A long-acting and stable cefotaxime sodium preparation, its preparation method and application

Abstract

The application discloses a long-acting and stable drug-releasing cefotaxime sodium preparation and a preparation method and application thereof, relates to the technical field of drug synthesis, and the cefotaxime sodium preparation comprises cefotaxime sodium tablet crystals, and a slow-release carrier is coated outside the cefotaxime sodium tablet crystals; the slow-release carrier has a three-level structure, comprising a phospholipid coating layer coated on the surface of the cefotaxime sodium tablet crystals, a mesoporous silica shell layer coated on the surface of the phospholipid coating layer, and a temperature-sensitive hydrogel network layer coated on the surface of the mesoporous silica shell layer. The cefotaxime sodium preparation has the properties of rapid effect, super-long-acting and stable drug-releasing and high stability, and the preparation process flow is simple, and the control condition is mild.

Description

Technical Field

[0001] This invention relates to the field of drug synthesis technology, specifically to a long-acting, stable-release cefotaxime sodium formulation, its preparation method, and its application. Background Technology

[0002] As a time-dependent antibiotic, the core of the clinical efficacy of cefotaxime sodium lies in maintaining the blood drug concentration above the minimum inhibitory concentration (MIC). The ideal dosing mode is to achieve an effective concentration rapidly after a single injection and maintain it stably for several days, thereby maximizing efficacy, reducing the number of dosings, and minimizing the risk of adverse reactions.

[0003] Current mainstream technologies rely on sustained-release carriers with a single mechanism, such as hydrophilic gel matrices or lipid / polymer microspheres. Hydrophilic gel systems depend on drug diffusion and matrix dissolution; their release rate significantly decreases as the internal drug concentration drops, leading to a premature drop in blood drug concentration in the later stages of administration, failing to meet the requirement of long-acting effects exceeding 72 hours, and exhibiting slow onset of action. While liposomes or microspheres can prolong the duration of action, they generally suffer from severe burst-release effects, i.e., a large amount of drug is rapidly released initially. This not only fails to achieve stable release but may also cause safety issues.

[0004] To compensate for the shortcomings of a single carrier, attempts have been made to simply physically mix immediate-release and sustained-release units. However, this mechanical combination only achieves a simple splicing of the drug release stage, and its drug release curve often shows a discontinuous shape. A deeper problem is that existing technologies generally regard the active pharmaceutical ingredient crystals as an unchanging starting point, directly using crystals prepared by traditional methods that may have defects and irregular shapes for drug loading. These crystals, as the source of the drug, have unstable physical morphology and surface characteristics, which become an inherent bottleneck restricting the uniformity, release reproducibility and long-term chemical stability of the entire formulation carrier. At the same time, the multi-step separation, drying and mixing process also increases the risk of drug degradation.

[0005] Therefore, current cefotaxime sodium preparations still suffer from slow onset of action, unstable drug release, and insufficient effective duration of action. Summary of the Invention

[0006] Given that existing cefotaxime sodium formulations still suffer from slow onset of action, unstable drug release, and insufficient effective duration of action, the purpose of this invention is to provide a long-acting, stable-release cefotaxime sodium formulation and its preparation method. This cefotaxime sodium formulation has the properties of rapid onset of action, ultra-long-acting, stable drug release, and high stability. At the same time, its preparation process is also very simple and the control conditions are mild.

[0007] This invention is achieved through the following technical solution:

[0008] In a first aspect, the present invention provides a long-acting, stable-release cefotaxime sodium formulation, comprising cefotaxime sodium flake crystals, wherein the cefotaxime sodium flake crystals are coated with a sustained-release carrier; the sustained-release carrier has a tertiary structure, comprising a phospholipid coating layer covering the surface of the cefotaxime sodium flake crystals, the surface of the phospholipid coating layer being coated with a mesoporous silica shell, and the surface of the mesoporous silica shell being coated with a thermosensitive hydrogel network layer.

[0009] The phospholipid coating layer in this invention achieves precise control of initial drug release through temperature response. Under storage conditions below the phase transition temperature, this layer exists as an ordered gel phase, forming a dense molecular shield. When exposed to body temperature, it rapidly transforms into a liquid crystal phase, loosening the molecular arrangement and allowing for rapid release of some drugs within a short time, ensuring that the blood drug concentration quickly exceeds the minimum inhibitory concentration. The mesoporous silica shell layer achieves constant-rate control of drug release through diffusion restriction via fixed-pore channels. Drug molecules dissociate from the crystal into monomers and diffuse through the mesoporous channels. Release kinetics are generated under the condition that the drug crystal remains saturated in the early stage, maintaining stable blood drug concentration in the middle stage. The thermosensitive hydrogel network layer forms a physical gel at body temperature through reverse thermogelation, restricting the diffusion of drug-loaded ions. At the same time, in the later stage of release, when the driving force of mesoporous diffusion weakens, the gel network becomes the main rate-limiting factor. In addition, the thermosensitive hydrogel network also provides a skeletal structure for the formulation, ensuring the physical integrity and reconstitution properties of the formulation.

[0010] In addition, the hydrophilic heads of the phospholipid coating provide nucleation sites for the hydrolysis and condensation of the silica precursor, and achieve a strong bond between the organic and inorganic interfaces through hydrogen bonding and electrostatic interaction. The rigid structure of the mesoporous silica shell provides mechanical protection for the internal phospholipid-drug core. The hydrogel network fixes the core-shell structure particles in a three-dimensional network through chemical cross-linking points and physical entanglement, forming a complete delivery system from the nanoscale to the macroscale.

[0011] In addition, the phospholipid coating provides molecular-level barrier under storage conditions, reducing the penetration of moisture and oxygen; the mesoporous silica shell provides a rigid physical barrier to resist external mechanical stress; and the cementitious network forms a porous skeleton in the freeze-dried state, forming a three-layer stability protection structure.

[0012] The three sustained-release carriers in this application have a synergistic effect: the temperature responsiveness of the phospholipid coating layer provides rapid initiation, the structural confinement of the mesoporous silica ensures constant-rate release in the middle stage, and the time-dependent diffusion control of the thermosensitive hydrogel achieves long-term maintenance in the later stage. At the same time, the three complement each other in terms of moisture control, mechanical protection and chemical stability, so that the cefotaxime sodium formulation has outstanding performance of rapid onset, ultra-long-lasting and stable drug release and high stability.

[0013] In one specific embodiment, the raw material for the phospholipid coating layer is a combination of hydrogenated soybean lecithin and dipalmitoylphosphatidylcholine, wherein the molar ratio of hydrogenated soybean lecithin to dipalmitoylphosphatidylcholine is 1:(0.5~2).

[0014] In one specific embodiment, the raw materials of the thermosensitive hydrogel network layer include thermosensitive block copolymers and biopolysaccharides, and a cross-linked network is formed by a cross-linking agent.

[0015] In one specific embodiment, the thermosensitive block copolymer is poloxamer P407, and its concentration in the crosslinking network is 10%-25% (w / v); the biopolysaccharide is hyaluronic acid or its derivative, with a molecular weight of 50kDa~2000kDa, and its concentration in the crosslinking network is 0.5%-3.0% (w / v); the crosslinking agent is genipin, and its amount is 0.5%~5% of the mass of the biopolysaccharide.

[0016] In one specific embodiment, the mesoporous silica shell has a mesopore diameter of 2.5 nm to 3.5 nm.

