Microneedle patch mold, microneedle patch and preparation method of microneedle patch

Abstract

The invention provides a microneedle patch mold, a microneedle patch and a preparation method of the microneedle patch, the microneedle mold is formed by sequentially connecting a needle tip area, a connecting area and a base, the needle tip area is a rectangular pyramid, the connecting area is a quadrangular frustum pyramid, the base is a cube, and the included angle between the rectangular pyramid and the side edge of the quadrangular frustum pyramid is smaller than or equal to 180 degrees; the microneedle patch is manufactured by the microneedle patch mold, when a needle point solution is injected into the needle point area of the mold, the overflowing needle point solution can be temporarily stored in the connecting area and flows back into the needle point area during curing, and the needle point solution cannot be left on the base and does not need to be scraped off by a knife; meanwhile, the formula composition of the needle tip solution and the substrate solution is also screened, and the affinity adsorption between the needle tip solution and the substrate solution and a mold material is reduced, so that quantitative drug loading is really realized, the consistency of drug administration each time is ensured, and the curative effect is improved.

Description

[0001] This application claims the priority of the Chinese prior application, application number: 2024100941723, filing date January 23, 2024; all contents thereof are regarded as part of the present invention. Technical Field

[0002] The present invention belongs to the field of microneedle technology, and in particular, relates to a microneedle patch mold, a microneedle patch and a preparation method thereof. Background Art

[0003] Microneedle patch is a new type of drug dosage form that delivers drugs into the human body by piercing the skin. It avoids incomplete absorption and first-pass liver effect of oral administration. It is also more efficient than traditional skin patches in drug delivery. Traditional skin patches are difficult to penetrate the stratum corneum of the skin, resulting in poor drug absorption, and some drugs cannot even penetrate the stratum corneum, so they cannot be made into patches. However, since the microneedle dosage form penetrates the stratum corneum, many drugs can be delivered to the body through this route, solving the problem that some drugs cannot be delivered transdermally or have poor delivery effects. In addition, since the microneedle is only 900μm, it is less likely to touch the pain nerves. Therefore, using microneedle patches is not painful, avoiding the disadvantage of injection pain. However, it is difficult for current microneedle patches to load drugs to the tip of the microneedle, and the drug loading of each microneedle is consistent and controllable.

[0004] The current mainstream method for preparing microneedle patches is:

[0005] S1: Pour the needle tip solution on the microneedle mold, centrifuge or vacuum, and fill the needle cavity with the needle tip solution. Since there is no connection area in the mold, only the needle tip area and the base, and the base is in the shape of a platform, the needle tip solution has a large content in the liquid state and will overflow the needle cavity. Therefore, it is necessary to scrape off the excess solution that has not entered the needle cavity with a blade or scraper. Then dry it in a dryer to obtain a dry needle tip.

[0006] S2: pouring the substrate solution into the mold containing the dry needle tip, centrifuging or evacuating to allow the substrate solution to fill the unfilled needle cavity, drying in a desiccator, and demolding to obtain a microneedle patch.

[0007] However, the disadvantage of this method is that in step S1, a blade or scraper is used to scrape off the excess solution that has not entered the needle cavity. During the scraping process, it is difficult to achieve a consistent amount of drug scraped each time, resulting in inconsistent drug loading and inability to quantify. Moreover, after scraping, there will always be a small amount of drug that cannot be scraped clean in the gap between the needle cavities, resulting in that after the microneedle patch is made, not only the needle tip is loaded with drug, but also the gap between the needle tips is loaded with drug. Therefore, this method is difficult to prepare a microneedle patch that only loads drug at the needle tip and loads drug quantitatively.

[0008] In order to achieve quantitative drug loading at the needle tip, a method of high-pressure quantitative injection of drugs into each needle cavity has been developed. This method can achieve quantitative drug loading at the needle tip. However, there is a probability that the sample location is inaccurate and the sample amount is wrong. In addition, the sample speed is slow, and it takes a lot of time to point each needle cavity.

[0009] In addition, most of the microneedle patches nowadays have microneedles connected to the base plane, and the needle seat is too small. The microneedles are easily tilted when piercing the skin, causing some microneedles to fail to penetrate the skin, resulting in inconsistent drug delivery.

