New application of flexible liposome and composition with improved permeation effect

Abstract

The invention belongs to the field of new daily chemical materials, and discloses an application of a flexible liposome as a permeation enhancing carrier of a fat-soluble active component. When the flexible liposome is used as a permeation promoting carrier, the flexible liposome comprises liposome and a solvent, the liposome is prepared from cholesterol and hydrogenated lecithin; the solvent is composed of glycerol, 1, 3-butanediol and water according to the weight ratio of (15-25): (30-50): (35-45); the weight ratio of the liposome to the solvent is (2-4): (96-98). In the application, polyhydric alcohol compounded by butanediol and glycerol is adopted, and the ratio of the polyhydric alcohol to water is controlled, so that the cholesteryl and the hydrogenated lecithin can exist in a more flexible state, and when the cholesteryl and the hydrogenated lecithin act on the skin, a more excellent permeation enhancing effect on active ingredients can be shown. Meanwhile, the invention also provides a composition with improved permeation effect.

Description

Technical Field

[0001] The invention relates to the field of new daily chemical materials, in particular to a new use of flexible liposomes and a composition with improved penetration effect. Background Art

[0002] Liposomes are liposomes made of lecithin and other auxiliary substances. They have a bilayer structure that is the same as the skin cell membrane structure and have an excellent moisturizing effect on the skin. In particular, liposomes coated with moisturizing substances such as hyaluronic acid and polyglucosidase are better moisturizers. In addition, liposomes are also widely used as drug carriers, enabling them to better deliver drugs into cells.

[0003] Liposomes are now increasingly used in the field of daily chemicals because they have a similar structure to skin.

[0004] The most commonly used shell materials are lecithin and cholesterol, and the cosolvent is generally selected as a polyol. Because liposomes have a double-layer structure (some liposomes can also be single-layer structures), they can encapsulate oil-soluble active ingredients and water-soluble active ingredients. Liposomes have good affinity with the skin and can increase the skin retention time of active ingredients, thereby improving the delivery efficiency of active ingredients.

[0005] Generally speaking, liposomes improve skin delivery of active ingredients based on their prolonged residence time; it is not generally believed that they can improve the penetration efficiency of active ingredients in the same amount of time.

[0006] The technical problems solved in this case are: how to improve the delivery efficiency of liposomes for active ingredients and how to improve the permeability of active ingredients. Summary of the invention

[0007] The purpose of the present invention is to provide a new use of flexible liposomes. In this application, a polyol compounded with butanediol and glycerol is used, and the ratio of the polyol to water is controlled so that cholesterol and hydrogenated lecithin can exist in a more flexible state. When acting on the skin, it can show a better penetration-enhancing effect on active ingredients.

[0008] Meanwhile, the present invention also provides a composition with improved penetration effect.

[0009] To achieve the above object, the present invention provides the following technical solutions:

[0010] Application of flexible liposome as a penetration-enhancing carrier for fat-soluble active ingredients;

[0011] When the flexible liposome is used as a penetration-promoting carrier, it includes liposomes and a solvent; the liposomes are composed of cholesterol and hydrogenated lecithin; the solvent is composed of glycerol, 1,3-butanediol, and water in a weight ratio of 15-25:30-50:35-45; the weight ratio of the liposomes to the solvent is 2-4:96-98.

[0012] The mechanism by which the liposome of the present invention can be used as a penetration-promoting carrier is that the solvent composed of glycerol, 1,3-butylene glycol and water in a weight ratio of 15-25:30-50:35-45 moisturizes the stratum corneum, enhances hydration, causes changes in the structure between keratinocytes, and provides an opportunity for fat-soluble drugs to enter the intercellular space through diffusion and capillary suction. At the same time, the liposome is composed of cholesterol and hydrogenated lecithin, which are similar to the lipids of the skin and can replace the lipids between cells and hair follicles or bind to these parts, relieve skin barrier dysfunction, and increase the fluidity of skin lipids. The two act synergistically to promote the delivery and penetration of active ingredients.

[0013] The core of this solution lies in the selection of shell materials and solvents. When selecting solvents, it is necessary to reasonably control the usage ratio of glycerol and butylene glycol to optimally enhance skin hydration and enable the liposome shell material to more fully replace and combine with skin lipids to promote better penetration of functional ingredients.

