A transdermal absorption promoting ointment and a preparation process thereof

Abstract

This application relates to the field of veterinary drug technology, and discloses a transdermal absorption-enhancing ointment and its preparation process. The ointment components include white petrolatum, anhydrous lanolin, caprylic / capric triglycerides, hydrophobic fumed silica, and a highly fluid active permeation-enhancing phase. The permeation-enhancing phase contains active drugs and soybean lecithin, which self-assemble to form an inverse micelle aggregate. Soybean lecithin cross-links with the silanol groups on the surface of silica to form an intermolecular hydrogen bond network, constructing a sterically hindered framework within a continuous lipid matrix to prevent the polar drug-loaded phase from permeating and separating upon heating. Simultaneously, the inverse micelle structure effectively improves the transdermal absorption rate of the drug. The preparation process controls the lipid crystallization kinetics through slow cooling under negative pressure and micro-shear dynamic rheology. This invention solves the problems of easy precipitation upon heating, low transdermal efficiency, and poor rheological properties in traditional ointments, resulting in a product with a stable physical structure and good pseudoplastic texture.

Description

Technical Field

[0001] This invention relates to the field of veterinary drug technology, specifically to a transdermal absorption-enhancing ointment and its preparation process. Background Technology

[0002] Transdermal ointments achieve local or systemic therapeutic effects through application to the skin surface. They are convenient and have good compliance when delivering broad-spectrum antibacterial and antiparasitic drugs (such as florfenicol and ivermectin). Typical ointment bases often use non-polar lipid materials such as white petrolatum and lanolin, while many active drugs often require polar solvents for dissolution to achieve the required drug loading in clinical practice. In practical applications and long-term storage, traditional ointment systems exhibit poor physical stability under heat conditions. Due to insufficient thermodynamic compatibility between the non-polar continuous matrix and the polar drug-loaded phase, and the lack of effective steric hindrance structures within the system, the polar drug-loaded phase is prone to interfacial migration and drug crystallization during temperature fluctuations, ultimately leading to macroscopic phase separation and shortening the product's shelf life.

[0003] Meanwhile, the lipid bilayer of the stratum corneum of mammalian skin forms a dense physical barrier. Drugs in traditional ointments, which are in a free or simply dissolved state, cannot effectively disrupt and penetrate this lipid structure. As a result, the amount of drug retained in the local skin is greater than the amount that penetrates, and the transdermal absorption efficiency is low, which directly affects the bioavailability of the drug and the final therapeutic effect.

[0004] Furthermore, existing ointment preparation processes often lack precise control over the internal rheological state and temperature gradient during the cooling and crystallization stage. Conventional forced cooling or simple stirring cooling can generate a large radial temperature gradient within the reactor, causing the lipid matrix to undergo rapid condensation and condensation on the cold walls of the reactor, forming locally supercooled hard lumps. This uneven crystallization kinetics disrupts the crystalline network formed during the precipitation of the lipid mixture, resulting in a semi-fluid ointment with uneven texture and poor rheological properties. Consequently, the product struggles to exhibit good thixotropy and pseudoplasticity during subsequent extrusion and application. Summary of the Invention

[0005] To address the shortcomings of existing technologies, this invention provides a transdermal absorption-enhancing ointment and its preparation process, which solves the problems of phase separation caused by the easy migration and precipitation of the polar drug-carrying phase under heating conditions, low transdermal absorption efficiency of active drugs, and poor texture and rheological properties of the ointment due to uneven crystallization during the cooling process.

[0006] To achieve the above objectives, the present invention provides the following technical solution: In a first aspect, the present invention provides a transdermal absorption-enhancing ointment comprising the following parts by weight: 27.0–59.6 parts of white petrolatum; 3.0–14.9 parts of anhydrous lanolin; 10.0–30.0 parts of caprylic / capric triglyceride; 2.0–4.0 parts of hydrophobic fumed silica; and 13.5–36.0 parts of a highly fluid active transdermal absorption-enhancing phase.

[0007] By employing the above technical solution, a continuous lipid matrix is ​​constructed using white petrolatum, anhydrous lanolin, and caprylic / capric triglycerides. Hydrophobic fumed silica and a highly fluid active permeation-enhancing phase are then dispersed within this matrix, resulting in a stable ointment phase, prevention of phase separation, and improved transdermal drug absorption efficiency. Specifically, the mechanism of action lies in the fact that white petrolatum combined with anhydrous lanolin provides a sebum-like sealing structure to block water evaporation, while the addition of caprylic / capric triglycerides effectively reduces the system viscosity and enhances its affinity for the stratum corneum. Furthermore, because the surface of the hydrophobic fumed silica retains incompletely sealed silanol groups, when the highly fluid active permeation-enhancing phase is dispersed within it, the phosphate groups of the internal phospholipid molecules interact with the free silanol groups, forming a cross-linked intermolecular hydrogen bond network. This non-covalent network constructs a sterically hindered framework within the continuous lipid matrix, binding the thermodynamic movement of the polar drug-loaded phase under heating conditions, fundamentally preventing the polar phase from permeating or precipitating outwards.

[0008] Preferably, the composition comprises the following components by weight: 46.8 parts white petrolatum; 7.2 parts anhydrous lanolin; 20.0 parts caprylic / capric triglyceride; 3.0 parts hydrophobic fumed silica; and 23.0 parts high-flowability active permeation-enhancing phase.

[0009] By adopting the above technical solution, a specific ratio enables the viscosity of the continuous lipid matrix and the dispersion state of the permeation-enhancing phase to reach a dynamic physical equilibrium, which can effectively resist micro-phase separation caused by gravity sedimentation or external temperature fluctuations in actual storage.

[0010] Preferably, the high-flowability active permeation-enhancing phase comprises the following components by weight: 1.0–5.0 parts of active pharmaceutical ingredient; 3.0–8.0 parts of diethylene glycol monoethyl ether; 2.0–5.0 parts of oleic acid; 0.5–2.0 parts of 1-dodecylazacycloheptan-2-one; 5.0–12.0 parts of isopropyl myristate; and 2.0–4.0 parts of soybean lecithin.

[0011] By employing the above technical solution, the system utilizes a multi-component co-solvent composed of diethylene glycol monoethyl ether, oleic acid, and 1-dodecylazine-heptane-2-one to dissociate the active pharmaceutical ingredient into a molecularly dispersed state. Based on this, upon the intervention of soybean lecithin and isopropyl myristate, soybean lecithin spontaneously assembles into an inverse micelle aggregate with a polar solvent and drug core and lipophilic carbon chains pointing outwards. These micelles not only remain stably suspended within a non-polar ointment matrix, but also, upon contact with the skin, disrupt the conventional arrangement of the stratum corneum lipid bilayer due to the flow characteristics of the surfactant, thereby encapsulating the active pharmaceutical ingredient and facilitating its penetration through the skin barrier.

[0012] Preferably, the active pharmaceutical ingredient is selected from florfenicol or ivermectin.

[0013] By adopting the above technical solutions, the existing permeation-enhancing phase system provides matching solubility parameters for veterinary clinical broad-spectrum antibacterial and antiparasitic drugs with specific molecular structures, thereby ensuring that the drug maintains a high loading capacity inside the ointment carrier and is not prone to crystallization and precipitation.

