Liposome gel loaded with triphenylphosphine-modified cerium oxide and all-trans retinoic acid

Abstract

The present invention provides a liposome gel carrying triphenylphosphine-modified cerium oxide and all-trans retinoic acid. All-trans retinoic acid can inhibit the excessive proliferation of keratinocytes, and cerium oxide nanoparticles can reduce the oxidative stress effect. The combination of the two can inhibit the inflammatory response through different mechanisms and enhance the therapeutic effect of psoriasis. At the same time, the flexible nanoliposome gel is used to achieve efficient delivery of drugs to skin tissue, providing a new idea for the development of therapeutic preparations for psoriasis.

Description

Technical Field

[0001] The invention belongs to a drug composition, and specifically relates to a flexible nanoliposome gel co-loaded with triphenylphosphine-modified cerium oxide nanoparticles and all-trans retinoic acid, a preparation method thereof, and an application thereof in preparing drugs for treating psoriasis. Background Art

[0002] In recent years, the incidence of psoriasis has been increasing year by year. Globally, psoriasis patients account for about 2%-4% of the world's population. However, the pathogenesis of the disease is unclear, the existing treatment methods are limited in effect, and it is easy to relapse, which brings great pain to patients. Psoriasis is often accompanied by diseases such as type 2 diabetes, hypertension, and hypercholesterolemia. Its complications include psoriatic arthritis, depression, insomnia, etc. Psoriasis symptoms recur, which in turn affects the patient's psychological, physiological, social and economic conditions. Clinically, only symptomatic treatment can be used and the disease cannot be cured. The treatment and rehabilitation of psoriasis has become a major problem that needs to be solved in today's medical community.

[0003] Most patients with psoriasis present with mild to moderate local lesions on the skin surface, and topical drug treatment is a common treatment method. At present, the treatment drugs for psoriasis are mainly anti-inflammatory and inhibiting epidermal hyperplasia. Common ones include retinoids, vitamin D3 derivatives, glucocorticoids, anthralin, calcineurin inhibitors, coal tar, etc. Although these drugs have certain efficacy, they have obvious side effects. For example, retinoids are severely irritating to the skin, long-term use of glucocorticoids can cause skin atrophy, anthralin can cause skin staining, and calcineurin inhibitors may increase the risk of lymphoma and skin cancer in patients, which seriously affects the quality of life of patients. The emergence of biological agents has brought hope to patients with psoriasis. Although these drugs have obvious advantages in the treatment of psoriasis, their high prices and inability to eradicate the disease limit their widespread clinical application.

[0004] Inhibiting abnormal proliferation of keratinocytes is one of the drug delivery strategies for the treatment of psoriasis. All-trans retinoic acid is a first-generation retinoid drug. Its mechanism for treating psoriasis is to improve the excessive proliferation of keratinocytes, promote inflammation resolution, and reduce the expression of inflammatory markers such as interleukin-6 by regulating abnormal differentiation of keratinocytes after binding to retinoic acid receptors. However, all-trans retinoic acid cannot be used during the day due to its poor water solubility and stability, and its sensitivity to light. In addition, high concentrations of all-trans retinoic acid have a certain irritating effect on the skin, and burning, erythema, desquamation or itching will occur at the site of skin medication. At the same time, because psoriasis causes excessive proliferation of the stratum corneum, the epidermal barrier function is further strengthened, and the difficulty of all-trans retinoic acid to be absorbed in the skin layer around the lesion also limits its clinical use. Therefore, it is necessary to design a reasonable drug carrier to increase the stability and transdermal efficiency of all-trans retinoic acid, improve the efficacy, and reduce adverse reactions.

[0005] In addition, some studies have also suggested that the occurrence and development of psoriasis is closely related to oxidative stress. When the skin produces oxidative stress, highly active molecules such as reactive oxygen species are overproduced, which can regulate the expression of transcription factors of multiple signaling pathways and mediate cell proliferation, differentiation and inflammation. Cerium dioxide nanoparticles are a type of cerium oxide that can show the activity of scavenging reactive oxygen species through cyclic changes between trivalent cerium and tetravalent cerium. Mitochondria are an important source of reactive oxygen species. Excessive production can cause mitochondrial dysfunction and then stimulate the body's inflammatory response. Studies have shown that there is a close connection between mitochondrial damage and enhanced oxidative stress. Triphenylphosphine is a lipophilic cation that can target mitochondria using negative mitochondrial membrane potential. The use of triphenylphosphine to modify cerium dioxide nanoparticles allows cerium dioxide nanoparticles to anchor epidermal keratinocyte mitochondria and accurately remove intracellular reactive oxygen species. However, as an inorganic nanoparticle, triphenylphosphine-modified cerium dioxide nanoparticles are also difficult to absorb in the skin layer around the lesion due to the barrier effect of the stratum corneum. Therefore, a carrier needs to be designed to improve its transdermal efficiency.

[0006] As a skin disease, one of the main pathological characteristics of psoriasis is the excessive proliferation and abnormal differentiation of epidermal keratinocytes. Therefore, designing a drug delivery system for epidermal keratinocytes is also one of the keys to treat psoriasis. Flexible nanoliposomes are a new type of transdermal drug delivery carrier. Due to the addition of softeners such as ethanol, propylene glycol, polysorbate-80, bile salts, etc., the lipid bilayer phospholipid membrane has high deformability and high flexibility. At the same time, it has the characteristics of high permeability to the stratum corneum of the skin. Flexible nanoliposomes can form a drug reservoir in the epidermis dermis, so that the drug is slowly released and exerts its efficacy locally and lastingly, significantly improving the bioavailability of the drug. However, the liposome solution is directly applied to the body surface, which is prone to problems such as short retention time, low drug delivery effect, and low bioavailability. Therefore, on the basis of the flexible nanoliposome solution, a gel material is added to form a nanogel.

[0007] The present invention inhibits the excessive proliferation of keratinocytes by using all-trans retinoic acid, and at the same time achieves mitochondrial targeting by modifying cerium oxide nanoparticles with triphenylphosphine, thereby efficiently removing reactive oxygen species. Using flexible nanoliposomes as carriers can improve the drug's stratum corneum penetration efficiency by virtue of their own high deformability and excellent permeability while improving drug stability, significantly increase the accumulation of drugs in the dermis, and utilize the drug reservoir and sustained-release properties of liposomes to maintain drug efficacy for a long time and reduce drug toxicity and side effects. Dispersing flexible nanoliposomes into gel to form a uniform and stable gel mesh structure can improve the adhesion and spreadability of flexible nanoliposomes to the skin, prolong the drug action time, improve the therapeutic effect of the drug, and ultimately achieve safe and accurate treatment of psoriasis. Summary of the invention

[0008] The purpose of the present invention is to provide a liposome gel carrying cerium oxide and retinoic acid, a preparation method thereof and an application thereof in preparing a medicine for treating psoriasis.

