A high-penetration soluble microneedle patch containing small-molecule PDRN and a preparation method thereof

Abstract

This invention relates to a highly penetrating soluble microneedle patch containing small molecule PDRN. It comprises a functional needle body and a base. The functional needle body is prepared from components comprising the following parts by weight: 4-7 parts sodium hyaluronate, 1-3 parts PDRN, 1-2 parts p-hydroxyacetophenone, 1-3 parts hydroxypropyl cellulose, 2-4 parts glutathione, 0.1-0.3 parts tranexamic acid, and 5-7 parts centella asiatica. The base is prepared from a polymer matrix material. This invention is the first to add PDRN to a soluble microneedle patch, using PDRN of different molecular weights and concentrations to prepare soluble microneedle patches with different penetration properties. This effectively solves the problems of insufficient hardness, poor penetration, and poor penetration rate of existing soluble microneedle patches, enabling it to penetrate skin with different stratum corneum thicknesses and making it applicable to various skin conditions with a wide range of applications.

Description

Technical Field

[0001] This invention relates to a highly penetrating, soluble microneedle patch containing small molecule PDRN and its preparation method, belonging to the field of skin care technology. Background Technology

[0002] PDRN, also known as polydeoxyribonucleotide, is a natural low-molecular-weight DNA molecule with a length between 50 and 2000 bp. Its natural sources are mainly human placenta or trout testes. The DNA base composition of salmon has a 98% similarity to that of human DNA. PDRN contains more than 95% active ingredients but does not contain pharmacologically active proteins and peptides, so it has very low requirements for transportation conditions, which greatly increases its circulation stability. Moreover, the components have high compatibility. PDRN can synthesize DNA from damaged or hypoxic tissues, and has anti-inflammatory, tissue repair and wound regeneration effects. It can effectively repair enlarged pores, redness caused by telangiectasia, and rosacea. At the same time, it can promote human cell regeneration, quickly heal wounds, and reduce scar formation. It is often used in cosmetics and medical aesthetics.

[0003] With the improvement of modern living standards, more and more women are pursuing higher levels of beauty, seeking more efficient whitening, spot-fading, stratum corneum repair, and anti-aging treatments. They are no longer satisfied with routine skincare and are seeking faster and more noticeable beauty solutions. Currently, Chinese patent document CN116492241A discloses a micro-cosmetic skin repair liquid with anti-aging effects, and Chinese patent document CN116077367A discloses a freeze-dried powder composition with skin repair functions. Although these repair liquids and freeze-dried skin repair powders contain PDRN, they are limited to surface skincare and have a slow effect. Chinese patent document CN116460545A discloses a method for manufacturing a microneedle roller. Although this metal microneedle can penetrate the skin to achieve cosmetic effects, it requires a high level of skill and a suitable operating environment. The resulting skin wounds are large, causing significant pain, and a recovery period is required after use, posing safety risks. Chinese patent document CN113197814A discloses a method for preparing hyaluronic acid microneedle patches, which belong to soluble microneedle patches. However, these soluble microneedle patches have the disadvantages of insufficient hardness, poor penetration and penetration rate. They cannot penetrate skin with a thick stratum corneum and cannot be used on different skin conditions at the same time, thus limiting their applicability. Summary of the Invention

[0004] To address the shortcomings of existing technologies, this invention provides a highly penetrating, soluble microneedle patch containing small molecule PDRN and its preparation method.

[0005] The technical solution of the present invention is as follows:

[0006] A highly penetrable, soluble microneedle patch containing small molecule PDRN, consisting of a functional needle and a substrate;

[0007] The functional needle body is prepared from components comprising the following parts by weight:

[0008] Sodium hyaluronate 4-7 parts, PDRN 1-3 parts, p-hydroxyacetophenone 1-2 parts, hydroxypropyl cellulose 1-3 parts, glutathione 2-4 parts, tranexamic acid 0.1-0.3 parts, centella asiatica 5-7 parts;

[0009] The substrate is made of a polymer matrix material.

