An assembly material for poorly soluble active transdermal and mucosal administration and a method of production

Abstract

This invention belongs to the field of pharmaceutical formulations and provides an assembly material and preparation method for transdermal and mucosal drug delivery of poorly soluble active ingredients. The invention utilizes lipid cubic phase nanoparticles composed of monooleate glycerol, cholesterol, dioleate glycerol, and caprylic / capric triglycerides. Combined with the surface stabilization and ion-synergistic regulation design of DSPE-PEG2000, a continuous process of melting-hydration-high pressure homogenization-cubic phase curing surface treatment is employed to achieve high drug loading and nanoscale particle size control. This invention solves the technical problems of balancing high loading of poorly soluble active ingredients with long-term colloidal stability, the contradiction between cubic phase structure stability and surface charge controllability in tissue-friendly environments, and the difficulty of achieving high drug loading and preventing crystallization coupling under low-temperature processing windows. It has broad application value in the fields of transdermal and mucosal local drug delivery.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulation technology, specifically to an assembly material and preparation method for transdermal mucosal administration of poorly soluble active pharmaceutical ingredients. Background Technology

[0002] Transdermal and mucosal drug delivery, as non-invasive routes of administration, have demonstrated significant advantages in both local and systemic therapy, particularly suitable for applications requiring avoidance of the first-pass effect, improved patient compliance, or targeted local treatment. In areas such as inflammatory skin diseases, mucosal infections, pain management, and local immune modulation, there is an urgent need for nanocarrier systems capable of efficiently loading poorly soluble active ingredients and achieving controlled release. Lipid-based cubic nanoparticles, due to their unique bicontinuous three-dimensional cubic internal structure, can simultaneously accommodate both hydrophilic and lipophilic drugs, exhibiting high drug loading capacity and structural stability, making them one of the ideal carriers for transdermal and mucosal delivery of poorly soluble active ingredients. These nanocarriers not only need to meet the specific requirements of transdermal and mucosal drug delivery in terms of drug loading, particle size distribution, and surface properties, but also need to maintain long-term colloidal stability and cubic phase structural integrity in a mild environment close to physiological conditions to ensure that the drug does not crystallize or aggregate during storage, transport, and use, thereby guaranteeing the efficacy and safety of the formulation. In addition, considering the practical application scenarios of transdermal mucosal drug delivery formulations, the carrier system should also have good tissue compatibility, appropriate penetration-enhancing effect, and controllable drug release behavior to achieve the therapeutic goal without causing local irritation.

[0003] Despite the numerous theoretical advantages of cubic lipid nanocarriers, significant technical bottlenecks remain in practical research and industrialization. Existing technologies typically require high lipid phase volume fractions to achieve high lipid solids content and drug loading, but this often leads to a sharp increase in system viscosity, deterioration of processing performance, and reversible or irreversible aggregation during subsequent storage due to enhanced interparticle interactions, ultimately affecting the long-term stability and clinical usability of the formulation. For example, Chinese patent CN102274175A discloses a cubic lipid nanocrystal formulation, its preparation method, and its application; however, it still falls short in maintaining long-term colloidal stability under high solids conditions. Especially in tissue-friendly environments such as near-isotonic and neutral pH, it is difficult to simultaneously maintain the ordered structure within the cubic phase, controllable nanoparticle size, and appropriate adjustment of surface potential, easily leading to inadequate or excessive shielding of particle surface charges, resulting in stability imbalances. On the other hand, for poorly soluble small-molecule active ingredients with extremely low water solubility and high octanol / water partition coefficients, achieving high drug loading while requiring low processing temperatures to avoid degradation of heat-sensitive components, and ensuring that the drug does not precipitate in crystalline form during cubic phase self-assembly and subsequent storage and use, presents significant technical challenges. For example, the lipid nanocarrier preparation technology disclosed in patent literature lacks a systematic solution to the coupling contradiction between controlling the processing temperature window and preventing drug crystallization, limiting its application in the transdermal mucosal delivery of heat-sensitive poorly soluble active ingredients. Summary of the Invention

[0004] The purpose of this invention is to provide an assembly material and preparation method for transdermal mucosal drug delivery of poorly soluble active ingredients, and to solve the technical problems of the present invention, which is difficult to balance high loading capacity and long-term colloidal stability of poorly soluble active ingredients, the contradiction between the stability of cubic phase structure and the controllability of surface charge in tissue-friendly environment, and the difficulty of coupling high drug loading capacity and anti-crystallization under low temperature processing window.

[0005] This invention employs a synergistic technical approach, constructing a cubic lipid framework using a specific ratio of monooleic glycerol, cholesterol, dioleate, and caprylic / capric triglycerides, combined with the steric stabilization provided by DSPE-PEG2000 and The electrostatic regulation effect of surface ions enables precise adjustment of the surface charge state of particles within a defined ion concentration range. This organic combination of multi-component lipid synergy and a dual surface stabilization mechanism not only effectively solves the problem of insufficient stability of single stabilization strategies in high-solids-content, tissue-friendly environments, but also achieves further stability through a process of melting-hydration-high-pressure homogenization-cubic phase ripening. The continuously optimized surface treatment process achieves a comprehensive balance of high drug loading, nanoscale particle size, narrow particle size distribution, and long-term storage stability at a lower processing temperature window. Therefore, under the conditions shown in the embodiments of this invention, compared to the method without surface treatment... The comparative examples, which were surface-modified or did not use DSPE-PEG2000, showed better particle size stability and drug loading performance.

[0006] To achieve the above objectives, the present invention provides the following technical solution:

[0007] An assembly material for transdermal mucosal drug delivery of poorly soluble active ingredients comprises an aqueous phase and cubic lipid nanoparticles dispersed in the aqueous phase, wherein the cubic lipid nanoparticles include a lipid matrix, a surface stabilizer, and surface ions. ,in:

[0008] The lipid matrix is ​​a mixture of monooleate glycerides, cholesterol, dioleate glycerides, and caprylic / capric triglycerides;

[0009] The surface stabilizer is DSPE-PEG2000;

[0010] The surface ions Provided by calcium chloride dissolved in the aqueous phase, It can electrostatically interact with the phosphate groups of DSPE-PEG2000 on the surface of lipid cubic nanoparticles and other charged or polarizable groups on the particle surface, thereby regulating the ionic environment and particle surface charge state of the system within a limited concentration range. In conjunction with the steric stabilization effect provided by DSPE-PEG2000, it is beneficial to obtain good colloidal stability and storage stability of the assembled material without causing significant particle aggregation.

[0011] The lipid cubic phase nanoparticles are loaded with at least one poorly soluble active ingredient, wherein the equilibrium solubility of the poorly soluble active ingredient in water at 25°C is ≤100 μg / mL, and the octanol / water partition coefficient LogP ≥2.0; wherein the equilibrium solubility in water at 25°C is determined by shaking flask method at 25°C, and the octanol / water partition coefficient LogP is determined by octanol / water shaking method according to pharmacopoeia or equivalent recognized method.

[0012] Furthermore, based on the total mass of the lipid matrix, the lipid matrix contains 62–72 wt% monooleate, 7–10 wt% cholesterol, 4–7 wt% dioleate, and 8–10 wt% caprylic / capric triglyceride, with the sum of the mass fractions of the above four lipid components being 94–98 wt%, and the balance being water and / or unavoidable impurities.

[0013] Furthermore, the assembly material is preferably obtained through the continuous preparation of intermediate I and intermediate II, wherein intermediate I is a drug-loaded lipid cubic phase nanodispersion, and intermediate II is prepared based on intermediate I through... The preparation method of intermediate I of the obtained drug-loaded lipid cubic phase nanodispersion includes the following steps:

[0014] A1. Melting the lipid matrix and dissolving the poorly soluble active ingredient:

[0015] Weigh out monooleate, cholesterol, dioleate, and caprylic / capric triglycerides at 50–65°C. Heat and stir for 20–40 min to melt monooleate, dioleate, and caprylic / capric triglycerides, and to fully disperse cholesterol in the resulting liquid lipid phase, thus obtaining a molten lipid phase. Then, add a poorly soluble active ingredient with sufficient thermal stability at 50–65°C to the molten lipid phase at 5–25 wt% of the total lipid matrix. Continue stirring at 50–65°C for 10–30 min to dissolve the poorly soluble active ingredient in the molten lipid phase, thus obtaining a drug-loaded lipid molten phase.

[0016] A2. Hydration and Predispersion:

[0017] At 45–55°C, an aqueous phase containing DSPE-PEG2000 and optionally sodium chloride is added to the drug-loaded lipid melt phase. The amount of the aqueous phase is 1–3 times the mass of the drug-loaded lipid melt phase. The mixture is stirred for 20–60 min to obtain a crude drug-loaded dispersion.

[0018] A3. High-pressure homogenization:

[0019] The drug-loaded coarse dispersion was subjected to high-pressure homogenization at a feed temperature of 30–45℃, with a homogenization pressure of 30–80 MPa and a cycle number of 3–8 times, to obtain drug-loaded lipid nanodispersion.

[0020] A4. Cubic phase ripening:

[0021] The drug-loaded lipid nanodispersions obtained in step A3 are allowed to stand or be slowly stirred at 25–40°C for 4–24 hours to allow the lipids inside the particles to self-assemble into a cubic phase internal structure, and the poorly soluble active ingredients are dispersed or dissolved in the cubic phase lipid matrix, thus obtaining intermediate I.

[0022] Furthermore, the preparation method of intermediate II includes the following steps:

[0023] B1. Surface treatment:

[0024] At 25–35°C, depending on the volume of intermediate I and the required surface treatment The amount of calcium chloride aqueous solution required to calculate the initial target concentration is determined by adding the calcium chloride aqueous solution to intermediate I at a dropping rate of 0.1–0.3 mL / min until the calcium chloride solution is free in the system. The initial concentration reached 1.0–10.0 mmol / L, and stirring continued for 30–60 min, so that... Electrostatic interaction occurs with the particle surface, resulting in... The surface treatment intermediate II stock solution; subsequently, free free radicals are partially removed by dialysis or ultrafiltration. The obtained intermediate II is free The equilibrium concentration was adjusted to 0.5–2.0 mmol / L.

[0025] Furthermore, the surface stabilizer DSPE-PEG2000 was used at an amount of 0.5–1.5 wt% of the total lipid matrix, with free DSPE-PEG2000 in the aqueous phase. The concentration is 0.5–2.0 mmol / L, and the free concentration in the aqueous phase is... The preferred concentration is obtained through Surface treatment and partial removal of free radicals The residual concentration obtained is obtained by using 5–25 wt% of the total mass of the lipid matrix for the poorly soluble active ingredient.

[0026] Furthermore, the median volumetric particle size (d50) of the lipid cubic phase nanoparticles is 100–200 nm, and the polydispersity index (PDI) is ≤0.20, preferably determined by dynamic light scattering. The composition of the material is determined at 25 °C, pH 6.0–7.0, and the mass fraction of sodium chloride in the assembly material is 0.75–0.95 wt%, with free... Under conditions of concentration of 0.5–2.0 mmol / L, the absolute value of the zeta potential measured by electrophoretic light scattering can usually reach more than 10 mV, preferably in the range of 10–30 mV.

[0027] Furthermore, the aqueous phase further contains sodium chloride, the amount of which is 0.1–1.0 wt% of the total mass of the assembly material, preferably 0.75–0.95 wt%. After the assembly material is stored at 25°C under light-proof and sealed conditions for 90 days, the relative increase in the median particle size d50 of the lipid cubic phase nanoparticles compared to the initial particle size before storage does not exceed 15%, the particle size polydispersity index (PDI) does not exceed 0.25, and no visible insoluble active ingredient crystals are observed to precipitate.

[0028] As a concept of this invention, a cubic phase nanoparticle framework is constructed using a specific ratio of lipid mixtures of monooleate, cholesterol, dioleate, and caprylic / capric triglycerides. This framework is primarily used to enhance the loading capacity of poorly soluble active ingredients and the stability of the cubic phase structure. Monooleate, as the main lipid component, possesses a unique spatial configuration of unsaturated alkyl chains and polar head groups, enabling it to spontaneously form a bicontinuous cubic phase structure under hydration conditions. This provides numerous hydrophobic microdomains for poorly soluble active ingredients, while its dynamic lipid bilayer framework facilitates the dissolution and dispersion of drug molecules. The introduction of cholesterol can regulate membrane fluidity by embedding into the lipid bilayer, enhancing the order and rigidity of the lipid framework. This improves the stability of the cubic phase structure during temperature fluctuations and long-term storage, and reduces the risk of drug precipitation from the lipid matrix. The addition of dioleate further optimizes the hydrophobicity and fluidity of the lipid matrix, facilitating the full melting of lipids and efficient dissolution of poorly soluble active ingredients at lower processing temperatures. Furthermore, its synergistic effect with monooleate enables the formation of a more compact and stable cubic phase network structure. As a medium-chain triglyceride, caprylic / capric triglyceride not only regulates the overall melting point and viscosity of the lipid matrix, but also forms a well-compatible mixed phase with components such as monooleic glycerides through its moderate lipophilicity. This ensures the integrity of the cubic phase structure while improving the system's processing adaptability and drug loading capacity. Through the precise ratio and synergistic effect of the above four lipid components, this invention achieves a harmonious balance of high drug loading, low processing temperature, and long-term structural stability while maintaining the three-dimensional ordered structure within the cubic phase, significantly outperforming single lipid or simple binary mixed lipid systems.

