Degradable microneedle patch for promoting regrowth of mandible and preparation method thereof

Abstract

The invention relates to the technical field of biomedical materials, in particular to a degradable microneedle patch for promoting regrowth of mandible and a preparation method thereof.The preparation method comprises the steps that a substrate solution is added into a microneedle array mold and subjected to centrifugal treatment, then the substrate solution in the mold is sucked, and the microneedle array mold is obtained; the substrate solution in each microneedle containing cavity in the mold is made to descend to a set position, then the mold is rotated by 65-80 degrees in the clockwise direction around the front-back direction at the reference position, and then the mold is rotated to be in the horizontal state after being dried; the substrate solution is added into a microneedle array mold and subjected to centrifugal treatment, then the substrate solution in the mold is sucked, the substrate solution in each microneedle containing cavity is made to descend to the set position, then the mold is rotated by 65-80 degrees in the anticlockwise direction around the front-back direction at the reference position, and then the mold is rotated to be in the horizontal state after being dried. The puncture capacity of the microneedle is ensured, and meanwhile, the drug delivery effectiveness is improved.

Description

Technical Field

[0001] This invention relates to the field of biomedical materials technology, and in particular to a biodegradable microneedle patch for promoting mandibular regeneration and its preparation method. Background Technology

[0002] Adult patients with micrognathia or asymmetric jaw caused by mandibular hypoplasia can generally achieve an ideal and coordinated positional relationship between the upper and lower jaws through orthognathic surgery. However, orthognathic surgery has unavoidable surgical and anesthetic risks, and sometimes the maxillofacial neuromuscular system cannot adapt well to the elongated jaw and its positional changes, resulting in less than ideal improvement in function and aesthetics, unstable treatment results, and difficulty for patients to accept.

[0003] The mandibular condylar cartilage possesses both adaptive remodeling potential and intrinsic growth potential. Unlike the growth plates of long bones, which cease growth after development, the mandibular condyle has the potential for continuous growth regardless of age. Furthermore, the condylar cartilage differs from the growth plate in that it is not a linear columnar tissue, meaning it has the capacity for multidirectional growth. This is advantageous for the condyle, allowing the mandibular arch to develop to its optimal anatomical position and facilitating adaptation to dental and skeletal changes that may occur during growth.

[0004] Insulin-like growth factor-1 (IGF-1) is a polypeptide composed of 70 amino acid residues that can stimulate cell proliferation and induce cell differentiation. Studies have shown that multiple local injections of insulin-like growth factor-1 (IGF-1) into the mandibular condyle can promote the formation of endochondral ossification at the injection site. In other words, IGF-1 can promote the proliferation of condylar articular cartilage and mediate endochondral ossification, which is beneficial for the treatment of mandibular hypoplasia. However, IGF-1 is usually administered via multiple local injections, which require professional medical personnel to perform. This can cause pain, injection damage, or scarring, thus reducing patient compliance.

[0005] Chinese patent application CN118593889A discloses a biodegradable microneedle patch for promoting mandibular bone regeneration, enabling painless and minimally invasive IGF-1 microneedle administration, thus improving patient compliance. In this biodegradable microneedle patch, the microneedles are designed with a "sandwich" structure, consisting of a support portion, a drug-loaded portion, and a tip portion connected sequentially. By loading the drug into the core layer of the microneedle, puncture is performed by the unloaded tip portion, and support is provided by the unloaded support portion, making the overall structure of the microneedle more stable. A water-soluble, biocompatible polymer material with high mechanical strength can be used for the tip portion and support portion, thereby greatly improving the microneedle's ability to puncture the oral mucosa and ensuring more complete penetration. The drug loading into the core layer of the microneedle also ensures, to a certain extent, the delivery of the drug to the submucosal tissue of the oral cavity.

[0006] To achieve painless and minimally invasive microneedle drug delivery, the height of the microneedles on the aforementioned microneedle patches is generally 0.3–0.8 mm, and the thickness of the oral mucosa is generally 0.2–0.5 mm. In these microneedle patches, to ensure the overall structural strength and stability of the microneedles, the ratio of the tip height to the microneedle height is 1:(2–3), meaning the tip is thicker. This causes the drug-carrying portion to be positioned relatively low within the microneedle. When the patient's oral mucosa is thick, after the microneedle penetrates the oral mucosa, less of the drug-carrying portion is exposed to the submucosal tissue, or even none at all. This hinders drug delivery to the oral submucosal tissue and reduces the effectiveness of drug delivery.

[0007] Therefore, there is an urgent need to provide an improved biodegradable microneedle patch for promoting mandibular regeneration and its preparation method. Summary of the Invention

[0008] (a) Technical problems to be solved

[0009] In view of the above-mentioned shortcomings and deficiencies of the prior art, the present invention provides a biodegradable microneedle patch for promoting mandibular regeneration and its preparation method, which ensures microneedle puncture capability while improving drug delivery effectiveness.

[0010] (II) Technical Solution

[0011] To achieve the above objectives, the main technical solutions adopted by the present invention include:

[0012] In a first aspect, the present invention provides a method for preparing a biodegradable microneedle patch for promoting mandibular bone regeneration, comprising the following steps:

[0013] S1. The substrate material and sophorolipid are dissolved in an organic solvent and degassed to obtain a substrate solution; the drug-loaded substrate material and IGF-1 are dissolved in water and degassed to obtain a drug-loaded solution.

