Preparation process of microneedle patch and microneedle patch prepared by preparation process

Abstract

The invention belongs to the technical field of microneedles, and relates to a preparation process of a microneedle patch and the microneedle patch prepared by the preparation process. According to the preparation process of the micro-needle patch provided by the invention, the first section of active ingredient solution and the second section of soluble micro-needle skeleton solution are injected into the mold, and through uniform drying treatment, the zolmitriptan soluble micro-needles with uniformly connected bases or mutually independent bases can be prepared; in the drying process, the drying time of the peripheral microneedles and the inner microneedles of the array tends to be the same, and the situation that due to uneven drying, part of the microneedles are excessively dried, and the microneedles are broken after demolding is avoided; a first-section solution containing active ingredients and a second-section soluble microneedle skeleton solution can be connected more tightly, and bubbles formed due to non-uniform drying of the whole solution are avoided; and the yield of microneedle preparation is greatly improved.

Description

Technical Field

[0001] The present invention belongs to the technical field of microneedles, and relates to a preparation process of a microneedle patch and the microneedle patch prepared thereby. Background Art

[0002] Currently, between the gasket and the microneedles of a soluble microneedle patch, they mainly contact through the adhesive layer provided on the gasket and the microneedle solution. The adhesive layer is used to bond the microneedles formed in the microneedle female mold, so that the microneedles are fixedly bonded to the adhesive layer, facilitating the demolding and separation of the cured microneedles from the microneedle female mold to become a soluble microneedle patch.

[0003] However, after the soluble microneedle patch is placed for a long time, the adhesive material of the adhesive layer is prone to penetrate with the contacted microneedles, affecting the stability of the active drug inside the microneedles. Therefore, by directly contacting the gasket material without an adhesive material with the microneedles, the penetration and mutual influence between the adhesive material and the active drug of the microneedles are avoided.

[0004] When preparing microneedles with active drug components currently, after the microneedle solution with active components is filled into the microneedle groove mold and is in a liquid state, a non-adhesive gasket is directly attached to the surface of the microneedle solution, and then the microneedle patch is placed in the ambient temperature and humidity environment of the prior art for curing. When the microneedle solution is in a liquid state, the microneedle solutions on different microneedle grooves overflow and spread to connect into one piece. Due to the overflow of the microneedle solution at the root of the microneedle groove, notches and bubbles are formed at the microneedle base after drying, and the formability of the microneedles is poor. Moreover, during the drying process, since the gasket has the function of isolating air, compared with the center position of the gasket, the microneedle solution at the outer periphery of the gasket contacts the flowing air more fully and dries faster. When the microneedle solution of the microneedles in the center of the gasket dries, the microneedle solution at the outer periphery of the gasket dries excessively. Thus, when demolding, the microneedles at the outer periphery of the gasket are prone to breakage, resulting in a low yield rate of microneedle preparation. When preparing a microneedle patch, when the gasket is attached after the surface of the microneedle solution filled into the microneedle groove mold dries in the ambient temperature and humidity environment of the prior art, since the surface of the microneedle solution on the surface of the microneedle groove mold contacts the air and dries faster than the solution inside the microneedle groove, the microneedle solution dries unevenly, and is prone to breakage during demolding, resulting in a low yield rate of microneedle preparation. Summary of the Invention

[0005] Based on the problems and deficiencies in the existing technology, the present invention provides a preparation process for a microneedle patch and the microneedle patch prepared thereby. The preparation process for the microneedle patch provided by the present invention injects a first segment of active ingredient solution and a second segment of soluble microneedle skeleton solution into a mold. Through uniform drying treatment, soluble microneedles with uniformly connected bases or independent bases can be prepared. During the drying process, the drying time of the peripheral microneedles and the inner microneedles in the array can tend to be the same, avoiding the situation of some microneedles being over-dried and broken needles after demolding due to non-uniform drying. It can make the connection between the first segment of solution containing the active ingredient and the second segment of soluble microneedle skeleton solution tighter, avoiding the formation of air bubbles due to non-uniform overall drying of the solution. It greatly improves the yield rate of microneedle preparation.

[0006] Terms:

[0007] 1. PVP-K17: Polyvinylpyrrolidone;

[0008] 2. PVA: Polyvinyl alcohol;

[0009] 3. PVP: Vinylpyrrolidone.

