A supramolecular salicylic acid composite microneedle patch and its preparation method and application

Abstract

The present invention discloses a supramolecular salicylic acid composite microneedle patch and a preparation method and application. The needle tip array of the supramolecular salicylic acid composite microneedle patch is composed of the following components by mass fraction: 2% to 10% salicylic acid, 1% to 10% polyethylene glycol or its derivatives, 68.5% to 92.7% hyaluronic acid, 2% to 5% polyvinyl alcohol, 0.8% to 1.5% glycerol, 0.5% to 2% menthol, 0.5% to 1% bisabolol and 0.5% to 2% dipotassium glycyrrhizinate. The present invention improves the overall preparation process of microneedles and the components of microneedles, uses polymer surfactants and salicylic acid to form a supramolecular gel network, and salicylic acid is gradually released as substances such as polyethylene glycol in the supramolecular structure degrade, thereby achieving sustained release of salicylic acid. In addition, the prepared microneedles have high mechanical strength, which enhances the transdermal puncture ability of the microneedles.

Description

Technical Field

[0001] The present invention belongs to the technical field of biomedical materials, and more specifically, relates to a supramolecular salicylic acid composite microneedle patch and a preparation method and application thereof. Background Art

[0002] Acne is a common chronic inflammatory disease of hair follicles and sebaceous glands. Excessive keratinization of the funnel of the hair follicle is the pathological basis of acne aggravation and the main pathological mechanism of acne formation. Salicylic acid is lipophilic and can penetrate around the sebaceous gland unit and dissolve oil. It is currently recognized as a drug commonly used to inhibit this mechanism. Salicylic acid is a weak acid in the form of colorless crystals. It has a low solubility in water (2g / L, 20°C). It is usually necessary to add organic solvents such as ethanol, acetone, ether or sodium hydroxide to increase the solubility of salicylic acid. However, the use of organic solvents can irritate the skin, and the neutralization effect of sodium hydroxide can destroy the carboxyl group of salicylic acid, significantly reducing its efficacy. On this basis, Lv Shaoxiang et al. proposed in Chinese patent CN201610982443.4 that a thermosensitive gel forms a water-soluble intermolecular complex with a block copolymer in water to enhance the solubility / stability of water-soluble / water-insoluble drugs for use in the field of medicine / cosmetics. However, due to the obstruction of the skin's stratum corneum, these topical products are difficult to reach the dermis directly and cannot effectively dissolve oil to achieve the effect of thoroughly cleansing the skin.

[0003] Microneedles are an emerging transdermal drug delivery technology that can penetrate the stratum corneum barrier of the skin and directly deliver active ingredients into the skin, thereby improving the transdermal effect of active ingredients. In recent years, microneedles loaded with active ingredients have been widely used in the medical and beauty industries. In order to make microneedles have good biocompatibility, natural polysaccharide compounds such as hyaluronic acid, sodium alginate, gelatin, and chitosan are generally used as microneedle preparation materials. However, natural polysaccharide compounds have low mechanical strength and are not easy to pierce the skin after loading small molecule active ingredients; and polysaccharide compounds dissolve quickly, and the active ingredients cannot be released on demand. On the other hand, salicylic acid itself will cause certain irritation to the skin, and too fast release will cause strong irritation to the skin. Therefore, we need to control the release rate of salicylic acid to reduce irritation to the skin and prolong the onset time of salicylic acid in the skin. Currently, conventional controlled-release methods can use microspheres or microblocks of degradable biomedical polymers (such as PLA, PCL, PLGA, PGA) or stimuli-responsive cross-linked compounds (such as gelatin, hyaluronic acid) to load active ingredients to achieve controlled and sustained release of active ingredients. However, the preparation process is relatively complicated, the drug loading capacity is low, and polymer metabolism can easily cause local tissue acidity to be too high, which limits its application and development. Summary of the invention

[0004] In view of the above defects or improvement needs of the prior art, the present invention provides a supramolecular salicylic acid composite microneedle patch, a preparation method and an application, the purpose of which is to utilize amphiphilic surfactants, hyaluronic acid and salicylic acid to form a supramolecular gel network, thereby solving technical problems such as low salicylic acid drug loading and polymer metabolism that easily causes excessive acidity of local tissues.

[0005] To achieve the above-mentioned object, according to one aspect of the present invention, a supramolecular salicylic acid composite microneedle patch is provided, wherein the needle tip array of the supramolecular salicylic acid composite microneedle patch is composed of the following components in mass fraction: 2% to 10% salicylic acid, 1% to 10% polyethylene glycol or its derivatives, 68.5% to 92.7% hyaluronic acid, 2% to 5% polyvinyl alcohol, 0.8% to 1.5% glycerol, 0.5% to 2% menthol, 0.5% to 1% bisabolol and 0.5% to 2% dipotassium glycyrrhizinate.

[0006] Preferably, the salicylic acid, polyvinyl alcohol and polyethylene glycol or their derivatives can form a supramolecular gel network in an aqueous solution, thereby achieving sustained release of salicylic acid.

