Soluble microneedle patch, microneedle mask, microneedle smoking cessation patch and preparation method thereof

Abstract

The invention relates to the technical field of external preparations, in particular to a soluble microneedle patch, a microneedle mask, a microneedle smoking cessation patch and a preparation method thereof.The soluble microneedle patch comprises a microneedle layer and a backing layer, the microneedle layer is prepared from a microneedle matrix solution, the backing layer is prepared from a backing matrix solution, and the backing matrix solution comprises hyaluronic acid and povidone K30; the mass ratio of the hyaluronic acid to the povidone K30 is (3-4): 1, and the concentration of the backing matrix solution is 1.2-1.8 g / ml. The problems that a soluble microneedle is insufficient in mechanical strength, cannot penetrate into the skin for administration, is prone to fragmentation during administration, and is high in pain feeling and poor in comfort can be solved.

Description

Technical Field

[0001] The present invention relates to the technical field of external preparations, in particular to a soluble microneedle patch, a microneedle facial mask, a microneedle smoking cessation patch and a preparation method thereof. Background Art

[0002] Microneedles are tiny needles with a diameter of 30 to 80 μm and a length ranging from several hundred microns to several millimeters, made of silicon, metal or other polymer materials through microelectronic manufacturing technology or micromolding technology. They can break through the skin's stratum corneum barrier in a directional manner, forming multiple micron-level mechanical channels on the skin surface, and directly transport them to the epidermis or upper dermis, significantly improving the delivery efficiency of the active ingredients. According to different release mechanisms, microneedles can be divided into solid microneedles, hollow microneedles, coated microneedles, soluble microneedles and hydrogel microneedles. Among them, soluble microneedles refer to microneedles prepared by encapsulating the active ingredients in the needle body using biodegradable water-soluble polymers or polysaccharides. When used, the microneedle is inserted into the skin, the needle body dissolves after contact with the skin's interstitial fluid, and the active ingredients are released locally.

[0003] The soluble microneedle includes a microneedle layer and a backing layer. The microneedle layer includes a plurality of tiny needle-like structures, and the plurality of tiny needle-like structures are evenly distributed on the backing layer. The backing material used to prepare the backing layer can be divided into tough materials and brittle materials according to its mechanical properties. In the prior art, the commonly used backing materials are tough material hyaluronic acid (HA) and brittle material polyvinylpyrrolidone (PVP) K90. The tough material hyaluronic acid (HA) has good toughness and plasticity; the soluble microneedles prepared using HA are not easy to break, but the mechanical strength is insufficient and cannot penetrate the skin for drug administration. The brittle material polyvinylpyrrolidone (PVP) K90 has strong hardness and is not easy to deform; the microneedles prepared using PVP K90 have good mechanical strength, but they are easy to break during drug administration, the pain is strong, the comfort is poor, and the high concentration has certain cytotoxicity, which poses a safety hazard. Summary of the invention

[0004] The present invention provides a soluble microneedle patch, a microneedle facial mask, a microneedle smoking cessation patch and a preparation method thereof, which can solve the problems that the soluble microneedles have insufficient mechanical strength, cannot penetrate the skin to administer drugs, are easily broken during administration, have strong pain, and have poor comfort.

[0005] This application provides the following technical solutions:

[0006] A soluble microneedle patch comprises a microneedle layer and a backing layer, wherein the microneedle layer is made of a microneedle matrix solution, and the backing layer is made of a backing matrix solution. The backing matrix solution comprises hyaluronic acid and polyvinylpyrrolidone K30, wherein the mass ratio of hyaluronic acid to polyvinylpyrrolidone K30 is 3 to 4:1, and the concentration of the backing matrix solution is 1.2 to 1.8 g / ml.

[0007] A method for preparing a soluble microneedle patch comprises the following steps:

[0008] S1. Prepare a master mold. The microneedle shape of the master mold is conical, the microneedle height is 200-600 microns, and the diameter of the bottom of the microneedle is 500-800 microns.

[0009] S2. Evenly mix the polydimethylsiloxane and the polydimethylsiloxane curing agent, add them to the master mold, heat and cure them, and peel them off to obtain a microneedle mold.

[0010] S3. Take the microneedle matrix solution and add it to the surface of the microneedle mold. Centrifuge at 3000-4000 r / min for 10-20 min to remove excess solution on the mold surface.

[0011] S4. Dry and centrifuge at 3000-4000 r / min for 5-10 min.

[0012] S5. Take the backing matrix solution and add it to the microneedle mold, and centrifuge it at a speed of 3000-4000 r / min for 5-10 minutes.

