Anti-seepage microneedle patch

Abstract

The utility model discloses an anti-seepage microneedle patch which comprises a base and an anti-seepage microneedle arranged on the base. In the direction away from the substrate, the anti-seepage microneedle comprises a dissolution layer, an anti-seepage layer and a medicine carrying layer; in the direction parallel to the substrate, the maximum size of the impermeable layer is larger than the maximum size of the medicine carrying layer, and the maximum size of the impermeable layer is larger than the minimum size of the dissolution layer; the dissolving speed of the drug carrying layer is V1, the dissolving speed of the impermeable layer is V2, and the dissolving speed of the dissolving layer is V3, V1gt; v2, V3gt; v2; according to the technical scheme, quantitative dosing is achieved, and meanwhile exosmosis of a medicine solution is avoided.

Description

Technical Field

[0001] The utility model relates to the technical field of soluble microneedles, in particular to an anti-seepage microneedle patch. Background Art

[0002] Soluble microneedles are a new drug delivery technology that combines drugs with microneedle structures to carry drugs to the microneedles. When the microneedles penetrate the stratum corneum of the skin and penetrate the skin, they create micron-scale channels in the skin, allowing the active ingredients carried by the microneedles to quickly dissolve, penetrate, and be absorbed in the body, thereby improving the absorption efficiency of the drugs.

[0003] However, when the drug-carrying microneedles penetrate the stratum corneum and pierce the skin, the skin is elastic and will squeeze the pierced microneedles out of the skin when the skin recovers its deformation. Continuously applying external force to the microneedles keeps the microneedles in the skin. As the microneedles dissolve in the skin, there is a gap between the microneedles and the skin in the microneedle channel created by the microneedle puncturing the skin, and they cannot fit completely. After the microneedles dissolve in the intercellular fluid environment, the solution containing the drug easily seeps out of the skin surface along the microneedle channel, making it impossible to achieve precise control of the amount of drug delivery and reducing the utilization efficiency of the drug.

[0004] In the prior art, microneedles use structures such as arrowheads and barbs to anchor the microneedles in the skin after piercing the skin, so that the microneedles can be anchored in the skin after piercing the skin without continuous external force, and the microneedles will not be squeezed out due to the elastic deformation of the skin. However, as the microneedles embedded in the skin dissolve in the skin, the drug-loaded solution will still seep out of the skin surface along the microneedle channel. Therefore, although the microneedles with anchoring structures can anchor the microneedles in the skin without continuous external force, there is still a problem that the drug seepage cannot accurately control the drug administration amount and reduces the efficiency of drug administration.

[0005] In the prior art, some microneedles adopt segmented sustained release, which realizes the slow dissolution of the needle in the human body through sustained release of the needle tip and rapid dissolution of the needle column. However, due to the osmotic difference and the effect of atmospheric pressure, the solution of such microneedles will still seep out along the microneedle channel after the needle tip dissolves. There is still a problem that the drug leakage cannot accurately control the dosage, which affects the quantitative effect of drug use. Utility Model Content

[0006] The main purpose of the utility model is to provide an anti-seepage microneedle patch, which aims to achieve quantitative drug administration while avoiding the extravasation of drug solutions.

[0007] To achieve the above-mentioned purpose, the anti-seepage microneedle patch proposed by the utility model comprises a substrate and anti-seepage microneedles arranged on the substrate;

[0008] Along the direction away from the substrate, the impermeable microneedle includes a dissolving layer, an impermeable layer and a drug-carrying layer;

[0009] Along the direction parallel to the substrate, the maximum dimension of the impermeable layer is greater than the maximum dimension of the drug-carrying layer, and the maximum dimension of the impermeable layer is greater than the minimum dimension of the dissolving layer;

[0010] The dissolution rate of the drug-carrying layer is V1, the dissolution rate of the anti-seepage layer is V2, and the dissolution rate of the fault layer is V3, V1>V2, V3>V2.

[0011] In some embodiments of the present invention, the anti-seepage microneedle comprises a needle head segment and a needle body segment, the needle head segment is located at one end of the needle body segment, and the needle body segment is disposed on the substrate;

[0012] The dissolution layer is located on the needle body section, the drug-carrying layer is located on the needle tip section, the impermeable layer is located between the dissolution layer and the drug-carrying layer, and the impermeable layer may be entirely located on the needle tip section or partially located on the needle tip section and partially located on the needle body section.

[0013] In some embodiments of the present invention, along the axial direction of the anti-seepage microneedle, the height of the anti-seepage layer at the needle head section is h1, the height of the needle head section is H1, and h1 / H1≥1 / 10.