[0010] According to a preferred embodiment of the present invention, the functional needle body is prepared from the following components in parts by weight: 5.5-6.5 parts sodium hyaluronate, 2-3 parts PDRN, 1.5 parts p-hydroxyacetophenone, 1.5-2 parts hydroxypropyl cellulose, 3 parts glutathione, 0.1-0.25 parts tranexamic acid, and 5.5 parts centella asiatica.

[0011] According to a preferred embodiment of the present invention, the length of the PDRN is 50 to 1500 bp.

[0012] More preferably, the length of the PDRN is 50 to 500 bp.

[0013] According to a preferred embodiment of the present invention, the polymer matrix material is one or more combinations of polylactic acid, hydroxymethyl cellulose, chondroitin sulfate, maltose, lactose, or sucrose.

[0014] The preparation method of the above-mentioned highly penetrating soluble microneedle patch containing small molecule PDRN includes the following steps;

[0015] (1) Weigh out sodium hyaluronate, PDRN, p-hydroxyacetophenone, hydroxypropyl cellulose, glutathione, tranexamic acid and centella asiatica according to the formula, dissolve them in 23.7 to 35.9 parts by weight of water to prepare a 50-part system, mix them evenly at 35 to 45°C to obtain a functional injection solution.

[0016] (2) Dissolve the polymer matrix material in water and mix evenly. After autoclaving, obtain the base solution.

[0017] (3) The functional needle solution is added to the microneedle mold, vacuum dried, and then the base solution is added. After vacuum drying and freeze drying, a highly penetrating soluble microneedle patch containing small molecule PDRN is obtained.

[0018] According to a preferred embodiment of the present invention, in step (2), the mass ratio of the polymer matrix material to water is 1:3.

[0019] According to a preferred embodiment of the present invention, in step (3), the volume ratio of the functional needle solution to the base solution is 1:3.

[0020] According to a preferred embodiment of the present invention, in step (3), the vacuum drying is performed by drying for 1 to 1.5 hours under conditions of a pressure of 0.06 to 0.09 MPa and a temperature of 50°C.

[0021] According to a preferred embodiment of the present invention, in step (4), the vacuum drying is performed at a temperature of -20°C to -30°C for 24 to 36 hours.

[0022] The technical features and beneficial effects of this invention are as follows:

[0023] 1. This invention is the first to add PDRN to soluble microneedle patches. Soluble microneedle patches with different penetration properties were prepared by using PDRN with different molecular weights and concentrations. This effectively solves the problems of insufficient hardness, poor penetration and penetration rate of existing soluble microneedle patches. It can penetrate skin with different stratum corneum thicknesses and can be applied to various skin conditions, with a wide range of applications.

[0024] 2. The highly penetrating soluble microneedle patch containing small molecule PDRN provided by this invention uses sodium hyaluronate, glycerin, PDRN, and centella asiatica as its main ingredients. In addition to its skin care functions of removing wrinkles, brightening the skin, and eliminating acne marks, it also has anti-inflammatory and repairing effects and can effectively remove the damage to the skin caused by rosacea.

[0025] 3. The highly penetrable soluble microneedle patch containing small molecule PDRN provided by this invention has a small wound, is easy to operate, does not require a sterile environment, and can deliver the effective ingredients into the dermis of the skin through the functional needles, which is more conducive to skin absorption and achieves cosmetic effects. In addition, the microneedle patch is lightweight and compact, can be used for daily skin care, is convenient to carry and easy to operate.

[0026] 4. The preparation method of the highly penetrating soluble microneedle patch containing small molecule PDRN provided by the present invention has few steps, is simple to operate, uses green and safe raw materials, and has no adverse toxic side effects on the human body. Detailed Implementation

[0027] The present invention will be further illustrated below with specific embodiments, but these are not intended to limit the scope of protection of the present invention.

