Soluble microneedle combined patch as well as preparation method and application thereof

Abstract

The invention relates to a soluble microneedle combined patch as well as a preparation method and application thereof. The soluble microneedle combined patch comprises a microneedle patch and a permeation enhancing patch, the microneedle patch comprises a microneedle carrier and a soluble microneedle array distributed on the lower surface of the microneedle carrier; the microneedle carrier is provided with a plurality of through holes penetrating through the upper and lower surfaces; the soluble microneedle array at least comprises a water-soluble polymer and an active ingredient A; the permeation enhancing patch comprises a permeation enhancing carrier and a permeation enhancing active component loaded on the permeation enhancing carrier; the penetration enhancing patch is configured to be capable of being attached to the upper surface of the microneedle carrier and enabling the penetration enhancing active component to diffuse downwards along a microchannel formed after the soluble microneedle array is dissolved. According to the scheme provided by the invention, the microneedle patch and the penetration enhancing patch are utilized to synergistically push the drug to further diffuse to the deep layer of the skin, so that the effects of secondary drug delivery and penetration enhancement are realized, and the transdermal absorption efficiency and depth of the drug are remarkably improved.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of transdermal drug delivery, in particular to a dissolving microneedle combination patch and a preparation method and application thereof. BACKGROUND

[0002] Transdermal drug delivery system (TDDS) has become an important research direction for skin treatment, postoperative repair and macromolecular drug delivery due to its non-invasive, avoidance of liver first-pass effect, and sustained release of drugs. As a new type of transdermal drug delivery technology, dissolving microneedles (dMNs) are usually prepared by mixing biocompatible water-soluble polymers (such as hyaluronic acid, carboxymethyl cellulose, etc.) with active pharmaceutical ingredients. When used, the microneedles can penetrate the stratum corneum, the outermost layer of the skin, and quickly dissolve in the interstitial fluid, releasing the drug directly into the epidermis or dermis, achieving efficient delivery while being painless, minimally invasive, and eliminating the need for disposal of sharp medical waste.

[0003] However, although the microneedles can penetrate the stratum corneum to form microchannels, the drugs released after dissolution are mainly concentrated in the superficial epidermis or upper dermis, and the penetration process to the deeper layers of the skin will again face resistance from the active surface layer and other barriers. Especially for macromolecular drugs, due to factors such as poor flow of skin interstitial fluid and small osmotic pressure gradient, they are prone to problems such as retention in the epidermis and slow absorption, which restricts the further clinical application and development of dissolving microneedles. SUMMARY

[0004] To solve or partially solve the problems in the related art, the present application provides a dissolving microneedle combination patch and a preparation method and application thereof, which utilizes the synergy of the microneedle patch and the penetration-enhancing patch to further promote the diffusion of drugs into the deep layers of the skin, achieving secondary drug delivery and enhanced penetration, and significantly improving the efficiency and depth of transdermal drug absorption.

[0005] The first aspect of the present application provides a dissolving microneedle combination patch, comprising a microneedle patch and a penetration-enhancing patch; The microneedle patch comprises a microneedle carrier and a dissolving microneedle array distributed on the lower surface of the microneedle carrier; the microneedle carrier is provided with a plurality of through holes penetrating the upper and lower surfaces; the dissolving microneedle array comprises at least a water-soluble polymer and an active ingredient A; The penetration-enhancing patch comprises a penetration-enhancing carrier and a penetration-enhancing active component loaded on the penetration-enhancing carrier; The penetration-enhancing patch is configured to be attached to the upper surface of the microneedle carrier and to diffuse the penetration-enhancing active component downward along the microchannels formed after the dissolution of the dissolving microneedle array.

[0006] In some embodiments of the present application, the water-soluble polymer is selected from the group consisting of hyaluronic acid and its salts, polyvinyl alcohol, polyvinylpyrrolidone, chondroitin sulfate, sodium alginate, chitosan and its derivatives, carboxymethyl cellulose, polyglutamic acid, gelatin, polyacrylic acid salts, starch-acrylic acid graft copolymer, alpha-hydroxy acid, polyanhydride, polyortho ester, polyphosphazene, polyphosphoester, polyglycolide, polylactic acid, glycolic acid-lactic acid copolymer, polycaprolactone, and combinations of one or more thereof; preferably sodium hyaluronate.

[0007] In some embodiments of the present application, the sodium hyaluronate has a molecular weight of 5 kDa to 300 kDa; preferably 7 kDa to 250 kDa; more preferably 10 kDa to 200 kDa.

[0008] In some embodiments of the present application, the microneedle carrier is selected from the group consisting of hydrogel, medical non-woven fabric, medical PE film or medical PU film.

[0009] In some embodiments of the present application, the microneedle carrier has a through-hole area accounting for 25% to 80% of the total area of the microneedle carrier; preferably 30% to 60%.

[0010] In some embodiments of the present application, the soluble microneedle array has a height of 200 μm to 1500 μm, preferably 500 μm to 1000 μm, more preferably 530 μm to 600 μm.

[0011] In some embodiments of the present application, the penetration enhancer is selected from the group consisting of absorbent cotton, spunlace non-woven fabric, polymer film or hydrogel.

[0012] In some embodiments of the present application, the polymer film is selected from the group consisting of cellulose acetate, ethyl cellulose, ethylene-vinyl acetate copolymer, cellulose dipalmitate, polyoxyethylene, polyacrylic acid, polyhydroxypropyl methacrylate, high molecular weight polyethylene glycol, hydrophilic polypropylene, medical polyvinyl chloride or polyvinyl alcohol.

[0013] In some embodiments of the present application, the hydrogel is selected from the group consisting of hyaluronic acid hydrogel, polyvinyl alcohol hydrogel, polyacrylamide hydrogel, polyacrylic acid hydrogel, poloxamer hydrogel, carbomer hydrogel, chitosan-glycerol hydrogel, gelatin-based hydrogel or functionally modified hydrogel.

[0014] In some embodiments of the present application, the penetration enhancer active component comprises active ingredient B, and the active ingredient A and active ingredient B are each independently selected from small molecule drugs or macromolecular drugs.

[0015] In some embodiments of the present application, the penetration enhancer is selected from the group consisting of ethanol, 1,3-propanediol, 1,2-butanediol, 1,4-butanediol, 1,2-pentanediol, 1,2-hexanediol, azone, N-methyl-2-pyrrolidone (NMP), 2-pyrrolidone (2P), isosorbide dimethyl ether, inositol, or eucalyptus oil.

[0016] The second aspect of the present application provides a preparation method of the above-mentioned dissolvable microneedle combination patch, comprising: S1: preparing a microneedle patch The water-soluble polymer, active ingredient A, and solvent are mixed to obtain a microneedle matrix solution; the microneedle matrix solution is injected into a microneedle mold, and the microneedle matrix solution fills the micropores of the mold; after drying, the microneedle matrix solution is removed from the mold to obtain a dissolvable microneedle array; the dissolvable microneedle array is attached to one side of a microneedle carrier to obtain a microneedle patch. S2: preparing a penetration enhancer patch The penetration enhancer, active ingredient B, and solvent are mixed to obtain a penetration enhancer active component solution; the penetration enhancer carrier is soaked in the penetration enhancer active component solution until the penetration enhancer carrier completely absorbs the penetration enhancer active component solution to obtain a penetration enhancer patch. S3: the microneedle patch and the penetration enhancer patch are packaged separately to obtain a dissolvable microneedle combination patch that can be used separately.

[0017] In some embodiments of the present application, the mixing temperature of the water-soluble polymer, active ingredient A, and solvent in step S1 is 30°C to 70°C.

[0018] In some embodiments of the present application, the microneedle matrix solution fills the micropores of the mold by centrifugation or vacuum-assisted method in step S1.

[0019] In some embodiments of the present application, the pH value of the penetration enhancer active component solution is controlled to be between 4.0 and 6.0 in step S2.

[0020] The third aspect of the present application provides the use of the above-mentioned dissolvable microneedle combination patch in the preparation of a transdermal delivery preparation.

[0021] In some embodiments of the present application, the components of the dissolvable microneedle array are as follows in terms of mass percentage: water-soluble polymer 2% to 20%, active ingredient A 0.1% to 5%, and the balance being water.

[0022] In some embodiments of the present application, the penetration enhancer active component is as follows in terms of mass percentage: active ingredient B 0.1% to 30%, penetration enhancer 0% to 95%, and the balance being water.

[0023] The third aspect of the present application provides application of the above-mentioned soluble microneedle combination patch in preparation of a skin soothing and repairing preparation.

[0024] In some embodiments of the present application, the components of the water-soluble microneedle array are 2-20% water-soluble polymer, 0.1-5% menthol, and the balance is water.

[0025] In some embodiments of the present application, the components of the water-soluble microneedle array are 2-20% water-soluble polymer, 0.1-5% menthol, and the balance is water.

