Hydroxyasia glycoside liposome composition, preparation method and application

Abstract

This invention relates to the field of asiaticoside technology, and discloses asiaticoside liposome compositions, preparation methods, and applications. Specifically, based on molecular design principles, monoprotonated tertiary amine permeation enhancers and diprotonated tertiary amine permeation enhancers are synthesized. Using egg yolk lecithin, cholesterol, monoprotonated or diprotonated tertiary amine permeation enhancers, and asiaticoside as raw materials, asiaticoside liposome compositions are prepared by thin-film dispersion. The liposome composition exhibits a transdermal permeability of >90% after 48 hours, demonstrating excellent transdermal performance, and also possesses excellent encapsulation and drug loading properties, making it suitable for preparing gel formulations for treating skin lesions.

Description

Technical Field

[0001] This invention relates to the field of asiaticoside technology, specifically to asiaticoside liposome compositions, preparation methods, and applications. Background Technology

[0002] asiaticoside possesses various pharmacological effects, including scar repair, antioxidation, antibacterial, anti-inflammatory, anti-ulcer, and fibroblast regeneration promotion. Clinically, it is often used to treat surgical wounds, burns, and other skin traumas. However, asiaticoside is a triterpenoid saponin with a relatively large molecular weight (approximately 1000 Da). The permeability of the stratum corneum to molecules larger than 500 Da is significantly reduced. Furthermore, as a glycoside, asiaticoside contains multiple hydrophilic sugar and hydroxyl groups, resulting in strong water solubility and poor lipid solubility. The stratum corneum of the skin is a strongly lipophilic barrier, making it difficult for hydrophilic molecules to distribute and diffuse through this lipid region. Therefore, without external assistance, most of the asiaticoside applied to the skin may only remain on the outermost layer, failing to reach its target layer to fully exert its repair, anti-inflammatory, and collagen-stimulating effects.

[0003] Studies have found that penetration enhancers can improve barrier permeability by temporarily altering the lipid arrangement of the stratum corneum or enhancing cell membrane fluidity, thereby increasing the solubility of liposomes in the skin and accelerating drug diffusion and absorption. Summary of the Invention

[0004] Due to its limited physicochemical properties (large molecular weight and poor lipid solubility), asiaticoside has weak transdermal permeability. To address this issue, this invention has developed a topical penetration enhancer that can improve the transdermal performance of asiaticoside. This penetration enhancer achieves a strong and long-lasting penetration-enhancing effect through multiple synergistic mechanisms.

[0005] A hydroxyascorbic acid liposome composition comprising the following raw materials in parts by weight:

[0006] 7-9 parts phospholipid matrix;

[0007] 0.5-1.5 parts flowability modifier;

[0008] 0.5-1.5 parts of monoprotonated tertiary amine type permeation enhancer or diprotonated tertiary amine type permeation enhancer;

[0009] 1-2 parts of asiaticoside;

[0010] Preferably, the phospholipid matrix is ​​egg yolk lecithin or soybean lecithin.

[0011] Preferably, the flow modifier is one of cholesterol, β-sitosterol, and stigmasterol.

[0012] Preferably, the hydroxyasiaticoside liposome composition has an average particle size of 250-260 nm, a drug loading of 8.0-9.0%, and a transdermal transdermal rate of >90% after 48 h.

[0013] The preparation method of the asiaticoside liposome composition is as follows: The asiaticoside liposome composition is prepared by thin film dispersion method. First, the prescribed amount of phospholipid matrix, flow regulator and monoprotonated tertiary amine type permeation enhancer or diprotonated tertiary amine type permeation enhancer are dissolved in chloroform to form a lipid solution. The chloroform is removed by rotary evaporation. After drying, a phospholipid film is formed. The prescribed amount of asiaticoside PBS buffer solution is added to the phospholipid film. The mixture is dispersed by ultrasonic oscillation under ice water bath. The mixture is then filtered through a microporous membrane to obtain the asiaticoside liposome composition.

[0014] The hydroxyasiaticoside PBS buffer solution has a pH of 7 and a concentration of 45-55 mg / mL.

[0015] Preferably, the preparation method of the single-protonated tertiary amine type permeation enhancer is as follows:

[0016] Under the action of a platinum catalyst, intermediate I is generated by the addition reaction between the Si-H functional group of 1 molar equivalent of heptaphenyl-1 hydrogen POSS and the alkenyl functional group of 1.01-1.09 molar equivalent of dimethylaminoethyl methacrylate.

