Anti-aging transdermal drug delivery microneedle preparation solution, preparation method and application thereof and transdermal drug delivery soluble microneedle

Abstract

The invention discloses an anti-aging transdermal drug delivery microneedle preparation solution, a preparation method and application of the anti-aging transdermal drug delivery microneedle preparation solution and a transdermal drug delivery soluble microneedle, and belongs to the technical field of microneedle preparation. Comprising 0.25%-10% of an anti-sugar and anti-oxidation component, 0.1%-10% of an anti-ultraviolet damage component, 0.1%-10% of a cell and collagen regeneration component, 10%-30% of an extracellular matrix supplement component, 0.05%-3.1% of a nerve inhibition component and the balance of water. The transdermal drug delivery microneedle preparation solution disclosed by the invention can be used for preparing a transdermal drug delivery soluble microneedle, and the transdermal drug delivery soluble microneedle can be used for rapidly improving the intercellular capacity, so that the effects of improving the material transportation speed, the cell division and differentiation speed and the construction speed of extracellular matrixes such as collagen and the like are achieved; therefore, the purpose of recovering the tough and elastic young state of the skin is achieved.

Description

Technical Field

[0001] The present invention belongs to the technical field of microneedle preparation, and particularly relates to an anti-aging transdermal drug delivery microneedle preparation solution, its preparation method, application, and transdermal drug delivery soluble microneedles. Background Art

[0002] Aging is a rather complex process, and the main reasons include: 1. Free radical damage; 2. Ultraviolet damage; 3. Non-enzymatic glycosylation in organisms; 5. Carbonyl toxicity-induced aging; 6. Free radical-Maillard reaction-induced aging.

[0003] Aging occurs simultaneously at all levels of the skin. Macroscopically, the manifestations of skin aging are the appearance of wrinkles and pigmentation. Microscopically, the thickness of each layer of the skin decreases, the total number of cells decreases, the proportion of healthy cells decreases, the content of extracellular matrix proteins decreases, and the amount of metabolic waste increases, etc. Therefore, it is necessary to solve the problems of cellular aging and extracellular matrix aging at the microscopic level to achieve the purpose of anti-aging and wrinkle removal.

[0004] The active ingredients of cosmetics need to be transported to the corresponding action sites to exert their effects. However, the transdermal absorption of ordinary skin care products is limited and the transdermal depth is shallow, making it difficult to achieve the purpose of anti-aging and wrinkle removal.

[0005] Microneedles are a new type of transdermal drug delivery technology. Through this technology, the efficiency of transdermal drug delivery can be greatly improved. In theory, the transdermal efficiency of the product can reach 100%, with the advantages of small dosage and high efficiency. Due to its special drug delivery method, it can help certain drugs take effect quickly and exert their effects.

[0006] Currently, there are a variety of anti-aging and wrinkle-removing drugs. However, after retrieval, no research has been found on improving the absorption of active substances by improving the extracellular matrix space. Therefore, the research of the present invention is of great significance. Summary of the Invention

[0007] In order to solve the above technical problems, the present invention provides an anti-aging transdermal drug delivery microneedle preparation solution, its preparation method, application, and transdermal drug delivery soluble microneedles. The transdermal drug delivery microneedle preparation solution of the present invention can quickly improve the rate of material transport between cells, and create space for cell proliferation and the construction of the extracellular matrix. Furthermore, it can accelerate the rate of cell division and differentiation, as well as the construction rate of extracellular matrix such as collagen, thereby achieving the young state of the skin being restored to be strong and elastic.

[0008] To achieve the above object, the present invention adopts the following technical solutions:

[0009] In a first aspect, the present invention provides a transdermal administration microneedle preparation solution for anti-aging, which, by weight percentage, comprises 0.25 - 10% of an anti-glycation and antioxidant component, 0.1 - 10% of an anti-ultraviolet damage component, 0.1 - 10% of a cell and collagen regeneration component, 10 - 30% of an extracellular matrix supplement component, 0.05 - 3.1% of a nerve inhibition component, and the balance being water.