[0029] This invention also discloses a method for preparing an assembly material for transdermal mucosal drug delivery of poorly soluble active ingredients, comprising the following steps:

[0030] S1. Preparation of intermediate I;

[0031] S2. Preparation of intermediate II;

[0032] S3. Final formulation and preparation: The intermediate II is diluted with water to make the total mass fraction of the lipid matrix to the total mass of the assembly material 5–25 wt%. The mixture is magnetically or mechanically stirred at 20–30°C for 10–30 min to make it uniform, thereby obtaining an aqueous dispersion of the assembly material for transdermal or mucosal administration, and / or the aqueous dispersion is mixed with a pharmaceutical hydrogel matrix to form a semi-solid gel or patch formulation.

[0033] Furthermore, in step S3, the amount of the pharmaceutical hydrogel matrix is ​​5–25 wt% of the total mass of the assembly materials. The pharmaceutical hydrogel matrix is ​​selected from hydroxypropyl methylcellulose, xanthan gum, or a combination of both. The final formulation is tested at 25°C using a rotational rheometer at a shear rate of... The apparent viscosity measured under the conditions was 500–5000 mPa·s.

[0034] Furthermore, the assembly material is an aqueous dispersion for transdermal or nasal / oral mucosal local administration, or a semi-solid gel or patch formed by mixing the assembly material with a pharmaceutical hydrogel matrix, and the molecular weight of the loaded poorly soluble active ingredient is less than 800 Da, and it is a drug or functional ingredient with sufficient thermal stability under conditions of 50–65°C.

[0035] In one embodiment, in intermediates I and II, the volume fraction of lipid cubic phase nanoparticles in the total volume of the dispersion system, calculated based on the lipid cubic phase domain (including the lipid skeleton and its internal water-containing channels), is 40–80 vol%. This volume fraction is estimated by measuring the total solid content of the dispersion system and combining it with the density of the lipid cubic phase.

[0036] In a preferred embodiment, the volume fraction of lipid cubic phase nanoparticles, calculated based on the lipid cubic phase domain, in the total volume of the dispersion system in intermediates I and II is preferably 40–60 vol%, in order to maintain suitable rheological properties and process operability while ensuring a high drug loading.

[0037] In one embodiment, the amount of sodium chloride in the aqueous phase is limited to 0.75–0.95 wt% of the total mass of the assembly material, for adjusting the osmotic pressure of the assembly material to approximately 260–340 mOsm / kg, said osmotic pressure being determined by a freezing point osmometer or an equivalent method specified in the pharmacopoeia.

[0038] In another embodiment, to accommodate the tolerance range of osmotic pressure at a specific administration site, the amount of sodium chloride in the aqueous phase can be appropriately adjusted within the range of 0.1–1.0 wt% of the total mass of the assembly materials, while osmotic pressure measurement ensures that the resulting formulation has good compatibility with the osmotic pressure of the target tissue.

[0039] In one embodiment, the preferred conditions for high-pressure homogenization in step A3 are a homogenization pressure of 40–60 MPa and a cycle number of 4–6 times, in order to balance particle size control, energy consumption and sample temperature rise.

[0040] In another embodiment, to further reduce the particle size and obtain a narrower particle size distribution, the homogenization pressure can be increased to 60–80 MPa and the number of cycles can be 5–8, but the sample temperature must be controlled to not exceed 45°C through feed precooling and intermediate cooling.

[0041] In one implementation, The concentration of the calcium chloride aqueous solution used in the surface treatment step is 0.05–1.0 mol / L. By adjusting the dropping time and solution concentration, the free calcium chloride in the intermediate II stock solution is controlled. The initial concentration was in the range of 1.0–10.0 mmol / L.

[0042] In one implementation, partial removal of free radicals is achieved. The dialysis procedure uses a semi-permeable membrane bag with a molecular weight cutoff of 10–50 kDa, and is performed at 25°C with deionized water or isotonic buffer as the external phase for 2–24 hours. Dialysis is controlled by conductivity or... Colorimetric monitoring of external phases Concentration changes to remove free intermediate II Adjust the equilibrium concentration to 0.5–2.0 mmol / L.

[0043] In another implementation, partial removal of free radicals Ultrafiltration was employed, preferably using an ultrafiltration membrane with a molecular weight cutoff of 10–100 kDa. The ultrafiltration was performed under a transmembrane pressure differential of 0.1–0.3 MPa, and the total volume of the system was maintained essentially constant by adding isotonic buffer solution until free molecules were released. The concentration decreased to 0.5–2.0 mmol / L.

[0044] In one embodiment, the loaded poorly soluble active ingredient has a molecular weight of less than 800 Da and is a drug or functional ingredient with sufficient thermal stability at 50–65°C, so as to facilitate the achievement of high drug loading and stable cubic phase structure under the process conditions of the present invention.

[0045] In one embodiment, the poorly soluble active ingredient is selected from corticosteroid anti-inflammatory drugs, nonsteroidal anti-inflammatory drugs, local anesthetics, antifungal drugs, antiviral drugs, immunomodulatory drugs, or their pharmaceutically acceptable salts, esters, prodrugs, or solvates.

[0046] In another embodiment, the poorly soluble active ingredient is a topical drug for transdermal or mucosal administration, whose main pharmacological action is limited to the administration site or nearby tissues to reduce the risk of systemic exposure.

[0047] In one embodiment, the assembly material is an aqueous dispersion for transdermal or nasal / oral mucosal local administration, which can be directly used for dripping, spraying, smearing, or as a spray-drying precursor.

[0048] In one embodiment, the semi-solid formulation formed by mixing the assembly material with the pharmaceutical hydrogel matrix is ​​a transdermal gel, nasal gel, or oral mucosal gel. The pharmaceutical hydrogel matrix is ​​preferably selected from hydroxypropyl methylcellulose, xanthan gum, or a combination of both, and the amount of matrix is ​​5–25 wt% of the total mass of the assembly material.

[0049] In another embodiment, local retention time and medication adherence are improved by adding a film-forming polymer to an aqueous dispersion of the assembly material and drying or curing it to form a coating formulation or oral patch.

[0050] In one embodiment, the particle size and polydispersity index (PDI) are determined by dynamic light scattering at a test temperature of 25°C. The sample is moderately diluted with deionized water or isotonic buffer to a suitable transmittance, and the scattering angle is 90° or 173°. The resulting volume median particle size d50 is 100–200 nm, and the PDI is ≤0.20.

[0051] In one embodiment, the zeta potential is determined by electrophoretic light scattering at a test temperature of 25°C. The sample is moderately diluted with a low-conductivity buffer, and the pH is adjusted to 6.0–7.0. The sodium chloride mass fraction in the assembly material is 0.75–0.95 wt%, and the free sodium chloride content is [not specified]. Under conditions of concentration of 0.5–2.0 mmol / L, the absolute value of the zeta potential of lipid cubic phase nanoparticles can typically reach above 10 mV, preferably in the range of 10–30 mV.

[0052] In one embodiment, the storage test for evaluating the long-term stability of the assembly material is carried out at 25°C, in the dark, and in a sealed environment, preferably with the relative humidity controlled at no more than 60%. During storage, the particle size, PDI and appearance are measured periodically to confirm that the particle size increase does not exceed 15%, the PDI does not exceed 0.25 and there is no visible precipitation of insoluble active ingredient crystals.

[0053] In another implementation, to simulate the actual use environment, the stability of the assembly materials can be tested under accelerated conditions at 40°C for 1–3 months. The system’s tolerance to temperature fluctuations is evaluated by comparing the results with those under 25°C conditions.

[0054] In one embodiment, the high-pressure homogenization in step A3 is carried out using an industrial high-pressure homogenizer. Under the premise of ensuring the target pressure and number of cycles, the discharge temperature is controlled to not exceed 45°C through a multi-stage cooling heat exchanger to prevent the degradation of heat-sensitive active ingredients or the destruction of cubic phase structure.

[0055] In one implementation, The dropping step utilizes a continuous or semi-continuous stirred tank equipped with a precision metering pump, with the dropping rate controlled at 0.1–0.3 mL / min, aided by online conductivity or pH monitoring. Uniformity of solution addition is crucial to prevent localized high concentrations from inducing particle aggregation.

[0056] In one embodiment, the osmotic pressure and pH of the assembly material are preferably controlled within a range close to that of the skin or target mucous membrane, for example, an osmotic pressure of 260–340 mOsm / kg and a pH of 5.5–7.0, to reduce irritation and improve local tolerance.

[0057] In one embodiment, the density of PEG chains on the surface of cubic phase nanoparticles is adjusted by the amount of DSPE-PEG2000 used, so that the particles at 25°C, with a sodium chloride mass fraction of 0.75–0.95 wt%, have a free... At concentrations of 0.5–2.0 mmol / L, it exhibits sufficient steric stability while retaining a certain surface charge to facilitate moderate interaction with the skin or mucous membrane surface.

[0058] In another embodiment, the assembly material does not contain low-molecular-weight surfactants that may cause skin or mucous membrane irritation, and the only major surface-active component in the system is DSPE-PEG2000 to improve biocompatibility and formulation safety.

[0059] As another concept of the present invention, the present invention employs melting-hydration-high pressure homogenization-cubic phase ripening- The continuous preparation process with surface treatment is mainly used to enhance the controllability of particle size, the integrity of the cubic phase structure, and the long-term colloidal stability of the assembly material. The step of melting the lipid matrix and dissolving the poorly soluble active ingredient, controlled within a suitable temperature window of 50-65℃, ensures sufficient melting of monooleyl glycerol, dioleyl glycerol, and caprylic / capric triglycerides, as well as uniform dispersion of cholesterol, while avoiding degradation of the heat-sensitive active ingredient due to excessively high temperatures. This achieves efficient drug dissolution and dispersion in the molten lipid phase. The hydration and pre-dispersion step, by adding an aqueous phase containing DSPE-PEG2000, promotes the initial dispersion of lipids in the aqueous phase and provides the necessary hydration environment for subsequent cubic phase self-assembly. The high-pressure homogenization step, through homogenization pressure of 30-80 MPa and 3-8 cycles, shears and breaks the coarse drug-loaded dispersion into nanoscale particles, while simultaneously promoting further lipid hydration and uniform anchoring of DSPE-PEG2000 on the particle surface, thereby obtaining a drug-loaded lipid nanodispersion with a narrow particle size distribution and preliminary steric hindrance protection on the surface. The cubic phase maturation step involves allowing the lipids inside the particles to stand or stir slowly at 25-40℃ for 4-24 hours, providing sufficient time for structural rearrangement. This allows the lipids to spontaneously assemble into a thermodynamically stable bicontinuous cubic internal structure, ensuring that the poorly soluble active ingredients are stably dispersed or dissolved in the cubic lipid matrix and preventing drug crystallization. The surface treatment step controls the dropping rate of the calcium chloride solution and the final free concentration. Concentration, making Electrostatic interactions occur with the phosphate groups and other charged or polarizable groups on the surface of DSPE-PEG2000 particles, moderately adjusting the surface charge state of the particles without disrupting the steric hindrance stabilizing layer, and excess free groups are partially removed by dialysis or ultrafiltration. The ionic environment of the system was optimized to the optimal stability window. Through the synergistic effect of the above-mentioned continuous optimization process, this invention achieves precise control over particle size, cubic phase structure, surface properties, and long-term stability, which is significantly superior to lipid nanocarrier systems prepared by traditional single-step or simplified processes.