[0026] In some embodiments of the present application, the components of the water-soluble microneedle array are 2-20% water-soluble polymer, 0.1-5% menthol, and the balance is water.

[0027] In some embodiments of the present application, the penetration-promoting active components are 0.1-1% bisabolol, 0.5-10% panthenol, 2-10% hyaluronic acid, 0.01-0.5% ascorbic acid, and 0.01-95% ethanol, and the balance is water.

[0028] In some embodiments of the present application, the penetration-promoting active components are 0.1-1% bisabolol, 0.5-10% panthenol, 2-10% hyaluronic acid, 0.01-0.5% ascorbic acid, and 0.01-95% ethanol, and the balance is water.

[0029] The fourth aspect of the present application provides application of the above-mentioned soluble microneedle combination patch in preparation of a skin anti-wrinkle and firming preparation.

[0030] In some embodiments of the present application, the components of the water-soluble microneedle array are 2-20% water-soluble polymer, 0.1-5% menthol, and the balance is water.

[0031] In some embodiments of the present application, the components of the water-soluble microneedle array are 2-20% water-soluble polymer, 0.1-5% menthol, and the balance is water.

[0032] In some embodiments of the present application, the penetration-promoting active components are 0.1-1% bisabolol, 0.5-10% panthenol, 2-10% hyaluronic acid, 0.01-0.5% ascorbic acid, and 0.01-95% ethanol, and the balance is water.

[0033] In some embodiments of the present application, the penetration-promoting active component comprises, by mass percentage, 0.12-0.5% of farnesol, 0.6-5% of panthenol, 4-8% of hyaluronic acid, 0.05-0.3% of ascorbic acid, 1-10% of ethanol, and the balance of water.

[0034] The technical solution provided by the present application can include the following benefits: the microchannels formed after the skin is pierced by the soluble microneedle array can provide a basic path for transdermal delivery of active ingredients; the through holes of the microneedle carrier can break the physical barrier of the carrier to the penetration-promoting component, avoid the delay of the effect caused by the retention of the penetration-promoting active component in the carrier, and enable the active ingredient released by the penetration-promoting patch to precisely reach the microchannel region, in which the active ingredient B cooperates with the active ingredient A to form a double active ingredient cooperative delivery, avoid the limitation of the effect of a single active ingredient, and use physical microchannels and penetration promoters to further promote the diffusion of drugs to the deep layer of the skin, thereby achieving the effects of secondary administration and enhanced penetration, and significantly improving the efficiency and depth of transdermal drug absorption. Further, when the penetration-promoting active component contains a penetration promoter, the penetration effect of the microchannels can be further amplified by changing the lipid structure of the stratum corneum, and the problems of limited drug loading capacity of the microneedle and poor effect of the penetration promoter used alone can be solved.

[0035] The microneedle patch and the penetration-promoting patch are prepared and used in combination, and the preparation and use are simple and convenient, facilitating large-scale industrial production and user use. The composition and content of the penetration promoter and the active ingredient in the penetration-promoting patch can be customized according to the skin condition of the user, thereby significantly improving the use effect of the soluble microneedle combination patch.

[0036] The soluble microneedle combination patch for skin soothing and repairing contains a soluble microneedle array in the microneedle patch containing menthol, which can pierce the stratum corneum to form a micron-scale channel and produce a cooling sensation at the moment of piercing to mask the pain. After the needle body dissolves in the interstitial fluid of the skin, the active ingredient carried is released to the target skin layer. The penetration-promoting patch enhances the transdermal drug delivery technology, can synergistically act with chemical or biological penetration promoters and physical penetration channels, improves the drug loading capacity of the soluble microneedle combination patch, and significantly improves the absorption efficiency and depth of action of the active ingredient. In addition, the components in the penetration-promoting patch can synergistically balance the effects of penetration promotion, treatment, soothing, and moisturizing. The combination of the penetration-promoting patch and the microneedle patch can amplify the above-mentioned soothing and repairing effects, and is particularly suitable for the care of sensitive skin and damaged skin.

[0037] The application discloses a soluble microneedle combination patch for skin anti-wrinkle and firming, wherein a snake venom-like peptide is a macromolecular substance, a micrometer-scale microchannel is formed after the soluble microneedle array physically penetrates the skin, the physical channel of the snake venom-like peptide is directly opened, the skin permeability is further improved by combining the effect of a penetration patch, the snake venom-like peptide is assisted to penetrate along the microchannel to the deep layer of the dermis, and the transdermal absorption rate and the action depth of the snake venom-like peptide are significantly improved. In addition, sodium hyaluronate and the snake venom-like peptide can simultaneously provide a humid environment for the snake venom-like peptide to play an anti-wrinkle effect, promote the absorption of the macromolecular snake venom-like peptide by the skin, and more comprehensively improve static wrinkles and dynamic wrinkles and improve the overall firmness of the skin compared with a single-component preparation.

[0038] It should be understood that the foregoing general description and the following detailed description are only exemplary and explanatory and are not restrictive of the application. BRIEF DESCRIPTION OF DRAWINGS

[0039] The above and other objects, features and advantages of the present application will become more apparent from the following detailed description when taken in conjunction with the accompanying drawings in which like reference characters refer to like parts throughout the figures, and in which:

[0040] Figure 1 is a schematic diagram of the overall structure of the soluble microneedle combination patch shown in the embodiment 1 of the application; Figure 2 is a schematic diagram of the structure of the microneedle patch in the soluble microneedle combination patch shown in the embodiment 1 of the application; Figure 3 is a partial pattern display diagram of the through hole of the microneedle carrier shown in the embodiment 1 of the application; Figure 4 and Figure 5 is a schematic diagram of the experiment of inserting the microneedle patch into a Parafilm film obtained in the embodiment of the application; Figure 6 is a schematic diagram of the cumulative release rate of the drug after the microneedle patch and the penetration patch are used in combination obtained in the embodiment of the application; Figure 7 is a schematic diagram of the dissolution and diffusion of the microneedle patch and the penetration patch in gelatin solution at 1h, 2h, 4h, 8h, 12h and 24h after the microneedle patch and the penetration patch are used in combination obtained in the embodiment of the application; Figures 8-10 is a schematic diagram of the penetration of the microneedle patch and the penetration patch in gelatin solution at 1h, 2h, 4h, 8h, 12h and 24h after the microneedle patch and the penetration patch are used in combination obtained in the embodiment of the application; Figure 11 is the influence of the soluble microneedle combination patch for skin soothing and repairing obtained in the embodiment of the application on the activity of hyaluronidase after use; Figure 12The influence of the soluble microneedle combination patch for skin tightening and wrinkle resistance obtained by the embodiment of the present application on elastase activity after use.

[0041] Reference signs: 1, soluble microneedle combination patch; 2, microneedle patch; 21, microneedle carrier; 211, through hole; 22, soluble microneedle array; 3, penetration promoting patch. DETAILED DESCRIPTION

[0042] The embodiments of the present application will be described in more detail below. It should be understood that the present application can be implemented in various forms and should not be limited by the embodiments set forth herein. Rather, these embodiments are provided so that the present application will be thorough and complete, and will fully convey the scope of the present application to those skilled in the art.

[0043] The terminology used in the present application is for the purpose of describing particular embodiments only and is not intended to be limiting of the present application. Unless otherwise defined, all terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present application, the preferred methods and materials are now described.

[0044] It should be understood that although the terms "first", "second", "third", etc. can be employed in this application to describe various information, these information should not be limited by these terms. These terms are only used to distinguish one piece of information from another piece of information of the same type. The features limited by "first", "second" can explicitly or implicitly include one or more features. The singular form "a", "an" and "the" used in this application and the appended claims are also intended to include the plural form, unless the context clearly indicates otherwise. It should also be understood that the term "and / or" used herein means and includes any or all possible combinations of one or more associated listed items.

[0045] Where a range of values is provided, it is understood that each intervening value, to the upper and lower limit, and any other stated or intervening value in that stated range is encompassed. That the upper and lower limits of these smaller ranges can independently be included in the smaller ranges, and are also encompassed, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included. In the description of the application, the meaning of "a", "an", and "the" includes two or more, unless the context clearly dictates otherwise.

[0046] Although microneedles can penetrate the stratum corneum to form microchannels, the drugs released after dissolution are mainly concentrated in the superficial epidermis or upper dermis. The penetration process into deeper skin tissues faces resistance from barriers such as the active surface layer. This is especially true for large molecule drugs, which are prone to problems such as epidermal retention and slow absorption due to factors like poor fluidity and small osmotic pressure gradients in skin tissues, thus hindering the further clinical application and development of soluble microneedles. While some studies have attempted to incorporate chemical penetration enhancers into microneedle formulations, these enhancers are rapidly released along with the drug at the microneedle tip, resulting in a short-lived and superficial effect that fails to provide sustained and effective support for long-term drug efficacy and deep penetration.