[0014] Preferably, the preparation steps of the high-flowability active permeation-enhancing phase include: dissolving the active pharmaceutical ingredient in a mixture of diethylene glycol monoethyl ether, oleic acid, and 1-dodecylazine-heptane-2-one at a temperature of 20-30°C, then adding isopropyl myristate and soybean lecithin, and continuously stirring at a speed of 150-250 rpm until the system is optically transparent and homogeneous, thereby obtaining a high-flowability active permeation-enhancing phase in the form of an inverted micelle aggregate.

[0015] By employing the above technical solution, the process deliberately limits the operating temperature to room temperature, guiding the components to complete spontaneous assembly through a low shear force field. This not only avoids irreversible damage to the fragile inverse micelle structure caused by high-intensity mechanical shear, but also enables the formed transparency-enhancing phase to maintain a thermodynamically stable state with optical transparency and uniformity for a long time.

[0016] Secondly, the present invention provides a preparation process for a transdermal absorption-enhancing ointment, comprising the following steps: S1: White petrolatum, anhydrous lanolin, and caprylic / capric triglycerides are heated and melted into a homogeneous liquid, and then hydrophobic fumed silica is added for shear dispersion to obtain the matrix system; S2: Under constant temperature conditions, the highly fluid active permeation-enhancing phase is pumped into the matrix system after cooling in step S1 using vacuum suction, and maintained for a predetermined time under negative pressure vacuum and shear conditions. S3: Maintain pressure to keep the vacuum and turn off high shear. Under micro-shear dynamic rheology, use an external cooling source to cool the system to the discharge temperature, break the vacuum, and discharge and fill to obtain the ointment product in a semi-fluid pseudoplastic state.

[0017] By adopting the above technical solution, a uniform and rheologically stable semi-fluid pseudoplastic ointment was finally obtained. The physicochemical evolution of the entire process is as follows: during the heating and melting stage, the solid lipid phase transforms into a Newtonian fluid. After the powder is added, the original agglomerates are broken by mechanical shearing, causing the hydrophobic fumed silica to suspend in the form of native particles and expose the active silanol groups. Subsequently, a transverse micelle phase is introduced under a constant temperature and negative pressure environment. This utilizes negative pressure to forcibly remove the entrained air bubbles to eliminate the damage to the micelles caused by the gas-liquid interfacial tension. On the other hand, moderate shearing promotes frequent collisions between soybean lecithin molecules and silanol groups, and rapidly establishes hydrogen bond anchoring. After the skeleton is constructed, the high-intensity shearing is turned off and a micro-shear dynamic rheological state is entered to implement forced heat transfer and cooling. This gentle physical intervention controls the crystallization kinetics of the lipids, causing petrolatum and lanolin to precipitate a fine and uniform crystalline network and encapsulate the cross-linked skeleton within it. This completely eliminates localized overcooling and hardening caused by temperature gradients, giving the ointment good thixotropic and pseudoplastic properties.

[0018] Preferably, in step S1, the heating and melting temperature is 80-90°C, and the shearing and dispersion is carried out by turning on a high-shear homogenizer with a set rotation speed of 2500-3000 rpm, while simultaneously turning on an anchor-type wall scraper with a set rotation speed of 30-50 rpm, and continuing the shearing and dispersion for 15-30 minutes.

[0019] By adopting the above technical solution, the heating zone ensures complete melting of lipids while avoiding the risk of thermal oxidation and degradation. The synergy between high-shear homogenization and anchor-type wall-scraping stirring creates a composite flow field with macroscopic circulation interwoven with microscopic shear, eliminating dead zones for material exchange within the vessel and forcing inorganic powders to disperse to the required nanoscale.

[0020] Preferably, before pumping in the highly fluid active permeation-enhancing phase in step S2, a cooling pretreatment step for the matrix system is also included, specifically including: cooling the matrix to 42-48°C at a cooling rate of 1.5-3.0°C / min, and reducing the rotation speed of the anchor-type wall scraper agitator to 20-40 rpm during the cooling process.

[0021] By employing the above technical solution, the matrix system is pre-cooled to a narrow operating window slightly above its freezing point. This pre-emptively eliminates the high-temperature potential energy accumulated in the matrix, preventing the subsequently pumped permeation-enhancing phase from suffering overheating shocks that could lead to adverse consequences such as solvent boiling, drug thermal degradation, or thermodynamic depolymerization of reverse micelles.

[0022] Preferably, the specific process parameters for step S2 are as follows: after feeding is completed, the high-shear homogenizer is turned on and the speed is set to 1000-2000 rpm, and the vacuum pump is turned on simultaneously to control the internal absolute vacuum at -0.08 to -0.09 MPa, and the vacuum and shear state are maintained for 10-20 minutes.

[0023] By adopting the above technical solution, a specific negative pressure environment combined with moderate shear force promotes the continuous renewal and uniform mixing of the interface between lipid droplets and aqueous drug-loaded micelles; at the same time, the upper limit of shear stress is strictly limited to prevent excessive mechanical work from tearing the newly formed hydrogen bond cross-linking network.

[0024] Preferably, in step S3, the cooling parameters under micro-shear dynamic rheology are: retain the anchor-type scraper agitator and reduce the rotation speed to 10-15 rpm, and cool down to 25-30℃ at a cooling rate of 0.5-1.0℃ / min; the filled finished product needs to be stored at room temperature for 24 hours.

[0025] By employing the above technical solution, using an extremely low cooling rate coupled with slow wall scraping and agitation, the radial temperature gradient inside the reactor is effectively smoothed, preventing the formation of a rapid condensation layer on the cold wall surface of the reactor. This slow cooling mechanism allows the ointment to smoothly transition from the liquid phase to the semi-solid phase crystallization period under low stress. In addition, the subsequent room temperature settling allows the internal crystal form of the system to be finally reorganized and stabilized, fundamentally locking in the long-term rheological structure of the ointment product.

[0026] This invention provides a transdermal absorption-enhancing ointment and its preparation process. It has the following beneficial effects: 1. This invention disperses hydrophobic fumed silica and a highly fluid active permeation-enhancing phase containing soybean lecithin in a continuous lipid matrix composed of white petrolatum, anhydrous lanolin, and caprylic / capric triglycerides. This allows the incompletely sealed silanol groups on the silica surface to interact with the phosphate groups of soybean lecithin molecules, forming an intermolecular hydrogen bond network. Therefore, a sterically hindered framework can be built inside the continuous lipid matrix, restricting the thermodynamic movement of the polar phase at high temperatures, thereby avoiding phase separation within the ointment. 2. This invention uses diethylene glycol monoethyl ether, oleic acid and 1-dodecylazine-heptane-2-one as a multi-component co-solvent to dissolve the drug into a molecular-level dispersion. It also combines isopropyl myristate and soybean lecithin to form an inverse micelle complex with a polar solvent and drug as the core. Therefore, it can exist stably in a non-polar ointment matrix. When applied to the skin, the surface active ingredients it carries can change the arrangement structure of the lipid bilayer of the stratum corneum, allowing the active drug inside to penetrate the skin barrier smoothly. 3. This invention, through the process cooling stage, employs a method of shutting off high-intensity shear and maintaining negative pressure, and utilizes an external cooling source for slow cooling under micro-shear dynamic rheology. This physically intervenes and controls the crystallization kinetics of the lipid mixture. The extremely low cooling rate, combined with low-speed wall scraping and tumbling, reduces the radial temperature gradient within the reactor, causing petrolatum and lanolin to precipitate a fine and uniform crystalline network. This eliminates localized overcooling and hardening caused by the temperature gradient, resulting in a semi-fluid paste with good thixotropic and pseudoplastic properties. Attached Figure Description