[0014] In some embodiments of the present invention, along the axial direction of the impermeable microneedle, the height of the dissolution layer is h2, the length of the needle body section is H2, and h2 / H2≥1 / 3.

[0015] In some embodiments of the present invention, along the axial direction of the impermeable microneedle, the height of the dissolution layer is h2, the length of the needle body section is H2, and h2 / H2=1.

[0016] In some embodiments of the present invention, the complete dissolution time of the impermeable layer is T1, the complete dissolution time of the dissolving layer is T2, and the complete dissolution time of the drug-carrying layer is T3;

[0017] T0=T1-T2, then T0≥15min;

[0018] Tr=T1-T3, then Tr≥15min.

[0019] In some embodiments of the present invention, along a direction parallel to the substrate, the difference between the maximum size of the anti-seepage layer and the minimum size of the solution layer is L, and L≥5μm.

[0020] In some embodiments of the present invention, the anti-seepage layer is an anti-seepage layer made of one or more of silk protein, polylactic acid-glycolic acid copolymer (PLGA), polylactic acid (PLA), polycaprolactone (PCL), ethyl cellulose, and cellulose derivatives.

[0021] In some embodiments of the present invention, the anti-seepage layer is an anti-seepage layer made of 15% ethyl cellulose and 5% PLGA, or an anti-seepage layer made of 10% silk protein.

[0022] In some embodiments of the present invention, the dissolving layer is a dissolving layer made of one or more film-forming polymer materials such as trehalose, polyvinyl pyrrolidone (PVP), sodium hyaluronate (HA), polyvinyl alcohol (PVA), hydroxypropyl methylcellulose (HPMC), starch, polyethylene glycol, and methyl cellulose.

[0023] The technical scheme of the utility model is that the needle section and the needle body section pierce the skin, and the maximum diameter of the needle section is larger than the connecting end of the needle body section, so that after piercing the skin, a concave anchoring structure is formed between the needle section and the connecting end, and is embedded in the skin; the skin is in a state of wrapping the needle section between the needle sections, so that a microneedle puncture channel with a narrowed portion is formed, which is different from a conventional straight-cylindrical microneedle puncture channel, and the narrowed channel mouth structure blocks the leakage of the needle section solution from the outside; by arranging a drug-carrying layer and an impermeable layer on the needle section, and making the dissolution time of the impermeable layer longer than the dissolution time of the drug-carrying layer, the drug-carrying layer is dissolved in the After dissolution, the anti-seepage layer is still in an incompletely dissolved state, which can achieve a barrier and anti-seepage effect on the drug-carrying layer, so that the solution of the drug-carrying layer can only flow from the side of the anti-seepage layer to the outside. Due to the diameter difference between the needle section and the connecting end, the narrowing and wrapping effect of the skin on the needle section further improves the barrier and anti-seepage effect of the drug-carrying layer on the needle section, and by providing a dissolving layer, when the dissolving layer dissolves in the skin, the dissolving separation from the anti-seepage layer is achieved, so that the skin can gradually heal after the dissolving layer dissolves and separates, further narrowing the channel formed after the anti-seepage microneedle is inserted, thereby achieving quantitative drug delivery of the drug-carrying layer while improving the anti-seepage effect. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] In order to more clearly illustrate the embodiments of the utility model or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the utility model. For ordinary technicians in this field, other drawings can be obtained based on the structures shown in these drawings without paying creative work.

[0025] Figure 1 This is one of the structural schematic diagrams of the anti-seepage microneedle of the utility model;

[0026] Figure 2 This is the second structural schematic diagram of the anti-seepage microneedle of the utility model;

[0027] Figure 3 This is the third structural schematic diagram of the anti-seepage microneedle of the utility model;

[0028] Figure 4 This is the fourth structural schematic diagram of the anti-seepage microneedle of the utility model;

[0029] Figure 5 This is the fifth structural schematic diagram of the anti-seepage microneedle of the utility model;

[0030] Figure 6 This is the sixth structural schematic diagram of the anti-seepage microneedle of the utility model;

[0031] Figure 7 The microneedle penetration and absorption test results of the embodiments and comparative examples of the present utility model are shown in FIG.

[0032] Figure 8 The microneedle diagrams of the embodiments and comparative examples of the present utility model.