[0010] Therefore, it is urgent to find a microneedle mold that can achieve quantitative drug loading, so as to prepare a microneedle patch that can accurately and quantitatively load drugs and improve the therapeutic effect. Summary of the invention

[0011] In view of the defects of the prior art, the present invention provides a microneedle patch mold, a microneedle patch and a preparation method thereof, wherein the microneedle mold is composed of a needle tip area, a connection area and a base connected in sequence, the needle tip area is a quadrangular pyramid, the connection area is a quadrangular pyramid, the base is a cube, and the side angle between the quadrangular pyramid and the quadrangular pyramid is less than or equal to 180 degrees; the microneedle patch is made from the microneedle patch mold, when the needle tip solution is injected into the needle tip area of ​​the mold, the overflowed needle tip solution will be temporarily stored in the connection area and reflux into the needle tip area during solidification, and will not remain on the base, and there is no need to scrape it off with a knife; at the same time, the present invention also screens the formula composition of the needle tip solution and the base solution to reduce the affinity and adsorption between them and the mold material, thereby truly realizing quantitative drug loading, ensuring the consistency of each drug administration, and improving the efficacy.

[0012] On the one hand, the present invention provides a microneedle patch mold, comprising a needle tip area, a connection area and a base, wherein the needle tip area is connected to the connection area, and the connection area is connected to the base; when a needle tip solution is injected into the needle tip area of ​​the mold, the overflowed needle tip solution will be temporarily stored in the connection area and will flow back to the needle tip area during the curing process, and will not remain on the base.

[0013] The existing microneedle patch mold usually only includes a needle tip area and a base, and the side of the needle tip is almost at a 90-degree angle with the base, that is, the base is in a platform shape. In the process of using the mold preparation, when the needle tip solution with medicine is loaded into the needle tip area, considering that the volume of the needle tip solution will become smaller after solidification, the needle tip solution usually needs to fill the needle tip area, but this easily causes the needle tip solution to overflow the needle tip area and remain on the platform of the base. Before adding the substrate solution, it is necessary to use a blade or a scraper to scrape off the excess solution that has not entered the needle tip area, which eventually leads to a deviation in the drug loading. The microneedle patch mold provided by the present invention adds a connection area between the needle tip area and the base, so that the outer angle between the side of the cross section of the needle tip area and the side of the cross section of the connection area is less than or equal to 180 degrees, so that in the process of preparing the microneedle patch, the needle tip solution overflowed from the needle tip area will be temporarily stored in the connection area, and the volume of the needle tip solution will gradually decrease during the solidification process of the needle tip area, so the needle tip solution temporarily stored in the connection area will slowly flow back into the needle tip area, and will not remain in the base of the mold, truly realizing quantitative drug loading.

[0014] Furthermore, the needle tip area is a quadrangular pyramid, the connection area is a quadrangular pyramid, and the base is a cube; the outer angle between the side edge of the quadrangular pyramid and the side edge of the quadrangular pyramid is greater than 90 degrees and less than or equal to 180 degrees.

[0015] It can be understood that the needle tip area can be a triangular pyramid, a quadrangular pyramid, a pentagonal pyramid, a hexagonal pyramid, a heptagonal pyramid, an octagonal pyramid, etc., or even a cone. The connecting area can be a triangular prism, a quadrangular prism, a pentagonal prism, a hexagonal prism, a heptagonal prism, an octagonal prism, etc., which are matched with the needle tip area, and can even be a truncated cone. As long as the outer angle between the side of the cross-section of the needle tip area and the side of the cross-section of the connecting area is less than or equal to 180 degrees, the needle tip solution that did not enter the needle tip area at the beginning can slowly flow into the needle tip area during the curing process and will not remain at the base of the mold.

[0016] Research has shown that the use of tetrahedral and tetrahedral table designs can not only facilitate production and manufacturing, but also better ensure that the needle tip solution that has not entered the needle tip area at the beginning will slowly flow into the needle tip area during the curing process and will not remain in the connection area of ​​the mold.

[0017] Furthermore, the outer side angle between the side edge of the quadrangular pyramid and the side edge of the quadrangular pyramid is 100-160 degrees.

[0018] In some embodiments, the outer side angle between the side edge of the quadrangular pyramid and the side edge of the quadrangular pyramid is 135 degrees.

[0019] Furthermore, the height of the quadrangular pyramid is 600-1200 μm, and the side length of the base is 200-600 μm; the side length of the upper prism of the quadrangular pyramid is consistent with the side length of the base of the quadrangular pyramid; the side length of the base of the lower prism of the quadrangular pyramid is 200-1000 μm, and the height is 200-600 μm; the side lengths of the upper and lower bases of the cube are 900-20000 μm, and the height is 300-500 μm.

[0020] In some embodiments, the quadrangular pyramid has a height of 900 μm, a square base and a side length of 400 μm; the upper prism of the quadrangular pyramid is a square with a side length of 400 μm, and the lower prism is a square with a side length of 1000 μm and a height of 200 μm.