[0047] To address the aforementioned issues, this application provides a soluble microneedle combination patch, its preparation method, and its application. This patch, along with a penetration-enhancing patch, synergistically promotes drug diffusion into deeper layers of the skin, achieving secondary drug delivery and enhanced penetration, significantly improving the efficiency and depth of transdermal drug absorption.

[0048] Combination Figure 1 and Figure 2 As shown, the soluble microneedle combination patch 1 of this application embodiment includes a microneedle patch 2 and a penetration-enhancing patch 3. The microneedle patch 2 includes a microneedle carrier 21 and a soluble microneedle array 22 distributed on the lower surface of the microneedle carrier 21. The microneedle carrier 21 has several through holes 211 penetrating both the upper and lower surfaces. The soluble microneedle array 22 specifically includes a base portion and a needle body portion, wherein the base portion and the needle body portion are integrally formed. The base portion is planar, with one side connected to the needle body portion and the other side connected to the microneedle carrier 21; the needle body portion is composed of several evenly arranged pointed needles.

[0049] The soluble microneedle array 22 contains at least a water-soluble polymer and an active ingredient A. The soluble microneedle array 22 can act on the skin and can penetrate the stratum corneum of the skin surface. During the puncture process, the needle body forms several small channels in the stratum corneum of the skin, providing a channel for the active ingredient to enter the skin. Then, under the action of high water content in the skin, it dissolves layer by layer and releases the encapsulated target ingredient.

[0050] The permeation-enhancing patch 3 includes a permeation-enhancing carrier and a permeation-enhancing active component loaded on the permeation-enhancing carrier. The permeation-enhancing patch 3 is configured to adhere to the upper surface of the microneedle carrier 21 and allow the permeation-enhancing active component to diffuse downward along the microchannels formed after the soluble microneedle array 22 is dissolved.

[0051] In the use of the soluble microneedle combination patch 1 of this application embodiment, the microneedle patch 2 is first applied to the skin so that the soluble microneedle array 22 on its lower surface can physically puncture the stratum corneum of the skin to form microchannels. Then, the penetration-enhancing patch 3 is attached to the upper surface of the microneedle patch 2 and acts on the skin together with the microneedle patch 2.

[0052] Thus, the microchannels formed after the soluble microneedle array 22 pierces the skin can provide a basic passage for the transdermal delivery of the active ingredient A. The through-hole 211 of the microneedle carrier 21 can break the physical barrier of the carrier to the penetration-enhancing active component, avoid the delay of the action caused by the retention of the penetration-enhancing active component in the carrier, make the penetration-enhancing patch 3 release the penetration-enhancing active component to accurately reach the microchannel region, make it cooperatively change the lipid structure of the stratum corneum, further amplify the penetration effect of the microchannel, and cooperatively act with the active ingredient A to form a double-active-ingredient synergistic delivery, avoid the limitation of the action of a single active ingredient, and can significantly improve the transdermal absorption efficiency and penetration depth of the active ingredient.

[0053] In some embodiments, the height of the soluble microneedle array is 200 μm to 1500 μm, preferably 500 μm to 1000 μm, and more preferably 530 μm to 600 μm. Specifically, it can be 200 μm, 300 μm, 400 μm, 500 μm, 530 μm, 550 μm, 580 μm, 600 μm, 700 μm, 800 μm, 900 μm, 1000 μm, 1500 μm, or any value within the above range. The height of the soluble microneedle array is greater than 200 μm, which can ensure accurate penetration of the stratum corneum of the skin and break the transdermal barrier, while the upper limit of 1500 μm can avoid piercing the deep dermis containing dense nerves and blood vessels, and avoid the risk of pain, bleeding, and infection; at the same time, the microneedle within this height range can achieve a good drug loading capacity.

[0054] In some embodiments, the water-soluble polymer can be selected from polymer materials with water solubility, high adsorbability, and degradability. Specifically, it can be selected from one or more of the following: hyaluronic acid and its salts, polyvinyl alcohol, polyvinylpyrrolidone, chondroitin sulfate, sodium alginate, chitosan and its derivatives, carboxymethyl cellulose, polyglutamic acid, gelatin, polyacrylic acid salts, starch-acrylic acid graft copolymer, alpha-hydroxy acid, polyanhydride, polyortho ester, polyphosphazene, polyphosphate, polyglycolide, polylactic acid, glycolic acid-lactic acid copolymer, and polycaprolactone. The above water-soluble polymers have good biocompatibility and water solubility, can be completely dissolved in the interstitial fluid of the skin, and have no residual foreign body sensation or irritation risk, which can avoid the skin safety hazards of traditional non-water-soluble polymer microneedles.

[0055] The water-soluble polymer in the embodiments of the present application is preferably sodium hyaluronate; more preferably sodium hyaluronate with a molecular weight of 5-300 kDa, preferably 7-250 kDa; and more preferably 10-200 kDa. The molecular weight thereof can be specifically 5 kDa, 10 kDa, 20 kDa, 50 kDa, 100 kDa, 150 kDa, 250 kDa, 280 kDa, 300 kDa, or any value within the above range. Sodium hyaluronate is a natural component of human skin, has extremely low toxicity, and has a moisturizing property, which can relieve the dry feeling of the skin after microneedle puncture and improve the user's comfort.

[0056] Sodium hyaluronate within this molecular weight range can simultaneously meet the microneedle forming requirement and the dissolution and release requirement; if the molecular weight is too low, the mechanical strength is insufficient and the puncture effect cannot be guaranteed; and if the molecular weight is too low or too high, the slow release effect of the active ingredient in the interstitial fluid of the skin cannot be met. Therefore, selecting a suitable water-soluble polymer in the dissolvable microneedle array can guarantee the puncture effectiveness and skin safety of the dissolvable microneedle array, realize the controlled release of the active ingredient, and adapt to the delivery requirements of different types of active ingredients.

[0057] In some embodiments, the microneedle carrier can be selected from a hydrogel, a medical non-woven fabric, a medical PE (polyethylene) film, or a medical PU (polyurethane) film. The above microneedle carrier materials have excellent skin adhesion, can tightly fix the microneedle patch to the skin surface, avoid the microneedle from falling off due to skin activities such as facial expressions and limb movements, improve the stability of the microneedle patch during use, ensure that the microneedle can continuously act on the stratum corneum, guarantee the continuous delivery of the active ingredient, and adapt to skin parts with high activity such as the face and joints; and also have good air permeability, can allow the skin to breathe normally, avoid the discomfort such as skin stuffiness and sweat accumulation caused by traditional non-breathable carriers, and reduce the discomfort risk of sensitive skin groups.

[0058] As can be understood, the hydrogel described in the embodiments of the present application is a kind of hydrophilic polymer with three-dimensional network structure, which can combine with water molecules through its hydrophilic groups (such as hydroxyl, carboxyl, amino, etc.) in water (or body fluid, skin secretion, etc. water-containing environment), realize high water absorption and swelling, while maintaining structural integrity, and finally form a gel-like substance. Typical hydrogels include, for example, hyaluronic acid and its salts, chitosan, gelatin, pectin, sodium alginate, polyacrylic acid, polyvinyl alcohol, polyvinylpyrrolidone, etc.

[0059] In some embodiments, the penetration enhancer is a thin, flexible material, specifically selected from absorbent cotton, spunlace nonwoven fabric, polymer membrane, or hydrogel. These materials have high liquid absorbency, allowing them to fully adsorb and store the penetration-enhancing active components, avoiding sudden release that could cause local skin irritation. Simultaneously, they enable slow, continuous release of the penetration-enhancing active components, prolonging the duration of action and achieving uniform, controllable release. This ensures penetration efficiency while reducing the risk of skin irritation. Different penetration enhancer options can be adapted to different application scenarios; for example, nonwoven fabric is suitable for large areas of skin, while hydrogel is suitable for curved skin, improving the product's adaptability to various applications.

[0060] The polymer membrane can be selected from cellulose acetate, ethyl cellulose, ethylene-vinyl acetate copolymer, cellulose dipalmitate, polyoxyethylene, polyacrylic acid, polymethyl methacrylate, high molecular weight polyethylene glycol, hydrophilic polypropylene, medical-grade polyvinyl chloride, or polyvinyl alcohol. Its structural characteristics allow for adjustment of the release rate of the penetration-enhancing components, adapting to the penetration requirements of different active ingredients.

[0061] The hydrogel can be selected from hyaluronic acid hydrogel, polyvinyl alcohol hydrogel, polyacrylamide hydrogel, polyacrylic acid hydrogel, poloxamer hydrogel, carbomer hydrogel, chitosan-glycerol hydrogel, gelatin-based hydrogel, or functionalized modified hydrogel. Functionalized modified hydrogels include, for example, stimulus-responsive pH-sensitive gels and enzyme-responsive hydrogels. The hydrogel exhibits good skin adhesion, tightly adhering to the surface of the microneedle carrier, ensuring that the penetration-enhancing components can efficiently pass through the pores of the microneedle carrier to reach the microchannels.

