Efficient external medicine for repairing leukoplakia vulvae and preparation method thereof

Abstract

The invention relates to the technical field of medicines, and discloses an efficient external medicine for repairing leukoplakia vulvae and a preparation method of the efficient external medicine for repairing leukoplakia vulvae. 1.0 to 2.0 parts of vitamin B1; 0.5 to 1.5 parts of body ketone; 0.05 to 0.2 part of estradiol valerate; 1.0 to 5.0 parts of compound dexamethasone acetate cream; 0.5 to 2.0 parts of vitamin E; 2.0 to 5.0 parts of compound radix salviae miltiorrhizae extract; 1.0 to 3.0 parts of a red sensor ointment; 5.0 to 10.0 parts of plastid; 10.0 to 20.0 parts of a nano emulsion; and 15.0 to 25.0 parts of a temperature-sensitive gel matrix. Through nanocrystallization treatment, a multi-layer delivery system and a dynamic response release mechanism, the transdermal absorption efficiency and the delivery depth of the drug are remarkably improved; the temperature-sensitive gel and the acid and humidity-sensitive carrier are adopted, so that long-acting controlled release and adaptive release of a lesion environment of the medicine are realized; multi-component collaborative design comprehensively covers inflammation inhibition, fibrosis reversal and epithelium repair, and the treatment effect is improved.

Description

Technical Field

[0001] The invention relates to the field of medical technology, in particular to a highly effective external medicine for repairing vulvar leukoplakia and a preparation method thereof. Background Art

[0002] Vulvar leukoplakia is a common chronic skin disease, which is mainly manifested by local skin keratinization, epithelial thickening and fibrosis, often accompanied by uncomfortable symptoms such as itching and pain. The conventional method for treating vulvar leukoplakia is mainly local topical medications, including hormone creams, vitamin preparations and ordinary ointments, which achieve the treatment purpose by relieving inflammation, promoting epithelial repair and improving metabolic function. In the prior art, this type of topical medication is usually based on a single active ingredient, supplemented by a simple cream or gel system, and relies on the natural penetration mechanism of the skin to achieve drug absorption. However, due to the special anatomical structure of the vulva and the abnormal skin barrier in the area of ​​leukoplakia lesions, the efficacy of this type of traditional topical medication is often not ideal in the treatment of vulvar leukoplakia.

[0003] Although the topical drugs in the prior art have alleviated the symptoms of vulvar leukoplakia to a certain extent, their structure and design still have many deficiencies. First, the transdermal absorption efficiency of the drug is low, especially in the lesion areas with thickened stratum corneum and severe fibrosis, the drug mostly stays on the surface of the skin and is difficult to reach the deep layer of the lesion; second, the drug release mechanism of the traditional dosage form is relatively single, which cannot adapt to the dynamic lesion environment of the vulvar leukoplakia area, showing a mismatch between the drug release rate and the lesion requirements; third, the existing preparations are insufficiently protective of the active ingredients, and molecules such as progesterone and vitamin B are easily inactivated under light, heat and humidity, further reducing the therapeutic effect; in addition, the drug action mode of a single active ingredient cannot fully cover a variety of pathological processes such as inflammation inhibition, fibrosis reversal and epithelial repair; finally, the drug release time is short, it is difficult to form a local long-term effect, and frequent use brings inconvenience to patients. Therefore, the existing topical drug technology has many limitations in terms of absorption efficiency, dynamic response ability, drug stability, therapeutic mechanism and long-term effectiveness, and it is urgently needed to improve the therapeutic effect. Summary of the invention

[0004] In view of the deficiencies of the prior art, the present invention provides a highly effective topical medicine for repairing vulvar leukoplakia and a preparation method thereof, which solves the problems of low transdermal absorption efficiency, insufficient dynamic release capacity, poor drug stability and incomplete therapeutic effect of topical medicines in the prior art.

[0005] To achieve the above objectives, the present invention is implemented by the following technical scheme: a highly effective external medicine for repairing vulvar leukoplakia and a preparation method thereof, comprising the following components in parts by weight: Vitamin B6: 1.0-2.0 parts; Vitamin B1: 1.0-2.0 parts; Progesterone: 0.5-1.5 parts; Estradiol valerate: 0.05-0.2 parts; Compound dexamethasone acetate cream: 1.0-5.0 parts; Vitamin E: 0.5-2.0 parts; Compound salvia miltiorrhiza extract: 2.0-5.0 parts; Red Minsu Ointment: 1.0-3.0 parts; Liposome: 5.0-10.0 parts; Nanoemulsion: 10.0-20.0 parts; Thermosensitive gel matrix: 15.0-25.0 parts; Acid-sensitive carrier: 1.0-5.0 parts; Moisture-sensitive materials: 2.0 to 8.0 parts; Propylene glycol: 5.0-10.0 parts; Lactic acid buffer (pH 6.5): 10.0-15.0 parts.

[0006] Preferably, the vitamin B6 and vitamin B1 are dissolved in a lactic acid buffer as a solvent to form an aqueous solution, and the pH value of the lactic acid buffer is 6.5.

[0007] Preferably, the progesterone is prepared into nanoparticles with a particle size of 100 to 200 nm by a high-pressure homogenization method.

[0008] Preferably, the liposome is prepared from phospholipid and cholesterol, the mass fraction of phospholipid is 8.0 to 12.0 parts, and the mass fraction of cholesterol is 2.0 to 4.0 parts.

[0009] Preferably, the nanoemulsion is prepared by high shear emulsification, the oil phase is MCT oil, the weight fraction is 10.0-15.0 parts, and the surfactant is Pluronic F127, the weight fraction is 2.0-5.0 parts.

[0010] Preferably, the thermosensitive gel matrix is ​​prepared by mixing Pluronic F127 and PEG-PLA, the mass fraction of Pluronic F127 is 15.0 to 20.0 parts, and the mass fraction of PEG-PLA is 5.0 to 10.0 parts.

[0011] Preferably, the acid-sensitive carrier is prepared from a chitosan derivative, the mass fraction of chitosan is 1.0 to 3.0 parts, and the cross-linking agent used is glutaraldehyde.

[0012] Preferably, the moisture-sensitive material is sodium carboxymethyl cellulose, and its mass fraction is 2.0 to 5.0 parts.

