A preparation method of a nano-carrier-based post-anesthesia sedative drug sustained-release preparation for children

Abstract

The application discloses a preparation method of a nano-carrier-based post-anesthesia sedative drug sustained-release preparation for children, and belongs to the technical field of pharmaceutical preparations, and comprises the following steps: (1) organic phase preparation, (2) emulsification treatment, (3) volatilization solidification, (4) purification treatment, (5) blending treatment and (6) finished product preparation. The method steps are clear, the conditions are mild, no complex chemical reactions or toxic organic solvent residue risks are involved, good operability and large-scale production potential are achieved, and the core difficulties that smooth drug release, targeted delivery and child adaptability are difficult to be considered in the prior art are effectively solved.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical formulation technology, specifically relating to a sustained-release formulation of a pediatric post-anesthesia sedative drug based on a nanocarrier and its preparation method. Background Technology

[0002] Postoperative sedation is a crucial aspect of pediatric anesthesia recovery management, aiming to alleviate agitation and pain, and ensure the child's safety and comfort. Currently, clinical practice for pediatric postoperative sedation primarily relies on traditional administration methods, the technological evolution and current status of which are as follows: 1. Limitations of Traditional Drug Administration Methods: Current technology involves routine intravenous infusion or intermittent injection of sedative drugs (such as dexmedetomidine and midazolam). While these methods offer rapid onset of action, they have significant drawbacks: the drugs distribute rapidly in the body and have relatively short elimination half-lives. To maintain effective blood drug concentrations, continuous infusion or frequent booster doses are required, leading to large fluctuations in blood drug concentrations and a tendency for peak-trough phenomena. Peak blood drug concentrations may cause excessive sedation risks such as respiratory depression and bradycardia; while troughs result in insufficient sedation, making children prone to agitation. Furthermore, repeated punctures or continuous infusions cause additional pain and fear for children and increase the workload of medical staff.

[0003] 2. Limitations of Existing Sustained-Release Formulation Technologies: To overcome the shortcomings of traditional drug delivery methods, sustained-release formulation technologies have been introduced. Existing technologies include studies using liposomes or polymer microspheres as drug carriers. For example, the journal "Journal of Controlled Release" reported the use of PLGA microspheres to encapsulate sedative drugs for long-acting release. However, directly applying these existing sustained-release technologies to postoperative sedation in children still faces the following specific problems: Particle size and targeting: Many existing microsphere formulations have large particle sizes (usually in the micrometer range), making it difficult to achieve tissue targeting. They mainly rely on passive diffusion after local injection, which is not suitable for postoperative scenarios that require systemic sedation.

[0004] Burst release effect and controlled release precision: Some drug delivery systems exhibit a significant initial "burst release" phenomenon, meaning a large amount of drug is released in a short period of time. This contradicts the need for stable sedation immediately after surgery, rather than a surge in doses, and safety risks remain. Furthermore, the release curve is difficult to precisely control to meet the individualized and predictable sedation duration requirements of children.

[0005] Drug loading and formulation suitability: Precise dosage in children requires formulations with high drug loading and consistent dosage units. Some existing nanocarrier formulations have low drug loading or complex manufacturing processes, making it difficult to guarantee batch-to-batch uniformity, and are therefore unsuitable for children and other special populations sensitive to dosage errors.

[0006] 3. The unique physiological characteristics of children and the challenges of adapting technology: Children, especially young children, have underdeveloped liver and kidney functions, resulting in significant differences in pharmacokinetics compared to adults. Existing sustained-release technologies developed based on adult data often lack specific design considerations for children's physiological characteristics (such as higher metabolic rates and faster volumes of distribution), leading to unpredictable drug release behavior and difficulty in achieving "precise sedation." Simply converting adult formulations to body weight for children is a common but risky practice in current clinical settings.