[0062] In the embodiments of this application, the microneedle patch and the penetration-enhancing patch may be the same or different in size. Specifically, the size and shape of the microneedle patch and the penetration-enhancing patch can be designed to be completely identical, thereby ensuring that the penetration-enhancing active ingredient on the penetration-enhancing patch penetrates deep into the microchannel region along the pores of the microneedle carrier.

[0063] The shapes of the microneedle patches and the penetration-enhancing patches can be designed as circles, polygons (such as triangles, squares, rectangles, trapezoids, pentagons, hexagons, etc.), teardrops, flowers, animals, stars, crescents, etc., and this application does not limit them.

[0064] In addition, combined Figure 3 As shown, the shape of the through hole on the microneedle carrier 21 can also be designed as a circle, a polygon (such as a triangle, square, rectangle, trapezoid, pentagon, hexagon, etc.), a teardrop shape, a flower shape, an animal shape, a star shape, a crescent shape, etc., and this application embodiment does not limit this.

[0065] The shapes of the microneedle patches and microneedle carriers described above can be combined arbitrarily.

[0066] However, it should be noted that the through holes of the microneedle carrier need to satisfy: the area of the through holes on the microneedle carrier accounts for 25% to 80% of the total area of the microneedle carrier; preferably 30% to 60%. Specific examples include 25%, 28%, 30%, 32%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or any value within the above range. By limiting the total area of the through holes on the microporous carrier, it can be avoided that the number or area ratio of the through holes is too low to cause the transmission of the penetration-promoting active component to be blocked, so as to ensure that the penetration-promoting active component accurately reaches the microchannels, maximize the synergistic transdermal effect, and at the same time, retain sufficient substrate area to support the microneedle puncture, prevent deformation and fracture, match the release rate of the penetration-promoting active component with the dissolution rate of the microneedle, avoid the loss of synergy, and prolong the action time of the microchannels.

[0067] In some embodiments, the penetration-promoting active component at least contains active ingredient B. The active ingredient A and the active ingredient B are each independently selected from small molecule drugs or large molecule drugs. Specifically, it can be selected from one or more combinations of polypeptides, proteins, gene drugs, cells, viruses, probiotics. The specific components of the active ingredient A and the active ingredient B can be completely the same, partially overlapping or completely different, and can be selected according to the actual efficacy.

[0068] The combination patch formed by the microneedle patch and the penetration-promoting patch is beneficial to overcome the diffusion resistance of the active ingredient in the skin epidermis and dermis, expand the application range of the drugs of the combination patch, and is particularly suitable for polypeptides, proteins and other large molecule drugs which are difficult to be effectively administered by traditional transdermal systems.

[0069] The penetration-promoting agent can be, for example, ethanol, 1,3-propanediol, 1,2-butanediol, 1,4-butanediol, 1,2-pentanediol, 1,2-hexanediol, azone, N-methyl-2-pyrrolidone (NMP), 2-pyrrolidone (2P), isosorbide dimethyl ether, inositol or eucalyptus oil.

[0070] The present application also provides a preparation method of the soluble microneedle combination patch, which comprises the following steps: S1: preparing a microneedle patch The water-soluble polymer, the active ingredient A and the solvent are mixed to obtain a microneedle matrix solution; the microneedle matrix solution is injected into a microneedle mold, and the microneedle matrix solution fills the micropores of the mold; after drying, the mold is removed to obtain a soluble microneedle array; the soluble microneedle array is attached to one side of the microneedle carrier to obtain the microneedle patch; S2: preparing a penetration-promoting patch The penetration-promoting agent, the active ingredient B and the solvent are mixed to obtain a penetration-promoting active component solution; the penetration-promoting carrier is soaked in the penetration-promoting active component solution until the penetration-promoting carrier completely absorbs the penetration-promoting active component solution to obtain the penetration-promoting patch; S3: The microneedle patch and the penetration enhancer patch are packaged separately to obtain a detachable combination of the soluble microneedle combination patch.

[0071] In the embodiment of the present application, the mixing of the water-soluble polymer, the active ingredient A and the solvent in the preparation process of the microneedle patch in step S1 can be carried out at 30-70°C, for example, 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, 70°C, or any value within the above range. The mixing temperature in this range can improve the solubility of the water-soluble polymer and the active ingredient A, avoid insufficient dissolution at low temperature, and at the same time, the temperature is lower than the denaturation temperature of most active ingredients, which can ensure the biological activity of the active ingredient A.

[0072] In the preparation process of the microneedle patch in step S1, the microneedle matrix solution can be filled into the micropores of the mold by centrifugation or vacuum assisted forming. The speed of centrifugation can be 1000-3000 r / min, and the centrifugation time can be 5-15 min. The vacuum degree of vacuum assisted forming can be -0.08-0.1 MPa, and the holding time can be 10-20 min. Centrifugation or vacuum assisted forming can remove air bubbles in the microneedle mold micropores, avoid defects such as hollow or tip damage after microneedle forming, and ensure the effect of microneedle piercing the stratum corneum.

[0073] In step S1, the soluble microneedle array is attached to one side of the microneedle carrier, which can also be referred to as a backing. The prepared microneedle patch is stored in a desiccator for standby.

[0074] In step S2, the soaking method can make the penetration enhancer active component uniformly penetrate into the penetration enhancer carrier, avoid uneven distribution of the component leading to local difference in penetration effect. Specifically, the soaking temperature can be 25-35°C, the penetration enhancer patch is stored in the penetration enhancer active component solution, and bagged and sealed, and the penetration enhancer patch can be taken out when needed.

[0075] Moreover, the pH value of the penetration enhancer active component solution in step S2 is controlled between 4.0 and 6.0. The penetration enhancer active component solution in this pH range not only approaches the natural pH of the skin surface, but also avoids damaging the skin barrier due to too high or too low pH of the penetration enhancer active component, and stabilizes the active ingredient in the penetration enhancer active component, avoiding denaturation of the penetration enhancer active component.

[0076] Therefore, the split packaging and storage of the microneedle patch and the penetration enhancer patch can be ensured, the active ingredients or the penetration enhancer in the microneedle patch and the penetration enhancer patch are prevented from being in contact in advance to cause partial components to react with each other and become invalid, the performance stability of the two in the storage period is ensured, the use process is simplified, the user can directly take out the penetration enhancer patch for use without the need of performing operations such as solution reconstitution and immersion, the difficulty in the preparation process and the use process is reduced, and the industrialized large-scale production and user use are facilitated.

[0077] The use method of the soluble microneedle combination patch provided in the embodiments of the present application is as follows: the microneedle carrier of the microneedle patch is first attached to the action site on the surface of the skin, so that the soluble microneedle array of the microneedle patch is in contact with the skin and pierces the stratum corneum of the skin to form a plurality of microchannels; and then the penetration enhancer patch is attached to the surface of the microneedle carrier to act on the use part together with the microneedle patch, so that the penetration active component passes through the through hole of the microneedle carrier and acts on the skin along the microchannels to promote the absorption of the active component by the skin, thereby achieving a synergistic treatment effect.

[0078] The soluble microneedle combination patch provided in the embodiments of the present application can be used in the field of transdermal delivery of preparations.

[0079] Specifically, the soluble microneedle combination patch for transdermal delivery of preparations comprises a microneedle patch and a penetration enhancer patch. The components of the water-soluble microneedle array in the microneedle patch are as follows in terms of mass percentage: 2% to 20% of a water-soluble polymer, 0.1% to 5% of an active component A, and the balance of water. The penetration active component is as follows in terms of mass percentage: 0.1% to 30% of an active component B, 0% to 95% of a penetration enhancer, and the balance of water.

[0080] The combination patch provided in the embodiments of the present application can effectively promote the release of the active component in the microchannels through the synergistic mechanism of the physical microchannels formed by the microneedle patch and the penetration active component improving the permeability of the stratum corneum, ensure that the active component can cross the stratum corneum barrier and enter the dermis, avoid the problem that some macromolecular drugs cannot penetrate due to large particle size, make the soluble microneedle combination patch suitable for the delivery of both macromolecular drugs and small molecular drugs, significantly improve the transdermal bioavailability of the active component, solve the limitation that traditional transdermal preparations such as ointments and ordinary patches can only deliver small molecules, and be suitable for medical fields and cosmetic product fields.

[0081] Further, the soluble microneedle combination patch provided in the embodiments of the present application can be specifically used in the field of skin soothing and repairing preparations.

[0082] The soluble microneedle combination patch for skin soothing and repairing provided in the embodiments of the present application comprises a microneedle patch and a penetration enhancer patch.

[0083] The soluble microneedle array in the microneedle patch is formed by a microneedle matrix solution in a mold. Specifically, the components of the water-soluble microneedle array are as follows in terms of mass percentage: 2% to 20% of water-soluble polymer, 0.1% to 5% of menthol, and the balance of water. In the components of the soluble microneedle array, the mass percentage of sodium hyaluronate is 2% to 20%, preferably 5% to 15%, and more preferably 5%; the mass percentage of menthol is 0.1% to 5%, preferably 0.3% to 1.5%, and more preferably 1.0%; and the mass percentage of water is 50% to 95%, preferably 80% to 92%, and more preferably 90%.