[0013] S6, drying, demoulding, and obtaining a soluble microneedle patch.

[0014] Application of soluble microneedle patch in the preparation of microneedle facial mask or microneedle smoking cessation patch.

[0015] Beneficial effects: Hyaluronic acid (HA) is an acidic mucopolysaccharide with good moisturizing properties and biocompatibility. It can help keep the skin moist, reduce dryness and irritation, and enhance the skin's barrier function. At the same time, hyaluronic acid has good toughness and plasticity. Polyvidone (PVP) K30 is a water-soluble polymer with good film-forming and adhesion properties. It can enhance the mechanical strength and flexibility of the backing layer while providing good adhesion. Low molecular weight HA and PVP K30 are selected as the backing materials, and the soluble microneedles produced are both tough and brittle. The mechanical strength of the soluble microneedles is guaranteed to ensure that the microneedles penetrate the skin to deliver the drug, with little pain and high comfort, and can effectively avoid the phenomenon of microneedles breaking during drug delivery.

[0016] During the preparation of the soluble microneedle patch, the geometric parameters of the microneedles can be precisely controlled through the master mold to ensure that the microneedles can effectively penetrate the skin and improve the transdermal absorption rate of the drug. The needle spacing can ensure that the microneedles are evenly distributed on the skin and avoid skin damage caused by excessive concentration. The polydimethylsiloxane (PDMS) mold can replicate the microneedle structure of the master mold with high precision to ensure that the shape and size of the microneedles are consistent. The PDMS mold is soft and easy to peel off, which is convenient for subsequent preparation steps and can be used multiple times, reducing the preparation cost. Centrifugation is used to ensure that the microneedle matrix solution is evenly filled into the micropores of the microneedle mold to avoid the generation of bubbles and voids. The centrifugation process removes excess solution on the mold surface, ensures the effective connection between the microneedles and the backing layer, and ensures that the microneedles have both toughness and brittleness. Drying can effectively reduce the mass transfer phenomenon between the microneedle matrix solution and the backing matrix solution to ensure the efficacy of the microneedles. Centrifugation can accelerate the drying of the microneedle matrix solution. The backing matrix solution is ensured to be evenly covered on the microneedle layer through the centrifugation process, avoiding the generation of bubbles and voids, so that the backing layer provides physical support, and enhances the adhesion and stability of the microneedle patch or microneedle mask. The dried soluble microneedles are easy to remove from the mold, while avoiding deformation and dissolution caused by excessive humidity. The soluble microneedles prepared by this technical solution are of high precision, the microneedles can effectively penetrate the skin, improve the transdermal absorption rate of drugs, and achieve efficient drug delivery. The size and shape design of the microneedles ensure that it is almost painless when penetrating the skin, improving the comfort of the patient. The backing layer provides physical support and protection to ensure the stability and effectiveness of the microneedles.

[0017] The effective ingredients in traditional facial masks are generally macromolecular substances. Due to the skin barrier effect, substances above 500 Daltons cannot penetrate the skin barrier and exert their effects. Only 10-20% of the ingredients can penetrate the skin to take effect, and the others only diffuse on the skin surface, resulting in the generally poor effects of traditional cosmetic facial masks. This technical solution applies soluble microneedles to patches or facial masks. The microneedles can break through the skin stratum corneum barrier and have a high delivery efficiency. This technical solution applies soluble microneedle patches to facial masks. Compared with traditional facial masks, the amount of core effective ingredients used is less, the shelf life is longer, and the therapeutic effect is significantly better than similar traditional facial masks. Moreover, polymer microneedles are small in shape, strong in toughness, easy to penetrate the skin, with little pain, and safer and more comfortable to use.

