Erasable effervescent microneedle as well as preparation method and application thereof

Abstract

The invention relates to an erasable effervescent microneedle as well as a preparation method and application thereof, compared with the prior art, the erasable effervescent microneedle has the advantages that an effervescent component is uniformly dispersed in a backing layer, so that the backing layer is bubbled under the condition that water is added to the outside, and an effervescent reaction can be quickly generated by pressing and smearing with fingers, so that quick erasure of the backing layer is realized. According to the erasable effervescent microneedle provided by the invention, the needle tip array and the effervescent backing material can be directly connected at room temperature or connected through a low-temperature freeze-drying technology so as to reduce the mutual dissolution influence between the needle tip array and the effervescent backing material. According to the erasable effervescent microneedle, the use convenience and effectiveness of the microneedle are remarkably improved, and a more efficient application mode is provided for percutaneous delivery of the microneedle.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to an erasable effervescent microneedle and a preparation method and application thereof. Background Art

[0002] As a new type of transdermal drug delivery technology, microneedles can penetrate the stratum corneum of the skin to form microporous channels, thereby promoting the penetration and absorption of drugs. Compared with traditional injection dosage forms, the use of microneedles for drug delivery can not only reduce the pain of patients, but also improve the compliance of patients with medication; compared with traditional patches, microneedles can directly penetrate the stratum corneum to release active ingredients, especially for water-soluble and large molecular components, which can effectively avoid the barrier effect of the stratum corneum and greatly improve the utilization rate of drugs. For large-molecule biotechnology drugs, this technology has broken through the previous limitation that they can only be administered by injection. In addition, in the field of beauty and medical beauty, microneedles help small and large molecule beauty active ingredients to break through the skin barrier and penetrate into the skin more effectively, thereby improving the medical beauty effect. In the past few decades, microneedles have attracted much attention in the field of transdermal delivery, with rapid development and broad prospects.

[0003] However, there are still certain defects in the current microneedle drug delivery. Due to the pulling effect of the backing layer and the resilience of the skin itself, it is often difficult for microneedles to be fully inserted into the skin. In practical applications, it is usually necessary to press the skin continuously for a certain period of time, ranging from 1-5 minutes to 10-30 minutes. Even if a pressure-sensitive adhesive patch or a gel patch is used for fixation afterwards, the problem of needle tip rebound cannot be completely avoided; in addition, this method of use is not convenient and the patient's compliance is poor. Industry and academia recommend the use of drug delivery devices (such as spring pressure devices) to assist microneedles in instantly breaking through skin barriers, in order to evenly apply pressure and insert the microneedles into the skin to the greatest extent, but the effect of such methods is still limited, and the microneedles will still rebound after insertion. At the same time, such devices also have problems such as poor portability, inconvenience in use, and high cost, which further limits the popularization and application of microneedle technology.

[0004] In view of the above situation, the industry has been exploring ways to solve the problem of more effective microneedle needle entry into the skin. Several solutions have been developed and achieved certain results, such as designing the needle tip array into a structure with barbed thorns, or adding flexible components to the backing. Among them, the more prominent technology is the strategy of adopting "effervescent microneedles", which was first applied to contraceptive microneedles by Praut scholars. Effervescent technology was originally used for the rapid disintegration of effervescent tablets. By introducing effervescent components into the microneedle array matrix or the backing matrix, the microneedles absorb interstitial fluid after being inserted into the skin, and the acid-base reaction of the backing or the backing-needle array junction is used to generate bubbles, thereby promoting the rapid separation of the needle tip and the backing layer, ensuring that the needle tip array remains in the skin to exert local or systemic effects, while the backing can be easily removed without residue.

[0005] However, this type of design still has shortcomings. The length of microneedles commonly used in the field of medical beauty is generally less than 300 microns, which means that only half to one-third of the length of the needle tip array can actually enter the skin, making it difficult to contact sufficient interstitial fluid. Therefore, this type of effervescent strategy may have limited effect on medical beauty microneedles; for microneedles longer than 300 microns, due to the small amount of interstitial fluid and slow flow rate, the interstitial fluid cannot effectively penetrate into the backing layer, making the amount of liquid available to trigger effervescence very limited. Most of the published effervescent microneedle literature is tested in an aqueous environment, and the effervescent needle-breaking effect is verified by adding an external water source, but the actual effervescent needle-breaking effect under real skin conditions has not yet been verified or characterized. Even if this method is feasible under ideal conditions, due to the large individual differences in the exudation of tissue fluid in the body, and affected by factors such as the depth of insertion, physical condition, and usage techniques, it is still prone to problems such as unstable effervescence or insufficient needle breaking, thereby reducing drug utilization.