[0084] The penetration-promoting active components in the penetration-promoting patch are as follows in terms of mass percentage: 0.1% to 1% of farnesol, 0.5% to 10% of panthenol, 2% to 10% of hyaluronic acid, 0.01% to 0.5% of ascorbic acid, 0.01% to 95% of ethanol, and the balance of water. In the penetration-promoting active components, the mass percentage of farnesol is 0.1% to 1%, preferably 0.12% to 0.5%, and more preferably 0.15%; the mass percentage of panthenol is 0.5% to 10%, preferably 0.6% to 5.0%, and more preferably 1.0%; the mass percentage of hyaluronic acid is 2% to 10%, preferably 4% to 8%, and more preferably 5%; the mass percentage of ascorbic acid is 0.01% to 0.5%, preferably 0.05% to 0.3%, and more preferably 0.1%; the mass percentage of ethanol is 0.01% to 95%, preferably 1% to 10%, and more preferably 5%; and the mass percentage of water is 10% to 50%, preferably 15% to 25%, and more preferably 20%.

[0085] The preparation method of the soluble microneedle combination patch for skin soothing and repairing provided in the embodiments of the present application includes the following steps: (1) Mix water, sodium hyaluronate, and menthol in a proportion, then place them in an oven at 30°C to 70°C to dissolve and stir, so that the components are fully mixed, to obtain a microneedle matrix solution.

[0086] (2) Add the microneedle matrix solution to a mold, inject the solution into each micropore of the mold under a centrifugal method or a vacuum-assisted forming method, then air dry at room temperature, and demold under natural drying or heating drying conditions to obtain a soluble microneedle array; attach a backing patch to the soluble microneedle array to obtain a microneedle patch, and store the microneedle patch in a desiccator containing a drying agent for storage and standby use.

[0087] (3) Take absorbent cotton as a base material, mix water, farnesol, panthenol, hyaluronic acid, ascorbic acid, and ethanol in a proportion to obtain a penetration-promoting active component solution, and control the pH value of the solution to be 4.0 to 6.0.

[0088] (4) The defatted cotton is punched and cut into the shape of the backing patch by a mold, soaked in the penetration-promoting active component solution, bagged and sealed to obtain the penetration-promoting patch.

[0089] The soluble microneedle array in the microneedle patch containing menthol can pierce the stratum corneum to form a micron-level channel and produce a cooling sensation at the moment of puncture to mask the stinging, and the needle body is dissolved in the skin interstitial fluid to release the active ingredients carried to the target skin layer; the penetration-promoting patch enhances the transdermal drug delivery technology, can synergize the chemical or biological penetration enhancer with the physical penetration channel, improve the drug loading capacity of the soluble microneedle combination patch, and significantly improve the absorption efficiency and action depth of the active ingredients. The ethanol in the penetration-promoting patch not only promotes the deeper penetration of panthenol, bisabolol, ascorbic acid and hyaluronic acid, but also effectively acts on the skin to play the roles of moisturizing and repairing, anti-inflammatory soothing and antioxidant and melanin inhibition. Panthenol, bisabolol, ascorbic acid and hyaluronic acid can also reduce the discomfort caused by the action of ethanol on the skin, and the synergy of the two can effectively balance the penetration, treatment, soothing and moisturizing effects. The combination of the penetration-promoting patch and the microneedle patch can amplify the effects of soothing and repairing, and is especially suitable for the care of sensitive skin and damaged skin.

[0090] In order to make the present application easier to understand, the present application will be further described in detail below in conjunction with examples, which are only illustrative and do not limit the scope of application of the present application. The raw materials or components used in the present application can be prepared by commercial means or conventional methods if not specifically stated. Since the active ingredients are not limited to those mentioned in the present application, other active ingredients cannot be understood as limiting the scope of protection of the present application.

[0091] Example 1a microneedle patch A 5g of sodium hyaluronate (molecular weight 100kDa) was weighed and added to 50mL of distilled water, and stirred and dissolved with a glass rod to obtain a 10% sodium hyaluronate solution; 10% sodium hyaluronate solution was added to the microneedle mold, and the solution was injected into each micropore of the microneedle mold by vacuum assisted molding method to form a soluble microneedle array containing needle bodies and bases. After air drying at room temperature, natural drying and demolding, backing was attached to obtain pure sodium hyaluronate microneedle patch A.

[0092] Example 1b microneedle patch B 5g of sodium hyaluronate (molecular weight 100kDa) was weighed and added to 50mL of distilled water, and stirred and dissolved with a glass rod to obtain a 10% sodium hyaluronate solution; 0.2g of rhodamine B (dye, which can emit strong orange-red fluorescence under external light irradiation) was added to 50mL of 10% sodium hyaluronate solution, and stirred and dissolved to obtain a rhodamine B-containing sodium hyaluronate solution.

[0093] The rhodamine B-containing sodium hyaluronate solution was added to the microneedle mold, and the solution was injected into each microwell of the microneedle mold by the vacuum-assisted molding method to form a soluble microneedle array comprising needle bodies and bases. After air drying at room temperature, the microneedle array was naturally dried and demolded, a backing was attached, and a rhodamine B-containing sodium hyaluronate microneedle patch B was obtained.

[0094] Example 1c Microneedle patch C The rhodamine B-containing sodium hyaluronate solution obtained in Example 2 was added to the microneedle mold, and the surface of the mold was leveled (without vacuum suction) to form a soluble microneedle array comprising needle bodies and bases. After air drying at room temperature, the microneedle array was naturally dried and demolded, a backing was attached, and a rhodamine B-containing sodium hyaluronate microneedle patch C without needle bodies was obtained.

[0095] Example 1d Microneedle patch D 0.5 mL of ethanol was measured and added to 19.5 mL of the rhodamine B-containing sodium hyaluronate solution in Example 2 to obtain an ethanol-rhodamine B-sodium hyaluronate solution with a mass percentage concentration of 2.5%.

[0096] The 2.5% ethanol-rhodamine B-sodium hyaluronate solution was added to the microneedle mold, and the solution was injected into each microwell of the microneedle mold by the vacuum-assisted molding method to form a soluble microneedle array comprising needle bodies and bases. After air drying at room temperature, the microneedle array was naturally dried and demolded, a backing was attached, and a 2.5% ethanol-rhodamine B-containing sodium hyaluronate microneedle patch D was obtained.

[0097] Example 1e Microneedle patch E 5 g of sodium hyaluronate (molecular weight 100 kDa) was weighed and added to 50 mL of distilled water, and a glass rod was used to stir and dissolve the solution to obtain a 10% sodium hyaluronate solution by mass percentage concentration. 0.2 g of menthol was weighed and added to 20 mL of the 10% sodium hyaluronate solution, and the solution was heated and dissolved in a 45°C oven to obtain a 1.0% menthol-sodium hyaluronate solution by mass percentage concentration.

[0098] The 1.0% menthol-sodium hyaluronate solution was added to the microneedle mold, and the solution was injected into each microwell of the microneedle mold by the vacuum-assisted molding method to form a soluble microneedle array comprising needle bodies and bases. After air drying at room temperature, the microneedle array was naturally dried and demolded, a backing was attached, and a 1.0% menthol-containing sodium hyaluronate microneedle patch E was obtained.

[0099] Example 1f Microneedle patch F Take 5 g of sodium hyaluronate (molecular weight 100 kDa) and add it to 50 mL of distilled water. Stir with a glass rod to dissolve, obtaining a 10% sodium hyaluronate solution by mass percentage. Take 0.1 g of the snake venom peptide and add it to 20 mL of the 10% sodium hyaluronate solution, obtaining a 0.5% snake venom peptide sodium hyaluronate solution by mass percentage.

[0100] Add the 0.5% snake venom peptide sodium hyaluronate solution to the microneedle mold. Inject the solution into each micropore of the microneedle mold by vacuum-assisted molding to form a soluble microneedle array containing a needle body and a base. After air-drying at room temperature, naturally dry and demold, attach a backing, and obtain a 0.5% snake venom peptide sodium hyaluronate microneedle patch F.

[0101] Example 2a Penetration enhancer patch A Take 30 mg of bisabolol, 100 mg of panthenol, 500 mg of hyaluronic acid, 20 mg of ascorbic acid, and 0.5 mL of ethanol in sequence and add them to 19.5 mL of distilled water. Stir to dissolve, control the pH of the solution to be between 4.0 and 6.0, and form a penetration enhancer active component solution.

[0102] Soak the cut dehydrated cotton in the penetration enhancer active component solution, pack and seal individually, and obtain the penetration enhancer patch A.