[0014] In relevant verification experiments, using too much or too little glycerin and butylene glycol will reduce the penetration of active ingredients. The possible reasons are: too little glycerin and butylene glycol cannot completely moisturize the stratum corneum, resulting in little change in the structure between keratin cells; too much glycerin and butylene glycol will cause dehydration and affect skin health;

[0015] At the same time, in the process of experimental verification, the selection of lecithin types is equally important. Hydrogenated lecithin has better penetration-enhancing effect than other types of lecithin. The possible reasons are: 1. Hydrogenated lecithin is a partial hydrolyzate of lecithin with enhanced hydrophilicity. Through the catalytic hydrogenation process, the double bonds of unsaturated fatty acids in soybean lecithin molecules disappear, and the molecular structure becomes more stable. Hydrogenated lecithin can be combined with other ingredients such as ceramide to form a composition with amphiphilic penetration-enhancing function, thereby improving the permeability.

[0016] In the above application, the weight ratio of cholesterol to hydrogenated lecithin is 1:1.5-3.

[0017] In the above application, the weight ratio of glycerol, 1,3-butanediol and water is: 17-23: 35-45: 35-42.

[0018] In the above application, the preparation method of the flexible liposome is: all raw materials are weighed in proportion and order, then heated to 75-80°C, stirred at 40-50rpm to mix evenly to obtain a uniform liquid, then fully homogenized at 2000-3000rpm for 3-8min, defoamed, cooled, and filled after passing the inspection.

[0019] At the same time, the present invention also discloses a composition with improved penetration effect, comprising flexible liposomes and fat-soluble active ingredients; the flexible liposomes comprise liposomes and solvents; the liposomes are composed of cholesterol and hydrogenated lecithin; the solvent is composed of glycerol, 1,3-butylene glycol and water in a weight ratio of 15-25:30-50:35-45; the weight ratio of the liposomes to the solvent is 2-4:96-98;

[0020] The weight ratio of the fat-soluble active ingredient to the flexible liposome is 0.5-6:100.

[0021] In the above composition, the fat-soluble active ingredient is one or more combinations of bakuchiol, retinol, 4-butylresorcinol, idebenone, resveratrol, tetrahydrocurcumin, and green tea polyphenols.

[0022] In the above composition, the weight ratio of cholesterol to hydrogenated lecithin is 1:1.5-3.

[0023] In the above composition, the weight ratio of glycerol, 1,3-butylene glycol and water is: 17-23: 35-45: 35-42.

[0024] Compared with the prior art, the present invention has the following beneficial effects:

[0025] The present invention adopts polyols compounded with butylene glycol and glycerol, and controls the ratio of polyols to water, so that cholesterol and hydrogenated lecithin can exist in a more flexible state, which can show a better penetration-promoting effect on active ingredients when acting on the skin. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 This is the appearance of the sample of Example 5 at day 0;

[0027] Figure 2 This is the appearance of the sample of Example 5 after 60 days;

[0028] Figure 3 This is the appearance of the sample of Example 5 after 100 days;

[0029] Figure 4 is the particle size distribution diagram of the sample of Example 5 at day 0;

[0030] Figure 5is the particle size distribution diagram of the sample of Example 5 after 60 days;

[0031] Figure 6 is the particle size distribution diagram of the sample of Example 5 after 100 days;

[0032] Figure 7 is a transmission electron microscope image of the sample of Example 5;

[0033] Figure 8 This is a comparison sample of pigskin penetration retention photos;

[0034] Fig. 9 This is a photograph of the pigskin penetration retention of Example 5. DETAILED DESCRIPTION

[0035] The technical solution of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0036] Part I Preparation of Freshly Prepared Flexible Liposomes

[0037] Example

[0038] Preparation of flexible liposomes

[0039] All raw materials are weighed in proportion and order, then heated to 75-80°C, stirred and mixed at a speed of 40-50rpm to obtain a uniform liquid, then fully homogenized at a speed of 2000-3000rpm for 3-8min, defoamed, cooled, and filled after passing the inspection.

[0040] The active ingredient is curcumin.

[0041] The specific formula of the flexible liposome can be found in Table 1;

[0042] Table 1 Recipe

[0043]

[0044] Comparative Example 5

[0045] The same as Example 5, except that the hydrogenated lecithin is replaced by an equal amount of soybean lecithin.

[0046] Comparative Example 6

[0047] The same as Example 5, except that the hydrogenated lecithin is replaced by an equal amount of egg yolk lecithin.