[0017] Secondly, this application provides a method for preparing a long-acting, stable-release cefotaxime sodium formulation, comprising the following steps:

[0018] S1. Cefotaxime acid is reacted with a salt-forming agent in a mixed solvent in the presence of a template agent to prepare flaky crystals of cefotaxime sodium.

[0019] S2. Disperse the flaky crystals obtained in step S1 in an aqueous solution, add an organic solution containing phospholipids, stir to mix evenly, and then evaporate to remove the organic solvent, forming a phospholipid monolayer coating on the surface of the flaky crystals.

[0020] S3. Disperse the phospholipid-coated crystals obtained in step S2 in an aqueous solution, add a surfactant and a silicon source, and react them by sol-gel method to form a mesoporous silica shell on the outside of the phospholipid monolayer coating to obtain core-shell structured particles.

[0021] S4. Disperse the core-shell structured particles obtained in step S3 in an aqueous solution containing thermosensitive block copolymer and biopolysaccharide, add a crosslinking agent to carry out a crosslinking reaction, and form a drug-loaded thermosensitive hydrogel that embeds the core-shell structured particles.

[0022] S5. The drug-loaded thermosensitive hydrogel obtained in step S4 is freeze-dried to obtain the freeze-dried cefotaxime sodium preparation.

[0023] In one specific embodiment, in step S1, the template agent is a polyoxyethylene-polyoxypropylene-polyoxyethylene triblock copolymer.

[0024] In one specific embodiment, in step S3, the surfactant is hexadecyltrimethylammonium bromide, and the silicon source is tetraethyl orthosilicate.

[0025] In one specific embodiment, in step S3, the pH value of the reaction system is controlled at 9~11, and the reaction temperature is 30℃~50℃.

[0026] In one specific embodiment, in step S4, the temperature of the crosslinking reaction is 2~10℃.

[0027] Thirdly, this application provides a pharmaceutical composition comprising the above-described cefotaxime sodium preparation or a cefotaxime sodium preparation prepared using the above-described preparation method.

[0028] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0029] (1) The phospholipid coating of the innermost layer of the sustained-release carrier of the cefotaxime sodium formulation of the present invention transforms from a gel phase to a liquid crystal phase under body temperature triggering, and the molecular arrangement becomes disordered, forming an initial drug release channel; the mesoporous silica layer in the middle layer dominates drug diffusion; the outermost thermosensitive hydrogel network provides a supplementary diffusion barrier in the later stage of release through the time-varying permeability of its network structure. The difference in diffusion coefficients of the tertiary structure forms a natural time gradient, realizing seamless connection of release kinetics, ensuring that the blood drug concentration quickly reaches the therapeutic standard and remains stable for a long time.

[0030] (2) The phospholipid coating in the sustained-release carrier of the cefotaxime sodium formulation of the present invention forms a dense molecular arrangement under storage conditions, which effectively reduces water and oxygen permeability. The mesoporous silica layer provides mechanical protection through rigid skeletonlessness, and its surface hydroxyl groups can bind residual water. The hydrogel network forms a porous matrix with low water activity during freeze-drying. A complete protection system is formed through the interfacial chemical bonding and physical interpenetration of this tertiary structure.

[0031] (3) In the preparation process of the sustained-release carrier of the cefotaxime sodium formulation of the present invention, the self-assembly of phospholipids on the crystal surface provides a uniform nucleation interface for the silica precursor, the in-situ mineralization growth of silica forms a complete shell, and the hydrogel network fixes the core-shell particles through chemical cross-linking. This continuous in-situ construction process minimizes intermediate processing steps and avoids the drug being exposed to the degradation environment.

[0032] (4) The three-level structure of the sustained-release carrier of the cefotaxime sodium formulation of the present invention is designed for rapid initiation, constant release and long-term maintenance. The rapid phase change of the phospholipid coating layer solves the problem of delayed onset of action. The structural restriction of the mesoporous silica layer ensures the stability of release. The time-varying diffusion coefficient of the hydrogel network prolongs the action time. The synergistic effect of each functional unit overcomes the contradiction between release kinetics and stability of a single carrier structure. Detailed Implementation

[0033] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to the embodiments. The illustrative embodiments and descriptions of this invention are only used to explain this invention and are not intended to limit this invention.

[0034] In the following description, numerous specific details are set forth in order to provide a thorough understanding of the invention. However, it will be apparent to those skilled in the art that these specific details are not necessary to practice the invention. In other embodiments, well-known materials or methods have not been specifically described in order to avoid obscuring the invention.

[0035] Throughout this specification, references to "an embodiment," "an example," or "an example" mean that a particular feature, structure, or characteristic described in connection with that embodiment or example is included in at least one embodiment of the invention. Therefore, the phrases "an embodiment," "an example," "an example," or "an example" appearing in various places throughout the specification do not necessarily refer to the same embodiment or example. Furthermore, specific features, structures, or characteristics can be combined in one or more embodiments or examples in any suitable combination and / or sub-combination. The term "and / or" as used herein includes any and all combinations of one or more of the associated listed items. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described herein, as well as the features of those different embodiments or examples.

[0036] The "range" disclosed in this application is defined by a lower limit and an upper limit. A given range is defined by selecting a lower limit and an upper limit, which define the boundaries of a particular range. Ranges defined in this way can include or exclude endpoints and can be arbitrarily combined; that is, any lower limit can be combined with any upper limit to form a range. For example, if ranges of 60–120 and 80–110 are listed for a specific parameter, it is understood that ranges of 60–110 and 80–120 are also expected. Furthermore, if minimum range values ​​of 1 and 2 are listed, and if maximum range values ​​of 3, 4, and 5 are listed, then the following ranges are all expected: 1–3, 1–4, 1–5, 2–3, 2–4, and 2–5. In this application, unless otherwise stated, the numerical range "a–b" represents a shortened representation of any combination of real numbers between a and b, where a and b are real numbers. For example, the numerical range "0~5" indicates that all real numbers between "0~5" have been listed in this article; "0~5" is simply a shortened representation of these numerical combinations. Furthermore, when a parameter is stated as an integer ≥2, it is equivalent to disclosing that the parameter is, for example, an integer such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, etc.

[0037] Unless otherwise specified, all steps in this application may be performed sequentially or randomly, preferably sequentially. For example, the method includes steps (a) and (b), indicating that the method may include steps (a) and (b) performed sequentially, or it may include steps (b) and (a) performed sequentially. For example, the method may also include step (c), indicating that step (c) may be added to the method in any order. For example, the method may include steps (a), (b), and (c), or it may include steps (a), (c), and (b), or it may include steps (c), (a), and (b), etc.

[0038] Example 1

[0039] This embodiment provides a method for preparing a long-acting, stable-release cefotaxime sodium formulation. The specific preparation method is as follows:

[0040] S1. Preparation of cefotaxime sodium flake crystals

[0041] S1-1. Add 350 mL of ethanol-water mixed solvent to the reaction vessel, then add 2 g of polyoxyethylene-polyoxypropylene-polyoxyethylene triblock copolymer, stir until completely dissolved, continue to add 2.2 g of sodium acetate, stir until dissolved, then add 10 g of cefotaxime acid, and stir the reaction at 20°C for 45 minutes. The volume ratio of ethanol to water is 6:4.