[0007] Preferably, the polyethylene glycol or its derivatives and polyvinyl alcohol form a hydrogen-bonded supramolecular gel network in an aqueous solution, thereby enhancing the interaction between the components in the microneedle tip and improving the mechanical strength of the formed microneedle tip.

[0008] In the present invention, the supramolecular gel network is a gel structure formed by supramolecular interactions, and the supramolecular interactions include hydrogen bonds, host-guest interactions, ionic bonds, etc. The hydrogen-bonded supramolecular gel network is a gel structure formed by hydrogen bonds.

[0009] Preferably, the substrate of the supramolecular salicylic acid composite microneedle patch is hyaluronic acid.

[0010] According to another aspect of the present invention, a method for preparing a supramolecular salicylic acid composite microneedle patch is provided, comprising the following steps:

[0011] Step (1), polyethylene glycol (polyethylene glycol or its derivatives), hyaluronic acid, polyvinyl alcohol, glycerol, menthol, bisabolol, dipotassium glycyrrhizinate, salicylic acid are uniformly mixed to obtain a mixed solution, and the mixed solution is filled into a PDMS mold by centrifugation. At this time, the polymer surfactant (i.e., polyethylene glycol or its derivatives, polyvinyl alcohol) and salicylic acid can form a supramolecular gel network, thereby achieving sustained release of salicylic acid. Polyethylene glycol or its derivatives and polyvinyl alcohol form a hydrogen bond supramolecular gel network in an aqueous solution, thereby enhancing the interaction between the components in the microneedle tip and improving the mechanical strength of the microneedle tip after forming.

[0012] Step (2), after the liquid in the mold is dried, the mixed solution is added again and centrifuged to dry.

[0013] Step (3), repeating step (2) until the liquid in the mold is dry and no more mixed solution can be added.

[0014] Step (4), add hyaluronic acid solution to the mold surface and centrifuge to make the base formed by hyaluronic acid closely connected with the needle tip array, and demould after drying to obtain the supramolecular salicylic acid composite microneedle patch. Preferably, the mixed solution is an aqueous solution with a mass fraction of 20%, and the mass fraction of the hyaluronic acid solution in the transparent step (4) is 25%.

[0015] According to another aspect of the present invention, there is provided a use of a supramolecular salicylic acid composite microneedle patch in the preparation of a transdermal drug delivery preparation.

[0016] Preferably, the transdermal administration preparation is a transdermal administration preparation of a freckle-removing cosmetic drug, an acne-removing drug, or an anti-inflammatory drug.

[0017] In general, compared with the prior art, the above technical solution conceived by the present invention can at least achieve the following beneficial effects.

[0018] (1) The supramolecular salicylic acid composite microneedle provided by the present invention comprises salicylic acid, polyethylene glycol or its derivatives, and polyvinyl alcohol, wherein the polymer surfactant (i.e., polyethylene glycol or its derivatives, polyvinyl alcohol) and salicylic acid can form a supramolecular gel network, thereby achieving sustained release of salicylic acid. The problem of high irritation caused by rapid release of salicylic acid is avoided. In addition, the form of the supramolecular gel network can increase the loading amount of salicylic acid in the microneedle tip; the use of organic solvents and alkalis is avoided, and the efficacy of salicylic acid is guaranteed. After the microneedle patch is inserted into the skin, the microneedle dissolves rapidly, releasing the active ingredient, and the needle tip forms supramolecular micelles in the skin, which continuously release salicylic acid.

[0019] (2) Polyethylene glycol or its derivatives form a hydrogen-bonded supramolecular gel network with polyvinyl alcohol in aqueous solution, which can improve the mechanical strength of the prepared microneedles and enhance the transdermal puncture ability of the microneedles.

[0020] (3) The present invention adopts a two-stage microneedle structure. After the hyaluronic acid in the base part is quickly dissolved, the supramolecular salicylic acid composite needle tip in the needle tip part can be completely released into the skin, thereby avoiding waste. The microneedle of the present invention can directly deliver salicylic acid to the vicinity of the sebaceous glands, thereby achieving the purpose of quickly and thoroughly cleaning grease.

[0021] (4) The other additives in the present invention can further enhance the effect of the microneedles. For example, menthol has a sedative and analgesic effect; the bisabolol has a protective effect on allergic skin; and dipotassium glycyrrhizinate has an antibacterial and anti-allergic effect. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 Schematic diagram of the supramolecular salicylic acid composite microneedle structure.

[0023] Figure 2 This is an optical microscope photograph of the supramolecular salicylic acid composite microneedles prepared in Example 1.

[0024] Figure 3 The microneedles prepared in Example 1 were inserted into the back skin of a depilated mouse, and the photo of the mouse's back was taken 24 hours later.