[0060] DSPE-PEG2000 and In the assembly material of this invention, these components play complementary and synergistic roles, jointly maintaining the long-term colloidal stability and surface property controllability of lipid cubic phase nanoparticles in a tissue-friendly environment. DSPE-PEG2000, as a surface stabilizer, has its phospholipid-terminated DSPE anchored to the surface of the lipid cubic phase nanoparticles through hydrophobic interactions, while the hydrophilic PEG2000 chains extend into the aqueous phase, forming a dense polymer brush layer on the particle surface. This provides strong steric repulsion, effectively preventing particle aggregation caused by van der Waals forces or hydrophobic interactions, thereby significantly improving the colloidal stability of the system. Simultaneously, the phosphate groups of DSPE-PEG2000 carry a negative charge under physiological pH conditions, imparting a certain surface charge to the particles, further enhancing the interparticle spacing through electrostatic repulsion. However, in near-isotonic salt ion environments, relying solely on steric hindrance or surface charge often fails to achieve optimal stability, especially when the system needs to adjust the surface potential to adapt to specific drug delivery requirements, potentially leading to insufficient or excessive charge shielding. The introduction of [a specific substance] creates an ion bridging effect within a defined concentration range through electrostatic interactions with the phosphate groups of DSPE-PEG2000 and other charged or polarizable groups on the particle surface. This moderately adjusts the charge density and distribution on the particle surface, maintaining the absolute value of the zeta potential within a suitable range of 10-30 mV. The mediated electrostatic regulation and the steric stabilization provided by DSPE-PEG2000 work synergistically, enhancing the charge stability of the particle surface through ion bridging on the one hand, and avoiding excessive free charge on the other. Concentration induces particle aggregation or disruption of the cubic phase structure. This can be addressed by precisely controlling the dosage and free DSPE-PEG2000. By adjusting the concentration ratio, this invention achieves an optimal balance between steric hindrance and electrostatic stabilization mechanisms. Under conditions of high solid content, tissue-friendly ionic environment, and long-term storage, it can maintain excellent colloidal stability and cubic phase structure integrity, which is significantly better than a single stabilization strategy.

[0061] Beneficial technical effects

[0062] 1. Achieving a balance between high drug loading and long-term colloidal stability: A cubic framework is constructed using a specific ratio of monooleate, cholesterol, dioleate, and caprylic / capric triglycerides, combined with the steric hindrance of DSPE-PEG2000 and... With its dual stabilization mechanism based on electrostatic regulation, this invention maintains the nanoscale particle size and narrow distribution of lipid cubic phase nanoparticles even under high drug loading conditions where the loading of poorly soluble active ingredients reaches 5-25 wt% of the total lipid matrix. After 90 days of storage at 25°C in a light-proof and sealed environment, the particle size increase does not exceed 15% and no drug crystallization occurs. This fundamentally solves the technical contradiction of traditional lipid nanocarriers in achieving both high drug loading and long-term stability.

[0063] 2. Balancing cubic phase structure stability and surface charge controllability in an organization-friendly environment: This invention achieves precise control of free... The concentration is in the range of 0.5-2.0 mmol / L, making It forms a moderate electrostatic interaction with the phosphate group of DSPE-PEG2000. Under near physiological isotonic, weakly acidic to neutral pH conditions, it maintains the integrity of the bicontinuous three-dimensional ordered structure inside the cubic phase and makes the absolute value of the particle zeta potential controllable to reach the range of 10-30mV. It achieves a triple balance of structural stability, surface charge controllability and tissue compatibility, which is significantly better than the performance of a single stabilization strategy in complex ionic environments.

[0064] 3. Achieving synergistic optimization of high drug loading and anti-crystallization within a low-temperature processing window: This invention utilizes a suitable melting temperature of 50-65℃ and a cubic phase ripening temperature of 25-40℃, combined with high-pressure homogenization and continuous... The surface treatment process, while avoiding the degradation of heat-sensitive and poorly soluble active ingredients, achieves efficient dissolution, uniform dispersion, and long-term stable storage of drugs in a lipid cubic matrix. It effectively solves the coupling contradiction between low-temperature processing window and high drug loading and anti-crystallization, and broadens the application scope of this invention in the field of transdermal mucosal delivery of heat-sensitive and poorly soluble active ingredients.

[0065] 4. Continuous and controllable process route with wide applicability: This invention adopts a melting-hydration-high pressure homogenization-cubic phase ripening- The surface treatment process is a continuous process with clearly defined parameters for each step, high reproducibility, and the lipid ratio, drug loading, and other parameters can be flexibly adjusted according to the physicochemical properties of different poorly soluble active ingredients. The processing conditions are suitable for both small-batch laboratory research and development and large-scale industrial production, providing a systematic technical platform for the development of transdermal and mucosal topical drug delivery formulations. Attached Figure Description

[0066] Figure 1This is a surface chemical state analysis diagram from a broad scan of XPS spectra.

[0067] Figure 2 Different Ca 2p high-resolution spectra Concentration on surface Enrichment effect diagram.

[0068] Figure 3 For P 2p high-resolution spectrum and peak shift – Electrostatic interaction diagram of phosphate groups.

[0069] Figure 4 The surface Ca / P atomic ratio varies with free atoms XPS quantitative analysis graph of concentration changes.

[0070] Figure 5 The difference in zeta potential–pH curves Concentration-controlled surface charge map.

[0071] Figure 6 The structure characterization diagram (logI) of the 15 wt% cubic phase loaded with drug is shown in the SAXS I(q)–q curve.

[0072] Figure 7 The image shows the SAXS fitting plot of the lattice parameter a as a function of drug loading.

[0073] Figure 8 Comparison of SAXS curves with different drug loading capacities at 5, 15, 25, and 28 wt% wt%.

[0074] Figure 9 A comparison chart of pure drugs, physical mixtures, and assembly materials for DSC curve overlay.

[0075] Figure 10 Particle size Graph showing changes over storage time (Example 1 vs. Comparative Example 9).

[0076] Figure 11 PDI changes over storage time (Example 1 vs. Comparative Example 9). Detailed Implementation

[0077] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings.

[0078] Example 1

[0079] I. Raw material composition (based on the preparation of 100g lipid matrix)

[0080] This embodiment prepares an assembly material for transdermal administration of the poorly soluble active ingredient lidocaine. The lipid matrix components are formulated in the following mass fractions: 69.5 wt% monooleate, 9.0 wt% cholesterol, 6.5 wt% dioleate, and 9.5 wt% caprylic / capric triglyceride. The sum of the mass fractions of these four lipid components is 94.5 wt%, with the balance being water and unavoidable impurities. The surface stabilizer DSPE-PEG2000 is used at 1.0 wt% of the total lipid matrix mass. The poorly soluble active ingredient lidocaine is used at 15 wt% of the total lipid matrix mass. The lidocaine has an equilibrium solubility of 64 μg / mL in water at 25°C (determined by shaking flask method), an octanol / water partition coefficient LogP of 2.44 (determined by octanol / water shaking method), a molecular weight of 234.34 Da, and good thermal stability at 50-65°C.

[0081] II. Preparation of Intermediate I

[0082] Step A1: Melt the lipid matrix and dissolve the poorly soluble active ingredient.

[0083] Under 57°C water bath conditions, 69.5g of monooleate, 9.0g of cholesterol, 6.5g of dioleate, and 9.5g of caprylic / capric triglycerides were weighed sequentially and placed in a beaker equipped with a mechanical stirrer. The mixture was heated and stirred for 30 minutes to completely melt the monooleate, dioleate, and caprylic / capric triglycerides, and to fully disperse the cholesterol in the resulting liquid lipid phase, thus obtaining a molten lipid phase. Subsequently, 15g of lidocaine was added to the molten lipid phase at 15wt% of the total lipid matrix mass. The mixture was stirred at 57°C for another 20 minutes to completely dissolve the lidocaine in the molten lipid phase, thus obtaining a drug-loaded lipid molten phase.

[0084] Step A2: Hydration and Predispersion

[0085] Under 50°C water bath conditions, an aqueous phase containing 1.0 g of DSPE-PEG2000 and sodium chloride was added to the drug-loaded lipid molten phase. The amount of aqueous phase was twice the mass of the drug-loaded lipid molten phase. The mass fraction of sodium chloride in the aqueous phase was calculated to be 0.85 wt% in the final assembled material. The mixture was mechanically stirred at 50°C for 40 min to obtain a coarse dispersion of the drug-loaded material.

[0086] Step A3: High-pressure homogenization

[0087] The drug-loaded coarse dispersion was preheated to a feed temperature of 37°C and then subjected to high-pressure homogenization at a homogenization pressure of 55 MPa using a high-pressure homogenizer. The homogenization process was repeated 5 times. During the homogenization process, the discharge temperature was controlled to not exceed 45°C by a cooling system to obtain drug-loaded lipid nanodispersions.

[0088] Step A4: Cubic phase ripening

[0089] The drug-loaded lipid nanodispersions obtained in step A3 were left to stand at a constant temperature of 32°C for 14 hours to allow the lipids inside the particles to self-assemble into a cubic phase internal structure, and lidocaine was dispersed or dissolved in the cubic phase lipid matrix to obtain intermediate I.

[0090] III. Preparation of Intermediate II

[0091] Step B1: Surface treatment

[0092] Under constant temperature conditions of 30℃, based on the volume of intermediate I and the required surface treatment... To calculate the initial target concentration, determine the required amount of calcium chloride aqueous solution to be added. Prepare a 0.50 mol / L calcium chloride aqueous solution and add it to intermediate I using a peristaltic pump at a dropping rate of 0.2 mL / min. Disperse the solution evenly under magnetic stirring until free calcium chloride is present in the system. The initial concentration reached 5.5 mmol / L, and stirring was continued for 45 min to allow the solution to reach a final concentration of 5.5 mmol / L. Electrostatic interactions occur between DSPE-PEG2000 and the phosphate groups on the surface of lipid cubic nanoparticles, as well as other charged or polarizable groups on the particle surface, to obtain... The surface treatment intermediate II stock solution was then subjected to dialysis using a semi-permeable membrane bag with a molecular weight cutoff of 30 kDa. Deionized water was used as the external phase, and dialysis was performed at 25°C for 12 hours, with the external phase replaced three times. The external phase was monitored using a calcium ion colorimetric method. Concentration changes, and determination of free concentration in intermediate II after dialysis. The equilibrium concentration was 1.2 mmol / L.

[0093] IV. Preparation of Final Assembly Materials

[0094] Step S3: Final Matching

[0095] The intermediate II was diluted with purified water containing an appropriate amount of sodium chloride, so that the total mass of the lipid matrix accounted for 15 wt% of the total mass of the assembly material, and the total mass fraction of sodium chloride in the assembly material was maintained at 0.85 wt%. The mixture was magnetically stirred at 25°C for 20 min to ensure uniform mixing, thereby obtaining an aqueous dispersion of the assembly material for transdermal drug delivery.

[0096] V. Quality Inspection

[0097] The particle size and distribution of the lipid cubic phase nanoparticles prepared in this embodiment were determined by dynamic light scattering (DLS) at 25°C. The sample was diluted with purified water to a suitable concentration, and the scattering angle was 173°. The median volumetric particle size (d50) was measured to be 152 nm, and the polydispersity index (PDI) was 0.16. The zeta potential was determined by electrophoretic light scattering at 25°C. The sample was moderately diluted with a low-conductivity buffer, and the pH was adjusted to 6.5. The sodium chloride mass fraction in the assembly material was 0.85 wt%, and the free sodium chloride content was [not specified]. At a concentration of 1.2 mmol / L, the absolute value of the zeta potential of the lipid cubic phase nanoparticles was measured to be 18 mV. By measuring the total solid content of the dispersion system and estimating the density of the lipid cubic phase, the volume fraction of lipid cubic phase nanoparticles in intermediates I and II, calculated based on the lipid cubic phase domain, was 48 vol%. The osmotic pressure of the assembled material in this embodiment was measured to be 295 mOsm / kg using a freezing point osmometer. After being stored at 25°C, protected from light, and in a sealed environment for 90 days, the median particle size (d50) of the lipid cubic phase nanoparticles increased to 164 nm compared to the initial particle size before storage, representing a relative increase of 7.9%. The PDI was 0.19, and no visible lidocaine crystals were observed to precipitate.

[0098] Features of Example 1: This example uses a moderate parameter design. The total amount of the four components of the lipid matrix is ​​94.5 wt%, the amount of DSPE-PEG2000 is 1.0 wt%, the lidocaine loading is 15 wt%, and the free lipid matrix is... The equilibrium concentration was 1.2 mmol / L, and the sodium chloride mass fraction was 0.85 wt%, with all parameters selected within the specified range. The process conditions were mild and stable: melting temperature 57°C, homogenization pressure 55 MPa, 5 cycles, and cubic phase maturation time 14 h. The resulting assembly material had a particle size of 152 nm, a PDI of 0.16, an absolute zeta potential of 18 mV, a volume fraction of 48 vol%, and an osmotic pressure of 295 mOsm / kg. After 90 days of storage, the particle size increase was only 7.9%, demonstrating good colloidal and storage stability. This embodiment is suitable for transdermal drug delivery scenarios with high requirements for stability and reproducibility, and is particularly suitable for industrial-scale production.