[0013] The preparation method of a highly effective external medicine for repairing vulvar leukoplakia comprises the following steps: Dissolve vitamin B6 and vitamin B1 in lactic acid buffer to form a basic drug solution; Progesterone nanoparticles are prepared by mixing progesterone with ethanol to form a solution, adding the solution dropwise to a lactate buffer solution, and then preparing the solution by high pressure homogenization; To prepare liposomes, phospholipids and cholesterol are dissolved, the solvent is removed by rotary evaporation, water is added for hydration, and ultrasonic emulsification is performed; To prepare nanoemulsion, MCT oil and surfactant are mixed and then high shear emulsified; To prepare the thermosensitive gel, Pluronic F127 and PEG-PLA were dissolved in lactic acid buffer and stirred at low temperature to form a gel; The final drug is prepared by mixing, and each component is evenly mixed and packaged according to the mass ratio.

[0014] Preferably, during the liposome preparation process, the rotary evaporation temperature is 40° C. to 50° C., and the ultrasonic emulsification power is 300 to 400W.

[0015] The present invention provides a highly effective external medicine for repairing vulvar leukoplakia and a preparation method thereof, which has the following beneficial effects: 1. The present invention adopts a multi-layer transdermal delivery system and realizes the precise layered delivery of drugs in the stratum corneum, epidermis and dermis through the coordinated design of nanoemulsion, liposome and thermosensitive gel. Compared with the transdermal absorption mechanism of a single cream dosage form in the prior art, it significantly improves the penetration depth and absorption efficiency of the drug, and solves the problem that traditional topical drugs have limited effects in the deep layer of lesions.

[0016] 2. The present invention introduces acid-sensitive and moisture-sensitive responsive materials and dynamically adjusts the release behavior of the drug so that it can adapt to the inflammatory acidic environment and moist characteristics of the vulvar leukoplakia area. Unlike the drugs with fixed release patterns in the prior art, the drug of the present invention can release active ingredients according to changes in the microenvironment, thereby enhancing the local targeting and adaptability of the drug and solving the problem of single and unstable local effects of traditional drugs.

[0017] 3. The present invention utilizes a combination of antioxidant technology and nanocarrier encapsulation technology to significantly improve the stability of active ingredients in drugs. Through the synergistic effect of propylene glycol and vitamin E, highly active ingredients such as progesterone and vitamin B are protected from oxidation, light, heat and humidity. Compared with the limitations of the prior art that active ingredients are easily degraded and efficacy is attenuated, the present invention extends the shelf life of the drug and improves the reliability of treatment.

[0018] 4. The present invention optimizes the composition ratio of the thermosensitive gel and designs a long-acting drug release system that can form a local drug reservoir. The system is converted into a gel state when it comes into contact with human body temperature, which slows down the diffusion rate of the drug and achieves a long-term drug effect locally. Compared with the problems of short drug release time and easy removal by washing or friction in the prior art, the present invention significantly enhances the retention and sustained treatment ability of the drug. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 It is a schematic diagram of the method flow of the present invention. DETAILED DESCRIPTION

[0020] The following will be combined with the drawings in the specification of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0021] Please see attached Figure 1 The embodiment of the present invention provides a highly effective external-use medicine for repairing vulvar leukoplakia and a preparation method thereof, comprising: Vitamin B6: 1.0-2.0 parts Vitamin B6 promotes cell regeneration and damage repair by participating in protein metabolism and amino acid synthesis; it also has anti-inflammatory effects and helps improve metabolic disorders in diseased tissues.

[0022] Vitamin B1: 1.0-2.0 parts Vitamin B1, as a key coenzyme in cellular energy metabolism, can increase the metabolic activity of local cells, promote energy supply, and enhance repair capacity.

[0023] Progesterone: 0.5-1.5 parts Progesterone regulates local hormone levels, reduces the progression of fibrosis, promotes the repair of damaged epithelial tissue, and improves tissue microenvironment. Through nano-processing, progesterone can effectively break through the skin barrier and enhance targeting.

[0024] Estradiol valerate: 0.05-0.2 parts As an estrogen, estradiol valerate can promote the proliferation of epithelial cells and the repair of the keratinized layer, and improve the abnormal keratinization of diseased tissues.

[0025] Compound dexamethasone acetate cream: 1.0-5.0 parts Dexamethasone is a highly effective glucocorticoid that can rapidly inhibit the release of inflammatory factors, reduce local inflammatory responses and tissue edema, and work with other drug ingredients to improve repair efficiency.

[0026] Vitamin E: 0.5-2.0 parts Vitamin E acts as an antioxidant, protecting tissues from oxidative damage by capturing free radicals and enhancing the stability of the skin barrier, helping to maintain the long-term activity of local drugs.

[0027] Compound Danshen extract: 2.0-5.0 parts Compound Danshen extract contains active ingredients such as tanshinone, which can significantly improve local microcirculation, promote blood supply to the diseased area, and enhance repair ability.

[0028] Red Mineral Ointment: 1.0-3.0 parts Rubramin has anti-allergic and anti-inflammatory effects, which can relieve local itching and inflammation symptoms while repairing the damaged epidermal barrier.

[0029] Liposome: 5.0-10.0 parts Liposomes mimic the structure of cell membranes and significantly enhance the transdermal absorption of drugs by fusing with skin cells, while protecting the stability of active ingredients during the delivery process.

[0030] Nanoemulsion: 10.0-20.0 parts Nanoemulsions distribute active ingredients in extremely small particles through high dispersibility, which can effectively reduce the diffusion resistance of the skin barrier and thus increase the absorption rate of drugs.

[0031] Thermosensitive gel matrix: 15.0-25.0 parts Thermosensitive gel is liquid at room temperature and quickly changes to a gel state after contacting human body temperature, forming a drug reservoir, which helps to prolong the drug release time and improve the sustainability of local effects.

[0032] Acid-sensitive carrier (chitosan derivative): 1.0-5.0 parts Chitosan undergoes protonation in the acidic microenvironment of the vulvar leukoplakia lesion area, resulting in structural rupture and rapid release of the encapsulated drug, thereby achieving smart responsive release.

[0033] Moisture-sensitive material (sodium carboxymethyl cellulose): 2.0 to 8.0 parts Sodium carboxymethyl cellulose enhances the adhesion of drugs in a wet environment by hygroscopic expansion, thereby further increasing the drug's local residence time and absorption efficiency.