[0025] Figure 4 This is an optical microscope photograph of skin tissue sections and H&E staining 5 minutes after the microneedles prepared in Example 1 were inserted into the skin of depilated mice. DETAILED DESCRIPTION

[0026] In order to make the purpose, technical solutions and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention. In addition, the technical features involved in the various embodiments of the present invention described below can be combined with each other as long as they do not conflict with each other.

[0027] Example 1

[0028] This embodiment provides a supramolecular salicylic acid composite microneedle patch, see Figure 1 and Figure 2 , and its preparation process mainly includes the following steps:

[0029] (1) A 1 cm × 1 cm polydimethylsiloxane (PDMS) mold with a bottom diameter of 300 μm, a height of 700 μm, and a center-to-center distance of 750 μm was etched using a laser engraving machine, and then ultrasonically washed with ethanol for later use;

[0030] (2) Weigh the following components in proportion: 5% salicylic acid, 8% polyethylene glycol (PEG 100k ), 80.5% hyaluronic acid (HA 25k ), 3% polyvinyl alcohol (degree of alcoholysis: 87-89 mol%), 1% glycerol, 1% menthol, 0.5% bisabolol, 1% dipotassium glycyrrhizate, and then dissolve the above powders in water to prepare a 20% aqueous solution by mass;

[0031] (3) Add the above solution dropwise onto the PDMS mold cleaned in (1), and place the mold in a horizontal centrifuge for centrifugation (8000 rpm, 10 min, 2 times). Use centrifugal force to fill the above mixed solution into the PDMS mold, and repeat the filling 3 times;

[0032] (4) After the solution in the PDMS mold in step (3) is dried, add 25% hyaluronic acid solution (HA 10k ), evacuate (-50 kPa, 10 minutes) to make the hyaluronic acid tightly connected to the needle tip;

[0033] (5) After the hyaluronic acid is dried, the mold is removed to obtain a supramolecular salicylic acid composite microneedle patch.

[0034] Embodiment 2-6

[0035] The preparation steps of Examples 2-6 are the same as those of Example 1, except that the proportions of the components are different, as shown in Table 1 below:

[0036] Table 1 Proportions of the components in Examples 2-6

[0037]

[0038]

[0039] Application Example 1

[0040] The salicylic acid composite microneedle patch prepared in Example 1 was inserted into the back of a depilated Balb / c mouse for 5 minutes, and the recovery of the mouse back skin after microneedle insertion was monitored using an optical microscope. The mouse back skin after microneedle insertion was also taken and fixed with 4% paraformaldehyde solution, and tissue sections and H&E staining analysis were performed.

[0041] See also Figure 3 and Figure 4 It can be seen that the salicylic acid composite microneedle patch provided by the present invention can effectively pierce the skin and deliver the salicylic acid composite microneedle tips into the skin.

[0042] It will be easily understood by those skilled in the art that the above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing a supramolecular salicylic acid composite microneedle patch, characterized in that: The following steps are involved: (1) A 1 cm × 1 cm PDMS mold with a bottom diameter of 300 μm, a height of 700 μm, and a center distance of 750 μm between adjacent microneedles was etched using a laser engraving machine, and then ultrasonically washed with ethanol and set aside for later use; (2) weighing the following components in proportion: 5% salicylic acid, 8% polyethylene glycol, 80.5% hyaluronic acid, 3% polyvinyl alcohol, 1% glycerol, 1% menthol, 0.5% bisabolol, and 1% dipotassium glycyrrhizinate, and then dissolving the above substances in water to prepare an aqueous solution with a mass fraction of 20%; the alcoholysis degree of the polyvinyl alcohol is 87-89 mol%; (3) dripping the mixed solution onto the PDMS mold cleaned in (1), and placing the mold in a horizontal centrifuge for centrifugation at 8000 rpm for 10 minutes twice, using centrifugal force to fill the mixed solution into the PDMS mold, and repeating the filling three times; (4) After the solution in the PDMS mold in step (3) is dried, add 25% hyaluronic acid solution to the surface of the mold and evacuate at -50 kPa for 10 minutes to allow the hyaluronic acid to be tightly connected to the needle tip; (5) after the hyaluronic acid is dried, demolding is performed to obtain the supramolecular salicylic acid composite microneedle patch; The needle tip array of the supramolecular salicylic acid composite microneedle patch is composed of 5% salicylic acid, 8% polyethylene glycol, 80.5% hyaluronic acid, 3% polyvinyl alcohol, 1% glycerol, 1% menthol, 0.5% bisabolol, and 1% dipotassium glycyrrhizinate by mass fraction, and the substrate is hyaluronic acid.

2. A supramolecular salicylic acid composite microneedle patch obtained by the preparation method as claimed in claim 1.

3. Use of the supramolecular salicylic acid composite microneedle patch as claimed in claim 2 in the preparation of a transdermal drug delivery preparation.

4. The use according to claim 3, characterized in that The transdermal drug delivery preparation is a transdermal drug delivery preparation for anti-freckle beauty drugs, anti-acne drugs, and anti-inflammatory drugs.

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