[0006] Chinese patent CN116531312A discloses an effervescent microneedle for releasing drugs deep into the skin, wherein the effervescent component is added to the needle tip array portion; Chinese patent CN116251079A discloses an effervescent soluble microneedle patch of platelet-rich plasma, wherein the effervescent component is also added to the needle tip array portion. The above existing patents all place the effervescent component at the needle tip rather than the backing layer, aiming to further push the drug into the deep layer of the skin by generating gas. However, this type of solution relies on a small amount of interstitial fluid of the body itself to achieve effervescence, which has individual differences and uncertainties, and it is difficult to ensure sufficient effervescence. Even if it can be fully effervescent, the backing still needs to be attached to the skin surface for a long time and cannot be removed, so that it continues to be affected by the pulling effect of the backing on the skin and the skin's resilience, which ultimately makes it difficult for the needle tip to fully stay in the skin. It can be seen that the existing microneedle technology still has deficiencies in terms of ease of use and patient compliance, and it is difficult to meet actual needs. Summary of the invention

[0007] The purpose of the present invention is to overcome the shortcomings of the practical application of existing microneedles, and to provide a removable effervescent microneedle and its preparation method and application. The present invention disperses the effervescent component evenly throughout the backing layer, so that the backing layer quickly foams after adding water externally, significantly improving the decomposition rate of the backing layer under water conditions, and then implements the smearing action through the outside (such as fingers), thereby achieving both rapid removal of the backing layer and retention of the needle tip array in the skin to play a role. In the removable effervescent microneedle described in the present invention, the needle tip array and the backing material containing the effervescent component can be directly dried and connected at room temperature, or can be connected by low-temperature freeze-drying. The removable effervescent microneedle provided by the present invention not only significantly improves the portability and efficiency of the microneedle, but also provides a more efficient and feasible form of administration for transdermal administration.

[0008] The purpose of the present invention can be achieved by the following technical solutions:

[0009] The first object of the present invention is to provide a removable effervescent microneedle, comprising a backing layer and a needle tip array fixed on the backing layer;

[0010] The backing layer is prepared from the following raw materials according to the following relative contents:

[0011]

[0012] The needle tip array is prepared from the following raw materials according to the following relative contents:

[0013]

[0014] Furthermore, the first water-soluble high molecular polymer in the backing layer is selected from any one or more of polyvinyl pyrrolidone (PVP), polyvinyl alcohol (PVA), highly substituted hydroxypropyl cellulose or methyl cellulose.

[0015] As a preferred technical solution, the PVP is selected from any one or more of PVP K-30, PVP K-60 or PVP K-90.

[0016] Furthermore, the effervescent alkali source is selected from sodium carbonate or sodium bicarbonate.

[0017] Furthermore, the effervescent acid source is selected from any one or more of citric acid, malic acid, boric acid, tartaric acid or fumaric acid.

[0018] Furthermore, the first solvent is anhydrous ethanol.

[0019] Furthermore, the high molecular polymer in the needle tip array is selected from a second water-soluble high molecular polymer or a water-insoluble high molecular polymer;

[0020] Wherein, the second water-soluble high molecular polymer is preferably selected from any one or more of hyaluronic acid, PVP, PVA or sodium carboxymethyl cellulose;

[0021] The poorly water-soluble high molecular polymer is preferably selected from polylactic acid and / or polylactic-co-glycolic acid (PLGA).

[0022] As a preferred technical solution, the PLGA is selected from PLGA 75:25 or PLGA 50:50.

[0023] Furthermore, the target drugs include biotechnology drugs and chemical drugs, etc.; wherein the biotechnology drugs include medical drugs and medical cosmetic drugs, and the chemical drugs include medical drugs and medical cosmetic drugs.

[0024] As a preferred technical solution, the medical drug is selected from insulin, glucagon-like peptide-1 (GLP-1) analogs, growth hormone, calcitonin, vaccines, interferon, monoclonal antibodies, blood coagulation factors, mRNA or RNA, etc.;

[0025] The medical cosmetic drugs are selected from botulinum toxin, hyaluronic acid, collagen, recombinant protein growth factors, stem cell extracts and derived proteins, coenzyme Q10 or glutathione, etc.

[0026] As a preferred technical solution, the medical drug is selected from minoxidil, tacrolimus, lidocaine, finasteride or methotrexate;

[0027] The drug for medical cosmetics is selected from tranexamic acid, azelaic acid, retinoic acid, retinoic acid esters, niacinamide, ascorbic acid or arbutin, etc.

[0028] Furthermore, the second solvent is selected from ethanol, water or DMSO.

[0029] Furthermore, the additives include anti-allergic and anti-inflammatory agents and / or preservatives.

[0030] As a preferred technical solution, the anti-allergic and anti-inflammatory agent is selected from any one or more of loratadine, chlorpheniramine, erythromycin or ofloxacin, etc., to relieve the skin redness and pain symptoms that may occur after the use of the removable effervescent microneedle;

[0031] The preservative is selected from any one or more of benzoic acid, methylparaben, ethylparaben, propylparaben or butylparaben.

[0032] Furthermore, the needle length of the microneedle is 100 to 1000 microns, and the needle shape of the microneedle is not limited to a regular quadrangular pyramid, a cone, or the like.

[0033] The second object of the present invention is to provide a method for preparing an erasable effervescent microneedle, the specific steps of which are as follows:

[0034] S1, adding a high molecular weight polymer, an additive and a target drug into a second solvent for dissolution to prepare a needle tip solution;

[0035] S2, adding a first water-soluble high molecular polymer, an effervescent base source, an effervescent acid source and an additive into a first solvent and dissolving them to obtain a backing solution;

[0036] S3, adding the needle tip solution prepared in step S1 into the microneedle mold to form a needle tip array, and then applying the backing solution prepared in step S2 to the base surface of the needle tip array, and forming a backing layer after drying, thereby preparing an erasable effervescent microneedle.

