate temperature increase (37°C) helps reduce the solution viscosity.

[0380] Experimental Example 3 Development Effect of Supersaturated Solution of Iopromide in Anhydrous Ethanol

[0381] After the developing powder injection of Example 1 was completely dissolved, it was aspirated using a 1 ml syringe and photographed under X-ray using a Guangzhou Bolu Teng small animal imaging instrument for development. As shown in Figure 7, the results show that concentrations of 0.1-0.8 g / ml in Example 1 can be developed, and the higher the concentration, the more obvious the contrast effect. From left to right, the concentration range is 0.1-0.8 g / ml, and the development effect increases with increasing iopromide concentration.

[0382] Experimental Example 4 Effect of Anhydrous Ethanol on Rat Tail Vein Embolization

[0383] According to Example 17, after lyophilization, one bottle of developing powder injection was taken and 5 ml of anhydrous ethanol was added to prepare a supersaturated ethanol solution with an IOP concentration of 0.3 g / ml and a crystallization inhibitor, PVPK12, at a concentration of 0.6 g / ml. With anhydrous ethanol as the control group and anhydrous ethanol supersaturated solution as the experimental group, SD rats were injected with 0.2 ml of anhydrous ethanol and 0.2 ml of anhydrous ethanol supersaturated solution at 0.3 g / ml, respectively, via the tail vein. The embolic effect was then examined. As shown in Figure 8, after 0.2 ml of anhydrous ethanol was injected into the rat's tail vein, the ethanol was rapidly diluted by the blood. Only a transient blackening line appeared near the injection point. Due to the thicker skin layer of the tail, wound damage was observed in the epidermis around three days later. The damage was extensive and remained in this state, with slow recovery. Figure 8 shows, from left to right, the results immediately, 3 days, 10 days, and 20 days after the 0.2 ml tail injection.

[0384] As shown in Figure 9, after rats were injected with 0.2 ml of a 0.3 g / ml absolute ethanol solution (composition PVPK12: iopromide = 2:1) via the tail vein, the solution's higher viscosity reduced its fluidity and ability to be flushed by blood, allowing it to remain at the injection site for a longer period. The wound damage to the tail vessels was greater than that caused by the absolute ethanol solution, and scab formation and recovery began after a longer period. Figure 9 shows, from left to right, the effects of administering 0.2 ml of the 0.3 g / ml iopromide absolute ethanol solution to the tail 7 days, 14 days, 21 days, and 30 days after administration.

[0385] Experimental results: Anhydrous ethanol in the control group had a hardening effect on blood vessels, but after the use of the developer powder injection of the present invention with anhydrous ethanol in the experimental group, the viscosity increased, and it could stay in the blood vessels for a longer time, exerting a stronger effect, enhancing the hardening effect, and effectively slowing down the diffusion of ethanol to both ends of the blood vessels, indicating that the efficacy of the experimental group was better.

[0386] Experimental Example 5: Effect of light-induced embolization of interosseous membrane vessels in rat lower limbs

[0387] SD rats were anesthetized and their thigh hair was shaved. Anhydrous ethanol and a supersaturated solution of anhydrous ethanol from Example 17 (drug concentrations of 0.1 and 0.3 g / ml) were injected proximally into the interosseous membrane vessels of the lower limbs. Sclerosis and embolism were examined by transillumination.

[0388] Experimental Results: As shown in Figures 10-16, the interosseous membrane vessels of the rat lower limbs do not appear normal under illumination, but rather appear blackened, damaged by ethanol. Three days later, the treated vessels became visible to the naked eye (without illumination). Furthermore, the length of the blackened vessels in rats treated with the drug-containing ethanol solution was significantly longer than that in rats treated with the absolute ethanol solution alone, suggesting that the drug-containing absolute ethanol solution, due to its increased viscosity, exhibited a more effective embolic effect.

[0389] According to the above embodiments, the developer powder injection of the present invention can be dissolved in anhydrous ethanol to form a supersaturated solution. The use of a crystallization inhibitor stabilizes the supersaturated solution for a certain period of time. This can not only adjust the viscosity of the solution and reduce the degree of anhydrous ethanol being washed away by the blood, but also monitor the injection of anhydrous ethanol to prevent ethanol from overflowing from the lesion site, thereby improving safety and reducing complications.

Claims

1. A pharmaceutical composition comprising a contrast agent and a crystallization inhibitor, wherein the pharmaceutical composition is an amorphous composition.

2. The composition of claim 1, wherein the crystallization inhibitor is selected from one or more of polyethylene glycols, povidones, surfactants, cellulose derivatives, sugars, and organic acids.

3. The composition according to claim 2, wherein the crystallization inhibitor is selected from one or more of poloxamer, polyethylene glycol, and povidone; wherein, The poloxamer is preferably poloxamer 188 / 407; the polyethylene glycol is preferably PEG4000 or PEG6000; and the povidone is preferably PVP K12, PVP K17, PVP K25 or PVP K30.

4. The composition of any one of claims 1 to 3, wherein the contrast agent is selected from one or more of the iodine contrast agents iopromide, iohexol, iopamidol, iodixanol, and meglumine diatrizoate.

5. The composition according to any one of claims 1 to 4, wherein the ratio of the contrast agent to the crystallization inhibitor is 3:1 to 1:5; preferably, the ratio is 2:1, 1:1 or 1:

2.

6. A developer powder injection, comprising a contrast agent and a crystallization inhibitor, wherein the crystallinity of the powder injection is less than 1%.

7. The powder injection according to claim 6, wherein the contrast agent is selected from one or more of the iodine contrast agents iopromide, iohexol, iopamidol, iodixanol, and meglumine diatrizoate.

8. The powder injection according to claim 6 or 7, wherein the crystallization inhibitor is selected from one or more of polyethylene glycols, povidones, surfactants, cellulose derivatives, sugars, and organic acids.

9. The powder injection according to any one of claims 6 to 8, wherein the crystallization inhibitor is selected from one or more of poloxamer, polyethylene glycol, and povidone; wherein, The poloxamer is preferably poloxamer 188 / 407; the polyethylene glycol is preferably PEG4000 or PEG6000; and the povidone is preferably PVP K12, PVP K17, PVP K25 or PVP K30.

10. The powder injection according to any one of claims 6 to 9, wherein the ratio of the contrast agent to the crystallization inhibitor is 3:1 to 1:5; preferably, the ratio is 2:1, 1:1 or 1:

2.

11. A method for preparing the pharmaceutical composition according to claims 1-5 or the powder injection according to claims 6-10, comprising a freeze-drying step.

12. A method for preparing the pharmaceutical composition according to claims 1-5 or the powder injection according to claims 6-10, comprising a spray drying step.

13. Use of the pharmaceutical composition according to claims 1-5, the powder injection according to claims 6-10, or the product prepared according to claims 11-12 for preparing an anhydrous ethanol-based developer and hardener.

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