Madecassoside liposome composition as well as preparation method and application thereof

Abstract

The invention relates to the technical field of madecassoside, and discloses a madecassoside liposome composition as well as a preparation method and application thereof, specifically, based on a molecular design principle, a monoprotonated tertiary amine penetration enhancer and a diprotonated tertiary amine penetration enhancer are synthesized; yolk lecithin, cholesterol, a monoprotonated tertiary amine penetration enhancer or a diprotonated tertiary amine penetration enhancer and madecassoside are used as raw materials, the madecassoside lipidosome composition is prepared through a film dispersion method, and the transdermal rate of the lipidosome composition after 48 hours is gt; according to the present invention, the prepared hydrogel has excellent transdermal performance, excellent encapsulation performance and excellent drug loading performance, and can be used for preparing a gel preparation for treating skin injury.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of hydroxyl asiaticoside, in particular to a hydroxyl asiaticoside liposome composition, a preparation method and an application. BACKGROUND

[0002] Hydroxyl asiaticoside has multiple pharmacological effects such as scar repair, antioxidant, antibacterial, anti-inflammatory, anti-ulcer and promotion of fibroblast regeneration, and is often used in clinical treatment of skin trauma diseases such as surgical trauma, scald and burn. However, hydroxyl asiaticoside is a triterpenoid saponin with a large molecular weight (about 1000 Da), and the permeability of the stratum corneum of the skin to molecules larger than 500 Da is significantly reduced. In addition, as a glycoside, hydroxyl asiaticoside contains multiple hydrophilic sugar groups and hydroxyl groups, resulting in strong water solubility and poor lipid solubility. The stratum corneum of the skin is a strong lipophilic barrier, and hydrophilic molecules are difficult to partition and diffuse through this lipid area. Therefore, without the aid of external force, most of the hydroxyl asiaticoside applied to the skin may only stay on the surface of the skin, and cannot reach the target layer to fully exert the effects of repair, anti-inflammatory and stimulation of collagen production.

[0003] Research has found that penetration enhancers can improve barrier permeability by temporarily changing the lipid arrangement of the stratum corneum or enhancing the fluidity of the cell membrane, thereby enhancing the solubility of liposomes in the skin and accelerating the diffusion and absorption of drugs. SUMMARY

[0004] Due to the limitations of physicochemical properties (large molecular weight and poor lipid solubility), hydroxyl asiaticoside has weak transdermal ability. To solve this problem, the present application develops an external use penetration enhancer for improving the transdermal performance of hydroxyl asiaticoside. The penetration enhancer can achieve efficient and persistent penetration promotion through multiple synergistic mechanisms.

[0005] The hydroxyl asiaticoside liposome composition comprises the following raw materials by weight: 7-9 parts of a phospholipid base; 0.5-1.5 parts of a flowability regulator; 0.5-1.5 parts of a monoprotonated tertiary amine type penetration enhancer or a diprotonated tertiary amine type penetration enhancer; 1-2 parts of hydroxyl asiaticoside; Preferably, the phospholipid base is egg yolk lecithin or soybean lecithin.

[0006] Preferably, the flowability regulator is one of cholesterol, beta-sitosterol and stigmasterol.

[0007] Preferably, the average particle size of the hydroxyl asiaticoside liposome composition is 250-260 nm, the drug loading capacity is 8.0-9.0%, and the transdermal rate after 48 h is >90%.

[0008] The preparation method of the madecassoside liposome composition is as follows: the madecassoside liposome composition is prepared by using a thin film dispersion method, first, a phospholipid base, a flowability regulator, and a monoprotonated tertiary amine type penetration enhancer or a diprotonated tertiary amine type penetration enhancer are dissolved in chloroform to form a lipid solution in a formula amount, the chloroform is removed by rotary evaporation, and a phospholipid film is formed after drying; the madecassoside PBS buffer solution in a formula amount is added to the phospholipid film, and the phospholipid film is dispersed by ultrasonic oscillation under ice water bath, and then filtered by a microporous filter to obtain the madecassoside liposome composition. Preferably, the pH of the madecassoside PBS buffer solution is 7, and the concentration is 45-55 mg / mL.

