Anti-seepage microneedle patch

Abstract

The invention discloses an anti-seepage microneedle patch which comprises a substrate and an anti-seepage microneedle arranged on the substrate. 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 drug administration is achieved, and meanwhile exosmosis of a drug solution is avoided.

Description

Technical Field

[0001] This invention relates to the field of soluble microneedle technology, and in particular to a leak-proof microneedle patch. Background Technology

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

[0003] However, when drug-loaded microneedles penetrate the stratum corneum of the skin, the skin's elasticity causes it to recover its shape, pushing the microneedles out. Continuous application of external force to the microneedles, keeping them embedded in the skin, leads to gaps between the microneedles and the skin as they dissolve. After dissolving in the intercellular fluid, the drug-containing solution easily seeps out along the microneedle channels, hindering precise dosage control and reducing drug utilization efficiency.

[0004] Existing microneedles utilize structures such as arrowheads and barbs to anchor the microneedles within the skin after insertion. This achieves the effect of anchoring the microneedles in the skin without the need for continuous external force, preventing them from being squeezed out due to skin elasticity. However, because the microneedles are embedded in the skin, the drug-loaded solution still seeps out along the microneedle channels as the microneedles dissolve. Therefore, while anchoring microneedles achieve the effect of anchoring the microneedles without continuous external force, the problem of inaccurate drug delivery control and reduced drug delivery efficiency remains.

[0005] In existing technologies, some microneedles employ segmented sustained release, achieving slow dissolution of the needle tip within the body through sustained release at the needle tip and rapid dissolution of the needle column. However, due to osmotic differences and atmospheric pressure, the solution still seeps out along the microneedle channel after the needle tip dissolves, resulting in the inability to precisely control the dosage of the drug and affecting the quantitative effect of drug use. Summary of the Invention

[0006] The main objective of this invention is to provide a transdermal microneedle patch that aims to achieve quantitative drug delivery while preventing the extravasation of the drug solution.

[0007] To achieve the above objectives, the present invention proposes an anti-seepage microneedle patch, comprising a substrate and anti-seepage microneedles disposed on the substrate;

[0008] Along a direction away from the substrate, the impermeable microneedles include a dissolution layer, an impermeable layer, and a drug-loaded layer;

[0009] Along a direction parallel to the substrate, the maximum size of the impermeable layer is greater than the maximum size of the drug-loaded layer, and the maximum size of the impermeable layer is greater than the minimum size of the dissolution layer;

[0010] The dissolution rate of the drug-loaded layer is V1, the dissolution rate of the impermeable layer is V2, and the dissolution rate of the fracture layer is V3, where V1>V2 and V3>V2.

[0011] In some embodiments of the present invention, the anti-seepage microneedle includes a needle tip segment and a needle body segment, wherein the needle tip 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 segment, the drug-loaded layer is located on the needle tip segment, and the anti-permeability layer is located between the dissolution layer and the drug-loaded layer. The anti-permeability layer may be entirely located on the needle tip segment or partially located on the needle tip segment and partially located on the needle body segment.

[0013] In some embodiments of the present invention, along the axial direction of the anti-seepage microneedle, the height of the dissolution layer is h2, the length of the needle body segment is H2, and h2 / H2≥1 / 3.

[0014] In some embodiments of the present invention, along the axial direction of the anti-seepage microneedle, the height of the dissolution layer is h2, the length of the needle body segment is H2, and h2 / H2=1.

[0015] In some embodiments of the present invention, the complete dissolution time of the impermeable layer is T1, the complete dissolution time of the cleavage layer is T2, and the complete dissolution time of the drug-loaded layer is T3.

[0016] If T0 = T1 - T2, then T0 ≥ 15 min;

[0017] If Tr = T1 - T3, then Tr ≥ 15min.

[0018] In some embodiments of the present invention, if the difference between the maximum size of the impermeable layer and the minimum size of the solution fracture layer along the direction parallel to the substrate is L, then L≥5μm.

