Microneedle composition containing active component, and preparation method therefor and use thereof

Abstract

The present invention relates to the technical field of medicine. More specifically, the present invention relates to a microneedle composition containing an active component, and a preparation method therefor and the use thereof. The microneedle composition containing an active component contains an active component, a biodegradable polymer material, a surfactant, and the balance of a solvent, wherein on the basis of the total weight of the microneedle composition, the weight percentage of the active component is 1-15%, the weight percentage of the biodegradable polymer material is 0.1-15%, and the weight percentage of the surfactant is 0.05-5%.

Description

A microneedle composition containing an active ingredient, its preparation method and uses Technical Field

[0001] This invention relates to the field of pharmaceutical technology. More specifically, it relates to a microneedle composition containing an active ingredient, its preparation method, and its uses. Background Technology

[0002] Smegglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist used to treat type 2 diabetes and obesity, primarily administered orally or by injection. Oral administration results in extremely low bioavailability (only about 1%) due to first-pass metabolism in the gastrointestinal tract, increasing treatment costs for patients. On the other hand, existing injectable formulations can lead to poor patient compliance, pain, skin redness and swelling, and even secondary infections, as well as the generation of medical waste. Furthermore, the production, transportation, and storage of these injectable products require cryogenic conditions to maintain their activity, further increasing costs.

[0003] Transdermal drug delivery is a painless method of systemic drug administration that can provide a non-invasive alternative to parenteral routes. However, the natural penetration of active macromolecules through the stratum corneum of the skin is a challenge for transdermal drug delivery.

[0004] Smegglutide injection (trade name: WEGVOY) is used for chronic weight management in adult patients, assisting in reducing food intake and increasing physical activity. Its long-term dosage is maintained at 2.4 mg. Novo Nordisk has launched a Phase III clinical trial of smegglutide, NCT05649137, increasing the dosage to 7.2 mg for weight loss in obese patients. Achieving high-dose percutaneous delivery of large molecule drugs is also challenging.

[0005] The same problem exists for other types of GLP-1 receptor agonist peptides.

[0006] Therefore, there is still a significant unmet need in clinical practice for the transdermal delivery of large doses of active macromolecular components. Summary of the Invention

[0007] To address the shortcomings of existing technologies, this invention provides a microneedle composition containing active components, its preparation method, and its uses.

[0008] According to one embodiment of the present invention, a microneedle composition containing an active ingredient is provided, comprising the active ingredient, a biodegradable polymer material, and a surfactant, with the balance being a solvent, wherein, based on the total weight of the microneedle composition, the weight percentage of the active ingredient is 1-15%, the weight percentage of the biodegradable polymer material is 0.1-15%, and the weight percentage of the surfactant is 0.05-5%.

[0009] According to one embodiment of the present invention, the weight percentage of the active ingredient is, for example, 1-13%, 1-12%, 1-10%, 2-10%, 1-8%, 1-7%, 1-6%, 2-6%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%, 10.5%, 11%, 11.5%, 12%, 12.5%, 13%, 13.5%, 14%, 14.5%, 15%, and any range thereof.

[0010] According to one embodiment of the present invention, the weight percentage of the biodegradable polymer material is, for example, 0.5-15%, for example, 1-13%, for example, 1-12%, for example, 1-10%, for example, 2-10%, for example, 1-8%, for example, 1-7%, for example, 1-6%, for example, 2-6%, for example, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%, 10.5%, 11%, 11.5%, 12%, 12.5%, 13%, 13.5%, 14%, 14.5%, 15%, and any value between them, and any range of these values.

[0011] According to one embodiment of the present invention, the surfactant is, for example, 0.05-4%, 0.05-3%, 0.1-3%, 0.1-2%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2%, and any value between them, and any range of these values.

[0012] According to one embodiment of the present invention, the active ingredient is a GLP-1 receptor agonist polypeptide.