[0028] All raw materials and equipment used in the examples are conventional and can be purchased commercially.

[0029] Example 1

[0030] A highly penetrable, soluble microneedle patch containing small molecule PDRN, consisting of a functional needle and a substrate;

[0031] The functional needle body is prepared from components comprising the following parts by weight:

[0032] Sodium hyaluronate 5g, PDRN 3g, p-hydroxyacetophenone 1.5g, hydroxypropyl cellulose 1.5g, glutathione 3g, tranexamic acid 0.1g, Centella asiatica 5.5g, wherein the length of the PDRN is 100bp;

[0033] The substrate is made of polylactic acid.

[0034] The preparation method of the above-mentioned highly penetrating soluble microneedle patch containing small molecule PDRN includes the following steps;

[0035] (1) Weigh out sodium hyaluronate, PDRN, p-hydroxyacetophenone, hydroxypropyl cellulose, glutathione, tranexamic acid and centella asiatica according to the formula, and make up to 50g of system with 30.4g of pure water. Mix and homogenize at 40℃ and then cool to 25℃ to obtain functional needle solution.

[0036] (2) Dissolve 37.5g of polylactic acid in 112.5g of water and mix well. Place the mixture in an autoclave and sterilize at 121°C for 15 minutes to obtain the base solution.

[0037] (3) Spread 50g of functional needle solution evenly on the surface of the mold until it is full. Place the mold in a horizontal vacuum dryer and dry it for 1.2h at a pressure of 0.08mpa and a temperature of 50℃. Add 150g of base solution and continue to dry it for 1.2h at a pressure of 0.08mpa and a temperature of 50℃. Then freeze dry it at -20℃ for 30h in a freeze dryer. Slowly remove it from the mold to obtain a highly penetrating soluble microneedle patch containing small molecule PDRN.

[0038] Example 2

[0039] A highly penetrable, soluble microneedle patch containing small molecule PDRN, consisting of a functional needle and a substrate;

[0040] The functional needle body is prepared from components comprising the following parts by weight:

[0041] Sodium hyaluronate 4g, PDRN 2g, p-hydroxyacetophenone 1.5g, hydroxypropyl cellulose 2g, glutathione 3g, tranexamic acid 0.25g, Centella asiatica 5.5g; the PDRN has a length of 500bp;

[0042] The substrate is made of polylactic acid.

[0043] The preparation method of the above-mentioned highly penetrating soluble microneedle patch containing small molecule PDRN includes the following steps;

[0044] (1) Weigh out sodium hyaluronate, PDRN, p-hydroxyacetophenone, hydroxypropyl cellulose, glutathione, tranexamic acid and centella asiatica according to the formula, and make up to 50g of system with 31.75g ​​of pure water. Mix and homogenize at 40℃ and then cool to 25℃ to obtain functional needle solution.

[0045] (2) Dissolve 37.5g of polylactic acid in 112.5g of water and mix well. Place the mixture in an autoclave and sterilize at 121°C for 15 minutes to obtain the base solution.

[0046] (3) Spread 50g of functional needle solution evenly on the surface of the mold until it is full. Place the mold in a horizontal vacuum dryer and dry it for 1.2h at a pressure of 0.08mpa and a temperature of 50℃. Add 150g of base solution and continue to dry it for 1.2h at a pressure of 0.08mpa and a temperature of 50℃. Then freeze dry it at -20℃ for 30h in a freeze dryer. Slowly remove it from the mold to obtain a highly penetrating soluble microneedle patch containing small molecule PDRN.

[0047] Example 3

[0048] A highly penetrable, soluble microneedle patch containing small molecule PDRN, consisting of a functional needle and a substrate;

[0049] The functional needle body is prepared from components comprising the following parts by weight:

[0050] Sodium hyaluronate 6.5g, PDRN 1.25g, p-hydroxyacetophenone 1.5g, hydroxypropyl cellulose 2g, glutathione 3g, tranexamic acid 0.25g, Centella asiatica 5.5g; the PDRN has a length of 1500bp;

[0051] The substrate is made of polylactic acid.