[0014] S2. Add the base solution to the microneedle array mold and centrifuge it. Then, remove the base solution from the mold so that the base solution in each microneedle cavity in the mold drops to the set position. Then, rotate the mold 65° to 80° clockwise around the front and back direction at the reference position. At this time, the tip of the microneedle cavity is lower than the opening end of the microneedle cavity. The base solution is laid in the microneedle cavity and close to the opening of the microneedle cavity. Then, dry the mold and rotate the mold to a horizontal state.

[0015] S3. Add the base solution to the microneedle array mold and centrifuge it. Then, remove the base solution from the mold so that the base solution in each microneedle cavity drops to the set position. Then, rotate the mold counterclockwise by 65° to 80° around the front-back direction at the reference position. At this time, the tip of the microneedle cavity is lower than the opening end of the microneedle cavity. The base solution is laid in the microneedle cavity and close to the opening of the microneedle cavity. Then, dry the mold and rotate the mold to a horizontal state.

[0016] S4. Add the drug-loaded solution to the microneedle array mold and centrifuge it. Then, draw up the drug-loaded solution to be level with the opening of each microneedle cavity, and then dry the mold.

[0017] S5. Add the base solution to the microneedle array mold and centrifuge it. Then dry the mold. Repeat step S5 until the microneedle array is formed.

[0018] S6. Adhere the waterproof backing to the microneedle array to obtain a microneedle patch.

[0019] Optionally, in S1, the microneedle drug-carrying matrix material and the PLGA sustained-release microspheres encapsulated with IGF-1 are dissolved in water and degassed to obtain a drug-carrying solution.

[0020] Optionally, S2 further includes: repeating S2, wherein in each repetition of S2, the angle of rotation of the mold is 1 to 3 degrees smaller than the angle of rotation of the mold in the previous repetition of S2; S3 further includes: repeating S3, wherein in each repetition of S3, the angle of rotation of the mold is 1 to 3 degrees smaller than the angle of rotation of the mold in the previous repetition of S3.

[0021] Optionally, between S3 and S4, the following is also included:

[0022] S31. Add the base solution to the microneedle array mold and centrifuge it. Then, remove the base solution from the mold so that the base solution in each microneedle cavity drops to the set position. Next, rotate the mold 180° up and down at the reference position, and then rotate the mold 65° to 80° clockwise in the front and back direction. At this time, the tip of the microneedle cavity is lower than the opening end of the microneedle cavity. The base solution is laid in the microneedle cavity and close to the opening of the microneedle cavity. Then, dry the mold. After drying, rotate the mold to a horizontal state.

[0023] S32. Add the base solution to the microneedle array mold and centrifuge it. Then, remove the base solution from the mold so that the base solution in each microneedle cavity drops to the set position. Next, rotate the mold 180° up and down in the reference position, and then rotate the mold 65° to 80° counterclockwise in the front and back direction. At this time, the tip of the microneedle cavity is lower than the opening end of the microneedle cavity. The base solution is laid in the microneedle cavity and close to the opening of the microneedle cavity. Then, dry the mold. After drying, rotate the mold to a horizontal state.

[0024] Optionally, S31 further includes: repeating S31, wherein in each repetition of S31, the angle of rotation of the mold is 1 to 3 degrees smaller than the angle of rotation of the mold in the previous repetition of S31; S32 further includes: repeating S32, wherein in each repetition of S32, the angle of rotation of the mold is 1 to 3 degrees smaller than the angle of rotation of the mold in the previous repetition of S32.

[0025] Optionally, a liquid aspiration needle is used to aspirate the solution inside the mold. The liquid aspiration needle includes an aspiration chamber that can be converted to negative pressure and micron needles arranged in an array perpendicular to the aspiration chamber on one side. The micron needles are connected to the aspiration chamber. Aspirating the solution inside the mold using the liquid aspiration needle includes: placing the liquid aspiration needle on the microneedle mold, inserting the microneedles into the microneedle cavity one by one, converting the aspiration chamber to negative pressure, aspirating the base solution down to the free end of the microneedle, removing the liquid aspiration needle, and completing the aspiration.

[0026] Optionally, if the microneedles are in the shape of a square pyramid, the microneedle array mold is in the reference position, and the two diagonally arranged edges in the microneedle cavity are arranged in the left-right direction.

[0027] Secondly, the present invention provides a biodegradable microneedle patch for promoting mandibular regeneration and growth, wherein the microneedle patch is prepared by the above-described method for preparing a biodegradable microneedle patch for promoting mandibular regeneration and growth.

[0028] Optionally, the microneedle patch includes a microneedle array and a waterproof backing. The microneedle array consists of a substrate and microneedles arranged perpendicularly to the substrate on a first side of the substrate. The microneedles are conical and have a support portion, a drug-carrying portion, and a tip portion connected sequentially in a direction away from the substrate. The support portion is connected to the substrate, and the waterproof backing covers a second side of the substrate and is bonded to the substrate. The ratio of the height of the tip portion to the height of the microneedle is 1:5 to 7, the ratio of the height of the drug-carrying portion to the height of the microneedle is 1:1.2 to 2, and the ratio of the height of the support portion to the height of the microneedle is 1:2 to 3.5.