[0048] Part II Investigation of the permeability of different fat-soluble active ingredients

[0049] The same as Example 5, except that the fat-soluble active ingredient is replaced by bakuchiol, retinol, and 4-butylresorcinol in equal weight, to obtain flexible liposome 1, flexible liposome 2, and flexible liposome 3;

[0050] The penetration properties of the flexible liposomes 1 to 3 were tested respectively, and the penetration properties of the essential oil containing the active ingredient were tested separately under the same test conditions.

[0051] Part III Performance Test

[0052] 1. Liposome stability test

[0053] The liposomes obtained in Example 5 were placed at room temperature and the stability from 0 to 100 days as well as the liposome particle size and potential were observed.

[0054] 2. Transmission electron microscopy test

[0055] The samples in the above stability test for 100 days were subjected to transmission electron microscopy test.

[0056] 3. Piglet skin permeability test

[0057] 3.1 Preparation of ex vivo suckling pig skin

[0058] The back skin of one-month-old suckling piglets stored at -20°C was thawed with deionized water at room temperature and repeatedly rinsed with PBS buffer.

[0059] 3.2 Determination of transdermal absorption capacity

[0060] 1) First, fix the pig skin between the supply chamber and the receiving chamber of the Franz cell diffusion tank, with the stratum corneum layer of the pig skin facing the supply chamber and the dermis layer facing the receiving chamber;

[0061] 2) Add 7.0 mL of receiving solution into the receiving chamber, tighten and fix the pig skin, then add 1.5 mL of receiving solution (PBS) into the receiving chamber through a sampler, exhaust the air, and make the dermis layer of the skin in close contact with the receiving solution;

[0062] 3) Sample loading: Add the sample to the skin surface in the supply chamber. The effective penetration area S is about 3.14 cm 2 . Add the sample to the surface of the pig skin and spread the sample evenly from the center of the skin to the edge. Each sample was repeated 3 times in parallel (three replicates were made from skin from specific parts of independent donors);

[0063] 4) Infiltration: Turn on the electromagnetic stirrer and stir at a speed of 300 rpm, maintain a constant temperature water bath at 32±1°C, and ensure that there are no bubbles in the water bath interlayer;

[0064] 5) Collect skin samples at 1h, 5h, and 10h. Use a sampler to extract 2.0mL of receiving solution through the sampling tube, and then place it in a 2mL EP tube. In addition, add an equal amount of receiving solution after each sampling.

[0065] 3.3 Transdermal content test

[0066] After 10 hours of penetration, the target substance content on the skin, in the skin, and under the skin of different experimental groups was tested by HPLC. The specific processing method is as follows:

[0067] 1) Test of the unpenetrated part of the skin: After 10 hours, use a 1 mL pipette to repeatedly blow and clean the skin surface. Wash the receiving solution 5 times for a total of 5 mL, and place it in a 5 mL centrifuge tube for testing;

[0068] 2) Test of the skin: Use a sterile scalpel to cut the skin along the inner edge of the supply chamber, cut the skin into pieces, add 5 mL of receiving solution and ultrasonically extract for 60 minutes. After the ultrasonication is completed, aspirate the supernatant and wait for testing;

[0069] 3) Subcutaneous part test: At each time point, 2 mL of receiving solution was drawn from the receiving chamber and placed in a 2 mL centrifuge tube for testing.

[0070] The comparative sample is a Tween aqueous solution of curcumin, the concentration of Tween (Guangdong Runhua Chemical Co., Ltd.) is 4wt%, and the concentration of curcumin is the same as that in Example 1.

[0071] The test results are as follows:

[0072] 1. The stability test results show that it is stable from 0 to 100 days. Figures 1 to 3 , Figure 1 For the 0-day appearance, Figure 2 For the 60-day appearance, Figure 3 For the 100 day appearance.

[0073] At 0 days, the particle size was 212 nm (reference Figure 4 ), 60 days is 230.6nm (reference Figure 5 ), 100 days is 214.3nm (reference Figure 6 ). The zeta potential of each stage is -40--50.5mV.

[0074] 2. Transmission electron microscopy test results are as follows Figure 7 , indicating that it is a stable liposome structure.