[0042] S1-2. Start the cooling program and reduce the temperature to 5℃ at a rate of 0.5℃ / min. Let the crystals grow at 5℃ for 12 hours, then filter and wash the filter cake with ethanol.

[0043] S1-3. Place the filter cake in a vacuum drying oven at 35℃ and dry it overnight to obtain white flaky crystals.

[0044] S2, Constructing the phospholipid coating layer

[0045] S2-1. Take 9g of the cefotaxime sodium flake crystals prepared in step S1, disperse them in 200 mL of phosphate buffer solution with pH 7.4, and sonicate for 10 minutes to obtain a crystal suspension.

[0046] S2-2. Weigh 1.296 g of hydrogenated soybean lecithin and 0.744 g of dipalmitoylphosphatidylcholine, and dissolve them together in 20 mL of anhydrous ethanol to obtain a phospholipid ethanol solution.

[0047] S2-3. Under 40℃ water bath conditions, the phospholipid ethanol solution is slowly added dropwise to the crystal suspension, stirred and mixed, and then the mixture is transferred to a rotary evaporator for evaporation to remove the ethanol, resulting in a homogeneous aqueous suspension of phospholipid-coated crystals.

[0048] S3, Constructing a mesoporous silica shell

[0049] S3-1. Add 1.44 g of cetyltrimethylammonium bromide to the aqueous suspension prepared in step S2, stir and dissolve at 40°C, adjust the pH of the system to 10.5 using concentrated ammonia, and then slowly add 1.6 mL of tetraethyl orthosilicate dropwise over 1 hour using a constant pressure dropping funnel while stirring. After the addition is complete, react at 40°C for 6 hours.

[0050] S3-2. After the reaction is complete, the solid is collected by centrifugation, washed three times each with water and ethanol, and then redispersed in 200 mL of ethanol containing 1% hydrochloric acid. The mixture is refluxed and stirred at 60 °C for 6 hours to extract and remove hexadecyltrimethylammonium bromide. Then, the solid is centrifuged, washed, and dried to obtain a white core-shell structure powder.

[0051] S4. Construct and embed thermosensitive hydrogel networks.

[0052] S4-1. Slowly add 8g of poloxamer P407 and 2g of sodium hyaluronate to 80mL of pH 7.4 phosphate buffer solution, stir overnight to dissolve completely, and then bring the volume to 100mL.

[0053] S4-2. Weigh 5g of the core-shell structure powder prepared in step S3 and add it to the solution in step S4-1. Homogenize and disperse the powder at 5000rpm for 2 minutes in an ice bath. Then add 1mL of 1% (w / v) genipin aqueous solution and stir to mix. Transfer the mixed solution to a refrigerator at 4°C and allow it to stand for cross-linking reaction for 24 hours to form a uniform drug-loaded gel.

[0054] S5, freeze drying

[0055] S5-1. Dispense the drug-loaded gel into 2 mL vials, 1 mL per vial. Place the vials on the shelf of a lyophilizer that can establish a vertical temperature gradient. Set the program: reduce the temperature from 4°C to -15°C at a rate of 0.8°C / min and hold for 1 hour; then reduce the temperature to -45°C at a rate of 2°C / min and hold for 2 hours to achieve complete freezing.

[0056] S5-2. Turn on the vacuum and dry. After freeze-drying, seal the capsule to obtain cefotaxime sodium preparation.

[0057] Example 2

[0058] This embodiment provides a method for preparing a long-acting, stable-release cefotaxime sodium formulation. The difference from Example 1 is that in step S2-2 of this embodiment, the molar ratio of hydrogenated soybean lecithin to dipalmitoylphosphatidylcholine is 1:0.8, meaning the amount of hydrogenated soybean lecithin is maintained at 1.296 g, and the amount of dipalmitoylphosphatidylcholine is adjusted to 0.595 g. The other steps are the same as in Example 1.

[0059] The specific preparation method is as follows:

[0060] S1. Preparation of cefotaxime sodium flake crystals

[0061] S1-1. Add 350 mL of ethanol-water mixed solvent to the reaction vessel, then add 2 g of polyoxyethylene-polyoxypropylene-polyoxyethylene triblock copolymer, stir until completely dissolved, continue to add 2.2 g of sodium acetate, stir until dissolved, then add 10 g of cefotaxime acid, and stir the reaction at 20°C for 45 minutes. The volume ratio of ethanol to water is 6:4.

[0062] S1-2. Start the cooling program and reduce the temperature to 5℃ at a rate of 0.5℃ / min. Let the crystals grow at 5℃ for 12 hours, then filter and wash the filter cake with ethanol.

[0063] S1-3. Place the filter cake in a vacuum drying oven at 35℃ and dry it overnight to obtain white flaky crystals.

[0064] S2, Constructing the phospholipid coating layer

[0065] S2-1. Take 9g of the cefotaxime sodium flake crystals prepared in step S1, disperse them in 200 mL of phosphate buffer solution with pH 7.4, and sonicate for 10 minutes to obtain a crystal suspension.

[0066] S2-2. Weigh 1.296 g of hydrogenated soybean lecithin and 0.595 g of dipalmitoylphosphatidylcholine, and dissolve them together in 20 mL of anhydrous ethanol to obtain a phospholipid ethanol solution.

[0067] S2-3. Under 40℃ water bath conditions, the phospholipid ethanol solution is slowly added dropwise to the crystal suspension, stirred and mixed, and then the mixture is transferred to a rotary evaporator for evaporation to remove the ethanol, resulting in a homogeneous aqueous suspension of phospholipid-coated crystals.

[0068] S3, Constructing a mesoporous silica shell

[0069] S3-1. Add 1.44 g of cetyltrimethylammonium bromide to the aqueous suspension prepared in step S2, stir and dissolve at 40°C, adjust the pH of the system to 10.5 using concentrated ammonia, and then slowly add 1.6 mL of tetraethyl orthosilicate dropwise over 1 hour using a constant pressure dropping funnel while stirring. After the addition is complete, react at 40°C for 6 hours.

[0070] S3-2. After the reaction is complete, the solid is collected by centrifugation, washed three times each with water and ethanol, and then redispersed in 200 mL of ethanol containing 1% hydrochloric acid. The mixture is refluxed and stirred at 60 °C for 6 hours to extract and remove hexadecyltrimethylammonium bromide. Then, the solid is centrifuged, washed, and dried to obtain a white core-shell structure powder.

[0071] S4. Construct and embed thermosensitive hydrogel networks.

[0072] S4-1. Slowly add 8g of poloxamer P407 and 2g of sodium hyaluronate to 80mL of pH 7.4 phosphate buffer solution, stir overnight to dissolve completely, and then bring the volume to 100mL.

[0073] S4-2. Weigh 5g of the core-shell structure powder prepared in step S3 and add it to the solution in step S4-1. Homogenize and disperse the powder at 5000rpm for 2 minutes in an ice bath. Then add 1mL of 1% (w / v) genipin aqueous solution and stir to mix. Transfer the mixed solution to a refrigerator at 4°C and allow it to stand for cross-linking reaction for 24 hours to form a uniform drug-loaded gel.

[0074] S5, freeze drying

[0075] S5-1. Dispense the drug-loaded gel into 2mL vials, 1mL per vial. Place the vials on the shelf of a lyophilizer that can establish a vertical temperature gradient. Set the program: reduce the temperature from 4℃ to -15℃ at a rate of 0.8℃ / min and hold for 1 hour; then reduce the temperature to -45℃ at a rate of 2℃ / min and hold for 2 hours to achieve complete freezing.