[0052] The preparation method of the above-mentioned highly penetrating soluble microneedle patch containing small molecule PDRN includes the following steps;

[0053] (1) Weigh out sodium hyaluronate, PDRN, p-hydroxyacetophenone, hydroxypropyl cellulose, glutathione, tranexamic acid and centella asiatica according to the formula, and make up to 50g of system with 30g of pure water. Mix and homogenize at 40℃ and then cool to 25℃ to obtain functional needle solution.

[0054] (2) Dissolve 37.5g of polylactic acid in 112.5g of water and mix well. Place the mixture in an autoclave and sterilize at 121°C for 15 minutes to obtain the base solution.

[0055] (3) Spread 50g of functional needle solution evenly on the surface of the mold until it is full. Place the mold in a horizontal vacuum dryer and dry it for 1.2h at a pressure of 0.08mpa and a temperature of 50℃. Add 150g of base solution and continue to dry it for 1.2h at a pressure of 0.08mpa and a temperature of 50℃. Then freeze dry it at -20℃ for 30h in a freeze dryer. Slowly remove it from the mold to obtain a highly penetrating soluble microneedle patch containing small molecule PDRN.

[0056] Example 4

[0057] A highly penetrating, soluble microneedle patch containing small molecule PDRN, with the same functional needle components as in Example 1, except that the substrate is made of hydroxymethyl cellulose.

[0058] Example 5

[0059] A highly penetrating, soluble microneedle patch containing small molecule PDRN, with the same functional needle components as in Example 1, except that the substrate is made from maltose.

[0060] Comparative Example 1

[0061] A soluble microneedle patch, consisting of a functional needle and a substrate;

[0062] The functional needle body is prepared from components comprising the following parts by weight:

[0063] Sodium hyaluronate 5g, PDRN 3g, p-hydroxyacetophenone 1.5g, hydroxypropyl cellulose 1.5g, glutathione 3g, tranexamic acid 0.1g, Centella asiatica 5.5g, wherein the PDRN is in filamentous or powdered form.

[0064] The substrate is made of polylactic acid.

[0065] The difference between this comparative example and Example 1 is that the PDRN is a non-uniform PDRN, a mixture of PDRNs of different lengths (500-2000 bp), with poor solubility, and the solubility is only 0.3% to 2%.

[0066] The specific preparation method of the comparative example soluble microneedle patch is the same as that in Example 1.

[0067] Comparative Example 2

[0068] A soluble microneedle patch, consisting of a functional needle and a substrate;

[0069] The functional needle body is prepared from components comprising the following parts by weight:

[0070] Sodium hyaluronate 5g, p-hydroxyacetophenone 1.5g, hydroxypropyl cellulose 1.5g, glutathione 3g, tranexamic acid 0.1g, centella asiatica 5.5g.

[0071] The substrate is made of polylactic acid.

[0072] The difference between this comparative example and Example 1 is that it does not contain small molecule PDRN.

[0073] The specific preparation method of the comparative example soluble microneedle patch is the same as that in Example 1.

[0074] Comparative Example 3

[0075] A soluble microneedle patch, consisting of a functional needle and a substrate;

[0076] The functional needle body is prepared from components comprising the following parts by weight:

[0077] PDRN 0.15g, snow lotus extract 3.5g, centella asiatica extract 2.5g, nicotinamide 5g, hyaluronic acid 2.5g, glycerin 4g, polyacrylic acid 1g, p-hydroxyacetophenone 0.25g, hydrogenated castor oil 0.1g, citric acid 0.05g, wherein the length of the PDRN is 100bp;

[0078] The substrate is made of polylactic acid.

[0079] The specific preparation method of the comparative example soluble microneedle patch is the same as that in Example 1.