[0033] Description of Figure Numbers:

[0034] 100, needle head section; 110, needle tip; 200, needle body section; 210, needle column; 220, needle seat; 300, drug-carrying layer; 400, anti-seepage layer; 500, dissolution layer;

[0035] Among them, S1, S2, S3, S4, S5, S6 and S7 respectively represent the microneedle pictures prepared in Examples 1-7, and D1, D2, D3, D4, D5 and D6 respectively represent the segmented microneedle pictures prepared in Comparative Examples 1-6.

[0036] The realization of the purpose, functional features and advantages of the utility model will be further explained in conjunction with embodiments and with reference to the accompanying drawings. DETAILED DESCRIPTION

[0037] The following will be combined with the drawings in the embodiments of the utility model to clearly and completely describe the technical solutions in the embodiments of the utility model. Obviously, the described embodiments are only part of the embodiments of the utility model, not all of the embodiments. Based on the embodiments of the utility model, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the utility model.

[0038] The utility model provides an impermeable microneedle patch, which includes a substrate and an impermeable microneedle arranged on the substrate. Along the direction away from the microneedle patch substrate, the impermeable microneedle at least includes a dissolving layer 500, an impermeable layer 400 and a drug-carrying layer 300 in sequence. The dissolving layer 500 can be quickly dissolved after the impermeable microneedle is inserted into the skin to disconnect the impermeable layer 400 from the substrate; the impermeable layer 400 is used to block the microneedle channel to prevent the dissolved liquid of the drug-carrying layer 300 from seeping out along the microneedle channel and affecting the precise amount of microneedle drug delivery; the drug-carrying layer 300 carries the effective ingredients to achieve drug delivery.

[0039] Along the direction parallel to the substrate, the maximum dimension of the impermeable layer 400 is greater than the maximum dimension of the drug-carrying layer 300, and the maximum dimension of the impermeable layer 400 is greater than the minimum dimension of the dissolution layer 500. The dissolution rate of the drug-carrying layer 300 in the intercellular fluid environment is V1, the dissolution rate of the impermeable layer 400 in the intercellular fluid environment is V2, and the dissolution rate of the dissolution layer 500 in the intercellular fluid environment is V3, V1>V2, V3>V2. When the impermeable microneedle penetrates the skin, the drug-carrying layer 300 dissolves in the intercellular fluid environment, the dissolving layer 500 dissolves in the intercellular fluid environment, and the impermeable layer 400 does not dissolve or dissolves slowly in the intercellular fluid environment, so that the dissolving layer 500 can be dissolved earlier than the impermeable layer 400, so that the impermeable layer 400 is separated from the substrate, and the drug-carrying layer 300 and the impermeable layer 400 are embedded in the skin, so that the impermeable layer 400 blocks the drug-carrying layer 300 from the outside penetration, thereby preventing the dissolved liquid of the drug-carrying layer 300 from seeping out of the microneedle channel.

[0040] The utility model anti-seepage microneedle comprises a needle section 100 and a needle body section 200, wherein the needle section 100 is located at one end of the needle body section 200, and the needle body section 200 is disposed on a substrate. The dissolution layer 500 is located at the needle body section 200, the drug-carrying layer 300 is located at the needle section 100, the anti-seepage layer 400 is located between the dissolution layer 500 and the drug-carrying layer 300, and the anti-seepage layer 400 may be located entirely at the needle section 100 or partially at the needle section 100 and partially at the needle body section 200. Among them, the needle body section 200 may be cylindrical, truncated cone, frustum, or other shapes such as a multi-segment combination, which are not specifically limited here.

[0041] The needle segment 100 of the anti-seepage microneedle of the utility model can be conical, elliptical, olive, or candle-shaped, etc., with a structure protruding in a direction parallel to the base. The specific structure of the needle segment 100 is not specifically limited here; by using the needle segment 100 with a structure protruding in a direction parallel to the base, the size difference along the direction parallel to the base is achieved by utilizing the needle segment 100 and the needle body segment 200, thereby achieving an anchoring effect when the anti-seepage microneedle penetrates the skin.