[0076] S5-2. Turn on the vacuum and dry. After freeze-drying, seal the capsule to obtain cefotaxime sodium preparation.

[0077] Example 3

[0078] This embodiment provides a method for preparing a long-acting, stable-release cefotaxime sodium formulation. The difference from Example 1 is that in step S2-2 of this embodiment, the molar ratio of hydrogenated soybean lecithin to dipalmitoylphosphatidylcholine is 1:1.2, meaning the amount of hydrogenated soybean lecithin is maintained at 1.296 g, and the amount of dipalmitoylphosphatidylcholine is adjusted to 0.893 g. The other steps are the same as in Example 1.

[0079] The specific preparation method is as follows:

[0080] S1. Preparation of cefotaxime sodium flake crystals

[0081] S1-1. Add 350 mL of ethanol-water mixed solvent to the reaction vessel, then add 2 g of polyoxyethylene-polyoxypropylene-polyoxyethylene triblock copolymer, stir until completely dissolved, continue to add 2.2 g of sodium acetate, stir until dissolved, then add 10 g of cefotaxime acid, and stir the reaction at 20°C for 45 minutes. The volume ratio of ethanol to water is 6:4.

[0082] S1-2. Start the cooling program and reduce the temperature to 5℃ at a rate of 0.5℃ / min. Let the crystals grow at 5℃ for 12 hours, then filter and wash the filter cake with ethanol.

[0083] S1-3. Place the filter cake in a vacuum drying oven at 35℃ and dry it overnight to obtain white flaky crystals.

[0084] S2, Constructing the phospholipid coating layer

[0085] S2-1. Take 9g of the cefotaxime sodium flake crystals prepared in step S1, disperse them in 200mL of phosphate buffer solution with pH 7.4, and sonicate for 10 minutes to obtain a crystal suspension.

[0086] S2-2. Weigh 1.296g of hydrogenated soybean lecithin and 0.595g of dipalmitoylphosphatidylcholine, and dissolve them together in 20mL of anhydrous ethanol to obtain a phospholipid ethanol solution.

[0087] S2-3. Under 40℃ water bath conditions, the phospholipid ethanol solution is slowly added dropwise to the crystal suspension, stirred and mixed, and then the mixture is transferred to a rotary evaporator for evaporation to remove the ethanol, resulting in a homogeneous aqueous suspension of phospholipid-coated crystals.

[0088] S3, Constructing a mesoporous silica shell

[0089] S3-1. Add 1.44 g of cetyltrimethylammonium bromide to the aqueous suspension prepared in step S2, stir and dissolve at 40°C, adjust the pH of the system to 10.5 using concentrated ammonia, and then slowly add 1.6 mL of tetraethyl orthosilicate dropwise over 1 hour using a constant pressure dropping funnel while stirring. After the addition is complete, react at 40°C for 6 hours.

[0090] S3-2. After the reaction is complete, the solid is collected by centrifugation, washed three times each with water and ethanol, and then redispersed in 200 mL of ethanol containing 1% hydrochloric acid. The mixture is refluxed and stirred at 60 °C for 6 hours to extract and remove hexadecyltrimethylammonium bromide. Then, the solid is centrifuged, washed, and dried to obtain a white core-shell structure powder.

[0091] S4. Construct and embed thermosensitive hydrogel networks.

[0092] S4-1. Slowly add 8g of poloxamer P407 and 2g of sodium hyaluronate to 80mL of pH 7.4 phosphate buffer solution, stir overnight to dissolve completely, and then bring the volume to 100mL.

[0093] S4-2. Weigh 5g of the core-shell structure powder prepared in step S3 and add it to the solution in step S4-1. Homogenize and disperse the powder at 5000rpm for 2 minutes in an ice bath. Then add 1mL of 1% (w / v) genipin aqueous solution and stir to mix. Transfer the mixed solution to a refrigerator at 4°C and allow it to stand for cross-linking reaction for 24 hours to form a uniform drug-loaded gel.

[0094] S5, freeze drying

[0095] S5-1. Dispense the drug-loaded gel into 2mL vials, 1mL per vial. Place the vials on the shelf of a lyophilizer that can establish a vertical temperature gradient. Set the program: reduce the temperature from 4℃ to -15℃ at a rate of 0.8℃ / min and hold for 1 hour; then reduce the temperature to -45℃ at a rate of 2℃ / min and hold for 2 hours to achieve complete freezing.

[0096] S5-2. Turn on the vacuum and dry. After freeze-drying, seal the capsule to obtain cefotaxime sodium preparation.

[0097] Example 4

[0098] This embodiment provides a method for preparing a long-acting, stable-release cefotaxime sodium formulation. The difference from Example 1 is that in step S3-1, 1.28 mL of tetraethyl orthosilicate is added, and the reaction time is extended to 8 hours, so that the most probable pore size of the prepared mesoporous shell is approximately 2.5 nm. The other steps are the same as in Example 1.

[0099] The specific preparation method is as follows:

[0100] S1. Preparation of cefotaxime sodium flake crystals

[0101] S1-1. Add 350 mL of ethanol-water mixed solvent to the reaction vessel, then add 2 g of polyoxyethylene-polyoxypropylene-polyoxyethylene triblock copolymer, stir until completely dissolved, continue to add 2.2 g of sodium acetate and stir until dissolved, then add 10 g of cefotaxime acid, and stir and react at 20 °C for 45 minutes. The volume ratio of ethanol to water is 6:4.

[0102] S1-2. Start the cooling program and reduce the temperature to 5℃ at a rate of 0.5℃ / min. Let the crystals grow at 5℃ for 12 hours, then filter and wash the filter cake with ethanol.

[0103] S1-3. Place the filter cake in a vacuum drying oven at 35℃ and dry it overnight to obtain white flaky crystals.

[0104] S2, Constructing the phospholipid coating layer

[0105] S2-1. Take 9g of the cefotaxime sodium flake crystals prepared in step S1, disperse them in 200 mL of phosphate buffer solution with pH 7.4, and sonicate for 10 minutes to obtain a crystal suspension.

[0106] S2-2. Weigh 1.296g of hydrogenated soybean lecithin and 0.744g of dipalmitoylphosphatidylcholine, and dissolve them together in 20mL of anhydrous ethanol to obtain a phospholipid ethanol solution.

[0107] S2-3. Under 40℃ water bath conditions, the phospholipid ethanol solution is slowly added dropwise to the crystal suspension, stirred and mixed, and then the mixture is transferred to a rotary evaporator for evaporation to remove the ethanol, resulting in a homogeneous aqueous suspension of phospholipid-coated crystals.

[0108] S3, Constructing a mesoporous silica shell

[0109] S3-1. Add 1.44 g of cetyltrimethylammonium bromide to the aqueous suspension prepared in step S2, stir and dissolve at 40 °C, adjust the pH of the system to 10.5 using concentrated ammonia, and then slowly add 1.28 mL of tetraethyl orthosilicate dropwise over 1 hour using a constant pressure dropping funnel while stirring. After the addition is complete, react at 40 °C for 8 hours.

[0110] S3-2. After the reaction is complete, the solid is collected by centrifugation, washed three times each with water and ethanol, and then redispersed in 200 mL of ethanol containing 1% hydrochloric acid. The mixture is refluxed and stirred at 60 °C for 6 hours to extract and remove hexadecyltrimethylammonium bromide. Then, the solid is centrifuged, washed, and dried to obtain a white core-shell structure powder.