[0009] In order to achieve the above object, the present invention adopts the following technical solution:

[0010] In a first aspect, the present invention provides a (flexible nano) liposome gel carrying triphenylphosphine-modified cerium oxide and all-trans retinoic acid, wherein the liposome gel carrying triphenylphosphine-modified cerium oxide and all-trans retinoic acid is obtained by mixing a blank gel and a flexible liposome dispersion;

[0011] Based on the blank gel, the blank gel is basically composed of the following components in mass concentration: Carbomer 940 is 0.528% to 0.851%, glycerol is 5.283% to 8.509%, the solvent is water, and the pH is 6-8 (preferably pH 6.5);

[0012] The flexible liposome dispersion is prepared as follows: soybean lecithin, Tween 80, all-trans retinoic acid, and triphenylphosphine-modified cerium oxide nanoparticles are uniformly dispersed in anhydrous ethanol, ultrasonically mixed, and light-proofed and rotary evaporated (in one embodiment of the present invention, the rotary evaporation conditions are 40° C. and 120 rpm) until a film is completely formed (the solvent is evaporated), PBS buffer with a pH of 6.5-7.4 (preferably pH 6.8) is added for hydration, hand-shaking with the aid of water bath ultrasound to completely remove the film, and probe ultrasound under ice bath conditions (in one embodiment of the present invention, the ultrasound time is 5 minutes) to obtain the flexible liposome dispersion; the mass ratio of soybean lecithin to Tween 80 is 1-10:1 (preferably 5:1), and the mass ratio of Tween 80, all-trans retinoic acid, and cerium contained in the triphenylphosphine-modified cerium oxide nanoparticles is 5-40:1-3:1 (preferably 20:3:1);

[0013] The mass ratio of cerium contained in the triphenylphosphine-modified cerium oxide nanoparticles to the blank gel is 0.01-0.06:100 (preferably 0.017-0.054:100, most preferably 0.017:100).

[0014] "Substantially" means that the above components are the main components of the liposome gel, and other components may be appropriately added. The other components are excipients acceptable to the human body.

[0015] Furthermore, the liposome gel carrying triphenylphosphine-modified cerium oxide and all-trans retinoic acid can also include human-acceptable excipients with a mass concentration of less than 1%, such as preservatives, antioxidants and stabilizers. In one embodiment of the present invention, the antioxidant or stabilizer is disodium ethylenediaminetetraacetate; the preservative is ethyl parahydroxybenzoate.

[0016] Furthermore, the auxiliary materials are disodium ethylenediaminetetraacetate with a mass concentration of 0.053% to 0.085% and ethyl p-hydroxybenzoate with a mass concentration of 0.053% to 0.085%.

[0017] Preferably, the pH of the blank gel is adjusted with a pH regulator, and conventional pH regulators in the art include triethanolamine, sodium hydroxide, ethylenediamine, laurylamine, sodium bicarbonate, etc. In one embodiment of the present invention, the pH of the blank gel is adjusted with triethanolamine. Triethanolamine is the most commonly used neutralizer for acidic polymer gels containing carbomer, etc. Triethanolamine neutralizes with the carboxyl group of carbomer to form a stable polymer structure, thereby achieving thickening and moisturizing application effects.

[0018] In one embodiment of the present invention, the volume of the anhydrous ethanol is 25 mL / g based on the mass of the soybean lecithin; the volume of the PBS buffer is 10 mL / g based on the mass of the soybean lecithin.

[0019] Furthermore, the parameters of the probe ultrasound are working time 2s, interval 3s, and power 400W.

[0020] Further, the triphenylphosphine-modified cerium oxide nanoparticles are prepared according to the literature Yu H, Jin F, Liu D, et al. ROS-responsive nano-drug delivery system combining mitochondria-targeting ceria nanoparticles with atorvastatin for acute kidney injury [J]. Theranostics, 2020, 10 (5): 2342-2357. In one embodiment of the present invention, the cerium oxide nanoparticles are prepared according to the following method:

[0021] Cerium acetate hydrate, oleylamine and triphenylphosphine are dissolved in xylene, stirred at room temperature for 18 hours, heated in a water bath at 90°C under an argon atmosphere until the liquid is clear, deionized water is quickly added, and stirring is continued for 3 hours until the liquid turns light yellow, and the mixture is allowed to stand and cool to room temperature. Ethanol is added to precipitate nanoparticles, and the mixture is centrifuged (in one embodiment of the present invention, centrifuged at 4000 rpm for 15 minutes), and the supernatant is discarded to obtain triphenylphosphine-modified cerium oxide nanoparticles; the mass ratio of cerium acetate hydrate, oleylamine and triphenylphosphine is 1:5:2.44; and the volume ratio of deionized water to xylene is 1:15.

[0022] Furthermore, the volume of the xylene is 35 mL / g based on the mass of the cerium acetate hydrate.

[0023] In order to maintain the physicochemical properties of the obtained triphenylphosphine-modified cerium oxide nanoparticles, they were stored in chloroform for future use. After the concentration was measured, a certain volume of the dispersion was directly added during addition.

[0024] In one embodiment of the present invention, based on the blank gel, the blank gel is composed of the following components in mass concentration: carbomer 940 is 0.528% to 0.851%, glycerol is 5.283% to 8.509%, disodium ethylenediaminetetraacetate is 0.053% to 0.085%, ethyl paraben is 0.053% to 0.085%, and the solvent is water. However, those skilled in the art should know that the addition of other compatible medical excipients is also within the scope of the present invention.

[0025] The present invention particularly recommends that the blank gel is composed of the following components in mass concentration: 0.851% of Carbomer 940, 8.509% of glycerol, 0.085% of disodium ethylenediaminetetraacetate, and 0.085% of ethyl paraben.

[0026] Preferably, the blank gel is prepared as follows:

[0027] Take the formulated amount of Carbomer 940 and put it into water to swell for 24 hours, add the formulated amount of glycerol, disodium ethylenediaminetetraacetate and ethylparaben (to disperse evenly, they can be dispersed in water before adding), make up the mass of water, add triethanolamine to adjust the pH to 6.5, and obtain the blank gel.