[0010] In some embodiments, the anti-glycation and antioxidant component is at least one of glutathione, vitamin C ethyl ether, VCIP, carnosine, SOD, tetrabutyl resorcinol, ethyl bisiminomethyl guaiacol manganese chloride, dibutylhydroxytoluene, anthocyanin, astaxanthin, tea polyphenols, arbutin, and ergothioneine; preferably at least one of glutathione, vitamin C ethyl ether, VCIP, carnosine, SOD, and tetrabutyl resorcinol; more preferably SOD, VCIP, and carnosine, and even more preferably, the weight ratio of SOD, VCIP, and carnosine is 1:2 - 4:2 - 5.

[0011] In some embodiments, the anti-ultraviolet damage component is at least one of glucosyl rutin, ectoine, vitamin E, resveratrol, and apigenin; preferably ectoine.

[0012] In some embodiments, the cell and collagen regeneration component is at least one of hydroxypinacolone retinoate, recombinant type III collagen, retinol palmitate, type XVII collagen, fibronectin, DNA-sodium, copper peptide, asiaticoside, madecassoside, and aloe extract; preferably at least one of hydroxypinacolone retinoate, retinol palmitate, recombinant type III collagen, type XVII collagen, fibronectin, DNA-sodium, and aloe extract; more preferably hydroxypinacolone retinoate, recombinant type III collagen, type XVII collagen, and fibronectin; and even more preferably, the weight ratio of hydroxypinacolone retinoate, recombinant type III collagen, type XVII collagen, and fibronectin is 1:50 - 110:1 - 2:5 - 10.

[0013] In some embodiments, the extracellular matrix supplement component comprises a small molecule dispersive filling structure A and a cross-linked macromolecular supporting structure B. The small molecule dispersive filling structure A includes at least one of sodium hyaluronate, collagen, chondroitin sulfate, and carboxymethyl cellulose. Preferably, the molecular weight of the small molecule dispersive filling structure A does not exceed 100 kDa; more preferably 1 - 100 kDa. The macromolecular supporting structure B includes cross-linked sodium hyaluronate and / or macromolecular collagen. Preferably, the molecular weight of the macromolecular supporting structure B is not less than 110 kDa, more preferably 110 - 220 kDa. Preferably, the mass ratio of the small molecule dispersive filling structure A to the cross-linked macromolecular supporting structure B is 5 - 200:1.

[0014] In some embodiments, the nerve inhibitory component is conotoxin and / or venom-like peptide; preferably conotoxin and venom-like peptide; more preferably, the weight ratio of conotoxin to venom-like peptide is 1:10 - 30.

[0015] In a second aspect, the present invention provides a method for preparing the transdermal administration microneedle preparation solution, comprising the following steps:

[0016] Step 1: Mix and dissolve the formula amounts of the cell and collagen regeneration component, anti-glycation and antioxidant component, anti-ultraviolet damage component, nerve inhibitory component and deionized water to obtain solution A;

[0017] Step 2: Mix and dissolve the formula amount of the extracellular matrix supplement component and the remaining formula amount of water to obtain solution B;

[0018] Step 3: Mix solution A obtained in step 1 and solution B obtained in step 2 to obtain the product.

[0019] In a third aspect, the present invention provides the use of the above transdermal administration microneedle preparation solution or the transdermal administration microneedle preparation solution prepared by the above preparation method in the preparation of anti-aging and anti-wrinkle transdermal administration soluble microneedles.

[0020] In a fourth aspect, the present invention provides an anti-aging and anti-wrinkle transdermal administration soluble microneedle, which is made from the transdermal administration microneedle preparation solution.

[0021] The anti-aging and anti-wrinkle transdermal administration soluble microneedle of the present invention is of an integral type or a multi-segment type.

[0022] In a fifth aspect, the present invention provides a method for preparing the anti-aging and anti-wrinkle transdermal administration soluble microneedle, comprising the following steps:

[0023] Inject the aforementioned transdermal administration microneedle preparation solution into a microneedle mold, dry and peel to obtain the product.

[0024] The "injection" in the present invention is a conventional perfusion method in the art, including but not limited to high-pressure jetting, centrifugal perfusion, vacuum adsorption or self-leveling.