[0013] According to one embodiment of the present invention, the active ingredient is liraglutide, semaglutide, dulaglutide, exenatide microspheres, benaglutide, or polyethylene glycol loxenatide.

[0014] According to one embodiment of the present invention, the active ingredient is smegglutinin.

[0015] According to one embodiment of the present invention, the single dose of the active ingredient is greater than or equal to 0.5 mg.

[0016] According to one embodiment of the present invention, the biodegradable polymer material comprises both macromolecular framework materials and small molecule rapidly dissolving materials.

[0017] In this invention, the macromolecular framework material helps maintain the integrity of the microneedles without hindering drug release; the small molecule rapidly dissolving material enables rapid drug delivery. The combination of these two materials produces microneedles with a high loading of active ingredients, an extremely thin basement membrane, and the ability to be completely demolded, while also possessing sufficient mechanical strength to penetrate the skin.

[0018] According to one embodiment of the present invention, the macromolecular backbone material includes one or more of hyaluronic acid, polyvinylpyrrolidone, and sodium alginate; the small molecule rapidly dissolving material includes one or more of water-soluble cyclodextrin, dextran, trehalose, sucrose, polyglutamic acid, pullulan, and Bletilla striata polysaccharide.

[0019] According to one embodiment of the present invention, the hyaluronic acid has a molecular weight of 80,000 to 800,000, for example 80,000 to 400,000, for example 120,000 to 240,000, for example 80,000, 240,000, 400,000, 800,000, etc.; the polyvinylpyrrolidone is polyvinylpyrrolidone (K60), polyvinylpyrrolidone (K90) or polyvinylpyrrolidone (K120); the dextran has a molecular weight of 40,000 or 70,000.

[0020] According to one embodiment of the present invention, the water-soluble cyclodextrin is selected from one or more of sodium sulfobutyl ether beta-cyclodextrin, methyl beta-cyclodextrin, and hydroxypropyl beta-cyclodextrin.

[0021] According to one embodiment of the present invention, the surfactant is selected from one or more of Tween, Span, propylene glycol, glycerin, and polyethylene glycol.

[0022] According to one embodiment of the present invention, Tween is, for example, Tween 80, Span is, for example, Span 60, and polyethylene glycol is, for example, polyethylene glycol 400.

[0023] According to one embodiment of the present invention, the solvent is water for injection.

[0024] According to one embodiment of the present invention, the weight ratio of the active ingredient to the biodegradable polymer material is 5:1-1:10, for example 4:1-1:10, for example 2:1-1:10, for example 1:1-1:4, for example 4:1-1:8, for example 4:1-1:5, for example 3:1-1:6, for example 2:1-1:5, for example 3:1-1:2; for example 5:1, 4.5:1, 4:1, 3.5:1, 3:1. 2.5:1, 2.33:1, 2:1, 1.7:1, 1.5:1, 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, 1:5.5, 1:6, 1:6.5, 1:7, 1:7.5, 1:8, 1:8.5, 1:9, 1:9.5, 1:10, and any values ​​between them, as well as any range of these values.

[0025] According to one embodiment of the present invention, the weight ratio of the macromolecular framework material to the small molecule rapidly dissolving material is 5:1-1:10, for example 4:1-1:10, for example 2:1-1:10, for example 1:1-1:4, for example 4:1-1:8, for example 4:1-1:5, for example 3:1-1:6, for example 2:1-1:5, for example 3:1-1:2; for example 5:1, 4.5:1, 4:1, 3.5:1, 3:1, 2.5:1, 7:3, 2.33 :1, 2.34:1, 2:1, 19:11, 1.72:1, 1.73:1, 1.7:1, 1.5:1, 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, 1:5.5, 1:6, 1:6.5, 1:7, 1:7.5, 1:8, 1:8.5, 1:9, 1:9.5, 1:10, and any values ​​between them, and any range of these values.