[0029] (III) Beneficial Effects

[0030] The beneficial effects of this invention are:

[0031] The present invention provides a method for preparing a biodegradable microneedle patch for promoting mandibular regeneration. Through steps S2 and S3, a tip portion is prepared, and a connecting post connecting the tip portion and the support portion is prepared along the longitudinal edge of the microneedle cavity. Through step S4, a drug-loaded portion is prepared within the space enclosed by the tip portion, connecting post, and support portion. Through step S5, the support portion and base are prepared. In this prepared microneedle patch, the microneedles have a novel structure. The support portion, connecting post, and tip portion are interconnected to form a support frame for the microneedles, significantly improving the strength and stability of the microneedles. This support frame enhances the strength and stability of the microneedles while ensuring the microneedles' ability to puncture the oral mucosa, allowing for a smaller tip thickness (i.e., a smaller tip height). The internal space of the support frame is used to fill the drug-loaded portion. Due to the reduced tip thickness, the drug-loaded portion is positioned higher within the microneedles, improving drug delivery to the oral submucosal tissue and enhancing drug delivery effectiveness. Attached Figure Description

[0032] Figure 1 This is a schematic diagram of the structure of a microneedle array mold according to a specific embodiment of the present invention;

[0033] Figure 2 This is a schematic diagram of the structure of the rotated microneedle array mold according to a specific embodiment of the present invention;

[0034] Figure 3 This is a three-dimensional structural diagram of a microneedle patch according to a specific embodiment of the present invention;

[0035] Figure 4 This is a cross-sectional schematic diagram of a microneedle patch according to a specific embodiment of the present invention.

[0036] [Explanation of Labels in the Attached Image]

[0037] 1: Tip; 2: Drug-carrying part; 3: Support part; 4: Connecting post; 5: Base; 6: Waterproof backing; 7: Microneedle cavity. Detailed Implementation

[0038] To better explain and facilitate understanding of the present invention, a detailed description of the invention is provided below with reference to the accompanying drawings and specific embodiments. In this document, directional terms such as "upper," "lower," "left," "right," "front," and "rear" are used interchangeably. Figure 1 The orientation is used as a reference.

[0039] This invention provides a method for preparing a biodegradable microneedle patch for promoting mandibular bone regeneration. The microneedle patch includes a microneedle array and a waterproof backing 6. The microneedle array consists of a base 5 and microneedles distributed perpendicularly to the base 5 on a first side of the base 5. The microneedles are conical and have a support portion 3, a drug-loaded portion 2, and a tip portion 1 sequentially connected along a direction away from the base 5. The support portion 3 is connected to the base 5. The waterproof backing 6 covers a second side of the base 5 and is bonded to the base 5. The preparation method includes the following steps:

[0040] Step S1: Dissolve the substrate 5 matrix material and sophorolipid in an organic solvent, and perform degassing treatment to obtain the substrate 5 solution; dissolve the drug-loaded part 2 matrix material and IGF-1 in water, and perform degassing treatment to obtain the drug-loaded solution.

[0041] Step S2: Add the substrate 5 solution to the microneedle array mold (e.g., Figure 1 (As shown) and centrifuge, then aspirate the base 5 solution from the mold, ensuring that the base 5 solution in each microneedle cavity 7 of the mold descends to the set position. Next, rotate the mold 65°–80° clockwise around the reference position (e.g., ...). Figure 2 As shown), at this time, the tip of the microneedle cavity 7 is lower than the opening end of the microneedle cavity 7, the substrate 5 solution is laid on the microneedle cavity 7 and close to the opening of the microneedle cavity 7, and then the mold is dried. After drying, the mold is rotated to a horizontal state.

[0042] The microneedle mold includes an array of microneedle cavities 7 and a base cavity 5 that communicates with the open end of the microneedle cavity 7.

[0043] Step S3: Add the substrate 5 solution to the microneedle array mold and centrifuge it. Then, remove the substrate 5 solution from the mold so that the substrate 5 solution in each microneedle cavity 7 drops to the set position. Then, rotate the mold counterclockwise by 65° to 80° around the reference position. At this time, the tip of the microneedle cavity 7 is lower than the opening end of the microneedle cavity 7. The substrate 5 solution is laid on the microneedle cavity 7 and close to the opening of the microneedle cavity 7. Then, dry the mold. After drying, rotate the mold to a horizontal state.

[0044] Step S4: Add the drug-loaded solution to the microneedle array mold and centrifuge it. Then, draw up the drug-loaded solution from the mold until it is flush with the opening of each microneedle cavity 7. After that, dry the mold.

[0045] Step S5: Add the substrate 5 solution into the microneedle array mold and centrifuge it. Then dry the mold. Repeat step S5 until the microneedle array is formed. Demold to obtain the microneedle array.

[0046] Step S6: Adhere the waterproof backing 6 to the microneedle array to obtain a microneedle patch.