[0009] Preferably, the preparation method of the monoprotonated tertiary amine type penetration enhancer is as follows: Under the action of a platinum catalyst, an addition reaction occurs between 1 mole equivalent of Si-H functional groups of heptaphenyl monohydrogen POSS and 1.01-1.09 mole equivalents of alkenyl functional groups of dimethylaminoethyl methacrylate to generate an intermediate I; Under the action of a Lewis acid catalyst, a Friedel-Crafts alkylation reaction occurs between 1 mole equivalent of phenyl functional groups of the intermediate I and 7.01-7.09 mole equivalents of alkenyl functional groups of 1-dodecene to generate the monoprotonated tertiary amine type penetration enhancer.

[0010] Preferably, the preparation method of the diprotonated tertiary amine type penetration enhancer is as follows: An amine-alkene addition reaction occurs between 1 mole equivalent of amino functional groups of heptaphenyl monamino propyl POSS and 2.01-2.09 mole equivalents of α,β-alkenyl functional groups of dimethylaminoethyl methacrylate to generate an intermediate II; Under the action of a Lewis acid catalyst, a Friedel-Crafts alkylation reaction occurs between 1 mole equivalent of phenyl functional groups of the intermediate II and 7.01-7.09 mole equivalents of alkenyl functional groups of 1-dodecene to generate the diprotonated tertiary amine type penetration enhancer.

[0011] Preferably, the Lewis acid catalyst is one of aluminum trichloride, iron trichloride, tin tetrachloride, and zinc dichloride.

[0012] The madecassoside liposome composition is used for preparing a preparation for treating skin damage. Preferably, the application method of the madecassoside liposome composition is as follows: 1-5 parts by weight of carbomer 940 is dispersed in 50-150 parts by weight of water at high speed to prepare a carbomer 940 solution, then 0.5-1.0 parts by weight of triethanolamine is added under slow stirring, the pH is adjusted to 6-7, and a gel base is obtained. 3-10 parts by weight of the gel base, 0.3-1 parts by weight of the Madecassoside liposome composition and 0.05-0.2 parts by weight of glycerol are uniformly mixed to obtain a gel preparation containing the Madecassoside liposome composition.

[0013] Preferably, the application method of the gel preparation is as follows: the gel preparation containing the Madecassoside liposome composition is applied to the skin damage site, 1-2 times per day, and the amount of each application is 0.1-0.3 g / cm 2 , continuously for 10-13 days, which plays a role in treating skin damage.

[0014] Advantages: The application is based on the principle of molecular design, and two new penetration enhancers (monoprotonated tertiary amine type and diprotonated tertiary amine type) are synthesized. The penetration enhancer combines the rigid nano effect of POSS, the lipid disturbance ability of long-chain alkyl and the bioadhesion of the protonatable tertiary amine group at physiological pH. The penetration mechanism is as follows: the rigid nano effect of POSS can open the keratin layer lipid like a molecular wedge, opening a channel for Madecassoside molecules; the long-chain alkyl group helps to dissolve and disturb the order of the lipid, increasing its fluidity; and the protonatable tertiary amine group can enhance the adsorption with the negatively charged skin surface by protonation under the weakly acidic environment of the skin. In vitro transdermal experiments show that the penetration effect of the two enhancers on Madecassoside is significantly better than that of the traditional single-mechanism enhancer (laurocapram), showing excellent synergistic effect. DETAILED DESCRIPTION Example 1:

[0015] The monoprotonated tertiary amine type penetration enhancer is prepared as follows: Process 1: Trihydrosilane heptaphenyl POSS (CAS No. 444315-26-8) is used as the raw material, and trichlorosilane is used as the capping reagent. A heptaphenyl monohydrogen POSS is synthesized by the top corner-capping method, and the chemical structural formula is as follows: ; Process 2: Under the action of a platinum catalyst, an addition reaction occurs between 1 mole equivalent of the Si-H functional group of heptaphenyl monohydrogen POSS and 1.06 mole equivalents of the alkenyl functional group of dimethylaminoethyl methacrylate to generate an intermediate I, and the chemical structural formula is as follows: ; Process 3: Under the action of a Lewis acid catalyst, a Friedel-Crafts alkylation reaction occurs between 1 mole equivalent of the phenyl functional group of the intermediate I and 7.05 mole equivalents of the alkenyl functional group of 1-dodecene to generate a monoprotonated tertiary amine type penetration enhancer, and the chemical structural formula is as follows: ; wherein the Lewis acid catalyst can be selected from one of aluminum trichloride, iron trichloride, tin tetrachloride, zinc dichloride; and the embodiment selects to use aluminum trichloride; The specific experimental steps for preparing the monoprotonated tertiary amine type penetration promoter are as follows: Under the protection of nitrogen, 9.3 g of trisilanol heptaphenyl POSS and 90 mL of anhydrous tetrahydrofuran were added to a three-necked flask, stirred at room temperature until completely dissolved, then placed in an ice water bath, 1.5 mL of triethylamine and 10 mL of anhydrous tetrahydrofuran solution dissolved with 1.4 g of trichlorosilane were added dropwise to the three-necked flask, stirred in the ice water bath for 1 h, then the ice water bath was removed, and the reaction was continued to stir at room temperature for 8 h. The solvent was removed by rotary evaporation, concentrated to a saturated solution, treated with acetonitrile for sedimentation, filtered, and dried to obtain heptaphenyl monohydrogen POSS; Under the protection of nitrogen, 9.3 g of trisilanol heptaphenyl POSS and 90 mL of anhydrous tetrahydrofuran were added to a three-necked flask, stirred at room temperature until completely dissolved, then placed in an ice water bath, 1.5 mL of triethylamine and 10 mL of anhydrous tetrahydrofuran solution dissolved with 1.4 g of trichlorosilane were added dropwise to the three-necked flask, stirred in the ice water bath for 1 h, then the ice water bath was removed, and the reaction was continued to stir at room temperature for 8 h. The solvent was removed by rotary evaporation, concentrated to a saturated solution, treated with acetonitrile for sedimentation, filtered, and dried to obtain heptaphenyl monohydrogen POSS; Under the protection of nitrogen, 9.3 g of trisilanol heptaphenyl POSS and 90 mL of anhydrous tetrahydrofuran were added to a three-necked flask, stirred at room temperature until completely dissolved, then placed in an ice water bath, 1.5 mL of triethylamine and 10 mL of anhydrous tetrahydrofuran solution dissolved with 1.4 g of trichlorosilane were added dropwise to the three-necked flask, stirred in the ice water bath for 1 h, then the ice water bath was removed, and the reaction was continued to stir at room temperature for 8 h. The solvent was removed by rotary evaporation, concentrated to a saturated solution, treated with acetonitrile for sedimentation, filtered, and dried to obtain heptaphenyl monohydrogen POSS; The proton nuclear magnetic resonance spectrum of the monoprotonated tertiary amine type penetration promoter is as follows: 1 H NMR (CDCI3, 400 MHz) δ: 0.86-0.90 (t, 21H), 1.14-1.16 (d, 3H), 1.23-1.36 (m, 126H), 1.55-1.69 (m, 14H), 1.86-1.88 (d, 2H), 2.38-2.47 (m, 1H), 2.54-2.75 (m, 14H), 2.83 (s, 6H), 3.38-3.41 (t, 2H), 4.23-4.26 (t, 2H), 7.12-7.34 (m, 28H). Example Two:

[0016] The preparation process of the monoprotonated tertiary amine type penetration promoter is as follows: Process one: using trisilanol heptaphenyl POSS (CAS No. 444315-26-8) as raw material, using 3-aminopropyl triethoxysilane as capping reagent, heptaphenyl mono-aminopropyl POSS is synthesized by corner-capping method, and the chemical structural formula is as follows: ; Process two: through the amine-ene addition reaction between the amino functional group of 1 mole equivalent of heptaphenyl mono-aminopropyl POSS and the α, β-alkenyl functional group of 2.03 mole equivalents of dimethylaminoethyl methacrylate, an intermediate II is generated, and the chemical structural formula is as follows: ; Process three: under the action of Lewis acid catalyst, through the Friedel-Crafts alkylation reaction between the phenyl functional group of 1 mole equivalent of intermediate II and the alkenyl functional group of 7.05 mole equivalents of 1-dodecene, a double-protonated tertiary amine type penetration enhancer is generated, and the chemical structural formula is as follows: ; Among them, the Lewis acid catalyst can be selected from one of aluminum chloride, iron trichloride, tin tetrachloride and zinc dichloride; in this embodiment, aluminum chloride is selected; The specific experimental steps for preparing the double-protonated tertiary amine type penetration enhancer are as follows: Under the action of nitrogen protection, 9.3g of trisilanol heptaphenyl POSS and 90mL of anhydrous tetrahydrofuran are added to a three-necked flask, stirred at room temperature until completely dissolved, then placed in an ice water bath, 10mL of anhydrous tetrahydrofuran solution containing 2.2g of 3-aminopropyl triethoxysilane is added dropwise into the three-necked flask, stirred in the ice water bath for 1h, then remove the ice water bath, continue to stir at room temperature for 12h, remove the solvent by rotary evaporation, concentrate to saturation solution, use acetonitrile for sedimentation treatment, filter, and dry to obtain heptaphenyl mono-aminopropyl POSS; Under the action of nitrogen protection, 5.1g of heptaphenyl mono-aminopropyl POSS and 50mL of anhydrous tetrahydrofuran are added to a three-necked flask, stirred at room temperature until completely dissolved, then 10mL of anhydrous tetrahydrofuran solution containing 1.7g of dimethylaminoethyl methacrylate is added dropwise into the three-necked flask, heated to 70℃ and stirred to reflux for 8h, cooled to room temperature, removed the solvent by rotary evaporation, and dried to obtain intermediate II; 4.4g of intermediate II, 4.0g of 1-dodecene, 2.1g of anhydrous aluminum trichloride and 90mL of 1,2-dichloroethane are added to a three-necked flask, stirred and dissolved at room temperature for 30min, heated to 85℃ and stirred to reflux for 24h, cooled to room temperature, removed the solvent by rotary evaporation, washed with deionized water, and dried to obtain the double-protonated tertiary amine type penetration enhancer; The proton nuclear magnetic resonance spectrum of the double-protonated tertiary amine type penetration enhancer is as follows: 1H NMR (CDC13, 400 MHz) δ: 0.71-0.75 (t, 2H), 0.86-0.90 (t, 21H), 1.12-1.14 (d, 6H), 1.23-1.42 (m, 126H), 1.54-1.78 (m, 14H), 1.90-1.97 (m, 2H), 2.35-2.44 (m, 2H), 2.48-2.51 (t, 2H), 2.56-2.74 (m, 14H), 2.84 (s, 12H), 3.05-3.07 (d, 4H), 3.40-3.43 (t, 4H), 4.19-4.23 (t, 4H), 7.13-7.34 (m, 28H). Example Three:

[0017] A hydroxyl asiatic acid glycoside liposome composition I includes the following raw materials in parts by weight: 8 parts of egg yolk lecithin (liposome skeleton matrix); 1 part of cholesterol (flowability regulator); 1 part of monoprotonated tertiary amine type penetration enhancer (functional additive); 1.5 parts of hydroxyl asiatic acid glycoside (active ingredient, CAS No. 34540-22-2). Example Four:

[0018] A preparation method of a hydroxyl asiatic acid glycoside liposome composition I includes the following steps: Step one: dissolve hydroxyl asiatic acid glycoside in PBS buffer solution (pH = 7) to prepare a hydroxyl asiatic acid glycoside PBS buffer solution with a concentration of 50 mg / mL; Step two: prepare the hydroxyl asiatic acid glycoside liposome composition I by using the film dispersion method, add 8 g of egg yolk lecithin, 1 g of cholesterol, 1 g of monoprotonated tertiary amine type penetration enhancer and 50 mL of chloroform into a reaction bottle, stir and dissolve at room temperature for 30 min to form a lipid solution, then remove the chloroform by rotary evaporation under the condition of 30°C and 100 r / min, dry under vacuum at 40°C for 3 h to form a phospholipid film, add 30 mL of the hydroxyl asiatic acid glycoside PBS buffer solution prepared in step one (control the addition amount of hydroxyl asiatic acid glycoside to be 1.5 g) to the phospholipid film, place it in an ice water bath and ultrasonically oscillate and disperse for 10 min, filter by using a microporous filter membrane with a pore size of 0.45 μm to obtain the hydroxyl asiatic acid glycoside liposome composition I. Example Five:

[0019] A hydroxyl asiatic acid glycoside liposome composition II includes the following raw materials in parts by weight: 8 parts of egg yolk lecithin; 1 part of cholesterol; 1 part of diprotonated tertiary amine type penetration enhancer; 1.5 parts of madecassoside; The preparation method of the madecassoside liposome composition II is the same as that of the madecassoside liposome composition I. Example Six:

[0020] An application method of the madecassoside liposome composition, comprising the following steps: Step one: 2g of carbomer 940 is dispersed in 100mL of water at high speed, mixed uniformly to prepare a carbomer 940 solution, then 10mL of an aqueous solution dissolving 0.8g of triethanolamine is added dropwise under slow stirring, and the addition is stopped after the pH is adjusted to 6.5 to obtain a gel matrix; Step two: 5g of the gel matrix and 0.5g of the madecassoside liposome composition are mixed uniformly, and then 0.1g of glycerol is added, and the gel preparation containing the madecassoside liposome composition is obtained after stirring uniformly; Step three: the gel preparation containing the madecassoside liposome composition is applied to the skin scar or injury site, 0.2g / cm 2 of the madecassoside liposome composition is applied once a day, and the treatment is continuously performed for 12 days; The madecassoside liposome composition can be selected from the madecassoside liposome composition I or the madecassoside liposome composition II, and the madecassoside liposome composition I is selected for application experiment in this embodiment, and the gel preparation containing the madecassoside liposome composition I is prepared. Performance test:

[0021] I. The Nano ZS Malvern particle size analyzer is used to test the average particle size and particle size distribution of the madecassoside liposome composition; II. The encapsulation performance and drug loading performance test of the madecassoside liposome composition: the standard curve equation is drawn to characterize the encapsulation capacity and drug loading capacity of the madecassoside liposome composition, and the specific test steps are as follows: (1) Madecassoside is dissolved in distilled water to prepare a madecassoside aqueous solution with a concentration of 1mg / mL, and the madecassoside aqueous solution is scanned by a UV-visible spectrophotometer at full wavelength, and the maximum absorption wavelength λmax is recorded as 205nm; (2) 0.05 g of madecassoside was added into a 100 mL volumetric flask, and distilled water was added to constant volume to prepare a madecassoside stock solution. 0.1 mL, 0.5 mL, 1 mL, 2 mL and 4 mL of the stock solution were respectively taken into 10 mL volumetric flasks, and distilled water was added to constant volume, and then shaken to prepare madecassoside standard solutions with concentrations of 5 µg / mL, 25 µg / mL, 50 µg / mL, 100 µg / mL and 200 µg / mL. The five standard solutions were quantitatively analyzed by using an Agilent 1260 high performance liquid chromatograph, the peak area of the standard solution was determined, and the standard curve of madecassoside was drawn by taking the concentration as the abscissa and the peak area as the ordinate for linear regression analysis; The chromatographic conditions and parameters are as follows: A Neptune C18 chromatographic column (200 mm x 4.6 mm, 5 µm) was used; The column temperature was 30°C; The detection wavelength was 205 nm; The column flow rate was 1 mL / min; The injection volume was set to 20 µL; Acetonitrile was used as mobile phase A, and water was used as mobile phase B, and the volume ratio of acetonitrile to water was 26:74; (3) The dialysis method was used to test the encapsulation efficiency and drug loading of the madecassoside liposome composition. 1 mL of the madecassoside liposome composition was transferred into a dialysis bag, which was sealed on both sides and placed in 20 mL of PBS buffer (pH = 7) at room temperature and in the dark. The dialysis was stirred at a speed of 300 r / min until equilibrium was reached. The concentration (C1) of madecassoside in the dialysate was detected by using an Agilent 1260 high performance liquid chromatograph, and the encapsulation efficiency and drug loading were calculated. The specific calculation method is as follows: Encapsulation efficiency (%) = (1 - m1 / m0) x 100%; Drug loading (%) = {(m0-m1) / m} x 100% = {(m0-m1) / (m0-m1+m2)} x 100% Wherein, m1 is the mass of free madecassoside in the dialysate after dialysis, in mg, at this time m1 = C1 x V, V is the volume of PBS buffer 20 mL; m0 is the total mass of madecassoside before dialysis, in mg, at this time m0 = 1 mL x 50 mg / mL = 50 mg; m is the sum of the mass of madecassoside encapsulated in the liposome composition and the mass of the membrane material, in mg, at this time m = (m0-m1) + m2; m2 is the mass of the membrane material, in mg, at this time m2 = {(8 g + 1 g + 1 g) / 30 mL} x 1 mL = 333 mg; III. The transdermal performance of the madecassoside liposome composition is tested, and the specific test steps are as follows: (1) Treatment of the skin: 250 g of SD rats are mechanically shaved on the back, and then the remaining fur is removed with an 8 wt% aqueous sodium sulfide solution. After 24 h, the rats are sacrificed, and the back skin is taken and carefully removed from the subcutaneous fat. The skin is washed three times with normal saline and the surface moisture is absorbed. The skin is stored in a -10°C refrigerator for later use; (2) Transdermal test: Franz transdermal apparatus is used for in vitro transdermal experiment of rats, and the specific operation process is as follows: Process one: the rat skin is taken out from the refrigerator, thawed in normal saline at room temperature, and then clamped between the receiving pool (located below, with a volume of 6.5 mL) and the diffusion pool (located above, with a volume of 6.5 mL), with the horny layer facing up. The receiving pool is filled with normal saline, and the air bubbles under the skin are discharged; Process two: 1 mL of madecassoside liposome composition is evenly applied to the rat skin, and the diffusion pool is sealed with plastic wrap. The receiving pool is placed in a magnetic stirrer, and the temperature is controlled at 37°C with constant stirring at 200 r / min; Process three: at 1 h, 4 h, 12 h, 24 h, and 48 h, 0.5 mL of sample is taken from the receiving pool, and the volume is adjusted to 1 mL with 10 wt% triton solution (which can destroy the liposomes that may have penetrated, release the madecassoside wrapped therein, and accurately measure the concentration). The sample is filtered through a microporous filter with a pore size of 0.45 μm, and 0.5 mL of normal saline is added to the receiving pool; Process four: the concentration of madecassoside in the receiving pool is detected by Agilent 1260 high performance liquid chromatograph, and the transdermal rate of the madecassoside liposome composition is calculated, and the specific calculation method is as follows: 1h transdermal rate (%) = (C 1h × V0) / M × 100%; 4h transdermal rate (%) = {(C 4h × V0) + (C 1h × V)} / M × 100%; 12h transdermal rate (%) = {(C 12h × V0) + (C 1h × V) + (C 4h × V)} / M × 100%; 24h transdermal rate (%) = {(C 24h × V0) + (C 1h × V) + (C 4h × V) + (C 12h × V)} / M × 100%; 48h transdermal rate (%) = {(C 48h×V0) + (C 1h ×V) + (C 4h ×V) + (C 12h ×V) + (C 24h ×V)} / M×100%; Wherein, C 1h , C 4h , C 12h , C 24h , C 48h are the concentrations of hydroxyl asiaticoside in the receiving pool at 1h, 4h, 12h, 24h, 48h, respectively, in mg / mL; V0 is the total volume of the receiving pool, in mL, at this time V0 = 6.5mL; V is the sampling volume of the receiving pool, in mL, at this time V = 0.5mL; M is the mass of hydroxyl asiaticoside in the hydroxyl asiaticoside liposome composition, in mg, at this time M = 1mL × 50mg / mL = 50mg; The above test results are shown in Tables 1-2 as follows: Table 1 Performance test results of hydroxyl asiaticoside liposome composition I