[0026] According to one embodiment of the present invention, a method for preparing a solution of a microneedle composition is provided, comprising the following steps: dissolving an active ingredient in a solvent containing a surfactant, then adding a biodegradable polymer material, stirring to dissolve, and forming a solution of the microneedle composition.

[0027] According to one embodiment of the present invention, a method for preparing a solution of a microneedle composition is provided, comprising the following steps: dissolving an active ingredient in a solvent containing a surfactant, adding a small molecule fast-dissolving material, adding a macromolecular framework material, stirring to dissolve, and forming a solution of the microneedle composition.

[0028] According to another aspect of the invention, a soluble microneedle patch is provided, comprising a substrate and needles on the substrate; the substrate and needles are made of the same material and comprise the microneedle composition as described above.

[0029] According to another aspect of the present invention, a soluble microneedle patch is provided, comprising a substrate and needles on the substrate; the substrate and needles are made of the same material and are obtained by dropping a solution of the microneedle composition as described above into a mold and then drying and demolding.

[0030] When the delivered drug is a large molecule, the dosage delivered by layered microneedles is usually limited, which cannot achieve good bioequivalence with existing dosage forms, and the preparation process is relatively complex. It should be noted that the microneedles in this invention are either integral microneedles or spliced ​​microneedles. Those skilled in the art can also prepare microneedles with other structural types based on the microneedle composition solution formulation provided in this invention, and this invention does not impose further limitations in this regard.

[0031] According to one embodiment of the present invention, the microneedle is an integrated microneedle.

[0032] The drug loading of the microneedle patch is, for example, greater than or equal to 1 mg / 0.75 cm. 2 For example, 1 mg / 0.75 cm 2 -8mg / 0.75cm 2 1mg / 0.75cm 2 -6mg / 0.75cm 2 1mg / 0.75cm 2 -5mg / 0.75cm 2 1mg / 0.75cm 2 -4mg / 0.75cm 2 1mg / 0.75cm 2 -3.5mg / 0.75cm 2 1mg / 0.75cm 2 -3.3mg / 0.75cm 2 1mg / 0.75cm 2 -3mg / 0.75cm 2 For example, 1 mg / 0.75 cm 2 1.5mg / 0.75cm 2 2mg / 0.75cm 2 2.5mg / 0.75cm 2 3mg / 0.75cm 2 3.5mg / 0.75cm 2 4mg / 0.75cm 2 4.5mg / 0.75cm 2 5mg / 0.75cm 2 5.5mg / 0.75cm 26mg / 0.75cm 2 7mg / 0.75cm 2 8mg / 0.75cm 2 , and any values ​​between them, and any range consisting of these values, etc.

[0033] According to one embodiment of the present invention, the film thickness of the substrate is 10-60 μm, for example 10-40 μm, for example 10-35 μm, for example 10 μm, 11 μm, 12 μm, 13 μm, 15 μm, 18 μm, 19 μm, 20 μm, 21 μm, 22 μm, 23 μm, 24 μm, 25 μm, 30 μm, 31 μm, 33 μm, 35 μm, 40 μm, 42 μm, 43 μm, 45 μm, 50 μm, 52 μm, 53 μm, 55 μm, 58 μm, 60 μm, and any value between them, and any range composed of these values, etc.

[0034] According to another aspect of the present invention, a method for preparing the soluble microneedle patch as described above is provided, comprising the following steps: taking a solution of the microneedle composition, adding it dropwise into a mold, coating it evenly, applying negative pressure, drying, and demolding to obtain the soluble microneedle patch.

[0035] According to one embodiment of the present invention, a method for preparing the soluble microneedle patch as described above is provided, comprising the following steps: dissolving the active ingredient in a solvent containing a surfactant, then adding a biodegradable polymer material, stirring to dissolve, forming a solution of the microneedle composition; taking the solution of the microneedle composition, dropping it into a mold, coating it evenly, applying negative pressure, drying, and demolding to obtain the soluble microneedle patch.

