Preparation method of water-guided mold filling microneedle

Abstract

The invention relates to the technical field of medical instruments, and discloses a preparation method of a water-guided mold filling microneedle, which mainly comprises the following two steps: firstly, filling pure water into a microneedle hole through vacuumizing and removing excessive water, and secondly, pouring a pre-prepared polymer solution or flowable gel into a mold and drying in a dryer. The preparation method provided by the invention solves the problem that a vacuum mold filling method cannot be suitable for a high-viscosity solution or flowable gel in the preparation process of the microneedle patch, and is very suitable for large-scale microneedle production.

Description

Technical Field

[0001] This invention patent relates to the field of medical device technology, and in particular to a method for preparing a water-guided filling microneedle. Background Technology

[0002] Microneedling technology, as a unique, painless, and minimally invasive next-generation percutaneous delivery technology, has become a focus of attention, offering an opportunity to overcome the shortcomings of subcutaneous injections and transdermal patches (European Journal of Medicinal Chemistry, 2024, 278, 116793). Microneedle patches mainly consist of two parts: a base and micron-sized needles (100-3000 μm) located on the base. They can penetrate the natural barrier of the stratum corneum and have been applied to the delivery of drugs, antibiotics, vitamins, antibodies, proteins, vaccines, nucleic acids, and cells. Currently, microneedles are mainly prepared using centrifugal molding and vacuum molding methods. Vacuum molding is more efficient and easier to scale up; however, it cannot effectively fill high-concentration polymer solutions or flowable gels into the mold, generating numerous air bubbles during the molding process, severely affecting the morphology of the microneedles (Journal of Controlled Release, 2018, 288, 173-188). Therefore, further improvements to the vacuum method are needed. Summary of the Invention

[0003] This invention provides a method for preparing water-guided filling microneedles, which solves the problem that the vacuum method is not applicable to the preparation of microneedles in high-concentration polymer solutions or flowable gels.

[0004] To solve the above problems, the present invention is implemented through the following technical solution:

[0005] A method for preparing water-guided filling microneedles includes the following steps:

[0006] S1: Use a photopolymer 3D printer to manufacture 16-64 microneedle resin molds continuously. The height of the microneedles is 0.8-1.5mm and the bottom diameter is 0.2-0.8mm.

[0007] S2: Take 10-40g of polyvinyl alcohol, add water, and then dissolve it to prepare a polymer solution;

[0008] S3: Take 10-40g of phenylboronic acid modified polylysine, add water, and then sonicate to dissolve it. Mix the polyvinyl alcohol solution and the phenylboronic acid modified polylysine solution to form a flowable gel.

[0009] S4: Fill the microneedle mold with pure water, evacuate to -10 to -15 psi and hold for a few seconds to allow water to enter the needle hole, then discard any excess water that does not enter the needle hole.

[0010] S5: Pour 30-50g of the pre-prepared polymer solution or flowable gel into the microneedle mold, let it stand to level out and remove air bubbles;

[0011] S6: Dry in an oven or desiccator at a temperature below 50°C for 48-96 hours to obtain water-guided filling microneedles.

[0012] As a preferred technical solution, the amount of water added in step S2 is 100 mL.

[0013] As a preferred technical solution, the dissolution temperature in step S2 is 100℃ and the dissolution time is 8h.

[0014] As a preferred technical solution, the concentrations of the polymer solution in step S2 and the flowable gel in step S3 are 100-400 mg / mL.

[0015] As a preferred technical solution, the amount of water added in step S3 is 100 mL, and the ultrasonic time is 30 min.

[0016] As a preferred technical solution, in step S3, the polyvinyl alcohol solution and the phenylboronic acid modified polylysine solution are blended in equal volumes.

[0017] As a preferred technical solution, the number of seconds in step S4 is 60s.

[0018] As a preferred technical solution, the microneedle mold in steps S4 and S5 is made of resin or PDMS material.

[0019] As a preferred technical solution, the settling time in step S5 is 12 hours.

[0020] As a preferred technical solution, step S5 does not require vacuuming or centrifugation.

[0021] Compared with the prior art, the present invention has the following technical advantages:

[0022] (1) This invention utilizes the principle of water diffusion from bottom to top during the drying process of microneedles to gradually guide the polymer chains outside the microneedle pores into the pores to form microneedles. This invention expands the polymer solution concentration for vacuum preparation of microneedles, which is beneficial for the large-scale preparation of microneedles.

[0023] (2) The present invention can avoid the problem of residual monomers and initiators in the microneedles during the polymerization preparation process, and at the same time avoid the problem of drug loss caused by the centrifugation preparation process.