[0034] Propylene glycol: 5.0-10.0 parts Propylene glycol is a transdermal absorption enhancer that reduces the barrier function of the stratum corneum while stabilizing active molecules to prevent their degradation.

[0035] Lactic acid buffer (pH 6.5): 10.0-15.0 parts Lactic acid buffer regulates the acid-base balance of the drug system, avoids the influence of the external environment on the drug, and maintains the stability of the active ingredients.

[0036] Preparation method In order to achieve the multi-layer delivery and dynamic response functions of the above-mentioned pharmaceutical composition, the following preparation process is adopted (parameters of each step are given as range values): Preparation of active ingredients Preparation of vitamin solution Dissolve vitamin B6 (1.0-2.0 parts) and vitamin B1 (1.0-2.0 parts) in lactic acid buffer (10.0-15.0 parts), and stir at room temperature (20°C-25°C) for 15-30 minutes to form a uniform solution.

[0037] Lactic acid buffer maintains a stable acid-base environment, preventing the degradation of vitamin molecules during the dissolution process and ensuring their activity.

[0038] Preparation of progesterone nanoparticles Progesterone (0.5-1.5 parts) was dissolved in ethanol (10%-20%) to form solution A.

[0039] Solution A was slowly added dropwise into the lactic acid buffer, and a progesterone nanoparticle solution with a particle size of 100 to 200 nm was prepared by a high-pressure homogenizer (150 to 250 MPa, 3 to 6 cycles).

[0040] Nano-processing significantly reduces the particle size of progesterone and increases the specific surface area of ​​the drug, thereby enhancing its transdermal absorption performance.

[0041] Preparation of transdermal carriers Liposome preparation Phospholipids (8.0-12.0 parts) and cholesterol (2.0-4.0 parts) were dissolved in ether and methanol (3:1), and the solvent was removed by rotary evaporation to form a lipid film.

[0042] Lactic acid buffer was added to the lipid film, and liposomes (particle size 100-300 nm) were formed by ultrasonic emulsification (frequency 20-40 kHz, power 300-400 W, 10-20 minutes).

[0043] Liposomes fuse with skin cell membranes through the lipophilicity of the phospholipid bilayer, improving the penetration efficiency of drugs.

[0044] Nanoemulsion preparation MCT oil (10.0-15.0 parts) and a surfactant (Pluronic F127, 2.0-5.0 parts) were mixed, lactic acid buffer was added, and a nanoemulsion with a particle size of 50-100 nm was prepared using a high shear emulsifier (rotation speed 6000-8000 rpm).

[0045] The high dispersibility and low interfacial tension of nanoemulsions enhance the diffusion of drugs and further reduce the resistance of the skin barrier.

[0046] Thermosensitive gel preparation Pluronic F127 (15.0-20.0 parts) and PEG-PLA (5.0-10.0 parts) were dissolved in lactic acid buffer (cooled to 4°C-8°C) and stirred for 12-24 hours to form a gel matrix.

[0047] Thermosensitive gel quickly gels at body temperature to form a drug reservoir, preventing the drug from being lost due to local friction.

[0048] This technical solution achieves efficient absorption and deep action of vulvar leukoplakia repair drugs through multi-layer delivery structure, dynamic response release and stability protection. The proposed formula and process not only optimize the physical and chemical properties of the drug, but also significantly improve its therapeutic targeting and sustained effect.

[0049] Example 1: Preparation of multi-layer transdermal drug delivery for vulvar leukoplakia repair 1. Preparation of active ingredients Weigh 1.5 parts of vitamin B6 and 1.5 parts of vitamin B1, add to lactic acid buffer (pH 6.5, 15 parts), stir at 400 rpm with a magnetic stirrer for 20 minutes at room temperature (25°C) until completely dissolved to form a uniform basic aqueous solution.

[0050] Weigh 1.0 part of progesterone and dissolve it in 20% ethanol (solution A). Add solution A dropwise into lactate buffer (10 parts) at a rate of 0.5 mL / min. Use a high-pressure homogenizer to cycle 5 times at a pressure of 200 MPa to prepare progesterone nanoparticles with an average particle size of 150 nm.

[0051] 2. Liposome Preparation Weigh 10 parts of phospholipids and 3 parts of cholesterol, dissolve them in a mixture of ether and methanol (3:1). Place the solution in a rotary evaporator, set the temperature to 45°C and the speed to 80 rpm, evaporate the solvent and form a uniform lipid film.

[0052] 10 parts of lactic acid buffer were added to the film and allowed to stand for 30 minutes, followed by emulsification treatment for 15 minutes using an ultrasonic emulsifier at a power of 350 W and a frequency of 25 kHz to obtain a liposome suspension with a particle size of 200 nm.

[0053] 3. Nanoemulsion Preparation In a 60°C water bath, 12 parts of MCT oil and 3 parts of Pluronic F127 were mixed and stirred for 30 minutes to form a uniform oil phase.

[0054] The oil phase was mixed with 12 parts of lactic acid buffer in a ratio of 1:1. The mixture was homogenized at 7000 rpm for 10 minutes using a high shear emulsifier to prepare a nanoemulsion with a particle size of 80 nm.

[0055] 4. Preparation of Thermosensitive Gel Matrix 18 parts of Pluronic F127 and 6 parts of PEG-PLA were dissolved in a lactic acid buffer cooled to 4° C. Stirring was carried out at low temperature for 20 hours to form a transparent thermosensitive gel solution.

[0056] 5. Drug mixing and molding Mix the following proportions: 5 parts of vitamin solution, 8 parts of progesterone nanoparticle solution, 10 parts of liposomes, 15 parts of nanoemulsion, and 25 parts of thermosensitive gel. Stir with a homogenizer at 300 rpm for 20 minutes until a uniform drug preparation is formed.

[0057] The preparation was loaded into a sterile tube and refrigerated at 4°C for 12 hours. The finished product was ready for use.

[0058] Effect This embodiment significantly improves the transdermal absorption capacity of the drug through the synergistic effect of the multi-layer delivery system (nanoemulsion, liposome, thermosensitive gel). The nano-design of progesterone nanoparticles breaks through the skin barrier, allowing it to act directly on the lesion tissue. The deep delivery capacity of the drug is much higher than that of traditional creams, solving the problem of insufficient lesion depth.

[0059] Example 2: Preparation of topical drugs based on dynamic response mechanism 1. Preparation of acid-sensitive carrier Dissolve 2 parts of chitosan in 1% acetic acid solution (10 parts) and stir for 40 minutes to form a uniform solution.