[0042] Along the direction parallel to the substrate, the maximum size of the impermeable layer 400 is larger than the maximum size of the drug-carrying layer 300 and the minimum size of the dissolution layer 500. The skin is deformed due to the penetration of the impermeable microneedle. After the microneedle is penetrated, the skin recovers its deformation. The size difference between the impermeable layer 400 and the dissolution layer 500 causes the skin that recovers its deformation to close near the dissolution layer 500. The part of the impermeable layer 400 protruding from the dissolution layer 500 is embedded in the skin to form an anchoring effect. When the skin continues to recover its deformation and pushes the impermeable microneedle out of the skin, the part of the impermeable layer 400 protruding from the dissolution layer 500 is further penetrated into the skin to form a secondary embedding, so that the impermeable microneedle is stably embedded in the skin, and the impermeable layer 400 is completely fitted with the skin. As the dissolution layer 500 is dissolved in the intercellular fluid environment, the skin around the dissolution layer 500 continues to recover its deformation, thereby wrapping the drug-carrying layer 300 and the impermeable layer 400 in the skin. At this time, the drug-carrying layer 300 has also dissolved in the intercellular fluid environment. Since the anti-seepage layer 400 is not dissolved or slightly dissolved, the anti-seepage layer 400 is still completely attached to the skin, blocking the microneedle channel like a cork, thereby preventing the dissolved liquid of the drug-carrying layer 300 from seeping out of the microneedle channel.

[0043] At present, the overall length of common microneedles on the market is 100-1200μm, of which the length of the needle section is 30-300μm. Figure 1 As shown, the impermeable microneedle of this embodiment includes a needle section 100, a needle column 200 and a base, wherein the needle column 200 and the base 500 constitute a needle body section. The needle section 100 includes a drug-carrying layer 300 and an impermeable layer 400, and the maximum diameter of the impermeable layer 400 is R, wherein 20 μm ≤ R ≤ 520 μm; to prevent the needle section 100 from being too large to penetrate the skin well.

[0044] The distance between the edge of the anti-seepage layer 400 at the needle section at the maximum dimension parallel to the substrate direction and the needle column 200 is L, and L is ≥ 5 μm; by ensuring that the anchoring distance of the needle section 100 is ≥ 5 μm, the anchoring and wrapping effect between the skin and the needle section 100 is improved, so that the skin can have a sufficient barrier and wrapping effect, and a narrowed channel is formed at the connection between the needle section 100 and the needle column 200 to prevent the drug solution of the drug-carrying layer 300 from seeping out of the microneedle channel from the surrounding side of the anti-seepage layer 400 to the outside of the skin.

[0045] Specifically, along the axis direction of the anti-seepage microneedle, the height or thickness of the anti-seepage layer 400 at the needle section 100 is h1, and the height of the needle section 100 is H1, then h1 / H1≥1 / 10. When the thickness of the anti-seepage layer 400 is small, the strength of the anti-seepage layer 400 is small. As the drug-carrying layer 300 dissolves, the anti-seepage layer 400 is too thin and easy to break and cannot block the microneedle channel, or cannot be embedded or re-embedded into the skin and cannot block the microneedle channel. The molecules of the dissolved liquid in the drug-carrying layer penetrate the anti-seepage layer, causing the drug solution in the drug-carrying layer to seep out from the outside, and ultimately cannot achieve a good blocking and anti-seepage effect on the overflow of the dissolved solution in the drug-carrying layer from the microneedle channel.

[0046] like Figure 1 As shown, along the axis direction of the impermeable microneedle, the height of the dissolving layer is h2, and the length of the needle body segment is H2, then h2 / H2≥1 / 3. Since the epidermal stratum corneum has a poor dissolving effect on the impermeable microneedle, when the length of the dissolving layer is short, the probability that the dissolving layer is located in the stratum corneum increases, and it cannot enter the epidermis or dermis where the intercellular fluid is relatively rich, so that the dissolving layer cannot be fully dissolved and separated. h2 / H2≥1 / 3 ensures that the dissolving layer can enter the epidermis or dermis, so that the intercellular fluid quickly dissolves the dissolving layer, the skin recovers its deformation and wraps the needle segment 100 in the skin, and even the microneedle channel forms a closed end on the surface of the skin, so as to prevent the dissolved drug solution of the drug-carrying layer from seeping out along the microneedle channel after the impermeable layer is dissolved.

[0047] Among them, after the impermeable microneedle is inserted into the skin, the time for the impermeable layer 400 to completely dissolve in the skin is T1, the time for the dissolution layer 500 to completely dissolve in the skin is T2, and the time for the drug-carrying layer 300 to completely dissolve in the skin is T3. T1 is at least 15 minutes longer than T2, and T0 is the time difference between T1 and T2, that is, T0≥15min. T1 is at least 15 minutes longer than T3, and Tr is the time difference between T1 and T3, that is, Tr≥15min. T0≥15min allows the impermeable layer 400 to have enough time to be embedded and re-embedded in the skin. When the dissolution layer is completely dissolved, the needle section 100 is embedded and wrapped in the skin, and the impermeable layer can still be embedded in the microneedle channel and block the microneedle channel until the skin recovers its deformation or even closes the microneedle channel. Tr≥15min allows the anti-seepage layer 400 to have sufficient time to embed and re-embed into the skin. After the drug-carrying layer 300 is completely dissolved in the intercellular fluid environment, the anti-seepage layer can still be embedded in the skin, so that the drug-carrying layer solution forms a "dammed lake" in the microneedle channel until the drug-carrying solution is gradually absorbed by the skin, thereby preventing the drug-carrying layer solution from seeping out of the microneedle channel.