[0037] Furthermore, in step S3, after the needle tip solution is injected into the microneedle mold, vacuum filling is performed, and bubbles are scraped off, and the excess solution is removed after repeating 2 to 3 times, and the needle tip array is obtained after drying; then, the backing solution is applied to the base surface of the needle tip array, and vacuum filling is performed again and bubbles are scraped off, and the process is repeated 2 to 3 times, and the backing layer is formed after complete drying, thereby obtaining a removable effervescent microneedle.

[0038] Furthermore, when the polymer is a second water-soluble polymer, the needle tip solution prepared in step S1 is added to the microneedle mold, and the excess solution is removed after vacuum filling and air bubble removal for 2 to 3 times, and the needle tip array is obtained by freeze drying; the backing solution prepared in step S2 is pre-cooled to 4°C, and then coated on the base surface of the needle tip array, and vacuum filling and air bubble removal are performed for 2 to 3 times, and the backing layer is formed after being completely dried, so as to obtain a removable effervescent microneedle;

[0039] Furthermore, after step S3 is completed, step S4 can be added: a thin protective film is coated on the surface of the erasable effervescent microneedles by spraying to prevent the effervescent components contained in the backing layer from absorbing moisture and deteriorating in the air, thereby improving the storage stability of the product and enhancing the mechanical strength of the needle tip array.

[0040] As a preferred technical solution, the protective film is made of polyethylene or polypropylene material, which protects the surface of the removable effervescent microneedle and can be easily torn off during use.

[0041] The third object of the present invention is to provide a method for preparing an erasable effervescent microneedle, the specific steps of which are as follows:

[0042] S1, adding a high molecular weight polymer, an additive and a target drug into a second solvent for dissolution to prepare a needle tip solution;

[0043] S2, adding a first water-soluble high molecular polymer, an effervescent base source, an effervescent acid source, and an additive into a first solvent and dissolving them to obtain a backing solution;

[0044] S3, adding the backing solution prepared in step S2 into the microneedle mold without vacuuming, and allowing it to completely dry under natural conditions to form a backing layer without a needle tip array;

[0045] S4. Add the needle tip solution prepared in step S1 into the microneedle mold for vacuum filling. Repeat 2 to 3 times and scrape off the excess solution on the surface. Then, place the backing layer prepared in step S3 into the microneedle mold at an inclined angle to avoid bringing in air as much as possible so that the needle tip solution and the backing layer are bonded. After being completely dried, package the microneedle to obtain a removable effervescent microneedle.

[0046] The fourth object of the present invention is to provide an application of an erasable effervescent microneedle, wherein the erasable effervescent microneedle is used to deliver constant-release drugs, rapid-release drugs or sustained-release drugs.

[0047] Furthermore, the specific method of using the erasable effervescent microneedle is as follows:

[0048] After the removable effervescent microneedle is inserted into the skin, water is added to the surface of the backing layer, and pressure is applied vertically up and down with fingers. The backing layer can be seen to bubble rapidly with the naked eye, and the backing layer gradually liquefies and disappears by pressing and applying with fingers.

[0049] Furthermore, the method of adding water externally is: spraying or dripping purified water onto the surface of the backing layer of the erasable effervescent microneedle through a nozzle, a dropper or a similar device, and realizing rapid liquefaction, bubbling and disappearance of the backing layer by pressing and applying.

[0050] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0051] 1. External water addition trigger, quickly wipe off the backing layer

[0052] The present invention innovatively disperses the effervescent components evenly in the backing layer, and presses and applies the backing layer after adding water externally, which can significantly accelerate the liquefaction and foaming of the backing layer, achieve rapid wiping of the backing layer, and avoid the limitation of traditional needle breaking that relies on interstitial fluid.

[0053] 2. Low temperature freeze drying and pre-cooling process, the preparation process is more stable

[0054] One of the processes of the present invention combines low-temperature freeze-drying of the needle tip with pre-cooling of the backing solution, which can effectively reduce the mutual dissolution of the water-soluble needle tip and the backing layer during the preparation process, ensure stable microneedle molding and complete appearance, and further ensure drug activity and overall quality.

[0055] 3. The needle breaks quickly and the effervescent effect is stable

[0056] The synergistic effect of the effervescent components in the backing layer makes the needle breaking process faster, reducing the risk of pulling and needle tip falling off when the backing is traditionally removed. At the same time, the effervescence of the backing layer is triggered by external water replenishment, and the foaming effect is more stable and thorough.

[0057] 4. Deep penetration of the skin is enhanced, and the skin recovers quickly

[0058] During use, moderate pressure can be applied to increase the penetration depth of the needle tip and prolong the duration of drug action in the body. After the backing layer is removed, no covering remains, which helps the needle hole close and heal faster.

[0059] 5. Easy to use, no need for additional patch fixation

[0060] The erasable effervescent microneedle of the present invention does not need to be fixed with a patch, and no residue is left on the skin surface after use, and clothes are not contaminated, which significantly improves the convenience of operation and cleaning.

[0061] 6. Widely applicable and compatible with various drug delivery requirements

[0062] It can simultaneously achieve effective loading of water-soluble and water-insoluble needle tips, and is suitable for a variety of drugs such as regular release, rapid release, and sustained release, meeting different clinical and cosmetic care needs.