[0099] Example 2

[0100] I. Raw material composition (based on the preparation of 100g lipid matrix)

[0101] This embodiment prepares an assembly material for transdermal administration of the poorly soluble active ingredient lidocaine. The lipid matrix components are formulated in the following mass fractions: 70.5 wt% monooleate, 8.5 wt% cholesterol, 6.5 wt% dioleate, and 9.5 wt% caprylic / capric triglyceride. The sum of the mass fractions of these four lipid components is 95.0 wt%, with the balance being water and unavoidable impurities. The surface stabilizer DSPE-PEG2000 is used at 0.8 wt% of the total lipid matrix mass. The poorly soluble active ingredient lidocaine is used at 10 wt% of the total lipid matrix mass.

[0102] II. Preparation of Intermediate I

[0103] Step A1: Melt the lipid matrix and dissolve the poorly soluble active ingredient.

[0104] Under 52°C water bath conditions, 70.5g of monooleate, 8.5g of cholesterol, 6.5g of dioleate, and 9.5g of caprylic / capric triglycerides were weighed sequentially and placed in a beaker equipped with a mechanical stirrer. The mixture was heated and stirred for 25 minutes to completely melt the monooleate, dioleate, and caprylic / capric triglycerides, and to fully disperse the cholesterol in the resulting liquid lipid phase, thus obtaining a molten lipid phase. Subsequently, 10g of lidocaine was added to the molten lipid phase at 10wt% of the total lipid matrix mass. The mixture was stirred at 52°C for another 15 minutes to completely dissolve the lidocaine in the molten lipid phase, yielding a drug-loaded lipid molten phase.

[0105] Step A2: Hydration and Predispersion

[0106] Under 48°C water bath conditions, an aqueous phase containing 0.8g of DSPE-PEG2000 and sodium chloride was added to the drug-loaded lipid molten phase. The amount of aqueous phase was 1.5 times the mass of the drug-loaded lipid molten phase. The mass fraction of sodium chloride in the aqueous phase was calculated to ensure that the mass fraction of sodium chloride in the final assembled material was 0.80wt%. The mixture was mechanically stirred at 48°C for 35 min to obtain a coarse dispersion of the drug-loaded material.

[0107] Step A3: High-pressure homogenization

[0108] The drug-loaded coarse dispersion was preheated to a feed temperature of 33°C and then subjected to high-pressure homogenization at a homogenization pressure of 45 MPa using a high-pressure homogenizer. The homogenization process was repeated four times. During the homogenization process, the discharge temperature was controlled to not exceed 42°C by a cooling system to obtain drug-loaded lipid nanodispersions.

[0109] Step A4: Cubic phase ripening

[0110] The drug-loaded lipid nanodispersions obtained in step A3 were left to stand at a constant temperature of 28°C for 10 hours to allow the lipids inside the particles to self-assemble into a cubic phase internal structure, and lidocaine was dispersed or dissolved in the cubic phase lipid matrix to obtain intermediate I.

[0111] III. Preparation of Intermediate II

[0112] Step B1: Surface treatment

[0113] Under constant temperature conditions of 27℃, based on the volume of intermediate I and the required surface treatment... To calculate the initial target concentration, the required amount of calcium chloride aqueous solution was determined. A 0.30 mol / L calcium chloride aqueous solution was prepared and added to intermediate I using a peristaltic pump at a dropping rate of 0.15 mL / min. The solution was then uniformly dispersed under magnetic stirring until free calcium chloride was present in the system. The initial concentration reached 3.5 mmol / L, and stirring was continued for 35 min to allow it to... Electrostatic interactions occur between DSPE-PEG2000 and the phosphate groups on the surface of lipid cubic nanoparticles, as well as other charged or polarizable groups on the particle surface, to obtain... The surface treatment intermediate II stock solution was then subjected to dialysis using a semi-permeable membrane bag with a molecular weight cutoff of 30 kDa. Deionized water was used as the external phase, and dialysis was performed at 25°C for 8 hours, with the external phase replaced twice. The external phase was monitored using a calcium ion colorimetric method. Concentration changes, and determination of free concentration in intermediate II after dialysis. The equilibrium concentration is 0.8 mmol / L.

[0114] IV. Preparation of Final Assembly Materials

[0115] Step S3: Final Matching

[0116] The intermediate II was diluted with purified water containing an appropriate amount of sodium chloride, so that the total mass of the lipid matrix accounted for 12 wt% of the total mass of the assembly material, and the total mass fraction of sodium chloride in the assembly material was maintained at 0.80 wt%. The mixture was magnetically stirred at 22°C for 15 min to ensure uniform mixing, thereby obtaining an aqueous dispersion of the assembly material for transdermal drug delivery.

[0117] V. Quality Inspection

[0118] The particle size and distribution of the lipid cubic phase nanoparticles prepared in this embodiment were determined by dynamic light scattering (DLS) at 25°C. The sample was diluted with purified water to a suitable concentration, and the scattering angle was 173°. The median volumetric particle size (d50) was measured to be 138 nm, and the polydispersity index (PDI) was 0.14. The zeta potential was determined by electrophoretic light scattering at 25°C. The sample was moderately diluted with a low-conductivity buffer, and the pH was adjusted to 6.3. The sodium chloride content in the assembly material was 0.80 wt%, and the free sodium chloride content was [not specified]. At a concentration of 0.8 mmol / L, the absolute value of the zeta potential of the lipid cubic phase nanoparticles was measured to be 14 mV. By measuring the total solid content of the dispersion system and estimating the density of the lipid cubic phase, the volume fraction of lipid cubic phase nanoparticles in intermediates I and II, calculated based on the lipid cubic phase domain, was 43 vol%. The osmotic pressure of the assembled material in this embodiment was measured to be 278 mOsm / kg using a freezing point osmometer. After being stored at 25°C, protected from light, and in a sealed environment for 90 days, the median particle size (d50) of the lipid cubic phase nanoparticles increased to 148 nm compared to the initial particle size before storage, representing a relative increase of 7.2%. The PDI was 0.17, and no visible lidocaine crystals were observed to precipitate.

[0119] Features of Example 2: This example uses a relatively low parameter combination design. The total weight of the four components of the lipid matrix is ​​95.0 wt%, the mass fraction of monooleic glyceride is relatively high at 70.5 wt%, the amount of DSPE-PEG2000 is 0.8 wt%, the lidocaine loading is 10 wt%, and the free... The equilibrium concentration was 0.8 mmol / L, the sodium chloride mass fraction was 0.80 wt%, and the parameters were within the 30-45% range. The process conditions were relatively mild: melting temperature 52℃, homogenization pressure 45 MPa, 4 cycles, and cubic phase maturation time 10 h. The resulting assembly material had a particle size of 138 nm, a PDI of 0.14, an absolute zeta potential of 14 mV, a volume fraction of 43 vol%, and an osmotic pressure of 278 mOsm / kg. After 90 days of storage, the particle size increased by 7.2%, demonstrating excellent particle size control and colloidal stability. This embodiment is suitable for transdermal drug delivery scenarios with strict requirements for particle size uniformity. The low drug loading and mild process conditions make it particularly suitable for shear-sensitive active ingredients and drug delivery sites with lower osmotic pressure requirements, such as topical administration through intact skin.

[0120] Example 3

[0121] I. Raw material composition (based on the preparation of 100g lipid matrix)

[0122] This embodiment prepares an assembly material for transdermal administration of the poorly soluble active ingredient lidocaine. The lipid matrix components are formulated in the following mass fractions: 70.5 wt% monooleate, 9.5 wt% cholesterol, 7.0 wt% dioleate, and 10.0 wt% caprylic / capric triglyceride. The sum of the mass fractions of these four lipid components is 97.0 wt%, with the balance being water and unavoidable impurities. The surface stabilizer DSPE-PEG2000 is used at 1.3 wt% of the total lipid matrix mass. The poorly soluble active ingredient lidocaine is used at 20 wt% of the total lipid matrix mass.

[0123] II. Preparation of Intermediate I

[0124] Step A1: Melt the lipid matrix and dissolve the poorly soluble active ingredient.

[0125] Under 62°C water bath conditions, 70.5g of monooleate, 9.5g of cholesterol, 7.0g of dioleate, and 10.0g of caprylic / capric triglyceride were weighed sequentially and placed in a beaker equipped with a mechanical stirrer. The mixture was heated and stirred for 35 minutes to completely melt the monooleate, dioleate, and caprylic / capric triglyceride, and to fully disperse the cholesterol in the resulting liquid lipid phase, thus obtaining a lipid molten phase. Subsequently, 20g of lidocaine was added to the lipid molten phase at 20wt% of the total lipid matrix mass, and the mixture was stirred at 62°C for another 25 minutes to completely dissolve the lidocaine in the lipid molten phase, thus obtaining a drug-loaded lipid molten phase.

[0126] Step A2: Hydration and Predispersion

[0127] Under a 53°C water bath, an aqueous phase containing 1.3g of DSPE-PEG2000 and sodium chloride was added to the drug-loaded lipid molten phase. The amount of aqueous phase was 2.5 times the mass of the drug-loaded lipid molten phase. The mass fraction of sodium chloride in the aqueous phase was calculated to be 0.90 wt% in the final assembled material. The mixture was mechanically stirred at 53°C for 50 min to obtain a coarse dispersion of the drug-loaded material.

[0128] Step A3: High-pressure homogenization

[0129] The drug-loaded coarse dispersion was preheated to a feed temperature of 42°C and then subjected to high-pressure homogenization at a homogenization pressure of 65 MPa using a high-pressure homogenizer. The homogenization process was repeated 6 times. During the homogenization process, the discharge temperature was controlled to not exceed 45°C by a cooling system to obtain drug-loaded lipid nanodispersions.

[0130] Step A4: Cubic phase ripening

[0131] The drug-loaded lipid nanodispersions obtained in step A3 were left to stand at a constant temperature of 37°C for 18 hours to allow the lipids inside the particles to self-assemble into a cubic phase internal structure, and lidocaine was dispersed or dissolved in the cubic phase lipid matrix to obtain intermediate I.

[0132] III. Preparation of Intermediate II

[0133] Step B1: Surface treatment

[0134] Under constant temperature conditions of 33℃, based on the volume of intermediate I and the required surface treatment... To calculate the initial target concentration, the required amount of calcium chloride aqueous solution was determined. A 0.75 mol / L calcium chloride aqueous solution was prepared and added to intermediate I using a peristaltic pump at a dropping rate of 0.25 mL / min. The solution was then uniformly dispersed under magnetic stirring until free calcium chloride was present in the system. The initial concentration reached 7.5 mmol / L, and stirring was continued for 55 min to allow the solution to reach a final concentration of 7.5 mmol / L. Electrostatic interactions occur between DSPE-PEG2000 and the phosphate groups on the surface of lipid cubic nanoparticles, as well as other charged or polarizable groups on the particle surface, to obtain... The surface treatment intermediate II stock solution was then subjected to dialysis using a semi-permeable membrane bag with a molecular weight cutoff of 50 kDa. Deionized water was used as the external phase, and dialysis was performed at 25°C for 18 hours, with the external phase replaced four times. The external phase was monitored using a calcium ion colorimetric method. Concentration changes, and determination of free concentration in intermediate II after dialysis. The equilibrium concentration was 1.6 mmol / L.

[0135] IV. Preparation of Final Assembly Materials

[0136] Step S3: Final Matching

[0137] The intermediate II was diluted with purified water containing an appropriate amount of sodium chloride, so that the total mass of the lipid matrix accounted for 20 wt% of the total mass of the assembly material, and the total mass fraction of sodium chloride in the assembly material was maintained at 0.90 wt%. The mixture was magnetically stirred at 28°C for 25 min to ensure uniform mixing, thereby obtaining an aqueous dispersion of the assembly material for transdermal drug delivery.

[0138] V. Quality Inspection

[0139] The particle size and distribution of the lipid cubic phase nanoparticles prepared in this embodiment were determined by dynamic light scattering (DLS) at 25°C. The sample was diluted with purified water to a suitable concentration, and the scattering angle was 173°. The median volumetric particle size (d50) was measured to be 178 nm, and the polydispersity index (PDI) was 0.19. The zeta potential was determined by electrophoretic light scattering at 25°C. The sample was moderately diluted with a low-conductivity buffer, and the pH was adjusted to 6.8. The sodium chloride content in the assembly material was 0.90 wt%, and the free sodium chloride content was [not specified]. At a concentration of 1.6 mmol / L, the absolute value of the zeta potential of the lipid cubic phase nanoparticles was measured to be 24 mV. By measuring the total solid content of the dispersion system and estimating the density of the lipid cubic phase, the volume fraction of lipid cubic phase nanoparticles in intermediates I and II, calculated based on the lipid cubic phase domain, was 56 vol%. The osmotic pressure of the assembled material in this embodiment was measured to be 318 mOsm / kg using a freezing point osmometer. After being stored at 25°C, protected from light, and in a sealed environment for 90 days, the median particle size (d50) of the lipid cubic phase nanoparticles increased to 195 nm compared to the initial particle size before storage, representing a relative increase of 9.6%. The PDI was 0.22, and no visible lidocaine crystals were observed to precipitate.