[0021] In some embodiments, the upper and lower bases of the cube are squares with a side length of 18000 μm and a height of 500 μm.

[0022] Furthermore, the number of the needle tip area and the connection area includes one or more, and the number of the needle tip area and the connection area is consistent; when the number of the needle tip area and the connection area is multiple, multiple connection areas share one base.

[0023] Furthermore, the connection areas are arranged on the base in an array, including any one or more of 3×3, 5×5, 10×10, 16×16, and 20×20 arrays.

[0024] In some embodiments, the connection areas are arranged in a 16×16 array on the base.

[0025] On the other hand, the present invention provides a microneedle patch, which is prepared using the microneedle patch mold described above, and the prepared microneedle patch includes a needle tip, a connecting platform and a substrate connected in sequence; the needle tip is made by solidifying a needle tip solution, and the needle tip solution includes a drug and a biodegradable material, and the biodegradable material includes any one or more of sodium hyaluronate, polyvinyl alcohol, dextran, sodium carboxymethyl cellulose, and polyvinyl pyrrolidone; the connecting platform and the substrate are made by solidifying a substrate solution, and the substrate solution includes a biodegradable material, and the biodegradable material includes any one or more of sodium hyaluronate, polyvinyl alcohol, dextran, sodium carboxymethyl cellulose, and polyvinyl pyrrolidone.

[0026] In another aspect, the present invention provides a method for preparing a microneedle patch, comprising the following steps:

[0027] (1) adding a needle tip solution to the needle tip area of ​​the microneedle patch mold described above, centrifuging or evacuating the needle tip solution to fill the needle cavity, and drying and solidifying;

[0028] (2) Adding the substrate solution to the connection area and base of the microneedle patch mold described in step (1), drying and demoulding, thereby obtaining a microneedle patch.

[0029] Furthermore, the needle tip solution in step (1) comprises drugs and biodegradable materials, and the biodegradable materials comprise any one or more of sodium hyaluronate, polyvinyl alcohol, dextran, sodium carboxymethyl cellulose, and polyvinyl pyrrolidone.

[0030] In some embodiments, by comparing the drug content of microneedle patches prepared from needle tip solutions containing different biodegradable materials, it is shown that sodium hyaluronate as a needle tip skeleton material can make the prepared microneedle patch better demolding.

[0031] Furthermore, the needle tip solution in step (1) also includes a drug dissolution promoter and a pigment, including an artificial pigment and a natural pigment, for marking the location of the drug.

[0032] The artificial pigments include but are not limited to carmine, trypan blue, methylene blue, methyl green, gentian violet, etc.; the natural pigments include but are not limited to beetroot red, cochineal red, turmeric, carotene, etc.

[0033] In some embodiments, the uniformity and aesthetics of the drug marking are compared with different pigments, preferably carmine.

[0034] In some embodiments, by comparing the drug content at the needle tip of a microneedle patch prepared from needle tip solutions containing different drug dissolution-promoting agents, it is shown that citric acid as a drug dissolution-promoting agent can better dissolve the drug.

[0035] Furthermore, the base solution in step (2) comprises a biodegradable material, and the biodegradable material comprises any one or more of sodium hyaluronate, polyvinyl alcohol, dextran, sodium carboxymethyl cellulose, and polyvinyl pyrrolidone.

[0036] In some embodiments, by comparing the content of biodegradable materials in the connecting platform and the substrate in the microneedle patch prepared from substrate solutions containing different biodegradable materials, it is shown that PVPK60 as a substrate skeleton material can enable the prepared microneedle patch to be better demolded.

[0037] In some methods, the microneedle patch mold provided by the present invention is prepared into microneedle patches containing different drugs, and the drug content of the needle tip is detected, indicating that the microneedle patch mold provided by the present invention is suitable for preparing microneedle patches with multiple drugs, and the prepared microneedle patches achieve precise quantitative drug loading, ensuring the consistency of each drug administration.