[0022] Table 2 Performance test results of hydroxyl asiaticoside liposome composition II

[0023] Note: The difference between the comparative examples in Tables 1 and 2 and the hydroxyl asiaticoside liposome composition I is that the formulation is: 8 parts by weight of egg yolk lecithin, 1 part by weight of cholesterol, 1 part by weight of laurocapram and 1.5 parts by weight of hydroxyl asiaticoside (i.e. using a traditional single mechanism penetration enhancer (laurocapram) to replace a single protonated tertiary amine type penetration enhancer); Through comprehensive analysis of the above experimental results, the following conclusions can be drawn: (1) The hydroxyl asiaticoside liposome composition prepared by using the self-developed penetration enhancer has a significant improvement in transdermal performance compared with the hydroxyl asiaticoside liposome composition using a traditional single mechanism penetration enhancer (laurocapram); (2) The hydroxyl asiaticoside liposome composition prepared by the present application also exhibits excellent encapsulation and drug loading performance, and has excellent comprehensive performance and practical application value.

[0024] Four, the application effect test of the gel preparation containing the hydroxyl asiaticoside liposome composition I is carried out, and the specific test steps are as follows: (1) Establishing a secondary scald model of rats, taking 250g of SD rats, after anesthesia, mechanically shaving the back of the rats, then removing the remaining rat hair with 8wt% sodium sulfide aqueous solution, placing a screw with a diameter of 14mm in 100℃ boiling water for 1min, and placing it on the back of the rat for 20s to form a secondary scald wound and obvious blisters; (2) The scalded wound is bandaged with sterile gauze for two days, and after scabbing, the gel preparation containing hydroxyl asiaticoside liposome composition I is applied on the wound, once a day, the amount of drug is 0.2g / cm 2 , continuously for 12 days, the diameter change of the scalded wound is measured every 3 days according to the cross-over method, and the efficacy index of wound healing is calculated, the specific calculation method is as follows: Efficacy index (%)=(1-D i / D0)×100%; Wherein, D i is the diameter of the scalded wound on the 3rd, 6th, 9th and 12th day, unit: mm; D0 is the diameter of the scalded wound before drug administration, unit: mm, at this time D0=14mm; The efficacy index is an important indicator for evaluating wound healing: When the efficacy index is <30%, it is considered that the wound healing effect is poor; When 30%≤the efficacy index<70%, it is considered that the wound healing effect is moderate; When 70%≤the efficacy index<100%, it is considered that the wound healing effect is obvious; When the efficacy index=100%, it is considered that the wound is completely healed; The above test results are shown in Table 3 as follows: Table 3 Application test results of hydroxyl asiaticoside liposome composition

[0025] Through analyzing the experimental results of Table 3, the following conclusions can be drawn: The gel preparation prepared by using hydroxyl asiaticoside liposome composition I has an efficacy index of 99.5% after 12 days of use, which is close to complete cure, and has a significant effect on treating skin damage.

Claims

1. A liposomal composition of madecassoside, characterized in that, The raw materials include the following by weight: 7-9 parts of phospholipid base; 0.5-1.5 parts of flowability regulator; 0.5-1.5 parts of monoprotonated tertiary amine type penetration enhancer or diprotonated tertiary amine type penetration enhancer; 1-2 parts of hydroxyl asiaticoside; The chemical structural formula of the monoprotonated tertiary amine type penetration enhancer is: ； The chemical structural formula of the diprotonated tertiary amine type penetration enhancer is: 。 2. The liposomal hydroxyethyl rhein composition according to claim 1, characterized in that, The phospholipid base is egg yolk lecithin or soybean lecithin.

3. The liposomal hydroxyethyl rhein composition according to claim 1, characterized in that, The flowability regulator is one of cholesterols, beta-sitosterol and stigmasterol.

4. The liposomal hydroxyethyl rhein composition of claim 1, wherein, The average particle size of the hydroxyl asiaticoside liposome composition is 250-260 nm, the drug loading is 8.0-9.0%, and the transdermal rate after 48 h is > 90%.