[0028] The present invention also provides the use of the above-mentioned triphenylphosphine-modified cerium oxide and all-trans retinoic acid liposome gel in the preparation of a drug for treating psoriasis. The results of in vitro transdermal studies show that the cumulative skin permeability and skin retention of the flexible nanoliposome gel loaded with triphenylphosphine-modified cerium oxide nanoparticles and all-trans retinoic acid are higher than those of the all-trans retinoic acid gel. The results of histopathology and immunohistochemistry studies show that compared with the all-trans retinoic acid gel, the flexible nanoliposome gel loaded with triphenylphosphine-modified cerium oxide nanoparticles and all-trans retinoic acid is used for the treatment of imiquimod-induced psoriasis mice. The epidermal thickness and inflammatory cell infiltration of the mice are significantly reduced, acanthosis is almost not observed, and the CD3 expression is significantly reduced, almost reaching the normal level.

[0029] Compared with the prior art, the beneficial effects of the present invention are as follows: the present invention uses triphenylphosphine-modified cerium oxide nanoparticles, all-trans retinoic acid, flexible nanoliposomes, and gel to prepare flexible nanoliposome gels co-loaded with mitochondrial-targeted cerium oxide nanoparticles and all-trans retinoic acid, and achieves the therapeutic purpose of psoriasis through all-trans retinoic acid and triphenylphosphine-modified cerium oxide nanoparticles. The flexible nanoliposome gels co-loaded with mitochondrial-targeted cerium oxide nanoparticles and all-trans retinoic acid provided by the present invention can enhance the therapeutic effect of psoriasis by inhibiting inflammatory reactions through different mechanisms, and utilize flexible nanoliposome gels to achieve efficient drug delivery to skin tissue, providing new ideas for the treatment of psoriasis and formulation development. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 is the infrared spectrum of cerium oxide nanoparticles (Example 1)

[0031] Figure 2 This is a transmission electron micrograph of a flexible nanoliposome loaded with triphenylphosphine-modified cerium oxide nanoparticles and all-trans retinoic acid (Example 1)

[0032] Figure 3 The cumulative skin permeability results of the flexible nanoliposome gel containing triphenylphosphine-modified cerium oxide nanoparticles and all-trans retinoic acid (Example 11)

[0033] Figure 4 The skin retention results of the flexible nanoliposome gel containing triphenylphosphine-modified cerium oxide nanoparticles and all-trans retinoic acid (Example 11)

[0034] Figure 5 The histopathological and immunohistochemical results of the flexible nanoliposome gel containing triphenylphosphine-modified cerium oxide nanoparticles and all-trans retinoic acid (Example 11) DETAILED DESCRIPTION

[0035] The present invention is further described in conjunction with the accompanying drawings and embodiments.

[0036] In the following examples, ethylparaben and ethylparaben both refer to ethylparaben.

[0037] Example 1 Preparation of Flexible Nanoliposome Gel Loaded with Triphenylphosphine-Modified Cerium Oxide Nanoparticles and All-trans Retinoic Acid

[0038] 1. Synthesis of triphenylphosphine-modified cerium oxide nanoparticles

[0039] 0.43g of cerium (III) acetate hydrate (Dalian Meilun Biotechnology Co., Ltd.), 2.14g of oleylamine (Shanghai McLean Biochemical Technology Co., Ltd., O815176) and 1.05g of triphenylphosphine were dissolved in 15mL of xylene, stirred at room temperature for 18h, heated in a water bath at 90°C under an argon atmosphere until the liquid was clear, 1mL of deionized water was quickly added, heated and stirred at 90°C for 3h until the liquid turned light yellow, allowed to stand and cool to room temperature, 100mL of ethanol was added, centrifuged at 4000rpm for 15min, the supernatant was discarded, and triphenylphosphine-modified cerium oxide nanoparticles were obtained, which were stored in 10ml of chloroform. The cerium content in the cerium oxide nanoparticles was measured to be 11.2mg / mL by inductively coupled plasma mass spectrometry. The nanoparticle size was measured by a nanoparticle size potentiometer to be 5.82±0.24nm, and the nanoparticle morphology and size were observed by transmission electron microscopy. The results of infrared spectroscopy are shown in Figure 1 As shown, it was verified that triphenylphosphine had been successfully modified on the surface of the nanoparticles.

[0040] 2. Preparation of Flexible Nanoliposomes Co-loaded with All-trans Retinoic Acid and Triphenylphosphine-modified CeO2 Nanoparticles

[0041] Dissolve 400 mg of soybean lecithin, 80 mg of Tween 80, 12 mg of all-trans retinoic acid, and 357 μL of chloroform dispersion of nanoparticles in 10 mL of anhydrous ethanol, transfer to a round-bottom flask after ultrasonic mixing, and perform rotary evaporation at 40°C and 120 rpm in the dark for 90 min until a film is completely formed. Then add 4 mL of PBS buffer with a pH of 6.8 to hydrate, shake by hand with water bath ultrasound to completely remove the film, and ultrasonicate with an ice bath probe for 5 min (working 2 s, interval 3 s, power 400 W) to obtain flexible nanoliposomes co-loaded with all-trans retinoic acid and triphenylphosphine-modified cerium oxide nanoparticles. The liposome particle size was measured by a nanoparticle size potentiometer to be 63.70 ± 1.44 nm, and the liposome morphology was observed by transmission electron microscopy. The results are as follows Figure 2 As shown, the particle size of the liposomes is relatively uniform. The drug loading of all-trans retinoic acid and cerium in cerium oxide nanoparticles was measured by high performance liquid chromatography and inductively coupled plasma mass spectrometry to be 2.03±0.09% and 0.75±0.02% respectively, and the encapsulation efficiency was 99.62±0.02% and 99.67±0.05% respectively.

[0042] 3. Preparation of Flexible Nanoliposome Gels Co-loaded with All-trans Retinoic Acid and Triphenylphosphine-modified CeO2 Nanoparticles

[0043] Take the prescribed amount of Carbomer 940 and put it into purified water to swell for 24 hours, add glycerol, disodium ethylenediaminetetraacetate and ethylparaben aqueous solution, make up the mass of deionized water, add triethanolamine to adjust the pH to 6.5, and obtain blank gel, take the blank gel and mix it with the flexible nanoliposome solution to obtain flexible nanoliposome gel. Ensure that the mass concentration of each substance in the blank gel is: Carbomer 940 is 0.851%, glycerol is 8.509%, disodium ethylenediaminetetraacetate and ethylparaben are both 0.085%, and water is 90.469%; the mass of the flexible nanoliposome is calculated based on the theoretical mass of cerium contained in it, the mass ratio of cerium in the flexible nanoliposome to the blank gel is 0.017:100, and the content of all-trans retinoic acid incorporated is calculated to be 0.051%, soybean lecithin is 1.702%, and Tween-80 is 0.34%.