[0019] In some embodiments of the present invention, the impermeable layer comprises one or more of silk fibroin, polylactic acid-glycolic acid copolymer (PLGA), polylactic acid (PLA), polycaprolactone (PCL), ethyl cellulose, and cellulose derivatives.

[0020] In some embodiments of the present invention, the impermeable layer is made of 15% ethyl cellulose and 5% PLGA, or of 10% silk protein.

[0021] In some embodiments of the present invention, the material of the dissolving layer includes one or more of the following: high molecular weight trehalose, polyvinylpyrrolidone (PVP), sodium hyaluronate (HA), polyvinyl alcohol (PVA), hydroxypropyl methylcellulose (HPMC), starch, polyethylene glycol, and methylcellulose.

[0022] The fracture layer comprises a film-forming polymer material.

[0023] In this invention, the needle tip and body segments are inserted into the skin. The maximum diameter of the needle tip is larger than the connecting end of the body segment, creating a recessed anchoring structure between the needle tip and the connecting end after insertion, embedding the needle into the skin. The skin envelops the needle tip segments, creating a narrowed microneedle puncture channel, unlike conventional straight-cylindrical channels. This narrowed channel prevents the solution from leaking out. Furthermore, the needle tip segment incorporates a drug-loaded layer and an anti-permeability layer, with the anti-permeability layer dissolving faster than the drug-loaded layer, ensuring the drug-loaded layer dissolves more efficiently. Afterwards, the impermeable layer remains in an incompletely dissolved state, effectively blocking the drug-loaded layer from seepage. This allows the drug-loaded solution to flow only from the periphery of the impermeable layer. Due to the diameter difference between the needle tip and the connecting end, the skin's narrowing and wrapping effect on the needle tip further enhances the impermeability of the drug-loaded layer. Furthermore, by incorporating a dissolution layer, once the dissolution layer dissolves within the skin, it separates from the impermeable layer, allowing the skin to gradually heal after the dissolution layer dissolves and separates. This further narrows the channel formed after the impermeable microneedle is inserted, achieving both quantitative drug delivery and improved impermeability. Attached Figure Description

[0024] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on the structures shown in these drawings without creative effort.

[0025] Figure 1 This is one of the structural schematic diagrams of the anti-permeability microneedles of the present invention;

[0026] Figure 2 This is the second schematic diagram of the anti-seepage microneedle structure of the present invention;

[0027] Figure 3 This is the third schematic diagram of the anti-seepage microneedle structure of the present invention;

[0028] Figure 4 This is the fourth schematic diagram of the anti-seepage microneedle structure of the present invention;

[0029] Figure 5This is the fifth schematic diagram of the anti-seepage microneedle structure of the present invention;

[0030] Figure 6 This is the sixth schematic diagram of the anti-seepage microneedle structure of the present invention;

[0031] Figure 7 The figures show the microneedle insertion and absorption test results of the embodiments and comparative examples of the present invention;

[0032] Figure 8 These are microneedle diagrams for embodiments and comparative examples of the present invention. Attached image description:

[0034] 100. Needle tip; 110. Needle tip; 200. Needle body; 210. Needle column; 220. Needle seat; 300. Drug-loaded layer; 400. Impermeable layer; 500. Dissolution layer;

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

[0036] The realization of the objective, functional features and advantages of the present invention will be further explained in conjunction with the embodiments and with reference to the accompanying drawings. Detailed Implementation

[0037] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0038] This invention proposes a transdermal microneedle patch, comprising a substrate and transdermal microneedles disposed on the substrate. Along a direction away from the substrate, the transdermal microneedles sequentially include at least a dissolution layer 500, a transdermal layer 400, and a drug-loaded layer 300. The dissolution layer 500 dissolves rapidly upon insertion of the transdermal microneedles into the skin, severing the transdermal layer 400 from the substrate. The transdermal layer 400 blocks the microneedle channels, preventing the solution of the drug-loaded layer 300 from seeping out along the microneedle channels and affecting the precise dosage of the drug. The drug-loaded layer 300 carries the active ingredient for drug delivery.