[0027] Figure 1 The diagrams are for verifying the rheological properties and network recombination mechanism of the present invention. (a) is a comparison diagram of the static yield stress of each embodiment and the comparative example, and (b) is a comparison diagram of the viscosity retention rate of each embodiment and the comparative example after shear recovery. Figure 2 The following is a test diagram of the cooling heat transfer and discharge performance under the large-scale production simulation of the present invention. Among them, (a) is a comprehensive comparison distribution diagram of the temperature difference between the center and the vessel wall at the end of the cooling period and the residual rate of the matrix on the inner wall of the reactor, and (b) is a state comparison diagram of the total discharge time of the rotor pump. Figure 3 This is a comprehensive comparison chart of the extreme thermodynamic stability and oil seepage resistance of the present invention. In the chart, the solid dotted line on the left Y-axis represents the oil separation rate (volume percentage) of each sample after accelerated centrifugation, and the dashed square line on the right Y-axis represents the macroscopic phase separation status score of each sample after being placed at 45°C for 30 days. Figure 4 The above is a comparison test chart of the freeze-thaw cycle anti-aging and content uniformity of the present invention. Among them, (a) is a comparison chart of the spatial content uniformity of API in each group, and (b) is a comparison chart of the grit feel score of each group after freeze-thaw. Figure 5 The above is a comparative test diagram of the transdermal absorption kinetics of thick-skinned animals in vitro according to the present invention. Among them, (a) is a kinetic curve of the cumulative permeation of each test sample over 24 hours as a function of time, and (b) is a comparative diagram of the steady-state transdermal flux distribution of each test sample. Detailed Implementation

[0028] The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0029] The main raw materials and reagents used in the following examples and comparative examples have the following sources and specifications. Reagents not specifically mentioned are all commercially available analytical grade or higher grade products.

[0030] Diethylene glycol monoethyl ether, with the molecular formula C6H 14 O3, CAS number 111-90-0.

[0031] Oleic acid, with the molecular formula C 18 H 34 O2, CAS number 112-80-1.

[0032] 1-Dodecylazine-2-one, also known as azoketone, has the molecular formula C2. 18 H 35 NO, CAS number is 59227-89-3.

[0033] Isopropyl myristate, with the molecular formula C 17 H 34 O2, CAS number 110-27-0.

[0034] Caprylic / capric triglyceride is a mixed ester formed by caprylic acid and capric acid with glycerol, with CAS number 65381-09-1.

[0035] Soybean lecithin is a liquid homogeneous product. Its main active ingredient is phosphatidylcholine, and its CAS number is 8002-43-5.

[0036] Hydrophobic fumed silica is fumed silica that has undergone surface hydrophobication treatment with dimethylsilyl groups, with some incompletely sealed silanol groups remaining on the surface. CAS number is 68611-44-9.

[0037] Preparation Example 1: This preparation example provides a method for preparing a highly fluid active permeation-enhancing phase, comprising the following steps: In a separate mixing tank, at 20°C, 1.0 part by weight of florfenicol was completely dissolved in a mixture of 3.0 parts by weight of diethylene glycol monoethyl ether, 2.0 parts by weight of oleic acid, and 0.5 parts by weight of azone. After complete dissolution, 5.0 parts by weight of isopropyl myristate and 2.0 parts by weight of soybean lecithin were added sequentially. The mixture was stirred at a low speed of 150 rpm until it became optically transparent and homogeneous, thus completing the preparation of the reversed micelle aggregate.

[0038] Preparation Example 2: This preparation example provides a method for preparing a highly fluid active permeation-enhancing phase, comprising the following steps: In a separate mixing tank, at 25°C, 3.0 parts by weight of florfenicol were completely dissolved in a mixture of 5.0 parts by weight of diethylene glycol monoethyl ether, 3.0 parts by weight of oleic acid, and 1.0 parts by weight of azone. After complete dissolution, 8.0 parts by weight of isopropyl myristate and 3.0 parts by weight of soybean lecithin were added sequentially. The mixture was stirred at a low speed of 200 rpm until it became optically transparent and homogeneous, thus completing the preparation of the reversed micelle aggregate.

[0039] Preparation Example 3: This preparation example provides a method for preparing a highly fluid active permeation-enhancing phase, comprising the following steps: In a separate mixing tank, at 30°C, 5.0 parts by weight of ivermectin were completely dissolved in a mixture of 8.0 parts by weight of diethylene glycol monoethyl ether, 5.0 parts by weight of oleic acid, and 2.0 parts by weight of azone. After complete dissolution, 12.0 parts by weight of isopropyl myristate and 4.0 parts by weight of soybean lecithin were added sequentially. The mixture was stirred at a low speed of 250 rpm until it became optically transparent and homogeneous, thus completing the preparation of the reversed micelle aggregate.

[0040] Preparation Example 4: This preparation example provides a method for preparing a highly fluid active permeation-enhancing phase, comprising the following steps: In a separate mixing tank, at 25°C, 3.0 parts by weight of ivermectin were completely dissolved in a mixture of 5.0 parts by weight of diethylene glycol monoethyl ether, 3.0 parts by weight of oleic acid, and 1.0 part by weight of azone. After complete dissolution, 8.0 parts by weight of isopropyl myristate and 3.0 parts by weight of soybean lecithin were added sequentially. The mixture was stirred at a low speed of 200 rpm until it became optically transparent and homogeneous, thus completing the preparation of the reversed micelle aggregate.

[0041] Example 1: This example provides a method for preparing a transdermal absorption-enhancing ointment, comprising the following steps: Step 1: Add 59.6 parts by weight of white petrolatum, 14.9 parts by weight of anhydrous lanolin, and 10.0 parts by weight of caprylic / capric triglycerides to a vacuum emulsifying vessel. Turn on the jacket heating and control the temperature at 80°C. Maintain this temperature until the lipids are completely melted into a homogeneous liquid. Then add 2.0 parts by weight of hydrophobic fumed silica to the vessel. Turn on the high-shear homogenizer and set the speed to 2500 rpm. Simultaneously turn on the anchor-type wall-scraping agitator and set the speed to 30 rpm. Continue shearing and dispersing for 15 minutes.

[0042] Step 2: Take the highly fluid active permeation-enhancing phase prepared in Preparation Example 1 for later use.

[0043] Step 3: Turn off the high-shear homogenizer of the emulsification vessel, and introduce cooling water into the jacket. Cool the matrix inside the vessel to 48°C at a cooling rate of 1.5°C / min. During the cooling process, reduce the speed of the anchor-type wall scraper agitator to 20 rpm.

[0044] Step 4: Under the condition of maintaining a constant temperature of 48°C in the emulsification kettle, use vacuum suction to pump the high-flowability active permeation-enhancing phase prepared in Step 2 into the emulsification kettle. After the feeding is completed, turn on the high-shear homogenizer and set the speed to 1000 rpm, and simultaneously turn on the vacuum pump to control the absolute vacuum degree in the kettle at -0.08 MPa, and maintain this vacuum degree and shear state for 10 minutes.