[0018] The main active ingredient of the smoking cessation patch currently on the market is nicotine, with the chemical name: 3-(1-methyl-2-pyrrolidinyl)pyridine. It slowly and continuously absorbs a small amount of nicotine through the skin, thereby gradually desensitizing the nicotine acetylcholine receptors in the brain. After using it for a period of time, the nicotine intake of smokers gradually drops to a minimum, thereby playing a role in quitting smoking. It is used to treat tobacco dependence, can reduce nicotine cravings and withdrawal symptoms, and thus assist smokers who are willing to quit smoking to quit smoking. The smoking cessation patch is used to remove the protective aluminum foil, stick it on clean, dry, and intact skin, and press it with the palm of your hand for 10 seconds. However, there are two problems during use: First, there is usually a more serious skin allergic reaction, because the patch is applied for a long time, and the use site is prone to adverse reactions such as burning, edema, erythema, itching, eczema, urticaria and small blisters. Second, the dosage of the patch is unstable, and transdermal absorption is affected by the skin surface barrier, resulting in uneven dosage entering the skin, which may cause some side effects of the central nervous system such as headache, dizziness, nausea and sleep disorders. This technical solution combines soluble microneedles with smoking cessation drugs, and uses microneedles to break through the skin stratum corneum barrier, with a higher delivery efficiency. Compared with traditional nicotine patches, it has several advantages: First, it can ensure that more effective ingredients are delivered to the epidermis or upper dermis, and a small amount of effective ingredients can be used to achieve the effect of traditional patches, thereby reducing the cost of core effective ingredients. Second, the microneedle method is faster in drug administration. The microneedle tip enters the human skin, and the tip quickly dissolves and releases the drug, reducing the application time of the patch backing, thereby effectively reducing the irritation reaction to the skin surface. Third, compared with traditional smoking cessation patches, the microneedle unit drug loading is more accurate, which can ensure that the drug dosage entering the human body is more accurate, thereby effectively avoiding skin adverse reactions caused by uneven drug dosage.

[0019] Furthermore, after the microneedle matrix solution in step S4 is dried, hyaluronic acid is added to the microneedle mold and centrifuged at a speed of 3000 to 4000 r / min for 10 to 20 minutes.

[0020] The hyaluronic acid enters the micropores of the mold and fills the mold to form a split microneedle. This can increase the structural strength of the microneedle, making it easier to penetrate the skin and reduce the risk of breakage.

[0021] Further, in the drying described in step S6, the microneedle mold is placed in a dryer containing a saturated potassium carbonate solution and a silica gel dryer in sequence for drying.

[0022] Saturated potassium carbonate solution can provide a mild drying environment to prevent the water in the microneedle matrix solution from evaporating too quickly, causing structural deformation. Silica gel is an efficient desiccant that can quickly absorb surrounding moisture and provide a low-humidity drying environment to ensure that the moisture in the microneedle matrix solution is completely removed. Compared with using one dryer, the combination of two dryers can ensure the drying effect of the microneedles, ensure the integrity of the microneedles and the stability of the active ingredients.

[0023] A soluble microneedle mask comprises a soluble microneedle patch. A microneedle matrix solution of a microneedle layer comprises the following components in parts by weight: 10-15 parts of arbutin, 1-5 parts of fullerene, 5-10 parts of nicotinamide, 3-10 parts of vitamin E, 3-5 parts of tranexamic acid, 0.5-3 parts of ergostayine, 1-3 parts of ectoine, 5-10 parts of glutathione, and 0.05-0.1 parts of methylparaben.

[0024] The preparation method of the microneedle matrix solution of the microneedle layer is as follows:

[0025] 1) Add deionized water to 10-15 parts of arbutin, 1-5 parts of fullerene, 3-10 parts of vitamin E, 0.5-3 parts of ergostin, 1-3 parts of ectoine, and 0.05-0.1 parts of methylparaben according to the weight ratio, stir evenly, and prepare solution I;

[0026] 2) Take deionized water, add sodium hydroxide solution to adjust the pH to 9.0, add 5-10 parts of nicotinamide, 3-5 parts of tranexamic acid, and 5-10 parts of glutathione, stir evenly, and prepare solution II;

[0027] 3) Mix solution I and solution II, adjust the pH to 6.8-7.0 with triethanolamine or sodium hydroxide, and make up to volume with deionized water to prepare a microneedle matrix solution for the microneedle layer.

[0028] The microneedle matrix solution contains a variety of effective ingredients, which have multiple biological activities and can work synergistically to improve the drug delivery efficiency and therapeutic effect. The ratio of multiple effective ingredients is the best ratio formula screened out after multiple laboratory formula studies. After zebrafish animal test efficacy test and human sensory test surface, the prepared microneedle mask has obvious whitening effect. Arbutin and tranexamic acid have whitening effects, can inhibit the production of melanin and improve skin color. Fullerene and vitamin E have strong antioxidant capacity, can remove free radicals and reduce skin aging. Glutathione and ergothioneine have the effect of repairing skin damage and promoting cell regeneration, and enhance the self-repair ability of the skin. Ecdoin has good moisturizing properties, can maintain the moisture of the skin, reduce dryness and wrinkles. Methylparaben, as a preservative, can effectively prevent the growth of microorganisms and ensure the long-term stability of the microneedle matrix solution. By precisely controlling the ratio and pH value of each component, the low irritation of the microneedle matrix solution is ensured, and irritation and allergic reactions to the skin are reduced.