[0036] According to one embodiment of the present invention, a method for preparing a smegglutinin microneedle patch is provided, comprising the following steps: dissolving smegglutinin in a solvent containing a surfactant, then adding a biodegradable polymer material, stirring and dissolving to form a solution of a microneedle composition; taking the solution of the microneedle composition, dropping it into a mold, coating it evenly, applying negative pressure, drying, and demolding to obtain the smegglutinin microneedle patch.

[0037] According to one embodiment of the present invention, a method for preparing the soluble microneedle patch as described above is provided, comprising the following steps: dissolving the active ingredient in a solvent containing a surfactant, adding a small molecule fast-dissolving material, then adding a macromolecular framework material, stirring and dissolving to form a solution of the microneedle composition; taking the solution of the microneedle composition, dropping it into a mold, coating it evenly, applying negative pressure, drying, and demolding to obtain the soluble microneedle patch.

[0038] According to one embodiment of the present invention, a method for preparing a smegglutide microneedle patch is provided, comprising the following steps: dissolving smegglutide in a solvent containing a surfactant, adding a small molecule fast-dissolving material, then adding a macromolecular backbone material, stirring and dissolving to form a solution of a microneedle composition; taking the solution of the microneedle composition, dropping it into a mold, coating it evenly, applying negative pressure, drying, and demolding to obtain the smegglutide microneedle patch.

[0039] The surfactant in this invention helps the microneedle composition solution to spread easily on the mold.

[0040] According to another aspect of the present invention, the use of the microneedle composition as described above, the soluble microneedle patch as described above, or the soluble microneedle patch prepared by the above preparation method is provided in the preparation of a medicament for treating metabolic-related diseases.

[0041] According to one embodiment of the present invention, the metabolic-related disease is selected from diabetes, hyperglycemia, and obesity.

[0042] According to one embodiment of the present invention, the diabetes mellitus is selected from type II diabetes mellitus, childhood diabetes mellitus, and diabetes mellitus complicated with nephropathy.

[0043] The beneficial effects of this invention are as follows:

[0044] The soluble microneedle patch of this invention has an extremely thin basement membrane, allowing the drug to be distributed as widely as possible at the needle site. It dissolves rapidly within minutes of being applied to the skin; simultaneously, it possesses sufficient mechanical strength to penetrate the skin. The process is simple, with a one-step preparation method, making it suitable for industrial production. The microneedle patch of this invention, or a microneedle patch prepared using the method of this invention, can deliver large amounts of drug to the human body in a small area, improving patient compliance and achieving therapeutic effects equivalent to injections by delivering large doses of macromolecular drugs via microneedle patches. Furthermore, the microneedle patch of this invention avoids first-pass metabolism in the gastrointestinal tract, minimizing toxic side effects and reducing pain and skin redness caused by injection. The microneedle patch also improves the storage stability of the active ingredient, saving on cold chain costs. Attached Figure Description

[0045] The specific embodiments of the present invention will be described in further detail below with reference to the accompanying drawings.

[0046] Figure 1 shows a stereomicroscopic image of the smegglutinin microneedle composition in Example 1.

[0047] Figure 2 shows the basement membrane thickness of the smegglutinin microneedle composition in Example 1 (Figure 2(A)) and Comparative Example 3 (Figure 2(B)).

[0048] Figure 3 shows the puncture test diagram (Figure 3(A)) and residual patch dissolution test diagram (Figure 3(B)) of the smegglutinin microneedle composition in Example 2.

[0049] Figure 4 shows the mechanical properties of the smegglutinin microneedle composition of Example 3.

[0050] Figure 5 shows the in vitro release curves of three batches of the smegglutinin microneedle composition of Example 4.

[0051] Figure 6 shows the pharmacokinetic curves of the smegglutide microneedle composition prepared in Example 4 at high, medium, and low doses and as an injection solution. Detailed Implementation

[0052] To more clearly illustrate the present invention, the following description, in conjunction with preferred embodiments and accompanying drawings, further explains the invention. Similar components in the drawings are indicated by the same reference numerals. Those skilled in the art should understand that the specific description below is illustrative rather than restrictive and should not be construed as limiting the scope of protection of the present invention.