[0048] In this embodiment, the needle body section includes a needle column and a base. The base is in a frustum shape, and the needle column is arranged at one end of the base away from the substrate. When the anti-seepage microneedle is inserted into the skin, the base increases the force-bearing area, improves the structural stability of the anti-seepage microneedle during insertion, improves the puncture effect, and ensures that the needle head section of the anti-seepage microneedle is better inserted into the skin.

[0049] The anti-seepage microneedle of the utility model has the following features: Figure 1 The specific structure can also be set to other specific structures. Figure 2 As shown, the impermeable microneedle includes a needle section and a needle body section, the needle section is a needle tip 110, and the needle body section is a base 220. The end of the needle tip 110 away from the base 220 is a drug-carrying layer 300 carrying drugs, and the end of the needle tip 110 close to the base 220 is an impermeable layer 400 that prevents the drug from seeping out of the microneedle channel after the microneedle penetrates into the skin and dissolves. The height or thickness of the impermeable layer 400 located at the needle section 110 is h1, and the height of the needle section 110 is H1, then h1 / H1≥1 / 10. The height of the dissolution layer is h2, and the length of the needle body section is H2, then h2 / H2≥1 / 3. In the direction parallel to the substrate, the maximum size of the impermeable layer 400 is greater than the maximum size of the drug-carrying layer 300. The end of the base 220 close to the impermeable layer 400 is a dissolution layer 500. In the direction parallel to the substrate, the maximum size of the impermeable layer 400 is greater than the minimum size of the dissolution layer 500. Thus, when the impermeable microneedle penetrates the skin, the needle tip 110 is anchored and embedded in the skin. Because T0≥15min, the lytic layer 500 is dissolved, and the skin recovers its deformation to wrap the needle tip 110 in the skin. Because Tr≥15min, the drug-carrying layer 300 is dissolved in the intercellular fluid, while the impermeable layer 400 is not dissolved or slightly dissolved, so that the skin recovers its deformation and fits tightly and completely with the impermeable layer 400, blocking the microneedle channel like a bottle stopper, so that the dissolved liquid of the drug-carrying layer forms a "dammed lake" in the microneedle channel, thereby preventing the drug solution from seeping out of the microneedle channel.

[0050] The specific structure of the utility model anti-seepage microneedle can also be as follows Figure 3 As shown, the needle tip section is a needle tip 110, the needle body section includes a needle column 210 and a base 220, the drug-carrying layer 300 and the impermeable layer 400 are arranged on the needle tip 110, and the dissolving layer 500 is arranged on the needle column 210 near one end of the impermeable layer 400, or as shown in FIG. Figure 4As described, the drug-carrying layer 400 is disposed on the needle tip 110, and the dissolving layer 400 is partially disposed at one end of the needle tip 110 close to the needle column 210, and partially disposed at one end of the needle column 210 close to the needle tip 110. The maximum dimension of the portion of the impermeable layer 400 located at the needle section is greater than the maximum dimension of the drug-carrying layer 300, and is also greater than the dimension of the portion of the impermeable layer 400 located at the needle column 210, and the minimum dimension of the portion of the dissolving layer 500 located at the needle column 210 is less than the maximum dimension of the impermeable layer 400. The height or thickness of the portion of the impermeable layer 400 located at the needle section 110 is h1, and the height of the needle section 110 is H1, then h1 / H1≥1 / 10. The height of the dissolving layer is h2, and the length of the needle body section is H2, then h2 / H2≥1 / 3. Thus, when the impermeable microneedle 1 penetrates the skin, the needle tip 110 is anchored and embedded in the skin. Because T0≥15min, the lytic layer 500 is dissolved, and the skin recovers its deformation to wrap the drug-carrying layer 110 and the impermeable layer 400 in the skin. Because Tr≥15min, the drug-carrying layer 300 is dissolved in the intercellular fluid, while the impermeable layer 400 is not dissolved or slightly dissolved, so that the skin recovers its deformation and fits tightly and completely with the impermeable layer 400, blocking the microneedle channel like a cork, so that the drug-carrying layer solution forms a "dammed lake" in the microneedle channel, thereby preventing the drug-carrying layer solution from seeping out of the microneedle channel.