[0029] A soluble microneedle smoking cessation patch comprises a soluble microneedle patch, wherein a microneedle matrix solution of a microneedle layer comprises the following components in parts by weight: 5 parts of nicotine, 30 parts of mint and 25 parts of borneol.

[0030] The preparation method of the microneedle matrix solution of the microneedle layer is as follows: 5 parts of nicotine, 30 parts of mint, and 25 parts of borneol are added according to mass fractions, and deionized water is added to dissolve to prepare the microneedle matrix solution of the microneedle layer, wherein each 1 ml of the microneedle matrix solution contains 7 mg of nicotine.

[0031] Nicotine is a commonly used smoking cessation aid. Microneedle delivery can improve the transdermal absorption rate of nicotine and reduce the side effects of oral administration. Mint has a cooling and sedative effect, which can relieve discomfort and improve the comfort of users. Borneol has a cooling and anti-inflammatory effect, which can further enhance the effect of mint and reduce skin irritation. Each 1ml of microneedle matrix solution contains 7mg of nicotine. The microneedle smoking cessation patch prepared by the microneedle matrix solution has a more obvious smoking cessation and reduction effect, and has a milder irritation reaction to the skin surface. It has obvious clinical drug advantages and broad application market prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 Schematic diagram of the preparation method of a soluble microneedle patch, a microneedle facial mask and a microneedle smoking cessation patch of the present invention; wherein ①: mother mold, ②: microneedle mold, ③: adding microneedle matrix solution to the surface of the microneedle mold, ④: the microneedle matrix solution enters the micropores after centrifugation, ⑤: removing excess microneedle matrix solution, ⑥: drying, ⑦: adding a backing matrix solution to the microneedle mold, ⑧: centrifugation to form a backing layer, ⑨: drying and demoulding to obtain the product.

[0033] Figure 2This is a microneedle needle shape diagram of a master mold of a method for preparing a soluble microneedle patch, a microneedle facial mask, and a microneedle smoking cessation patch of the present invention.

[0034] Figure 3 This is a zebrafish melanin area and grayscale analysis diagram of a soluble micro-mask in Example 1 of the present invention; zebrafish embryos were treated with test samples of different concentrations for 24 hours, and back photos were collected, such as Figure 3 The melanin area and gray value were obtained using imageJ software, and statistical analysis was performed using Graphpad Prism 8.0. Figure 3 NC represents negative control, PC represents positive control. ***, P<0.001: extremely significant difference, n=3.

[0035] Figure 4 This is a comparison chart of human sensory test results of a soluble micro mask according to Example 1 of the present invention. DETAILED DESCRIPTION

[0036] The following is further described in detail through specific implementation methods:

[0037] Embodiment 1

[0038] A soluble microneedle facial mask comprises a soluble microneedle patch, which comprises a microneedle layer and a backing layer. The microneedle layer is made of a microneedle matrix solution, and the backing layer is made of a backing matrix solution.

[0039] The microneedle matrix solution of the microneedle layer includes the following components in parts by weight: 10-15 parts of arbutin, 1-5 parts of fullerene, 5-10 parts of niacinamide, 3-10 parts of vitamin E, 3-5 parts of tranexamic acid, 0.5-3 parts of ergostayine, 1-3 parts of ectoine, 5-10 parts of glutathione, and 0.05-0.1 parts of methylparaben.

[0040] The backing matrix solution of the backing layer includes hyaluronic acid and povidone K30, the mass ratio of hyaluronic acid to povidone K30 is 3-4:1, and the concentration of the backing matrix solution is 1.2-1.8 g / ml. Preferably, the mass ratio of hyaluronic acid to povidone K30 is 3:1, the concentration of the backing matrix solution is 1.5 g / ml, and the hyaluronic acid is low molecular weight hyaluronic acid.

[0041] A method for preparing a soluble microneedle mask, such as Figure 1 As shown, the following steps are included:

[0042] S1. Prepare a microneedle matrix solution for a microneedle layer, the preparation method is as follows:

[0043] S1-1. Take an appropriate amount of boiled and cooled deionized water, filter it through a 0.22um sterile filter, and set aside.

[0044] S1-2. Add 10-15 parts of arbutin, 1-5 parts of fullerene, 3-10 parts of vitamin E, 0.5-3 parts of ergostin, 1-3 parts of ectoine, and 0.05-0.1 parts of methylparaben according to their mass proportions, add appropriate amount of deionized water, stir well, and prepare solution I.

[0045] S1-3. Take an appropriate amount of deionized water, add sodium hydroxide solution to adjust the pH to 9.0, add 5-10 parts of nicotinamide, 3-5 parts of tranexamic acid, and 5-10 parts of glutathione in sequence, stir evenly, and prepare solution II.