[0044] Example 2 Preparation of Flexible Nanoliposome Gel Loaded with Triphenylphosphine-Modified Cerium Oxide Nanoparticles and All-trans Retinoic Acid

[0045] 1. Synthesis of triphenylphosphine-modified cerium oxide nanoparticles

[0046] The synthesis steps are the same as those in Example 1. The cerium content in the cerium oxide nanoparticles was measured by inductively coupled plasma mass spectrometry to be 11.2 mg / mL. The nanoparticle size was measured by a nanoparticle size potentiometer to be 4.21 ± 0.18 nm, and the nanoparticle morphology and size were observed by transmission electron microscopy. Infrared spectroscopy verified that triphenylphosphine had been successfully modified on the surface of the nanoparticles.

[0047] 2. Preparation of Flexible Nanoliposomes Co-loaded with All-trans Retinoic Acid and Triphenylphosphine-modified CeO2 Nanoparticles

[0048] 400 mg of soybean lecithin, 40 mg of Tween 80, 4 mg of all-trans retinoic acid, and 357 μL of chloroform dispersion of nanoparticles were dissolved in 10 mL of anhydrous ethanol, and transferred to a round-bottom flask after ultrasonic mixing. The mixture was rotary evaporated at 40°C and 120 rpm in the dark for 90 min until a film was completely formed. Then 4 mL of PBS buffer with a pH of 6.8 was added for hydration, and the film was completely removed by hand shaking and water bath ultrasound. The probe was ultrasonicated for 5 min (working 2 s, interval 3 s, power 400 W) in an ice bath to obtain flexible nanoliposomes co-loaded with all-trans retinoic acid and triphenylphosphine-modified cerium oxide nanoparticles. The liposome particle size was measured by a nanoparticle size potentiometer to be 60.53 ± 2.24 nm, and the liposome morphology was observed by transmission electron microscopy. The drug loading of all-trans retinoic acid and cerium in cerium oxide nanoparticles were measured by high performance liquid chromatography and inductively coupled plasma mass spectrometry to be 0.87±0.01% and 0.80±0.02%, respectively, and the encapsulation efficiency was 99.58±0.12% and 99.01±0.27%, respectively.

[0049] 3. Preparation of Flexible Nanoliposome Gels Co-loaded with All-trans Retinoic Acid and Triphenylphosphine-modified CeO2 Nanoparticles

[0050] Take the prescribed amount of Carbomer 940 and put it into purified water to swell for 24 hours, add glycerol, disodium ethylenediaminetetraacetate and ethylparaben aqueous solution, make up the mass of deionized water, add triethanolamine to adjust the pH to 6.5, and obtain blank gel, take the blank gel and mix it with the flexible nanoliposome solution to obtain flexible nanoliposome gel. Ensure that the mass concentration of each substance in the blank gel is: Carbomer 940 is 0.53%, glycerol is 5.297%, disodium ethylenediaminetetraacetate and ethylparaben are both 0.053%, and water is 94.067%. The mass of the flexible nanoliposome is calculated based on the theoretical mass of cerium contained in it, and the mass ratio of cerium to blank gel in the flexible nanoliposome is 0.053:100, and the content of all-trans retinoic acid incorporated is calculated to be 0.053%, soybean lecithin is 5.297%, and Tween-80 is 0.53%.

[0051] Example 3 Preparation of flexible nanoliposome gel containing triphenylphosphine-modified cerium oxide nanoparticles and all-trans retinoic acid

[0052] 1. Synthesis of triphenylphosphine-modified cerium oxide nanoparticles

[0053] The synthesis steps are the same as those in Example 1. The cerium content in the cerium oxide nanoparticles was measured by inductively coupled plasma mass spectrometry to be 11.2 mg / mL. The nanoparticle size was measured by a nanoparticle size potentiometer to be 5.36 ± 0.79 nm, and the nanoparticle morphology and size were observed by transmission electron microscopy. Infrared spectroscopy verified that triphenylphosphine had been successfully modified on the surface of the nanoparticles.

[0054] 2. Preparation of Flexible Nanoliposomes Co-loaded with All-trans Retinoic Acid and Triphenylphosphine-modified CeO2 Nanoparticles

[0055] 400mg soybean lecithin, 80mg Tween 80, 4mg all-trans retinoic acid, and 357μL of chloroform dispersion of nanoparticles were dissolved in 10mL of anhydrous ethanol, and transferred to a round-bottom flask after ultrasonic mixing. The mixture was rotary evaporated at 40°C and 120rpm in the dark for 90min until a film was completely formed. Then 4mL of PBS buffer with a pH of 6.8 was added for hydration. The film was completely detached by hand shaking and water bath ultrasound. The probe was ultrasonicated for 5min (working 2s, interval 3s, power 400W) in an ice bath to obtain flexible nanoliposomes co-loaded with all-trans retinoic acid and triphenylphosphine-modified cerium oxide nanoparticles. The liposome particle size was measured by a nanoparticle size potentiometer to be 90.83±1.12nm, and the liposome morphology was observed by transmission electron microscopy. The drug loading of all-trans retinoic acid and cerium in cerium oxide nanoparticles were measured by high performance liquid chromatography and inductively coupled plasma mass spectrometry to be 0.80±0.01% and 0.78±0.09%, respectively, and the encapsulation efficiency was 98.98±0.11% and 98.76±0.12%, respectively.

[0056] 3. Preparation of Flexible Nanoliposome Gels Co-loaded with All-trans Retinoic Acid and Triphenylphosphine-modified CeO2 Nanoparticles

[0057] Take the prescribed amount of Carbomer 940 and put it into purified water to swell for 24 hours, add glycerol, disodium ethylenediaminetetraacetate and ethylparaben aqueous solution, make up the mass of deionized water, add triethanolamine to adjust the pH to 6.5, and obtain blank gel, take the blank gel and mix it with the flexible nanoliposome solution to obtain flexible nanoliposome gel. Ensure that the mass concentration of each substance in the blank gel is: Carbomer 940 is 0.533%, glycerol is 5.325%, disodium ethylenediaminetetraacetate and ethylparaben are both 0.053%, and water is 94.036%. The mass of the flexible nanoliposome is calculated based on the theoretical mass of cerium contained in it, and the mass ratio of cerium to blank gel in the flexible nanoliposome is 0.053:100, and the content of all-trans retinoic acid incorporated is calculated to be 0.053%, soybean lecithin is 5.325%, and Tween-80 is 1.065%.

[0058] Example 4 Preparation of Flexible Nanoliposome Gel Loaded with Triphenylphosphine-Modified Cerium Oxide Nanoparticles and All-trans Retinoic Acid

[0059] 1. Synthesis of triphenylphosphine-modified cerium oxide nanoparticles

[0060] The synthesis steps are the same as those in Example 1. The cerium content in the cerium oxide nanoparticles was measured by inductively coupled plasma mass spectrometry to be 11.2 mg / mL. The nanoparticle size was measured by a nanoparticle size potentiometer to be 5.63 ± 0.46 nm, and the nanoparticle morphology and size were observed by transmission electron microscopy. Infrared spectroscopy verified that triphenylphosphine had been successfully modified on the surface of the nanoparticles.