[0063] 7. Green production, low cost

[0064] The production process of the present invention does not require a large amount of organic solvents and explosion-proof measures, nor does it rely on high-temperature treatment. It is environmentally friendly and can effectively reduce costs, making it easy to promote on a large scale.

[0065] In summary, the present invention is superior to the prior art in terms of operational convenience, drug delivery efficiency and manufacturing cost, and has broad application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0066] Figure 1 It is a schematic diagram of the effect when the concentration of the first water-soluble high molecular polymer is 2%, 5%, and 12%;

[0067] Figure 2 It is a schematic diagram of the effect when the concentration of the first water-soluble high molecular polymer is 18%;

[0068] Figure 3 This is a schematic diagram of the skin penetration test in performance test example 2;

[0069] Figure 4 Schematic diagram of the cumulative permeation concentration-time curve of ascorbic acid in performance test example 3. DETAILED DESCRIPTION

[0070] The present invention is described in detail below in conjunction with the accompanying drawings and specific embodiments. This embodiment is implemented based on the technical solution of the present invention, and provides a detailed implementation method and specific operation process, but the protection scope of the present invention is not limited to the following embodiments.

[0071] In the following examples, the sources of the materials are as follows:

[0072] The polyvinyl pyrrolidone (PVP-K90, PVP-K60, PVP-K30) and highly substituted hydroxypropyl cellulose (H-HPC) were purchased from Adamas-

[0073] The tartaric acid, malic acid, citric acid monohydrate, sodium bicarbonate, sodium carbonate, potassium carbonate, methylene blue and other reagents were purchased from Sinopharm Chemical Reagent Co., Ltd.;

[0074] The SD rats were purchased from Shanghai Bikai Experimental Animal Co., Ltd.

[0075] The following is a further description of the embodiments of the present invention in conjunction with the accompanying drawings. In the absence of conflict, the following embodiments and their features can be combined with each other.

[0076] Example 1

[0077] This embodiment provides a method for preparing a backing layer in an erasable effervescent microneedle, and the specific steps are as follows:

[0078] S1. According to the prescription ratio of "Example 1" in Table 1, weigh polymer backing material PVP-K90 (5 g), sodium bicarbonate (5 g) and citric acid monohydrate (4 g), add 100 mL of anhydrous ethanol to dissolve, and prepare a backing solution;

[0079] S2. Add the backing solution prepared in step S1 into the microneedle mold, and the backing solution filling thickness is 1000 microns; without vacuum treatment, place the mold in a sealed drying box at room temperature, and form a backing layer without an array after it is completely dried.

[0080] The backing layer preparation methods provided in Comparative Examples 1-4 have the same process steps as Example 1, except that the formula ratios of the polymer backing material PVP-K90, sodium bicarbonate, citric acid monohydrate and anhydrous ethanol are configured according to the corresponding prescription in Table 1.

[0081] Table 1 Prescription ratio of Example 1 and Comparative Examples 1-4

[0082]

[0083] Performance Test Example 1

[0084] This test case aims to study the effect of different backing material concentrations on the effervescent effect. The specific experimental operation is as follows:

[0085] According to the prescription ratio in Table 1, backing layers with different concentrations of components in Example 1 and Comparative Examples 1-4 were prepared respectively, and 3 backing layers were prepared for each group to avoid accidental interference and ensure the reliability of the experimental results.

[0086] 4 mL of purified water was added dropwise to the backing layer prepared above, and a pressing force of about 1 N was applied in the vertical direction to simulate the effervescent performance and dissolution of the backing layer.

[0087] The experimental results are shown in Table 2:

[0088] Comparison of Example 1 and Comparative Examples 1-2: Too low a concentration of PVP-K90 (Comparative Example 2) will result in poor backing molding effect, while too high a concentration (Comparative Example 1) will reduce the effervescent performance of the backing, produce more residues, and affect the use effect.

[0089] Comparative Example 1 with Comparative Examples 3-4: Too low a concentration or no effervescent component at all (Comparative Example 3) will significantly reduce the dissolution rate of the backing, making it difficult to achieve rapid effervescence and complete dissolution; while too high a concentration of effervescent components (Comparative Example 4) can increase the dissolution rate, but will affect the molding stability of the backing and increase the viscosity, which may affect the user experience.

[0090] In summary, the prescription ratio of Example 1 achieves a good balance between backing molding and effervescent effect, and has the comprehensive advantages of stable molding, rapid dissolution, and no residue.

[0091] Table 2 Experimental results of backing performance of Example 1 and Comparative Examples 1-4

[0092]

[0093]

[0094] Example 2

[0095] This embodiment provides a method for preparing a removable effervescent microneedle made of a water-soluble needle tip material, and the specific steps are as follows:

[0096] S1. Add 3 g PVP-K90, 0.1 g chlorpheniramine and 250 mg ascorbic acid into 10 mL purified water and fully dissolve to prepare a needle tip solution;

[0097] S2, 0.5 g PVP-K90, 0.5 g sodium bicarbonate and 0.4 g citric acid monohydrate were dissolved in 10 mL anhydrous ethanol to prepare a backing solution;

[0098] S3, adding the needle tip solution prepared in step S1 into the microneedle mold, vacuum filling and scraping off the bubbles, repeating 2 to 3 times, removing the excess solution, and freeze-drying to form a needle tip array, the array length is 300 microns, and the array shape is conical;

[0099] S4. Precool the backing solution obtained in step S2 to 4°C, apply it to the base surface of the needle tip array, vacuum fill it and scrape off the bubbles. Repeat 2 to 3 times to allow the backing solution to fully connect with the needle tip. After it is completely dried, a backing layer is formed to obtain a removable effervescent microneedle.