[0060] 0.8 parts of glutaraldehyde was added dropwise, and stirring was continued for 2 hours to prepare acid-sensitive chitosan particles.

[0061] The particles were collected by high-speed centrifuge (rotation speed 10,000 rpm), dried and used for later use. The particle size was controlled at 200 nm.

[0062] 2. Preparation of Moisture-sensitive Materials Weigh 3.5 parts of sodium carboxymethyl cellulose (CMC) and dissolve it in a 50°C lactic acid buffer. Stir for 30 minutes to form a high viscosity solution.

[0063] 3. Preparation of compound drug matrix Weigh the following proportions: 5 parts of progesterone nanoparticle solution, 3 parts of acid-sensitive carrier, 6 parts of moisture-sensitive material, 10 parts of liposomes, and 20 parts of thermosensitive gel. Add them one by one into the nanoemulsion matrix (the proportion is 20 parts) and stir for 25 minutes until they are completely evenly dispersed.

[0064] forming The preparation was dispensed into ointment tubes and refrigerated at 4°C for 12 hours to complete the final preparation.

[0065] Effect This embodiment introduces acid-sensitive and moisture-sensitive response technology. The drug can be dynamically released in the acidic and moist environment of the vulvar leukoplakia area, solving the technical problems of insufficient drug retention and uneven release in the lesion area.

[0066] Example 3: Preparation of long-acting release drugs 1. Thermosensitive gel optimization Prepare in the following proportions: 720 parts of Pluronic F12, 8 parts of PEG-PLA, and 72 parts of lactic acid buffer. Stir at low temperature for 24 hours to form a high-concentration thermosensitive gel.

[0067] At 37°C, the thermosensitive gel conversion time is controlled within 60 seconds.

[0068] 2. Liposome and nanoemulsion composite Take liposomes with a particle size of 200 nm (10 parts), mix them with nanoemulsions with a particle size of 80 nm (20 parts), stir them with a homogenizer for 15 minutes, and form a highly efficient transdermal delivery matrix.

[0069] 3. Drug Combinations 5 parts of vitamin solution, 8 parts of progesterone nanoparticle solution, 5 parts of compound salvia miltiorrhiza extract solution, 30 parts of composite matrix (liposome + nanoemulsion), 35 parts of thermosensitive gel. Add the components in order and stir at low speed for 30 minutes to obtain a uniform mixed preparation.

[0070] Effect The thermosensitive gel forms a drug reservoir locally, and the drug can be slowly released to the lesion area, significantly prolonging the drug's action time. This embodiment improves the continuity of treatment and solves the limitation of short release time of traditional topical drugs.

[0071] Example 4: Preparation of multi-component combined preparation 1. Progesterone and estradiol valerate combination 1.0 part of progesterone and 0.1 part of estradiol valerate were dissolved in 20% ethanol, mixed and added dropwise to lactate buffer, and combined nanoparticles (particle size 150 nm) were prepared by high-pressure homogenization.

[0072] 2. Preparation of comprehensive transdermal matrix Liposome (8 parts), nanoemulsion (15 parts), acid-sensitive chitosan (3 parts) and thermosensitive gel (25 parts) were prepared and stirred evenly.

[0073] During the final mixing, add vitamin B1 and B6 (1.5 parts each) solution to prepare the finished drug product.

[0074] Effect This embodiment achieves multi-component synergistic repair, and through the combination of hormone regulation and transdermal delivery technology, it comprehensively covers the vitiligo lesion area and enhances the stability of the therapeutic effect and the depth of treatment.

[0075] Comparative Example 1: Multi-layer transdermal delivery system in Example 1 Comparative Example Preparation Process: Active ingredient preparation: As in Example 1, vitamin B6 and vitamin B1 were dissolved in lactic acid buffer to prepare a basic solution; For progesterone particles that were not nano-processed, progesterone was directly dissolved in ethanol (15%), and a buffer solution was added and stirred for 20 minutes to form a suspension without using high-pressure homogenization, and the particle size ranged from 2 to 10 μm.

[0076] Transdermal carriers: When preparing liposomes, no rotary evaporation treatment is performed, and only a simple phospholipid-cholesterol solution is mixed with a buffer solution and stirred for 30 minutes without ultrasonic emulsification, forming liposomes with uneven particle size (particle size is about 500-1000nm).

[0077] The nanoemulsion was prepared by low-speed stirring (2000 rpm) without adding Pluronic F127 surfactant and mixing only a single lactic acid buffer with MCT oil. The particle size ranged from about 300 to 800 nm.

[0078] Thermosensitive gel: The ratio of Pluronic F127 and PEG-PLA was adjusted to 10%:3% to prepare a low-concentration gel solution, which remained liquid at room temperature, had incomplete gelation at 37°C, and the release rate was accelerated.

[0079] Key Differences: Non-nanosized progesterone particles result in large particle size and low absorption efficiency.

[0080] Liposomes and nanoemulsions have large particle sizes and uneven distribution, which affects the layered delivery of drugs.

[0081] The proportion of thermosensitive gel is low and the release control ability is significantly weakened.

[0082] Comparative Example 2: Dynamic response release in Example 2 Comparative Example Preparation Process: Acid-sensitive carriers: The carrier was prepared using high molecular weight chitosan (50 kDa), which was dissolved in acetic acid solution without adding glutaraldehyde for cross-linking. Instead, it was directly dried to form coarse particles with a particle size of 1 to 3 μm.

[0083] Moisture sensitive materials: The mass fraction of CMC was reduced to 1.0%, and it was dissolved at room temperature without heating or stirring to form a low viscosity solution.

[0084] Drug combinations: The acid-sensitive carrier and the moisture-sensitive material are added into the liposome and the nanoemulsion, and the ratio is not adjusted during mixing. The ratio of the acid-sensitive material is 1.0%, and the ratio of the moisture-sensitive material is 0.5%.

[0085] Key Differences: The acid sensitivity of high molecular weight chitosan is significantly reduced, resulting in limited responsive release characteristics.

[0086] The proportion of moisture-sensitive materials is low and the dispersion is insufficient, and the drug has weak adaptability in a humid environment.

[0087] The dynamic response mechanism is difficult to fully reflect.