[0061] 2. Preparation of Flexible Nanoliposomes Co-loaded with All-trans Retinoic Acid and Triphenylphosphine-modified CeO2 Nanoparticles

[0062] 400mg soybean lecithin, 160mg Tween 80, 4mg all-trans retinoic acid, and 357μL of chloroform dispersion of nanoparticles were dissolved in 10mL of anhydrous ethanol, and transferred to a round-bottom flask after ultrasonic mixing. The mixture was rotary evaporated at 40°C and 120rpm in the dark for 90min until a film was completely formed. Then 4mL of PBS buffer with a pH of 6.8 was added for hydration. The film was completely detached by hand shaking and water bath ultrasound. The probe was ultrasonicated for 5min (working 2s, interval 3s, power 400W) in an ice bath to obtain flexible nanoliposomes co-loaded with all-trans retinoic acid and triphenylphosphine-modified cerium oxide nanoparticles. The liposome particle size was measured by a nanoparticle size potentiometer to be 110.31±1.14nm, and the liposome morphology was observed by transmission electron microscopy. The drug loading of all-trans retinoic acid and cerium in cerium oxide nanoparticles were measured by high performance liquid chromatography and inductively coupled plasma mass spectrometry to be 0.70±0.01% and 0.67±0.09%, respectively, and the encapsulation efficiency was 99.59±0.19% and 99.35±0.81%, respectively.

[0063] 3. Preparation of Flexible Nanoliposome Gels Co-loaded with All-trans Retinoic Acid and Triphenylphosphine-modified CeO2 Nanoparticles

[0064] Take the prescribed amount of Carbomer 940 and put it into purified water to swell for 24 hours, add glycerol, disodium ethylenediaminetetraacetic acid and ethylparaben aqueous solution, make up the mass of deionized water, add triethanolamine to adjust the pH to 6.5, and obtain blank gel, take the blank gel and mix it with the flexible nanoliposome solution to obtain flexible nanoliposome gel. Ensure that the mass concentration of each substance in the blank gel is: Carbomer 940 is 0.538%, glycerol is 5.383%, disodium ethylenediaminetetraacetic acid and ethylparaben are both 0.54%, and water is 93.971%. The mass of the flexible nanoliposome is calculated based on the theoretical mass of cerium contained in it, and the mass ratio of cerium to blank gel in the flexible nanoliposome is 0.054:100, and the content of all-trans retinoic acid incorporated is calculated to be 0.054%, soybean lecithin is 5.383%, and Tween-80 is 2.153%.

[0065] Example 5 Preparation of Flexible Nanoliposome Gel Loaded with Triphenylphosphine-Modified Cerium Oxide Nanoparticles and All-trans Retinoic Acid

[0066] 1. Synthesis of triphenylphosphine-modified cerium oxide nanoparticles

[0067] The synthesis steps are the same as those in Example 1. The cerium content in the cerium oxide nanoparticles was measured by inductively coupled plasma mass spectrometry to be 11.2 mg / mL. The nanoparticle size was measured by a nanoparticle size potentiometer to be 5.27 ± 0.62 nm, and the nanoparticle morphology and size were observed by transmission electron microscopy. Infrared spectroscopy verified that triphenylphosphine had been successfully modified on the surface of the nanoparticles.

[0068] 2. Preparation of Flexible Nanoliposomes Co-loaded with All-trans Retinoic Acid and Triphenylphosphine-modified CeO2 Nanoparticles

[0069] 400 mg of soybean lecithin, 80 mg of Tween 80, 8 mg of all-trans retinoic acid, and 357 μL of chloroform dispersion of nanoparticles were dissolved in 10 mL of anhydrous ethanol, and transferred to a round-bottom flask after ultrasonic mixing. The mixture was rotary evaporated at 40°C and 120 rpm in the dark for 90 min until a film was completely formed. Then 4 mL of PBS buffer with a pH of 6.8 was added for hydration, and the film was completely removed by hand shaking and water bath ultrasound. The ice bath probe was ultrasonicated for 5 min (working 2 s, interval 3 s, power 400 W) to obtain flexible nanoliposomes co-loaded with all-trans retinoic acid and triphenylphosphine-modified cerium oxide nanoparticles. The liposome particle size was measured by a nanoparticle size potentiometer to be 80.76 ± 2.67 nm, and the liposome morphology was observed by transmission electron microscopy. The drug loading of all-trans retinoic acid and cerium in cerium oxide nanoparticles were measured by high performance liquid chromatography and inductively coupled plasma mass spectrometry to be 1.58±0.23% and 0.77±0.06%, respectively, and the encapsulation efficiency was 99.18±0.21% and 99.04±0.45%, respectively.

[0070] 3. Preparation of Flexible Nanoliposome Gels Co-loaded with All-trans Retinoic Acid and Triphenylphosphine-modified CeO2 Nanoparticles

[0071] Take the prescribed amount of Carbomer 940 and put it into purified water to swell for 24 hours, add glycerol, disodium ethylenediaminetetraacetate and ethylparaben aqueous solution, make up the mass of deionized water, add triethanolamine to adjust the pH to 6.5, and obtain blank gel, take the blank gel and mix it with the flexible nanoliposome solution to obtain flexible nanoliposome gel. Ensure that the mass concentration of each substance in the blank gel is: Carbomer 940 is 0.774%, glycerol is 7.738%, disodium ethylenediaminetetraacetate and ethylparaben are both 0.077%, and water is 91.333%. The mass of the flexible nanoliposome is calculated based on the theoretical mass of cerium contained in it, and the mass ratio of cerium to blank gel in the flexible nanoliposome is 0.026:100. The content of all-trans retinoic acid incorporated is calculated to be 0.052%, soybean lecithin is 2.579%, and Tween-80 is 0.516%.

[0072] Example 6 Preparation of Flexible Nanoliposome Gel Loaded with Triphenylphosphine-Modified Cerium Oxide Nanoparticles and All-trans Retinoic Acid

[0073] 1. Synthesis of triphenylphosphine-modified cerium oxide nanoparticles

[0074] The synthesis steps are the same as those in Example 1. The cerium content in the cerium oxide nanoparticles was measured by inductively coupled plasma mass spectrometry to be 11.2 mg / mL. The nanoparticle size was measured by a nanoparticle size potentiometer to be 5.03 ± 0.66 nm, and the nanoparticle morphology and size were observed by transmission electron microscopy. Infrared spectroscopy verified that triphenylphosphine had been successfully modified on the surface of the nanoparticles.