[0051] The specific structure of the utility model anti-seepage microneedle can also be as follows Figure 5 As shown, the needle tip section is a needle tip 110, the needle body section is a needle column 210, the drug-carrying layer 300 and the impermeable layer 400 are arranged on the needle tip 110, and the dissolving layer 500 is arranged on the needle column 210 near one end of the impermeable layer, or as shown in FIG. Figure 6 As shown, the drug-carrying layer 400 is disposed on the needle tip 110, and the impermeable layer 400 is partially disposed on the end of the needle head close to the needle column 210 and partially disposed on the end of the needle column 210 close to the needle tip 110. The dissolving layer 500 is disposed on the needle column 210. The height or thickness of the impermeable layer 400 located at the needle section 110 is h1, and the height of the needle section 110 is H1, then h1 / H1≥1 / 10. The height of the dissolving layer is h2, and the length of the needle body section is H2, then h2 / H2≥1 / 3; T0≥15min, Tr≥15min; After the impermeable microneedle is inserted into the skin, the dissolving layer 500 is dissolved before the impermeable layer 400, and the dissolved liquid of the drug-carrying layer 300 forms a "dammed lake" in the microneedle channel, thereby preventing the dissolved liquid of the drug-carrying layer 300 from seeping out of the microneedle channel.

[0052] Specifically, the material of the anti-seepage layer 400 includes one or more of silk protein, polylactic acid-glycolic acid copolymer (PLGA), polylactic acid (PLA), polycaprolactone (PCL), ethyl cellulose, and cellulose derivatives, so as to achieve slow dissolution of the anti-seepage layer 400 in the skin and achieve a blocking and anti-seepage effect on the drug-carrying layer 300.

[0053] The material of the dissolving layer 500 includes one or more of polymer trehalose, polyvinyl pyrrolidone (PVP), sodium hyaluronate (HA), polyvinyl alcohol (PVA), hydroxypropyl methylcellulose (HPMC), starch, polyethylene glycol, and methylcellulose; the dissolving layer 500 has a quick-dissolving effect, so that the drug-carrying layer 300 and the impermeable layer 400 of the needle section 100 are buried in the skin and dissolved.

[0054] Specifically, the dissolving layer 500 includes a film-forming polymer material, which forms a covering film after dissolution, filling the microneedle channel and the skin surface, preventing the microneedles from dissolving and seeping out after the drug-carrying layer 300 is dissolved, further improving the absorption efficiency of the drug-carrying layer 300 and avoiding extravasation.

[0055] The drug-carrying layer 300 includes drug components, and different drug types are selected according to different needs to achieve precise drug delivery, which will not be listed one by one here.

[0056] The formulas of Examples 1-7 and Comparative Examples 1-6 are shown in Table 1

[0057] Table 1

[0058]

[0059]

[0060]

[0061] The corresponding dissolution times of Examples 1-7 and Comparative Examples 1-6 are shown in Table 2.

[0062] Table 2

[0063] Group Drug layer dissolution time Dissolution time of impermeable layer Dissolution time of the fault Example 1 2min 30min 6min Example 2 2min 25min 4min Example 3 2min 20min 5min Example 4 5min 20min 5min Example 5 3min >60min 6min Example 6 2min 60min 6min Example 7 3min 27min 6min Comparative Example 1 2min 60min 6min Comparative Example 2 2min 60min 6min Comparative Example 3 2min 10min 5min Comparative Example 4 2min 5min 4min Comparative Example 5 2min 60min 6min Comparative Example 6 2min 60min 6min

[0064] The drug-carrying layer 300, the impermeable layer 400 and the dissolving layer 500 are prepared into separate microneedles respectively, and the microneedles with different formulations are placed in water to dissolve, and the dissolution state of the microneedles is observed to obtain the corresponding dissolution time.

[0065] The HPLC residue detection of Examples 1-7 and Comparative Examples 1-6 is shown in Table 3

[0066] Table 3

[0067]

[0068]

[0069]

[0070] By performing three parallel experiments on each embodiment / comparative example, the average HPLC residue detection result was obtained.

[0071] The dilution volume refers to the volume of the sample after it is dissolved. The experiment in Table 3 is to dilute 1 ml of dissolved sample to 2 ml volume;

[0072] Retention time refers to the time from when a sample component enters the chromatographic system (injection) to when the component reaches its maximum concentration after the column (i.e., the apex of the chromatographic peak).

[0073] Peak area ratio refers to the total area above the background line in the chromatogram, which indicates the content of the analyte. The larger the area, the higher the content.