[0017] Under the action of Lewis acid catalyst, a Friedel-Crafts alkylation reaction is carried out between the phenyl functional group of 1 molar equivalent intermediate I and the alkenyl functional group of 7.01-7.09 molar equivalent 1-dodecene to generate a monoprotonated tertiary amine type permeation enhancer.

[0018] Preferably, the preparation method of the diprotonated tertiary amine type permeation enhancer is as follows:

[0019] Intermediate II is generated by an amino-enyl addition reaction between the amino functional group of 1 molar equivalent of heptaphenylmonopropyl POSS and the α,β-alkenyl functional group of 2.01-2.09 molar equivalents of dimethylaminoethyl methacrylate.

[0020] Under the action of Lewis acid catalyst, a Friedel-Crafts alkylation reaction is carried out between the phenyl functional group of 1 molar equivalent intermediate II and the alkenyl functional group of 7.01-7.09 molar equivalent 1-dodecene to generate a diprotonated tertiary amine type permeation enhancer.

[0021] Preferably, the Lewis acid catalyst is one of aluminum trichloride, ferric trichloride, tin tetrachloride, and zinc dichloride.

[0022] Application of hydroxyascorbic acid liposome composition in the preparation of formulations for treating skin lesions;

[0023] Preferably, the method of applying the hydroxyascorbic acid liposome composition is as follows:

[0024] Carbomer 940 solution was prepared by high-speed shear dispersion of 1-5 parts by weight in 50-150 parts by weight of water. Then, 0.5-1.0 parts by weight of triethanolamine was added under slow stirring to adjust the pH to 6-7, thus obtaining the gel matrix.

[0025] Mix 3-10 parts by weight of gel matrix, 0.3-1 parts by weight of asiaticoside liposome composition and 0.05-0.2 parts by weight of glycerol evenly to obtain a gel formulation containing asiaticoside liposome composition.

[0026] Preferably, 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.

[0027] Beneficial effects:

[0028] Based on molecular design principles, this invention synthesizes two novel penetration enhancers (monoprotonated tertiary amine type and diprotonated tertiary amine type). These penetration enhancers combine the rigid nano-effect of POSS, the lipid perturbation ability of long-chain alkyl groups, and the bioadhesiveness of protonable tertiary amine groups at physiological pH. The penetration-enhancing mechanism is as follows: the rigid nano-effect of POSS can open up the lipids of the stratum corneum like a molecular wedge, creating a channel for asiaticoside molecules; the long-chain alkyl groups help dissolve and disrupt the lipid order, increasing their fluidity; and the protonable tertiary amine groups, after protonation in the weakly acidic environment of the skin, become positively charged, which can enhance adsorption to the negatively charged skin surface.

[0029] In vitro transdermal experiments demonstrated that both of these promoters significantly enhanced the permeation of asiaticoside compared to traditional single-mechanism permeation enhancers (laurocapram), exhibiting remarkable synergistic effects. Detailed Implementation Example 1:

[0030] The preparation process of a monoprotonated tertiary amine type permeation enhancer is as follows:

[0031] Process 1: Using trisilyl heptaphenyl POSS (CAS No. 444315-26-8) as the raw material and trichlorosilane as the capping reagent, heptaphenyl monohydroPOSS was synthesized via the apex-capping method. Its chemical structural formula is as follows:

[0032] ;

[0033] Process 2: Under the action of a platinum catalyst, an addition reaction occurs between the Si-H functional group of 1 molar equivalent of heptaphenyl-1-hydroPOSS and the alkenyl functional group of 1.06 molar equivalent of dimethylaminoethyl methacrylate to generate intermediate I, whose chemical structural formula is as follows:

[0034] ;

[0035] Process 3: Under the action of Lewis acid catalyst, a Friedel-Crafts alkylation reaction occurs between the phenyl functional group of 1 molar equivalent intermediate I and the alkenyl functional group of 7.05 molar equivalent 1-dodecene, generating a monoprotonated tertiary amine type permeation enhancer with the following chemical structure:

[0036] ;

[0037] The Lewis acid catalyst can be selected from one of aluminum trichloride, ferric trichloride, tin tetrachloride, and zinc dichloride; in this embodiment, aluminum trichloride is selected.