[0039] Along the direction parallel to the substrate, the maximum size of the impermeable layer 400 is greater than the maximum size of the drug-loaded layer 300, and the maximum size of the impermeable layer 400 is greater than the minimum size of the dissolution layer 500. The dissolution rate of the drug-loaded 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, where V1>V2 and V3>V2. When the anti-permeability microneedle is inserted into the skin, the drug-loaded layer 300 dissolves in the intercellular fluid environment, the dissolution layer 500 dissolves in the intercellular fluid environment, while the anti-permeability layer 400 remains undissolved or dissolves slowly in the intercellular fluid environment. This allows the dissolution layer 500 to dissolve earlier than the anti-permeability layer 400, enabling the anti-permeability layer 400 to separate from the substrate. This satisfies the requirement that the drug-loaded layer 300 and the anti-permeability layer 400 be embedded in the skin, achieving the external permeation and sealing of the drug-loaded layer 300 by the anti-permeability layer 400, thereby preventing the dissolving solution of the drug-loaded layer 300 from seeping out of the microneedle channel.

[0040] The present invention relates to a permeability-preventing microneedle comprising a needle tip segment 100 and a needle body segment 200, wherein the needle tip segment 100 is located at one end of the needle body segment 200, and the needle body segment 200 is disposed on a substrate. A dissolution layer 500 is located in the needle body segment 200, a drug-loaded layer 300 is located in the needle tip segment 100, and a permeability-preventing layer 400 is located between the dissolution layer 500 and the drug-loaded layer 300. The permeability-preventing layer 400 may be entirely located in the needle tip segment 100 or partially located in the needle body segment 200. The needle body segment 200 may be cylindrical, frustum-shaped, truncated cone-shaped, or a multi-segment combination, or other shapes, without specific limitations herein.

[0041] The needle tip segment 100 of the anti-permeability microneedle of the present invention can be conical, elliptical, olive-shaped, or candle-shaped, etc., with a structure that protrudes along the direction parallel to the base. The specific structure of the needle tip segment 100 is not specifically limited here. By using the needle tip segment 100 with a structure that protrudes along the direction parallel to the base, the size difference between the needle tip segment 100 and the needle body segment 200 along the direction parallel to the base is achieved, thereby realizing the anchoring effect when the anti-permeability microneedle is inserted into 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-loaded layer 300 and the minimum size of the dissolution layer 500. The skin deforms due to the insertion of the impermeable microneedles. After the microneedles are inserted, the skin recovers its shape. The size difference between the impermeable layer 400 and the dissolution layer 500 causes the deformed skin to form a closure near the dissolution layer 500. The portion of the impermeable layer 400 protruding from the dissolution layer 500 embeds itself in the skin, providing an anchoring effect. As the skin continues to deform and pushes the impermeable microneedles outward, the portion of the impermeable layer 400 protruding from the dissolution layer 500 is further embedded into the skin, forming a secondary embedding. This ensures the impermeable microneedles are stably embedded in the skin, and the impermeable layer 400 is completely adhered to the skin. As the dissolution layer 500 dissolves in the intercellular fluid environment, the skin around the dissolution layer 500 continues to deform, thus encapsulating the drug-loaded layer 300 and the impermeable layer 400 within the skin. At this time, the drug-loaded layer 300 has also dissolved in the intercellular fluid environment. Since the impermeable layer 400 is not dissolved or only slightly dissolved, the impermeable layer 400 is still completely adhered to the skin, blocking the microneedle channel like a stopper, thereby preventing the drug-loaded layer 300 solution from seeping out of the microneedle channel.

[0043] Currently, the overall length of ordinary microneedles on the market is 100-1200μm, of which the needle tip is 30-300μm long. Figure 1 As shown, the anti-permeability microneedle in this embodiment includes a needle tip segment 100, a needle column 200, and a base 500, wherein the needle column 200 and the base 500 constitute the needle body segment. The needle tip segment 100 includes a drug-loaded layer 300 and an anti-permeability layer 400, the maximum diameter of the anti-permeability layer 400 being R, where 20μm≤R≤520μm; this avoids the needle tip segment 100 being too large to properly pierce the skin.