[0080] Experimental Example 1

[0081] The microneedle patches prepared in Examples 1-3 and Comparative Examples 1-2 were subjected to mechanical strength and skin puncture tests using a universal testing machine. The results are shown in Table 1.

[0082] 1. Mechanical strength test

[0083] Take a 5×5 microneedle array, needles facing upwards, and place it on the base of the universal testing machine. Adjust the probe to be approximately 0.5 cm from the needle tip, and control the probe to press vertically downwards onto the microneedle at a speed of 0.05 mm / s. When the needle tip shows significant deformation, stop pressing down. According to the pressure (N)-displacement (mm) curve, the force on the microneedle at this point is 1.6 N / needle, and the final displacement is 0.6 mm. The curve is continuous without an inflection point, indicating that the needle tip deformed but did not break.

[0084] 2. Skin puncture test

[0085] Take 6 3x3 sheets Membranes (each 130 μm thick) were stacked on the base of a universal testing machine to simulate human skin. A 10 × 10 microneedle array, needles facing down, was placed on the membrane. The probe was controlled to apply pressure to the array at 30 N for 2 minutes. The array was then removed, the membranes were separated, and the number of micropores in each layer was observed using an optical microscope to calculate the puncture rate.

[0086] Table 1. Penetration Test Results

[0087]

[0088] As shown in Table 1, adding PDRN to the soluble microneedle patch significantly improved its mechanical strength and puncture rate. Example 1 achieved a force of 0.28 N, with a film thickness of 520 μm and a puncture rate of 94%, while the film thickness of 650 μm achieved a puncture rate of 33%. Furthermore, the force and puncture rates of Examples 2 and 3 were significantly higher than those of Comparative Examples 1 and 2. This indicates that the present invention, by adding PDRN to the soluble microneedle patch, effectively solves the problems of insufficient hardness, poor penetration, and low penetration rate found in existing soluble microneedle patches. Moreover, the molecular weight and uniformity of PDRN determine the hardness of the soluble microneedle patch; lower molecular weight PDRN has higher solubility and higher hardness after freeze-drying, making it more conducive to puncture and more suitable for soluble microneedle patch materials. Simultaneously, the mechanical strength and puncture rate of the soluble microneedle patch with added PDRN were higher than those of Comparative Example 2 without added PDRN.

[0089] Experiment Example 2

[0090] The microneedle patches prepared in Examples 1-3 and Comparative Examples 1 and 2 were tested for acne and whitening using a universal testing machine. The results are shown in Tables 2 and 3.

[0091] (1) Experimental instruments

[0092] The skin color meter has eight evenly distributed LED white light sources inside the probe. The emitted light is scattered in all directions inside the probe; some light passes through the skin, and some is scattered by the skin. Only the reflected light from the skin is received by the XYZ sensor inside the probe, so skin color can be measured using the XYZ trichromatic method. The test results are displayed in three ways: XYZ numerical method (trichromatic method), L*a*b value method (L is luminance, a and b are the two chromaticity components), and RGB method (red, green, and blue).

[0093] (2) Experimental volunteers

[0094] Two hundred female volunteers aged 21-40 with acne and brown acne scars were selected for the trial. Participants were divided into five groups, each using one of five different soluble microneedle patch products. Each group was further divided into five subgroups of eight participants. Test areas were designated for each participant, and the test sites were uniformly and gently cleaned before the tests were conducted.

[0095] (3) Testing and experimental environment requirements

[0096] The test was conducted in a constant temperature and humidity environment: temperature: 22±1℃, humidity: 50±5%; the subjects were required to wait in this environment for 20 to 30 minutes before the test.

[0097] (4) Test methods

[0098] Soluble microneedle patches prepared according to Examples 1, 2, 3, Comparative Example 1, and Comparative Example 3 were used as test samples 1-5. The five groups of test subjects used the five different soluble microneedle patches, applying them three times a week for eight weeks. Correspondingly, during the experimental period, the test subjects did not change their daily cleansing habits, and their basic skincare routine consisted only of commercially available "Little Red Box" essence lotion; no other cosmetics were used on the test areas.