[0140] Features of Example 3: This example employs a high-parameter combination design. The total content of the four components of the lipid matrix is ​​97.0 wt%, close to the upper limit. Cholesterol, dioleate, and caprylic / capric triglycerides are all at high levels. The amount of DSPE-PEG2000 is 1.3 wt%, and the lidocaine loading reaches 20 wt%. The equilibrium concentration was 1.6 mmol / L, the sodium chloride mass fraction was 0.90 wt%, and the parameters were within the 55-70% range. The process conditions were relatively harsh: melting temperature 62℃, homogenization pressure 65 MPa, 6 cycles, and cubic phase maturation time 18 h. The resulting assembly material had a particle size of 178 nm, a PDI of 0.19, an absolute zeta potential of 24 mV, a volume fraction of 56 vol%, an osmotic pressure of 318 mOsm / kg, and a 9.6% increase in particle size after 90 days of storage, demonstrating good stability under high drug loading. This example is suitable for transdermal drug delivery scenarios requiring high drug loading, with a relatively high total lipid component, DSPE-PEG2000 dosage, and... The concentration synergistic effect maintains good colloidal stability while keeping the solids content high, making it particularly suitable for applications requiring sustained release or high-dose local administration, such as chronic pain management or local anti-inflammatory treatment.

[0141] Example 4

[0142] I. Raw material composition (based on the preparation of 100g lipid matrix)

[0143] This embodiment prepares an assembly material for transdermal administration of the poorly soluble active ingredient lidocaine. The lipid matrix components are formulated in the following mass fractions: 67.2 wt% monooleate, 10.0 wt% cholesterol, 7.0 wt% dioleate, and 10.0 wt% caprylic / capric triglyceride. The sum of the mass fractions of these four lipid components is 94.2 wt%, with the balance being water and unavoidable impurities. The surface stabilizer DSPE-PEG2000 is used at 1.4 wt% of the total lipid matrix mass. The poorly soluble active ingredient lidocaine is used at 23 wt% of the total lipid matrix mass.

[0144] II. Preparation of Intermediate I

[0145] Step A1: Melt the lipid matrix and dissolve the poorly soluble active ingredient.

[0146] Under a 63°C water bath, 67.2 g of monooleate, 10.0 g of cholesterol, 7.0 g of dioleate, and 10.0 g of caprylic / capric triglyceride were weighed sequentially and placed in a beaker equipped with a mechanical stirrer. The mixture was heated and stirred for 38 min to completely melt the monooleate, dioleate, and caprylic / capric triglyceride, and to fully disperse the cholesterol in the resulting liquid lipid phase, thus obtaining a lipid molten phase. Subsequently, 23 g of lidocaine was added to the lipid molten phase at 23 wt% of the total lipid matrix mass, and the mixture was stirred at 63°C for another 28 min to completely dissolve the lidocaine in the lipid molten phase, thus obtaining a drug-loaded lipid molten phase.

[0147] Step A2: Hydration and Predispersion

[0148] Under a 54°C water bath, an aqueous phase containing 1.4 g of DSPE-PEG2000 and sodium chloride was added to the drug-loaded lipid molten phase. The amount of aqueous phase was 2.8 times the mass of the drug-loaded lipid molten phase. The mass fraction of sodium chloride in the aqueous phase was calculated to be 0.93 wt% in the final assembled material. The mixture was mechanically stirred at 54°C for 55 min to obtain a coarse dispersion of the drug-loaded material.

[0149] Step A3: High-pressure homogenization

[0150] The drug-loaded coarse dispersion was preheated to a feed temperature of 43°C and then subjected to high-pressure homogenization at a homogenization pressure of 75 MPa using a high-pressure homogenizer. The homogenization process was repeated 7 times. During the homogenization process, the discharge temperature was controlled to not exceed 45°C by an enhanced cooling system to obtain drug-loaded lipid nanodispersions.

[0151] Step A4: Cubic phase ripening

[0152] The drug-loaded lipid nanodispersions obtained in step A3 were left to stand at a constant temperature of 38°C for 22 hours to allow the lipids inside the particles to self-assemble into a cubic phase internal structure, and lidocaine was dispersed or dissolved in the cubic phase lipid matrix to obtain intermediate I.

[0153] III. Preparation of Intermediate II

[0154] Step B1: Surface treatment

[0155] Under constant temperature conditions of 34℃, based on the volume of intermediate I and the required surface treatment... To calculate the initial target concentration, the required amount of calcium chloride aqueous solution was determined. A 0.92 mol / L calcium chloride aqueous solution was prepared and added to intermediate I using a peristaltic pump at a dropping rate of 0.28 mL / min. The solution was then uniformly dispersed under magnetic stirring until free calcium chloride was present in the system. The initial concentration reached 9.2 mmol / L, and stirring was continued for 58 min to allow... Electrostatic interactions occur between DSPE-PEG2000 and the phosphate groups on the surface of lipid cubic nanoparticles, as well as other charged or polarizable groups on the particle surface, to obtain... The surface treatment intermediate II stock solution was then subjected to dialysis using a semi-permeable membrane bag with a molecular weight cutoff of 50 kDa. Dialysis was performed at 25°C for 20 h with deionized water as the external phase, during which the external phase was replaced 5 times. The external phase was monitored using a calcium ion colorimetric method. Concentration changes, and determination of free concentration in intermediate II after dialysis. The equilibrium concentration was 1.85 mmol / L.

[0156] IV. Preparation of Final Assembly Materials

[0157] Step S3: Final Matching

[0158] The intermediate II was diluted with purified water containing an appropriate amount of sodium chloride, so that the total mass of the lipid matrix accounted for 23 wt% of the total mass of the assembly material, and the total mass fraction of sodium chloride in the assembly material was maintained at 0.93 wt%. The mixture was magnetically stirred at 29°C for 28 min to ensure uniform mixing, thereby obtaining an aqueous dispersion of the assembly material for transdermal drug delivery.

[0159] V. Quality Inspection

[0160] The particle size and distribution of the lipid cubic phase nanoparticles prepared in this embodiment were determined by dynamic light scattering (DLS) at 25°C. The sample was diluted with purified water to a suitable concentration, and the scattering angle was 173°. The median volumetric particle size (d50) was measured to be 186 nm, and the polydispersity index (PDI) was 0.20. The zeta potential was determined by electrophoretic light scattering at 25°C. The sample was moderately diluted with a low-conductivity buffer, and the pH was adjusted to 6.9. The sodium chloride mass fraction in the assembly material was 0.93 wt%, and the free sodium chloride content was [not specified]. At a concentration of 1.85 mmol / L, the absolute value of the zeta potential of the lipid cubic phase nanoparticles was measured to be 27 mV. By measuring the total solid content of the dispersion system and estimating the density of the lipid cubic phase, the volume fraction of lipid cubic phase nanoparticles in intermediates I and II, calculated based on the lipid cubic phase domain, was 58 vol%. The osmotic pressure of the assembled material in this embodiment was measured to be 332 mOsm / kg using a freezing point osmometer. After being stored at 25°C, protected from light, and in a sealed environment for 90 days, the median particle size (d50) of the lipid cubic phase nanoparticles increased to 200 nm compared to the initial particle size before storage, representing a relative increase of 7.5%. The PDI was 0.23, and no visible lidocaine crystals were observed to precipitate.

[0161] VI. Preparation of Gel Formulations

[0162] Take 50g of the aqueous dispersion of the assembly material prepared in step S3 above, and slowly add 5g of pre-swollen hydroxypropyl methylcellulose hydrogel matrix (accounting for 10wt% of the total mass of the assembly material) at 25℃. Stir with a mechanical stirrer at 300rpm for 30min until homogeneous to obtain a semi-solid gel formulation. Use a rotational rheometer at 25℃ and a shear rate of... The apparent viscosity of the obtained gel formulation was 2800 mPa·s under the specified conditions.

[0163] Features of Example 4: This example employs a boundary value validation design. The total content of the four components of the lipid matrix is ​​94.2 wt%, close to the lower limit. Cholesterol, dioleate, and caprylic / capric triglycerides all reach the upper limits of 10.0 wt%, 7.0 wt%, and 10.0 wt%, respectively. The amount of DSPE-PEG2000 is 1.4 wt%, close to the upper limit of 1.5 wt%. The lidocaine loading is 23 wt%, close to the upper limit of 25 wt%. The equilibrium concentration was 1.85 mmol / L, close to the upper limit of 2.0 mmol / L; the sodium chloride mass fraction was 0.93 wt%, close to the upper limit of 0.95 wt%; the lipid matrix accounted for 23 wt% of the assembly material, close to the upper limit of 25 wt%; and all parameters were selected within the 85-95% range. The process conditions were close to the upper limits: the melt temperature was 63℃, close to the upper limit of 65℃; the homogenization pressure was 75 MPa, close to the upper limit of 80 MPa; the cycle count was 7, close to the upper limit of 8; and the cubic phase maturation time was 22 h, close to the upper limit of 24 h. The initial concentration of 9.2 mmol / L is close to the upper limit of 10.0 mmol / L. The resulting assembly material has a particle size of 186 nm, close to the upper limit of 200 nm, a PDI of 0.20, reaching the upper limit, an absolute zeta potential of 27 mV, close to the preferred upper limit of 30 mV, a volume fraction of 58 vol%, close to the preferred upper limit of 60 vol%, and an osmotic pressure of 332 mOsm / kg, close to the upper limit of 340 mOsm / kg. After 90 days of storage, the particle size increased by 7.5%, and the PDI was 0.23, meeting the storage stability requirement of not exceeding 0.25. This embodiment fully verifies the feasibility of the claims within the upper limit, demonstrating that even under conditions close to the process and formulation parameter limits, an assembly material meeting quality standards can still be prepared through optimized parameter combinations, and can be further prepared into a semi-solid gel formulation. This embodiment is particularly suitable for high-intensity transdermal drug delivery applications requiring maximum drug loading, high solid content, and strong osmotic pressure regulation, such as local high-concentration drug delivery, transdermal absorption enhancement, or drug delivery to thick stratum corneum skin. Simultaneously, the gel formulation improves the retention time of the formulation on the skin surface and patient compliance.

[0164] Comparative Example 1: Basically the same as Example 1, except that the mass fraction of monooleic glyceride is 58 wt%, and the other components are adjusted accordingly to keep the total of the four components at 94.5 wt%. The amount of other components and the preparation conditions remain unchanged.

[0165] Comparative Example 2: Basically the same as Example 1, except that the mass fraction of monooleic glyceride is 75 wt%, and the other components are adjusted accordingly to keep the total of the four components at 94.5 wt%. The amount of other components and the preparation conditions remain unchanged.

[0166] Comparative Example 3: Basically the same as Example 1, except that the mass fraction of cholesterol is 5 wt%, and the other components are adjusted accordingly to keep the total of the four components at 94.5 wt%. The amount of other components and the preparation conditions remain unchanged.

[0167] Comparative Example 4: Basically the same as Example 1, except that the mass fraction of cholesterol is 12 wt%, and the other components are adjusted accordingly to keep the total of the four components at 94.5 wt%. The amount of other components and the preparation conditions remain unchanged.

[0168] Comparative Example 5: Basically the same as Example 1, except that the amount of DSPE-PEG2000 used was 0.3wt%, while the amounts of other components and preparation conditions remained unchanged.

[0169] Comparative Example 6: Basically the same as Example 1, except that the amount of DSPE-PEG2000 used was 1.8 wt%, while the amounts of other components and preparation conditions remained unchanged.

[0170] Comparative Example 7: Basically the same as Example 1, except that the lidocaine loading is 3wt%, while the amounts of other components and preparation conditions remain unchanged.

[0171] Comparative Example 8: Basically the same as Example 1, except that the lidocaine loading was 28 wt%, while the amounts of other components and preparation conditions remained unchanged.

[0172] Comparative Example 9: Basically the same as Example 1, except that no [further details are needed]. Surface treatment step, i.e., free in intermediate II The concentration was 0 mmol / L, with other component amounts and preparation conditions remaining unchanged. This comparative example was used for verification. The necessity of a coordinated stability mechanism.

[0173] Comparative Example 10: Basically the same as Example 1, except that intermediate II contains free... The equilibrium concentration was adjusted to 2.5 mmol / L by reducing dialysis time or dialysis intensity, while the amounts of other components and preparation conditions remained unchanged.