[0010] The technical solution of the present invention is as follows:

[0011] On the one hand, the present invention provides a preparation method for a microneedle patch, characterized in that the preparation method includes the following steps:

[0012] (1) Inject a first segment of active ingredient solution into a mold;

[0013] (2) Inject a second segment of soluble microneedle skeleton solution into the mold, so that the second segment of solution bulges from the surface of the mold to form a bulging droplet;

[0014] (3) Perform uniform drying treatment on the mold injected with the first segment of active ingredient solution and the second segment of soluble microneedle skeleton solution; the uniform drying treatment includes the first uniform drying treatment or the first uniform drying treatment and the second uniform drying treatment, so that the bulging droplet becomes a viscous colloidal bulge;

[0015] (4) Press a gasket onto the colloidal bulge in step (3), dry, and demold to obtain a soluble microneedle patch.

[0016] Specifically, specifically, the temperature of the first uniform drying treatment in step (3) is 20 - 30 °C.

[0017] Specifically, the humidity of the first uniform drying treatment in step (3) is 80% - 95%.

[0018] Specifically, the time of the first uniform drying treatment in step (3) is 6 - 20 h.

[0019] Specifically, the temperature of the second uniform drying treatment described in step (3) is 20-30°C.

[0020] Specifically, the humidity of the second uniform drying treatment described in step (3) is 30-70%.

[0021] Preferably, the humidity of the second uniform drying treatment described in step (3) is 40-60%.

[0022] Specifically, the time of the second uniform drying treatment described in step (3) is 1-5 min.

[0023] Preferably, the time of the second uniform drying treatment described in step (3) is 3-5 min.

[0024] Specifically, the drying humidity described in step (4) is 10%-90%.

[0025] Specifically, the drying temperature described in step (4) is 20-30°C.

[0026] Specifically, the drying time described in step (4) is 15-72 h.

[0027] Specifically, the mass of the raised droplets described in step (2) is 100-400 nanoliters per droplet; the distance between adjacent raised droplets is 200-400 micrometers.

[0028] Preferably, the mass of the raised droplets described in step (2) is 150-350 nanoliters per droplet; the distance between adjacent raised droplets is 250-300 micrometers.

[0029] Specifically, the 1-component active ingredient solution described in step (1) includes, but is not limited to, the following combinations:

[0030] Combination 1: Zolmitriptan, organic acid, polyvinyl alcohol;

[0031] Combination 2: PVP;

[0032] Combination 3: Chondroitin sulfate, dextran.

[0033] Preferably, the organic acid includes one or more of formic acid, acetic acid, propionic acid, butyric acid, octanoic acid, adipic acid, oxalic acid, malonic acid, succinic acid, maleic acid, tartaric acid, benzoic acid, phenylacetic acid, phthalic acid, terephthalic acid, valeric acid, hexanoic acid, decanoic acid, stearic acid, palmitic acid, acrylic acid, glacial acetic acid, succinic acid, citric acid.

[0034] More preferably, the organic acid includes one or more of tartaric acid, glacial acetic acid, succinic acid, citric acid.

[0035] Preferably, the content of each component in the active ingredient solution is:

[0036] Combination 1: Zolmitriptan (30%-45%), organic acid (8%-16%), and polyvinyl alcohol (0.5%-3.0%);

[0037] Combination 2: PVP (10%);

[0038] Combination 3: Chondroitin sulfate (5%), dextran (5%).

[0039] Specifically, the two-segment soluble microneedle skeleton solution described in step (2) is a polymer solution.

[0040] More specifically, the polymer solution includes at least two of dextran 70, polyvinyl alcohol, PVP-K17, sucrose, and water for injection.

[0041] Preferably, the polymer solution includes, but is not limited to, the following combinations:

[0042] Combination 1: Dextran 70, water for injection;

[0043] Combination 2: Polyvinyl alcohol, PVP-K17, water for injection;

[0044] Combination 3: Polyvinyl alcohol, sucrose, water for injection;

[0045] Combination 4: Polyvinyl alcohol, water for injection;

[0046] More preferably, the contents of the components in the polymer solution are:

[0047] Combination 1: Dextran 70 (30%-50%), water for injection (the balance);

[0048] Combination 2: Polyvinyl alcohol (10%-30%), PVP-K17 (10%-30%), water for injection (the balance);

[0049] Combination 3: Polyvinyl alcohol (10%-20%), sucrose (10%-20%), water for injection (the balance);

[0050] Combination 4: Polyvinyl alcohol (20%-40%), water for injection (the balance).