[0024] (3) This invention only requires filling the mold with pure water, which can avoid the bubbles generated in the polymer solution during the vacuum method of microneedle preparation, improve the morphological integrity of the microneedles, and at the same time reduce the time required for filling the mold and improve the microneedle preparation efficiency. Attached Figure Description

[0025] 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 these drawings without creative effort.

[0026] Figure 1 This is a schematic diagram of the preparation process of the present invention;

[0027] Figure 2 This is a diagram of a resin mold for 3D printing that can continuously manufacture 16 microneedles according to the present invention.

[0028] Figure 3 This is a photograph of the microneedles prepared by the method of this invention;

[0029] Figure 4 This is a comparison diagram of microneedles prepared by the method of this invention and microneedles prepared by the traditional vacuum method;

[0030] Figure 5 Here is a picture of the microneedles prepared using Example 3;

[0031] Figure 6 The image shows a physical picture of the microneedles prepared using Example 4. Detailed Implementation

[0032] The present invention will now be described in more detail with reference to the accompanying drawings and embodiments. However, the present invention is not limited thereto. For those skilled in the art, several improvements and modifications can be made without departing from the principles of the present invention, and these improvements and modifications are also considered to be within the scope of protection of the present invention. Contents not described in detail in this specification are prior art known to those skilled in the art.

[0033] In this invention, a method for preparing a water-guided filling microneedle includes the following steps:

[0034] S1: Use a photopolymer 3D printer to manufacture 16-64 microneedle resin molds continuously. The height of the microneedles is 0.8-1.5mm and the bottom diameter is 0.2-0.8mm.

[0035] S2: Take 10-40g of polyvinyl alcohol, add water, and then dissolve it to prepare a polymer solution;

[0036] S3: Take 10-40g of phenylboronic acid modified polylysine, add water, and then sonicate to dissolve it. Mix the polyvinyl alcohol solution and the phenylboronic acid modified polylysine solution to form a flowable gel.

[0037] S4: Fill the microneedle mold with pure water, evacuate to -10 to -15 psi and hold for a few seconds to allow water to enter the needle hole, then discard any excess water that does not enter the needle hole.

[0038] S5: Pour 30-50g of the pre-prepared polymer solution or flowable gel into the microneedle mold, let it stand to level out and remove air bubbles;

[0039] S6: Dry in an oven or desiccator at a temperature below 50°C for 48-96 hours to obtain water-guided filling microneedles.

[0040] To make the present invention more fully disclosed, more specific embodiments are described below.

[0041] Example 1

[0042] A method for preparing water-guided filling microneedles, as follows: Figure 1 As shown, the specific preparation method is as follows: A resin mold capable of continuously manufacturing 16 microneedles is printed using a 3D printer. The height and bottom diameter of the microneedles are 1.2 × 0.2 mm. Figure 2 Take 10g of polyvinyl alcohol, add 100mL of water, and dissolve at 100℃ for 8h to prepare a polymer solution. Fill the resin mold with pure water, evacuate to -15psi and hold for 60s to allow water to enter the needle holes, then discard the excess water that does not enter the needle holes. Pour 30g of polyvinyl alcohol solution into the microneedle mold, let it stand for 12h to level and remove air bubbles. Place it in a desiccator and dry at room temperature for 48h to obtain the desired product. Figure 3 The microneedles shown. Figure 3 This demonstrates that a method for preparing water-guided filling microneedles can produce multiple microneedles at once, all of which have regular morphologies.

[0043] Example 2

[0044] A method for preparing water-guided filling microneedles, as follows: Figure 1 As shown, the specific preparation method is as follows: A resin mold capable of continuously producing 16 microneedles is printed using a 3D printer. The height of the microneedles is 1.2 mm, and the bottom diameter is 0.2, 0.3, 0.4, 0.6, and 0.8 mm. 20 g of polyvinyl alcohol is added to 100 mL of water and dissolved at 100 °C for 8 hours to prepare a polymer solution. Pure water is used to fill the resin mold, and a vacuum is drawn to -15 psi and held for 60 seconds to allow water to enter the needle holes. Excess water that does not enter the needle holes is discarded. 30 g of polyvinyl alcohol solution is poured into the microneedle mold and allowed to stand for 12 hours to level and remove air bubbles. The mold is then placed in a desiccator and dried at room temperature for 48 hours to obtain the desired microneedle solution. Figure 4 The microneedles shown. Figure 4 This indicates that a method for preparing water-guided filling microneedles is applicable to the preparation of microneedles of different sizes, and the morphology of the prepared microneedles is superior to that of the traditional vacuum method.