[0174] Comparative Example 11: Basically the same as Example 1, except that the high-pressure homogenization pressure was 20 MPa, the number of cycles was 3, and the amount of other components and preparation conditions remained unchanged.

[0175] Comparative Example 12: Basically the same as Example 1, except that the high-pressure homogenization pressure is 90 MPa, the number of cycles is 9, and the discharge temperature is controlled to not exceed 45°C by enhanced cooling during the homogenization process. The dosage of other components and preparation conditions remain unchanged.

[0176] Comparative Example 13: Essentially the same as Example 1, except that the cubic phase ripening step was shortened to 2 hours and carried out at a constant temperature of 32°C. The amounts of other components and preparation conditions remained unchanged. This comparative example was used to verify the importance of sufficient ripening time for the formation of the internal structure of the cubic phase.

[0177] Performance testing:

[0178] Experiment 1 was an experiment to determine particle size and particle size distribution. This experiment used an aqueous dispersion of lipid cubic phase nanoparticles as the test object, aiming to evaluate the median volumetric diameter (d50) and polydispersity index (PDI) of the nanoparticles, verifying the technical specifications of a d50 of 100 to 200 nm and a PDI not greater than 0.20. The experiment employed dynamic light scattering, based on the intensity fluctuations of scattered light caused by the Brownian motion of the particles. The hydrodynamic diameter distribution of the particles was calculated through photon correlation spectroscopy analysis, and the diffusion coefficient was converted to particle size using the Stokes-Einstein equation. Specifically, the assembly material sample was diluted with purified water to a suitable concentration to achieve a transmittance of approximately 80% to 90%. After equilibration at room temperature for 15 min, the sample was transferred to a cuvette and measured using a laser particle size analyzer at 25℃ and a scattering angle of 173°. Each sample was measured in triplicate, and the median volumetric diameter (d50) and PDI were recorded. The instrument was calibrated with polystyrene microsphere standards before the test. Key parameters include a test temperature of 25±0.5℃, a sample dilution factor of 50 to 200 times, a scattering angle of 173°, automatic optimization of measurement time, and an equilibration time of no less than 15 min. For data processing, the arithmetic mean of the d50 values ​​from three parallel measurements is used as the result. The relative standard deviation (RSD) should not exceed 5%, and the PDI is expressed as the average of the three measurements, accurate to two decimal places.

[0179] Experiment 2 was a zeta potential measurement experiment. This experiment used an aqueous dispersion of lipid cubic nanoparticles as the test object to evaluate the surface charge state of the nanoparticles and verify... The electrostatic interaction between the phosphate groups of DSPE-PEG2000 and the effect on colloidal stability were investigated to confirm the technical specification that the absolute value of the zeta potential is not less than 10 mV. The electrophoretic mobility of the particles under an applied electric field was determined using electrophoretic light scattering, and the zeta potential was calculated using the Smoluchowski or Henry equations to reflect the double-layer potential of the particle surface. Specifically, the assembly material sample was diluted to a suitable concentration with a low-conductivity buffer (0.01 mol / L phosphate buffer, pH 6.5) to ensure that the sodium chloride mass fraction in the sample was maintained between 0.75 and 0.95 wt% and that the sodium chloride was free. Concentrations ranging from 0.5 to 2.0 mmol / L were equilibrated at room temperature for 20 min before being transferred to a folded capillary electrophoresis pool. Electrophoretic light scattering was performed at 25°C, with each sample measured in triplicate. Key parameters included a test temperature of 25 ± 0.5°C, pH ranging from 6.0 to 7.0, automatic optimization of the electric field strength, at least five measurements, and a sample conductivity of less than 2 mS / cm. Outliers were removed from the data, and the average value was taken. The relative standard deviation (RSD) should not exceed 10%. Results were expressed in mV, accurate to the nearest integer, and the zeta potential distribution width was recorded.

[0180] Experiment 3 was a drug loading and encapsulation efficiency determination experiment. This experiment used drug-loaded lipid cubic phase nanoparticles as the test object to quantitatively determine the actual drug loading and encapsulation efficiency of the poorly soluble active ingredient lidocaine in the assembly material, verifying the feasibility of the high drug loading design and the distribution of the drug in the cubic phase matrix. High-performance liquid chromatography (HPLC) was used to determine the total drug load and free drug load. Free drug was separated by ultrafiltration or ultracentrifugation. The encapsulation efficiency was calculated by subtracting the ratio of the total drug load to the free drug load and multiplying by 100%. The specific procedure involved accurately weighing approximately 0.5 g of the assembly material, extracting it using a methanol-water mixture at a volume ratio of 7:3, sonicating for 15 min, and then bringing the volume to 50 mL. The extract was filtered through a 0.22 μm filter and the total drug content was determined by HPLC. Separately, 1 mL of the assembly material was centrifuged at 4000 g for 30 min using an ultrafiltration tube with a molecular weight cutoff of 10 kDa, and the free drug content of the filtrate was determined. The HPLC conditions were: a C18 column (250 mm × 4.6 mm, 5 μm packing material), a mobile phase of phosphate buffer (pH 7.0) and acetonitrile (60:40 volume ratio), a flow rate of 1.0 mL / min, a detection wavelength of 220 nm, and a column temperature of 30℃. Key parameters included an extraction solvent ratio of 7:3, sonication time of 15 min, ultrafiltration conditions (centrifugation at 4000 g for 30 min), and an HPLC injection volume of 20 μL. For data processing, a lidocaine standard curve was established with a concentration range of 5 to 100 μg / mL and a correlation coefficient r of not less than 0.999. The drug loading was calculated by multiplying the total drug load by 100% of the sample mass. The encapsulation efficiency was calculated using the above formula. Each sample was measured in triplicate, and the results were expressed as the mean ± standard deviation.

[0181] Experiment 4 was a storage stability evaluation experiment. This experiment used an aqueous dispersion of the assembly material as the test object to evaluate the colloidal and physicochemical stability of the assembly material under long-term storage conditions at 25℃ in a light-proof, sealed environment. It verified the technical indicators that after 90 days of storage, the particle size increase should not exceed 15%, the PDI should not exceed 0.25, and no crystal precipitation should occur. The experiment comprehensively evaluated the aggregation tendency, structural stability, and drug crystallization risk of cubic phase nanoparticles during storage by periodically measuring particle size, PDI, appearance changes, and drug content retention. Specifically, the assembly material was dispensed into brown glass bottles, sealed, and stored in a constant temperature incubator at 25±2℃ and a relative humidity not exceeding 60% in the light-proof environment. Samples were taken at 0, 7, 14, 30, 60, and 90 days. Particle size and PDI were measured according to the method in Experiment 1. Visual inspection was conducted to check for precipitation, stratification, or crystal formation. Drug content was measured according to the method in Experiment 3. The relative increase in particle size was calculated as the ratio of the storage d50 minus the initial d50 to the initial d50 multiplied by 100%. Key parameters include storage temperature of 25±2℃, relative humidity not exceeding 60%, light protection and airtight sealing, sampling time points of 0 / 7 / 14 / 30 / 60 / 90 days, and a sample volume of approximately 2 mL each time. During data processing, particle size-time curves and drug content-time curves are plotted. The particle size increase over 90 days should not exceed 15%, the PDI should not exceed 0.25, the drug content retention rate should not be less than 95%, and there should be no visible particles or sediment. Data are expressed as mean ± standard deviation (n = 3).

[0182] Experiment 5 was an X-ray diffraction (XRD) experiment to characterize the cubic phase structure. This experiment used lyophilized powder of drug-loaded lipid cubic phase nanoparticles as the test object, aiming to characterize the space group type and lattice parameters of the ordered structure within the cubic phase using small-angle and wide-angle X-ray diffraction, verifying the success of lipid self-assembly to form a cubic phase and its inhibitory effect on drug crystallization. Based on the characteristic small-angle diffraction peaks of cubic phase lipids, the cubic phase type was determined according to peak ratios such as √2:√3:√4 corresponding to the Pn3m space group and √6:√8:√14 corresponding to the Im3m space group. The lattice parameter a was calculated according to the Bragg equation d = λ divided by 2 times sinθ. The presence or absence of drug crystallization peaks was detected in the wide-angle region. The specific operation involved freeze-drying an assembly material sample for 48 hours to prepare powder. An X-ray diffractometer was used with a Cu Kα radiation source at a wavelength of 0.154 nm. The small-angle scanning range was 0.5 to 5° (2θ value), with a step size of 0.02° and a scanning rate of 1° / min; the wide-angle scanning range was 5 to 40° (2θ value), with a step size of 0.02° and a scanning rate of 2° / min. The operating voltage was 40 kV and the operating current was 40 mA. Key parameters included the radiation source Cu Kα, small-angle range of 0.5 to 5°, wide-angle range of 5 to 40°, step size of 0.02°, voltage of 40 kV, current of 40 mA, and freeze-drying time of 48 hours. During data processing, the peak ratio is calculated based on the characteristic peak position in the small-angle region to determine the space group type. The lattice parameter a is calculated using the first diffraction peak. If there are no drug characteristic peaks in the wide-angle region, such as the crystal peaks of lidocaine near 15° and 20°, it indicates that the drug is encapsulated in a cubic phase in an amorphous state. The data is exported in ASCII or CSV format for plotting and analysis in Origin.

[0183] Experiment 6 was an in vitro release behavior assay. This experiment used aqueous dispersions or gel formulations of drug-loaded assembly materials as test subjects to evaluate the in vitro release kinetics of poorly soluble active ingredients from lipid cubic nanoparticles, and to verify the ability of cubic phase carriers to control drug release and its relationship with dosage form. The experiment used dialysis or the Franz diffusion cell method to simulate the in vitro release environment. Drug concentration in the receiving solution was measured by timed sampling, cumulative release curves were plotted, and a release kinetic model was fitted. The specific procedure involves accurately measuring 1 mL of assembly material containing approximately 1.5 mg of lidocaine, placing it in a dialysis bag with a molecular weight cutoff of 12 to 14 kDa, sealing both ends, and immersing it in 100 mL of phosphate-buffered saline (PBS) at pH 7.4 containing 0.5% Tween 80 for solubilization. The bag is then placed in a constant-temperature water bath at 37 ± 0.5 °C and shaken at a constant speed of 100 rpm. At 0.5, 1, 2, 4, 6, 8, 12, and 24 h, 5 mL of the receiving solution is collected and an equal volume of fresh medium is added. The sample is filtered through a 0.22 μm filter, and the drug concentration is determined by HPLC, and the cumulative release percentage is calculated. Key parameters include a dialysis bag MWCO of 12 to 14 kDa, a receiving solution volume of 100 mL, a temperature of 37 ± 0.5 °C, a shaking speed of 100 rpm, and sampling time points of 0.5 / 1 / 2 / 4 / 6 / 8 / 12 / 24 h. During data processing, the cumulative release rate Q percentage was calculated as the sum of Vr multiplied by Cn plus V0 multiplied by Cn and multiplied by 100% of the total drug amount, where Vr is the replenishment volume, V0 is the total volume of the receiving fluid, and Cn is the concentration of the nth sample. Q-t curves were plotted, and zero-order, first-order, Higuchi, and Korsmeyer-Peppas models were fitted. The optimal model was selected based on the correlation coefficient R². The data were expressed as mean ± standard deviation n = 3.

[0184] Figure 1 This is a surface chemical state analysis image obtained using XPS broadband spectroscopy. The goal is to confirm that the surface of lipid cubic nanoparticles simultaneously contains key elements such as C, O, P, and Ca. –The synergistic stabilization mechanism of DSPE-PEG2000 provides an elemental basis. Fixed parameters include a lipid matrix composed of monooleic glycerol, cholesterol, dioleate, and caprylic / capric triglycerides in proportions within the range of Examples 1-4; a uniform surface stabilizer of 0.5–1.5 wt% DSPE-PEG2000; and a poorly soluble active ingredient with a lidocaine loading of 5–25 wt%. All samples were processed according to the following steps: melting – hydration – high-pressure homogenization – cubic phase ripening. The surface treatment process was carried out within the 50–65 °C and 25–40 °C windows, and the film was dried at 25 °C. The varying parameters were the slight differences in relative peak intensity caused by the lipid ratio and drug loading in different examples. Characteristic peaks of C 1s, O 1s, P 2p, and Ca 2p appeared in the spectra near approximately 285 eV, 532 eV, 133 eV, and 347 eV, respectively. P 2p originated from the phosphate head group of DSPE-PEG2000, and Ca 2p originated from the surface provided by calcium chloride. This demonstrates that a phosphorus-containing PEGylated layer and surface can be stably obtained under the formulation and process described in the appendix instructions. The coexisting lipid cubic phase nanoparticles provide a basis for subsequent... The results of combining phosphate groups to regulate zeta potential and stability provide a structural basis.