[0103] Example 2b Penetration enhancer patch B Take 30 mg of bisabolol, 100 mg of panthenol, 500 mg of hyaluronic acid, and 20 mg of ascorbic acid in sequence and add them to 20 mL of distilled water. Stir to dissolve, control the pH of the solution to be between 4.0 and 6.0, and form a penetration enhancer active component solution.

[0104] Soak the cut dehydrated cotton in the penetration enhancer active component solution, pack and seal individually, and obtain the penetration enhancer patch B.

[0105] Example 2c Penetration enhancer patch C Take 30 mg of bisabolol, 100 mg of panthenol, 500 mg of hyaluronic acid, 20 mg of ascorbic acid, and 0.5 mL of ethanol in sequence and add them to 19.5 mL of distilled water. Stir to dissolve, control the pH of the solution to be between 4.0 and 6.0, and then add 0.2 g of rhodamine B to form a penetration enhancer active component solution.

[0106] Soak the cut dehydrated cotton in the penetration enhancer active component solution, pack and seal individually, and obtain the penetration enhancer patch C.

[0107] Example 2d Penetration enhancer patch D Take 30 mg of farnesol, 100 mg of panthenol, 500 mg of hyaluronic acid, 20 mg of ascorbic acid and 0.2 mL of ethanol in 19.8 mL of distilled water in turn, stir and dissolve, control the pH value of the solution at 4.0~6.0, form the penetration enhancer active component solution.

[0108] Cut the defatted cotton into pieces, immerse them in the penetration enhancer active component solution, pack and seal them to obtain the penetration enhancer patch D.

[0109] Example 2e Penetration enhancer patch E Take 30 mg of farnesol, 100 mg of panthenol, 500 mg of hyaluronic acid, 20 mg of ascorbic acid and 0.2 mL of ethanol in 19.8 mL of distilled water in turn, stir and dissolve, control the pH value of the solution at 4.0~6.0, form the penetration enhancer active component solution.

[0110] Cut the defatted cotton into pieces, immerse them in the penetration enhancer active component solution, pack and seal them to obtain the penetration enhancer patch E.

[0111] Example 2f Penetration enhancer patch F Take 30 mg of farnesol, 100 mg of panthenol, 500 mg of hyaluronic acid, 20 mg of ascorbic acid and 1.0 mL of ethanol in 19.0 mL of distilled water in turn, stir and dissolve, control the pH value of the solution at 4.0~6.0, form the penetration enhancer active component solution.

[0112] Cut the defatted cotton into pieces, immerse them in the penetration enhancer active component solution, pack and seal them to obtain the penetration enhancer patch F.

[0113] Example 2g Penetration enhancer patch G Take 30 mg of farnesol, 100 mg of panthenol, 500 mg of hyaluronic acid, 20 mg of ascorbic acid and 2.0 mL of ethanol in 18.0 mL of distilled water in turn, stir and dissolve, control the pH value of the solution at 4.0~6.0, form the penetration enhancer active component solution.

[0114] Cut the defatted cotton into pieces, immerse them in the penetration enhancer active component solution, pack and seal them to obtain the penetration enhancer patch G.

[0115] Example 2h Penetration enhancer patch H Take 30 mg of farnesol, 100 mg of panthenol, 500 mg of hyaluronic acid, 20 mg of ascorbic acid and 1.0 mL of 1,3-propanediol in 19.0 mL of distilled water in turn, stir and dissolve, control the pH value of the solution at 4.0~6.0, form the penetration enhancer active component solution.

[0116] Cut the defatted cotton into pieces, immerse them in the penetration enhancer active component solution, pack and seal them to obtain the penetration enhancer patch H.

[0117] Example 2i Penetration-promoting patch I Take 30 mg of bisabolol, 100 mg of panthenol, 500 mg of hyaluronic acid, 20 mg of ascorbic acid and 1.0 mL of azone in turn, and add them to 19.0 mL of distilled water, stir and dissolve, control the pH value of the solution at 4.0-6.0, and form a penetration-promoting active component solution.

[0118] Soak the cut-off absorbent cotton in the penetration-promoting active component solution, pack and seal each piece, and obtain penetration-promoting patch G.

[0119] Example 2j Penetration-promoting patch J Take 30 mg of bisabolol, 100 mg of panthenol, 500 mg of hyaluronic acid, 20 mg of ascorbic acid and 1.0 mL of eucalyptus oil in turn, and add them to 19.0 mL of distilled water, stir and dissolve, control the pH value of the solution at 4.0-6.0, and form a penetration-promoting active component solution.

[0120] Soak the cut-off absorbent cotton in the penetration-promoting active component solution, pack and seal each piece, and obtain penetration-promoting patch J.

[0121] Performance test The microneedle patches prepared in the above examples were combined with penetration-promoting patches and tested as follows to observe the effect of the combination of the penetration-promoting patch and the microneedle patch.

[0122] I. Basic performance test of microneedle patch The shape and height of the microneedle patch prepared in Example 1 were analyzed by a microscope.

[0123] The microneedle patch prepared in Example 1 was observed by a video microscope, and the microneedle patch was obtained as shown in FIG. 1. Figure 2 The height of the soluble microneedle array was 545 (±2) μm.

[0124] II. Insertion ability test This test used Parafilm ® as a verified simulated skin model. The microneedle patch was applied to 8 layers of Parafilm ® (≈1 mm) under a pressure of 32 N / array for 30 s, and each layer had an average thickness of about 126 μm. The penetration depth and hole number of the microneedle were observed to evaluate the penetration ability of the microneedle.

[0125] Experimental procedure A 4x4 microneedle array was randomly cut from the soluble microneedle array prepared in Example 1e, and then the 4x4 microneedle array was pressed on 8 layers of Parafilm® film with a force of 32 N for 30 s, and then the 4x4 microneedle array was removed, and the bending change of the needle tip of the soluble microneedle array after pressing and the penetration depth of the microneedle were observed under a microscope.

[0126] Experimental results As shown in Figure 4 , wherein Figure 4 a represents the first layer of Parafilm film, Figure 4 b represents the second layer of Parafilm film, Figure 4 c represents the third layer of Parafilm film, Figure 4 d represents the fourth layer of Parafilm film. It can be seen that the soluble microneedle array can be inserted into the third layer of Parafilm film, and the insertion depth is 252 μm to 378 μm.

[0127] In addition, the bending of the needle tip of the soluble microneedle array after pressing was observed under a microscope, as shown in Figure 5 , wherein Figure 5 a represents the state before insertion of the soluble microneedle array, Figure 5 b represents the state after the soluble microneedle array is inserted into the Parafilm film. It can be seen that the needle body of the soluble microneedle array is not broken, and only part of the needle body has a slight bending of the tip, so the needle body of the soluble microneedle array prepared by the method described in the application has good strength.

[0128] III. Cumulative release experiment of drug Experimental steps A customized Franz diffusion cell was used, and the permeation area was 1 cm 2 . A piece of pigskin was taken, and the excess grease was removed, and the thickness was about 800 μm. The peeled skin sample was pre-equilibrated in PBS buffer for 3 minutes before the experiment started; the microneedle patch obtained in Example 1 was inserted into the skin using an applicator, and the penetration enhancer patch obtained in Example 2 was attached to the back of the microneedle patch of Example 1 for a control experiment. Then the skin of the microneedle combination patch was installed in the diffusion cell, and the PBS buffer was continuously stirred at a speed of 600 rpm, and was heated in a temperature cycle at 37°C. At predetermined time intervals (0 h, 1 h, 2 h, 4 h, 6 h, 8 h, 24 h, 48 h and 72 h), 5 mL of solution was taken from the receiving chamber, and an equal volume of fresh PBS buffer was replaced; the content of rhodamine B was detected by ultraviolet detection (triplicate for each group). The experimental results are shown in Figure 6 .

[0129] Experimental results In combination with the Figure 6It can be seen that, in the same time, the penetration enhancer (ethanol) added in Example 2a, the penetration enhancer patch A combined with the microneedle patch B of Example 1b, compared with the penetration enhancer patch B without the addition of penetration enhancer in Example 2b, can accelerate the penetration of rhodamine B in the microneedle patch through the pig skin, and the cumulative release of rhodamine B in 8 hours is 53%, and the cumulative release of rhodamine B in 8 hours is 35% when the penetration enhancer patch is combined with the microneedle patch without the addition of penetration enhancer.

[0130] In addition, both groups of experiments show that the cumulative release of rhodamine B in 72 hours is about 72%.

[0131] Four. Penetration and diffusion experiment of soluble microneedle combination patch Experimental steps Weigh 1.5g of gelatin powder and add it to 30mL of distilled water at a temperature of 65~95℃, stir and dissolve with a glass rod to obtain a gelatin solution with a mass percentage concentration of 5%, then pour the gelatin solution into a 60mm culture dish and cool and solidify.

[0132] The microneedle patch A obtained in Example 1a is applied to the gelatin, and then the penetration enhancer patch D (without the addition of penetration enhancer ethanol) obtained in Example 2d is applied to the microneedle patch A to obtain experimental group (1).