[0044] The distance between the edge of the impermeable layer 400 located at the maximum dimension along the direction parallel to the base and the needle post 200 is L, where L≥5μm. By ensuring that the anchoring distance of the needle segment 100 is ≥5μm, the anchoring and wrapping effect between the skin and the needle segment 100 is improved, so that the skin can have a sufficient barrier wrapping effect. A narrowing channel is formed at the connection between the needle segment 100 and the needle post 200 to prevent the drug solution of the drug-loaded layer 300 from seeping out of the skin from the periphery of the impermeable layer 400 through the microneedle channel.

[0045] Specifically, along the axis of the anti-permeability microneedle, the height or thickness of the anti-permeability layer 400 at the needle tip section 100 is h1, and the height of the needle tip section 100 is H1, then h1 / H1≥1 / 10. When the thickness of the anti-permeability layer 400 is small, the strength of the anti-permeability layer 400 is small. As the drug-loaded layer 300 dissolves, the anti-permeability layer 400, due to its thinness, is easily broken and cannot block the microneedle channel, or cannot be embedded or re-embedded into the skin to block the microneedle channel. The drug-loaded layer dissolution molecules permeate out of the anti-permeability layer, causing the drug solution of the drug-loaded layer to seep out from the outside, ultimately failing to achieve a good sealing and anti-permeability effect against the overflow of the drug-loaded layer dissolution solution from the microneedle channel.

[0046] like Figure 1 As shown, along the axis of the anti-permeability microneedle, the height of the dissolution layer is h2, and the length of the needle segment is H2. Therefore, h2 / H2 ≥ 1 / 3. Since the stratum corneum of the epidermis has a poor dissolving effect on the anti-permeability microneedle, when the length of the dissolution layer is short, the probability of the dissolution layer being entirely located in the stratum corneum increases, preventing it from fully entering the relatively fluid-rich epidermis or dermis. This results in insufficient dissolution and separation of the dissolution layer. h2 / H2 ≥ 1 / 3 ensures that the dissolution layer can enter the epidermis or dermis, allowing the intercellular fluid to quickly dissolve the dissolution layer. The skin then recovers its shape, encapsulating the needle segment 100 within the skin, and even forming a closed opening in the microneedle channel on the skin surface. This prevents the dissolved drug solution from seeping out along the microneedle channel after the anti-permeability layer dissolves.

[0047] Specifically, after the anti-permeability microneedle is inserted into the skin, the complete dissolution time of the anti-permeability layer 400 in the skin is T1, the complete dissolution time of the dissolution layer 500 in the skin is T2, and the complete dissolution time of the drug-loaded layer 300 in the skin is T3. T1 is at least 15 minutes longer than T2, and T0 is the time difference between T1 and T2, i.e., T0 ≥ 15 minutes. T1 is at least 15 minutes longer than T3, and Tr is the time difference between T1 and T3, i.e., Tr ≥ 15 minutes. T0 ≥ 15 minutes allows sufficient time for the anti-permeability layer 400 to embed and re-embed into the skin. After the dissolution layer has completely dissolved, the needle segment 100 is embedded and wrapped in the skin, and the anti-permeability layer can still be embedded in the microneedle channel and block the microneedle channel until the skin recovers its shape or even closes the microneedle channel. Tr≥15min allows sufficient time for the impermeable layer 400 to embed and re-embed into the skin. Even after the drug-loaded layer 300 is completely dissolved in the intercellular fluid environment, the impermeable layer can still be embedded in the skin, causing the drug-loaded layer solution to form a "dammed lake" in the microneedle channel until the drug-loaded solution is gradually absorbed by the skin, thereby preventing the drug-loaded layer solution from seeping out of the microneedle channel.