[0088] Comparative Example 3: Long-acting release system in Example 3 Comparative Example Preparation Process: Preparation of thermosensitive gel: The ratio of Pluronic F127 to PEG-PLA was adjusted to 10%:2% to form a low-concentration gel. The cooling time was shortened to 8 hours, resulting in an incomplete gel network structure.

[0089] Composite Matrix: The liposomes and nanoemulsions were mixed in a ratio of 1:3 instead of being evenly distributed, and the particle size of the liposomes was not controlled at 200 nm, but crude liposomes (particle size 600-800 nm) were used.

[0090] Drug combinations: The proportion of progesterone nanoparticles was reduced to 0.3%, and the proportion of vitamin B6 and B1 was reduced to 0.8%, and the overall drug concentration was insufficient.

[0091] Key Differences: Thermosensitive gels are not strong enough, release faster, and cannot form a local drug reservoir.

[0092] The particle sizes of liposome and nanoemulsion composite matrices are uneven, and the drug transdermal efficiency is significantly reduced.

[0093] The concentration of progesterone and vitamins is insufficient, and the long-term repair capacity is limited.

[0094] Comparative Example 4: Multi-component combined preparation in Example 4 Comparative Example Preparation Process: Progesterone combined with estradiol valerate: Without using nanotechnology, progesterone (1.0%) and estradiol valerate (0.1%) were directly dissolved in lactic acid buffer to form a solution with uneven drug distribution.

[0095] Transdermal carriers: When preparing liposomes, ultrasonic emulsification was not used, only simple stirring was used, and the particle size was >800nm.

[0096] The nanoemulsion did not add Pluronic F127, but only used a single buffer mixed with an oil phase, and the particle size was about 500 nm.

[0097] Thermosensitive gel matrix: When the PEG-PLA ratio in the gel matrix was adjusted to 1.0%, the gel could not be fully formed at 37°C.

[0098] Key Differences: The drug dissolution and distribution are uneven, resulting in decreased delivery efficiency.

[0099] The particle size of liposomes and emulsions is too large, which weakens their transdermal performance.

[0100] Thermosensitive gel failed and release control ability was insufficient.

[0101] Comparative Example 5: Inefficient Optimized Version of the Overall Formula Comparative Example Preparation Process: Overall formula simplification: Acid-sensitive carriers and moisture-sensitive materials were deleted, and only liposomes (10%) and nanoemulsions (20%) were used as transdermal carriers.

[0102] The proportion of thermosensitive gel was reduced to 8%, and the concentration of other components was reduced to 50%.

[0103] Simplified preparation method: After the drugs were mixed, they were stirred for 10 minutes without particle size control or refrigeration solidification.

[0104] Key Differences: Lack of response mechanisms and inability to adapt to the dynamic lesion environment.

[0105] The proportion of thermosensitive gel is low and the long-lasting release characteristics are lost.

[0106] The concentration of some ingredients in the drug formula is low, and the repair effect is weakened.

[0107] These comparative designs fully demonstrate the limitations of the prior art by adjusting key parameters (such as nano-processing, particle size control, dynamic response ratio, etc.). They are logically closely linked to the invention point and fully reflect the technical advantages of the present invention in terms of drug transdermal absorption efficiency, dynamic release regulation and long-term treatment.

[0108] Experiment 1: Transdermal absorption efficiency experiment Experimental Description Purpose By comparing Example 1 with Comparative Example 1, the effect of nano-processing and multi-layer delivery system on improving drug transdermal absorption efficiency was evaluated. sample: Example 1 Drug: Contains nanoemulsion, liposome, thermosensitive gel, and the particle size of progesterone is 150nm.

[0109] Comparative Example 1 Drug: Non-nano-sized progesterone (particle size 2-10 μm), the delivery system is uneven.

[0110] Experimental equipment: Franz diffusion cell (diffusion area 1 cm², receptor chamber volume 7 mL).

[0111] High performance liquid chromatography (HPLC).

[0112] Fresh ex vivo porcine skin (thickness 0.5 mm).

[0113] Reagents: PBS buffer (pH 7.4).

[0114] Acetonitrile (HPLC grade).

[0115] Experimental procedures Skin preparation: Fresh pig skin was obtained from a slaughterhouse and soaked in PBS buffer for 2 h to remove excess fat and subcutaneous tissue.

[0116] The skin was cut into circular pieces with a diameter of 1 cm, ensuring uniform thickness.

[0117] Diffusion experiment: The skin samples were mounted in Franz diffusion cells with the stratum corneum facing the donor chamber.

[0118] 7 mL of PBS buffer (pH 7.4) was added to the receptor chamber, the temperature was kept constant at 37 °C, and the stirring rate was 100 rpm.

[0119] 1 mL of the drug of Example 1 and 1 mL of the drug of Comparative Example 1 were added to the donor chamber, respectively, with 3 replicates in each group.

[0120] At diffusion times of 0, 2, 4, and 6 h, 500 μL of the liquid in the receptor chamber was taken and supplemented with an equal amount of PBS buffer to avoid affecting the diffusion equilibrium.

[0121] Concentration determination: The sample was filtered through a 0.22 μm filter membrane and subjected to HPLC analysis.

[0122] Acetonitrile-water (70:30) was used as the mobile phase, the progesterone detection wavelength was 245 nm, and the flow rate was 1 mL / min.

[0123] Determine the drug concentration (μg / mL).

[0124] Experimental data Table Name: Nano-processing has a significant effect on the transdermal absorption of drugs. In Example 1, the particle size of progesterone is only 150nm, which significantly increases the specific surface area. This design directly reduces the resistance of the diffusion path, allowing the drug to pass through the stratum corneum and epidermis more efficiently and enter deeper tissues. In contrast, Comparative Example 1 does not use nano-technology, the progesterone particle size is large, and the diffusion flux is significantly limited. This difference fully demonstrates that particle size optimization is the key to achieving enhanced transdermal absorption.

[0125] Through the synergistic effect of the multi-layer delivery system, the drug in Example 1 exhibits a strong transdermal ability. The division of labor between the nanoemulsion and the liposome in the delivery process is clear: the emulsion reduces the surface tension of the skin, and the liposome simulates the bimolecular structure of the cell membrane and has a higher affinity with the skin. Therefore, the drug can efficiently penetrate the skin barrier. In Comparative Example 1, the delivery system is simply designed and fails to fully utilize the advantages of different delivery carriers, so the absorption efficiency is greatly reduced.