[0038] The present invention has the following beneficial effects:

[0039] 1. By setting a connection area between the needle tip area and the base of the microneedle patch mold, and making the side angle between the needle tip area and the connection area less than or equal to 180 degrees, during the preparation of the microneedle patch, when the needle tip solution is injected into the needle tip area, the overflowed needle tip solution will be temporarily stored in the connection area. The volume of the needle tip solution in the needle tip area gradually decreases during the curing process, so the needle tip solution temporarily stored in the connection area will slowly flow back into the needle tip area and will not remain on the base of the mold. There is no need to scrape it with a knife, so that precise quantitative drug loading is achieved, ensuring the consistency of each drug administration;

[0040] 2. At the same time, the formula composition of the needle tip solution and the base solution was screened to reduce the adsorption of the needle tip solution and the base solution to the membrane material, making it difficult to remain, and making it easier to control the needle tip solution to not remain on the base when injected, thereby truly achieving accurate quantitative drug loading;

[0041] 3. The shape of the prepared microneedles is easy to penetrate into the skin, which solves the problem that the microneedles are difficult to penetrate into the skin and cannot complete the drug delivery. BRIEF DESCRIPTION OF THE DRAWINGS

[0042] Figure 1 This is a schematic diagram of the overall structure of the microneedle patch mold of Example 1;

[0043] Figure 2 This is a top view of the microneedle patch mold of Example 1;

[0044] Figure 3 This is a schematic diagram of the cross-sectional structure of the microneedle patch mold of Example 1;

[0045] Figure 4 This is a schematic diagram of the overall structure of a microneedle patch prepared from the microneedle patch mold of Example 1;

[0046] Figure 5 This is the situation after pouring the needle tip solution on the microneedle patch mold in Example 2;

[0047] Figure 6 This is the situation after the needle tip solution of Example 2 is dried on the microneedle patch mold;

[0048] Figure 7 This is the microneedle patch finally prepared using the microneedle patch mold in Example 2;

[0049] Figure 8 This is the condition after the microneedle patch prepared in Example 2 was pierced into the skin of a rat. DETAILED DESCRIPTION

[0050] The present invention is further described in detail below in conjunction with the accompanying drawings and embodiments. It should be pointed out that the embodiments described below are intended to facilitate the understanding of the present invention and do not have any limiting effect on the present invention.

[0051] Embodiment 1, a microneedle patch mold

[0052] like Figure 1-3 As shown, a microneedle patch mold includes a needle tip area 1, a connection area 2 and a base 3. The needle tip area 1 is connected to the connection area 2, and the connection area 2 is connected to the base 3, and multiple connection areas 2 share one base 3. The needle tip area 1 is a quadrangular pyramid, the connection area 2 is a quadrangular pyramid, and the base is a cube; the outer angle 4 between the side edges of the quadrangular pyramid and the side edges of the quadrangular pyramid is 135 degrees. The height of the quadrangular pyramid is 900μm, the bottom surface is a square, and the side length is 400μm; the upper prism of the quadrangular pyramid is a square with a side length of 400μm, and the lower prism is a square with a side length of 1000μm and a height of 200μm. The upper and lower bottom surfaces of the cube are squares with a side length of 18000μm and a height of 500μm. The connection areas 2 are arranged on the base in a 16×16 array.

[0053] It should be noted that the microneedle patch mold provided in this embodiment arranges the connection area 2 in a 16×16 array on the base 3. According to actual preparation needs, the connection area 2 can also be designed to be arranged in a 3×3, 5×5, 10×10, or 20×20 array on the base 3; in addition, according to actual preparation needs, the side lengths and heights of the needle tip area 1, the connection area 2, and the base 3 can also be changed.

[0054] In the process of preparing a microneedle patch using the microneedle patch mold, the needle tip solution added to the needle tip area 1 will overflow and be temporarily stored in the connecting area 2. The volume of the needle tip solution in the needle tip area 1 will gradually shrink during the curing process, and extra space will appear in the needle tip area 1. Due to the inclined surfaces of the quadrangular pyramid in the needle tip area 1 and the quadrangular pyramid in the connecting area 2, the needle tip solution temporarily stored in the connecting area 2 will slowly flow back into the needle tip area and will not remain in the base 3 of the mold, thereby achieving quantitative drug loading.

[0055] like Figure 4 As shown, the microneedle patch prepared using the above mold includes a microneedle 5, a connecting platform 6 and a substrate 7

[0056] Example 2: Preparation of microneedle patch

[0057] In this embodiment, zolmitriptan is used as an example to prepare a zolmitriptan soluble microneedle patch.

[0058] The components and ratios of the needle tip solution and the base solution are shown in Table 1 below.

[0059] Table 1. Composition ratio of zolmitriptan soluble microneedle patch

[0060]

[0061] 1. Preparation of needle tip solution:

[0062] (1) Weigh 2.24 g of citric acid according to the ratio in Table 1 and add it to a centrifuge tube. Add 2 mL of ultrapure water and stir to dissolve.