[0046] S1-4. Mix solution I and solution II, adjust the pH to 6.8-7.0 with triethanolamine or sodium hydroxide, and make up the volume with deionized water to prepare a microneedle matrix solution of a soluble microneedle layer. The total amount of the prepared microneedle matrix solution is 100 parts.

[0047] S2. Prepare a backing matrix solution for the backing layer, the preparation method is as follows:

[0048] The hyaluronic acid and povidone K30 are mixed evenly, and deionized water is added to prepare a backing matrix solution of the backing layer, wherein the mass ratio of hyaluronic acid to povidone K30 is 3:1, and the concentration of the backing matrix solution is 1.5 g / ml.

[0049] S3. According to the application requirements of soluble microneedles, a master mold is prepared by 3D printing technology, and the master mold is made of polymer resin material. Figure 2 As shown, the master mold includes a base 1, on which a plurality of microneedles 2 are arrayed. The microneedles are conical in shape, the microneedle height H is 200 microns, the spacing between the microneedles 2 is 1000 microns, the microneedle bottom diameter D is 500 microns, and the base diameter is 11.34 mm.

[0050] S4, reversely copy the master mold to obtain a PDMS microneedle mold. Mix polydimethylsiloxane (PDMS) and PDMS curing agent in a mass ratio of 9:1, add them to the master mold, heat and cure them at 80°C for 8-10 hours, and then peel off to obtain a polydimethylsiloxane (PDMS) mold. Cut and combine the PDMS mold to obtain a microneedle mold that meets the requirements.

[0051] S5. Take the microneedle matrix solution of the soluble microneedle layer prepared in step S1 and add it to the surface of the microneedle mold. Centrifuge at 3000-4000 r / min for 10-20 min to allow the microneedle matrix solution to enter the micropores of the mold and fill the needle tip part of the mold, and remove excess solution on the surface of the mold.

[0052] S6. Drying: centrifuging at 3000-4000 r / min for 5-10 min at room temperature to accelerate the drying of the microneedle matrix solution.

[0053] S7. Take the backing matrix solution prepared in step S2 and add it to the microneedle mold, and centrifuge it at a speed of 3000-4000 r / min for 5-10 min to form a backing layer of the microneedle.

[0054] S8. At room temperature, place the microneedle mold in a dryer containing a saturated potassium carbonate solution (relative humidity of about RH45%) and a silica gel dryer in turn. The total drying time is 24 to 48 hours (the drying time of the microneedle mold in the two dryers is the same), and then demold with tweezers to obtain a soluble microneedle mask.

[0055] Experiment 1: Efficacy test of soluble microneedle mask in zebrafish animal experiment

[0056] Take 1 soluble microneedle mask, cut it into pieces, dissolve it in 30ml deionized water, control the temperature at 38-40℃, remove the undissolved mask after 60 minutes, take the solution to prepare 0.001% and 0.002% solutions of ergothioneine, add them to 24-well multi-well culture plates, add 2ml to each well, put a zebrafish fertilized egg in each well, set up negative control group and positive control group at the same time, and repeat the experiment 3 times. The tyrosinase activity inhibition rate, melanin inhibition rate, melanin area and grayscale were tested respectively. The test results are shown in Table 1, Table 2, Table 3 and Figure 3 The test results showed that the tyrosinase activity inhibition rate of 0.002% sample was 41.56%. The melanin inhibition rate was 47.29%, the melanin area was reduced by 48.53%, the gray value was reduced by 48.62%, and the efficacy was evaluated as significant. The zebrafish in vitro test showed that the microneedle mask has a significant whitening effect.

[0057] Table 1. Tyrosinase activity inhibition rate (475nm absorbance value)

[0058]

[0059] Note: PC stands for positive control; NC stands for negative control; Repeat # 1~ # 3 represents three replicates; L-dopa represents the negative control with only L-dopa added

[0060] Table 2. Melanin inhibition rate (490nm absorbance value)

[0061]

[0062] Note: PC stands for positive control; NC stands for negative control; Repeat #1~ # 3 represents three replicates; NaOH represents the negative control with only NaOH added

[0063] Table 3. Melanin area and grayscale melanin area

[0064]

[0065] Melanin Grayscale

[0066]

[0067] Note: The zebrafish embryos were treated with different concentrations of the test samples for 24 hours, and the back photos were collected. The melanin area and gray value were obtained using imageJ software, and statistical analysis was performed using Graphpad Prism 8.0. NC represents the negative control, and PC represents the positive control.