[0048] In this embodiment, the needle body segment includes a needle column and a base. The base is frustoconical in shape, and the needle column is located at the end of the base away from the base. When the anti-permeability microneedle is inserted into the skin, the base increases the force-bearing area, improves the structural stability of the anti-permeability microneedle during insertion, improves the puncture effect, and ensures that the needle tip segment of the anti-permeability microneedle is better inserted into the skin.

[0049] In addition to the above, the anti-permeability microneedles of the present invention Figure 1 The specific structure can also be set to other specific structures. For example... Figure 2 As shown, the anti-permeability microneedle includes a needle tip segment and a needle body segment. The needle tip segment is the needle tip 110, and the needle body segment is the base 220. The end of the needle tip 110 away from the base 220 is a drug-loaded layer 300, and the end of the needle tip 110 near the base 220 is an anti-permeability layer 400 to prevent the drug from seeping out of the microneedle channel after the microneedle dissolves upon penetration into the skin. The height or thickness of the anti-permeability layer 400 in the portion of the needle tip segment 110 is h1, and the height of the needle tip segment 110 is H1, then h1 / H1≥1 / 10. The height of the anti-permeability layer is h2, and the length of the needle body segment is H2, then h2 / H2≥1 / 3. Along the direction parallel to the base, the maximum size of the anti-permeability layer 400 is greater than the maximum size of the drug-loaded layer 300. The end of the base 220 near the anti-permeability layer 400 is an anti-permeability layer 500. Along the direction parallel to the base, the maximum size of the anti-permeability layer 400 is greater than the minimum size of the anti-permeability layer 500. This allows the needle tip 110 to anchor and embed itself in the skin after the anti-permeability microneedle is inserted. Because T0 ≥ 15 min, the dissolution layer 500 dissolves, and the skin recovers its shape, encapsulating the needle tip 110 within the skin. Because Tr ≥ 15 min, the drug-loaded layer 300 dissolves in the intercellular fluid, while the anti-permeability layer 400 remains undissolved or only slightly dissolved. This ensures that after the skin recovers its shape, it adheres tightly and completely to the anti-permeability layer 400, acting like a stopper to block the microneedle channel. This creates a "dammed lake" of drug-loaded solution within the microneedle channel, preventing the drug solution from leaking out.

[0050] The specific structure of the anti-permeability microneedles of the present invention can also be as follows: Figure 3 As shown, the needle tip section is the needle tip 110, the needle body section includes the needle column 210 and the base 220, the drug-loaded layer 300 and the impermeable layer 400 are disposed on the needle tip 110, and the dissolution layer 500 is disposed on the needle column 210 near the end of the impermeable layer 400, or as shown in the figure. Figure 4The drug-loaded layer 400 is disposed on the needle tip 110, and the dissolution layer 400 is partially disposed at one end of the needle tip 110 near the needle column 210, and partially disposed at the other end of the needle column 210 near the needle tip 110. The maximum dimension of the impermeable layer 400 located in the needle tip section is greater than the maximum dimension of the drug-loaded layer 300, and also greater than the dimension of the impermeable layer 400 located in the needle column 210. The minimum dimension of the dissolution layer 500 located in the needle column 210 section is less than the maximum dimension of the impermeable layer 400. The height or thickness of the impermeable layer 400 located in the needle tip section 110 is h1, and the height of the needle tip 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. This allows the anti-permeability microneedle 1 to be inserted into the skin, with the needle tip 110 anchored and embedded in the skin. Because T0≥15min, the dissolution layer 500 dissolves, and the skin recovers its shape, encapsulating the drug-loaded layer 110 and the anti-permeability layer 400 within the skin. Because Tr≥15min, the drug-loaded layer 300 dissolves in the intercellular fluid, while the anti-permeability layer 400 remains undissolved or only slightly dissolved. This ensures that after the skin recovers its shape, it adheres tightly and completely to the anti-permeability layer 400, blocking the microneedle channel like a stopper. This causes the drug-loaded layer solution to form a "dammed lake" in the microneedle channel, thus preventing the drug-loaded layer solution from seeping out of the microneedle channel.