[0007] In summary, the existing technology lacks a drug delivery system specifically designed for postoperative sedation in children. The core challenges lie in simultaneously achieving: (1) stable and controllable drug release to eliminate fluctuations in blood drug concentration; (2) appropriate nanoscale to improve drug distribution behavior in vivo; (3) high drug loading and good batch uniformity to meet the precise drug administration needs of children; and (4) excellent biocompatibility and safety. Solving these common problems and developing a sustained-release formulation for postoperative sedation in children that provides stable onset, long-lasting effect, precise dosage, and safety has significant clinical implications and application value. Summary of the Invention

[0008] To address the aforementioned issues, this invention provides a novel "precise, stable, long-lasting, and safe" solution specifically designed for postoperative sedation in children. This solution overcomes the core challenge of simultaneously achieving stable drug release, targeted delivery, and pediatric suitability in existing technologies, as detailed below: A method for preparing a sustained-release formulation of a pediatric post-anesthesia sedative based on a nanocarrier includes the following steps: (1) Organic phase preparation: The drug, carrier and organic solvent are mixed evenly to form an organic phase for later use; (2) Emulsification treatment: The organic phase is added to the aqueous solution and stirred evenly to obtain the pre-emulsion for later use; (3) Evaporation and solidification: The primary emulsion is transferred to a rotary evaporator, and the organic solvent is removed by vacuum evaporation, and solidified to form a nanoparticle suspension for later use; (4) Purification treatment: The nanoparticle suspension is purified to remove free drugs and surfactants, and purified nanoparticles are obtained for later use; (5) Preparation and treatment: The purified nanoparticles were resuspended in buffer solution to obtain a sustained-release solution for later use; (6) Preparation of finished product: The sustained-release solution can be directly aseptically filled or freeze-dried to produce lyophilized powder injection.

[0009] Furthermore, the drug mentioned in step (1) is dexmedetomidine or midazolam; in actual use, it can be selected from a class of drugs suitable for postoperative sedation in children. These drugs have the advantages of rapid onset of action and definite sedation effect, and are used to produce and maintain the sedation and anti-anxiety effect required after surgery.

[0010] The carrier is a polylactic acid-glycolic acid copolymer. In practical applications, other biocompatible and biodegradable materials can also be selected, such as polycaprolactone, hydrogenated soybean lecithin, cholesterol, and DSPE-PEG (polyethylene glycol-modified phospholipids). This carrier acts as a diffusion barrier and degradation host, achieving programmed drug release through slow hydrolysis or enzymatic hydrolysis, effectively inhibiting initial burst release, protecting the drug from attack by enzymes in body fluids, and reducing non-specific binding of the drug to plasma proteins. When PEGylated materials are used, "invisible" nanoparticles can be formed, avoiding rapid clearance by the reticuloendothelial system, thereby prolonging the circulation time in vivo and achieving more stable systemic sedation.

[0011] The organic solvent is at least one of ethyl acetate, dichloromethane, and acetone.

[0012] Furthermore, the aqueous solution described in step (2) is an aqueous solution containing a surfactant; the surfactant is at least one of polyvinyl alcohol, poloxamer 188, Tween 80, and vitamin E TPGS. This reduces interfacial tension during preparation, helping to form a uniform and stable nanoemulsion or dispersion; and prevents nanoparticle aggregation and precipitation in the finished product, maintaining physical stability.

[0013] Furthermore, the stirring method described in step (2) is high-speed shear stirring or ultrasonic treatment.

[0014] Furthermore, the vacuum degree is controlled to be -0.08 to -0.09 MPa during the reduced pressure evaporation described in step (3).

[0015] Furthermore, the purification process described in step (4) is centrifugal purification or ultrafiltration purification.

[0016] Furthermore, the buffer solution in step (5) is primarily a phosphate buffer solution, which maintains the formulation within a suitable pH range (e.g., 5.0-7.4) to ensure the chemical stability of the drug and carrier material; it also contains at least one of an isotonic agent and a lyophilization protectant; the isotonic agent is a sucrose solution or a trehalose solution; and the lyophilization protectant is a glucose solution.

[0017] Furthermore, the freeze-drying described in step (6) is specifically performed using a vacuum freeze dryer.

[0018] A sustained-release formulation of a pediatric post-anesthesia sedative drug based on a nanocarrier, prepared by any of the methods described above.

[0019] Furthermore, the sustained-release formulation may be a solution or powder, or other medically acceptable dosage forms.

[0020] The release of the drug from the nanocarrier in this sustained-release formulation is a controlled process. Initially, a small amount of drug adsorbed on or near the surface of the carrier diffuses rapidly, achieving a mild onset of action. In the middle and later stages, the drug deeply embedded in the carrier or matrix is ​​slowly and continuously released through the formed micropores as the carrier material permeates the body fluids and degrades under the action of enzymes, thus achieving a stable blood drug concentration for several hours to tens of hours.