[0045] Step 5: Maintain a vacuum of -0.08 MPa, turn off the high-shear homogenizer, keep the anchor-type scraper agitator running and reduce its speed to 10 rpm, use jacket cooling water to cool the system to 30°C under micro-shear dynamic rheology (cooling rate is 1.0°C / min), break the vacuum, use a rotor pump to pump out the paste in a semi-fluid pseudoplastic state and fill it into tubes, and let the filled product stand at room temperature for 24 hours.

[0046] Example 2: This example provides a method for preparing a transdermal absorption-enhancing ointment, comprising the following steps: Step 1: Add 46.8 parts by weight of white petrolatum, 7.2 parts by weight of anhydrous lanolin, and 20.0 parts by weight of caprylic / capric triglycerides to a vacuum emulsifying vessel. Turn on the jacket heating and control the system temperature at 85°C. Maintain this temperature until the lipids are completely melted into a homogeneous liquid. Then add 3.0 parts by weight of hydrophobic fumed silica to the vessel. Turn on the high-shear homogenizer and set the speed to 2800 rpm. Simultaneously turn on the anchor-type wall-scraping agitator and set the speed to 40 rpm. Continue shearing and dispersing for 20 minutes.

[0047] Step 2: Take the highly fluid active permeation-enhancing phase prepared in Preparation Example 2 for later use.

[0048] Step 3: Turn off the high-shear homogenizer of the emulsification vessel, and introduce cooling water into the jacket. Cool the matrix inside the vessel to 45°C at a cooling rate of 2.0°C / min. During the cooling process, reduce the speed of the anchor-type wall scraper agitator to 30 rpm.

[0049] Step 4: Under the condition of maintaining a constant temperature of 45°C in the emulsification tank, use vacuum suction to pump the high-flowability active permeation-enhancing phase prepared in Step 2 into the emulsification tank. After the feeding is completed, turn on the high-shear homogenizer and set the speed to 1500 rpm, and simultaneously turn on the vacuum pump to control the absolute vacuum degree in the tank at -0.085 MPa, and maintain this vacuum degree and shear state for 15 minutes.

[0050] Step 5: Maintain a vacuum of -0.085 MPa, completely shut down the high-shear homogenizer, keep the anchor-type scraper agitator running and reduce its speed to 12 rpm, use jacket cooling water to cool the system to 25°C under micro-shear dynamic rheology (cooling rate is 0.5°C / min), break the vacuum, use a rotor pump to pump out the paste in a semi-fluid pseudoplastic state and fill it into tubes, and let the filled product stand at room temperature for 24 hours.

[0051] Example 3: This example provides a method for preparing a transdermal absorption-enhancing ointment, comprising the following steps: Step 1: Add 27.0 parts by weight of white petrolatum, 3.0 parts by weight of anhydrous lanolin, and 30.0 parts by weight of caprylic / capric triglycerides to a vacuum emulsifying vessel. Turn on the jacket heating and control the system temperature at 90°C. Maintain this temperature until the lipids are completely melted into a homogeneous liquid. Then add 4.0 parts by weight of hydrophobic fumed silica to the vessel. Turn on the high-shear homogenizer and set the speed to 3000 rpm. Simultaneously turn on the anchor-type wall-scraping agitator and set the speed to 50 rpm. Continue shearing and dispersing for 30 minutes.

[0052] Step 2: Take the highly fluid active permeation-enhancing phase prepared in Preparation Example 3 for later use.

[0053] Step 3: Turn off the high-shear homogenizer of the emulsification vessel, and introduce cooling water into the jacket to cool the matrix inside the vessel to 42°C at a cooling rate of 2.5°C / min. During the cooling process, reduce the speed of the anchor-type wall scraper agitator to 40 rpm.

[0054] Step 4: Under the condition of maintaining a constant temperature of 42°C in the emulsification kettle, use vacuum suction to pump the high-flowability active permeation-enhancing phase prepared in Step 2 into the emulsification kettle. After the feeding is completed, turn on the high-shear homogenizer and set the speed to 2000 rpm, and simultaneously turn on the vacuum pump to control the absolute vacuum degree in the kettle at -0.09 MPa, and maintain this vacuum degree and shear state for 20 minutes.

[0055] Step 5: Maintain a vacuum of -0.09 MPa, completely shut down the high-shear homogenizer, keep the anchor-type scraper agitator running and reduce its speed to 15 rpm, use jacket cooling water to cool the system to 25°C under micro-shear dynamic rheology (cooling rate is 1.0°C / min), break the vacuum, use a rotor pump to pump out the paste in a semi-fluid pseudoplastic state and fill it into tubes, and let the filled product stand at room temperature for 24 hours.

[0056] Example 4: This example provides a method for preparing a transdermal absorption-enhancing ointment, comprising the following steps: Step 1: Add 46.8 parts by weight of white petrolatum, 7.2 parts by weight of anhydrous lanolin, and 20.0 parts by weight of caprylic / capric triglycerides to a vacuum emulsifying vessel. Turn on the jacket heating and control the system temperature at 85°C. Maintain this temperature until the lipids are completely melted into a homogeneous liquid. Then add 3.0 parts by weight of hydrophobic fumed silica to the vessel. Turn on the high-shear homogenizer and set the speed to 2800 rpm. Simultaneously turn on the anchor-type wall-scraping agitator and set the speed to 40 rpm. Continue shearing and dispersing for 20 minutes.

[0057] Step 2: Take the highly fluid active permeation-enhancing phase prepared in Preparation Example 4 for later use.

[0058] Step 3: Turn off the high-shear homogenizer of the emulsification vessel, and introduce cooling water into the jacket. Cool the matrix inside the vessel to 45°C at a cooling rate of 2.0°C / min. During the cooling process, reduce the speed of the anchor-type wall scraper agitator to 30 rpm.

[0059] Step 4: Under the condition of maintaining a constant temperature of 45°C in the emulsification tank, use vacuum suction to pump the high-flowability active permeation-enhancing phase prepared in Step 2 into the emulsification tank. After the feeding is completed, turn on the high-shear homogenizer and set the speed to 1500 rpm, and simultaneously turn on the vacuum pump to control the absolute vacuum degree in the tank at -0.085 MPa, and maintain this vacuum degree and shear state for 15 minutes.

[0060] Step 5: Maintain a vacuum of -0.085 MPa, completely shut down the high-shear homogenizer, keep the anchor-type scraper agitator running and reduce its speed to 12 rpm, use jacket cooling water to cool the system to 25°C under micro-shear dynamic rheology (cooling rate is 0.5°C / min), break the vacuum, use a rotor pump to pump out the paste in a semi-fluid pseudoplastic state and fill it into tubes, and let the filled product stand at room temperature for 24 hours.