[0063] (2) Weigh 2.80 g of zolmitriptan according to the ratio in Table 1, add it to the solution prepared in step (1), and stir to dissolve;

[0064] (3) Weigh 1.12 g of sodium hyaluronate according to the ratio in Table 1, add it to the solution prepared in step (2), and stir to dissolve;

[0065] (4) According to the ratio in Table 1, 37.2 mg of carmine was weighed and added to the solution prepared in step (3), and the solution was stirred and dissolved to obtain a needle tip solution. The total volume of the needle tip solution was measured to be 8.73 mL.

[0066] 2. Preparation of base solution:

[0067] Weigh 9 g of PVPK60 into a centrifuge tube, add 30 mL of anhydrous ethanol, and stir in a 50°C water bath for 1 h to dissolve to obtain a PVPK60 substrate solution.

[0068] 3. Preparation of Zolmitriptan Soluble Microneedle Patch:

[0069] (1) Take 40 μL of the needle tip solution and cast it into the needle tip area of ​​the mold provided in Example 1, centrifuge or evacuate the solution to fill the needle cavity. Figure 5 As shown;

[0070] (2) Place the mold in a dryer and dry it for 3 hours in an environment of 25°C / 40% RH. Figure 6 As shown;

[0071] (3) Add 200 μL of the substrate solution to the connection area and substrate of the microneedle mold containing the solidified needle tip, and fill the connection area and substrate with the solution by vacuum or centrifugation; dry in a dryer at 25°C / 40% RH for 10 h, solidify and shape, and demold to obtain a zolmitriptan microneedle patch with only the needle tip loaded with drug, such as Figure 7 shown.

[0072] Furthermore, the effect of the microneedle patch prepared above on rat skin was tested. The specific method was as follows: SD rats were taken, the hair on the back was removed, and the prepared microneedle patch was used to pierce the back skin of the depilated SD rats. The skin was pressed for 1 minute, fixed with medical tape for 9 minutes, and then the microneedles were removed. The skin condition was observed. The effect was as follows: Figure 8 As shown, obvious holes can be seen on the skin, indicating that the needle patch is not easy to tilt when piercing the skin and can easily penetrate the skin.

[0073] Example 3, determination of drug loading on needle tip and substrate

[0074] The difference between this embodiment and embodiment 2 is that a microneedle patch without a connection area is prepared using a microneedle patch mold without a connection area, and the drug loading of the needle tip and the substrate of the microneedle patch prepared in this embodiment and embodiment 2 are compared.

[0075] The specific detection method is: take three pieces of each of the two microneedles and press them onto the surface of gelatin, dissolve the needle tip in the gelatin, and disconnect it from the base part, use high performance liquid chromatography to determine the content of zolmitriptan in each part, and calculate the average value of the two microneedle patches. The results are shown in Table 2. Theoretically, the content of zolmitriptan in one microneedle patch is 12.8 mg. It should be noted that the base part of the microneedle patch prepared by the microneedle patch mold containing the connection area includes a connection platform.

[0076] Table 2. Drug loading of the needle tip and base of different microneedle patches

[0077]

[0078] According to the data analysis in Table 2, the drug of the microneedle patch prepared by the microneedle patch mold containing the connection area will not be retained in the substrate, while a small part of the drug of the microneedle patch prepared by the microneedle patch mold without the connection area will be retained in the substrate during the curing process of the needle tip solution, resulting in poor drug consistency. It shows that the microneedle patch prepared by the microneedle patch mold containing the connection area provided by the present invention can solve the problem that the needle tip solution will be retained in the substrate during the curing process, and realize quantitative drug administration.

[0079] Example 4: Effect of microneedle patch molds with different outer angles on the preparation of microneedle patches

[0080] In this example, the outer angles of the side edges of the quadrangular pyramid and the side edges of the quadrangular pyramid in the microneedle patch mold provided in Example 1 are changed, and the different outer angles are 100 degrees, 115 degrees, 135 degrees, 140 degrees, and 160 degrees, respectively. Five microneedle patch molds with different outer angles are prepared, and five microneedle patches are prepared according to the method described in Example 2, and the drug content in the needle tips, connecting platforms, and substrates of the five microneedle patches is detected.

[0081] The specific detection method is as follows: take three pieces of each of the five microneedle patches and press them onto the gelatin surface, dissolve the needle tip part in the gelatin, thereby disconnecting it from the connecting platform and the base part, and use high performance liquid chromatography to determine the content of zolmitriptan in each part, and calculate the average value of the five microneedle patches. The results are shown in Table 3. Theoretically, the content of zolmitriptan in a microneedle patch is 12.8 mg.