[0045] Example 3

[0046] A method for preparing water-guided filling microneedles, as follows: Figure 1 As shown, the specific preparation method is as follows: Take 40g of polyvinyl alcohol, add 100mL of water, and dissolve at 100℃ for 8h to prepare a polymer solution. Fill the PDMS mold with pure water, evacuate to -10psi and hold for 60s to allow water to enter the needle holes, and discard the excess water that does not enter the needle holes. Pour 60g of polyvinyl alcohol solution into the microneedle mold, let it stand for 12h to level and remove air bubbles. Place it in a desiccator and dry at room temperature for 96h to obtain the desired product. Figure 5 The microneedles shown. Figure 5 This indicates that a method for preparing water-guided filling microneedles can also be applied to PDMS microneedle molds, and that microneedles can be successfully prepared even when the concentration of the polymer solution reaches 400 mg / mL.

[0047] Example 4

[0048] A method for preparing water-guided filling microneedles, as follows: Figure 1 As shown, the specific preparation method is as follows: A resin mold capable of continuously manufacturing 16 microneedles is printed using a 3D printer. The height of the microneedles is 1.2 mm, and the bottom diameter is 0.2, 0.3, 0.4, 0.6, and 0.8 mm. 10 g of polyvinyl alcohol is added to 100 mL of water and dissolved at 100 °C for 8 hours to prepare a polymer solution. 10 g of phenylboronic acid-modified polylysine is added to 100 mL of water and dissolved by sonication for 30 minutes. The polyvinyl alcohol solution and the phenylboronic acid-modified polylysine solution are mixed in equal volumes to form a flowable gel. Pure water is filled into the PDMS mold, and a vacuum is drawn to -10 psi and maintained for 60 seconds to allow water to enter the needle holes. Excess water that does not enter the needle holes is discarded. 30 g of the flowable gel is poured into the microneedle mold and allowed to stand for 12 hours to level and remove air bubbles. The mold is then placed in a desiccator and dried at room temperature for 48 hours. Figure 6 As shown. Figure 6 This indicates that a method for preparing water-guided filling microneedles can also be applied to the preparation of microneedles from flowable hydrogels, and the prepared microneedles have regular morphology.

Claims

1. A method for preparing water-guided filling microneedles, characterized in that, Includes the following steps: S1: Use a photopolymer 3D printer to manufacture 16-64 microneedle resin molds continuously. The height of the microneedles is 0.8-1.5mm and the bottom diameter is 0.2-0.8mm. S2: Take 10-40g of polyvinyl alcohol, add water, and then dissolve it to prepare a polymer solution; S3: Take 10-40g of phenylboronic acid modified polylysine, add water, and then sonicate to dissolve it. Mix the polyvinyl alcohol solution and the phenylboronic acid modified polylysine solution to form a flowable gel. S4: Fill the microneedle mold with pure water, evacuate to -10 to -15 psi and hold for a few seconds to allow water to enter the needle hole, then discard any excess water that does not enter the needle hole. S5: Pour 30-50g of the pre-prepared polymer solution or flowable gel into the microneedle mold, let it stand to level out and remove air bubbles; S6: Dry in an oven or desiccator at a temperature below 50°C for 48-96 hours to obtain water-guided filling microneedles.

2. The method for preparing a water-guided filling microneedle according to claim 1, characterized in that, The amount of water added in step S2 is 100 mL.

3. The method for preparing a water-guided filling microneedle according to claim 1, characterized in that, The dissolution temperature in step S2 is 100℃, and the dissolution time is 8 hours.

4. The method for preparing a water-guided filling microneedle according to claim 1, characterized in that, The concentrations of the polymer solution in step S2 and the flowable gel in step S3 are 100-400 mg / mL.

5. The method for preparing a water-guided filling microneedle according to claim 1, characterized in that, In step S3, 100 mL of water is added, and the sonication time is 30 min.

6. The method for preparing a water-guided filling microneedle according to claim 1, characterized in that, In step S3, the polyvinyl alcohol solution and the phenylboronic acid-modified polylysine solution are blended in equal volumes.

7. The method for preparing a water-guided filling microneedle according to claim 1, characterized in that, In step S4, the number of seconds is 60 seconds.

8. The method for preparing a water-guided filling microneedle according to claim 1, characterized in that, The microneedle molds mentioned in steps S4 and S5 are made of resin or PDMS material.

9. The method for preparing a water-guided filling microneedle according to claim 1, characterized in that, The settling time in step S5 is 12 hours.

10. The method for preparing a water-guided filling microneedle according to claim 1, characterized in that, Step S5 does not require further vacuuming or centrifugation.

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