[0068] Experiment 2: Human sensory test of soluble microneedle mask

[0069] like Figure 4 As shown in the figure, two human sensory testers were selected to clean their faces with water first, and then the corners of the eyes and cheeks were photographed under the same shooting conditions before and 60 minutes after using the microneedle mask. The results showed that after using the microneedle mask, wrinkles were reduced and the skin became whiter than before, indicating that the whitening and wrinkle removal effect was more obvious.

[0070] Embodiment 2

[0071] A soluble microneedle smoking cessation patch comprises a soluble microneedle patch, wherein the soluble microneedle patch comprises a microneedle layer and a backing layer, wherein the microneedle layer is made of a microneedle matrix solution, and the backing layer is made of a backing matrix solution.

[0072] The microneedle matrix solution of the microneedle layer includes the following components in parts by weight: 5 parts of nicotine, 30 parts of mint, and 25 parts of borneol.

[0073] The backing matrix solution of the backing layer includes hyaluronic acid and povidone K30, the mass ratio of hyaluronic acid to povidone K30 is 3-4:1, and the concentration of the backing matrix solution is 1.2-1.8 g / ml. Preferably, the mass ratio of hyaluronic acid to povidone K30 is 3:1, the concentration of the backing matrix solution is 1.5 g / ml, and the hyaluronic acid is low molecular weight hyaluronic acid.

[0074] A method for preparing a soluble microneedle smoking cessation patch comprises the following steps:

[0075] S1. Prepare a microneedle matrix solution for a microneedle layer, the preparation method is as follows:

[0076] According to the weight ratio, 5 parts of nicotine, 30 parts of mint and 25 parts of borneol were added, and deionized water was added to dissolve to prepare a microneedle matrix solution of the microneedle layer. Each 1 ml of the microneedle matrix solution contained 7 mg of nicotine.

[0077] S2. Prepare a backing matrix solution for the backing layer, the preparation method is as follows:

[0078] Hyaluronic acid and povidone K30 are mixed evenly, and deionized water is added to prepare a backing matrix solution of the backing layer, wherein the mass ratio of hyaluronic acid to povidone K30 is 3:1, and the concentration of the backing matrix solution is 1.5 g / ml.

[0079] S3. According to the application requirements of soluble microneedles, a master mold is prepared by 3D printing technology, and the master mold is made of polymer resin material. Among them, the microneedle needle shape of the master mold is conical, the microneedle height H is 600 microns, the spacing between microneedles is 1000 microns, the microneedle bottom diameter D is 800 microns, and the base diameter is 12.56 mm.

[0080] S4, reversely copy the master mold to obtain a PDMS microneedle mold. Mix polydimethylsiloxane (PDMS) and PDMS curing agent in a mass ratio of 9:1, add them to the master mold, heat and cure them at 80°C for 8-10 hours, and then peel off to obtain a polydimethylsiloxane (PDMS) mold. Cut and combine the PDMS mold to obtain a microneedle mold that meets the requirements.

[0081] S5. Take the microneedle matrix solution of the soluble microneedle layer prepared in step S1 and add it to the surface of the microneedle mold. Centrifuge at 3000-4000 r / min for 10-20 min to allow the microneedle matrix solution to enter the micropores of the mold and fill the needle tip part of the mold.

[0082] S6. Drying: centrifuging at 3000-4000 r / min for 5-10 min at room temperature to accelerate the drying of the microneedle matrix solution.

[0083] S7. Add 1.5 g / ml hyaluronic acid to the microneedle mold, centrifuge at 3000-4000 r / min for 10-20 min, allow the solution to enter the micropores of the mold and fill the mold, and dry the solution at the same time to form a split microneedle.

[0084] S8. Take the backing matrix solution prepared in step S2 and add it to the microneedle mold, and centrifuge it at a speed of 3000-4000 r / min for 5-10 min to form a backing layer of the microneedle.

[0085] S8. Place the mold in a constant temperature and humidity dryer (relative humidity of about RH45%), the drying temperature is 50°C, the drying time is 240 minutes, and after it is completely dried, remove the mold with tweezers to obtain a soluble microneedle smoking cessation patch. Drying at 50°C helps maintain the stability of the microneedle matrix solution and the backing matrix solution, ensures the activity of the drug during the drying process, avoids degradation or inactivation caused by high temperature, and ensures drying efficiency.

[0086] S9. Microneedle mechanical property testing: The microneedles were subjected to a mechanical property test by applying a vertical downward pressure perpendicular to the substrate. The results showed that the microneedles did not break during the mechanical property test, and their displacement increased with the increase of load, indicating that the microneedle array has good mechanical properties and will not break and remain in the skin during use.