[0025] The drying in the present invention is a conventional method for reducing moisture in the art, for example, drying at 15 - 30°C and a humidity of 10% - 90% for 15 - 72 hours.

[0026] The beneficial effects of the present invention are:

[0027] (1) The transdermal drug delivery microneedle preparation solution provided by the present invention can rapidly improve the rate of material transport between cells and create space for cell proliferation and the construction of the extracellular matrix. Furthermore, it can accelerate the rate of cell division and differentiation and the construction rate of extracellular matrix such as collagen, thereby achieving the rejuvenated state of the skin with strong toughness and elasticity.

[0028] (2) Among the components for supplementing the extracellular matrix used in the present invention, small molecules facilitate the release of macromolecules during dissolution in the skin without causing local aggregation. The cross-linked macromolecules can stay in the intercellular matrix for a long time to increase the intercellular space, the rate of material exchange, and the rate of cell movement. The two cooperate with each other to promote the absorption of other components, and at the same time provide space for cell proliferation and collagen network construction. The anti-glycation and antioxidant components protect the components for supplementing the extracellular matrix, collagen, and cells. Each component has a synergistic effect in anti-aging and anti-wrinkle effects.

[0029] (3) The anti-aging and anti-wrinkle transdermal drug delivery soluble microneedles prepared with the transdermal drug delivery microneedle preparation solution of the present invention transport the ultra-large molecular weight cross-linked macromolecular support structure dispersed in the small molecule dispersion filling structure to each layer of the skin through the microneedles, and at the same time transport the active substances to the action sites, with rapid onset, high bioavailability, low dosage, high safety and other characteristics. Description of the Drawings

[0030] Figure 1 It is an ultraviolet imaging diagram.

[0031] Figure 2 It is an anti-wrinkle effect diagram.

[0032] Figure 3 It is a diagram of the increased amount of collagen after 30 days of use. Detailed Embodiments

[0033] The following illustrates the embodiments of the present invention through specific specific examples. Those skilled in the art can easily understand other advantages and effects of the present invention from the content disclosed in this specification. The present invention can also be implemented or applied through other different specific embodiments, and various details in this specification can also be modified or changed based on different viewpoints and applications without departing from the spirit of the present invention.

[0034] Before further describing the specific embodiments of the present invention, it should be understood that the protection scope of the present invention is not limited to the specific embodiments described below; it should also be understood that the terms used in the embodiments of the present invention are for describing specific embodiments, rather than for limiting the protection scope of the present invention.

[0035] When numerical ranges are given in the embodiments, it should be understood that, unless otherwise specified in the present invention, both endpoints of each numerical range and any value therebetween can be selected. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the technical field to which the present invention pertains.

[0036] The present invention does not limit the sources of the raw materials used. Unless otherwise specified, the raw materials used in the present invention are all ordinary commercially available products in this technical field. Exemplarily, the SOD has a CAS number of 9054-89-1; VCIP has a CAS number of 183476-82-6; carnosine has a CAS number of 305-84-0; VC ethyl ether has a CAS number of 86404-04-8; glutathione has a CAS number of 70-18-8; tetrabutylresorcinol has a CAS number of 18979-61-8; glucosylrutin has a CAS number of 130603-71-3; VE has a CAS number of 7695-91-2; recombinant type III collagen is purchased from Jiangsu Chuangjian Medical Technology Co., Ltd.; type XVII collagen is purchased from Hangzhou Shiguang Xinya Biotechnology Co., Ltd.; fibronectin is purchased from Guangzhou Jike Meichuang Bioscience Co., Ltd.; DNA-sodium is purchased from Ruijiming (Shandong) Biotechnology Co., Ltd.; aloe extract is purchased from Xi'an Xiaocao Biotechnology Co., Ltd. (the aloe content of the aloe extract is 100%); sodium hyaluronate is purchased from Shandong Focus Biotechnology Co., Ltd.; macromolecular collagen and collagen are purchased from Jiangsu Chuangjian Medical Technology Co., Ltd. (the molecular weight of macromolecular collagen is 300 kDa, and the molecular weight of collagen is 3 kDa); chondroitin sulfate has a CAS number of 9007-28-7; carboxymethyl cellulose has a CAS number of 9004-32-4; cross-linked sodium hyaluronate has a CAS number of 105524-32-1; conotoxin peptide, 98%, has a CAS number of 936616-33-0; snake venom-like peptide has a CAS number of 823202-99-9; acetyl tetrapeptide-5 has a CAS number of 820959-17-9; acetyl hexapeptide-8 has a CAS number of 616204-22-9.