[0100] Example 3

[0101] This embodiment provides a method for preparing erasable effervescent microneedles, which is consistent with Example 2, but the length of the needle tip array is 600 microns, and the remaining steps are the same.

[0102] Example 4

[0103] This embodiment provides a method for preparing erasable effervescent microneedles, which is consistent with Example 2, but the length of the needle tip array is 800 microns, and the remaining steps are the same.

[0104] Example 5

[0105] This embodiment provides a method for preparing erasable effervescent microneedles, which is consistent with Example 2, but the length of the needle tip array is 950 microns, and the remaining steps are the same.

[0106] The removable effervescent microneedles with different needle tip lengths (300, 600, 800, 950 microns) prepared in Examples 2-5 all showed good transdermal performance in in vitro transdermal experiments, indicating that changes in needle tip length will not significantly affect its transdermal effect.

[0107] Example 6

[0108] This embodiment provides a method for preparing erasable effervescent microneedles, which is consistent with Example 2, but the shape of the needle tip array is changed to a regular quadrangular pyramid, and the remaining steps are the same.

[0109] The conical and regular quadrangular pyramid-shaped microneedles prepared in Examples 2 and 6 showed good transdermal performance in the in vitro transdermal experiment, indicating that the change in the shape of the needle tip has no obvious adverse effect on the transdermal effect.

[0110] Example 7

[0111] This embodiment provides a method for preparing a removable effervescent microneedle, which is consistent with Example 2, but in step S1, the content of PVP-K90 is changed to 1 g, and the remaining steps are the same.

[0112] Example 8

[0113] This embodiment provides a method for preparing a removable effervescent microneedle, which is consistent with Example 2, but in step S1, the content of PVP-K90 is changed to 5 g, and the remaining steps are the same.

[0114] The microneedles with different needle tip material concentrations prepared in Examples 7 and 8 showed good transdermal performance in the in vitro transdermal experiment. The mechanical strength of the needle tips was examined through physical property tests, and the mechanical strengths were measured to be 0.25N / Needle and 0.41N / Needle, respectively, which met the 0.24N / Needle required for piercing the skin.

[0115] Examples 2-8 verify that removable effervescent microneedles with different needle tip solution concentrations, different needle tip lengths and shapes all have good transdermal effects, further demonstrating the scope of application and process flexibility of the present invention.

[0116] Example 9

[0117] This embodiment provides a method for preparing a removable effervescent microneedle made of a water-insoluble needle tip material, and the specific steps are as follows:

[0118] S1. Add 3 g PLGA 75:25, 0.1 g chlorpheniramine and 300 mg minoxidil into 10 mL DMSO and fully dissolve to prepare a needle tip solution;

[0119] S2, 0.5 g PVP-K90, 0.5 g sodium bicarbonate and 0.4 g citric acid monohydrate were dissolved in 10 mL anhydrous ethanol to prepare a backing solution;

[0120] S3, adding the needle tip solution prepared in step S1 into the microneedle mold, vacuum filling and scraping off the bubbles, repeating 2 to 3 times, removing the excess solution, and drying at room temperature to form a needle tip array, the array length is 600 microns, and the array shape is conical;

[0121] S4, coating the backing solution prepared in step S2 on the base surface of the needle tip array, vacuum filling and scraping off the bubbles, repeating 2 to 3 times to allow the backing solution to be fully connected to the needle tip, and forming a backing layer after complete drying to obtain a removable effervescent microneedle.

[0122] The microneedles made of the poorly water-soluble needle tip material prepared in Example 9 have good formability and an ideal needle breaking effect.

[0123] Example 10

[0124] This embodiment provides a method for preparing an erasable effervescent microneedle, and the specific steps are as follows:

[0125] S1. 3 g PVP-K90 and 0.1 g chlorpheniramine were added to 10 mL purified water to dissolve, and then 300 mg insulin was added to dissolve to prepare a needle tip solution;

[0126] S2. According to the prescription ratio in Table 3, the first water-soluble high molecular polymer, the effervescent base source, and the effervescent acid source are added to the first solvent and dissolved to prepare a backing solution;

[0127] S3, adding the needle tip solution prepared in step S1 into the microneedle mold, vacuum filling and scraping off the bubbles, repeating 2 to 3 times, removing the excess solution, and then drying at room temperature to form a needle tip array;

[0128] S4. Precool the backing solution obtained in step S2 to 4°C, and then evenly apply it to the base surface of the needle tip array. After vacuum filling, scrape off the bubbles, repeat 2 to 3 times, and form a backing layer after complete drying to obtain a removable effervescent microneedle.

[0129] The preparation methods of Examples 11 to 23 are basically the same as those of Example 10, except for the prescription ratio of the backing solution, as shown in Table 3. The remaining steps, including the preparation of the needle tip solution, the formation of the needle tip array, and the coating operation of the backing, are consistent with those of Example 10.

[0130] like Figure 3 As shown, in the removable effervescent microneedles described in Examples 10-23, although there are certain differences in the effervescent effects of different backing solution prescription ratios, they all show excellent performance in general and can achieve the purpose of rapid wiping without residue after external addition of water.