[0185] Figure 2 Different Ca 2p high-resolution spectra Concentration on surface Enrichment effect diagrams aim to quantitatively compare free water phases. Concentration changes on particle surface The impact of coverage was investigated to verify the 0.5–2.0 range. To ensure the rationality of the effective synergistic window, the fixed parameters were the lipid formulation, DSPE-PEG2000 dosage, and lidocaine loading, all set according to Example 1: 69.5 wt% monooleate, 9.0 wt% cholesterol, 6.5 wt% dioleate, 9.5 wt% caprylic / capric triglyceride, 1.0 wt% DSPE-PEG2000, and 15 wt% lidocaine. The sample preparation process was melting – hydration – high-pressure homogenization – aging at 32 °C for 14 h. The measurement conditions were Al Kα radiation and high energy resolution, with the variable parameter being the aqueous phase free phase. The initial concentrations were 0, 1.2, and 2.5, respectively. The result showed 0. sample There is only a weak signal close to the background around 347.2 eV, 1.2 and 2.5 The sample showed clear double peaks and the peak area increased with... The significant increase in concentration demonstrates that the dropping and dialysis process described in the appendix instructions is feasible. Controllable enrichment on particle surface, and The dosage was positively correlated with surface coverage, which facilitated further testing using XPS Ca / P ratio and zeta potential. The optimal concentration window provides spectroscopic support.

[0186] Figure 3 For P 2p high-resolution spectrum and peak shift – The electrostatic interaction diagram of phosphate groups aims to prove… It is not a simple disordered adsorption, but rather a specific electrostatic or coordination interaction with the phosphate head group of DSPE-PEG2000, thereby altering the electronic environment around the phosphorus. The fixed parameters were: lipid matrix and DSPE-PEG2000 dosage consistent with Example 1; lidocaine loading of 15 wt%; melting temperature 57 ℃; high-pressure homogenization pressure 55 MPa; 5 cycles; aging at 32 ℃ for 14 h; and XPS testing conditions (energy resolution, energy calibration) consistent with Example 1. Figure 2 The same, the variable parameter is whether to perform. Surface treatment, compared with no treatment Sample and Add dropwise and dialyze until free Equilibrium concentration 1.2 The samples were analyzed, and a difference spectrum between the treated and untreated samples was plotted. The results showed that the P 2p main peak shifted from approximately 133.5 eV to approximately 133.1 eV, and the difference spectrum exhibited distinct positive and negative waveforms, indicating a systematic change in the charge distribution around the phosphate groups, thus confirming the findings presented in the appendix. The mechanism of forming a moderate electrostatic interaction with phosphate groups has a direct spectroscopic basis, providing a microscopic explanation for the enhanced surface potential in the subsequent zeta potential-pH curve.

[0187] Figure 4 The surface Ca / P atomic ratio varies with free atoms The goal of using XPS quantitative analysis plots of concentration changes is to construct a free aqueous phase... Concentration and particle surface The quantitative relationship between enrichment levels was verified to validate the 0.5–2.0 ratio in the appendix specification. of The equilibrium concentration range can indeed achieve effective surface regulation without inducing aggregation. The fixed parameters are: drug-loaded lipid cubic nanoparticle formulation and preparation process are the same as in Examples 1–3; DSPE-PEG2000 dosage is 0.8–1.3 wt%; lidocaine loading is 10–20 wt%; XPS quantification uses a uniform sensitivity factor and the same analytical depth; the variable parameter is the free lipids in intermediate II after dropwise addition and dialysis. The equilibrium concentrations were 0, 0.8, 1.2, 1.6, 2.0, and 2.5. Inter-atomic adjustment. Results show that the Ca / P atomic ratio is adjusted in the absence of... When it approaches 0, Concentration increases range from 0.8 to 1.6. It stabilizes within a range of approximately 0.8–1.5, and is above 2.0. The concentration continued to rise, but combined with the observation in Comparative Example 10, the risk of aggregation increased significantly, indicating that the 0.5–2.0 level proposed in the appendix was appropriate. free Within the range, surface It has formed a nearly saturated stable layer with the phosphate head group without excessive bridging, which reasonably supports the definition of "being able to regulate surface charge without inducing obvious aggregation".

[0188] Figure 5 The difference in zeta potential–pH curves The concentration-regulated surface charge map aims to show the change in particle surface charge with pH in a NaCl isotonic environment within the pH range of 3–9. The synergistic change pattern of concentration was studied to verify that a stable negative potential of 10–30 mV could be obtained under pH conditions near the skin and mucous membranes. The fixed parameters were the lipid cubic phase nanoparticle formulations corresponding to the medium, low, and high drug loading combinations in Examples 1–3, respectively. The NaCl mass fraction was controlled at 0.75–0.95 wt% to maintain an osmotic pressure of 260–340. , The addition and dialysis were performed according to procedure B1 of the instruction manual. The electrophoretic light scattering test temperature was 25 °C, and the buffer system was 0.01... Phosphate buffer, with varying parameters: free Equilibrium concentrations: 0, 1.2, 2.5 And the pH was scanned point-by-point within an artificially adjusted range of 3–9. The results showed that no additives were used. The particle's zeta potential is approximately -6 mV near pH 6.5, 1.2 It drops to approximately -21 mV, 2.5 The voltage further drops to approximately -37 mV, and the isoelectric point increases accordingly. The concentration has shifted slightly towards neutral, indicating that the attached instruction manual suggests adjusting the free... The idea that the concentration can stabilize the absolute value of the zeta potential in the range of 10–30 mV at pH 6.0–7.0 is supported by experimental curves, providing a basis for balancing structural stability and adjustable surface charge in a tissue-friendly environment.

[0189] Figure 6This is the SAXS I(q)–q curve characterization diagram of the 15 wt% cubic phase structure with drug loading (logI). The goal is to directly determine the cubic phase space group type and estimate the lattice parameters by the positional relationship of the scattering peaks, under the condition of consistent drug loading as in Example 1. The fixed parameters are the lipid matrix ratio and the amount of DSPE-PEG2000 used as set in Example 1. The lidocaine drug loading is 15 wt% of the total mass of the lipid matrix. The sample is prepared into powder by freeze-drying for 48 h. Small-angle scattering is performed using Cu Kα radiation, with q corresponding to 2θ of approximately 0.5–5°, a step size of approximately 0.02°, and a scan rate of... The varying parameter is the scattering vector q in the range of 0.2–1.8. The values ​​are within the range and the vertical axis is represented by log I(q). The measured curve shows characteristic peaks at a series of q positions, with a peak ratio of approximately √2:√3:√4:√6, corresponding to the Pn3m cubic phase space group. The lattice parameter a calculated from the first diffraction peak is approximately 12.8 nm, consistent with the value calculated by small-angle XRD in the specification. At the same time, no lidocaine crystal diffraction peaks were observed in the wide-angle region, proving that a regular bicontinuous cubic phase structure is formed inside the system under 15 wt% drug loading conditions, and the drug is encapsulated in an amorphous / molecular state, which corroborates the structural basis of "high drug loading and no crystallization".

[0190] Figure 7 The SAXS plot of lattice parameter 'a' as a function of drug loading was used to reveal the effect of lidocaine loading variation on cubic phase lattice expansion behavior, structurally supporting the statement in the specification that "the cubic phase structure is maintained even at high drug loading." Representative combinations of the four lipid matrix components and DSPE-PEG2000 dosage were selected within the range of Examples 1–4, with parameters fixed. Small-angle X-ray diffraction (SAXD) testing conditions were used. Figure 7 To maintain consistency, the parameters were adjusted incrementally between 0, 5, 10, 15, 20, 25, and 28 wt% for lidocaine loading. Fitting results showed that the lattice parameter 'a' increased approximately linearly from about 11.2 nm to 14.5 nm within the 5–25 wt% loading range, indicating that the drug molecules mainly functioned to moderately expand the cubic phase channels without disrupting the overall topology. When the loading increased to 28 wt%, the value of 'a' showed a slight deviation from linearity. Combined with the description in the instructions for Comparative Example 8 of increased particle size, decreased encapsulation efficiency, and worsened stability at 28 wt% loading, it is evident that the cubic phase structure was approaching its upper limit of loading capacity. This figure confirms the rationality of the instructions' designation of 5–25 wt% as a balance range between high drug loading and structural stability.

[0191] Figure 8This is a comparison of SAXS curves at 5, 15, 25, and 28 wt% for different drug loading amounts. The goal is to visually demonstrate the evolution of the retention and order of cubic phase characteristic peaks with increasing drug loading within the range specified in the product instructions. The experimental curves verify that 28 wt% is close to the structural limit. The parameters were fixed: the lipid formulation and the amount of DSPE-PEG2000 were taken from Example 2 (10 wt% low drug loading), Example 1 (15 wt% medium drug loading), and Example 3 (20 wt% relatively high drug loading), interpolated to 25 wt% and 28 wt% for Comparative Example 8, respectively. The SAXS testing conditions were the same as those in Comparative Example 8. Figure 7 Consistent with varying lidocaine loading parameters of 5 wt%, 15 wt%, 25 wt%, and 28 wt%, the results showed clear Pn3m multi-order diffraction peaks in the small-angle region within the 5–25 wt% range. The peak positions were largely overlapping, with only slight variations in peak height and width with increasing drug loading, indicating that the cubic phase network structure was stable within the high drug loading range specified in the product manual. However, at 28 wt%, the main peak broadened significantly, while higher-order peaks attenuated, consistent with the phenomena of increased particle size, deteriorated PDI, and worsened release behavior observed in Comparative Example 8. This demonstrates that defining 28 wt% as the high drug loading boundary in the product manual is not arbitrary but directly related to the decrease in internal order within the cubic phase.

[0192] Figure 9 This is a comparison chart of pure drug, physical mixture, and assembly material using DSC curve overlay. The goal is to further verify the conclusion that "drugs do not crystallize under high drug loading conditions" through differential scanning calorimetry melting behavior analysis. The fixed parameters are DSC instrument, heating rate, and temperature range. All samples were tested under nitrogen protection. The lipid matrix ratio and DSPE-PEG2000 dosage correspond to Examples 1–4. The varying parameters are that the sample types are pure lidocaine raw material powder, a physical mixture of lidocaine and lipid matrix (25 wt%), and drug-loaded lipid cubic phase assembly materials with lidocaine loading of 15 wt%, 25 wt%, and 28 wt%, respectively. The curve results show that pure lidocaine exhibits a sharp melting endothermic peak at approximately 68–70 °C. This peak is still present in the physical mixture, but its peak area is significantly reduced. In the 15 wt% and 25 wt% drug-loaded assembly materials, the lidocaine melting peak essentially disappears, leaving only a broad peak of lipid phase transition. The 28 wt% sample shows only a very weak residual melting peak. This indicates that the conclusion in the product information, based on XRD and storage stability, that the drug exists in an amorphous or molecular state is supported at the thermal analysis level, and that a small tendency for crystallization only appears when approaching the upper limit of 28 wt% drug loading.

[0193] Figure 10 Particle size The graph shows the changes over storage time (Example 1 vs. Comparative Example 9), aiming to introduce time-resolved DLS comparison. Synergistic regulation of particle size evolution behavior before and after, verifying the "free" in the specification. 0.5–2.0 The statement that "maintaining long-term particle size stability is key" was made with fixed parameters in Example 1 and Comparative Example 9, where the lipid formulation, DSPE-PEG2000 dosage, and lidocaine loading were identical, the NaCl mass fraction was approximately 0.85 wt%, and the osmotic pressure was approximately 295. Storage conditions are 25℃, protected from light, sealed, and relative humidity not exceeding 60%. DLS testing temperature is 25℃, scattering angle is 173°, and the variable parameter is whether or not it is performed. Surface treatment (Example 1 Free) Equilibrium concentration 1.2 The comparative example is 9, which is 0. The results showed that in Example 1, the storage times were 0, 7, 14, 30, 60, and 90 days. The particle size gradually increased from 152 nm to 164 nm, a relative increase of 7.9%, meeting the requirement of "not exceeding 15%" in the instructions. In contrast, the particle size in Comparative Example 9 rapidly increased to >300 nm within 7 days and to approximately 600 nm within 90 days, consistent with the deterioration data of d50 and PDI in Comparative Example 9 in Table 1. This indicates that under the same steric hindrance of PEG, Electrostatic control is an indispensable part of maintaining nanoscale particle size and inhibiting aggregation in the long term.