[0075] 2. Preparation of Flexible Nanoliposomes Co-loaded with All-trans Retinoic Acid and Triphenylphosphine-modified CeO2 Nanoparticles

[0076] 400 mg of soybean lecithin, 20 mg of Tween 80, 4 mg of all-trans retinoic acid, and 357 μL of chloroform dispersion of nanoparticles were dissolved in 10 mL of anhydrous ethanol, and transferred to a round-bottom flask after ultrasonic mixing. The mixture was rotary evaporated at 40°C and 120 rpm in the dark for 90 min until a film was completely formed. Then 4 mL of PBS buffer with a pH of 6.8 was added for hydration. The film was completely detached by hand shaking and water bath ultrasound. The probe was ultrasonicated for 5 min (working 2 s, interval 3 s, power 400 W) in an ice bath to obtain flexible nanoliposomes co-loaded with all-trans retinoic acid and triphenylphosphine-modified cerium oxide nanoparticles. The liposome particle size was measured by a nanoparticle size potentiometer to be 70.72 ± 0.67 nm. The liposome morphology was observed by transmission electron microscopy. The drug loading of all-trans retinoic acid and cerium in cerium oxide nanoparticles were measured by high performance liquid chromatography and inductively coupled plasma mass spectrometry to be 0.91±0.03% and 0.89±0.02%, respectively, and the encapsulation efficiency was 98.78±0.34% and 99.05±0.89%, respectively.

[0077] 3. Preparation of Flexible Nanoliposome Gels Co-loaded with All-trans Retinoic Acid and Triphenylphosphine-modified CeO2 Nanoparticles

[0078] Take the prescribed amount of Carbomer 940 and put it into purified water to swell for 24 hours, add glycerol, disodium ethylenediaminetetraacetic acid and ethylparaben aqueous solution, make up the mass of deionized water, add triethanolamine to adjust the pH to 6.5, and obtain blank gel, take the blank gel and mix it with the flexible nanoliposome solution to obtain flexible nanoliposome gel. Ensure that the mass concentration of each substance in the blank gel is: Carbomer 940 is 0.528%, glycerol is 5.283%, disodium ethylenediaminetetraacetic acid and ethylparaben are both 0.053%, and water is 94.083%. The mass of the flexible nanoliposome is calculated based on the theoretical mass of cerium contained in it, and the mass ratio of cerium to blank gel in the flexible nanoliposome is 0.053:100, and the content of all-trans retinoic acid incorporated is calculated to be 0.053%, soybean lecithin is 5.283%, and Tween-80 is 0.264%.

[0079] Example 7 Preparation of Flexible Nanoliposome Gel Loaded with Cerium Oxide Nanoparticles

[0080] 1. Synthesis of Cerium Oxide Nanoparticles

[0081] 0.43g of cerium acetate (III) hydrate (Dalian Meilun Biotechnology Co., Ltd.) and 3.21g of oleylamine (Shanghai McLean Biochemical Technology Co., Ltd., O815176) were dissolved in 15mL of xylene, stirred at room temperature for 18h, heated in a water bath at 90°C under an argon atmosphere until the liquid was clear, 1mL of deionized water was quickly added, heated and stirred at 90°C for 3h until the liquid turned light yellow, cooled to room temperature, added 100mL of ethanol, centrifuged at 4000rpm for 15min, and the supernatant was discarded to obtain cerium oxide nanoparticles. The cerium content in the cerium oxide nanoparticles was measured to be 11.8mg / mL by inductively coupled plasma mass spectrometry. The nanoparticle size was measured to be 5.73±0.51nm by a nanoparticle size potentiometer, and the nanoparticle morphology and size were observed by transmission electron microscopy.

[0082] 2. Preparation of Flexible Nanoliposomes Loaded with CeO2 Nanoparticles

[0083] 400mg soybean lecithin, 80mg Tween 80, 339μL chloroform dispersion of nanoparticles were dissolved in 10mL anhydrous ethanol, ultrasonically mixed and transferred to a round-bottom flask, and rotary evaporated at 40°C and 120rpm for 90min in a dark place until a film was completely formed. Then 4mL PBS buffer with a pH of 6.8 was added for hydration, and the film was completely detached by hand shaking with water bath ultrasound. The ice bath probe was ultrasonicated for 5min (working 2s, interval 3s, power 400W) to obtain flexible nanoliposomes loaded with cerium oxide nanoparticles. The liposome particle size was measured by a nanoparticle size potential meter to be 85.78±3.12nm, and the liposome morphology was observed by transmission electron microscopy. The drug loading of cerium in cerium oxide nanoparticles was 0.79±0.04% and the encapsulation efficiency was 98.11±0.06% by inductively coupled plasma mass spectrometry.

[0084] 3. Preparation of Flexible Nanoliposome Gels Loaded with CeO2 Nanoparticles

[0085] Take the prescribed amount of Carbomer 940 and put it into purified water to swell for 24 hours, add glycerol, disodium ethylenediaminetetraacetate and ethylparaben aqueous solution, make up the mass of deionized water, add triethanolamine to adjust the pH to 6.5, and obtain blank gel, take the blank gel and mix it with the flexible nanoliposome solution to obtain flexible nanoliposome gel. Ensure that the mass concentration of each substance in the blank gel is: cerium oxide nanoparticles are 0.018%, Carbomer 940 is 0.85%, glycerol is 7.654%, disodium ethylenediaminetetraacetate and ethylparaben are both 0.077%, and water is 91.342%. The mass of the flexible nanoliposome is calculated based on the theoretical mass of cerium contained in it, the mass ratio of cerium to blank gel in the flexible nanoliposome is 0.017:100, and the soybean lecithin incorporated is calculated to be 1.701% and Tween-80 is 0.34%.

[0086] Example 8 Preparation of Flexible Nanoliposome Gel Carrying Triphenylphosphine-Modified Cerium Oxide Nanoparticles

[0087] 1. Synthesis of triphenylphosphine-modified cerium oxide nanoparticles

[0088] The synthesis steps are the same as those in Example 1. The nanoparticle size was measured by a nanoparticle size potentiometer to be 5.05±0.26 nm, and the nanoparticle morphology and size were observed by a transmission electron microscope. Infrared spectroscopy confirmed that triphenylphosphine had been successfully modified on the surface of the nanoparticles.