[0051] The specific structure of the anti-permeability microneedles of the present invention can also be as follows: Figure 5 As shown, the needle tip section is the needle tip 110, the needle body section is the needle column 210, the drug-loaded layer 300 and the impermeable layer 400 are disposed on the needle tip 110, and the dissolution layer 500 is disposed on the needle column 210 near the impermeable layer end, or as shown in the diagram. Figure 6 As shown, the drug-loaded layer 400 is disposed on the needle tip 110, while the impermeable layer 400 is partially disposed at one end of the needle tip near the needle column 210 and partially disposed at the other end of the needle column 210 near the needle tip 110. The dissolution layer 500 is disposed on the needle column 210. The height or thickness of the impermeable layer 400 located in the needle tip section 110 is h1, and the height of the needle tip 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; T0≥15min, Tr≥15min; after the impermeable microneedle is inserted into the skin, the dissolution layer 500 dissolves before the impermeable layer 400, and the drug-loaded layer 300 solution forms a "dammed lake" in the microneedle channel, thereby preventing the drug-loaded layer 300 solution from seeping out of the microneedle channel.

[0052] Specifically, the materials of the impermeable layer 400 include one or more of the following: silk protein, polylactic acid-glycolic acid copolymer (PLGA), polylactic acid (PLA), polycaprolactone (PCL), ethyl cellulose, and cellulose derivatives, so as to achieve the slow dissolution of the impermeable layer 400 in the skin and achieve the sealing and impermeability effect of the drug-loaded layer 300.

[0053] The materials of the dissolving layer 500 include one or more of the following: high molecular weight trehalose, polyvinylpyrrolidone (PVP), sodium hyaluronate (HA), polyvinyl alcohol (PVA), hydroxypropyl methylcellulose (HPMC), starch, polyethylene glycol, and methylcellulose; to achieve the rapid dissolution effect of the dissolving layer 500, so that the drug-loaded layer 300 and the impermeable layer 400 of the needle segment 100 are embedded in the skin for dissolution.

[0054] Specifically, the dissolution layer 500 includes a film-forming polymer material that, after dissolution, forms a covering film that fills the microneedle channel and the skin surface, preventing the microneedles from leaking out after the drug-loaded layer 300 dissolves, further improving the absorption efficiency of the drug-loaded layer 300 and avoiding extravasation.

[0055] The drug-loaded layer 300 contains drug components. Different types of drugs can be selected according to different needs to achieve precise drug delivery. These will not be listed one by one here.

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

[0057] Table 1

[0058]

[0059]

[0060] The corresponding dissolution times of Examples 1-7 and Comparative Examples 1-6 are shown in Table 2.

[0061] Table 2

[0062] Group Drug-loaded layer dissolution time Dissolution time of the impermeable layer Dissolution time of the fracture layer 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

[0063] Specifically, individual microneedles were prepared by formulating the drug-loaded layer 300, the impermeable layer 400, and the dissolution layer 500, respectively. The dissolution state of the individual microneedles with different formulations was observed by placing them in water, and the corresponding dissolution time was determined.

[0064] The HPLC residue detection results of Examples 1-7 and Comparative Examples 1-6 are shown in Table 3.

[0065] Table 3

[0066]

[0067]

[0068]

[0069] The average HPLC residue detection result was obtained by performing three parallel experiments on each example / comparative example.

[0070] The dilution volume refers to the volume to which the sample is diluted after dissolving. The experiment in Table 3 is to dilute 1 ml of dissolved sample to a volume of 2 ml.

[0071] Retention time refers to the time elapsed from the moment a sample component enters the chromatographic system (injection) until the component reaches its maximum concentration (i.e., the peak of the chromatographic peak) after the column in chromatographic analysis.

[0072] Peak area ratio refers to the total area above the background line in a chromatogram, which indicates the content of the analyte. The larger the area, the higher the content.

[0073] The content is calculated based on the peak area and retention time of the API.