[0037] [Examples and Comparative Examples]

[0038] Prepare the transdermal soluble microneedles described in Tables 1 and 2 (parts by unit weight) according to the following preparation method.

[0039] Preparation method:

[0040] Step 1: Mix the formulated amounts of cells and collagen regeneration components, anti-glycation and antioxidant components, anti-ultraviolet damage components, nerve inhibition components and deionized water, and stir to dissolve to obtain Solution A;

[0041] Step 2: Mix the formulated amounts of extracellular matrix supplement components and the remaining formulated amount of water, and stir to dissolve to obtain Solution B;

[0042] Step 3: Mix the solution A obtained in Step 1 and the solution B obtained in Step 2 evenly to obtain the transdermal delivery microneedle preparation solution;

[0043] Step 4: Inject the transdermal delivery microneedle preparation solution obtained in Step 3 into the microneedle mold. Place the microneedle mold filled with the transdermal delivery microneedle preparation solution at a humidity of 50% and a temperature of 15°C for 10 min, then place it at a humidity of 80% and a temperature of 30°C for 2 min for semi-drying, and fix the gasket;

[0044] Step 5: Dry the microneedle mold with the gasket fixed in Step 4 at a humidity of 50% and a temperature of 23°C for 20 - 24 h. The microneedles adhere to the gasket simultaneously. Use an instrument to separate the microneedles and the gasket from the mold and cut them to obtain the transdermal delivery soluble microneedles.

[0045] Table 1 Formulations of the transdermal delivery soluble microneedles in Examples 1 - 7 (unit: mass percentage)

[0046]

[0047]

[0048] Table 2 Formulations of the transdermal delivery soluble microneedles in Comparative Examples 1 - 4 (unit: mass percentage)

[0049]

[0050] I. Transdermal water loss measurement

[0051] The transdermal water loss tester is an instrument that can detect the amount of water lost from the skin surface. The experimental probe is fixed on the test area, and after a certain period of time, the amount of water lost from the skin surface can be read.

[0052] The change in the transdermal water loss content of the subjects before and after using the soluble microneedles is measured by the transdermal water loss tester. The higher the transdermal water loss, the worse the moisturizing ability of the stratum corneum. On the contrary, the more complete the cutin and the better the skin structure. By comparing the change range of the transdermal water loss before and after use, it is judged whether the skin cutin and structure are more significant after using the transdermal delivery soluble microneedles of the present invention.

[0053] In each group of experiments, three people are tested. Three positions are selected on the cheek of each subject. The transdermal water loss of this area is measured before use. After using the corresponding group of products once, one week later, the change in the transdermal water loss of the corresponding area is measured, and the average value of the change values of the three people before and after use is taken.

[0054] The results are shown in Table 3. The results indicate that the changes in the transdermal water loss after using the transdermal delivery soluble microneedles prepared in Comparative Examples 1-4 are not obvious, while the transdermal water loss after using the transdermal delivery soluble microneedles prepared in Examples 1-7 has significantly decreased, indicating that the cutin is more intact and the skin structure is better.