[0082] Table 3. Drug content of each part of the microneedle patch prepared with microneedle patch molds containing different outer angles

[0083]

[0084] According to the data analysis in Table 3, when the outer angle between the side edge of the quadrangular pyramid and the side edge of the quadrangular pyramid in the microneedle patch mold is 135 degrees, the drug is only present in the needle tip part, and the connecting platform and the base part do not contain drugs, indicating that the needle tip solution overflowed during the preparation of the microneedle patch is all refluxed into the needle tip area during the curing process; when the outer angle is 100 degrees and 115 degrees, a part of the drug will remain in the connecting platform and the base part, because the outer angle is too small to make the slope of the quadrangular pyramid too gentle, resulting in the needle tip solution being difficult to reflux into the needle tip area during the curing process and solidifying in the connecting area; and when the outer angle is 140 degrees and 160 degrees, a part of the drug will also remain in the connecting platform and the base part, because the outer angle is too large to make the slope of the quadrangular pyramid too steep, resulting in the overflowed needle tip solution temporarily stored in the connecting area refluxing too fast, and the needle tip solution in the needle tip area quickly refluxes before the solidification volume of the needle tip solution in the needle tip area is reduced, so the space filled by the overflowed needle tip solution refluxes is still the connecting area.

[0085] In summary, the optimum outer angle between the side edges of the quadrangular pyramid and the side edges of the quadrangular pyramid in the microneedle patch mold is 135 degrees.

[0086] Example 5: Screening of biodegradable materials in needle tip solution

[0087] The difference between this embodiment and embodiment 2 is that the needle tip skeleton material is changed, as shown in the following Table 4.

[0088] Table 4. Different needle tip skeleton materials

[0089] Group Tip skeleton material 1 Sodium Hyaluronate 2 Polyvinyl alcohol 3 Dextran 4 Sodium Carboxymethyl Cellulose 5 PVPK60

[0090] Five kinds of zolmitriptan soluble microneedle patches were prepared using the above-mentioned different needle tip skeleton materials according to the preparation method described in Example 2, and the content of zolmitriptan in the needle tip of each microneedle patch was determined by high performance liquid chromatography according to the method in Example 4. Three pieces of each microneedle patch were taken for detection, and the average value was calculated. The test results are shown in Table 5 below. Theoretically, the content of zolmitriptan in the microneedle of one microneedle patch is 12.8 mg.

[0091] Table 5. Drug loading of microneedle patch tips prepared with tip solutions containing different tip skeleton materials

[0092]

[0093]

[0094] According to the results in Table 5, the drug loading of the microneedle patch prepared with the needle tip solution containing sodium hyaluronate in Group 1 was the highest, which was the same as the theoretical value, while the drug loading of the microneedle patch needle tips prepared in the other four groups was significantly different from the theoretical value, indicating that after sodium hyaluronate was solidified as the needle tip skeleton, the needle tip was almost completely demolded during demolding and would not adhere to the mold, while after polyvinyl alcohol, dextran, sodium carboxymethyl cellulose, and PVPK60 were solidified as the needle tip skeleton, part of the needle tip would adhere to the mold during demolding and could not be completely demolded, so the drug loading was reduced, resulting in inability to dosing quantitatively.

[0095] In summary, the biodegradable material in the needle tip solution is preferably sodium hyaluronate.

[0096] Example 6: Screening of biodegradable materials in substrate solution

[0097] The difference between this embodiment and embodiment 2 is that the base skeleton material is changed, as shown in the following Table 6.

[0098] Table 6. Different base skeleton materials

[0099] Group Base skeleton material 1 PVPK60 2 Polyvinyl alcohol 3 Dextran 4 Sodium Carboxymethyl Cellulose 5 Sodium Hyaluronate

[0100] Five kinds of zolmitriptan soluble microneedle patches were prepared using the above-mentioned different base skeleton materials according to the preparation method described in Example 2, and the content of the base skeleton materials in the five kinds of microneedle patches was detected. The detection method is: three pieces of each of the above-mentioned five kinds of microneedle patches were pressed onto the surface of gelatin, and the needle tip part was dissolved in the gelatin, thereby disconnecting from the connecting platform and the base part, and the base skeleton material content in the connecting platform and the base was determined by high performance liquid chromatography, and the average value was calculated. The detection results are shown in Table 7 below. Theoretically, the connecting platform and the base contain 56.7 mg of base skeleton material.