[0131] When the concentration of the first water-soluble high molecular polymer is 2%, 5%, and 12%, the effervescent dissolution of the backing layer is rapid (completed within 1 minute) and no residue is left (see Figure 1 When the concentration increased to 18%, the backing effervescence rate slowed down slightly (the dissolution time was extended to 1-2 minutes), and a small amount of residue appeared (see Figure 2 ).

[0132] The experimental results show that the prescription ratio of the backing solution will affect the molding and effervescent effect of the backing, but all combinations can well meet the requirements of rapid wiping and no residue.

[0133] Table 3 Prescription ratio of backing solution in Examples 10-23

[0134]

[0135]

[0136] Embodiment 24

[0137] This embodiment provides an erasable effervescent microneedle prepared with methylene blue as a dye, and the specific steps are as follows:

[0138] S1. Dissolve 3 g of PVP-K90 and an appropriate amount of methylene blue (used for color development, no precise amount required) in 10 mL of purified water to prepare a needle tip solution;

[0139] S2, adding 0.5 g PVP-K90, 0.4 g effervescent acid source (such as citric acid monohydrate), and 0.5 g effervescent base source (such as sodium bicarbonate) into 10 mL of anhydrous ethanol and dissolving to prepare a backing solution;

[0140] S3, adding the needle tip solution prepared in step S1 into the microneedle mold, vacuum filling and scraping off the bubbles, repeating 2 to 3 times, removing the excess solution, and drying at room temperature to form a needle tip array;

[0141] S4, precooling the backing solution obtained in step S2 to 4°C, coating it on the base surface of the needle tip array, vacuum filling and scraping off the bubbles, repeating 2 to 3 times, forming a backing layer after complete drying, and obtaining a removable effervescent microneedle.

[0142] Performance Test Example 2

[0143] This test example uses ex vivo pig ear skin to conduct a puncture experiment on the removable effervescent microneedle prepared in Example 24. The specific experimental steps are as follows:

[0144] Cut skin with a diameter of about 2 cm from the back of a fresh pig ear, trim the surface hair and clean it. Use the removable effervescent microneedle prepared in Example 21 to vertically pierce the pig ear skin and keep pressing for about 1 minute. Remove the contact between the finger and the backing, add 4 mL of purified water to the backing surface, and repeatedly apply pressure in the vertical direction until the backing is completely effervescently dissolved.

[0145] Take pictures like Figure 3 As shown, the experimental results show that the removable effervescent microneedles prepared in Example 24 exhibit the following characteristics: the backing layer effervesces rapidly after external water is applied, and no residue is left by pressing and applying with fingers; and the needle tip array is efficiently separated from the backing layer, and the needle tips are stably retained in the skin. The operation is simple and convenient.

[0146] Embodiment 25

[0147] This embodiment provides a method for preparing an erasable effervescent microneedle loaded with ascorbic acid, and the specific steps are as follows:

[0148] S1. Add 3 g PVP-K90 and 100 mg ascorbic acid drug into 10 mL purified water and stir until evenly dissolved to prepare a needle tip solution;

[0149] S2, adding 0.5 g PVP-K90, 0.4 g citric acid monohydrate and 0.5 g sodium bicarbonate into 10 mL anhydrous ethanol, stirring to dissolve, to prepare a backing solution;

[0150] S3, adding the needle tip solution prepared in step S1 to the microneedle mold, vacuuming to fill the microneedle grooves, scraping off the bubbles on the surface, repeating 2 to 3 times, removing the excess solution, and then placing the mold in a freeze dryer for freeze drying to form a needle tip array;

[0151] S4. Precool the backing solution obtained in step S2 to 4°C, apply it to the base of the needle tip array, use vacuum to make the backing solution fully fill the gaps, scrape off the bubbles on the surface, repeat the above operation 2 to 3 times, and form a backing layer after it is completely dried to obtain a removable effervescent microneedle.

[0152] Performance Test Example 3

[0153] This test example conducts a transdermal effect test on the removable effervescent microneedle prepared in Example 25, and the specific steps are as follows:

[0154] The in vitro percutaneous permeation test was carried out using a modified Franz diffusion cell, and the effective percutaneous diffusion area was 3.14 cm 2 The volume of the receiving pool is about 8 mL, and the receiving solution is 0.9% saline. The excised SD rat abdominal skin is fixed in the diffusion pool with the stratum corneum facing upwards, ensuring that the receiving solution is in full contact with the skin without bubbles.

[0155] Three parallel experimental groups were set up, namely:

[0156] Group A: After the removable effervescent microneedles prepared in Example 25 were inserted into the skin, a small amount of water was added to the backing, and the index finger was pressed and applied until the backing disappeared;

[0157] Group B: After the removable effervescent microneedles prepared in Example 25 were inserted into the skin, the backing was not removed;

[0158] Group C: ascorbic acid aqueous solution.

[0159] Among them, the theoretical drug loading of the three parallel experimental groups remained consistent.