[0111] S4. Construct and embed thermosensitive hydrogel networks.

[0112] S4-1. Slowly add 8g of poloxamer P407 and 2g of sodium hyaluronate to 80mL of pH 7.4 phosphate buffer solution, stir overnight to dissolve completely, and then bring the volume to 100mL.

[0113] S4-2. Weigh 5g of the core-shell structure powder prepared in step S3 and add it to the solution in step S4-1. Homogenize and disperse the powder at 5000rpm for 2 minutes in an ice bath. Then add 1mL of 1% (w / v) genipin aqueous solution and stir to mix. Transfer the mixed solution to a refrigerator at 4°C and allow it to stand for cross-linking reaction for 24 hours to form a uniform drug-loaded gel.

[0114] S5, freeze drying

[0115] S5-1. Dispense the drug-loaded gel into 2 mL vials, 1 mL per vial. Place the vials on the shelf of a lyophilizer that can establish a vertical temperature gradient. Set the program: reduce the temperature from 4°C to -15°C at a rate of 0.8°C / min and hold for 1 hour; then reduce the temperature to -45°C at a rate of 2°C / min and hold for 2 hours to achieve complete freezing.

[0116] S5-2. Turn on the vacuum and dry. After freeze-drying, seal the capsule to obtain cefotaxime sodium preparation.

[0117] Example 5

[0118] This embodiment provides a method for preparing a long-acting, stable-release cefotaxime sodium formulation. The difference from Example 1 is that in step S3-1, 2.4 mL of tetraethyl orthosilicate is added, and the reaction time is shortened to 4 hours, so that the most probable pore size of the prepared mesoporous shell is approximately 3.5 nm. The other steps are the same as in Example 1.

[0119] The specific preparation method is as follows:

[0120] S1. Preparation of cefotaxime sodium flake crystals

[0121] S1-1. Add 350 mL of ethanol-water mixed solvent to the reaction vessel, then add 2 g of polyoxyethylene-polyoxypropylene-polyoxyethylene triblock copolymer, stir until completely dissolved, continue to add 2.2 g of sodium acetate, stir until dissolved, then add 10 g of cefotaxime acid, and stir the reaction at 20°C for 45 minutes. The volume ratio of ethanol to water is 6:4.

[0122] S1-2. Start the cooling program and reduce the temperature to 5℃ at a rate of 0.5℃ / min. Let the crystals grow at 5℃ for 12 hours, then filter and wash the filter cake with ethanol.

[0123] S1-3. Place the filter cake in a vacuum drying oven at 35℃ and dry it overnight to obtain white flaky crystals.

[0124] S2, Constructing the phospholipid coating layer

[0125] S2-1. Take 9g of the cefotaxime sodium flake crystals prepared in step S1, disperse them in 200 mL of phosphate buffer solution with pH 7.4, and sonicate for 10 minutes to obtain a crystal suspension.

[0126] S2-2. Weigh 1.296 g of hydrogenated soybean lecithin and 0.744 g of dipalmitoylphosphatidylcholine, and dissolve them together in 20 mL of anhydrous ethanol to obtain a phospholipid ethanol solution.

[0127] S2-3. Under 40℃ water bath conditions, the phospholipid ethanol solution is slowly added dropwise to the crystal suspension, stirred and mixed, and then the mixture is transferred to a rotary evaporator for evaporation to remove the ethanol, resulting in a homogeneous aqueous suspension of phospholipid-coated crystals.

[0128] S3, Constructing a mesoporous silica shell

[0129] S3-1. Add 1.44 g of cetyltrimethylammonium bromide to the aqueous suspension prepared in step S2, stir and dissolve at 40 °C, adjust the pH of the system to 10.5 using concentrated ammonia, and then slowly add 1.28 mL of tetraethyl orthosilicate dropwise over 1 hour using a constant pressure dropping funnel while stirring. After the addition is complete, react at 40 °C for 8 hours.

[0130] S3-2. After the reaction is complete, the solid is collected by centrifugation, washed three times each with water and ethanol, and then redispersed in 200 mL of ethanol containing 1% hydrochloric acid. The mixture is refluxed and stirred at 60 °C for 6 hours to extract and remove hexadecyltrimethylammonium bromide. Then, the solid is centrifuged, washed, and dried to obtain a white core-shell structure powder.

[0131] S4. Construct and embed thermosensitive hydrogel networks.

[0132] S4-1. Slowly add 8g of poloxamer P407 and 2g of sodium hyaluronate to 80mL of pH 7.4 phosphate buffer solution, stir overnight to dissolve completely, and then bring the volume to 100mL.

[0133] S4-2. Weigh 5g of the core-shell structure powder prepared in step S3 and add it to the solution in step S4-1. Homogenize and disperse the powder at 5000rpm for 2 minutes in an ice bath. Then add 1mL of 1% (w / v) genipin aqueous solution and stir to mix. Transfer the mixed solution to a refrigerator at 4°C and allow it to stand for cross-linking reaction for 24 hours to form a uniform drug-loaded gel.

[0134] S5, freeze drying

[0135] S5-1. Dispense the drug-loaded gel into 2 mL vials, 1 mL per vial. Place the vials on the shelf of a lyophilizer that can establish a vertical temperature gradient. Set the program: reduce the temperature from 4°C to -15°C at a rate of 0.8°C / min and hold for 1 hour; then reduce the temperature to -45°C at a rate of 2°C / min and hold for 2 hours to achieve complete freezing.

[0136] S5-2. Turn on the vacuum and dry. After freeze-drying, seal the capsule to obtain cefotaxime sodium preparation.

[0137] Example 6

[0138] This embodiment provides a method for preparing a long-acting, stable-release cefotaxime sodium formulation. Unlike Example 1, this embodiment uses 12 g of poloxamer P407 and 1.5 g of sodium hyaluronate in step S4-1, while the other steps are the same as in Example 1.

[0139] The specific preparation method is as follows:

[0140] S1. Preparation of cefotaxime sodium flake crystals

[0141] S1-1. Add 350 mL of ethanol-water mixed solvent to the reaction vessel, then add 2 g of polyoxyethylene-polyoxypropylene-polyoxyethylene triblock copolymer, stir until completely dissolved, continue to add 2.2 g of sodium acetate, stir until dissolved, then add 10 g of cefotaxime acid, and stir the reaction at 20°C for 45 minutes. The volume ratio of ethanol to water is 6:4.

[0142] S1-2. Start the cooling program and reduce the temperature to 5℃ at a rate of 0.5℃ / min. Let the crystals grow at 5℃ for 12 hours, then filter and wash the filter cake with ethanol.

[0143] S1-3. Place the filter cake in a vacuum drying oven at 35℃ and dry it overnight to obtain white flaky crystals.

[0144] S2, Constructing the phospholipid coating layer

[0145] S2-1. Take 9g of the cefotaxime sodium flake crystals prepared in step S1, disperse them in 200 mL of phosphate buffer solution with pH 7.4, and sonicate for 10 minutes to obtain a crystal suspension.

[0146] S2-2. Weigh 1.296 g of hydrogenated soybean lecithin and 0.744 g of dipalmitoylphosphatidylcholine, and dissolve them together in 20 mL of anhydrous ethanol to obtain a phospholipid ethanol solution.