[0055] Table 3 Influence of Transdermal Delivery Soluble Microneedles on Transdermal Water Loss

[0056] Group <![CDATA[Amount of reduction in percutaneous water loss after use (g / m 2 *h)]]> Example 1 5.102 Example 2 4.857 Example 3 2.563 Example 4 2.59 Example 5 3.225 Example 6 2.565 Example 7 3.210 Comparative Example 1 0.755 Comparative Example 2 -0.439 Comparative Example 3 0.546 Comparative Example 4 -1.009

[0057] II. Evaluation of Antioxidant Effect

[0058] Three volunteers with healthy skin were selected. The transdermal delivery soluble microneedles with the formulation of the example were used on the skin of the inner side of the left arm, and the transdermal delivery soluble microneedles with the formulation of the comparative example were used on the right arm. After 30 minutes, the patches were removed, and the skin at the test site was wiped clean with pure water and a clean cotton ball. Then, 0.1 mL of iodine tincture solution was taken with a pipette and dropped on the skin at the test site, and the amount of the iodine tincture that did not fade after dropping was observed. The higher the content of the antioxidant component, the better the effect, and the more the amount that can reduce the iodine tincture to colorless. The results are shown in Table 4. The results show that the antioxidant effect of the transdermal delivery soluble microneedles prepared in Examples 1-7 is significantly better than that of Comparative Examples 1-4.

[0059] Table 4 Amount of Iodine Tincture Reduced by Transdermal Delivery Soluble Microneedles of Different Examples and Comparative Examples (Unit: mL)

[0060] Subject 1 Subject 2 Subject 3 Example 1 0.1 0.1 0.1 Example 2 0.5 0.5 0.6 Example 3 0.2 0.3 0.3 Example 4 0.5 0.5 0.4 Example 5 0.6 0.5 0.5 Example 6 0.5 0.4 0.6 Example 7 0.2 0.1 0.2 Comparative Example 1 0 0 0 Comparative Example 2 0 0.1 0.1 Comparative Example 3 0 0.1 0 Comparative Example 4 0 0 0

[0061] III. Test of Skin Ultraviolet Absorption Performance

[0062] Two volunteers with healthy skin were selected. The transdermal delivery soluble microneedles with soluble characteristics prepared in Examples 1-3 were used on the left side of the skin, and the transdermal delivery soluble microneedles with soluble characteristics prepared in Comparative Example 3 were used on the right side. After applying for half an hour, the transdermal delivery soluble microneedles were removed, and the skin surface was wiped with pure water until there was no foreign matter and no residue. Then, ultraviolet imaging of VISIA7 was used for detection. The darker the color, the more ectoine it absorbed as shown in Figure 1 shown. The results show that the transdermal absorption effect of the anti-ultraviolet damage component (ectoine) of the transdermal delivery soluble microneedles prepared in Examples 1-3 is good, and it is significantly better than that of Comparative Example 3.

[0063] IV. Test of Wrinkle-Removing Efficacy

[0064] Recruit 30 volunteers aged 35 - 45 years old, randomly divide them into two groups with 15 people in each group. Among them, the experimental group uses the transdermal soluble microneedles prepared in Examples 1 - 3, and the control group uses the transdermal soluble microneedles prepared in Comparative Example 3. Use the product three times a week. After two months, use the VISIA 7 skin detector for detection. The light green represents fine lines, and the dark green represents deep lines. The experimental results are as Figure 2 shown. The results show that the transdermal soluble microneedles prepared in Examples 1 and 3 can significantly reduce the number of eye wrinkles, and the anti-wrinkle effect is significantly better than that of Comparative Example 3.

[0065] V. Collagen Regeneration Effect Test

[0066] Select 30 volunteers with an average age of 36.84 ± 0.71 years old. Before the test, use an ultrasonic probe to detect the density of the skin collagen of the volunteers. Let the volunteers use the transdermal soluble microneedles twice a week. Use the transdermal soluble microneedles prepared in the examples on the left side and the transdermal soluble microneedles prepared in the comparative examples on the right side. During this period, avoid using other skin care products and drugs. After one month, use ultrasonic waves again to detect the change in collagen density. The results are as Figure 3 shown. The results show that Examples 1 - 3 have a significant increase in collagen content during the one-month usage period, while the effects of Comparative Examples 1 - 3 are relatively poor.

[0067] The above is a further description of the present invention in combination with specific embodiments, but these embodiments are merely exemplary and do not constitute any limitation to the scope of the present invention. Those skilled in the art should understand that the details and forms of the technical solutions of the present invention can be modified or replaced without departing from the spirit and scope of the present invention, but these modifications and replacements all fall within the protection scope of the present invention.