[0101] Table 7. Content of different substrate skeleton materials in the microneedle patch connection platform and substrate

[0102] Group Base skeleton material Content (mg) 1 PVPK60 56.4 2 Polyvinyl alcohol 53.2 3 Dextran 51.7 4 Sodium Carboxymethyl Cellulose 49.5 5 Sodium Hyaluronate 52.8

[0103] According to the data analysis in Table 7, the microneedle patch prepared with the base solution containing PVPK60 in Group 1 had the highest content of skeleton material in the connecting platform and the base, which was close to the theoretical value, while the drug loading of the microneedle patches prepared by the other four groups was significantly different from that of Group 1, indicating that after PVPK60 was solidified as the base skeleton, the connecting platform and the base were almost completely demolded during demolding and would not adhere to the mold, while after polyvinyl alcohol, dextran, sodium carboxymethyl cellulose, and sodium hyaluronate were solidified as the base skeleton and then demolded, part of the connecting platform and the base would adhere to the mold and could not be completely demolded.

[0104] In summary, the base skeleton material is preferably PVPK60.

[0105] Example 7: Preparation of microneedle patches containing different drugs

[0106] In Example 2, a zolmitriptan soluble microneedle patch was prepared. In this example, microneedle patches containing different drugs were prepared and the drug content of the needle tips of the microneedle patches containing different drugs was detected. The different drugs are shown in Table 8 below.

[0107] Table 8. Different drugs

[0108] Group drug 1 Semaglutide 2 Liraglutide 3 Colchicine 4 Envoylimab 5 Keytruda

[0109] The above drugs were prepared into microneedle patches according to the method described in Example 2 (microneedle patches were prepared according to the actual dosage of different drugs each time), and the drug content at the needle tip was detected according to the method described in Example 4. The test results and the theoretical drug content of microneedle patches with different drugs are shown in Table 9 below.

[0110] Table 9. Drug content at the needle tip of microneedle patches containing different drugs

[0111] drug Drug content at needle tip (mg) Theoretical drug content (mg) Semaglutide 4.56 4.56 Liraglutide 1.18 1.18 Colchicine 1.0 1.0 Envoylimab 200 200 Keytruda 0.01 0.01

[0112] According to the data analysis in Table 9, the drug content of the needle tips of the prepared microneedle patches containing different drugs is basically consistent with the theoretical value, indicating that the microneedle patch prepared by the microneedle patch mold provided by the present invention can achieve quantitative drug loading and ensure the consistency of each drug administration.

[0113] Example 8: Screening of drug dissolution-promoting agents in needle tip solution

[0114] The difference between this embodiment and embodiment 2 is that the drug dissolution promoting agent in the needle tip solution is changed, as shown in the following Table 10.

[0115] Table 10. Different drug dissolution enhancers

[0116] Group Drug dissolution enhancer 1 Citric Acid 2 tartaric acid 3 Gluconic acid 4 acetic acid

[0117] Four zolmitriptan soluble microneedle patches were prepared using the above different drug dissolution promoters according to the preparation method described in Example 2, and the content of zolmitriptan in the needle tip of each microneedle patch was determined according to the method described in Example 4. Three pieces of each microneedle patch were tested and the average value was calculated. The test results are shown in Table 11 below. Theoretically, the content of zolmitriptan in the needle tip of one microneedle patch is 12.8 mg.

[0118] Table 11. Drug loading of microneedle patches prepared from tip solutions containing different tip skeleton materials

[0119] Group Zolmitriptan content (mg) 1 12.8 2 11.6 3 11.2 4 10.7

[0120] According to the results in Table 11, the drug loading at the needle tip of the microneedle patch prepared with citric acid as the drug dissolution promoter in Group 1 was the highest, which was the same as the theoretical value, while the drug loading at the needle tip of the microneedle patch prepared in the other three groups was significantly different from the theoretical value, indicating that citric acid can make zolmitriptan dissolve better.

[0121] Furthermore, when the zolmitriptan drug was replaced with other drugs in Table 8 of Example 7, good dissolution-promoting effects were exhibited.

[0122] In summary, the drug dissolution promoting agent in the needle tip solution is preferably citric acid.

[0123] Example 9: Screening of pigments in needle tip solution

[0124] The difference between this embodiment and embodiment 2 is that the type of pigment in the needle tip solution is changed, as shown in Table 12 below.

[0125] Table 12. Different pigments

[0126] Group pigment 1 Carmine 2 Trypan blue 3 Methylene blue 4 Methyl green 5 Gentian Violet

[0127] The above-mentioned different pigments were used to prepare five kinds of zolmitriptan soluble microneedle patches according to the preparation method described in Example 2, and the content of zolmitriptan in the needle tip of each microneedle patch was determined according to the method described in Example 4. Three pieces of each microneedle patch were taken for testing, and the average value was calculated. The test results are shown in Table 13 below. Theoretically, the content of zolmitriptan in the needle tip of one microneedle patch is 12.8 mg.