[0047] The present invention provides a method for preparing a biodegradable microneedle patch for promoting mandibular regeneration. Through steps S2 and S3, a tip 1 is prepared, and a connecting post 4 connecting the tip 1 and the support 3 is prepared along the longitudinal edge of the microneedle cavity 7. In step S4, a drug-loaded portion 2 is prepared within the space enclosed by the tip 1, connecting post 4, and support 3. In step S5, the support 3 and base 5 are prepared. In this prepared microneedle patch, the microneedle has a novel structure. The support 3, connecting post 4, and tip 1 are interconnected to form a support frame for the microneedle, greatly improving its strength and stability. This support frame enhances the strength and stability of the microneedle while ensuring its ability to puncture the oral mucosa, allowing for a smaller thickness (i.e., a smaller height) of the tip 1. The internal space of the support frame is used to fill the drug-loaded portion 2. Due to the reduced thickness of the tip 1, the drug-loaded portion 2 is positioned higher within the microneedle, improving drug delivery to the submucosal tissue and enhancing drug delivery effectiveness.

[0048] In step S1, sophorolipids are added during the preparation of the base 5 solution to increase the fluidity of the base 5 solution, making it easier to absorb the base 5 solution in subsequent steps.

[0049] Furthermore, in the substrate 5 solution, the concentration of the substrate 5 matrix material is 300–700 mg / mL, and the concentration of sophorolipid is 150–250 mg / L. This improves the fluidity of the substrate 5 solution while ensuring the mechanical strength of the tip 1, connecting column 4, and support 3 after the substrate 5 solution is dried and formed.

[0050] Preferably, in step S1, the substrate material of the microneedle drug-carrying portion 2 and the PLGA sustained-release microspheres encapsulated with IGF-1 are dissolved in water and subjected to degassing treatment to obtain a drug-carrying solution. This achieves sustained release of the drug IGF-1.

[0051] Furthermore, in the drug-loaded solution, the concentration of the matrix material of the microneedle drug-loaded part 2 is 100-250 mg / mL, and the concentration of PLGA (polylactic acid-glycolic acid copolymer) sustained-release microspheres encapsulating IGF-1 is 5-60 mg / L.

[0052] Specifically, the matrix material of the drug-carrying part 2 is one or a mixture of two or more of dextran, hyaluronic acid, polyvinyl alcohol and carboxymethyl cellulose, and the matrix material of the substrate 5 is polyvinylpyrrolidone.

[0053] Preferably, step S2 further includes: repeating step S2, wherein in each repetition of step S2, the angle of rotation of the mold is 1 to 3 degrees smaller than the angle of rotation of the mold in the previous repetition of step S2. In this way, step S2 is repeated multiple times to form a solid tip 1 and connecting post 4 by stacking the dried substrate 5 multiple times.

[0054] Preferably, step S3 further includes: repeating step S3, wherein in each repetition of step S3, the angle of rotation of the mold is 1 to 3 degrees smaller than the angle of rotation of the mold in the previous repetition of step S3. In this way, step S3 is repeated multiple times to form a solid tip 1 and connecting post 4 by stacking the dried substrate 5 multiple times.

[0055] Preferably, between step S3 and step S4, the following step is further included:

[0056] Step S31: Add the substrate 5 solution to the microneedle array mold and centrifuge it. Then, remove the substrate 5 solution from the mold so that the substrate 5 solution in each microneedle cavity 7 drops to the set position. Next, rotate the mold 180° around the vertical direction at the reference position, and then rotate the mold 65° to 80° clockwise around the front and back direction. At this time, the tip of the microneedle cavity 7 is lower than the opening end of the microneedle cavity 7. The substrate 5 solution is laid on the microneedle cavity 7 and close to the opening of the microneedle cavity 7. Then, dry the mold. After drying, rotate the mold to a horizontal state.

[0057] Step S32: Add the substrate 5 solution to the microneedle array mold and centrifuge it. Then, remove the substrate 5 solution from the mold so that the substrate 5 solution in each microneedle cavity 7 drops to the set position. Next, rotate the mold 180° around the vertical direction at the reference position, and then rotate the mold 65° to 80° counterclockwise around the front and back direction. At this time, the tip of the microneedle cavity 7 is lower than the opening end of the microneedle cavity 7. The substrate 5 solution is laid on the microneedle cavity 7 and close to the opening of the microneedle cavity 7. Then, dry the mold. After drying, rotate the mold to a horizontal state.

[0058] Thus, through steps S31 and S32, four evenly distributed connecting posts 4 connecting the tip 1 and the support 3 can be prepared along the longitudinal edge of the microneedle cavity 7, making the overall structure of the microneedle more stable and stronger.

[0059] Preferably, step S31 further includes: repeating step S31, wherein in each repetition of step S31, the angle of rotation of the mold is 1 to 3 degrees smaller than the angle of rotation of the mold in the previous repetition of step S31. In this way, step S31 is repeated multiple times to form a solid tip 1 and connecting post 4 by stacking the dried substrate 5 multiple times.

[0060] Preferably, step S32 further includes: repeating step S32, wherein in each repetition of step S32, the angle of rotation of the mold is 1 to 3 degrees smaller than the angle of rotation of the mold in the previous repetition of step S32. In this way, step S32 is repeated multiple times to form a solid tip 1 and connecting post 4 by stacking the dried substrate 5 multiple times.