Claims

1. A transdermal delivery microneedle preparation solution for anti-aging, characterized in that, By weight percentage, it includes 0.25 - 10% of anti - glycation and antioxidant components, 0.1 - 10% of anti - UV damage components, 0.1 - 10% of cell and collagen regeneration components, 10 - 30% of extracellular matrix supplement components, 0.05 - 3.1% of nerve inhibition components and the balance of water; The anti - glycation and antioxidant components are at least one of glutathione, vitamin C ethyl ether, VCIP, carnosine, SOD, tetrabutyl resorcinol, ethyl bis - (iminomethyl) guaiacol manganese chloride, dibutyl hydroxytoluene, anthocyanin, astaxanthin, tea polyphenols, arbutin and ergothioneine; The anti - UV damage components are at least one of glucosyl rutin, ectoine, vitamin E, resveratrol and apigenin; The cell and collagen regeneration components are at least one of hydroxypinacolone retinoate, recombinant type III collagen, retinol palmitate, type XVII collagen, fibronectin, DNA - sodium, copper peptide, asiaticoside, madecassoside and aloe extract; The extracellular matrix supplement components contain a small - molecule dispersive filling structure and a cross - linked macromolecular supporting structure. The small - molecule dispersive filling structure includes at least one of sodium hyaluronate, collagen, chondroitin sulfate and carboxymethyl cellulose, and the macromolecular supporting structure includes cross - linked sodium hyaluronate and / or macromolecular collagen; The nerve inhibition components are conotoxin and / or snake venom - like peptide.

2. The transdermal administration microneedle preparation solution according to claim 1, characterized in that, The anti - glycation and antioxidant components are at least one of glutathione, vitamin C ethyl ether, VCIP, carnosine, SOD and tetrabutyl resorcinol; The cell and collagen regeneration components are at least one of hydroxypinacolone retinoate, retinol palmitate, recombinant type III collagen, type XVII collagen, fibronectin, DNA - sodium and aloe extract.

3. The transdermal drug delivery microneedle preparation solution according to claim 2, characterized in that, The anti - glycation and antioxidant components are SOD, VCIP and carnosine.

4. The transdermal administration microneedle preparation solution according to claim 2, characterized in that, The cell and collagen regeneration components are hydroxypinacolone retinoate, recombinant type III collagen, type XVII collagen and fibronectin.

5. The transdermal drug delivery microneedle preparation solution according to any one of claims 1-4, characterized in that, The weight ratio of the conotoxin to the snake venom - like peptide is 1:10 - 30.

6. The transdermal drug delivery microneedle preparation solution according to claim 1, wherein The weight ratio of SOD, VCIP and carnosine is 1:2 - 4:2 - 5; And / or the weight ratio of hydroxypinacolone retinoate, recombinant type III collagen, type XVII collagen and fibronectin is 1:50 - 110:1 - 2:5 - 10.

7. The transdermal drug delivery microneedle preparation solution according to claim 1, characterized in that, The mass ratio of the small - molecule dispersive filling structure to the cross - linked macromolecular supporting structure is 5 - 200:

1.

8. The preparation method of the transdermal drug delivery microneedle preparation solution according to any one of claims 1 to 7, characterized in that, It includes the following steps: Step 1: Mix and dissolve the formula - amount of cell and collagen regeneration components, anti - glycation and antioxidant components, anti - UV damage components, nerve inhibition components and deionized water to obtain solution A; Step 2: Mix and dissolve the formula - amount of extracellular matrix supplement components and the remaining formula - amount of water to obtain solution B; Step 3: Mix solution A obtained in Step 1 and solution B obtained in Step 2 to get the product.

9. Use of the transdermal drug - delivery microneedle preparation solution according to any one of claims 1 - 7 or the transdermal drug - delivery microneedle preparation solution prepared by the preparation method according to claim 8 in the preparation of anti - aging and anti - wrinkle soluble microneedles.

10. A transdermal soluble microneedle for anti-aging and wrinkle removal, characterized in that, It is made from the transdermal drug delivery microneedle preparation solution according to any one of claims 1-7 or the transdermal drug delivery microneedle preparation solution prepared by the preparation method according to claim 8.

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