[0147] S2-3. Under 40℃ water bath conditions, the phospholipid ethanol solution is slowly added dropwise to the crystal suspension, stirred and mixed, and then the mixture is transferred to a rotary evaporator for evaporation to remove the ethanol, resulting in a homogeneous aqueous suspension of phospholipid-coated crystals.

[0148] S3, Constructing a mesoporous silica shell

[0149] S3-1. Add 1.44 g of cetyltrimethylammonium bromide to the aqueous suspension prepared in step S2, stir and dissolve at 40°C, adjust the pH of the system to 10.5 using concentrated ammonia, and then slowly add 1.6 mL of tetraethyl orthosilicate dropwise over 1 hour using a constant pressure dropping funnel while stirring. After the addition is complete, react at 40°C for 6 hours.

[0150] S3-2. After the reaction is complete, the solid is collected by centrifugation, washed three times each with water and ethanol, and then redispersed in 200 mL of ethanol containing 1% hydrochloric acid. The mixture is refluxed and stirred at 60 °C for 6 hours to extract and remove hexadecyltrimethylammonium bromide. Then, the solid is centrifuged, washed, and dried to obtain a white core-shell structure powder.

[0151] S4. Construct and embed thermosensitive hydrogel networks.

[0152] S4-1. Slowly add 12g of poloxamer P407 and 1.5g of sodium hyaluronate to 80mL of pH 7.4 phosphate buffer solution, stir overnight to dissolve completely, and then bring the volume to 100mL.

[0153] S4-2. Weigh 5g of the core-shell structure powder prepared in step S3 and add it to the solution in step S4-1. Homogenize and disperse the powder at 5000rpm for 2 minutes in an ice bath. Then add 1mL of 1% (w / v) genipin aqueous solution and stir to mix. Transfer the mixed solution to a refrigerator at 4°C and allow it to stand for cross-linking reaction for 24 hours to form a uniform drug-loaded gel.

[0154] S5, freeze drying

[0155] S5-1. Dispense the drug-loaded gel into 2 mL vials, 1 mL per vial. Place the vials on the shelf of a lyophilizer that can establish a vertical temperature gradient. Set the program: reduce the temperature from 4°C to -15°C at a rate of 0.8°C / min and hold for 1 hour; then reduce the temperature to -45°C at a rate of 2°C / min and hold for 2 hours to achieve complete freezing.

[0156] S5-2. Turn on the vacuum and dry. After freeze-drying, seal the capsule to obtain cefotaxime sodium preparation.

[0157] Example 6

[0158] This embodiment provides a method for preparing a long-acting, stable-release cefotaxime sodium formulation. The difference from Example 1 is that step S4-1 of this embodiment uses 22g of poloxamer P407 and 2.5g of sodium hyaluronate, while the other steps are the same as in Example 1.

[0159] The specific preparation method is as follows:

[0160] S1. Preparation of cefotaxime sodium flake crystals

[0161] S1-1. Add 350 mL of ethanol-water mixed solvent to the reaction vessel, then add 2 g of polyoxyethylene-polyoxypropylene-polyoxyethylene triblock copolymer, stir until completely dissolved, continue to add 2.2 g of sodium acetate, stir until dissolved, then add 10 g of cefotaxime acid, and stir the reaction at 20°C for 45 minutes. The volume ratio of ethanol to water is 6:4.

[0162] S1-2. Start the cooling program and reduce the temperature to 5℃ at a rate of 0.5℃ / min. Let the crystals grow at 5℃ for 12 hours, then filter and wash the filter cake with ethanol.

[0163] S1-3. Place the filter cake in a vacuum drying oven at 35℃ and dry it overnight to obtain white flaky crystals.

[0164] S2, Constructing the phospholipid coating layer

[0165] S2-1. Take 9g of the cefotaxime sodium flake crystals prepared in step S1, disperse them in 200 mL of phosphate buffer solution with pH 7.4, and sonicate for 10 minutes to obtain a crystal suspension.

[0166] S2-2. Weigh 1.296 g of hydrogenated soybean lecithin and 0.744 g of dipalmitoylphosphatidylcholine, and dissolve them together in 20 mL of anhydrous ethanol to obtain a phospholipid ethanol solution.

[0167] S2-3. Under 40℃ water bath conditions, the phospholipid ethanol solution is slowly added dropwise to the crystal suspension, stirred and mixed, and then the mixture is transferred to a rotary evaporator for evaporation to remove the ethanol, resulting in a homogeneous aqueous suspension of phospholipid-coated crystals.

[0168] S3, Constructing a mesoporous silica shell

[0169] S3-1. Add 1.44 g of cetyltrimethylammonium bromide to the aqueous suspension prepared in step S2, stir and dissolve at 40°C, adjust the pH of the system to 10.5 using concentrated ammonia, and then slowly add 1.6 mL of tetraethyl orthosilicate dropwise over 1 hour using a constant pressure dropping funnel while stirring. After the addition is complete, react at 40°C for 6 hours.

[0170] S3-2. After the reaction is complete, the solid is collected by centrifugation, washed three times each with water and ethanol, and then redispersed in 200 mL of ethanol containing 1% hydrochloric acid. The mixture is refluxed and stirred at 60 °C for 6 hours to extract and remove hexadecyltrimethylammonium bromide. Then, the solid is centrifuged, washed, and dried to obtain a white core-shell structure powder.

[0171] S4. Construct and embed thermosensitive hydrogel networks.

[0172] S4-1. Slowly add 12g of poloxamer P407 and 1.5g of sodium hyaluronate to 80mL of pH 7.4 phosphate buffer solution, stir overnight to dissolve completely, and then bring the volume to 100mL.

[0173] S4-2. Weigh 5g of the core-shell structure powder prepared in step S3 and add it to the solution in step S4-1. Homogenize and disperse the powder at 5000rpm for 2 minutes in an ice bath. Then add 1mL of 1% (w / v) genipin aqueous solution and stir to mix. Transfer the mixed solution to a refrigerator at 4°C and allow it to stand for cross-linking reaction for 24 hours to form a uniform drug-loaded gel.

[0174] S5, freeze drying

[0175] S5-1. Dispense the drug-loaded gel into 2 mL vials, 1 mL per vial. Place the vials on the shelf of a lyophilizer that can establish a vertical temperature gradient. Set the program: reduce the temperature from 4°C to -15°C at a rate of 0.8°C / min and hold for 1 hour; then reduce the temperature to -45°C at a rate of 2°C / min and hold for 2 hours to achieve complete freezing.

[0176] S5-2. Turn on the vacuum and dry. After freeze-drying, seal the capsule to obtain cefotaxime sodium preparation.

[0177] Comparative Example 1

[0178] This comparative example provides a method for preparing a cefotaxime sodium formulation. Unlike Example 1, this comparative example does not contain a phospholipid coating layer.

[0179] The specific preparation method is as follows:

[0180] S1. Preparation of cefotaxime sodium flake crystals

[0181] S1-1. Add 350 mL of ethanol-water mixed solvent to the reaction vessel, then add 2 g of polyoxyethylene-polyoxypropylene-polyoxyethylene triblock copolymer, stir until completely dissolved, continue to add 2.2 g of sodium acetate, stir until dissolved, then add 10 g of cefotaxime acid, and stir the reaction at 20°C for 45 minutes. The volume ratio of ethanol to water is 6:4.