[0160] In the experiment, each group was applied to the skin surface, and a magnetic stirrer (speed 100 r / min) was started. -1 ) and maintain a constant temperature water bath at 37±0.2℃, take 1mL of receiving solution at 0.5, 1, 2, 4, 6, and 8h and add an equal amount of fresh receiving solution. The receiving solution was filtered through a 0.45μm filter membrane and the ascorbic acid concentration was determined by HPLC. The detection conditions include: PLATISILTMODS column (150×4.6mm, 5μm), mobile phase acetonitrile-water-glacial acetic acid (10:89:1), flow rate 0.6mL / min, detection wavelength 254nm, column temperature 25℃, injection volume 20μL. Quantification was performed by external standard method, and the cumulative permeate concentration was calculated.

[0161] Transdermal parameters are shown in Table 5 and the trend of change is shown in Figure 4The results showed that the backing layer in group A effervescent rapidly and thoroughly, the drug release was fast, and the steady-state transdermal rate was reached earlier. The skin permeation rate was significantly better than that of group B (removable microneedles without removing the backing) and group C (ascorbic acid aqueous solution). Compared with group B, group A significantly improved the drug transdermal efficiency due to the removal of the backing, indicating that the design of separating the backing from the needle tip helps to enhance the speed and extent of drug delivery.

[0162] Table 5 Changes of average cumulative osmotic concentration of each group over time

[0163]

[0164] Embodiment 26

[0165] This embodiment provides a method for preparing an erasable effervescent microneedle, and the specific steps are as follows:

[0166] S1. Dissolve 3 g PVP-K90 and 100 mg ascorbic acid in 10 mL anhydrous ethanol and stir to obtain a needle tip solution.

[0167] S2, dissolving 0.5 g PVP-K90, 0.4 g citric acid monohydrate and 0.5 g sodium bicarbonate in 10 mL anhydrous ethanol to prepare a backing solution;

[0168] S3, adding the backing solution prepared in step S2 into the microneedle mold without vacuuming, and allowing it to completely dry under natural conditions to form a backing layer without a needle tip array;

[0169] S4. Add the needle tip solution prepared in step S1 into the microneedle mold for vacuum filling. Repeat 2 to 3 times and scrape off the excess solution on the surface. Then, place the backing layer prepared in step S3 into the microneedle mold at an inclined angle to avoid bringing in air as much as possible so that the needle tip solution and the backing layer are bonded. After being completely dried, a removable effervescent microneedle is obtained.

[0170] Comparative Example 5

[0171] The backing layer prepared in this comparative example is different from that in Example 26 in that no effervescent component is added. Specifically, the needle tip solution is still prepared according to the ratio of 3 g of polymer to 100 mg of ascorbic acid per 10 mL of anhydrous ethanol, and the backing solution is prepared according to the prescription ratio of 0.5 g of polymer (such as PVP-K90) per 10 mL of anhydrous ethanol, and the remaining steps are the same as those in Example 26. Therefore, the microneedles prepared in Comparative Example 5 do not have the erasable effervescent property.

[0172] Performance Test Example 4

[0173] In this test example, the erasable effervescent microneedles prepared in Example 26 were subjected to a comparative experiment on the needle hole closure time and skin irritation. The specific steps are as follows:

[0174] Pretreatment method: 6 SD rats were used for the experiment. The hair on both sides of the rat spine was cut and treated with depilatory cream 24 hours before the experiment. The depilatory range was 3cm×3cm on each side, and it was ensured that the skin was not damaged.

[0175] Dosage method: Use the left and right side self-comparison method:

[0176] The left hair removal area (6 SD rats) was given the removable effervescent microneedles prepared in Example 26. The needle tip was loaded with ascorbic acid, the needle length was about 1200 μm, and after the insertion, the backing was quickly effervescent and removed by adding water externally.

[0177] The right hair removal area (6 SD rats) was given the microneedles prepared in Comparative Example 5, whose needle tips were loaded with methylene blue dye, but the backing did not contain effervescent components. The backing was not removed after the insertion was completed, and was fixed to the skin surface with medical tape. Each rat was kept in a single cage.

[0178] Experimental method: The timing starts after the puncture is completed. One rat is taken at 0.5h, 1h, 2h, 6h, 12h, and 24h, and the pinhole closure process and skin irritation of the puncture sites on both sides of the spine are observed and compared. The experimental data are shown in Table 6. The results show that compared with the microneedles prepared in Comparative Example 5, the erasable effervescent microneedles prepared in Example 26 do not need to be fixed for a long time after use, and the skin pinholes can be closed and restored faster in a natural state. No additives are added in the above embodiments, which is mainly intended to prove that the erasable effervescent microneedles themselves close the pinholes faster and without obvious irritation. If anti-allergic or anti-inflammatory drugs are added during preparation, it is impossible to verify whether the effect of the erasable effervescent microneedles themselves is affected by the additional ingredients.

[0179] Table 6 Comparative experiment on pinhole closure time and skin irritation in SD rats

[0180]

[0181] Embodiment 27

[0182] This embodiment provides a specific method for using an erasable effervescent microneedle, and the specific steps are as follows:

[0183] After inserting the removable effervescent microneedle into the skin, separate the thumb from the backing. Then, evenly add water to the backing surface and gently apply repeated pressure in a vertical direction with the thumb until the backing is completely effervescent and wiped off.

[0184] Comparative Example 6

[0185] This comparative example provides a specific method for using an erasable effervescent microneedle, and the specific steps are as follows:

[0186] After inserting the wipeable effervescent microneedle into the skin, apply water evenly to the backing surface without any form of wipe or pressure.