[0061] Example 5: This example provides a method for preparing a transdermal absorption-enhancing ointment, comprising the following steps: Step 1: Add 46.8 parts by weight of white petrolatum, 7.2 parts by weight of anhydrous lanolin, and 20.0 parts by weight of caprylic / capric triglycerides to a vacuum emulsifying vessel. Turn on the jacket heating and control the system temperature at 90°C. Maintain this temperature until the lipids are completely melted into a homogeneous liquid. Then add 3.0 parts by weight of hydrophobic fumed silica to the vessel. Turn on the high-shear homogenizer and set the speed to 3000 rpm. Simultaneously turn on the anchor-type wall-scraping agitator and set the speed to 50 rpm. Continue shearing and dispersing for 15 minutes.

[0062] Step 2: Take the highly fluid active permeation-enhancing phase prepared in Preparation Example 2 for later use.

[0063] Step 3: Turn off the high-shear homogenizer of the emulsification vessel, and introduce cooling water into the jacket to cool the matrix inside the vessel to 48°C at a cooling rate of 3.0°C / min. During the cooling process, reduce the speed of the anchor-type wall scraper agitator to 40 rpm.

[0064] Step 4: Under the condition of maintaining a constant temperature of 48°C in the emulsification kettle, use vacuum suction to pump the high-flowability active permeation-enhancing phase prepared in Step 2 into the emulsification kettle. After the feeding is completed, turn on the high-shear homogenizer and set the speed to 1000 rpm. At the same time, turn on the vacuum pump to control the absolute vacuum degree in the kettle at -0.08 MPa and maintain this vacuum degree and shear state for 10 minutes.

[0065] Step 5: Maintain a vacuum of -0.08 MPa, completely shut down the high-shear homogenizer, keep the anchor-type scraper agitator running and reduce its speed to 10 rpm, use jacket cooling water to cool the system to 30°C under micro-shear dynamic rheology (cooling rate is 0.6°C / min), break the vacuum, use a rotor pump to pump out the paste in a semi-fluid pseudoplastic state and fill it into tubes, and let the filled product stand at room temperature for 24 hours.

[0066] Comparative Example 1: Compared with Example 2, the difference is that soybean lecithin was not added in Preparation Example 2, and the missing weight parts were made up by isopropyl myristate, and the rest were the same.

[0067] Comparative Example 2: Compared with Example 2, the difference is that hydrophobic fumed silica was not added in step one, and the missing weight parts were made up by white petrolatum, while the rest are the same.

[0068] Comparative Example 3: Compared with Example 2, the difference is that caprylic / capric triglycerides were not added in step one, and the corresponding missing weight parts were replaced by an equal amount of white petrolatum, while the rest are the same.

[0069] Comparative Example 4: The difference from Example 2 is that isopropyl myristate was not added in Preparation Example 2, and the missing weight parts were made up by diethylene glycol monoethyl ether, while the rest were the same.

[0070] Comparative Example 5: Compared with Example 2, the difference is that the vacuum pump was not turned on in step four. The highly fluid active permeation-enhancing phase was pumped into the emulsification vessel under normal pressure and maintained in a shear state. All other aspects are the same.

[0071] Comparative Example 6: Compared with Example 2, the difference is that in step five, the anchor-type scraper agitator is completely shut down, and the vacuum is broken and the material is discharged only after static cooling to 25°C by relying solely on the jacket cooling water. The rest are the same.

[0072] Test Example 1: 1. Sample setup: Take ointment samples prepared by Examples 1 to 5, and Comparative Examples 1, 2, 5 and 6.

[0073] 2. Test steps: 2.1 Sample Pretreatment: Take an appropriate amount of each group of ointment samples after they have been stored at a constant temperature for 24 hours, and carefully transfer them to the lower test plate of the rotational rheometer using a stainless steel spatula. Maintain a smooth transfer motion to prevent additional large shear forces from damaging the initial gel structure. Set the instrument's temperature control module to maintain the test platform temperature at a constant 25℃. Before testing, allow the samples to stand on the plate for 5 minutes to eliminate residual stress.

[0074] 2.2 Yield Stress Determination: A cone-plate testing system with a diameter of 40 mm and a cone angle of 2 degrees was selected, and the test gap was set to the specified value. A shear stress scanning program was set so that the applied shear stress continuously increased from 0.1 Pa to 1000 Pa in a logarithmic increment, and the system simultaneously recorded the change curves of the storage modulus and loss modulus. The stress value corresponding to the intersection of the storage modulus and loss modulus was extracted and taken as the static yield stress of the system.

[0075] 2.3 Variable Hysteresis Loop Area Test: Under the same temperature conditions, the sample was tested using a steady-state shear rate scanning mode. The shear rate was set from 0.1 s⁻¹. -1 linearly increase to 100s -1 A rising curve is formed, and a constant shear rate is maintained at this highest shear rate for 10 seconds, followed by reducing the shear rate from 100 s. -1 Linearly decrease to 0.1s -1 This forms a downward curve. Using the instrument's built-in data processing software, the closed region enclosed by the upward and downward flow curves is integrated to obtain the overall thixotropic hysteresis loop area.

[0076] 2.4 Viscosity Retention Rate Assessment: For the damaged sample that has just completed the thixotropic hysteresis loop test, immediately switch to the ultra-low shear constant operating mode, setting the shear rate to 0.1 s. -1 The scan continued for 30 minutes. The apparent viscosity at the test endpoint was recorded and compared with the initial zero-shear viscosity measured at the same low shear rate before the first step of failure. The percentage of viscosity retention after shear recovery was obtained. The results are shown in Table 1. Table 1: Rheological performance test results of each embodiment and comparative example

[0077] According to Table 1 and Figure 1 The data shows that the static yield stress of each embodiment is generally maintained at a high level, and its thixotropic hysteresis loop area is significantly larger than that of each comparative example. Specifically, observing the parameter performance of Example 2, its yield stress reaches 268.7 Pa under optimal ratio and process control, and the structural recovery rate exceeds 95%, showing extremely excellent thixotropic reversibility. In contrast, Comparative Example 1, which lacks soybean lecithin, and Comparative Example 2, which does not add fumed silica, show a significant decrease in yield stress index, and the corresponding thixotropic hysteresis loop area is also greatly reduced. Furthermore, it was noted during the test that these samples have extremely weak resistance to deformation, and irreversible flow and scattering occur under slight external force. This objectively reflects that within the complex mixed polar system, the hydrogen bond crosslinking between the phosphate groups of the phase change phospholipid and the free silanol groups on the surface of inorganic particles constitutes the main steric hindrance framework against external force. Once any component is missing in the formulation, the expected polar gradient interlocking effect loses its physical structural support, and the entire system degenerates into a loose conventional physical mixture, resulting in thermodynamic phase separation. In the negative pressure verification dimension, although Comparative Example 5, which underwent phase recombination treatment under normal pressure, had the same raw material composition, its yield stress and viscosity retention rate were significantly lower than those of the corresponding examples. This was because a large number of microbubbles trapped inside the high-viscosity matrix under normal pressure could not be removed. These gas-phase cavities, at the microscopic level, blocked the close contact that should have occurred between the polar active phase and the non-polar framework. The insufficient anchoring density of intermolecular hydrogen bonds resulted in loose network nodes, significantly reducing the self-repairing ability after shear damage. Furthermore, Comparative Example 6, designed for large-scale production cooling processes, exhibited a seemingly anomalous high initial yield stress state, but its viscosity retention rate plummeted to 54.2% after one shear cycle. This was because the traditional static cooling method directly caused rapid condensation and agglomeration of the heat transfer boundary layer material on the reactor wall. The imbalance of the internal temperature gradient led to extreme non-uniformity of stress distribution, resulting in a gel network with severe rigid brittleness. Once this structure, caused by operating condition defects, breaks, it completely loses its basis for reconstruction. This further confirms that there is a deep physical linkage between the synergistic effect of the formulation components and the specific micro-shear negative pressure operation. It is under the protection of this mechanism that the semi-solid formulation can have thermodynamic stability to cope with complex stress changes and extreme temperature fluctuations.