[0089] 2. Preparation of Flexible Nanoliposomes Loaded with Triphenylphosphine-Modified CeO2 Nanoparticles

[0090] 400mg soybean lecithin, 80mg Tween 80, 357μL chloroform dispersion of nanoparticles were dissolved in 10mL anhydrous ethanol, ultrasonically mixed and transferred to a round-bottom flask, and rotary evaporated at 40°C and 120rpm for 90min in a dark place until a film was completely formed. Then 4mL of PBS buffer with a pH of 6.8 was added for hydration, and the film was completely detached by hand shaking and water bath ultrasound. The ice bath probe was ultrasonicated for 5min (working 2s, interval 3s, power 400W) to obtain flexible nanoliposomes co-loaded with all-trans retinoic acid and triphenylphosphine-modified cerium oxide nanoparticles. The liposome particle size was measured by a nanoparticle size potential meter to be 70.57±0.98nm, and the liposome morphology was observed by transmission electron microscopy. The drug loading of cerium in cerium oxide nanoparticles was 0.77±0.02% and the encapsulation efficiency was 99.01±0.15% by inductively coupled plasma mass spectrometry.

[0091] 3. Preparation of Flexible Nanoliposome Gels Loaded with Triphenylphosphine-Modified CeO2 Nanoparticles

[0092] Take the prescribed amount of Carbomer 940 and put it into purified water to swell for 24 hours, add glycerol, disodium ethylenediaminetetraacetate and ethylparaben aqueous solution, make up the mass of deionized water, add triethanolamine to adjust the pH to 6.5, and obtain blank gel, take the blank gel and mix it with the flexible nanoliposome solution to obtain flexible nanoliposome gel. Ensure that the mass concentration of each substance in the blank gel is: Carbomer 940 is 0.851%, glycerol is 8.505%, disodium ethylenediaminetetraacetate and ethylparaben are both 0.085%, and water is 90.474%. The mass of the flexible nanoliposome is calculated based on the theoretical mass of cerium contained in it, and the mass ratio of cerium in the flexible nanoliposome to the blank gel is 0.017:100, and the calculated soybean lecithin incorporated is 1.702% and Tween-80 is 0.34%.

[0093] Example 9 Preparation of Flexible Nanoliposome Gel Loaded with All-trans Retinoic Acid

[0094] 1. Preparation of Flexible Nanoliposomes Loaded with All-trans Retinoic Acid

[0095] 400mg soybean lecithin, 80mg Tween 80, 12mg all-trans retinoic acid were dissolved in 10mL anhydrous ethanol, ultrasonically mixed and transferred to a round-bottom flask, and rotary evaporated at 40°C and 120rpm for 90min in a dark place until a film was completely formed. Then 4mL of PBS buffer with a pH of 6.8 was added for hydration, and the film was completely detached by hand shaking with water bath ultrasound. The ice bath probe was ultrasonicated for 5min (working 2s, interval 3s, power 400W) to obtain flexible nanoliposomes loaded with cerium oxide nanoparticles. The liposome particle size was measured by a nanoparticle size potential meter to be ±nm, and the liposome morphology was observed by a transmission electron microscope. The drug loading of all-trans retinoic acid was measured by high performance liquid chromatography to be 2.35% ± 0.12%, and the encapsulation efficiency was 98.86 ± 0.08%.

[0096] 2. Preparation of Flexible Nanoliposome Gels Loaded with All-trans Retinoic Acid

[0097] Take the prescribed amount of Carbomer 940 and put it into purified water to swell for 24 hours, add glycerol, disodium ethylenediaminetetraacetic acid and ethylparaben aqueous solution, make up the mass of deionized water, add triethanolamine to adjust the pH to 6.5, and obtain blank gel, take the blank gel and mix it with the flexible nanoliposome solution to obtain flexible nanoliposome gel. Ensure that the mass concentration of each substance in the blank gel is: Carbomer 940 is 0.851%, glycerol is 7.657%, disodium ethylenediaminetetraacetic acid and ethylparaben are both 0.077%, and water is 91.339%. The mass of the flexible nanoliposome is calculated based on the theoretical mass of all-trans retinoic acid contained in it, and the mass ratio of all-trans retinoic acid to blank gel in the flexible nanoliposome is 0.051:100, and the calculated incorporated soybean lecithin is 1.702% and Tween-80 is 0.34%.

[0098] Example 10 Preparation of gel containing all-trans retinoic acid

[0099] Take the prescribed amount of Carbomer 940 and put it into purified water to swell for 24 hours, add glycerol, disodium ethylenediaminetetraacetic acid and ethylparaben aqueous solution, make up the mass of deionized water, add triethanolamine to adjust the pH to 6.5, and obtain blank gel. Mix the blank gel with the all-trans retinoic acid solution to obtain gel. Ensure that the mass concentration of each substance in the blank gel is: Carbomer 940 is 0.834%, glycerol is 7.504%, disodium ethylenediaminetetraacetic acid and ethylparaben are both 0.075%, and water is 91.512%. The mass ratio of all-trans retinoic acid to blank gel is 0.05:100.

[0100] Example 11 Application of flexible nanoliposome gel loaded with triphenylphosphine-modified cerium oxide nanoparticles and all-trans retinoic acid in the treatment of psoriasis

[0101] 1. In vitro transdermal permeation study of flexible nanoliposome gel loaded with triphenylphosphine-modified cerium oxide nanoparticles and all-trans retinoic acid

[0102] Preparation Example 1, Example 9, and Example 10. A PBS buffer solution with a pH of 6.8 containing 50% ethanol was used as the receiving medium, and the all-trans retinoic acid gel was used as the control group. The skin retention of the gel within 24 hours was investigated by a TP-6 ​​transdermal diffusion instrument at 37°C and 300 rpm, and the cumulative skin permeation rate and skin retention amount of the drug were used as the investigation indicators. The results of the cumulative skin permeation rate are shown in Figure 3As shown in the figure, the skin permeability of all-trans retinoic acid gel, flexible nanoliposome gel co-loaded with all-trans retinoic acid and triphenylphosphine-modified cerium oxide nanoparticles, and flexible nanoliposome gel loaded with all-trans retinoic acid alone were 0.026±0.004%, 0.056±0.001%, and 0.052±0.011%, respectively. It can be seen that the skin permeability of the flexible nanoliposome gel co-loaded with all-trans retinoic acid and triphenylphosphine-modified cerium oxide nanoparticles was significantly higher than that of the all-trans retinoic acid gel. The results of skin retention are shown in the figure. Figure 4 As shown, the drug skin retention of the flexible nanoliposome gel co-loaded with all-trans retinoic acid and triphenylphosphine-modified cerium oxide nanoparticles was significantly higher than that of the all-trans retinoic acid gel. Compared with the skin retention of the all-trans retinoic acid gel, the drug skin retention of the flexible nanoliposome gel co-loaded with all-trans retinoic acid and triphenylphosphine-modified cerium oxide nanoparticles and the flexible nanoliposome gel loaded with all-trans retinoic acid alone increased by 2.51 times and 1.74 times, respectively.