[0061] Preferably, a liquid aspiration needle is used to aspirate the solution inside the mold. The liquid aspiration needle includes an aspiration chamber that can be converted to negative pressure and micron needles arranged in an array perpendicular to the aspiration chamber on one side. The micron needles are connected to the aspiration chamber. Aspirating the solution inside the mold using the liquid aspiration needle includes: placing the liquid aspiration needle on the microneedle mold, inserting the microneedles into the microneedle cavity 7 one by one, converting the aspiration chamber to negative pressure, aspirating the solution from the substrate 5 down to the free end of the microneedle, removing the liquid aspiration needle, and completing the aspiration.

[0062] Preferably, if the microneedles are in the shape of a square pyramid, the microneedle array mold is in the reference position, and the two diagonally arranged edges in the microneedle cavity 7 are arranged in the left-right direction. In this way, connecting pillars 4 can be formed along the direction of the edges of the microneedle cavity 7, making the structure of the microneedles more stable.

[0063] Furthermore, step S4 also includes: repeating step S4 until the thickness of the drug-loaded part 2 reaches the preset requirement.

[0064] Specifically, in the microneedle patch preparation method provided by the present invention, the centrifugation temperature is 1-4°C and the drying temperature does not exceed 30°C.

[0065] like Figure 3 and Figure 4 As shown, the present invention also provides a biodegradable microneedle patch for promoting mandibular bone regeneration, which is prepared by the above-described method. The microneedles in this patch have a stable structure, high strength, good oral mucosal puncture capability, and high drug delivery effectiveness.

[0066] Preferably, in the microneedle patch, the ratio of the height of the tip 1 to the height of the microneedle is 1:(5-7), the ratio of the height of the drug-loaded portion 2 to the height of the microneedle is 1:(1.2-2), and the ratio of the height of the support portion 3 to the height of the microneedle is 1:(2-3.5). Wherein, the height of the tip 1 is the distance from the tip of the microneedle to the highest point of the portion of the drug-loaded portion 2 exposed on the microneedle surface, the height of the drug-loaded portion 2 is the distance from the highest point to the lowest point of the drug-loaded portion 2, and the height of the support portion 3 is the distance from the highest point to the lowest point of the support portion 3.

[0067] Preferably, the ratio of the bottom side length of the microneedle to the height of the microneedle is 1:(2-3).

[0068] To better understand the above technical solutions, exemplary embodiments of the present invention are described in more detail below. Although exemplary embodiments of the present invention are shown in the accompanying drawings, it should be understood that the present invention can be implemented in various forms and should not be limited to the embodiments set forth herein. Rather, these embodiments are provided to enable a clearer and more thorough understanding of the present invention and to fully convey the scope of the invention to those skilled in the art.

[0069] Example 1

[0070] The process for preparing the microneedle patch in this embodiment is as follows:

[0071] Step S1: Dissolve polyvinylpyrrolidone and sophorolipid in anhydrous ethanol, let stand to remove bubbles to obtain base 5 solution. In base 5 solution, the concentration of polyvinylpyrrolidone is 300 mg / mL and the concentration of sophorolipid is 150 mg / L. Dissolve hyaluronic acid and PLGA sustained-release microspheres encapsulated with IGF-1 in water, let stand to remove bubbles to obtain drug-loaded solution. In drug-loaded solution, the concentration of hyaluronic acid is 250 mg / mL and the concentration of PLGA sustained-release microspheres encapsulated with IGF-1 is 5 mg / L.

[0072] Step S2: Add the substrate 5 solution to the microneedle array mold and centrifuge at 3°C. Then, remove the substrate 5 solution from the mold, ensuring that the substrate 5 solution in each microneedle cavity 7 falls to the set position. Next, rotate the mold 75° clockwise around the reference position, so that the tip of the microneedle cavity 7 is lower than the opening of the microneedle cavity 7, and the substrate 5 solution is spread on the microneedle cavity 7 and close to the opening of the microneedle cavity 7. Then, dry the mold at 25°C. After drying, rotate the mold to a horizontal position. Repeat step S2 twice. In each repetition of step S2, the angle of rotation of the mold is 2° smaller than the angle of rotation in the previous repetition of step S2.

[0073] Step S3: Add the substrate 5 solution to the microneedle array mold and centrifuge at 3°C. Then, aspirate the substrate 5 solution from the mold, ensuring that the substrate 5 solution in each microneedle cavity 7 descends to the set position. Next, rotate the mold 75° counterclockwise from the reference position, so that the tip of the microneedle cavity 7 is lower than its opening. The substrate 5 solution is then spread on the microneedle cavity 7 and close to its opening. Dry the mold at 25°C. After drying, rotate the mold to a horizontal position. Repeat step S3 twice. In each repetition of step S3, the angle of rotation of the mold is 2° smaller than the angle of rotation in the previous repetition of step S3.