[0021] Furthermore, the suitable nanoparticle size allows it to avoid pulmonary capillary interception and smoothly enter the systemic circulation. PEGylation further enables it to "invisibly" circulate for a long time, reducing liver uptake and distributing more evenly, thereby achieving a stable systemic sedation effect, perfectly suited to the postoperative needs of children.

[0022] Ultimately, through the precise design and combination of active drugs, intelligent nanocarriers, and stable excipients, an advanced drug delivery system was constructed that can respond to the physiological characteristics of children and achieve "precise loading, programmed release, stable onset of action, and long-lasting maintenance".

[0023] The present invention has the following advantages over the prior art: (1) The formulation of the present invention has stable and controllable drug release characteristics: through the design and preparation process of specific nanocarriers, the drug can be released in vivo in zero-order or first-order kinetics, significantly inhibiting the initial "burst release" and ensuring that the blood drug concentration remains stable within the ideal therapeutic window for a long time.

[0024] (2) Advantages in particle size and targeting: Nanocarriers typically have a particle size of less than 200 nm, which can improve the distribution behavior of drugs in the body through passive targeting effect (EPR effect), making it more conducive to achieving stable sedation throughout the body and avoiding the risks caused by local drug accumulation.

[0025] (3) High drug loading and good batch uniformity: The optimized preparation process can achieve a high drug loading (not less than 10%) and encapsulation rate, while ensuring that the particle size and release curve of different batches of products are highly consistent, meeting the stringent requirements of dosage accuracy for children's medication.

[0026] (4) Good biocompatibility and safety: The selected carrier materials are all biodegradable polymers or natural / synthetic lipids that can be metabolized into non-toxic products in the body, significantly reducing the safety risks of long-term or high-dose use. The formulation itself and the degradation products are non-cytotoxic, making it suitable for children, a sensitive population.

[0027] (5) The preparation process is simple and easy to scale up industrially: The method of the present invention has clear steps, mild conditions, does not involve complex chemical reactions or the risk of toxic organic solvent residues, and has good operability and large-scale production potential. Detailed Implementation

[0028] To make the objectives, technical solutions, and advantages of this invention clearer, the technical solutions in the embodiments of this invention will be clearly and completely described below in conjunction with the embodiments of this invention. Obviously, the described embodiments are only a part of the embodiments of this invention, and not all of the embodiments. Based on the embodiments of this invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of this invention.

[0029] In the embodiments, it should be noted that any processes not specifically described below are those that can be implemented or understood by those skilled in the art by referring to existing technology. Reagents or instruments whose manufacturers are not specified are considered to be conventional products that can be purchased commercially. Example

[0030] A method for preparing a sustained-release formulation of a pediatric post-anesthesia sedative based on a nanocarrier includes the following steps: (1) Selection of ingredients: Active ingredient: Dexmedetomidine 10 mg; Carrier material: PLGA (MW 15kDa, LA:GA=75:25) 100 mg; Organic solvent: 2 mL of ethyl acetate; Aqueous phase: 20 mL of 1% (w / v) polyvinyl alcohol (PVA) aqueous solution; Lyophilization protectant: 5% (w / v) sucrose solution; (2) Organic phase preparation: 10 mg dexmedetomidine and 100 mg PLGA were dissolved together in 2 mL of ethyl acetate and magnetically stirred until completely clear. This step ensures that the drug and the carrier are mixed at the molecular level, which is a prerequisite for obtaining high encapsulation efficiency and a uniform matrix.

[0031] (3) Primary emulsification: The above organic phase was added dropwise to 20 mL of 1% PVA aqueous solution using a syringe at a constant rate (1 mL / min), while simultaneously shearing at 10,000 rpm for 3 minutes using a high-speed shear emulsifier. PVA, as an emulsifier and stabilizer, can rapidly reduce the oil / water interfacial tension, forming a fine-particle-size O / W type primary emulsion. The shear rate and time in this step are key to controlling the final nanoparticle size, directly affecting the in vivo distribution and release behavior of the formulation.

[0032] (4) Solvent evaporation and nanoparticle solidification: The primary emulsion was transferred to a round-bottom flask and rotary evaporated for 1 hour under reduced pressure in a 30°C water bath to completely remove ethyl acetate. As the organic solvent was removed, PLGA in the aqueous phase gradually precipitated and solidified, encapsulating the drug and forming solid nanoparticles. The mild low-temperature evaporation conditions avoided the degradation of the drug and polymer and prevented the aggregation of nanoparticles.