[0051] Even more preferably, the contents of the components in the polymer solution are:

[0052] Combination 1: Dextran 70 (40%), water for injection (the balance);

[0053] Combination 2: Polyvinyl alcohol (20%), PVP-K17 (20%), water for injection (the balance);

[0054] Composition III: Polyvinyl alcohol (18%), sucrose (18%), water for injection (the balance).

[0055] Composition IV: Polyvinyl alcohol (30%), water for injection (the balance).

[0056] Specifically, the gasket described in step (3) is a TPU gasket.

[0057] On the other hand, the present invention provides a zolmitriptan soluble microneedle patch, which is prepared by the above preparation method. The zolmitriptan soluble microneedle patch includes 1 segment of active ingredient solution and 2 segments of soluble microneedle skeleton solution.

[0058] Specifically, the component contents of the 1 segment of active ingredient solution are as follows: zolmitriptan 30%-45%, organic acid 8%-16%, polyvinyl alcohol 0.5%-3.0%.

[0059] Preferably, the organic acid includes one or more of tartaric acid, glacial acetic acid, succinic acid, and citric acid.

[0060] Specifically, the 2 segments of soluble microneedle skeleton solution are polymer solutions.

[0061] More specifically, the polymer solution includes at least two of dextran 70, polyvinyl alcohol, PVP-K17, sucrose, and water for injection.

[0062] Preferably, the polymer solution includes, but is not limited to, the following combinations:

[0063] Composition I: Dextran 70, water for injection;

[0064] Composition II: Polyvinyl alcohol, PVP-K17, water for injection;

[0065] Composition III: Polyvinyl alcohol, sucrose, water for injection;

[0066] Composition IV: Polyvinyl alcohol, water for injection;

[0067] More preferably, the component contents in the polymer solution are as follows:

[0068] Composition I: Dextran 70 (30%-50%), water for injection (the balance);

[0069] Composition II: Polyvinyl alcohol (10%-30%), PVP-K17 (10%-30%), water for injection (the balance);

[0070] Composition III: Polyvinyl alcohol (10%-20%), sucrose (10%-20%), water for injection (the balance);

[0071] Combination Four: Polyvinyl Alcohol (20%-40%), Water for Injection (the balance).

[0072] More preferably, the contents of the components in the polymer solution are as follows:

[0073] Combination One: Dextran 70 (40%), Water for Injection (the balance);

[0074] Combination Two: Polyvinyl Alcohol (20%), PVP-K17 (20%), Water for Injection (the balance);

[0075] Combination Three: Polyvinyl Alcohol (18%), Sucrose (18%), Water for Injection (the balance);

[0076] Combination Four: Polyvinyl Alcohol (30%), Water for Injection (the balance).

[0077] The beneficial effects of the present invention are as follows:

[0078] (1) The preparation process of the microneedle patch provided by the present invention can prepare soluble microneedles with bases uniformly connected or bases independent of each other.

[0079] (2) In the preparation process of the microneedle patch provided by the present invention, during the drying process, the drying time of the microneedles at the outer peripheral position of the TPU gasket and the microneedles at the central position of the TPU gasket can tend to be the same, avoiding the situation that the microneedles at the outer peripheral position of the TPU gasket are over-dried and the needles are broken after demolding due to uneven drying, and the qualified rate reaches more than 95%.

[0080] (3) The preparation process of the microneedle patch can make the connection between the 1-section microneedle solution containing the active ingredient and the 2-section soluble microneedle skeleton solution closer, avoiding the formation of bubbles due to uneven overall drying of the solution, and the qualified rate reaches more than 95%. Description of the Drawings

[0081] Figure 1 Microneedle patch diagrams prepared for Comparative Examples 1-2.

[0082] Figure 2 Microneedle patch diagram prepared for Comparative Example 3.

[0083] Figure 3 Microneedle patch diagram prepared for Comparative Example 4.

[0084] Figure 4 Microneedle patch diagrams prepared for Comparative Examples 5-6.

[0085] Figure 5 Microneedle patch diagram prepared for Comparative Example 7.

[0086] Figure 6Micro-needle patch base diagrams prepared in Examples 1-14.

[0087] Figure 7 Micro-needle patches prepared in Examples 1-14. Detailed implementation manners

[0088] The present invention will be described below in conjunction with specific embodiments. The following embodiments are not used to limit the present invention, but are only used to illustrate the present invention, so that the technical solutions of the present invention can be more easily understood and grasped. The experimental methods described in the following embodiments are all conventional methods unless otherwise specified; the reagents and materials can be obtained from commercial channels unless otherwise specified.