[0078] Test Example 2: 1. Sample setup: Take ointment samples prepared in Examples 1 to 5 and Comparative Example 6.

[0079] 2. Test steps: 2.1 Prepare a 100L capacity pilot-scale jacketed vacuum emulsification reactor. Arrange three high-precision PT100 temperature sensors inside the reactor. Fix the probes 1 cm from the inner wall of the jacket, half the radius of the reactor, and the central stirring shaft area. These three measuring points are used to capture the temperature distribution of the material in the spatial dimension in real time during the cooling stage.

[0080] 2.2. The raw materials were fed into the pilot-scale production according to the weight ratio of each embodiment and comparative example. The corresponding early melting and high shear dispersion steps were strictly implemented. When entering the cooling process, the heating source was cut off, and at the same time, 15°C industrial cooling water at a set flow rate was continuously introduced into the jacket.

[0081] 2.3 Record the temperature changes throughout the cooling process. When the temperature probe located in the center of the vessel reaches the critical point of the target discharge temperature set by each formula, the real-time temperature of the probe near the wall is read simultaneously, and the absolute difference between the two is calculated as the temperature difference data between the center and the vessel wall at the end of the cooling period.

[0082] 2.4. Break the vacuum inside the emulsification reactor, turn on the high-power constant-speed rotor pump connected to the discharge valve at the bottom of the reactor, and pump the semi-fluid paste-like material into the external metering and collection tank. Record the total time from the start of the rotor pump until the observation port shows that the material flow has stopped and the pump body is obviously running dry and can no longer suck up material, as the total time for a single discharge.

[0083] 2.5 After the discharge operation is completed, stop the rotor pump, open the top cover of the emulsification tank, and use a high-pressure solvent cleaning device to repeatedly flush the inner wall of the reactor, the scraper blades, and the residual paste in the dead corners of the bottom valve body. Collect all the cleaning waste liquid, evaporate, concentrate, and dry it. Weigh the dry residue and divide it by the initial theoretical total feed amount to obtain the matrix residue rate on the inner wall of the reactor. The results are shown in Table 2: Table 2: Simulation test results of large-scale production conditions for each embodiment and comparative example

[0084] According to Table 2 and Figure 2Data shows that in Comparative Example 6, which was designed for static cooling, a spatial temperature difference as high as 19.4℃ was observed. This severe thermal imbalance is due to the extremely low thermal conductivity of the high molecular weight lipid and petrolatum system. After the material loses the physical stripping effect of mechanical stirring, the outer matrix near the jacket cooling surface hardens due to the sudden temperature drop, forming a tightly adhered high thermal resistance boundary layer on the inner side of the reactor wall. This blocks the heat transfer from the central high-temperature material to the periphery, resulting in severe heterogeneity of the crystal nucleation environment inside the reactor. In contrast, the series of examples used a low-speed micro-shear operation of 10 to 15 rpm, and the temperature difference was generally compressed to within 3.1℃, especially Example 2, which controlled this index to 1.8℃. Therefore, this process setting targeting the shear-thinning characteristics of pseudoplastic fluids can continuously scrape off the condensate layer constantly generated on the heat transfer surface without destroying the internal hydrogen bond thixotropic network, forcing the material to maintain a macroscopic tumbling heat transfer state during the cooling stage. Furthermore, the discharge time of Comparative Example 6 was abnormally prolonged to 48.7 minutes. In the later stages of actual pumping, a large amount of hardened solid lumps adhered to the vessel wall and scraper structure. The rotor pump could only suck up the paste that remained flowing in the central area at the bottom of the vessel, after which dry rotation and cavitation occurred. The measured matrix residue rate as high as 15.3% would lead to unacceptable material loss and cleaning burden in real industrial settings with production capacities of several tons. However, micro-shear dynamic rheological cooling effectively maintained the paste in a slippery semi-solid state. The rotor pump discharge process of Examples 1 to 5 showed a high degree of continuity, with the discharge time consistently ranging from 12 to 16 minutes, and the residue rate on the inner wall was also controlled within the normal loss range. This process design, which relies on specific physical rheological methods to solve the bottlenecks in large-scale production, avoids the problem of sacrificing discharge smoothness in the traditional ointment preparation process to suppress crystallization. From a scaled-up perspective, it verifies the engineering value of the linkage between the formulation and the dynamic cooling process.

[0085] Test Example 3: 1. Sample setup: Take the ointment products prepared by Examples 1 to 5, and Comparative Examples 2, 3 and 5.

[0086] 2. Test steps: 2.1 Collect ointment samples from each group that have been allowed to stand and mature at room temperature for 24 hours. In order to accurately determine the percentage of oil separation under forced physical centrifugation, 15.0 grams of sample were accurately weighed into a specific size transparent graduated centrifuge tube using a precision balance, and the material was compacted using the matching polytetrafluoroethylene stopper to eliminate macroscopic voids.

[0087] 2.2. Place the filled centrifuge tubes symmetrically into the rotor of a benchtop high-speed centrifuge. Set the operating parameters to 4000 rpm, continuous centrifugation time for 30 minutes, and maintain the ambient temperature at 25℃. After centrifugation, remove the centrifuge tubes and immediately read the volume of the transparent or translucent clear liquid precipitated from the upper layer. Calculate the volume percentage based on the theoretical density of the sample and record it as the accelerated centrifugation oil separation rate.

[0088] 2.3 Simultaneously conduct high-temperature long-term accelerated aging tests. Take 50ml flat-bottomed wide-mouth glass bottles, put 30.0g of the same batch of samples into each bottle, seal them, and place them in a constant temperature incubator set at 45℃ for 30 consecutive days.

[0089] 2.4 After the storage period, remove the glass bottle, allow it to return to room temperature, and perform a macroscopic phase separation assessment. The assessment standard was set as a continuous scale from 1 to 10 points, where 1 point represents that the paste remains homogeneous with no liquid seepage, 3 points or less represents slight surface sweating without free droplets, 5 points represents obvious local liquid aggregation, 7 points or more represents severe macroscopic phase separation and aggregation with the upper oil phase, and 10 points represents the complete collapse of the matrix network into a liquid state. The results are shown in Table 3: Table 3: Thermodynamic stability and oil separation test data of each embodiment and comparative example