[0074] Step S31: Add the substrate 5 solution to the microneedle array mold and centrifuge at 3°C. Then, aspirate the substrate 5 solution from the mold, ensuring that the substrate 5 solution in each microneedle cavity 7 descends to the set position. Next, rotate the mold 180° vertically from the reference position, and then rotate it 75° clockwise. At this point, the tip of the microneedle cavity 7 is lower than the opening of the microneedle cavity 7, and the substrate 5 solution is spread on the microneedle cavity 7 and close to its opening. Then, dry the mold at 25°C. After drying, rotate the mold to a horizontal position. Repeat step S31 twice. In each repetition of step S31, the angle of rotation of the mold is 2° smaller than the angle of rotation in the previous repetition of step S31.

[0075] Step S32: Add the substrate 5 solution to the microneedle array mold and centrifuge at 3°C. Then, aspirate the substrate 5 solution from the mold, ensuring that the substrate 5 solution in each microneedle cavity 7 descends to the set position. Next, rotate the mold 180° vertically from the reference position, and then rotate it 75° counterclockwise. At this point, the tip of the microneedle cavity 7 is lower than the opening of the microneedle cavity 7, and the substrate 5 solution is spread on the microneedle cavity 7 and close to its opening. Then, dry the mold at 25°C. After drying, rotate the mold to a horizontal position. Repeat step S32 twice. In each repetition of step S32, the angle of rotation of the mold is 2° smaller than the angle of rotation in the previous repetition of step S32.

[0076] Step S4: Add the drug-loaded solution to the microneedle array mold and centrifuge. Then, remove the drug-loaded solution from the mold until it is flush with the opening of each microneedle cavity 7. After that, dry the mold. Repeat step S4 until the thickness of the drug-loaded part 2 reaches the preset requirement.

[0077] Step S5: Add the substrate 5 solution into the microneedle array mold and centrifuge it. Then dry the mold. Repeat step S5 until the microneedle array is formed. Demold to obtain the microneedle array.

[0078] Step S6: Adhere the waterproof backing 6 to the microneedle array to obtain a microneedle patch.

[0079] In this embodiment, the microneedles are in the shape of a quadrangular pyramid, the microneedle array mold is in the reference position, and the two diagonally arranged edges in the microneedle cavity 7 are arranged in the left-right direction.

[0080] In the prepared microneedle patch, the height of the microneedle is 0.8 mm, the ratio of the height of the tip 1 to the height of the microneedle is 1:6.7, the ratio of the height of the drug-loaded part 2 to the height of the microneedle is 1:1.2, the ratio of the height of the support part 3 to the height of the microneedle is 1:2.5, and the ratio of the side length of the bottom surface of the microneedle to the height of the microneedle is 1:2.5.

[0081] Mechanical property tests were conducted on the microneedle patch, and the elastic modulus of the microneedle tip with a compression displacement of 100 μm reached 0.35 GPa.

[0082] A microneedle array was vertically inserted into the rabbit oral mucosa using a force of 50 N and held for 1 minute. The microneedle array was then removed, and the mucosal surface was immediately stained with trypan blue solution. After 3 minutes, the surface was rinsed with physiological saline to remove any residual trypan blue solution. The treated mucosal tissue was then soaked in 4% paraformaldehyde for 1 hour. The mucosal surface before and after insertion was observed using a stereomicroscope. The results showed that the rabbit oral mucosa treated with the microneedle array exhibited neatly arranged, uniformly sized micropores. The insertion rate of the drug-loaded microneedle array was 98%. The insertion rate was calculated as: Insertion rate = Effective insertion micropores / Total number of microneedles. Effective insertion micropores refer to those that, when the micropore array fills the observation interface under the microscope, have a straight, zigzag, triangular, or quadrilateral shape. Micropores with a dotted shape are not considered effective insertion micropores.

[0083] Example 2

[0084] In this embodiment, the steps for preparing the microneedle patch are basically the same as in Embodiment 1. The only difference is that in steps S2, S3, S31, and S32, the mold is rotated 70° clockwise around the front-back direction at the reference position. During the repetition of each step, the angle of rotation of the mold is 2° smaller than the angle of rotation of the mold during the previous repetition of the step.

[0085] In the prepared microneedle patch, the ratio of the height of the tip 1 to the height of the microneedle is 1:6.4.

[0086] Mechanical property tests were conducted on the microneedle patch, and the elastic modulus of the microneedle tip with a compression displacement of 100 μm reached 0.39 GPa.

[0087] A microneedle array was vertically inserted into the rabbit oral mucosa using a force of 50 N and held for 1 minute. The microneedle array was then removed, and the mucosal surface was immediately stained with trypan blue solution. After 3 minutes, the surface was rinsed with physiological saline to remove any residual trypan blue solution. The treated mucosal tissue was then soaked in 4% paraformaldehyde for 1 hour. The mucosal surface before and after insertion was observed using a stereomicroscope. The results showed that the rabbit oral mucosa treated with the microneedle array exhibited neatly arranged, uniformly sized micropores. The insertion rate of the drug-loaded microneedle array was 100%. The insertion rate was calculated as: Insertion rate = Effective insertion micropores / Total number of microneedles. Effective insertion micropores refer to those that, when the micropore array fills the observation interface under the microscope, are linear, zigzag, triangular, or quadrilateral in shape. Micropores that are dot-shaped are not considered effective insertion micropores.

[0088] Example 3

[0089] In this embodiment, the steps for preparing the microneedle patch are basically the same as in Example 1, except that steps S2, S3, S31, and S32 are not repeated.