[0033] (5) Purification: The resulting suspension was centrifuged at 15,000 rpm for 30 minutes, and the supernatant (containing free drug, PVA, etc.) was discarded. The precipitated nanoparticles were resuspended in purified water and centrifuged again. This process was repeated 3 times. This step is crucial in removing unencapsulated free drug, thus fundamentally eliminating the "burst release source" in the formulation that may lead to the initial peak blood drug concentration.

[0034] (6) Formulation and lyophilization: The purified nanoparticle precipitate was quantitatively resuspended in 5% sucrose solution, and the pH was adjusted to 6.5-7.0 with phosphate buffer. After sterile filtration through a 0.22μm microporous membrane, it was dispensed into vials to prepare a liquid preparation.

[0035] Partially freeze-dried to form a powder: (pre-freezing: -40℃, 4h; sublimation: -20℃, 10Pa, 24h; desorption drying: 25℃, 10Pa, 6h), yielding a white, loose, blocky freeze-dried powder injection. Sucrose, as a freeze-drying protectant, can maintain the integrity of the nanoparticle structure during the drying process, ensuring that the particle size does not increase or aggregate after reconstitution.

[0036] The key parameters and efficacy of the above formulation were validated: Particle size and distribution: The average particle size was 120 ± 15 nm, as determined by dynamic light scattering, and the polydispersity index (PDI) was <0.15. The uniform nanoscale size ensures good dispersibility and long cycling potential.

[0037] Encapsulation efficiency and drug loading: High-performance liquid chromatography (HPLC) determined the encapsulation efficiency to be 92% and the drug loading to be 8.3%. The high encapsulation efficiency demonstrates the effectiveness of the preparation process, and the high drug loading meets the needs of precise, low-dose administration to children.

[0038] In vitro release: Release was achieved by shaking in phosphate buffer at pH 7.4 at 37°C. Results showed that approximately 15% was released cumulatively after 2 hours (mild onset of action); approximately 65% ​​was released cumulatively after 24 hours (stable release); and over 90% was released cumulatively after 72 hours (complete release). The release curve was smooth with no sudden release peak, perfectly demonstrating the "diffusion-erosion synergistic controlled release" mechanism and solving the core problem of blood drug concentration fluctuations.

[0039] Stability: After being stored at 4°C for 6 months, the lyophilized powder injection showed no significant changes in particle size, drug loading, and release behavior upon reconstitution, demonstrating its good physicochemical stability and suitability for industrial production and storage.

[0040] This invention combines a well-defined nanocarrier with a controllable preparation method. Its working principle is interconnected, ultimately realizing an intelligent drug delivery system that can actively overcome the defects of existing technologies (such as burst release, fluctuation, and poor compatibility with children). It provides a repeatable and mass-producible process route, ensuring the feasibility of this patented technology from principle to product. Example

[0041] A method for preparing a sustained-release formulation of a pediatric post-anesthesia sedative based on a nanocarrier includes the following steps: (1) Selection of ingredients: Active ingredient: Dexmedetomidine hydrochloride 10 mg; Carrier material: PLGA (MW 15kDa, LA:GA=75:25) 100 mg; Organic solvent: 1 mL dichloromethane + 1 mL acetone (mixed solvent); Aqueous phase: 25 mL of 2% (w / v) PVA aqueous solution; Lyophilization protectant: 6% (w / v) sucrose solution (used at a ratio of 1:1 to the final suspension of nanoparticles); Reconstitution medium: Water for injection (when in use).

[0042] The preparation method in this embodiment is the same as that in Example 1, except that the specific parameters of the following operations have been adjusted: Emulsification parameters during primary emulsification: shear rate 13,000 rpm, shear time 3 minutes.

[0043] Evaporation parameters for solvent evaporation and nanoparticle solidification: 35℃ water bath, vacuum degree ≤50 mbar, time 45 minutes.

[0044] Purification parameters: 18000 rpm, 4℃, 30 minutes, wash twice.

[0045] Freeze-drying parameters: pre-freeze -45℃ / 4h; first drying -15℃ / 0.1 mbar / 24h; second drying 25℃ / 0.1 mbar / 8h.