[0099] (5) Detection methods

[0100] The test was conducted five times, using microneedle patches, at the first 0 weeks, 1 week, 2 weeks, 4 weeks, and 8 weeks, with follow-up visits at the same time each week. Before the test, the participants cleaned the test site and sat quietly for 10–20 minutes, while the researchers collected data from the test site using testing instruments.

[0101] Table 2. Acne Test Results

[0102]

[0103] As shown in Table 2, the soluble microneedle patches prepared in Examples 1-3 of this invention significantly improved the treatment effect on acne. The reduction rate of acne lesions in the 8th week reached 97.3±1.3%, which was much higher than that in Comparative Example 1 and Comparative Example 3. The effect was extremely significant, especially for rosacea, where the treatment effect was better and faster.

[0104] Table 3. Whitening Test Results

[0105]

[0106] As shown in Table 3, the soluble microneedle patches prepared in Examples 1-3 of this invention exhibit significantly improved whitening effects, with increases in ITA of 4.9°, 5.4°, and 3.6° within 8 weeks, respectively, far exceeding those of Comparative Examples 1 and 3, indicating more significant effects. Furthermore, the reduced molecular weight of PDRN facilitates skin absorption, resulting in faster and more pronounced effects.

Claims

1. A high penetration soluble microneedle patch containing small molecule PDRN, characterized in that, It is made from a functional needle body and a substrate; The functional needle body is prepared from the following components in parts by weight: Sodium hyaluronate 4-7 parts, PDRN 1-3 parts, p-hydroxyacetophenone 1-2 parts, hydroxypropyl cellulose 1-3 parts, glutathione 2-4 parts, tranexamic acid 0.1-0.3 parts, Centella asiatica 5-7 parts; wherein, the PDRN is a uniform PDRN with a length of 100-1500 bp; The substrate is made of a polymer matrix material; the polymer matrix material is one or a combination of two of polylactic acid and hydroxymethyl cellulose.

2. The highly penetrating, soluble microneedle patch containing small molecule PDRN as described in claim 1, characterized in that, The functional needle is prepared from the following components in parts by weight: 5.5-6.5 parts sodium hyaluronate, 2-3 parts PDRN, 1.5 parts p-hydroxyacetophenone, 1.5-2 parts hydroxypropyl cellulose, 3 parts glutathione, 0.1-0.25 parts tranexamic acid, and 5.5 parts centella asiatica.

3. The method for preparing the highly penetrating, soluble microneedle patch containing small molecule PDRN as described in claim 1, characterized in that, The steps include the following: (1) Weigh out sodium hyaluronate, PDRN, p-hydroxyacetophenone, hydroxypropyl cellulose, glutathione, tranexamic acid and centella asiatica according to the formula, dissolve them in 23.7~35.9 parts by weight of water to prepare a 50-part system, mix them evenly at 35~45℃ to obtain a functional injection solution. (2) The polymer matrix material is dissolved in water and mixed evenly, and then sterilized by autoclaving to obtain the base solution; (3) Add the functional needle solution to the microneedle mold, vacuum dry it, add the base solution, continue vacuum drying, and then freeze dry it to obtain a highly penetrating soluble microneedle patch containing small molecule PDRN.

4. The preparation method according to claim 3, characterized in that, In step (2), the mass ratio of the polymer matrix material to water is 1:

3.

5. The preparation method according to claim 3, characterized in that, In step (3), the volume ratio of the functional needle solution to the base solution is 1:

3.

6. The preparation method according to claim 3, characterized in that, In step (3), the vacuum drying is performed by drying for 1 to 1.5 hours under conditions of pressure of 0.06 to 0.09 MPa and temperature of 50°C.

7. The preparation method according to claim 3, characterized in that, In step (4), the vacuum drying is performed at a temperature of -20℃ to -30℃ for 24 to 36 hours.

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