[0038] The specific experimental steps for preparing the monoprotonated tertiary amine type permeation enhancer are as follows:

[0039] Under nitrogen protection, 9.3 g of trisilyl alcohol heptaphenyl POSS and 90 mL of anhydrous tetrahydrofuran were added to a three-necked flask and stirred at room temperature until completely dissolved. Then, the flask was placed in an ice-water bath, and 1.5 mL of triethylamine and 10 mL of anhydrous tetrahydrofuran solution containing 1.4 g of trichlorosilane were added dropwise. The mixture was stirred in the ice-water bath for 1 h, then the ice-water bath was removed, and the mixture was stirred at room temperature for another 8 h. The solvent was removed by rotary evaporation, the solution was concentrated to saturation, and then precipitated using acetonitrile, filtered, and dried to obtain heptaphenyl monohydro POSS.

[0040] Under nitrogen protection, 4.8 g of heptaphenyl monohydroPOS and 40 mL of anhydrous tetrahydrofuran were added to a three-necked flask and stirred at room temperature until completely dissolved. Then, 10 mL of anhydrous tetrahydrofuran solution containing 0.9 g of dimethylaminoethyl methacrylate and 5 drops of Castrol catalyst were added dropwise to the three-necked flask. The mixture was heated to 70 °C and refluxed for 10 h. After cooling to room temperature, the solvent was removed by rotary evaporation. The mixture was washed repeatedly with ethanol and dried to obtain intermediate I.

[0041] 3.7 g of intermediate I, 4.0 g of 1-dodecene, 2.1 g of anhydrous aluminum trichloride and 80 mL of 1,2-dichloroethane were added to a three-necked flask and stirred at room temperature for 30 min to dissolve. The mixture was then heated to 85 °C and refluxed for 24 h. After cooling to room temperature, the solvent was removed by rotary evaporation. The mixture was washed with deionized water and dried to obtain a monoprotonated tertiary amine type permeation enhancer.

[0042] The proton NMR spectrum characterization of the unprotonated tertiary amine type permeation enhancer is as follows: 1 H NMR (CDCl3, 400MHz) 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), 2.3 8-2.47(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 2:

[0043] The preparation process of a diprotonated tertiary amine type permeation enhancer is as follows:

[0044] Procedure 1: Using heptaphenyltris(POSS) (CAS No. 444315-26-8) as the starting material and 3-aminopropyltriethoxysilane as the capping reagent, heptaphenylmonoaminopropylPOSS was synthesized via the apex-capping method. Its chemical structural formula is as follows:

[0045] ;

[0046] Process 2: An amino-enyl addition reaction occurs between the amino functional group of 1 molar equivalent of heptaphenylmonopropyl POSS and the α,β-alkenyl functional group of 2.03 molar equivalent of dimethylaminoethyl methacrylate to generate intermediate II, whose chemical structural formula is as follows:

[0047] ;

[0048] Process 3: Under the action of Lewis acid catalyst, a Friedel-Crafts alkylation reaction occurs between the phenyl functional group of 1 molar equivalent intermediate II and the alkenyl functional group of 7.05 molar equivalent 1-dodecene, generating a diprotonated tertiary amine type permeation enhancer with the following chemical structure:

[0049] ;

[0050] The Lewis acid catalyst can be selected from one of aluminum trichloride, ferric trichloride, tin tetrachloride, and zinc dichloride; in this embodiment, aluminum trichloride is selected.

[0051] The specific experimental steps for preparing the diprotonated tertiary amine type permeation enhancer are as follows:

[0052] Under nitrogen protection, 9.3 g of trisilyl alcohol heptaphenyl POSS and 90 mL of anhydrous tetrahydrofuran were added to a three-necked flask and stirred at room temperature until completely dissolved. Then, the flask was placed in an ice-water bath, and 10 mL of anhydrous tetrahydrofuran solution containing 2.2 g of 3-aminopropyltriethoxysilane was added dropwise. The mixture was stirred in the ice-water bath for 1 h, then the ice-water bath was removed, and the mixture was stirred at room temperature for another 12 h. The solvent was removed by rotary evaporation, the solution was concentrated to saturation, and then precipitated using acetonitrile, filtered, and dried to obtain heptaphenyl monoaminopropyl POSS.

[0053] Under nitrogen protection, 5.1 g of heptaphenyl monoaminopropyl POSS and 50 mL of anhydrous tetrahydrofuran were added to a three-necked flask and stirred at room temperature until completely dissolved. Then, 10 mL of anhydrous tetrahydrofuran solution containing 1.7 g of dimethylaminoethyl methacrylate was added dropwise to the three-necked flask. The mixture was heated to 70 °C and stirred under reflux for 8 h. After cooling to room temperature, the solvent was removed by rotary evaporation and dried to obtain intermediate II.