[0103] 2. Histopathological and immunohistochemical studies of flexible nanoliposome gels loaded with triphenylphosphine-modified cerium oxide nanoparticles and all-trans retinoic acid

[0104] Preparation Example 1, Example 7, Example 8, Example 9, Example 10. 5% imiquimod cream was applied to 2 cm of the back of BALB / c mice. 2 62.5 mg / day for 7 consecutive days can produce psoriasis-like pathological changes in the skin. After 2 days of adaptive feeding, BALB / c mice were randomly divided into 7 groups, including normal control group, model group, flexible nanoliposome gel group co-loaded with all-trans retinoic acid and triphenylphosphine-modified cerium oxide nanoparticles, flexible nanoliposome gel group loaded with all-trans retinoic acid alone, flexible nanoliposome gel group loaded with triphenylphosphine-modified cerium oxide nanoparticles alone, flexible nanoliposome gel group loaded with cerium oxide nanoparticles alone, and gel group loaded with all-trans retinoic acid alone, with 5 mice in each group. The hair on the back of each mouse was removed with 10% sodium sulfide aqueous solution (the depilation area was 2.5cm×2cm), and the picric acid solution (3%) used after depilation was applied to the mice and numbered. The medication was started after 24h of depilation. In addition to the blank gel applied to the mice in the normal control group, 5% imiquimod cream was applied to the 2cm back of the BALB / c mice in each group. 2Skin daily 62.5 mg / day, once a day. The treatment group started from the third day of imiquimod administration with 100 mg / day of medicated gel evenly applied to the skin of the back hair removal modeling area, once a day, and continued until the seventh day of the experiment. The interval between the medicated gel and imiquimod administration was 4 hours. After 7 consecutive days, the animals were immediately killed, and the skin samples of all animals were collected and fixed in 4% paraformaldehyde solution. Paraffin sections were prepared and HE staining was performed. Immunohistochemistry was used to observe the expression of CD3, and the effects of each group of gel on the lesion tissue were evaluated. The phenotype of the mouse back skin tissue and the HE staining results are shown in Figure 2. Figure 5 As shown, compared with the normal group, the model group had obvious skin histopathological characteristics of psoriasis; the epidermal thickness and inflammatory cell infiltration of the flexible nanoliposome gel group co-loaded with all-trans retinoic acid and triphenylphosphine-modified cerium oxide nanoparticles were significantly reduced, and acanthosis was almost unobservable; acanthosis was observed in the flexible nanoliposome gel group loaded with triphenylphosphine-modified cerium oxide nanoparticles and the flexible nanoliposome gel group loaded with cerium oxide nanoparticles alone, but the severity was less than that of the model group. The acanthosis phenomenon was the most obvious in the gel group loaded with all-trans retinoic acid alone, and the thickening of the epidermis did not recover after treatment, which may be related to the irritation of free all-trans retinoic acid. The results of immunohistochemistry experiments showed that compared with the normal group, a large amount of CD3 was expressed in the epidermis and dermis of the model group. After treatment with the flexible nanoliposome gel group co-loaded with all-trans retinoic acid and triphenylphosphine-modified cerium oxide nanoparticles, the expression of CD3 was significantly reduced, almost reaching the normal level. Compared with the flexible nanoliposome gel group co-loaded with all-trans retinoic acid and triphenylphosphine-modified cerium oxide nanoparticles, the expression of other groups was significantly increased. It can be concluded that the flexible nanoliposome gel co-loaded with all-trans retinoic acid and triphenylphosphine-modified cerium oxide nanoparticles has a good efficacy in the mouse psoriasis model.

Claims

1. Use of a liposome gel containing triphenylphosphine-modified cerium oxide and all-trans retinoic acid in the preparation of a drug for treating psoriasis, Features: The liposome gel carrying triphenylphosphine-modified cerium oxide and all-trans retinoic acid is obtained by mixing a blank gel and a flexible liposome dispersion; Based on the blank gel, the blank gel is basically composed of the following components in mass concentration: Carbomer 940 is 0.528% to 0.851%, glycerol is 5.283% to 8.509%, the solvent is water, and the pH is 6-8; The flexible liposome dispersion is prepared as follows: soybean lecithin, Tween 80, all-trans retinoic acid, and triphenylphosphine-modified cerium oxide nanoparticles are uniformly dispersed in anhydrous ethanol, ultrasonically mixed, and rotary evaporated in the dark until a film is completely formed, PBS buffer with a pH of 6.5-7.4 is added for hydration, and the film is completely removed by hand shaking with water bath ultrasound, and probe ultrasound is performed under ice bath conditions to obtain the flexible liposome dispersion; the mass ratio of soybean lecithin to Tween 80 is 1-10:1, and the mass ratio of Tween 80, all-trans retinoic acid, and cerium contained in the triphenylphosphine-modified cerium oxide nanoparticles is 5-40:1-3:1; The mass ratio of cerium contained in the triphenylphosphine-modified cerium oxide nanoparticles to the mass ratio of the blank gel is 0.01-0.06:

100.

2. The use according to claim 1, Features: The liposome gel carrying triphenylphosphine-modified cerium oxide and all-trans retinoic acid also includes auxiliary materials acceptable to human body with a mass concentration of less than 1%.

3. The use according to claim 2, Features: The auxiliary materials are disodium ethylenediaminetetraacetate with a mass concentration of 0.053% to 0.085% and ethyl p-hydroxybenzoate with a mass concentration of 0.053% to 0.085%.

4. The use according to claim 1, Features: The pH of the blank gel was adjusted with a pH adjuster.

5. The use according to claim 4, Features: The pH regulator is triethanolamine.

6. The use according to claim 1, Features: The volume of the anhydrous ethanol is 25 mL / g based on the mass of the soybean lecithin; The volume of the PBS buffer solution is 10 mL / g based on the mass of the soybean lecithin.

7. The use according to claim 1, Features: Based on the blank gel, the blank gel is composed of the following components in mass concentration: 0.528% to 0.851% of carbomer 940, 5.283% to 8.509% of glycerol, 0.053% to 0.085% of disodium ethylenediaminetetraacetate, 0.053% to 0.085% of ethyl p-hydroxybenzoate, and the solvent is water.

8. The use according to claim 1, Features: The mass ratio of the soybean lecithin to Tween 80 is 5:1, and the mass ratio of Tween 80, all-trans retinoic acid and cerium contained in the triphenylphosphine-modified cerium oxide nanoparticles is 20:3:

1.

9. The use according to claim 1, Features: The mass ratio of cerium contained in the triphenylphosphine-modified cerium oxide nanoparticles to the mass ratio of the blank gel is 0.017:100.

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