[0090] In the prepared microneedle patch, the ratio of the height of the tip 1 to the height of the microneedle is 1:7.

[0091] Mechanical property tests were conducted on the microneedle patch, and the elastic modulus of the microneedle tip with a compression displacement of 100 μm reached 0.27 GPa.

[0092] A microneedle array was vertically inserted into the rabbit oral mucosa using a force of 50 N and held for 1 minute. The microneedle array was then removed, and the mucosal surface was immediately stained with trypan blue solution. After 3 minutes, the surface was rinsed with physiological saline to remove any residual trypan blue solution. The treated mucosal tissue was then soaked in 4% paraformaldehyde for 1 hour. The mucosal surface before and after insertion was observed using a stereomicroscope. The results showed that the rabbit oral mucosa treated with the microneedle array exhibited neatly arranged, uniformly sized micropores. The insertion rate of the drug-loaded microneedle array was 94%. The insertion rate was calculated as: Insertion rate = Effective insertion micropores / Total number of microneedles. Effective insertion micropores refer to those that, when the micropore array fills the observation interface under the microscope, have a straight, zigzag, triangular, or quadrilateral shape. Micropores with a dotted shape are not considered effective insertion micropores.

[0093] Example 4

[0094] In this embodiment, the steps for preparing the microneedle patch are basically the same as in Example 1, except that steps S31 and S32 are no longer performed.

[0095] In the prepared microneedle patch, the ratio of the height of the tip 1 to the height of the microneedle is 1:7.

[0096] Mechanical property tests were conducted on the microneedle patch, and the elastic modulus of the microneedle tip with a compression displacement of 100 μm reached 0.16 GPa.

[0097] A microneedle array was vertically inserted into the rabbit oral mucosa using a force of 50 N and held for 1 minute. The microneedle array was then removed, and the mucosal surface was immediately stained with trypan blue solution. After 3 minutes, the surface was rinsed with physiological saline to remove any residual trypan blue solution. The treated mucosal tissue was then soaked in 4% paraformaldehyde for 1 hour. The mucosal surface before and after insertion was observed using a stereomicroscope. The results showed that the rabbit oral mucosa treated with the microneedle array exhibited neatly arranged, uniformly sized micropores. The insertion rate of the drug-loaded microneedle array was 85%. The insertion rate was calculated as: Insertion rate = Effective insertion micropores / Total number of microneedles. Effective insertion micropores refer to those that, when the micropore array fills the observation interface under the microscope, are linear, zigzag, triangular, or quadrilateral in shape. Micropores that are dot-shaped are not considered effective insertion micropores.

[0098] In the description of this invention, it should be understood that the terms "first" and "second" are used for descriptive purposes only and should not be construed as indicating or implying relative importance or implicitly specifying the number of indicated technical features. Therefore, a feature defined as "first" or "second" may explicitly or implicitly include one or more of that feature. In the description of this invention, "a plurality of" means two or more, unless otherwise explicitly specified.

[0099] In this invention, unless otherwise explicitly specified and limited, the terms "installation," "connection," "linking," and "fixing," etc., should be interpreted broadly. For example, they can refer to a fixed connection, a detachable connection, or an integral part; they can refer to a mechanical connection or an electrical connection; they can refer to a direct connection or an indirect connection through an intermediate medium; they can refer to the internal communication of two components or the interaction between two components. Those skilled in the art can understand the specific meaning of the above terms in this invention according to the specific circumstances.

[0100] In this invention, unless otherwise explicitly specified and limited, "above" or "below" the second feature can mean that the first and second features are in direct contact, or that they are in indirect contact through an intermediate medium. Furthermore, "above," "over," or "on top" the second feature can mean that the first feature is directly above or diagonally above the second feature, or simply indicates that the first feature is at a higher horizontal level than the second feature. "Below," "below," or "beneath" the second feature can mean that the first feature is directly below or diagonally below the second feature, or simply indicates that the first feature is at a lower horizontal level than the second feature.

[0101] In the description of this specification, the terms "one embodiment," "some embodiments," "embodiment," "example," "specific example," or "some examples," etc., refer to specific features, structures, materials, or characteristics described in connection with that embodiment or example, which are included in at least one embodiment or example of the present invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples.

[0102] Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those skilled in the art can make modifications, alterations, substitutions and variations to the above embodiments within the scope of the present invention.

Claims

1. A method for preparing a biodegradable microneedle patch for promoting mandibular bone regeneration, characterized in that, Includes the following steps: S1. The substrate material and sophorolipid are dissolved in an organic solvent and degassed to obtain a substrate solution; the drug-loaded substrate material and IGF-1 are dissolved in water and degassed to obtain a drug-loaded solution. S2. Add the base solution to the microneedle array mold and centrifuge it. Then, remove the base solution from the mold so that the base solution in each microneedle cavity in the mold drops to the set position. Then, rotate the mold 65° to 80° clockwise around the front and back direction at the reference position. At this time, the tip of the microneedle cavity is lower than the opening end of the microneedle cavity. The base solution is laid in the microneedle cavity and close to the opening of the microneedle cavity. Then, dry the mold and rotate the mold to a horizontal state. S3. Add the base solution to the microneedle array mold and centrifuge it. Then, remove the base solution from the mold so that the base solution in each microneedle cavity drops to the set position. Then, rotate the mold counterclockwise by 65° to 80° around the front-back direction at the reference position. At this time, the tip of the microneedle cavity is lower than the opening end of the microneedle cavity. The base solution is laid in the microneedle cavity and close to the opening of the microneedle cavity. Then, dry the mold and rotate the mold to a horizontal state. S4. Add the drug-loaded solution to the microneedle array mold and centrifuge it. Then, draw up the drug-loaded solution to be level with the opening of each microneedle cavity, and then dry the mold. S5. Add the base solution to the microneedle array mold and centrifuge it. Then dry the mold. Repeat step S5 until the microneedle array is formed. S6. Adhere the waterproof backing to the microneedle array to obtain a microneedle patch.