[0054] 4.4 g of intermediate II, 4.0 g of 1-dodecene, 2.1 g of anhydrous aluminum trichloride and 90 mL of 1,2-dichloroethane were added to a three-necked flask and stirred at room temperature for 30 min to dissolve. The mixture was then heated to 85 °C and refluxed for 24 h. After cooling to room temperature, the solvent was removed by rotary evaporation. The mixture was washed with deionized water and dried to obtain a diprotonated tertiary amine type permeation enhancer.

[0055] The proton NMR spectrum characterization of the diprotonated tertiary amine permeation enhancer is as follows: 1 H NMR (CDCl3, 400MHz) 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 3:

[0056] A hydroxyascorbic acid liposome composition I comprises the following raw materials in parts by weight:

[0057] 8 portions of egg yolk lecithin (liposome matrix);

[0058] 1 serving of cholesterol (fluidity regulator);

[0059] One part of monoprotonated tertiary amine type penetration enhancer (functional additive);

[0060] 1.5 parts of hydroxyascorbic acid (active ingredient, CAS No. 34540-22-2). Example 4:

[0061] A method for preparing a hydroxyascorbic acid liposome composition I includes the following steps:

[0062] Step 1: Dissolve asiaticoside in PBS buffer solution (pH=7) to prepare asiaticoside PBS buffer solution with a concentration of 50 mg / mL;

[0063] Step 2: Prepare asiaticoside liposome composition I using the thin-film dispersion method. Add 8g egg yolk lecithin, 1g cholesterol, 1g monoprotonated tertiary amine permeation enhancer and 50mL chloroform to a reaction flask, stir at room temperature for 30min to form a lipid solution, then remove chloroform by rotary evaporation at 30℃ and 100r / min, and vacuum dry at 40℃ for 3h to form a phospholipid film. Add 30mL of the asiaticoside PBS buffer solution prepared in Step 1 (controlling the amount of asiaticoside added to be 1.5g) to the phospholipid film, place it in an ice-water bath and sonicate for 10min, filter using a microporous membrane with a pore size of 0.45μm to obtain asiaticoside liposome composition I. Example 5:

[0064] A hydroxyascorbic acid liposome composition II, comprising the following raw materials in parts by weight:

[0065] 8 servings of egg yolk lecithin;

[0066] 1 serving of cholesterol;

[0067] 1 part of a diprotonated tertiary amine type penetration enhancer;

[0068] 1.5 parts asiaticoside;

[0069] The preparation method of asiaticoside liposome composition II is the same as that of asiaticoside liposome composition I. Example 6:

[0070] A method for applying a hydroxyascorbic acid liposome composition includes the following steps:

[0071] Step 1: Disperse 2g of Carbomer 940 in 100mL of water under high-speed shearing and mix well to prepare a Carbomer 940 solution. Then, add 10mL of aqueous solution containing 0.8g of triethanolamine dropwise while stirring slowly. Adjust the pH to 6.5 and then stop adding to obtain the gel matrix.

[0072] Step 2: Mix 5g of gel matrix and 0.5g of asiaticoside liposome composition evenly, then add 0.1g of glycerol, stir evenly to obtain a gel formulation containing asiaticoside liposome composition;

[0073] Step 3: Apply the gel containing the hydroxyascorbic acid liposome composition to the skin scar or damaged area once daily, using 0.2 g / cm² each time. 2 Administer the medication continuously for 12 days;

[0074] The asiaticoside liposome composition can be either asiaticoside liposome composition I or asiaticoside liposome composition II. In this embodiment, asiaticoside liposome composition I is selected for application experiments to prepare a gel formulation containing asiaticoside liposome composition I. Performance testing:

[0075] I. The average particle size and particle size distribution of the hydroxyasiaticoside liposome composition were tested using a Nano ZS Malvern particle size analyzer.

[0076] II. Encapsulation and Drug Loading Performance Testing of the Hydroxyacinoxoside Liposome Composition: The encapsulation and drug loading capabilities of the hydroxyasiaticoside liposome composition were characterized using standard curve equation plotting. The specific test steps are as follows:

[0077] (1) Dissolve asiaticoside in distilled water to prepare an aqueous solution of asiaticoside with a concentration of 1 mg / mL. Scan the aqueous solution of asiaticoside using a UV-Vis spectrophotometer at all wavelengths and record the maximum absorption wavelength λmax as 205 nm.