[0090] According to Table 3 and Figure 3Data shows that in existing technologies, once more than 15% of liquid polar solvents or neutral oil phases are mixed into the white petrolatum matrix, irreversible water seepage and oil floating phenomena are very likely to occur in the paste under high-temperature storage environments in summer. The example series effectively locked this mobile phase by introducing a hybrid hydrogen bond network. In particular, Example 2 not only suppressed the oil separation rate to an extremely low 0.12% under centrifugal gravity, but also showed almost no visible phase change after 30 days of high-temperature baking, with a score of only 1.0. Comparative Example 2, lacking hydrophobic fumed silica, lost the spatial steric constraint of the three-dimensional inorganic framework. The ointment could not build a yielding network that could resist external forces, resulting in a large amount of liquid components detaching from the long-chain alkane microcrystals under the strong centrifugal force of the centrifuge, with an oil separation rate as high as 12.43%. The most severe phase separation also occurred during high-temperature settling. Furthermore, in Comparative Example 3, due to the removal of the moderately polar oil phase of caprylic / capric triglyceride, a steep polarity fault was created between the highly polar diethylene glycol monoethyl ether and the weakly polar petrolatum. This strong hydrophobic repulsion led to a sharp increase in the chemical potential within the system, causing the polar droplets to spontaneously coalesce and be pushed outward during placement, ultimately forming macroscopic stratification. In contrast, Comparative Example 5, prepared under atmospheric pressure, although possessing a complete raw material composition, still exhibited an oil separation rate of 5.38% during centrifugation. This demonstrates that residual air bubbles within the material macroscopically weaken the contact area between the organic phase and the inorganic powder, reducing the density of multiple hydrogen bond anchoring. The non-dense rheological network undergoes local disintegration upon absorbing external heat energy, resulting in a moderate degree of phase separation. Multiple failure comparisons show that relying on a single matrix thickening method cannot fundamentally solve the problem of escape of the high oil-carrying phase. Only by constructing a smooth polar transition gradient and tightly nesting the free phase in a vacuum-induced dense hydrogen bond interlocking network can the ideal anti-dehydration and anti-oil-seepage effects be achieved.

[0091] Test Example 4: 1. Sample setup: Take the ointment products prepared by Examples 1 to 5, and Comparative Examples 1 and 6.

[0092] 2. Test steps: 2.1 Collect the finished ointment tubes from each group that have undergone network reconstruction and have been left to stand at room temperature. Place them uniformly in a programmable high and low temperature alternating test chamber. Set the test chamber's operating program to freeze at -20℃ for 12 hours, then automatically raise the temperature to 25℃ and hold for 12 hours, which constitutes one complete freeze-thaw cycle. All samples were subjected to five complete cycles of alternating hot and cold shocks.

[0093] 2.2 After the cycle test, remove the tube and allow it to equilibrate at room temperature for 4 hours. Then, take about 2 grams of the paste and place it on a flat, clean glass slide. Use another glass slide to spread the paste with constant pressure. The macroscopic gritty feel is rated by the frictional resistance feedback when pressing the glass slide with your finger, with a rating range of 0 to 5. A rating of 0 represents extremely smooth and unobstructed texture, while a rating of 5 represents the presence of a large number of coarse and hard particles.

[0094] 2.3 Then, using a custom-made hollow sampling probe, 0.5 grams of paste sample were precisely measured from the top outlet area, the middle tube body area, and the bottom sealing area of ​​each tube, and the spatial sampling points at different depths were recorded.

[0095] 2.4. Samples from each depth were placed in volumetric flasks, and sufficient high-purity methanol was added for ultrasonic demulsification extraction to completely release the active drug components encapsulated by the lipid network. After filtration and centrifugation, the supernatant was injected into a high-performance liquid chromatograph (HPLC) for quantitative determination. The relative standard deviation (RSD) of the drug content at three sampling points at different spatial depths within the same tubing was calculated as a quantitative indicator for evaluating the system's resistance to ripening sedimentation and component homogeneity. The results are shown in Table 4. Table 4: Test data on anti-aging and content uniformity of each example and comparative example

[0096] According to Table 4 and Figure 4Data shows that after repeated high and low temperature shocks, the test samples exhibited significant differences in physical properties regarding crystal growth control and drug spatial distribution. The specific reason is that traditional high-concentration liquid permeation enhancer formulations for thick-skinned animals are prone to phase instability under low-temperature conditions. Cooling causes a sharp decrease in the solubility of active ingredients such as macrolides or antibiotics in polar solvents such as diethylene glycol monoethyl ether. Once the supersaturation critical point is exceeded, crystal nucleation is induced. The observed results of the sample application in the example groups did not show this typical Oswald ripening phenomenon. In Example 2, the API spatial content relative standard deviation remained at a low level of 0.86%, and the application texture was smooth, indicating that the pre-constructed antiphase micelle microregions in the formulation effectively blocked the crystal evolution pathway. In contrast, Comparative Example 1, without added soybean lecithin, lacked the dipole interaction and spatial encapsulation effect of phase-change phospholipid molecules. In a physical environment of alternating hot and cold temperatures, free drug molecules are directly affected by thermodynamic fluctuations. Not only do they precipitate out in large quantities during cooling, but they also undergo a maturation process during temperature recovery, where small crystals dissolve and deposit onto the surface of larger crystals. This irreversible crystal growth leads to a macroscopic gritty texture score of 4.2. Simultaneously, the gravitational settling of large crystal particles causes severe spatial unevenness in drug concentration at different depths within the tubing, increasing the RSD value to 12.58%. Furthermore, the large-scale cooling process directly impacts the uniformity of the product's internal components. Although Comparative Example 6, employing conventional static cooling, possesses a complete anti-crystallization system in its ingredient list, premature condensation and hardening in the reactor wall region forms a high-viscosity boundary layer, hindering homogenization and heat transfer. The imbalance of the temperature gradient within the reactor causes localized enrichment of polar solvents in some reverse micelles before structural solidification, subsequently triggering microscopic aggregation of drug components. The rough phase generated by the cooling dead zone mixed into the finished product resulted in random high-concentration drug accumulation points within the final ointment, with a measured content deviation of 8.41%. Its frictional roughness of 2.8 also reduced the application compliance of the topical formulation. Therefore, the test results indicate that simply increasing the proportion of chemical solvents to improve the initial solubility of the drug is insufficient to maintain long-term thermodynamic stability. This solution utilizes specific amphiphilic assemblies to transform the free drug into a thermodynamically stable micellar encapsulated state, and combines this with a dynamic micro-shear process to eliminate heat transfer dead zones, thereby effectively solving the problems of crystallization and uneven content in semi-solid formulations under extreme environments.

[0097] Test Example 5: 1. Sample setup: The ointments prepared in Examples 1 to 5, as well as Comparative Examples 1 and 4, were used as samples.

[0098] 2. Test steps: 2.1 Select back skin from healthy slaughtered pigs as a barrier model. Carefully scrape off the pig hair from the skin surface using a skinning knife, and use surgical scissors and forceps to separate the subcutaneous fat and connective tissue. Rinse thoroughly in physiological saline. Measure the thickness of the treated skin using digital calipers, and select skin tissue with a thickness ranging from 1.8 to 2.2 mm for use.

[0099] 2.2. Fix the treated detached pigskin between the supply and receiving tanks of the modified Franz diffusion tank, with the keratinized side facing the supply tank and the dermis side facing the receiving tank. Fill the receiving tank with 15 mL of phosphate buffer (containing an appropriate amount of Tween-80 to maintain the swirl conditions) and remove all air bubbles. Turn on the constant temperature water bath circulation system to maintain the temperature of the receiving solution at 37±0.5℃, and set the magnetic stirring speed in the receiving tank to 300 rpm.