[0074] The content is calculated based on the peak area and retention time.

[0075] Combined with Table 1-2 and Appendix Figure 7 It can be seen that the green color is the drug-carrying layer 300 with added pigment, which is convenient for better observing the extravasation phenomenon of the drug-carrying layer 300. Figure 8 From the pigment overflow and the residual values ​​in Table 3, we can see that:

[0076] In Examples 1-7, by keeping the dissolution time, L, h1 / H1 and h2 / H2 within appropriate ranges, the residues on the skin surface of each Example are much lower than those on the skin surface of Comparative Examples 1-6;

[0077] Figure 8 As shown, the dissolution layer 500 of Example 4 does not have film-forming properties, and the time difference T0 and Tr between the impermeable layer 400 and the dissolution layer 500 and the drug-carrying layer 300 is short, both of which are 15 minutes. Therefore, the skin surface residue of Example 4 is higher than that of Examples 1-3, 5 and 6. In Example 7, although the dissolution layer 500 is a film-forming material, the values ​​of L spacing, h1 / H1 and h2 / H2 are small. Although the impermeable layer 400 can be embedded or re-embedded in the skin, the drug-carrying layer 300 dissolves in the microneedle channel to form a "dammed lake" effect, but due to the small values ​​of L spacing, h1 / H1 and h2 / H2, the drug-carrying solution still has a certain penetration effect, so that a small part of the drug-carrying solution seeps out of the skin surface through the microneedle channel, so the skin residue of Example 7 is higher than that of Examples 1-6.

[0078] The anti-seepage layer 400 of Example 5 and Example 6 has a long dissolution time and can effectively block the drug-carrying layer 300. Therefore, the skin residues of Example 5 and Example 6 are lower than those of Examples 1-4.

[0079] Comparative Example 1 is a common microneedle structure. In the direction parallel to the substrate, the maximum size of the needle segment 100 is ≤ the minimum size of the needle body segment 200. After the microneedle is inserted into the skin, it cannot be anchored in the skin. Moreover, the microneedle of Comparative Example 1 only includes the needle segment 100 loaded with drugs and the blank needle body segment 200 without drugs. The needle segment 100 and the needle body segment 200 have the same dissolution speed and complete dissolution time in the skin. After the microneedle is inserted into the skin, it has been squeezed out by the skin due to the skin recovering its deformation, and the microneedle channel is unobstructed. The dissolved liquid of the drug-carrying layer 300 easily seeps out from the microneedle channel to the skin surface. Its anti-seepage effect is weaker than that of Examples 1-7, and the difference is obvious. There is a large amount of residue on the skin surface.

[0080] Although the values ​​of h1 / H1 and h2 / H2 in Comparative Example 2 are ideal, the L spacing is small. After the microneedle penetrates the skin, the skin recovers its deformation and the microneedle is still easily squeezed out. Even if the microneedle remains in the microneedle channel under the action of external force, the needle segment 100 cannot form a "dammed lake" effect in the microneedle channel. The dissolved liquid of the drug-carrying layer 300 in the intercellular fluid environment is easy to seep along the microneedle channel, resulting in poor anti-seepage effect on the dissolved liquid of the drug-carrying layer 300, and a large amount of residue on the skin surface.

[0081] In Comparative Examples 3 and 4, although the L spacing is sufficient to allow the microneedles to be embedded in the skin after piercing the skin, T0<15min, Tr<15min, the complete dissolution time of the anti-seepage layer 400, the drug-carrying layer 300 and the dissolving layer 500 in the skin is too close, and insufficient time is provided for the anti-seepage layer 400 to be embedded or re-embedded in the skin to form a "dammed lake" effect. The dissolved liquid of the drug-carrying layer 300 in the intercellular fluid environment is easy to extravasate along the microneedle channel, resulting in poor anti-exudation effect of the drug-carrying layer 300 and a large amount of residue on the skin surface.

[0082] In comparative example 5, h1 / H1 is 1 / 11, and the thickness of the impermeable layer 400 is too small. The strength of the impermeable layer 400 is relatively small. As the drug-carrying layer 300 dissolves, the impermeable layer 400 is too thin and easily breaks and cannot block the microneedle channel, or cannot be embedded or re-embedded into the skin and cannot block the microneedle channel. The dissolved liquid of the drug-carrying layer 300 fails to form a "dammed lake" effect in the microneedle channel. The dissolved liquid of the drug-carrying layer 300 easily permeates the impermeable layer 400, causing the drug solution of the drug-carrying layer 300 to seep out of the microneedle channel to the skin surface, resulting in poor impermeability and a large amount of residue on the skin surface.