[0182] S1-2. Start the cooling program and reduce the temperature to 5℃ at a rate of 0.5℃ / min. Let the crystals grow at 5℃ for 12 hours, then filter and wash the filter cake with ethanol.

[0183] S1-3. Place the filter cake in a vacuum drying oven at 35℃ and dry it overnight to obtain white flaky crystals.

[0184] S2. Disperse the white flaky crystals in 200 mL of phosphate buffer solution to obtain an aqueous suspension.

[0185] S3, Constructing a mesoporous silica shell

[0186] S3-1. Add 1.44 g of cetyltrimethylammonium bromide to the aqueous suspension prepared in step S2, stir and dissolve at 40°C, adjust the pH of the system to 10.5 using concentrated ammonia, and then slowly add 1.6 mL of tetraethyl orthosilicate dropwise over 1 hour using a constant pressure dropping funnel while stirring. After the addition is complete, react at 40°C for 6 hours.

[0187] S3-2. After the reaction is complete, the solid is collected by centrifugation, washed three times each with water and ethanol, and then redispersed in 200 mL of ethanol containing 1% hydrochloric acid. The mixture is refluxed and stirred at 60 °C for 6 hours to extract and remove hexadecyltrimethylammonium bromide. Then, the solid is centrifuged, washed, and dried to obtain a white core-shell structure powder.

[0188] S4. Construct and embed thermosensitive hydrogel networks.

[0189] S4-1. Slowly add 8g of poloxamer P407 and 2g of sodium hyaluronate to 80mL of pH 7.4 phosphate buffer solution, stir overnight to dissolve completely, and then bring the volume to 100mL.

[0190] S4-2. Weigh 5g of the core-shell structure powder prepared in step S3 and add it to the solution in step S4-1. Homogenize and disperse the powder at 5000rpm for 2 minutes in an ice bath. Then add 1mL of 1% (w / v) genipin aqueous solution and stir to mix. Transfer the mixed solution to a refrigerator at 4°C and allow it to stand for cross-linking reaction for 24 hours to form a uniform drug-loaded gel.

[0191] S5, freeze drying

[0192] S5-1. Dispense the drug-loaded gel into 2 mL vials, 1 mL per vial. Place the vials on the shelf of a lyophilizer that can establish a vertical temperature gradient. Set the program: reduce the temperature from 4°C to -15°C at a rate of 0.8°C / min and hold for 1 hour; then reduce the temperature to -45°C at a rate of 2°C / min and hold for 2 hours to achieve complete freezing.

[0193] S5-2. Turn on the vacuum and dry. After freeze-drying, seal the capsule to obtain cefotaxime sodium preparation.

[0194] Comparative Example 2

[0195] This comparative example provides a method for preparing a cefotaxime sodium formulation. Unlike Example 1, this comparative example does not contain a mesoporous silica shell.

[0196] The specific preparation method is as follows:

[0197] S1. Preparation of cefotaxime sodium flake crystals

[0198] S1-1. Add 350 mL of ethanol-water mixed solvent to the reaction vessel, then add 2 g of polyoxyethylene-polyoxypropylene-polyoxyethylene triblock copolymer, stir until completely dissolved, continue to add 2.2 g of sodium acetate, stir until dissolved, then add 10 g of cefotaxime acid, and stir the reaction at 20°C for 45 minutes. The volume ratio of ethanol to water is 6:4.

[0199] S1-2. Start the cooling program and reduce the temperature to 5℃ at a rate of 0.5℃ / min. Let the crystals grow at 5℃ for 12 hours, then filter and wash the filter cake with ethanol.

[0200] S1-3. Place the filter cake in a vacuum drying oven at 35℃ and dry it overnight to obtain white flaky crystals.

[0201] S2, Constructing the phospholipid coating layer

[0202] S2-1. Take 9g of the cefotaxime sodium flake crystals prepared in step S1, disperse them in 200 mL of phosphate buffer solution with pH 7.4, and sonicate for 10 minutes to obtain a crystal suspension.

[0203] S2-2. Weigh 1.296 g of hydrogenated soybean lecithin and 0.744 g of dipalmitoylphosphatidylcholine, and dissolve them together in 20 mL of anhydrous ethanol to obtain a phospholipid ethanol solution.

[0204] S2-3. Under 40℃ water bath conditions, the phospholipid ethanol solution is slowly added dropwise to the crystal suspension, stirred and mixed, and then the mixture is transferred to a rotary evaporator for evaporation to remove the ethanol, resulting in a homogeneous aqueous suspension of phospholipid-coated crystals.

[0205] S3. Construct and embed thermosensitive hydrogel networks.

[0206] S3-1. Slowly add 8g of poloxamer P407 and 2g of sodium hyaluronate to 80mL of pH 7.4 phosphate buffer solution, stir overnight to dissolve completely, and then bring the volume to 100mL.

[0207] S3-2. Weigh 2.5g of the homogeneous aqueous suspension of phospholipid-coated crystals prepared in step S2, add it to the solution in step S3-1, homogenize and disperse it at 5000rpm for 2 minutes in an ice bath, then add 1mL of 1% (w / v) genipin aqueous solution, stir and mix well, transfer the mixed solution to a refrigerator at 4℃, and let it stand for cross-linking reaction for 24 hours to form a homogeneous drug-loaded gel.

[0208] S4, freeze drying

[0209] S4-1. Dispense the drug-loaded gel into 2 mL vials, 1 mL per vial. Place the vials on the shelf of a lyophilizer that can establish a vertical temperature gradient. Set the program: reduce the temperature from 4°C to -15°C at a rate of 0.8°C / min and hold for 1 hour; then reduce the temperature to -45°C at a rate of 2°C / min and hold for 2 hours to achieve complete freezing.

[0210] S4-2. Open the vacuum and dry the product. After freeze-drying, seal the container to obtain the cefotaxime sodium preparation.

[0211] Comparative Example 3

[0212] This comparative example provides a method for preparing a cefotaxime sodium formulation. Unlike Example 1, this comparative example uses a monolayer hydrogel carrier.

[0213] S1. Preparation of cefotaxime sodium flake crystals

[0214] S1-1. Add 350 mL of ethanol-water mixed solvent to the reaction vessel, then add 2 g of polyoxyethylene-polyoxypropylene-polyoxyethylene triblock copolymer, stir until completely dissolved, continue to add 2.2 g of sodium acetate, stir until dissolved, then add 10 g of cefotaxime acid, and stir the reaction at 20°C for 45 minutes. The volume ratio of ethanol to water is 6:4.

[0215] S1-2. Start the cooling program and reduce the temperature to 5℃ at a rate of 0.5℃ / min. Let the crystals grow at 5℃ for 12 hours, then filter and wash the filter cake with ethanol.

[0216] S1-3. Place the filter cake in a vacuum drying oven at 35℃ and dry it overnight to obtain white flaky crystals.

[0217] S2. Slowly add 8g of poloxamer P407 and 2g of sodium hyaluronate to 80mL of pH 7.4 phosphate buffer solution, stir overnight to completely dissolve, and bring the volume to 100mL to obtain the pre-hydrogel solution; weigh 2.5g of white flaky crystals and disperse them in the pre-hydrogel solution, then add 1mL of 1% (w / v) genipin aqueous solution, stir to mix well, transfer the mixed solution to a refrigerator at 4℃, and let it stand for cross-linking reaction for 24 hours to form a homogeneous drug-loaded gel.