[0128] Table 13. Drug loading of microneedle patches prepared from tip solutions containing different tip skeleton materials

[0129]

[0130]

[0131] According to the results analysis in Table 13, there is no significant difference in the drug content in the needle tip area of ​​the microneedle patches prepared with the five pigments. However, observation of the prepared microneedle patches revealed that carmine was more evenly distributed and had good solubility, ensuring the consistency and aesthetics of the drug appearance, while the other four pigments were not as effective as carmine. In addition, carmine has good stability, including light resistance and heat resistance.

[0132] In summary, the pigment in the needle tip solution is preferably carmine.

[0133] Although the present invention is disclosed as above, the present invention is not limited thereto. Any person skilled in the art can make various changes and modifications without departing from the spirit and scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the scope defined by the claims.

Claims

1. A microneedle patch mold, characterized in that: It includes a needle tip area, a connection area and a base, wherein the needle tip area is connected to the connection area, and the connection area is connected to the base; when the needle tip solution is injected into the needle tip area of ​​the mold, the overflowed needle tip solution will be temporarily stored in the connection area and will flow back to the needle tip area during the curing process, and will not remain on the base.

2. The microneedle patch mold according to claim 1, characterized in that: The needle tip area is a quadrangular pyramid, the connection area is a quadrangular pyramid, and the base is a cube; the outer angle between the side edge of the quadrangular pyramid and the side edge of the quadrangular pyramid is greater than 90 degrees and less than or equal to 180 degrees.

3. The microneedle patch mold according to claim 2, characterized in that: The outer side angle between the side edge of the quadrangular pyramid and the side edge of the quadrangular pyramid is 100-160 degrees.

4. The microneedle patch mold according to claim 3, characterized in that: The height of the quadrangular pyramid is 600-1200μm, and the side length of the bottom surface is 200-600μm; the side length of the upper prism of the quadrangular pyramid is consistent with the side length of the bottom surface of the quadrangular pyramid; the side length of the bottom surface of the lower prism of the quadrangular pyramid is 200-1000μm, and the height is 200-600μm; the side lengths of the upper and lower bottom surfaces of the cube are 900-20000μm, and the height is 300-500μm.

5. The microneedle patch mold according to claim 4, characterized in that: The number of the needle tip area and the connection area includes one or more, and the number of the needle tip area and the connection area is consistent; when the number of the needle tip area and the connection area is multiple, multiple connection areas share one base.

6. The microneedle patch mold according to claim 5, characterized in that: The connection areas are arranged on the base in an array, including any one or more of 3×3, 5×5, 10×10, 16×16, and 20×20 arrays.

7. A microneedle patch, characterized in that: The microneedle patch mold according to claims 1-6 is used for preparation, and the prepared microneedle patch includes a needle tip, a connecting platform and a substrate connected in sequence; the needle tip is made by solidifying a needle tip solution, and the needle tip solution includes a drug and a biodegradable material, and the biodegradable material includes any one or more of sodium hyaluronate, polyvinyl alcohol, dextran, sodium carboxymethyl cellulose, and polyvinyl pyrrolidone; the connecting platform and the substrate are made by solidifying a substrate solution, and the substrate solution includes a biodegradable material, and the biodegradable material includes any one or more of sodium hyaluronate, polyvinyl alcohol, dextran, sodium carboxymethyl cellulose, and polyvinyl pyrrolidone.

8. A method for preparing a microneedle patch, characterized in that: The following steps are involved: (1) adding a needle tip solution to the needle tip area of ​​the microneedle patch mold according to any one of claims 1 to 6, centrifuging or evacuating the needle tip solution to fill the needle cavity, and drying and solidifying; (2) Adding the substrate solution to the connection area and base of the microneedle patch mold described in step (1), drying and demoulding, thereby obtaining a microneedle patch.

9. The preparation method according to claim 8, characterized in that: The needle tip solution in step (1) comprises drugs and biodegradable materials, and the biodegradable materials comprise any one or more of sodium hyaluronate, polyvinyl alcohol, dextran, sodium carboxymethyl cellulose, and polyvinyl pyrrolidone.

10. The preparation method according to claim 9, characterized in that: The base solution in step (2) comprises a biodegradable material, and the biodegradable material comprises any one or more of sodium hyaluronate, polyvinyl alcohol, dextran, sodium carboxymethyl cellulose, and polyvinyl pyrrolidone.

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