[0078] (2) Add 0.05 g of asiaticoside to a 100 mL volumetric flask and dilute to volume with distilled water to prepare asiaticoside stock solution. Use a pipette to transfer 0.1 mL, 0.5 mL, 1 mL, 2 mL and 4 mL into 10 mL volumetric flasks respectively, dilute to volume with distilled water and shake well to prepare asiaticoside standard solutions with concentrations of 5 µg / mL, 25 µg / mL, 50 µg / mL, 100 µg / mL and 200 µg / mL. Use an Agilent 1260 high performance liquid chromatograph to perform quantitative analysis on the five standard solutions, determine the peak area of ​​the standard solutions, and perform linear regression analysis with concentration as the abscissa and peak area as the ordinate to draw the standard curve of asiaticoside.

[0079] The chromatographic conditions and parameters are as follows:

[0080] Configure a Neptune C18 column (200 mm × 4.6 mm, 5 μm);

[0081] The column temperature is 30℃;

[0082] The detection wavelength is 205nm;

[0083] The column flow rate is 1 mL / min;

[0084] The injection volume was set to 20 µL;

[0085] Acetonitrile was used as mobile phase A and water was used as mobile phase B, with a volume ratio of acetonitrile to water of 26:74.

[0086] (3) The encapsulation efficiency and drug loading of the asiaticoside liposome composition were tested by dialysis. 1 mL of the asiaticoside liposome composition was transferred to a dialysis bag, sealed on both sides, and placed in 20 mL of PBS buffer (pH=7). The mixture was stirred at room temperature in the dark until dialysis equilibrium was reached at a speed of 300 r / min. The concentration (C1) of asiaticoside in the dialysis solution was detected using an Agilent 1260 high performance liquid chromatograph. The encapsulation efficiency and drug loading were calculated. The specific calculation method is as follows:

[0087] Encapsulation efficiency (%) = (1 - m1 / m0) × 100%;

[0088] Drug loading (%) = {(m0-m1) / m} × 100% = {(m0-m1) / (m0-m1+m2)} × 100%

[0089] Where m1 is the mass of free hydroxyasiaticoside in the dialysate after dialysis, in mg, and m1 = C1 × V, where V is the volume of PBS buffer 20 mL.

[0090] m0 is the total mass of asiaticoside before dialysis, in mg. At this time, m0 = 1 mL × 50 mg / mL = 50 mg.

[0091] m is the sum of the mass of asiaticoside encapsulated in the liposome composition and the mass of the membrane material, in mg. At this time, m = (m0 - m1) + m2.

[0092] m2 is the mass of the membrane material, in mg. At this time, m2 = {(8g + 1g + 1g) / 30mL} × 1mL = 333mg;

[0093] III. The transdermal properties of the hydroxyascorbic acid liposome composition were tested, and the specific test steps are as follows:

[0094] (1) Skin treatment: Take 250g SD rats, mechanically shave the back hair, then remove the remaining hair with 8wt% sodium sulfide aqueous solution, euthanize after 24h, take the back skin, carefully remove the subcutaneous fat, wash with physiological saline 3 times, dry the surface moisture, and store in a -10℃ refrigerator for later use.

[0095] (2) Transdermal test: The Franz transdermal transdermal instrument was used to conduct in vitro transdermal experiments on rats. The specific operation procedure was as follows:

[0096] Procedure 1: Remove the mouse skin from the refrigerator and thaw it in physiological saline at room temperature. Then, place the mouse skin 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 stratum corneum facing upwards. Fill the receiving pool with physiological saline and remove any air bubbles under the skin.

[0097] Step 2: Apply 1 mL of hydroxyascorbic acid liposome composition evenly to mouse skin, seal the diffusion cell with plastic wrap, and place it in a magnetic stirrer. Stir at 37°C and 200 r / min in a constant temperature water bath.

[0098] Step 3: Take 0.5 mL samples from the receiving cell at 1h, 4h, 12h, 24h, and 48h, add 10wt% Triton solution (to destroy any permeable liposomes and release the encapsulated asiaticoside for accurate concentration measurement), and bring the volume to 1 mL. Filter the solution using a 0.45 μm microporous membrane, and simultaneously add 0.5 mL of physiological saline to the receiving cell.