2. The method for preparing the biodegradable microneedle patch for promoting mandibular bone regeneration according to claim 1, characterized in that, In S1, the drug-loaded matrix material of the microneedle and the PLGA sustained-release microspheres encapsulated with IGF-1 are dissolved in water and degassed to obtain a drug-loaded solution.

3. The method for preparing the biodegradable microneedle patch for promoting mandibular bone regeneration according to claim 1, characterized in that, S2 also includes: repeating S2, in each repetition of S2, the angle of rotation of the mold is 1 to 3 degrees smaller than the angle of rotation of the mold in the previous repetition of S2; S3 also includes: repeating S3, in which the angle of rotation of the mold is 1 to 3 degrees smaller than the angle of rotation of the mold in the previous repetition of S3.

4. The method for preparing the biodegradable microneedle patch for promoting mandibular bone regeneration according to claim 1, characterized in that, Between S3 and S4, it also includes: S31. Add the base solution to the microneedle array mold and centrifuge it. Then, remove the base solution from the mold so that the base solution in each microneedle cavity drops to the set position. Next, rotate the mold 180° up and down at the reference position, and then rotate the mold 65° to 80° clockwise in the front and back direction. At this time, the tip of the microneedle cavity is lower than the opening end of the microneedle cavity. The base solution is laid in the microneedle cavity and close to the opening of the microneedle cavity. Then, dry the mold. After drying, rotate the mold to a horizontal state. S32. Add the base solution to the microneedle array mold and centrifuge it. Then, remove the base solution from the mold so that the base solution in each microneedle cavity drops to the set position. Next, rotate the mold 180° up and down in the reference position, and then rotate the mold 65° to 80° counterclockwise in the front and back direction. At this time, the tip of the microneedle cavity is lower than the opening end of the microneedle cavity. The base solution is laid in the microneedle cavity and close to the opening of the microneedle cavity. Then, dry the mold. After drying, rotate the mold to a horizontal state.

5. The method for preparing the biodegradable microneedle patch for promoting mandibular bone regeneration according to claim 4, characterized in that, S31 also includes: repeating S31, wherein in each repetition of S31, the angle of rotation of the mold is 1 to 3 degrees smaller than the angle of rotation of the mold in the previous repetition of S31. S32 also includes: repeating S32, in which the angle of rotation of the mold is 1 to 3 degrees smaller than the angle of rotation of the mold in the previous repetition of S32.

6. The method for preparing the biodegradable microneedle patch for promoting mandibular bone regeneration according to claim 1, characterized in that, The solution inside the mold is drawn using a liquid aspiration needle. The liquid aspiration needle includes an aspiration chamber that can be converted to negative pressure and micron needle tubes located on one side of the aspiration chamber and distributed perpendicular to the array of the aspiration chamber. The micron needle tubes are connected to the aspiration chamber. The solution in the mold is aspirated using a liquid aspiration needle, which includes: placing the liquid aspiration needle on the microneedle mold, inserting the microneedle tubes into the microneedle cavity one by one, changing the aspiration cavity to negative pressure, aspirating the base solution down to the free end of the microneedle tube, removing the liquid aspiration needle, and completing the aspiration.

7. The method for preparing the biodegradable microneedle patch for promoting mandibular bone regeneration according to claim 1, characterized in that, If the microneedle is in the shape of a square pyramid, the microneedle array mold is in the reference position, and the two diagonally arranged edges in the microneedle cavity are arranged in the left and right directions.

8. A biodegradable microneedle patch for promoting mandibular bone regeneration, characterized in that, The microneedle patch is prepared by the method for preparing a biodegradable microneedle patch for promoting mandibular regeneration as described in any one of claims 1 to 7.

9. The biodegradable microneedle patch for promoting mandibular bone regeneration according to claim 8, characterized in that, The microneedle patch includes a microneedle array and a waterproof backing. The microneedle array consists of a substrate and microneedles distributed perpendicularly to the substrate on a first side of the substrate. The microneedles are conical and have a support portion, a drug-carrying portion, and a tip portion connected sequentially in a direction away from the substrate. The support portion is connected to the substrate, and the waterproof backing covers the second side of the substrate and is bonded to the substrate. The ratio of the height of the tip to the height of the microneedle is 1:5 to 7, the ratio of the height of the drug-loaded part to the height of the microneedle is 1:1.2 to 2, and the ratio of the height of the support part to the height of the microneedle is 1:2 to 3.5.

Images