[0126] In addition, the role of the thermosensitive gel cannot be ignored. In Example 1, the gel matrix quickly takes shape after contacting body temperature, effectively preventing the drug from diffusing and losing in the donor chamber, and further prolonging the retention time of the drug. In Comparative Example 1, no thermosensitive gel is used, and the drug solution is more easily diffused into the surrounding environment, so the amount actually absorbed into the skin is greatly reduced. This design difference shows that controlling the residence of the drug on the skin surface is an important step in improving absorption efficiency.

[0127] Experiment 2: Dynamic release response experiment Experimental Description Purpose Verify whether the dynamic release ability of the acid-sensitive and moisture-sensitive materials in Example 2 is better than that of the uncross-linked acid-sensitive carrier and low-concentration moisture-sensitive material design in Comparative Example 2, and evaluate its drug release behavior in a simulated lesion environment.

[0128] Experimental Materials sample: Example 2 Drug: Contains cross-linked acid-sensitive chitosan and high-concentration moisture-sensitive CMC (2.0% to 8.0%).

[0129] Comparative Example 2 Drug: Acid-sensitive carrier prepared from uncross-linked chitosan (high molecular weight chitosan, 50 kDa), CMC concentration reduced to 1.0%.

[0130] Experimental equipment: Constant temperature shaking incubator.

[0131] UV spectrophotometer (detection wavelength: progesterone 245nm, vitamin E 292nm).

[0132] Reagents: Simulated lesion environment solution (pH 5.5, humidity 80%).

[0133] Neutral control environmental solution (pH 7.4, humidity 50%).

[0134] Experimental procedures Sample preparation: The drug of Example 2 and the drug of Comparative Example 2 were respectively prepared into uniform smears, and equal amounts of the drugs (1 mL) were taken and loaded into sealed dialysis bags.

[0135] Simulated environment preparation: Prepare two experimental groups: Acidic and humid environment group: solution pH 5.5, humidity 80%, simulating the pathological characteristics of vulvar leukoplakia.

[0136] Neutral dry environment group: solution pH 7.4, humidity 50%, served as control.

[0137] The dialysis bags were placed in the solutions of the two environments respectively to ensure that the drug was released only in the solution.

[0138] Dynamic release assay: The samples were placed in a 37°C constant temperature shaking incubator (shaking rate 100 rpm).

[0139] 0.5 mL of the sample solution was taken at 0, 1, 2, 4, and 6 hours, and the drug concentration was detected by ultraviolet spectrophotometer.

[0140] An equal amount of fresh solution was added after each sampling to ensure stable release conditions.

[0141] Data Records: The cumulative release amounts of progesterone and vitamin E (μg / mL) were recorded respectively.

[0142] Experimental data Table Name: This experiment fully demonstrated the significant responsiveness of acid-sensitive chitosan and moisture-sensitive CMC in pathological environments. In Example 2, the acid-sensitive carrier formed by chitosan cross-linking with glutaraldehyde can release the encapsulated drug by protonation under pH 5.5. In contrast, Comparative Example 2 uses uncross-linked chitosan, and its acid-sensitive performance is obviously insufficient, and the release rate is much lower than that of the embodiment. The concentration of the moisture-sensitive material is also particularly important. The high-concentration CMC in the embodiment absorbs moisture and expands sufficiently, which accelerates the diffusion of the drug, while the moisture-sensitive response ability of the comparative example is significantly weakened due to the low CMC concentration.

[0143] In a dynamic environment, the combined effects of humidity and pH are particularly prominent. In an acidic and humid environment, the cumulative release of the drug in the example is significantly higher than that in a neutral environment, showing strong environmental adaptability. In the comparative example, due to incomplete acid-sensitive carriers and insufficient moisture-sensitive materials, the differences in drug release are small, and the release behavior cannot be adjusted according to environmental changes. This shows that the optimized carrier design in the example is more in line with the characteristics of the lesions.

[0144] In addition, the mechanism of dynamic release is closely related to the carrier design. In Example 2, cross-linked chitosan not only enhances the stability of the carrier structure, but also increases the release rate of the drug in a wet environment. The moisture-sensitive material and the acid-sensitive carrier work together to form a good synergistic effect. However, the single response characteristic in the comparative example is weak, and the integrated application of the two characteristics cannot be achieved, which is obviously difficult to meet the complex requirements of the dynamic environment of vulvar leukoplakia.

[0145] Experiment 3: Long-term release experiment Experimental Description Purpose Verify whether the high-concentration thermosensitive gel matrix in Example 3 has a stronger long-acting release ability, and compare the low-concentration thermosensitive gel design in Comparative Example 3 to evaluate the effect of gel concentration on drug release rate and time.

[0146] Experimental Materials sample: Example 3 Drug: High concentration thermosensitive gel containing 20% ​​Pluronic F127 and 8% PEG-PLA.

[0147] Comparative Example 3 Drug: low concentration thermosensitive gel containing 10% Pluronic F127 and 2% PEG-PLA.

[0148] Experimental equipment: Constant temperature incubator.

[0149] High performance liquid chromatography (HPLC).

[0150] Reagents: PBS buffer (pH 7.4).

[0151] Experimental procedures Sample preparation: Example 3 and Comparative Example 3 were prepared into 1 mL uniform gel samples, placed in dialysis bags, and sealed for later use.

[0152] Release medium preparation: Prepare PBS buffer (pH 7.4) at 37°C to simulate the in vivo environment.

[0153] 7 mL of buffer was added to each group of samples to ensure consistent release conditions.

[0154] Experimental setup: The samples were placed in a constant temperature incubator (37°C).

[0155] Every 2 hours, 0.5 mL of buffer was removed and an equal amount of fresh PBS was added to avoid disruption of the release balance.

[0156] The concentration of progesterone was detected by HPLC, and the cumulative release amount (μg / mL) of each group at different time points was recorded.

[0157] Release time: Observe and record the drug release pattern within 12 hours.

[0158] Experimental data Table Name: Thermosensitive gel matrix shows significant advantages in the long-term release of drugs. In Example 3, the gel concentration reaches 20% PluronicF127, forming a tighter three-dimensional network structure. This high-strength gel can not only significantly delay drug diffusion, but also continuously control the drug release rate. In Comparative Example 3, the low-concentration gel strength is insufficient, the release time is shortened, and a large amount of drugs are released rapidly in the early stage. This release mode cannot meet the needs of long-term treatment. The retention capacity of high-concentration gel is obviously more suitable for the treatment of diseases that require sustained release.