[0087] S10. Microneedle penetration performance test: The pig skin treated with microneedles was stained with methylene blue solution. The results showed that the array microchannels formed by the microneedles were swollen and the microneedles maintained mechanical toughness in the swollen state, so that the microneedles could be completely removed from the skin.

[0088] Experiment 3: Human efficacy test of soluble microneedle smoking cessation patch

[0089] Two smokers were randomly selected as human efficacy testers, and three days before the test, a questionnaire survey was conducted to confirm that their average daily smoking volume was 25 to 30 cigarettes.

[0090] After the test started, at 9 am, 2 pm and 7 pm, the soluble microneedle smoking cessation patch was applied to clean, dry and intact skin. After applying the soluble microneedle smoking cessation patch, press the palm of your hand for 10 seconds to ensure that the microneedles enter the human skin. After 1 hour, wait for the microneedle tips to dissolve in the skin and then remove the soluble microneedle smoking cessation patch. On the day of the statistical test, the total number of cigarettes smoked by the two testers was 16 and 20 respectively, which was significantly lower than the average smoking amount in the previous three days. The survey showed that during the medication process, they sometimes felt that they did not want to smoke, but they did not have symptoms such as headaches, dizziness, and nausea.

[0091] After an interval of 3 days, at 9 am, 2 pm and 7 pm, commercially available nicotine patches were applied to clean, dry, intact skin, and pressed with the palm of the hand for 10 seconds after applying the commercially available nicotine patches. The application time was 4 hours. On the day of the statistical test, the total number of cigarettes smoked by the two testers was 21 and 25 respectively, which was a certain decrease compared with the average smoking volume in the previous three days, but the downward trend was not obvious. The survey reflected that they felt panic during the medication process, and occasionally had symptoms such as headache and dizziness, which was probably caused by the uneven release of the patch. Moreover, due to the long application time of traditional patches, obvious adverse reactions such as erythema can be seen on the skin surface.

[0092] Experiment 4: Animal Experimental Test of Soluble Microneedle Smoking Cessation Patch

[0093] Experimental method name: Determination of nicotine concentration in dog plasma by liquid phase tandem mass spectrometry.

[0094] Instruments: Ultra-high performance liquid chromatograph (LC-30AD, Shimadzu Corporation); triple quadrupole mass spectrometer (TQ6500, AB Corporation).

[0095] Standard: nicotine; Internal standard: carbamazepine.

[0096] Sample pretreatment method: direct protein precipitation method; injection volume: 8μL.

[0097] Linear range: Nicotine 5-400ng / mL.

[0098] Experimental method: Two pieces of commercially available nicotine patch and two pieces of soluble microneedle smoking cessation patch were attached to the abdominal hair removal area of ​​two dogs as the reference group and the experimental group, and then venous blood was collected from the dogs at 0h before administration and 30min, 1h, 2h, 3h, 5h, 7h, 1d, and 2d after administration. The blood was collected into pre-labeled EDTA anticoagulation vacuum blood collection tubes, mixed and centrifuged (1700g, 4℃, 10min), and the mixed whole blood was centrifuged within 2h and stored at -80℃ for testing.

[0099] The standard curve samples and quality control samples were prepared by diluting different stock solutions. The concentrations of the 8 standard curve samples were 5, 10, 20, 40, 80, 120, 200, and 400 ng / mL. The lower limit of quantification (LLOQ) was 5 ng / mL, and the upper limit of quantification (ULOQ) was 400g / mL. The concentrations of the quality control samples were 20, 80, 200, and 20000 ng / mL. The standard curve samples and quality control samples were prepared using EDTA-anticoagulated canine plasma. The standard curve samples and quality control samples were prepared before the unknown samples were measured and stored at -80°C. Before each sample test, they were taken out, melted, and injected together with the unknown samples.

[0100] The internal standard working solution was carbamazepine solution, and the working solution concentration was 10 ng / mL. The internal standard working solution was prepared and packaged before the unknown sample was determined and stored at 4°C. Before each test, the internal standard working solution was taken out and restored to room temperature for use. The standard curve was obtained: Y = 0.028357X + 0.019835. The precision and accuracy of the intra-batch and inter-batch sample tests met the requirements.

[0101] The test results are shown in Table 4. The experimental results show that the blood drug concentration data of the soluble microneedle smoking cessation patch group are significantly higher than the commercially available nicotine patch group at the same sampling time point, so the nicotine content in the blood of the animals is higher, and the smoking cessation effect is significantly better.