[0187] Comparative Example 7

[0188] This comparative example provides a specific method for using an erasable effervescent microneedle, and the specific steps are as follows:

[0189] After inserting the removable effervescent microneedle into the skin, press the microneedle backing with your thumb. After adding water to the backing surface, apply repeated pressure in the vertical direction with your thumb and apply along the periphery until the backing is completely wiped off.

[0190] Comparative Example 8

[0191] This comparative example provides a specific method for using an erasable effervescent microneedle, and the specific steps are as follows:

[0192] After piercing the removable effervescent microneedle into the skin, separate the thumb from the backing, add water to the backing surface, and apply pressure in a circular direction until the backing is completely effervescent and wiped off.

[0193] By comparing the specific use methods of the erasable effervescent microneedles in Example 27 with those in Comparative Examples 6-8, the experimental results show that the needle tip retention rate in the use methods in Comparative Examples 6-8 is 60%-70%, while the needle tip retention rate in the use method of Example 27 reaches more than 85%. The image corresponding to the use method of Example 27 is shown in FIG. Figure 3 As shown, the method can significantly promote the rapid effervescence of the backing, and effectively improve the needle tip retention rate (reaching more than 85%), thereby achieving efficient separation of the backing and the needle tip.

[0194] The above description of the embodiments is intended to facilitate the understanding and use of the present invention by those skilled in the art. It is obvious that those skilled in the art can easily make various modifications to these embodiments and apply the general principles described herein to other embodiments without creative work. Therefore, the present invention is not limited to the above embodiments, and improvements and modifications made by those skilled in the art based on the disclosure of the present invention without departing from the scope of the present invention should be within the scope of protection of the present invention.

Claims

1. A removable effervescent microneedle, characterized in that: It includes a backing layer and a needle tip array fixed on the backing layer; The backing layer is prepared from the following raw materials according to the following relative contents: The needle tip array is prepared from the following raw materials according to the following relative contents:

2. The erasable effervescent microneedle according to claim 1, characterized in that: The first water-soluble high molecular polymer in the backing layer is selected from any one or more of polyvinyl pyrrolidone, polyvinyl alcohol, highly substituted hydroxypropyl cellulose or methyl cellulose; The effervescent alkali source is selected from sodium carbonate or sodium bicarbonate; The effervescent acid source is selected from any one or more of citric acid, malic acid, boric acid, tartaric acid or fumaric acid.

3. The erasable effervescent microneedle according to claim 1, characterized in that: The high molecular polymer in the needle tip array is selected from a second water-soluble high molecular polymer or a water-insoluble high molecular polymer.

4. The erasable effervescent microneedle according to claim 3, characterized in that: The second water-soluble high molecular polymer is selected from any one or more of hyaluronic acid, polyvinyl pyrrolidone, polyvinyl alcohol or sodium carboxymethyl cellulose; The poorly water-soluble high molecular polymer is selected from polylactic acid and / or polylactic acid-glycolic acid copolymer.

5. The erasable effervescent microneedle according to claim 1, characterized in that: The target drugs include biotechnology drugs and / or chemical drugs; The additional agents include anti-allergic, anti-inflammatory agents and / or preservatives.

6. The erasable effervescent microneedle according to claim 1, characterized in that: The needle length of the microneedle ranges from 100 to 1000 microns.

7. A method for preparing an erasable effervescent microneedle according to any one of claims 1 to 6, characterized in that: The specific steps are as follows: S1, adding a high molecular weight polymer, an additive and a target drug into a second solvent for dissolution to prepare a needle tip solution; S2, adding a first water-soluble high molecular polymer, an effervescent base source, an effervescent acid source and an additive into a first solvent and dissolving them to obtain a backing solution; S3, adding the needle tip solution prepared in step S1 into the microneedle mold to form a needle tip array, and then applying the backing solution prepared in step S2 to the base surface of the needle tip array, and forming a backing layer after drying, thereby obtaining an erasable effervescent microneedle.

8. A method for preparing the erasable effervescent microneedle as claimed in claim 7, characterized in that: When the polymer is a second water-soluble polymer, the needle tip solution is added to the microneedle mold and a needle tip array is formed by low-temperature freeze-drying; the backing solution is pre-cooled to 4°C and then coated on the base surface of the needle tip array to reduce the mutual dissolution between the backing and the needle tip, and after it is completely dried to form a backing layer, a removable effervescent microneedle is obtained.

9. A method for preparing an erasable effervescent microneedle according to any one of claims 1 to 6, characterized in that: The specific steps are as follows: S1, adding a high molecular weight polymer, an additive and a target drug into a second solvent for dissolution to prepare a needle tip solution; S2, adding a first water-soluble high molecular polymer, an effervescent base source, an effervescent acid source and an additive into a first solvent and dissolving them to obtain a backing solution; S3, adding the backing solution prepared in step S2 into the microneedle mold without vacuuming, and forming a backing layer without an array after drying; S4, adding the needle tip solution prepared in step S1 into the microneedle mold, and after vacuuming, placing the backing layer prepared in step S3 into the microneedle mold at an inclined angle to allow the needle tip solution to adhere to the backing layer, and obtaining an erasable effervescent microneedle after drying.

10. A use of the erasable effervescent microneedle according to any one of claims 1 to 6, characterized in that: The erasable effervescent microneedle is used for delivering regular release drugs, quick release drugs or sustained release drugs.

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