5. The process for the preparation of liposomal Madecassoside composition as claimed in any one of claims 1 to 4, wherein, Specifically, the hydroxyl asiaticoside liposome composition is prepared by using a thin film dispersion method. First, the formula amount of phospholipid base, flowability regulator and monoprotonated tertiary amine type penetration enhancer or diprotonated tertiary amine type penetration enhancer are dissolved in chloroform to form a lipid solution, and the chloroform is removed by rotary evaporation. After drying, a phospholipid film is formed. The formula amount of hydroxyl asiaticoside PBS buffer solution is added to the phospholipid film, and the mixture is dispersed by ultrasonic oscillation under ice water bath. The mixture is filtered by a microporous filter to obtain the hydroxyl asiaticoside liposome composition. The pH of the hydroxyl asiaticoside PBS buffer solution is 7, and the concentration is 45-55 mg / mL.

6. The process for preparing the liposomal hydroxyethyl rheoside composition according to claim 5, wherein, The preparation method of the monoprotonated tertiary amine type penetration enhancer is as follows: Under the action of a platinum catalyst, addition reaction occurs between 1 mole equivalent of Si-H functional groups of heptaphenyl monohydrogen POSS and 1.01-1.09 mole equivalents of alkenyl functional groups of dimethylaminoethyl methacrylate to generate intermediate I; Under the action of a Lewis acid catalyst, Friedel-Crafts alkylation reaction occurs between 1 mole equivalent of phenyl functional groups of intermediate I and 7.01-7.09 mole equivalents of alkenyl functional groups of 1-dodecene to generate the monoprotonated tertiary amine type penetration enhancer.

7. The process for preparing the liposomal hydroxyethyl rheoside composition as claimed in claim 5, wherein, The preparation method of the diprotonated tertiary amine type penetration enhancer is as follows: Amine-alkene addition reaction occurs between 1 mole equivalent of amino functional groups of heptaphenyl monohydrogen POSS and 2.01-2.09 mole equivalents of alpha, beta-alkenyl functional groups of dimethylaminoethyl methacrylate to generate intermediate II; Under the action of a Lewis acid catalyst, Friedel-Crafts alkylation reaction occurs between 1 mole equivalent of phenyl functional groups of intermediate II and 7.01-7.09 mole equivalents of alkenyl functional groups of 1-dodecene to generate the diprotonated tertiary amine type penetration enhancer.

8. The process for preparing the liposomal hydroxyethylpiperazineethanesulfonic acid (HEPES) composition according to claim 6 or 7, characterized in that, The Lewis acid catalyst is one of aluminum trichloride, iron trichloride, tin tetrachloride and zinc dichloride.

9. Use of the liposomal composition of madecassoside according to any one of claims 1 to 4, characterized in that, The application method of the hydroxyl asiaticoside liposome composition is as follows: 1-5 parts by weight of carbomer 940 is dispersed in 50-150 parts by weight of water at high speed to prepare a carbomer 940 solution. Then, 0.5-1.0 parts by weight of triethanolamine is added under slow stirring, and the pH is adjusted to 6-7 to obtain a gel matrix. The application method of the hydroxyl asiaticoside liposome composition is as follows: 1-5 parts by weight of carbomer 940 is dispersed in 50-150 parts by weight of water at high speed to prepare a carbomer 940 solution. Then, 0.5-1.0 parts by weight of triethanolamine is added under slow stirring, and the pH is adjusted to 6-7 to obtain a gel matrix. 3-10 parts by weight of the gel base, 0.3-1 parts by weight of the madecassoside liposome composition, and 0.05-0.2 parts by weight of glycerin are uniformly mixed to obtain a gel preparation containing the madecassoside liposome composition.

10. The use of the liposomal hydroxyethyl rheosille composition according to claim 9, characterized in that, The application method of the gel preparation is as follows: apply the gel preparation containing the hydroxyascorbic acid liposome composition to the skin lesion site, 1-2 times a day, with each application amount being 0.1-0.3 g / cm³. 2 Continuous use for 10-13 days can treat skin damage.

Images