[0100] 2.3 After the system has equilibrated for 30 minutes, accurately weigh 0.5 grams of each ointment sample and evenly apply it to the exposed stratum corneum surface in the supply tank. Seal the top of the supply tank with sealing film to prevent moisture and solvent evaporation.

[0101] 2.4. At 2, 4, 8, 12, 16, and 24 hours after drug administration, 1.0 mL of receiving solution was extracted from the sampling port of the receiving cell, and an isothermal and equal-volume blank receiving solution was immediately added. The extracted sample solution was filtered through a 0.22 μm microporous membrane, and the filtrate was collected for subsequent detection.

[0102] 2.5. The concentration of the active drug in the receiving solution at each time point was determined using high-performance liquid chromatography (HPLC). Based on the effective permeation area of ​​the diffusion cell, the cumulative permeation rate at different time points was calculated, and the permeation curve at steady state was linearly fitted to obtain the steady-state transdermal flux and permeation lag time. The results are shown in Table 5. Table 5: Ex vivo transdermal absorption kinetics test data for each embodiment and comparative example

[0103] According to Table 5 and Figure 5 The data shows that the permeation-enhancing efficiency of the example groups was higher than that of the comparative group. Among them, the permeation lag time of Example 2 was shortened to 1.25 hours, and the cumulative permeation volume in 24 hours reached 385.21 μg / cm³. 2 The specific reason lies in the phase reorganization of the mixed polar oil phase and phase-change phospholipids at the skin interface. Caprylic / capric triglycerides, utilizing their compatibility with sebum components, penetrate into the stratum corneum interstitial space, softening the solid lipid matrix and thus establishing a continuous polar transition channel at the microscopic interface. In contrast, Comparative Example 4, without the addition of isopropyl myristate, exhibited decreased skin surface extensibility during the procedure, with its steady-state transdermal flux decreasing to 8.15 μg / cm³.2 The penetration lag time was prolonged to 3.78 hours. Furthermore, the absence of the fluidized component caused a sudden change in the polarity distribution of the system. The high-viscosity nonpolar network formed by petrolatum increased mass transfer resistance, causing active molecules to remain inside the matrix and unable to effectively migrate to the moderately polar skin interface, ultimately resulting in a significant decrease in the in vitro drug release rate. The solubilizing effect of the amphiphilic carrier in cross-barrier transport was directly refuted by the data from Comparative Example 1, specifically: the sample without added soybean lecithin exhibited the lowest penetration efficiency, with a cumulative penetration amount of only 121.37 μg / cm³ over 24 hours. 2 Furthermore, lecithin, besides participating in the construction of the thixotropic network within the matrix, is also a key biocompatible excipient for maintaining the drug's solubility at the interface. Without this component, drug molecules detach from the encapsulation environment of the reverse micelles, resulting in a significant increase in permeation resistance when facing the complex multiphase structure of the stratum corneum, which alternates between hydrophilic and lipophilic components. By introducing multi-level polar excipient matching and spatial structural constraints, this approach ensures the macroscopic physical stability of the formulation while maintaining the solubility of the active ingredient at the microscopic level and the chemical potential gradient for continuous subcutaneous transfer, thereby achieving the expected in vitro absorption indicators in a thick skin barrier model.

[0104] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A transdermal absorption-enhancing ointment, characterized in that, Includes the following weight groups: White petrolatum: 27.0–59.6 parts; Anhydrous lanolin: 3.0–14.9 parts; Caprylic / capric triglycerides: 10.0–30.0 parts; Hydrophobic fumed silica: 2.0–4.0 parts; Highly fluid active permeation-enhancing phase: 13.5–36.0 parts.

2. The ointment according to claim 1, characterized in that, Includes the following weight groups: White petrolatum: 46.8 parts; anhydrous lanolin: 7.2 parts; caprylic / capric triglyceride: 20.0 parts; hydrophobic fumed silica: 3.0 parts; high-flowability active permeation-enhancing phase: 23.0 parts.

3. The ointment according to claim 1, characterized in that, The highly fluid active permeation-enhancing phase comprises the following components by weight: Active pharmaceutical ingredient: 1.0–5.0 parts; Diethylene glycol monoethyl ether: 3.0–8.0 parts; Oleic acid: 2.0–5.0 parts; 1-Dodecylazacycloheptan-2-one: 0.5–2.0 parts; Isopropyl myristate: 5.0–12.0 parts; Soy lecithin: 2.0–4.0 parts.

4. The ointment according to claim 3, characterized in that, The active drug is selected from florfenicol or ivermectin.

5. The ointment according to claim 3, characterized in that, The preparation steps of the high-fluidity active permeation-enhancing phase include: At a temperature of 20–30°C, the active pharmaceutical ingredient is dissolved in a mixture of diethylene glycol monoethyl ether, oleic acid, and 1-dodecylazine-2-one. Then, isopropyl myristate and soybean lecithin are added, and the mixture is stirred continuously at a speed of 150–250 rpm until the system becomes optically transparent and homogeneous, thus obtaining a highly fluid active permeation-enhancing phase in the form of an inverted micelle aggregate.

6. A preparation process for preparing a transdermal absorption-enhancing ointment as described in any one of claims 1-5, characterized in that, Includes the following steps: S1: White petrolatum, anhydrous lanolin, and caprylic / capric triglycerides are heated and melted into a homogeneous liquid, and then hydrophobic fumed silica is added for shear dispersion to obtain the matrix system; S2: Under constant temperature conditions, the highly fluid active permeation-enhancing phase is pumped into the matrix system after cooling in step S1 using vacuum suction, and maintained for a predetermined time under negative pressure vacuum and shear conditions. S3: Maintain pressure to keep the vacuum and turn off high shear. Under micro-shear dynamic rheology, use an external cooling source to cool the system to the discharge temperature, break the vacuum, and discharge and fill to obtain the ointment product in a semi-fluid pseudoplastic state.

7. The preparation process according to claim 6, characterized in that, In step S1, the heating and melting temperature is 80-90℃. The shearing and dispersion is carried out by turning on the high-shear homogenizer, setting the rotation speed to 2500-3000 rpm, and simultaneously turning on the anchor-type wall scraper stirring at a rotation speed of 30-50 rpm, and continuing the shearing and dispersion for 15-30 minutes.

8. The preparation process according to claim 6, characterized in that, Before pumping in the highly fluid active permeation-enhancing phase in step S2, a cooling pretreatment step for the matrix system is also included, specifically including: cooling the matrix to 42-48°C at a cooling rate of 1.5-3.0°C / min, and reducing the speed of the anchor-type wall scraper agitator to 20-40 rpm during the cooling process.

9. The preparation process according to claim 6, characterized in that, The specific process parameters for step S2 are as follows: After feeding is completed, turn on the high shear homogenizer and set the speed to 1000-2000 rpm, and simultaneously turn on the vacuum pump to control the internal absolute vacuum at -0.08 to -0.09 MPa, and maintain the vacuum and shear state for 10-20 minutes.

10. The preparation process according to claim 6, characterized in that, In step S3, the cooling parameters under micro-shear dynamic rheology are as follows: retain the anchor-type scraper agitator and reduce the rotation speed to 10-15 rpm, and cool down to 25-30℃ at a cooling rate of 0.5-1.0℃ / min; the filled finished product needs to be stored at room temperature for 24 hours.

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