[0089] Examples 1-14

[0090] The formulations of Examples 1-14 are shown in Table 1:

[0091] Table 1 Examples 1-14

[0092]

[0093]

[0094] Note: In Examples 1-7, 9, 11, 13, and 14, an ideal semi-curing effect can be achieved under the conditions of the first curing. In Examples 8, 10, and 12, the humidity of the first semi-curing is higher than that of Examples 7, 9, and 11, and it is difficult to directly reach the ideal semi-curing state. Therefore, short-time secondary semi-curing is required again.

[0095] Comparative Examples 1-11

[0096] The formulations of Comparative Examples 1-11 are shown in Table 2:

[0097] Table 2 Comparative Examples 1-11

[0098]

[0099]

[0100] The preparation methods of Examples 1-14 and Comparative Examples 1-11 are as follows:

[0101] 1. Inject the solution in section 1 into the mold, fill it at 25°C and 90% RH for 5-20 minutes;

[0102] 2. Inject two segments of soluble polymer solution into the mold so that the two segments of soluble polymer solution can completely fill the remaining needle cavity. Fill at 25°C and 90% RH for 30 - 180 minutes to obtain a mold filled with one segment of solution and two segments of soluble polymer solution. The mass of the raised droplets formed by injecting the two - segment solution is 150 - 350 nanoliters per drop, and the spacing between the raised droplets is 250 - 300 micrometers.

[0103] 3. Conduct the first uniform drying treatment to make the outside of the raised droplets semi - dry, presenting a gel - like state without fluidity and with a certain deformation ability. If the raised droplets still have fluidity after the first uniform drying, conduct the second drying treatment to make the outside of the raised droplets semi - dry, presenting a gel - like state without fluidity and with a certain deformation ability.

[0104] 4. Completely cover the TPU gasket above the droplets, and use a force of 1 - 5 N per square centimeter to vertically press the TPU from top to bottom. The raised droplets are all pressed into a state where each droplet is evenly connected, or all are pressed into an independent circular plane and are not connected to the surrounding droplets.

[0105] 5. Place the mold in an environment with a humidity of 10% - 90% and a temperature of 20°C - 30°C for drying for 15 - 72 hours. Use tools to separate the TPU from the mold, and the microneedles adhere to the TPU simultaneously.

[0106] The yield rates of Examples 1 - 14 and Comparative Examples 1 - 11 are shown in Table 3.

[0107] Table 3 Yield rates of Examples 1 - 14 and Comparative Examples 1 - 11

[0108]

[0109]

[0110] The experimental results show that:

[0111] In Comparative Example 1, due to the too - low humidity during the first uniform drying treatment, the overall drying of the microneedle solution was too fast, over - dried, unable to be flattened, and air bubbles and notches appeared on the needle body. In Comparative Example 2, due to the too - low humidity and too - short treatment time during the first uniform drying treatment, the drying was excessive, and it did not have adhesiveness when attaching the gasket and could not fit with the TPU. The microneedles prepared in Comparative Examples 1 - 2 are as Figure 1 shown. The solution raised on the horizontal plane of the mold was over - dried, resulting in the inability to flatten the raised solution when attaching the gasket, affecting the attachment of the microneedles to the gasket. At the same time, the mechanical strength of the microneedles with an uneven base will also be affected. The base is uneven, and the microneedles are prone to tipping during attachment.

[0112] In Comparative Example 3, if the second uniform drying treatment is too high, it is easy to cause individual micro - needle notches and bubbles, which affect the formability of the micro - needles, and the yield of micro - needle preparation is low. As Figure 2 shown.

[0113] The micro - needles prepared in Comparative Example 4 are as Figure 3 shown. Since the first uniform drying time is short, the moisture in the micro - needles cannot be evenly volatilized and dried. When drying at low humidity for a short time during the second uniform drying, the overall drying of the micro - needles is uneven. The solution on the raised part of the mold horizontal plane is semi - cured while the solution in the needle cavity is still in a relatively wet state. When the micro - needles are dried as a whole after applying the gasket, the solution in the needle cavity is likely to seep out and spread on the mold surface, easily forming air bubbles and notches at the micro - needle base, which affect the formability of the micro - needles.

[0114] The solutions of Comparative Example 5 and Comparative Example 6 are relatively dilute. When applying the gasket, they will spread into a sheet, easily causing air bubbles and notches at the micro - needle base. The micro - needles prepared in Comparative Example 5 and Comparative Example 6 are as Figure 4 shown.