[0194] Figure 11 The graph shows the change in PDI over storage time (Example 1 vs. Comparative Example 9). The aim is to monitor the change in particle size distribution width over time and to further evaluate... –The contribution of DSPE-PEG2000 synergistic stabilization design to maintaining a narrow particle size distribution, with fixed parameters being the sample formulation, storage conditions, and DLS testing method. Figure 10 Similarly, PDI was calculated according to the volume distribution pattern, with the variation parameters being the PDI values ​​of Example 1 and Comparative Example 9 at the aforementioned time points. The results show that the PDI of Example 1 increased slightly from 0.16 to approximately 0.19, never exceeding the 0.25 limit given in the specification, while the PDI of Comparative Example 9 rapidly increased from approximately 0.18 to approximately 0.68, highly consistent with the PDI of Comparative Example 9 (0.68–0.75) in Table 1, indicating that in the absence of… Under surface treatment conditions, even with the same dosage of DSPE-PEG2000, the particles struggle to maintain good colloidal stability under isotonic and pH 6.0–7.0 conditions. This figure confirms the statement in the instruction manual regarding particle size distribution. The conclusion is that "synergy with DSPE-PEG2000 is a key factor in maintaining long-term uniform nanodispersions".

[0195] As can be seen from the performance of the embodiments and comparative examples in Table 1, the four embodiments of the present invention exhibit significant advantages in particle size control, colloidal stability, drug loading and encapsulation, and release behavior. The particle size d50 of Examples 1-4 is strictly controlled within the range of 138-186 nm, and the PDI is ≤0.20, indicating uniform particle distribution and meeting the technical specifications; the absolute value of the zeta potential is within the range of 14-27 mV, proving... The synergistic stabilization mechanism with DSPE-PEG2000 effectively maintained the surface charge and prevented particle aggregation; the encapsulation efficiency reached 94.2-98.2%, fully verifying the efficient encapsulation capacity of the cubic phase lipid matrix for poorly soluble active ingredients; after 90 days of storage, the particle size increase was only 7.2-9.6%, far below the acceptable standard of 15%, and the PDI remained ≤0.23, demonstrating excellent long-term stability; the cumulative release rate after 24 hours was controlled at 58.6-72.3%, reflecting the sustained-release characteristics of the cubic phase nanocarrier. In contrast, Comparative Examples 1-5, due to deviations in lipid composition from the optimal range or insufficient DSPE-PEG2000 dosage, resulted in a significant increase in particle size to 245-328 nm, a deterioration in PDI to 0.35-0.52, a decrease in encapsulation efficiency to 72.3-85.6%, and a 90-day particle size increase as high as 24.2-42.3%, far exceeding the stability requirements; Comparative Examples 9 and 10, due to... When the concentration deviated from the preferred range, severe aggregation (particle size 385-425 nm, PDI 0.68-0.75) and surface charge imbalance occurred, resulting in a significant decrease in encapsulation efficiency to 65.8-68.2% and deterioration in storage stability (increase of 58.5-65.2%). Comparative Example 11 suffered from insufficient homogeneity, resulting in large particle size (358 nm) and imperfect structure, leading to a double loss in both encapsulation efficiency and stability. Comparative Example 13 suffered from insufficient ripening time, resulting in incomplete formation of an ordered structure within the cubic phase, with a particle size of 285 nm, an encapsulation efficiency of only 80.2%, and a particle size increase of up to 35.8% during storage. It is worth noting that although Comparative Examples 6 and 12 approached the levels of the actual examples in some indicators (e.g., the encapsulation efficiency of Comparative Example 6 was 95.8%, and the particle size of Comparative Example 12 was 195 nm), their excessive DSPE-PEG2000 or excessively high homogenization pressure led to a significant increase in preparation costs and energy consumption, thus lacking industrialization advantages. While Comparative Example 7 achieved good particle size and release performance with a low drug loading (3 wt%), its encapsulation efficiency was only 88.5%, and its drug utilization rate was low, failing to meet the design intent of high drug loading. Based on the above data, this invention achieves its goal through precise lipid matrix formulation and the application of DSPE-PEG2000 with… The system integration of synergistic stability, process parameter optimization, and ion environment control has successfully resolved the fundamental contradiction between high drug loading and long-term stability of poorly soluble active ingredients, providing a technically feasible, high-performance, and industrially promising assembly material solution for the transdermal and mucosal drug delivery field.

[0196] Table 1 Performance comparison data of the examples and comparative examples

[0197]

[0198] 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 it. Although the present invention has been described in detail with reference to the above embodiments, those skilled in the art should understand that any equivalent structural transformations made under the concept of the present invention and using the contents of the specification and drawings of the present invention should be covered within the scope of protection of the claims of the present invention.

Claims

1. An assembly material for transdermal mucosal administration of poorly soluble active drugs, characterized in that, The product comprises an aqueous phase and cubic lipid nanoparticles dispersed in the aqueous phase, wherein the cubic lipid nanoparticles include a lipid matrix, a surface stabilizer, and surface ions. ,in: The lipid matrix is ​​a mixture of monooleate glycerides, cholesterol, dioleate glycerides, and caprylic / capric triglycerides; The surface stabilizer is DSPE-PEG2000; The surface ions Provided by calcium chloride dissolved in the aqueous phase; The lipid cubic phase nanoparticles are loaded with at least one poorly soluble active ingredient, wherein the equilibrium solubility of the poorly soluble active ingredient in water at 25°C is ≤100 μg / mL, and the octanol / water partition coefficient LogP≥2.0; Based on the total mass of the lipid matrix, the lipid matrix contains 62–72 wt% monooleate, 7–10 wt% cholesterol, 4–7 wt% dioleate, and 8–10 wt% caprylic / capric triglyceride. The sum of the mass fractions of the above four lipid matrix components is 94–98 wt%, with the remainder being water and unavoidable impurities. The assembly material is obtained through the continuous preparation of intermediate I and intermediate II, wherein intermediate I is a drug-loaded lipid cubic phase nanodispersion, and intermediate II is prepared based on intermediate I through... The preparation method of intermediate I of the obtained drug-loaded lipid cubic phase nanodispersion includes the following steps: A1. Melting the lipid matrix and dissolving the poorly soluble active ingredient: A2. Hydration and pre-dispersion: Add an aqueous phase containing DSPE-PEG2000 and optionally sodium chloride to the drug-loaded lipid molten phase, stir, and obtain a crude drug-loaded dispersion; A3. High-pressure homogenization: The drug-loaded coarse dispersion is subjected to high-pressure homogenization at a pressure of 30–80 MPa to obtain drug-loaded lipid nanodispersions; A4. Cubic phase ripening: The drug-loaded lipid nanodispersions obtained in step A3 are allowed to stand or be slowly stirred at 25–40°C for 4–24 hours to allow the lipids inside the particles to self-assemble into a cubic phase internal structure, and the poorly soluble active ingredients are dispersed or dissolved in the cubic phase lipid matrix to obtain intermediate I. The preparation method of the intermediate II includes the following steps: B1. Surface treatment: The calcium chloride aqueous solution was added to intermediate I at a dropping rate of 0.1–0.3 mL / min until free calcium chloride was present in the system. The initial concentration reached 1.0–10.0 mmol / L, and stirring continued for 30–60 min, so that... Electrostatic interaction occurs with the particle surface, resulting in... The surface treatment intermediate II stock solution; subsequently, free free radicals are partially removed by dialysis or ultrafiltration. The obtained intermediate II is free The equilibrium concentration was adjusted to 0.5–2.0 mmol / L; The amount of surface stabilizer DSPE-PEG2000 used is 0.5–1.5 wt% of the total mass of the lipid matrix; The amount of poorly soluble active ingredient is 5–25 wt% of the total mass of the lipid matrix.

2. The assembly material for transdermal mucosal drug delivery of poorly soluble active ingredients as described in claim 1, characterized in that, The surface ions It can electrostatically interact with the phosphate groups of DSPE-PEG2000 on the surface of lipid cubic nanoparticles and other charged or polarizable groups on the particle surface, thereby regulating the ionic environment and particle surface charge state of the system within a limited concentration range. In conjunction with the steric stabilization effect provided by DSPE-PEG2000, it is beneficial to obtain good colloidal stability and storage stability of the assembled material without causing significant particle aggregation. The equilibrium solubility in water at 25°C was determined using the shaking flask method at 25°C, and the octanol / water partition coefficient LogP was determined using the octanol / water shaking method according to the pharmacopoeia or an equivalent recognized method. The specific steps of step A1 are as follows: Weigh out monooleate, cholesterol, dioleate, and caprylic / capric triglycerides at 50–65°C, heat and stir for 20–40 min to melt monooleate, dioleate, and caprylic / capric triglycerides, and fully disperse cholesterol in the resulting liquid lipid phase to obtain a lipid melt phase; then add a poorly soluble active ingredient with sufficient thermal stability at 50–65°C to the lipid melt phase at 5–25 wt% of the total lipid matrix, and continue stirring at 50–65°C for 10–30 min to dissolve the poorly soluble active ingredient in the lipid melt phase to obtain a drug-loaded lipid melt phase; In step A2, hydration and pre-dispersion are carried out at 45–55°C. An aqueous phase containing DSPE-PEG2000 and optionally sodium chloride is added to the drug-loaded lipid melt phase. The amount of the aqueous phase is 1–3 times the mass of the drug-loaded lipid melt phase. The mixture is stirred for 20–60 min to obtain a crude drug-loaded dispersion. Step A3 High-pressure homogenization: The drug-loaded coarse dispersion is subjected to high-pressure homogenization at a feed temperature of 30–45℃, a homogenization pressure of 30–80 MPa, and a cycle number of 3–8 times to obtain drug-loaded lipid nanodispersion. Step B1 Surface treatment is performed at 25–35°C, depending on the volume of intermediate I and the required surface treatment. The amount of calcium chloride aqueous solution required to calculate the initial target concentration is determined.

3. The assembly material for transdermal mucosal drug delivery of poorly soluble active ingredients as described in claim 1, characterized in that, Free in the aqueous phase The concentration is 0.5–2.0 mmol / L, and the free concentration in the aqueous phase is... Concentration is as described Surface treatment and partial removal of free radicals The residual concentration obtained afterwards.

4. The assembly material for transdermal mucosal drug delivery of poorly soluble active ingredients as described in claim 1, characterized in that, The median volumetric particle size (d50) of the lipid cubic phase nanoparticles was 100–200 nm, and the polydispersity index (PDI) was ≤0.20, as determined by dynamic light scattering. The composition of the nanoparticles was determined at 25 °C, pH 6.0–7.0, and with a sodium chloride mass fraction of 0.75–0.95 wt% in the assembly material. At concentrations of 0.5–2.0 mmol / L, the absolute value of the zeta potential measured by electrophoretic light scattering can typically reach above 10 mV, within the range of 10–30 mV.

5. The assembly material for transdermal mucosal drug delivery of poorly soluble active ingredients as described in claim 1, characterized in that, The aqueous phase further contains sodium chloride, the amount of which is 0.1–1.0 wt% of the total mass of the assembly material; after the assembly material is stored at 25°C under light-proof and sealed conditions for 90 days, the relative increase of the median particle size d50 of the lipid cubic phase nanoparticles relative to the initial particle size before storage is no more than 15%, the particle size polydispersity index (PDI) is no more than 0.25, and no visible insoluble active ingredient crystals are observed to precipitate.

6. A method for preparing an assembly material for transdermal mucosal drug delivery as described in any one of claims 1-5, characterized in that, Includes the following steps: S1. Preparation of intermediate I; S2. Preparation of intermediate II; S3. Final formulation and preparation: The intermediate II is diluted with water to make the total mass fraction of the lipid matrix to the total mass of the assembly material 5–25 wt%. The mixture is magnetically or mechanically stirred at 20–30°C for 10–30 min to make it uniform, thereby obtaining an aqueous dispersion of the assembly material for transdermal or mucosal administration, and / or the aqueous dispersion is mixed with a pharmaceutical hydrogel matrix to form a semi-solid gel or patch formulation.

7. The preparation method according to claim 6, characterized in that, In step S3, the amount of the pharmaceutical hydrogel matrix is ​​5–25 wt% of the total mass of the assembly materials. The pharmaceutical hydrogel matrix is ​​selected from hydroxypropyl methylcellulose, xanthan gum, or a combination of both. The final formulation is tested at 25°C using a rotational rheometer at a shear rate of 1... The apparent viscosity measured under the conditions was 500–5000 mPa·s.

8. The preparation method according to claim 6, characterized in that, The assembly material is an aqueous dispersion for transdermal or nasal / oral mucosal local administration, or a semi-solid gel or patch formed by mixing the assembly material with a pharmaceutical hydrogel matrix, wherein the molecular weight of the loaded poorly soluble active ingredient is less than 800 Da, and the drug component has sufficient thermal stability under conditions of 50–65°C.

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