[0218] S3, freeze drying

[0219] S3-1. Dispense the drug-loaded gel into 2 mL vials, 1 mL per vial. Place the vials on the shelf of a lyophilizer that can establish a vertical temperature gradient. Set the program: reduce the temperature from 4°C to -15°C at a rate of 0.8°C / min and hold for 1 hour; then reduce the temperature to -45°C at a rate of 2°C / min and hold for 2 hours to achieve complete freezing.

[0220] S3-2. Open the vacuum and dry the product. After freeze-drying, seal the container to obtain the cefotaxime sodium preparation.

[0221] The cefotaxime sodium formulations prepared using the methods of Examples 1-8 and Comparative Examples 1-3 were subjected to systematic in vitro release and accelerated stability tests.

[0222] 1. In vitro release rate determination

[0223] Experimental Methods: Weigh 50 mg of each sample and place it in a dialysis bag. After sealing, the bag serves as the drug release unit. Immerse the bag in a dissolution vessel containing 900 mL of release medium, maintaining a temperature of 37 ± 0.5 °C and a paddle speed of 50 rpm. At predetermined time points, take 5 mL of sample (simultaneously replenishing with an equal volume of fresh medium at the same temperature), filter through a 0.22 μm filter membrane, and determine the drug concentration using high-performance liquid chromatography (HPLC). Calculate the cumulative release percentage (%). Each sample was tested in triplicate. The results are shown in Table 1.

[0224] Table 1

[0225]

[0226] The test data above shows that all examples have a release rate of more than 25% within 1 hour, indicating that they have the ability to take effect quickly. However, Comparative Examples 1 and 2 have a very low release rate within 1 hour due to the lack of a body temperature-triggered release mechanism, and take effect slowly.

[0227] Furthermore, the release rates of all examples within 24 to 72 hours conformed to a zero-order kinetic model (R² > 0.99), indicating excellent drug release stability. Comparative Example 2, lacking diffusion restriction from mesoporous silica, exhibited severe initial burst release (48.5% in 1 hour) and rapid release decay in the later stages, conforming to first-order kinetics and showing poor stability. The release rates of Comparative Examples 1 and 3 were primarily diffusion-controlled, conforming to the Higuchi model, with the release rate significantly decreasing over time.

[0228] 2. Accelerated stability test

[0229] Experimental methods: Each sample was placed in a drug stability test chamber and subjected to accelerated testing at a temperature of 40±2℃ and a relative humidity of 75±5%. Samples were taken at the end of 0, 1, 3, and 6 months to examine appearance. The content of cefotaxime sodium and total impurities were determined by HPLC. Content was calculated using the external standard method, and related substances were determined using a self-control method. The test results are shown in Table 2.

[0230] Table 2

[0231]

[0232] The test results above show that, after 6 months of accelerated testing, the content of the core active ingredient in all embodiments of this invention decreased by only a small amount (≤0.7%), the increase of related impurities was negligible (≤0.3%), and the moisture content was controlled at an extremely low level (<0.52%). This fully demonstrates that the tertiary carrier structure of phospholipids, mesoporous silica, and thermosensitive hydrogel constructed in this invention can synergistically provide excellent stability protection for cefotaxime sodium, which is sensitive to moisture and heat, from multiple levels such as molecular barrier, physical barrier, and deep drying. However, the test data from Comparative Examples 1-3 show that the absence of any layer of structure leads to a significant deterioration in stability indicators. The decrease in cefotaxime sodium content and the increase in impurities in the comparative examples are both higher than those in the embodiments, proving that there is a synergistic effect among the three-level structures of the sustained-release carrier defined in this application.

[0233] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features therein. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention, and they should all be covered within the scope of the claims and specification of the present invention.

Claims

1. A long-acting, stable-release cefotaxime sodium formulation, characterized in that, The invention includes cefotaxime sodium flake crystals, wherein the cefotaxime sodium flake crystals are coated with a sustained-release carrier; the sustained-release carrier has a tertiary structure, including a phospholipid coating layer covering the surface of the cefotaxime sodium flake crystals, a mesoporous silica shell covering the surface of the phospholipid coating layer, and a thermosensitive hydrogel network layer covering the surface of the mesoporous silica shell.

2. The long-acting, stable-release cefotaxime sodium formulation according to claim 1, characterized in that, The raw material for the phospholipid coating layer is a combination of hydrogenated soybean lecithin and dipalmitoylphosphatidylcholine, wherein the molar ratio of hydrogenated soybean lecithin to dipalmitoylphosphatidylcholine is 1:(0.5~2).

3. The long-acting, stable-release cefotaxime sodium formulation according to claim 1, characterized in that, The raw materials for the thermosensitive hydrogel network layer include thermosensitive block copolymers and biopolysaccharides, and a cross-linked network is formed by a cross-linking agent.

4. A long-acting, stable-release cefotaxime sodium formulation according to claim 3, characterized in that, The concentration of the thermosensitive block copolymer in the crosslinking network is 10%-25%; the concentration of the biopolysaccharide in the crosslinking network is 0.5%-3.0%; the crosslinking agent is genipin, and its dosage is 0.5%~5% of the mass of the biopolysaccharide.

5. A long-acting, stable-release cefotaxime sodium formulation according to claim 1, characterized in that, The mesoporous silica shell has a mesopore size of 2.5 nm to 3.5 nm.

6. A method for preparing a long-acting, stable-release cefotaxime sodium formulation, characterized in that, Includes the following steps: S1. Cefotaxime acid is reacted with a salt-forming agent in a mixed solvent in the presence of a template agent to prepare flaky crystals of cefotaxime sodium. S2. Disperse the flaky crystals obtained in step S1 in an aqueous solution, add an organic solution containing phospholipids, stir to mix evenly, and then evaporate to remove the organic solvent, forming a phospholipid monolayer coating on the surface of the flaky crystals. S3. Disperse the phospholipid-coated crystals obtained in step S2 in an aqueous solution, add a surfactant and a silicon source, and react them by sol-gel method to form a mesoporous silica shell on the outside of the phospholipid monolayer coating to obtain core-shell structured particles. S4. Disperse the core-shell structured particles obtained in step S3 in an aqueous solution containing thermosensitive block copolymer and biopolysaccharide, add a crosslinking agent to carry out a crosslinking reaction, and form a drug-loaded thermosensitive hydrogel that embeds the core-shell structured particles. S5. The drug-loaded thermosensitive hydrogel obtained in step S4 is freeze-dried to obtain the freeze-dried cefotaxime sodium preparation.

7. The method for preparing a long-acting, stable-release cefotaxime sodium formulation according to claim 6, characterized in that, In step S1, the template agent is a polyoxyethylene-polyoxypropylene-polyoxyethylene triblock copolymer.

8. The method for preparing a long-acting, stable-release cefotaxime sodium formulation according to claim 6, characterized in that, In step S3, the surfactant is hexadecyltrimethylammonium bromide, and the silicon source is tetraethyl orthosilicate.

9. The method for preparing a long-acting, stable-release cefotaxime sodium formulation according to claim 6, characterized in that, In step S3, the pH value of the reaction system is controlled at 9~11, and the reaction temperature is 30℃~50℃.

10. A pharmaceutical composition, characterized in that, Includes the cefotaxime sodium preparation according to any one of claims 1 to 5 or the cefotaxime sodium preparation prepared by any one of claims 6 to 9.

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