[0099] Step 4: The concentration of asiaticoside in the receiving cell was detected using an Agilent 1260 high-performance liquid chromatograph, and the transdermal permeability of the asiaticoside liposome composition was calculated. The specific calculation method is as follows:

[0100] 1-hour transdermal penetration rate (%) = (C 1h ×V0) / M×100%;

[0101] 4h transdermal penetration rate (%) = {(C 4h ×V0)+(C 1h ×V)} / M×100%;

[0102] 12h transdermal penetration rate (%) = {(C 12h ×V0)+(C 1h ×V)+(C 4h ×V)} / M×100%;

[0103] 24h transdermal penetration rate (%) = {(C 24h ×V0)+(C 1h ×V)+(C 4h ×V)+(C 12h ×V)} / M×100%;

[0104] 48h transdermal penetration rate (%) = {(C 48h ×V0)+(C 1h ×V)+(C4h ×V)+(C 12h ×V)+(C 24h ×V)} / M×100%;

[0105] Among them, C 1h C 4h C 12h C 24h C 48h The concentrations of asiaticoside in the receiving cell at 1h, 4h, 12h, 24h, and 48h are given in mg / mL.

[0106] V0 is the total volume of the receiving cell, in mL. In this case, V0 = 6.5 mL.

[0107] V is the sampling volume of the receiving cell, in mL, where V = 0.5 mL.

[0108] M represents the mass of asiaticoside in the asiaticoside liposome composition, in mg. In this case, M = 1 mL × 50 mg / mL = 50 mg.

[0109] The test results are shown in Table 1-2 below;

[0110] Table 1. Experimental results of the performance of the hydroxyascorbic acid liposome composition.

[0111]

[0112] Table 2. Performance test results of the hydroxyascorbic acid liposome composition.

[0113]

[0114] Note: The only difference between the comparative examples in Tables 1 and 2 and the 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 asiaticoside (i.e., using a traditional single-mechanism permeation enhancer (laurocapram) instead of a monoprotonated tertiary amine permeation enhancer).

[0115] A comprehensive analysis of the above experimental results leads to the following conclusions:

[0116] (1) The hydroxyadenosine liposome composition prepared by the present invention using the self-developed penetration enhancer has achieved a significant improvement in transdermal performance compared with the hydroxyadenosine liposome composition using the traditional single-mechanism penetration enhancer (laurocapram).

[0117] (2) The hydroxyasiaticoside liposome composition prepared by the present invention also exhibits excellent encapsulation and drug loading properties, with excellent comprehensive performance and practical application value.

[0118] IV. The application effect of the gel formulation containing asiaticoside liposome composition I was tested. The specific test steps are as follows:

[0119] (1) To establish a rat model of secondary burns, 250g SD rats were taken, and the back hair was mechanically shaved after anesthesia. Then, the remaining hair was removed with 8wt% sodium sulfide aqueous solution. A screw with a diameter of 14mm was placed in boiling water at 100℃ and heated for 1min. It was placed on the back of the rat and kept for 20s to form a wound of secondary burns and obvious blisters appeared.

[0120] (2) The burn wound should be bandaged with sterile gauze for two days. After the scab forms, apply a gel preparation containing hydroxyascorbic acid liposome composition I to the wound once a day at a dosage of 0.2 g / cm³. 2 After 12 consecutive days of medication, the diameter of the burn wound was measured every 3 days using the cross-sectional method to calculate the wound healing efficacy index. The specific calculation method is as follows:

[0121] Efficacy Index (%) = (1-D) i / D0)×100%;

[0122] Among them, D i The diameter of the burn wounds on days 3, 6, 9, and 12 is shown in mm.

[0123] D0 represents day 0, which is the diameter of the burn wound before the medication is applied, in mm. At this time, D0 = 14 mm.

[0124] The efficacy index is an important indicator for evaluating wound healing:

[0125] When the efficacy index is less than 30%, the wound healing effect is considered poor;

[0126] When the efficacy index is less than 70%, the wound healing effect is considered to be moderate.

[0127] When 70% ≤ efficacy index < 100%, the wound healing effect is considered significant.

[0128] When the efficacy index = 100%, the wound is considered to be completely healed.

[0129] The test results are shown in Table 3 below;

[0130] Table 3. Experimental results of the application of the hydroxyascorbic acid liposome composition.

[0131]

[0132] The following conclusions can be drawn from the analysis of the experimental results in Table 3:

[0133] The gel preparation prepared using the hydroxyascorbic acid liposome composition I of this invention has an efficacy index of up to 99.5% after 12 days of use, which is close to a complete cure, and has a significant therapeutic effect on 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, wherein 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 Madecassoside liposome composition according to any one of claims 1 to 4 for the preparation of a gel formulation for the treatment of skin lesions, 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: 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. Use of the Madecassoside liposome composition according to claim 9 for the preparation of a gel formulation for the treatment of skin lesions, 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.

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