[0159] The difference in release behavior is not only related to the gel concentration, but also closely related to the matrix composition. The effect of PEG-PLA is more obvious in the high-concentration system. It increases the thermal sensitivity of the gel and allows the gel to solidify quickly at body temperature. This feature effectively reduces the loss of drugs in the donor environment. However, the presence of low-concentration PEG-PLA in Comparative Example 3 greatly reduces the coagulation of the gel, and some drugs are even washed into the solution in the initial stage. This shows that the optimization of gel design cannot be ignored in terms of drug stability and durability.

[0160] Example 3 also illustrates that the regulatory ability of the thermosensitive gel determines the therapeutic efficiency of the drug in vivo. With the support of high-concentration gel, the drug can form a stable "drug library" in the lesion area, gradually release the active ingredient, and prolong the therapeutic effect. However, the concentrated release of the drug in Comparative Example 3 easily leads to a rapid decrease in the local drug concentration and cannot achieve a long-term effect. This design gap fully illustrates the necessity of optimizing the ratio of thermosensitive gel and its important value in clinical applications.

[0161] Experiment 4: Transdermal delivery depth experiment Experimental Description Purpose By comparing Example 1 with Comparative Example 1, the effects of nano-processing and multi-layer delivery system on the transdermal drug delivery depth were evaluated, and the technical advantages of the present invention in terms of drug delivery efficiency and depth were verified.

[0162] Experimental Materials sample: Example 1 Drug: Nano-progesterone has a particle size of 150 nm and uses a multi-layer delivery system (nanoemulsion, liposome, thermosensitive gel).

[0163] Comparative Example 1 Drug: The particle size of non-nano-sized progesterone is 2-10 μm, and the delivery system is simple in design.

[0164] Experimental equipment: Cryostat.

[0165] Fluorescence microscopy.

[0166] Fluorescently labeled progesterone (FITC).

[0167] Reagents: PBS buffer (pH 7.4).

[0168] Experimental procedures Sample preparation: The drugs of Example 1 and Comparative Example 1 were respectively added into PBS buffer and dispersed evenly to form a smear with a working concentration of 1 mg / mL.

[0169] Progesterone was labeled with FITC fluorescence in the workbench to ensure stable and uniform drug fluorescence.

[0170] Skin Model: Fresh pig ear skin (thickness 1.5 mm) was taken, cut into 1 cm diameter discs, washed and allowed to stand to dry.

[0171] The skin sample was fixed in a breathable culture dish with the stratum corneum facing upwards.

[0172] Smear treatment: Evenly apply the medicine of Example 1 or Comparative Example 1 on the skin surface (100 μL per tablet).

[0173] The samples were placed in a constant temperature and humidified incubator at 37°C (humidity 80%) and incubated for 6 hours.

[0174] Slice preparation: The skin samples were taken out and vertical 10 μm thick skin slices were made using a freezing microtome.

[0175] Each skin sample was sliced ​​into 10 layers, and samples were taken at intervals to record the fluorescence distribution.

[0176] Fluorescence microscopy: The distribution of fluorescently labeled progesterone was observed under a fluorescence microscope, and the fluorescence intensity of each layer of skin was recorded.

[0177] Analyze the delivery depth and distribution of drugs in the stratum corneum, epidermis, and dermis.

[0178] Experimental data Table Name: The effect of drug particle size on delivery depth is particularly evident in this experiment. In Example 1, the progesterone particle size is 150nm, and the synergistic effect of liposomes and nanoemulsions enables the drug to effectively penetrate the stratum corneum and distribute to the deep dermis. In Comparative Example 1, the non-nanosized progesterone particle size is 2 to 10 μm, and its transdermal ability is significantly limited. Most of the drug only stays in the stratum corneum and epidermis, and deep delivery is insufficient. This difference shows that particle size optimization and carrier selection are the core of improving delivery depth.

[0179] In addition, the multi-layer delivery system plays an important role in the deep distribution of drugs. In Example 1, the nanoemulsion acts as a surface dispersion medium, significantly reducing the diffusion resistance on the skin surface; the liposome simulates the bilayer structure of the cell membrane and is highly compatible with skin lipids, further enhancing the delivery efficiency. In contrast, the delivery system in Comparative Example 1 is simple in design and lacks the ability to effectively break through the skin barrier, so the drug cannot fully penetrate. This fully demonstrates the advantages of the multi-layer delivery design.

[0180] The role of the thermosensitive gel cannot be ignored. In Example 1, the thermosensitive gel forms a stable drug reservoir on the skin surface, continuously providing drugs for diffusion. In Comparative Example 1, the drug is directly exposed to the culture environment and is easily lost due to lack of protection, further limiting its delivery depth. This difference in retention capacity makes Example 1 more suitable for the treatment of vulvar leukoplakia that requires deep repair.

[0181] Experiment 5: Multi-component joint repair ability experiment Experimental Description Purpose By comparing Example 4 with Comparative Example 4, the synergistic effect of nano-progesterone and estradiol valerate combined with a multi-component preparation in the repair of vulvar leukoplakia was evaluated, and the technical advantages of the present invention in promoting epithelial repair and reducing fibrotic lesions were verified.

[0182] Experimental Materials sample: Example 4 Drug: Nano-progesterone (particle size 150 nm) is combined with estradiol valerate, and is combined with liposomes, nanoemulsions and thermosensitive gels.

[0183] Drug of Comparative Example 4: non-nano-formed progesterone, not combined with estradiol valerate, simple cream system.

[0184] Animal Model: BALB / c female mice, weighing 18-22 g, were used to artificially establish a vulvar leukoplakia model (fibrosis and epithelial keratosis lesions were induced by applying 4% carbon tetrachloride).

[0185] Experimental equipment: microscope.

[0186] Pathological section staining instrument.

[0187] Reagents: HE staining kit (to observe changes in epithelial thickness).

[0188] Masson staining kit (to assess the degree of fibrosis).

[0189] Experimental procedures Model building: The mice were randomly divided into 4 groups, with 5 mice in each group.

[0190] 4% carbon tetrachloride was applied to the vulva area of ​​each mouse for 14 consecutive days, and a leukoplakia model with fibrosis and keratosis was successfully established.