[0075] 3. The permeability test results are shown in Tables 2 and 3 below;

[0076] Table 2 Permeability test results

[0077] 1h 5h 10h Comparison sample Not detected Not detected Not detected Example 1 1.29 7.53 11.78 Example 2 1.38 7.85 12.96 Example 3 1.40 7.95 13.26 Example 4 1.10 7.46 9.86 Example 5 1.41 7.97 13.44 Comparative Example 1 0.96 6.26 10.02 Comparative Example 2 0.95 6.25 8.70 Comparative Example 3 0.97 6.34 9.78 Comparative Example 4 1.08 7.49 10.51 Comparative Example 5 0.92 7.12 10.58 Comparative Example 6 0.89 7.10 10.56

[0078] Table 3 Permeability test results

[0079] 1h 5h 10h Flexible liposome 1-bakuchiol 1.79 9.96 16.48 Flexible Liposome 2-Retinol 1.50 8.32 15.89 Flexible liposome 3-4-butylresorcinol 1.39 7.96 15.23

[0080] Results Analysis

[0081] 1. The above stability and transmission electron microscopy test results show that the liposome structure of the present invention is stable and the system is uniform.

[0082] 2. As shown in Table 2, compared with the control sample, Example 5 has a significant penetration-promoting effect; Figure 8 (Comparison sample) to Fig. 9 (Example 5) It can be seen that there is obvious permeation retention in pig skin, and the retention amount is 4.22 μg cm -2 , curcumin is retained in the epidermis and dermis reservoirs under the stratum corneum and continues to exert its effects.

[0083] 3. As can be seen from Table 2, Example 5 has better permeability than Comparative Examples 1 to 3, indicating that the ratio and amount of triol, diol and water in the solvent system are relatively important and are an important means to achieve adequate hydration of the skin.

[0084] 4. As can be seen from Table 2, Example 5 has better permeability than Comparative Example 4, but Comparative Example 4 has better permeability than Comparative Examples 1-3, indicating that in the system of the present invention, the selection of the proportion of solvents is more critical.

[0085] 5. As can be seen from Table 2, Example 5 has better permeability than Comparative Examples 5 and 6, indicating that the selection of the type of lecithin is also crucial.

[0086] 6. As can be seen from Table 3, the liposomes of the present invention have good penetration-enhancing effects on different oil-soluble components.

[0087] It will be apparent to those skilled in the art that the invention is not limited to the details of the exemplary embodiments described above and that the invention can be implemented in other specific forms without departing from the spirit or essential features of the invention. Therefore, the embodiments should be considered exemplary and non-limiting in all respects, and the scope of the invention is defined by the appended claims rather than the foregoing description, and it is intended that all variations falling within the meaning and scope of the equivalent elements of the claims be included in the invention. Any reference numeral in a claim should not be considered as limiting the claim to which it relates.

Claims

1. Application of a flexible liposome as a penetration-enhancing carrier for fat-soluble active ingredients; When the flexible liposome is used as a penetration-promoting carrier, it includes liposomes and a solvent; the liposomes are composed of cholesterol and hydrogenated lecithin; the solvent is composed of glycerol, 1,3-butanediol, and water in a weight ratio of 15-25:30-50:35-45; the weight ratio of the liposomes to the solvent is 2-4:96-98.

2. The use according to claim 1, characterized in that: The weight ratio of cholesterol to hydrogenated lecithin is 1:1.5-3.

3. The use according to claim 1, characterized in that: The weight ratio of the glycerol, 1,3-butanediol and water is 17-23: 35-45: 35-42.

4. The use according to claim 1, characterized in that: The preparation method of the flexible liposome is as follows: all raw materials are weighed in proportion and order, then heated to 75-80°C, stirred at 40-50rpm to mix evenly to obtain a uniform liquid, then fully homogenized at 2000-3000rpm for 3-8min, defoamed, cooled, and filled after passing the inspection.

5. A composition with improved penetration effect, characterized in that: The invention comprises a flexible liposome and a fat-soluble active ingredient; the flexible liposome comprises a liposome and a solvent; the liposome is composed of cholesterol and hydrogenated lecithin; the solvent is composed of glycerol, 1,3-butylene glycol and water in a weight ratio of 15-25:30-50:35-45; the weight ratio of the liposome to the solvent is 2-4:96-98; The weight ratio of the fat-soluble active ingredient to the flexible liposome is 0.5-6:

100.

6. The composition according to claim 5, characterized in that The fat-soluble active ingredient is one or more combinations of bakuchiol, retinol, 4-butylresorcinol, idebenone, resveratrol, tetrahydrocurcumin, and green tea polyphenols.

7. The composition according to claim 5, characterized in that The weight ratio of cholesterol to hydrogenated lecithin is 1:1.5-3.

8. The composition according to claim 5, characterized in that The weight ratio of the glycerol, 1,3-butanediol and water is 17-23: 35-45: 35-42.

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