[0053] To more clearly illustrate the present invention, the following description, in conjunction with embodiments and accompanying drawings, further clarifies the invention. Those skilled in the art should understand that the specific descriptions below are illustrative rather than restrictive and should not be construed as limiting the scope of protection of the present invention.

[0054] In this invention, "drug-excipient ratio" refers to the weight ratio of the drug to the biodegradable polymer material. In the embodiments and comparative examples of this invention, "drug-excipient ratio" refers to the weight ratio of smegglutinin to the biodegradable polymer material.

[0055] Example 1

[0056] The ratio of raw materials and excipients in the smegglutinin dissolving microneedle composition in this example is shown in Table 1 below, where the drug-excipient ratio is 1:1.

[0057] Table 1. Raw material and excipient ratio of the smegglutinin microneedle composition

[0058] According to the raw material and excipient ratio in Table 1, prepare semaglutide dissolving microneedles according to the following steps:

[0059] (1) Preparation of microneedle matrix solution

[0060] Add the prescribed amount of Tween 80 to a centrifuge tube, then add the prescribed amount of water for injection, stir to dissolve, add the prescribed amount of Smeglucopyranoside, stir to dissolve, then add the prescribed amount of sodium betacyclodextrin and dextran (70,000 units) to the centrifuge tube, stir to dissolve, and finally add the prescribed amount of hyaluronic acid (240,000 units), stir until completely dissolved, place in a centrifuge, and centrifuge at 5000 rpm and 4°C for 3 minutes to remove air bubbles.

[0061] (2) Preparation of microneedle composition

[0062] 50 μL of the prepared matrix solution was added dropwise to the unit mold using a dispensing gun, spread evenly, and then the mold was subjected to negative pressure at room temperature until no solution remained on the mold surface. The microneedles were then allowed to dry naturally at room temperature before demolding. The theoretical drug content of the dissolved microneedles obtained in Example 1 was 3 mg / 0.75 cm³. 2 .

[0063] (3) The microneedle body microscope image prepared in Example 1 is shown in Figure 1.

[0064] Example 2

[0065] The ratio of raw materials and excipients in the semaglutide dissolving microneedle composition in this example is shown in Table 2 below, where the drug-excipient ratio is 2:1.

[0066] Table 2. Raw material and excipient ratio of the smegglutinin microneedle composition

[0067] According to the raw material and excipient ratio in Table 2, prepare semaglutide dissolving microneedles according to the following steps:

[0068] (1) Preparation of microneedle matrix solution

[0069] Add the prescribed amount of Tween 80 to a centrifuge tube, then add the prescribed amount of water for injection, stir to dissolve, add the prescribed amount of Smegglutinin, stir to dissolve, then add the prescribed amount of dextran (40,000) to the centrifuge tube, stir to dissolve, and finally add the prescribed amount of hyaluronic acid (800,000), stir until completely dissolved, place in a centrifuge, and centrifuge at 5000 rpm and 4°C for 3 minutes to remove air bubbles.

[0070] (2) Preparation of microneedle composition

[0071] 50 μL of the prepared matrix solution was added dropwise to the unit mold using a dispensing gun, spread evenly, and then the mold was subjected to negative pressure at room temperature until no solution remained on the mold surface. The microneedles were then allowed to dry naturally at room temperature before demolding. The theoretical drug content of the dissolved microneedles obtained in Example 2 was 3 mg / 0.75 cm³. 2 .

[0072] Example 3

[0073] The ratio of raw materials and excipients in the semaglutide dissolving microneedle composition in this example is shown in Table 3 below, where the drug-excipient ratio is 1:5.