[0074] Combine Table 1-2 and Appendix Figure 7 It can be seen that the green layer represents the drug-loaded layer 300 with added pigment, which facilitates better observation of the extravasation phenomenon of the drug-loaded layer 300, combined with the attached... Figure 8 From the pigment overflow situation and the residual values ​​in Table 3, we can see that:

[0075] Examples 1-7 achieved significantly lower skin surface residues on the skin surface compared to Comparative Examples 1-6 by keeping the dissolution time, L, h1 / H1, and h2 / H2 within appropriate ranges.

[0076] Figure 8 As shown, the dissolution layer 500 in Example 4 does not possess film-forming properties, and the time differences T0 and Tr between the complete dissolution of the impermeable layer 400 and the dissolution layer 500 and the drug-loaded layer 300 are relatively short, both being 15 minutes. Therefore, the skin surface residue in Example 4 is higher than that in Examples 1-3 and 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 relatively small. Although the impermeable layer 400 can be embedded or re-embedded in the skin, and the drug-loaded layer 300 dissolves in the microneedle channel to form a "dammed lake" effect, due to the small values ​​of L-spacing, h1 / H1, and h2 / H2, the drug-loaded solution still has a certain degree of permeability, causing a small portion of the drug-loaded solution to seep out of the skin surface through the microneedle channel. Therefore, the skin residue in Example 7 is higher than that in Examples 1-6.

[0077] The impermeable layer 400 in Examples 5 and 6 has a long dissolution time and can effectively block the drug-loaded layer 300 from seepage. Therefore, the skin residue in Examples 5 and 6 is lower than that in Examples 1-4.

[0078] Comparative Example 1 uses a conventional microneedle structure. Along the direction parallel to the substrate, the maximum size of the needle tip segment 100 is less than or equal to the minimum size of the needle body segment 200. After the microneedle is inserted into the skin, it cannot anchor itself. Furthermore, the microneedle in Comparative Example 1 only includes the drug-loaded needle tip segment 100 and the unloaded blank needle body segment 200. The dissolution rate and complete dissolution time of the needle tip segment 100 and the needle body segment 200 in the skin are the same. After the microneedle is inserted into the skin, it is squeezed out due to the skin's recovery and deformation. The microneedle channels are unobstructed, and the solution of the drug-loaded layer 300 easily seeps out from the microneedle channels to the skin surface. Its anti-seepage effect is weaker than that of Examples 1-7, showing a significant difference, and a larger amount of residue remains on the skin surface.

[0079] Although the values ​​of h1 / H1 and h2 / H2 in Comparative Example 2 are relatively ideal, the L-interval is small. After the microneedles are inserted into the skin, the skin can easily squeeze them out after it recovers its shape. Even if the microneedles are retained in the microneedle channel under external force, the needle tip 100 cannot form a "dammed lake" effect in the microneedle channel. The solution of the drug-loaded layer 300 in the intercellular fluid environment is easy to seep out along the microneedle channel, resulting in poor anti-seepage effect of the solution of the drug-loaded layer 300 and a large amount of residue on the skin surface.

[0080] In Comparative Examples 3 and 4, although the L-space was sufficient to allow the microneedles to embed themselves in the skin after insertion, T0 < 15 min and Tr < 15 min. The complete dissolution time of the impermeable layer 400, the drug-loaded layer 300, and the dissolution layer 500 in the skin was too close, failing to provide enough time for the impermeable layer 400 to embed itself or be re-embedded in the skin, thus forming a "dammed lake" effect. The solution of the drug-loaded layer 300 in the intercellular fluid environment easily seeped out along the microneedle channel, resulting in poor anti-permeation effect of the drug-loaded layer 300 and a large amount of residue on the skin surface.

[0081] In Comparative Example 5, h1 / H1 is 1 / 11, indicating that the thickness of the impermeable layer 400 is too small. The impermeable layer 400 has low strength, and as the drug-loaded layer 300 dissolves, its thinness makes it prone to breakage, preventing it from effectively blocking the microneedle channels. It may also fail to integrate or re-integrate into the skin, thus failing to block the microneedle channels. The solution from the drug-loaded layer 300 fails to create a "dammed lake" effect within the microneedle channels, allowing it to easily permeate out of the impermeable layer 400. This results in the drug solution from the drug-loaded layer 300 seeping from the microneedle channels onto the skin surface, leading to poor impermeability and a large amount of residue on the skin surface.