[0133] The microneedle patch A obtained in Example 1a is applied to the gelatin, and then the penetration enhancer patch C (with the addition of 2.5% ethanol as penetration enhancer) obtained in Example 2c is applied to the microneedle patch A to obtain experimental group (2).

[0134] The microneedle patch B obtained in Example 1b is applied to the gelatin, and then the penetration enhancer patch B (without the addition of penetration enhancer ethanol) obtained in Example 2b is applied to the microneedle patch A to obtain experimental group (3).

[0135] The microneedle patch B obtained in Example 1b is applied to the gelatin, and then the penetration enhancer patch A (with the addition of 2.5% ethanol as penetration enhancer) obtained in Example 2a is applied to the microneedle patch to obtain experimental group (4).

[0136] The microneedle patch C (without needle body) obtained in Example 1c is applied to the gelatin, and then the penetration enhancer patch C (with the addition of 2.5% ethanol as penetration enhancer) obtained in Example 2c is applied to the microneedle patch C to obtain experimental group (5).

[0137] The microneedle patch D obtained in Example 1d is applied to the gelatin, and then the penetration enhancer patch D (without the addition of penetration enhancer 2.5% ethanol) obtained in Example 2d is applied to the microneedle patch D to obtain experimental group (6).

[0138] The microneedle patch B obtained in Example 1b was applied to the gelatin, and then the penetration enhancer patch E (containing a penetration enhancer 1.0% ethanol) obtained in Example 2e was applied to the microneedle patch B, to obtain an experimental group (7).

[0139] The microneedle patch B obtained in Example 1b was applied to the gelatin, and then the penetration enhancer patch F (containing a penetration enhancer 5.0% ethanol) obtained in Example 2f was applied to the microneedle patch B, to obtain an experimental group (8).

[0140] The microneedle patch B obtained in Example 1b was applied to the gelatin, and then the penetration enhancer patch G (containing a penetration enhancer 10.0% ethanol) obtained in Example 2g was applied to the microneedle patch B, to obtain an experimental group (9).

[0141] The microneedle patch B obtained in Example 1b was applied to the gelatin, and then the penetration enhancer patch H (containing a penetration enhancer 5.0% 1,3 propanediol) obtained in Example 2h was applied to the microneedle patch B, to obtain an experimental group (10).

[0142] The microneedle patch B obtained in Example 1b was applied to the gelatin, and then the penetration enhancer patch I (containing a penetration enhancer 5.0% azone) obtained in Example 2i was applied to the microneedle patch B, to obtain an experimental group (11).

[0143] The microneedle patch B obtained in Example 1b was applied to the gelatin, and then the penetration enhancer patch J (containing a penetration enhancer 5.0% eucalyptus oil) obtained in Example 2j was applied to the microneedle patch B, to obtain an experimental group (12).

[0144] The penetration and diffusion of the microneedles were observed at 1h, 2h, 4h, 8h, 12h and 24h, respectively.

[0145] Experimental results 1. As shown in Table 1, the microneedle patch B obtained in Example 1b was applied to the gelatin, and then the penetration enhancer patch A (containing a penetration enhancer 5.0% ethanol) obtained in Example 2a was applied to the microneedle patch B, to obtain an experimental group (1). Figure 7The experimental results show that the rhodamine B in the experimental groups (1), (2), (3), (4), (5) and (6) starts to dissolve and diffuse at 1h, and the diffusion speed of the rhodamine B in the experimental group (2) is faster than that in the experimental group (1), which indicates that the addition of the penetration enhancer under the action of the micropore channel can improve the diffusion of the active ingredient in the penetration patch; the diffusion speed of the rhodamine B in the experimental group (4) is also better than that in the experimental group (3), which indicates that the addition of the penetration enhancer under the action of the micropore channel further improves the diffusion of the active ingredient in the microneedle patch; the diffusion speed of the rhodamine B in the experimental group (1) is also faster than that in the experimental group (5), which indicates that the micropore channel plays a role in penetration and helps the active ingredient in the penetration patch to diffuse; the diffusion speed of the rhodamine B in the experimental group (3) is equivalent to that in the experimental group (6), which indicates that when the penetration enhancer is fused in the soluble microneedle array, the penetration effect is not obvious, and it is speculated that the penetration enhancer may volatilize in the microneedle drying process, so that the subsequent penetration effect cannot be played, and mainly relies on the micropore channel formed by the microneedle to diffuse.

[0146] 2. As shown in the accompanying drawings, Figures 8-10 (1)-(12) correspond to the front views of the experimental groups (1)-(12), respectively.

[0147] As can be seen from the accompanying drawings, Figure 8 , the accompanying drawings Figure 9 and the accompanying drawings Figure 10 can be seen: ①At 1h, the rhodamine B in the experimental groups (1) and (2) did not penetrate into the gelatin; at 2h, the rhodamine B in the experimental group (2) began to have obvious penetration, and the penetration speed was faster than that of the rhodamine B in the experimental group (1). The rhodamine B in the experimental groups (3) and (4) began to penetrate into the gelatin at 1h; at 2h, the penetration speed of the rhodamine B in the experimental group (4) was faster than that of the rhodamine B in the experimental group (1), and the color was darker. It is indicated that the addition of the penetration patch can improve the penetration of the active ingredient in the soluble microneedle combination patch and change the permeability of the skin.

[0148] ②At 1h, the rhodamine B in the experimental group (5) did not penetrate into the gelatin; at 2h and 4h, there was a little penetration, which was obviously lower than that of other experimental groups, and the addition of the penetration enhancer in the needle body did not have obvious penetration effect on the rhodamine B in the experimental group (6), which was equivalent to the effect of the experimental group (3), which further indicates that the micropore channel is very important for penetration.

[0149] ③Within 1-10% of the ethanol content, the penetration effect can be achieved, and excessive penetration enhancer can destroy the lipid structure of the stratum corneum due to the high concentration of the penetration enhancer, resulting in barrier damage.

[0150] (4) Various penetration enhancers have certain penetration enhancing effect.

[0151] 3. Select t 4h The diffusion area and penetration depth of rhodamine B at t 4h The diffusion area and penetration depth of rhodamine B at t

[0152] Table 1 - Diffusion and penetration rates of different penetration enhancers at t 4h

[0153] As can be seen from the data in Table 1, as shown in experimental group (5), when no soluble microneedle array is used, the diffusion area and penetration depth of rhodamine B are obviously not as good as those of other experimental groups, indicating that the micropore channels formed by the soluble microneedle array play a key role in the penetration of active ingredients.

[0154] As shown in experimental groups (1) and (3), when no penetration enhancer is used, the diffusion and penetration performance of rhodamine B is relatively poor, and the diffusion and penetration rates of rhodamine B in experimental group (2) containing a penetration enhancer are better than those in experimental groups (1) and (3). As shown in experimental group (6), when the penetration enhancer is integrated into the soluble microneedle array, it does not significantly improve the diffusion area.

[0155] V. Soluble Microneedle Combination Patch Efficacy Experiment The soothing efficacy is mainly characterized by evaluating the inhibition rate of the test sample on hyaluronidase. The principle of the experiment of inhibiting hyaluronidase is that hyaluronidase catalyzes the enzyme substrate, and the absorbance changes after adding active substances. The size of the absorbance change reflects the inhibition rate of the hyaluronidase inhibitor.

[0156] Experimental steps Sample treatment: The microneedle patch E in Example 1e and the penetration enhancer (ethanol) added in Example 2c to prepare a penetration enhancer patch E were combined to form a combination patch sample, which was dissolved in distilled water at 1:1 as the test sample mother liquor.

[0157] Experimental process: Add buffer, different concentrations of sample diluent and hyaluronidase in a test tube, incubate at 37℃ for 20 min, add CaCl2 respectively, incubate at 37℃ for 20 min, add sodium hyaluronate, incubate at 37℃ for 90 min; Place at room temperature for 10 min, boil in water bath for 30 min; Ice bath for 10 min; Place at room temperature for 10 min, after P-DAB color development, measure the absorbance at a wavelength of 530 nm.

[0158] Each time 3 parallel samples were prepared. The effect of the sample on the activity of hyaluronidase was obtained.

[0159] Experimental results​ The microneedle patch E obtained in Example 1e was subjected to soothing efficacy laboratory evaluation. The evaluation results are shown in Table 5. Figure 11 As compared with the negative control, the inhibition rate of the microneedle patch E sample (i.e. MN) on hyaluronidase was about 67.8%, and the inhibition rate of the combination of the microneedle patch E sample + the penetration enhancer patch C sample (i.e. MN + penetration enhancer patch) on hyaluronidase was about 75.4%, both of which had certain inhibitory effects, indicating that the test sample had certain soothing effect, and the penetration enhancer patch could achieve synergistic therapeutic effect with the microneedle patch.