[0191] Drug treatment: Group 4 of Example: The drug of Example 4 (100 μL) was applied to the vulva area every day.

[0192] Comparative Example 4 group: Apply the Comparative Example 4 drug (100 μL) to the vulva area every day.

[0193] PBS control group: 100 μL PBS buffer was applied every day.

[0194] Untreated group: No treatment was performed and the natural progression of lesions was observed.

[0195] Continue medication for 14 days.

[0196] Sample collection: Vulvar tissues were collected from each group on the 7th and 14th days, and pathological sections were prepared and stained with HE and Masson.

[0197] HE staining was used to measure epithelial thickness, Masson staining was used to observe the degree of fibrosis, and record collagen distribution and deposition ratio.

[0198] Data Records: The cells were observed and photographed under a microscope, and the average epithelial thickness and fibrosis score of at least 3 high-power fields were recorded in each group.

[0199] Experimental data Table Name: The combined effect of nano-progesterone and estradiol valerate showed a very significant repair effect in this experiment. In Example 4, the nano-progesterone particle size is only 150nm, which has efficient transdermal absorption and can quickly penetrate the stratum corneum and fibrotic areas of the lesions. In contrast, the non-nano-progesterone used in Comparative Example 4 forms an accumulation on the skin surface, and the transdermal efficiency is limited, and it only works in the superficial area. This design difference shows that particle size optimization directly determines the absorption rate and repair depth of the drug.

[0200] The synergistic effect of multiple components is particularly evident in the epithelial repair process. Estradiol valerate in Example 4 promotes the regeneration of stratum corneum and epidermal cells, and synergizes with progesterone to accelerate tissue repair. In Comparative Example 4, due to the lack of coordination of the combined components, the repair mechanism of the drug is single, resulting in insufficient epithelial thickening. This shows that the multi-component combined design is the key to improving the therapeutic effect of the drug.

[0201] In addition, the optimization of the delivery system significantly reduced the degree of fibrosis. In Example 4, liposomes and nanoemulsions successfully acted on the dermis by enhancing the deep delivery of drugs, inhibiting the process of collagen deposition. In Comparative Example 4, most collagen fibers were not effectively alleviated due to insufficient drug delivery depth. This improvement in deep action ability fully reflects the synergistic advantages of the delivery system and the combined component design.

[0202] Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A highly effective external medicine for repairing vulvar leukoplakia, characterized in that: The composition includes the following components in parts by weight: Vitamin B6: 1.0-2.0 parts; Vitamin B1: 1.0-2.0 parts; Progesterone: 0.5-1.5 parts; Estradiol valerate: 0.05-0.2 parts; Compound dexamethasone acetate cream: 1.0-5.0 parts; Vitamin E: 0.5-2.0 parts; Compound salvia miltiorrhiza extract: 2.0-5.0 parts; Red Minsu Ointment: 1.0-3.0 parts; Liposome: 5.0-10.0 parts; Nanoemulsion: 10.0-20.0 parts; Thermosensitive gel matrix: 15.0-25.0 parts; Acid-sensitive carrier: 1.0-5.0 parts; Moisture-sensitive materials: 2.0 to 8.0 parts; Propylene glycol: 5.0-10.0 parts; Lactic acid buffer (pH 6.5): 10.0-15.0 parts.

2. The highly effective external-use medicine for repairing vulvar leukoplakia according to claim 1, characterized in that: The vitamin B6 and vitamin B1 are dissolved in a lactic acid buffer solution as a solvent to form an aqueous solution, and the pH value of the lactic acid buffer solution is 6.

5.

3. The highly effective external-use medicine for repairing vulvar leukoplakia according to claim 1, characterized in that: The progesterone is prepared into nanoparticles with a particle size of 100 to 200 nm by a high-pressure homogenization method.

4. The highly effective external-use medicine for repairing vulvar leukoplakia according to claim 1, characterized in that: The liposome is prepared from phospholipid and cholesterol, wherein the mass fraction of phospholipid is 8.0 to 12.0 parts, and the mass fraction of cholesterol is 2.0 to 4.0 parts.

5. The highly effective external-use medicine for repairing vulvar leukoplakia according to claim 1, characterized in that: The nanoemulsion is prepared by a high shear emulsification method, the oil phase is MCT oil, the weight fraction is 10.0-15.0 parts, and the surfactant is Pluronic F127, the weight fraction is 2.0-5.0 parts.

6. The highly effective external-use medicine for repairing vulvar leukoplakia according to claim 1, characterized in that: The thermosensitive gel matrix is ​​prepared by mixing Pluronic F127 and PEG-PLA, wherein the mass fraction of Pluronic F127 is 15.0 to 20.0 parts, and the mass fraction of PEG-PLA is 5.0 to 10.0 parts.

7. The highly effective external-use medicine for repairing vulvar leukoplakia according to claim 1, characterized in that: The acid-sensitive carrier is prepared from a chitosan derivative, the mass fraction of chitosan is 1.0 to 3.0 parts, and the cross-linking agent used is glutaraldehyde.

8. The highly effective external-use medicine for repairing vulvar leukoplakia according to claim 1, characterized in that: The moisture-sensitive material is sodium carboxymethyl cellulose, and its mass fraction is 2.0 to 5.0 parts.

9. A method for preparing a highly effective external medicine for repairing vulvar leukoplakia, according to any one of claims 1 to 8, characterized in that: The following steps are involved: Dissolve vitamin B6 and vitamin B1 in lactic acid buffer to form a basic drug solution; Progesterone nanoparticles are prepared by mixing progesterone with ethanol to form a solution, adding the solution dropwise to a lactate buffer solution, and then preparing the solution by high pressure homogenization; To prepare liposomes, phospholipids and cholesterol are dissolved, the solvent is removed by rotary evaporation, water is added for hydration, and ultrasonic emulsification is performed; To prepare nanoemulsion, MCT oil and surfactant are mixed and then high shear emulsified; To prepare the thermosensitive gel, Pluronic F127 and PEG-PLA were dissolved in lactic acid buffer and stirred at low temperature to form a gel; The final drug is prepared by mixing, and each component is evenly mixed and packaged according to the mass ratio.

10. The highly effective external-use medicine for repairing vulvar leukoplakia and the preparation method thereof according to claim 9, characterized in that: During the liposome preparation process, the rotary evaporation temperature is 40° C. to 50° C., and the ultrasonic emulsification power is 300 to 400W.

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