[0102] Table 4

[0103]

[0104] The above are only embodiments of the present invention. The invention is not limited to the field involved in this implementation case. The common knowledge such as the known specific structure and characteristics in the scheme is not described in detail here. It should be pointed out that for those skilled in the art, several deformations and improvements can be made without departing from the structure of the present invention, which should also be regarded as the protection scope of the present invention, and these will not affect the effect of the implementation of the present invention and the practicality of the patent. The scope of protection required by this application shall be based on the content of its claims, and the specific implementation methods and other records in the specification can be used to interpret the content of the claims.

Claims

1. A soluble microneedle patch, characterized in that: The soluble microneedle patch includes a microneedle layer and a backing layer, wherein the microneedle layer is made of a microneedle matrix solution, and the backing layer is made of a backing matrix solution. The backing matrix solution includes hyaluronic acid and polyvinylpyrrolidone K30, wherein the mass ratio of hyaluronic acid to polyvinylpyrrolidone K30 is 3 to 4:1, and the concentration of the backing matrix solution is 1.2 to 1.8 g / ml.

2. A method for preparing the soluble microneedle patch according to claim 1, characterized in that: The steps include: S1. Prepare a master mold, the microneedle shape of the master mold is conical, the microneedle height is 200-600 microns, and the diameter of the bottom of the microneedle is 500-800 microns; S2, mixing polydimethylsiloxane and polydimethylsiloxane curing agent evenly, adding to the master mold, heating and curing, and peeling off to obtain a microneedle mold; S3, adding the microneedle matrix solution to the surface of the microneedle mold, centrifuging at 3000-4000 r / min for 10-20 min to remove excess solution on the mold surface; S4, drying, centrifuging at 3000-4000 r / min for 5-10 min; S5, adding the backing matrix solution to the microneedle mold, and centrifuging at 3000-4000 r / min for 5-10 min; S6, drying, demoulding, and obtaining a soluble microneedle patch.

3. The method according to claim 2, characterized in that: After the microneedle matrix solution is dried in step S4, hyaluronic acid is added to the microneedle mold and centrifuged at a speed of 3000 to 4000 r / min for 10 to 20 minutes.

4. The method according to claim 2, characterized in that: In step S6, the microneedle mold is placed in a dryer containing a saturated potassium carbonate solution and a silica gel dryer in turn for drying.

5. Use of the soluble microneedle patch according to claim 1 or the soluble microneedle patch prepared by the method of any one of claims 2 to 4 in preparing a microneedle facial mask or a microneedle smoking cessation patch.

6. A soluble microneedle facial mask, characterized in that: The invention comprises the soluble microneedle patch of claim 1 or the soluble microneedle patch prepared by the method of any one of claims 2 to 4, wherein the microneedle matrix solution of the microneedle layer comprises the following components in parts by weight: 10-15 parts of arbutin, 1-5 parts of fullerene, 5-10 parts of nicotinamide, 3-10 parts of vitamin E, 3-5 parts of tranexamic acid, 0.5-3 parts of ergostayine, 1-3 parts of ectoine, 5-10 parts of glutathione, and 0.05-0.1 parts of methylparaben.

7. The soluble microneedle facial mask according to claim 6, characterized in that: The preparation method of the microneedle matrix solution of the microneedle layer is as follows: 1) Add deionized water to 10-15 parts of arbutin, 1-5 parts of fullerene, 3-10 parts of vitamin E, 0.5-3 parts of ergostin, 1-3 parts of ectoine, and 0.05-0.1 parts of methylparaben according to the weight ratio, stir evenly, and prepare solution I; 2) Take deionized water, add sodium hydroxide solution to adjust the pH to 9.0, add 5-10 parts of nicotinamide, 3-5 parts of tranexamic acid, and 5-10 parts of glutathione, stir well, and prepare solution II; 3) Mix solution I and solution II, adjust the pH to 6.8-7.0 with triethanolamine or sodium hydroxide, and make up to volume with deionized water to prepare a microneedle matrix solution for the microneedle layer.

8. A soluble microneedle smoking cessation patch, characterized by: The invention comprises the soluble microneedle patch of claim 1 or the soluble microneedle patch prepared by the method of any one of claims 2 to 4, wherein the microneedle matrix solution of the microneedle layer comprises the following components in parts by weight: 5 parts of nicotine, 30 parts of mint, and 25 parts of borneol.

9. The soluble microneedle smoking cessation patch according to claim 8, characterized in that: The preparation method of the microneedle matrix solution of the microneedle layer is as follows: 5 parts of nicotine, 30 parts of mint, and 25 parts of borneol are added according to mass fractions, and deionized water is added to dissolve to prepare the microneedle matrix solution of the microneedle layer, wherein each 1 ml of the microneedle matrix solution contains 7 mg of nicotine.

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