[0115] In Comparative Example 7, the yield of micro - needle preparation is low. Since the humidity during the first uniform drying is high, the moisture in the micro - needles cannot be evenly volatilized and dried. When drying at low humidity for a short time during the second uniform drying, the overall drying of the micro - needles is uneven. The solution on the raised part of the mold horizontal plane is semi - cured while the solution in the needle cavity is still in a relatively wet state. When the micro - needles are dried as a whole after applying the gasket, the solution in the needle cavity is likely to seep out and spread on the mold surface, easily forming air bubbles and notches at the micro - needle base, which affect the formability of the micro - needles. See Figure 5 .

[0116] In Comparative Example 9, the proportion of raw and auxiliary materials is too large, the viscosity of the prepared solution is too high, and the solution is easy to dry during micro - needle preparation, and the process is unstable, affecting the preparation efficiency. In Comparative Example 10, too much PVA will cause the solution viscosity to be too high, increasing the difficulty of the micro - needle preparation process. At the same time, it will increase the drying time of the micro - needles. If the solution in the first stage is difficult to dry, when the micro - needles are dried as a whole, the solution in the second stage will be over - dried, and it is easy to cause broken needles during demolding, affecting the yield of micro - needle preparation. The solution in the first stage in Comparative Example 11 has strong hygroscopicity. After micro - needle preparation, the solution absorbs moisture in the air and is prone to melting, thus affecting the preparation efficiency of the micro - needles.

[0117] Examples 1 - 14 are all normally formed, indicating that the preparation method of the soluble micro - needle patch provided by the present application can prepare micro - needles for different soluble micro - needle solutions, realizing that the bases are evenly connected or all independent of each other, the drying times of the outer - ring micro - needles and the inner - ring micro - needles tend to be the same (see Figure 6 ), a uniform semi - cured soluble micro - needle patch without air bubbles and without broken needles after demolding (see Figure 7 ).

[0118] The above detailed description is a specific description of one of the feasible embodiments of the present invention, and this embodiment is not intended to limit the patent scope of the present invention. It should be noted that all equivalent implementations or changes made without departing from the present invention should be included within the scope of the technical solution of the present invention. Therefore, the protection scope of the present invention shall be subject to the appended claims.

Claims

1. A preparation method of a microneedle patch, characterized in that, The preparation method comprises the following steps: (1) Inject a section of active ingredient solution into a mold; (2) Inject a second section of soluble microneedle skeleton solution into the mold, such that the second section of solution bulges from the surface of the mold to form a bulging droplet; (3) Perform a uniform drying treatment on the mold injected with the first section of active ingredient solution and the second section of soluble microneedle skeleton solution; the uniform drying treatment includes a first uniform drying treatment or a first uniform drying treatment and a second uniform drying treatment, such that the bulging droplet becomes a viscous colloidal bulge; (4) Press a gasket onto the colloidal bulge described in step (3), dry, and demold to obtain a microneedle patch.

2. The preparation method according to claim 1, characterized in that, For the first uniform drying treatment described in step (3), the temperature is 20 - 30 °C, the humidity is 80% - 95%, and the treatment time is 6 - 20 h.

3. The preparation method according to claim 1, characterized in that, For the second uniform drying treatment described in step (3), the temperature is 20 - 30 °C, the humidity is 30 - 70%, and the treatment time is 1 - 5 min.

4. The preparation method according to claim 1, characterized in that, For the drying described in step (4), the humidity is 10% - 90%; the time is 15 - 72 h; the temperature is 20 - 30 °C.

5. The preparation method according to claim 1, characterized in that, The mass of the bulging droplet described in step (2) is 150 - 350 nanoliters per droplet; the distance between adjacent bulging droplets is 250 - 300 micrometers.

6. The preparation method according to claim 1, characterized in that, The second section of soluble microneedle skeleton solution described in step (2) is a polymer solution.

7. The preparation method according to claim 1, characterized in that, The gasket described in step (4) is a TPU gasket.

8. A sumatriptan soluble microneedle patch, characterized in that, The sumatriptan soluble microneedle patch is prepared by the preparation method according to any one of claims 1 - 7, and comprises a first section of active ingredient solution and a second section of soluble microneedle skeleton solution.

9. The sumatriptan soluble microneedle patch according to claim 8, characterized in that, The first section of active ingredient solution comprises: 30% - 45% sumatriptan, 8% - 16% organic acid, 0.5% - 3.0% polyvinyl alcohol.

10. The sumatriptan soluble microneedle patch according to claim 9, wherein The organic acid includes one or more of tartaric acid, glacial acetic acid, succinic acid, and citric acid.

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