[0082] In Comparative Example 6, the h2 / H2 ratio was 1 / 4, and the length of the dissolution layer 500 was short. Due to the poor dissolution effect of the epidermal stratum corneum on the anti-permeability microneedles, the probability of the dissolution layer 500 being located entirely in the stratum corneum increased. It could not fully enter the epidermal or dermal layers with relatively abundant intercellular fluid, which increased the probability that the dissolution layer 500 could not achieve sufficient dissolution and separation. The dissolution time of the dissolution layer 500 in the skin was prolonged, and the skin could not form a closure near the dissolution layer 500. The "dammed lake" effect was weak, and the solution of the drug-loaded layer 300 easily permeated out of the anti-permeability layer 400, causing the drug solution of the drug-loaded layer 300 to seep out from the microneedle channel to the skin surface, resulting in poor anti-permeability effect of the drug-loaded layer 300 and more residue on the skin.

[0083] The above description is merely a preferred embodiment of the present invention and does not limit the patent scope of the present invention. Any equivalent structural transformations made using the contents of the present invention's specification and drawings under the inventive concept of the present invention, or direct / indirect applications in other related technical fields, are included within the patent protection scope of the present invention.

Claims

1. A leak-proof microneedle patch, characterized in that, Includes the substrate and the impermeable microneedles disposed on the substrate; Along a direction away from the substrate, the impermeable microneedles include a dissolution layer, an impermeable layer, and a drug-loaded layer; Along a direction parallel to the substrate, the maximum size of the impermeable layer is greater than the maximum size of the drug-loaded layer, and the maximum size of the impermeable layer is greater than the minimum size of the dissolution layer; The dissolution rate of the drug-loaded layer is V1, the dissolution rate of the impermeable layer is V2, and the dissolution rate of the fracture layer is V3, where V1>V2 and V3>V2.

2. The anti-seepage microneedle patch as described in claim 1, characterized in that, The anti-seepage microneedle includes a needle tip segment and a needle body segment, wherein the needle tip segment is located at one end of the needle body segment, and the needle body segment is disposed on the substrate; The dissolution layer is located on the needle body segment, the drug-loaded layer is located on the needle tip segment, and the anti-permeability layer is located between the dissolution layer and the drug-loaded layer. The anti-permeability layer may be entirely located on the needle tip segment or partially located on the needle tip segment and partially located on the needle body segment.

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

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

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

6. The anti-seepage microneedle patch as described in any one of claims 2, characterized in that, The complete dissolution time of the impermeable layer is T1, the complete dissolution time of the rupture layer is T2, and the complete dissolution time of the drug-loaded layer is T3. If T0 = T1 - T2, then T0 ≥ 15 min; If Tr = T1 - T3, then Tr ≥ 15min.

7. The anti-seepage microneedle patch as described in any one of claims 2-5, characterized in that, If the difference between the maximum size of the impermeable layer and the minimum size of the solution fracture layer along the direction parallel to the base is L, then L≥5μm.

8. The anti-seepage microneedle patch as described in claim 2, characterized in that, The impermeable layer comprises one or more of the following: silk fibroin, polylactic acid-glycolic acid copolymer (PLGA), polylactic acid (PLA), polycaprolactone (PCL), ethyl cellulose, and cellulose derivatives.

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

10. The anti-seepage microneedle patch as described in claim 2, characterized in that, The materials of the cleavage layer include one or more of the following: high molecular weight trehalose, polyvinylpyrrolidone (PVP), sodium hyaluronate (HA), polyvinyl alcohol (PVA), hydroxypropyl methylcellulose (HPMC), starch, polyethylene glycol, and methylcellulose. The fracture layer comprises a film-forming polymer material.

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