[0046] The formulation performance corresponding to Example 2: Particle size: 120 ± 15 nm; Encapsulation efficiency: >90%; Drug loading: 8%; In vitro release: 15% at 2h, 65% at 24h, >90% at 72h, no burst release.

[0047] This method employs a precise and controllable five-step process—organic phase preparation, emulsification, solidification, purification, and freeze-drying—combined with key equipment such as a high-speed shear emulsifier, rotary evaporator, and refrigerated centrifuge, to successfully prepare nano-sustained-release formulations with uniform particle size, high encapsulation efficiency, and stable release.

[0048] The following conclusions can be drawn from the above embodiments of the present invention: This invention effectively eliminates the dangerous "peak-valley" phenomenon: through a "diffusion-erosion synergistic controlled release" mechanism (e.g., the initial mild release and subsequent continuous degradation of PLGA nanoparticles), the drug release rate is precisely controlled. In vitro release experiments show that only about 15% is released in the initial 2 hours, avoiding the "burst release" of over 30% common in traditional injections or microsphere formulations. This fundamentally eliminates the risk of serious adverse reactions such as respiratory depression, bradycardia, and hypotension caused by peak blood drug concentrations. Simultaneously, the stable release avoids the risks of agitation and accidental extubation in children due to insufficient sedation during troughs.

[0049] Achieving precise maintenance within the therapeutic window: After a single dose, blood drug concentrations can be stably maintained within the pre-defined therapeutic window during the critical postoperative recovery period of up to 24-72 hours. This provides children with continuous, predictable, and physiologically appropriate depths of sedation, significantly improving the safety and controllability of clinical medication.

[0050] It effectively improves the convenience of medication use and patient compliance (operation and control), which directly improves clinical procedures and patients' medical experience.

[0051] This reduces the frequency of administration and the workload for healthcare professionals: Traditional continuous intravenous infusion requires frequent adjustments to the pump rate or changes to the infusion bag, while this formulation can be administered in a single dose (e.g., via intravenous bolus or intramuscular injection) to cover the entire postoperative sedation period. This greatly simplifies nursing procedures, reduces the workload of healthcare personnel, and lowers the medical risks caused by operational errors.

[0052] Reducing pain and fear in children: Compared to repeated intravenous punctures or prolonged indwelling infusions, single-dose administration (especially if subcutaneous or intramuscular injection) can significantly reduce children's pain and psychological fear, improve their medical experience, and increase treatment compliance, especially for young and uncooperative children.

[0053] Improved physicochemical stability: The use of lyophilized powder for injection (containing lyophilization protectants such as sucrose) allows the formulation to be stably stored at 4°C for more than 6 months, with no significant changes in particle size, drug loading, and release curve after reconstitution. This solves the problems of easy aggregation, leakage, and sedimentation of traditional solution-type or liposome nanosuspensions during storage, ensuring the quality stability of the product throughout its entire life cycle from production to use.

[0054] Ensuring batch-to-batch homogeneity: Optimized preparation processes (such as high-speed shear-solvent evaporation) can precisely control the particle size distribution of nanoparticles (PDI < 0.15), ensuring a high degree of consistency in drug loading and release behavior across different batches. This is crucial for pediatric patients requiring precise dosage adjustments, avoiding efficacy fluctuations or toxicity risks due to batch-to-batch variations in formulation.

[0055] This method effectively reduces overall production costs and energy consumption. Although the initial R&D investment is high, this technology has a cost-effective advantage from the perspective of the entire life cycle.

[0056] The preparation process is simple and mild: the main process (emulsification-solvent evaporation method) is carried out under normal pressure and low temperature (30℃) conditions, without the need for extreme conditions such as high temperature and high pressure, which reduces energy consumption in the production process.

[0057] Simplifying the drug delivery system saves manpower and resources: Single-injection drug delivery replaces continuous intravenous infusion systems (which require infusion pumps, tubing, monitoring equipment, etc.), directly reducing the use of consumables and the occupation of monitoring equipment, and saving nurses the labor costs of repeated operations. This is also a way to save social costs and energy.

[0058] In addition, other useful features have been added: Drug compatibility and scalability: Nanocarrier systems (such as PLGA, lipids, etc.) have strong versatility and can encapsulate different types of sedative, analgesic, or anti-anxiety drugs (such as dexmedetomidine, midazolam, fentanyl, etc.), and can achieve multi-drug combined delivery, providing a platform for the future development of more complex personalized pediatric medication regimens.