[0083] In comparative example 6, h2 / H2 is 1 / 4, and the length of the dissolution layer 500 is short. Since the epidermal stratum corneum has a poor dissolving effect on the impermeable microneedles, the probability that the dissolution layer 500 is located in the stratum corneum increases, and it is unable to completely enter the epidermis or dermis where the intercellular fluid is relatively rich, which increases the probability that the dissolution layer 500 cannot achieve sufficient dissolution and separation. The dissolution time of the dissolution layer 500 in the skin is prolonged, and the skin cannot form a closure near the dissolution layer 500, so the "dammed lake" effect is weak. The dissolved liquid of the drug-carrying layer 300 easily penetrates the impermeable layer 400, causing the drug solution of the drug-carrying layer 300 to seep out of the microneedle channel to the skin surface, resulting in poor impermeability effect on the drug-carrying layer 300 and more residues on the skin.

[0084] The above description is only a preferred embodiment of the present invention, and does not limit the patent scope of the present invention. All equivalent structural changes made by using the contents of the present invention specification and drawings under the inventive concept of the present invention, or directly / indirectly applied in other related technical fields are included in the patent protection scope of the present invention.

Claims

1. An anti-seepage microneedle patch, characterized in that: It includes a substrate and an impermeable microneedle disposed on the substrate; Along the direction away from the substrate, the impermeable microneedle includes a dissolving layer, an impermeable layer and a drug-carrying layer; Along the direction parallel to the substrate, the maximum dimension of the impermeable layer is greater than the maximum dimension of the drug-carrying layer, and the maximum dimension of the impermeable layer is greater than the minimum dimension of the dissolving layer; The dissolution rate of the drug-carrying layer is V1, the dissolution rate of the anti-seepage layer is V2, and the dissolution rate of the fault layer is V3, V1>V2, V3>V2.

2. The anti-seepage microneedle patch according to claim 1, characterized in that: The anti-seepage microneedle comprises a needle head section and a needle body section, wherein the needle head section is located at one end of the needle body section, and the needle body section is disposed on the substrate; The dissolution layer is located on the needle body section, the drug-carrying layer is located on the needle tip section, the impermeable layer is located between the dissolution layer and the drug-carrying layer, and the impermeable layer may be entirely located on the needle tip section or partially located on the needle tip section and partially located on the needle body section.

3. The anti-seepage microneedle patch according to claim 2, characterized in that: Along the axial direction of the anti-seepage microneedle, the height of the anti-seepage layer at the needle head section is h1, the height of the needle head section is H1, and h1 / H1≥1 / 10.

4. The anti-seepage microneedle patch according to claim 3, characterized in that: Along the axial direction of the impermeable microneedle, the height of the dissolution layer is h2, the length of the needle body section is H2, and h2 / H2≥1 / 3.

5. The anti-seepage microneedle patch according to claim 4, characterized in that: Along the axial direction of the impermeable microneedle, the height of the dissolution layer is h2, the length of the needle body section is H2, and h2 / H2=1.

6. The anti-seepage microneedle patch according to claim 2, characterized in that: The complete dissolution time of the impermeable layer is T1, the complete dissolution time of the fault layer is T2, and the complete dissolution time of the drug-carrying layer is T3; T0=T1-T2, then T0≥15min; Tr=T1-T3, then Tr≥15min.

7. The anti-seepage microneedle patch according to any one of claims 2 to 5, characterized in that: Along the direction parallel to the substrate, the difference between the maximum dimension of the anti-seepage layer and the minimum dimension of the solution layer is L, and L≥5μm.

8. The anti-seepage microneedle patch according to claim 2, characterized in that: The anti-seepage layer is made of one or more of silk protein, polylactic acid-glycolic acid copolymer (PLGA), polylactic acid (PLA), polycaprolactone (PCL), ethyl cellulose, and cellulose derivatives.

9. The anti-seepage microneedle patch according to claim 8, characterized in that: The anti-seepage layer is a layer made of 15% ethyl cellulose and 5% PLGA, or a layer made of 10% silk protein.

10. The anti-seepage microneedle patch according to claim 2, characterized in that: The dissolving layer is made of one or more film-forming polymer materials such as high molecular weight trehalose, polyvinyl pyrrolidone (PVP), sodium hyaluronate (HA), polyvinyl alcohol (PVA), hydroxypropyl methylcellulose (HPMC), starch, polyethylene glycol, and methylcellulose.

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