[0160] VI. Anti-wrinkle firming efficacy of soluble microneedle combination patch The test sample was subjected to experiment to verify whether it had the ability to inhibit elastase activity, so as to slow down the degradation rate of elastin, delay the skin relaxation and wrinkle, and thus prove whether the product had firming and anti-wrinkle effect. Judgment standard: calculate the elastase inhibition rate, which is higher than the blank inhibition rate.

[0161] Experimental procedure: a certain amount of the microneedle patch F sample prepared in Example 1f was weighed, the test sample was pretreated, the reactants were added and mixed; incubation was carried out in a 37℃ water bath for a period of time, washing was carried out, color developing agent was added, and incubation was continued for 15 minutes, and acid was added for termination; OD value was tested on the machine, and data were recorded.

[0162] Three parallel tests were carried out each time. The effect of the sample on elastase activity was obtained.

[0163] The microneedle patch F obtained in Example 1f was subjected to firming and anti-wrinkle efficacy laboratory evaluation. The evaluation results are shown in Table 6. Figure 12 As compared with the negative control, the inhibition rate of the microneedle patch F sample (i.e. MN) on elastase was about 38.5%, and the inhibition rate of the combination of the microneedle patch F sample + the penetration enhancer patch C sample (i.e. MN + penetration enhancer patch) on elastase was about 50.6%, both of which had certain inhibitory effects, indicating that the test sample had certain firming and anti-wrinkle effect, and the penetration enhancer patch could achieve synergistic therapeutic effect with the microneedle patch.

[0164] The above has described various embodiments of the present application, and the above description is exemplary, not exhaustive, and is not limited to the disclosed embodiments. Many modifications and changes are obvious to those skilled in the art without departing from the scope and spirit of the described embodiments. The selection of the terms used herein is intended to best explain the principles, practical applications, or improvements to the technology in the market of the embodiments, or to enable other ordinary skilled persons in the art to understand the embodiments disclosed herein.

Claims

1. A dissolvable microneedle combination patch, characterized by, The micro-needle patch and the penetration-enhancing patch are included. The micro-needle patch includes a micro-needle carrier and a soluble micro-needle array distributed on the lower surface of the micro-needle carrier; the micro-needle carrier is provided with a plurality of through holes penetrating the upper and lower surfaces; the soluble micro-needle array at least contains a water-soluble polymer and an active ingredient A. The penetration-enhancing patch includes a penetration-enhancing carrier and a penetration-enhancing active component loaded on the penetration-enhancing carrier. The penetration-enhancing patch is configured to be attached to the upper surface of the micro-needle carrier and to enable the penetration-enhancing active component to diffuse downward along the micro-channels formed after the soluble micro-needle array dissolves.

2. The dissolvable microneedle combination patch of claim 1, wherein: The water-soluble polymer is selected from the group consisting of hyaluronic acid and its salts, polyvinyl alcohol, polyvinylpyrrolidone, chondroitin sulfate, sodium alginate, chitosan and its derivatives, carboxymethyl cellulose, polyglutamic acid, gelatin, polyacrylate, starch-acrylic acid graft copolymer, alpha-hydroxy acid, polyanhydride, polyortho ester, polyphosphazene, polyphosphate, polyglycolide, polylactic acid, hydroxyacetic acid-lactic acid copolymer, polycaprolactone, or a combination of one or more thereof. Preferably, the polymer is sodium hyaluronate; more preferably, the molecular weight of the sodium hyaluronate is 5 kDa-300 kDa.

3. The dissolvable microneedle combination patch of claim 1, wherein: The micro-needle carrier is selected from the group consisting of hydrocolloid, medical non-woven fabric, medical PE film or medical PU film. The area of the through holes on the micro-needle carrier accounts for 25%-80% of the total area of the micro-needle carrier. The height of the soluble micro-needle array is 200 μm-1500 μm, preferably 500 μm-1000 μm, and more preferably 530 μm-600 μm.

4. The dissolvable microneedle combination patch of claim 1, wherein: The penetration-enhancing carrier is selected from the group consisting of defatted cotton, spunlace non-woven fabric, polymer film or hydrogel. Preferably, the polymer film is selected from the group consisting of cellulose acetate, ethyl cellulose, ethylene-vinyl acetate copolymer, cellulose dipalmitate, polyoxyethylene, polyacrylic acid, polyhydroxymethylpropylene acid alkyl ester, high molecular weight polyethylene glycol, hydrophilic polypropylene, medical polyvinyl chloride or polyvinyl alcohol. Preferably, the hydrogel is selected from the group consisting of hyaluronic acid hydrogel, polyvinyl alcohol hydrogel, polyacrylamide hydrogel, polyacrylic acid hydrogel, poloxamer hydrogel, carbomer hydrogel, chitosan-glycerol hydrogel, gelatin-based hydrogel or functionally modified hydrogel.

5. The dissolvable microneedle combination patch of claim 1, wherein: The penetration-enhancing active component contains active ingredient B, and the active ingredient A and the active ingredient B are each independently selected from small molecule drugs or large molecule drugs. Preferably, the penetration-enhancing active component further includes a penetration enhancer; more preferably, the penetration enhancer is selected from the group consisting of ethanol, 1,3-propanediol, 1,2-butanediol, 1,4-butanediol, 1,2-pentanediol, 1,2-hexanediol, azone, N-methyl-2-pyrrolidone, 2-pyrrolidone, isosorbide dimethyl ether, inositol or eucalyptus oil.

6. A method of making the dissolvable microneedle combination patch of any one of claims 1 to 5, wherein, The method includes: S1: preparing a micro-needle patch A water-soluble polymer, an active ingredient A and a solvent are mixed to obtain a micro-needle matrix solution; The micro-needle matrix solution is injected into a micro-needle mold, and the micro-needle matrix solution fills the micro-holes of the mold; after drying, the mold is removed to obtain a soluble micro-needle array; the soluble micro-needle array is attached to one side of a micro-needle carrier to obtain a micro-needle patch; S2: preparing a penetration-enhancing patch mixing the penetration enhancer, the active ingredient B and the solvent to obtain a penetration active component solution, soaking the penetration carrier in the penetration active component solution until the penetration active component solution is fully absorbed by the penetration carrier to obtain a penetration patch; S3: packaging the microneedle patch and the penetration patch separately to obtain a soluble microneedle combination patch which can be used in combination.

7. The method of claim 6, wherein: The mixing temperature of the water-soluble polymer, the active ingredient A and the solvent in step S1 is 30-70°C; And / or, the microneedle matrix solution is filled into the mold micropores by centrifugation or vacuum assisted forming in step S1. And / or, the pH value of the penetration active component solution is controlled to be 4.0-6.0 in step S2.

8. Use of the soluble microneedle combination patch of any one of claims 1-5 in the preparation of a transdermal delivery preparation. Preferably, the components of the water-soluble microneedle array are as follows in terms of mass percentage: water-soluble polymer 2-20%, active ingredient A 0.1-5%, and the balance being water. Preferably, the penetration active component is as follows in terms of mass percentage: active ingredient B 0.1-30%, penetration enhancer 0-95%, and the balance being water.

9. Use of the soluble microneedle combination patch of any one of claims 1-5 in the preparation of a skin soothing and repairing preparation. Preferably, the components of the water-soluble microneedle array are as follows in terms of mass percentage: sodium hyaluronate 2-20%, menthol 0.1-5%, and the balance being water; more preferably, the components are as follows in terms of mass percentage: sodium hyaluronate 5-15%, menthol 0.3-1.5%, and the balance being water. Preferably, the penetration active component is as follows in terms of mass percentage: bisabolol 0.1-1%, panthenol 0.5-10%, hyaluronic acid 2-10%, ascorbic acid 0.01-0.5%, and ethanol 0.01-95%, and the balance being water; more preferably, the penetration active component is as follows in terms of mass percentage: bisabolol 0.12-0.5%, panthenol 0.6-5%, hyaluronic acid 4-8%, ascorbic acid 0.05-0.3%, and ethanol 1-10%, and the balance being water.

10. Use of the soluble microneedle combination patch of any one of claims 1-5 in the preparation of a skin anti-wrinkle and firming preparation. Preferably, the components of the water-soluble microneedle array are as follows in terms of mass percentage: water-soluble polymer 2-20%, and the balance being water; more preferably, the components are as follows in terms of mass percentage: sodium hyaluronate 5-15%, and the balance being water. Preferably, the penetration-promoting active ingredient comprises, by mass percentage, 0.1% to 1% of bisabolol, 0.5% to 10% of panthenol, 2% to 10% of hyaluronic acid, 0.01% to 0.5% of ascorbic acid, 0.01% to 95% of ethanol, and the balance water; more preferably, the penetration-promoting active ingredient comprises, by mass percentage, 0.12% to 0.5% of bisabolol, 0.6% to 5% of panthenol, 4% to 8% of hyaluronic acid, 0.05% to 0.3% of ascorbic acid, 1% to 10% of ethanol, and the balance water.

Images