[0059] Improving drug distribution in vivo: Nanoscale and PEG surface modification endow nanoparticles with "long-cycle" properties, which can prolong the duration of drug action in vivo and may improve distribution through passive targeting, reduce excessive uptake in non-target tissues (such as the liver), and further improve the safety of systemic drug administration.

[0060] The beneficial effects of this invention are a synergistic systemic improvement: it ensures safety through a core stable drug release mechanism, enhances convenience through long-lasting effects, guarantees stability and precision through superior formulation processes, and ultimately brings potential cost-effectiveness advantages. These effects collectively address the core pain points of existing technologies in the application of pediatric postoperative sedation, demonstrating clear clinical translational value and significant technological advancement.

[0061] The above description is merely a preferred embodiment of the present invention and is not intended to limit the scope of protection of the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention are included within the scope of protection of the present invention.

Claims

1. A method for preparing a sustained-release formulation of a pediatric post-anesthesia sedative drug based on a nanocarrier, characterized in that, Includes the following steps: (1) Organic phase preparation: The drug, carrier and organic solvent are mixed evenly to form an organic phase for later use; (2) Emulsification treatment: The organic phase is added to the aqueous solution and stirred evenly to obtain the pre-emulsion for later use; (3) Evaporation and solidification: The primary emulsion is transferred to a rotary evaporator, and the organic solvent is removed by vacuum evaporation, and solidified to form a nanoparticle suspension for later use; (4) Purification treatment: The nanoparticle suspension is purified to remove free drugs and surfactants, and purified nanoparticles are obtained for later use; (5) Preparation and treatment: The purified nanoparticles were resuspended in buffer solution to obtain a sustained-release solution for later use; (6) Preparation of finished product: The sustained-release solution can be directly aseptically filled or freeze-dried to make lyophilized powder injection.

2. The method for preparing a sustained-release formulation of a pediatric post-anesthesia sedative drug based on a nanocarrier according to claim 1, characterized in that, The drug mentioned in step (1) is dexmedetomidine or midazolam; the carrier is polylactic acid-glycolic acid copolymer; and the organic solvent is at least one of ethyl acetate, dichloromethane, and acetone.

3. The method for preparing a sustained-release formulation of a pediatric post-anesthesia sedative drug based on a nanocarrier according to claim 1, characterized in that, The aqueous solution mentioned in step (2) is an aqueous solution containing a surfactant; the surfactant is at least one of polyvinyl alcohol, poloxamer 188, Tween 80, and vitamin E TPGS.

4. The method for preparing a sustained-release formulation of a pediatric post-anesthesia sedative drug based on a nanocarrier according to claim 1, characterized in that, The stirring method described in step (2) is high-speed shear stirring or ultrasonic treatment.

5. The method for preparing a sustained-release formulation of a pediatric post-anesthesia sedative drug based on a nanocarrier according to claim 1, characterized in that, In step (3), the vacuum degree is controlled to be -0.08 to -0.09 MPa during the reduced pressure evaporation.

6. The method for preparing a sustained-release formulation of a pediatric post-anesthesia sedative drug based on a nanocarrier according to claim 1, characterized in that, The purification process described in step (4) is centrifugal purification or ultrafiltration purification.

7. The method for preparing a sustained-release formulation of a pediatric post-anesthesia sedative drug based on a nanocarrier according to claim 1, characterized in that, The buffer solution in step (5) is mainly a phosphate buffer solution, and also contains at least one of an isotonic agent and a lyophilization protectant; the isotonic agent is a sucrose solution or a trehalose solution; the lyophilization protectant is a glucose solution.

8. The method for preparing a sustained-release formulation of a pediatric post-anesthesia sedative drug based on a nanocarrier according to claim 1, characterized in that, The freeze-drying process described in step (6) is specifically performed using a vacuum freeze dryer.

9. A sustained-release formulation of a pediatric post-anesthesia sedative drug based on a nanocarrier, characterized in that, Made by the method described in any one of claims 1-8.

10. A sustained-release formulation of a pediatric post-anesthesia sedative drug based on a nanocarrier according to claim 9, characterized in that, The sustained-release formulation may be a solution or powder, or other medically acceptable dosage form.