[0074] Table 3. Raw material and excipient ratios of the smegglutinin microneedle composition

[0075] According to the raw material and excipient ratio in Table 3, prepare the smegglutinin dissolving microneedles according to the following steps:

[0076] (1) Preparation of microneedle matrix solution

[0077] Add the prescribed amount of Tween 80 to a centrifuge tube, then add the prescribed amount of water for injection, stir to dissolve, add the prescribed amount of Smeglucopyranoside, stir to dissolve, then add the prescribed amount of sodium betacyclodextrin and dextran (70,000 units) to the centrifuge tube, stir to dissolve, and finally add the prescribed amount of hyaluronic acid (240,000 units), stir until completely dissolved, place in a centrifuge, and centrifuge at 5000 rpm and 4°C for 3 minutes to remove air bubbles.

[0078] (2) Preparation of microneedle composition

[0079] 150 μL of the prepared matrix solution was added dropwise to the unit mold using a dispensing gun, spread evenly, and then the mold was subjected to negative pressure at room temperature until no solution remained on the mold surface. The microneedles were then allowed to dry naturally at room temperature before demolding. The theoretical drug content of the dissolved microneedles obtained in Example 3 was 3 mg / 0.75 cm³. 2 .

[0080] Example 4

[0081] The ratio of raw materials and excipients in the smegglutide dissolving microneedle composition in this example is shown in Table 4 below, where the drug-excipient ratio is 1:1.

[0082] Table 4. Raw material and excipient ratio of the smegglutinin microneedle composition

[0083] Based on the raw material and excipient ratios in Table 4, prepare the smegglutinin dissolving microneedles according to the following steps:

[0084] (1) Preparation of microneedle matrix solution

[0085] Add the prescribed amount of Tween 80 to a centrifuge tube, then add the prescribed amount of water for injection, stir to dissolve, add the prescribed amount of Smegglutinin, stir to dissolve, then add the prescribed amount of dextran (40,000) to the centrifuge tube, stir to dissolve, finally add the prescribed amounts of hyaluronic acid (240,000) and hyaluronic acid (800,000), stir until completely dissolved, place in a centrifuge, centrifuge at 5000 rpm and 4°C for 3 minutes to remove air bubbles.

[0086] (2) Preparation of microneedle composition

[0087] 75 μL of the prepared matrix solution was added dropwise to the unit mold using a dispensing gun, spread evenly, and then the mold was subjected to negative pressure at room temperature until no solution remained on the mold surface. The microneedles were then allowed to dry naturally at room temperature before demolding. The theoretical drug content of the dissolved microneedles obtained in Example 4 was 3 mg / 0.75 cm³.2 .

[0088] Example 5

[0089] The ratio of raw materials and excipients in the smegglutide dissolving microneedle composition in this example is shown in Table 5 below, where the drug-excipient ratio is 2:1.

[0090] Table 5. Raw material and excipient ratios of the smegglutinin microneedle composition.

[0091] Based on the raw material and excipient ratios in Table 5, prepare the smegglutinin dissolving microneedles according to the following steps:

[0092] (1) Preparation of microneedle matrix solution

[0093] Add the prescribed amount of propylene glycol to a centrifuge tube, then add the prescribed amount of water for injection, stir to dissolve, add the prescribed amount of smegglutinin, stir to dissolve, then add the prescribed amount of sodium hydroxypropyl betacyclodextrin to the centrifuge tube, stir to dissolve, and finally add the prescribed amount of sodium alginate, stir until completely dissolved, place in a centrifuge, and centrifuge at 5000 rpm and 4°C for 3 minutes to remove air bubbles.

[0094] (2) Preparation of microneedle composition

[0095] 30 μL of the prepared matrix solution was added dropwise to the unit mold using a dispensing gun, spread evenly, and then the mold was subjected to negative pressure at room temperature until no solution remained on the mold surface. The microneedles were then allowed to dry naturally at room temperature before demolding. The theoretical drug content of the dissolved microneedles obtained in Example 5 was 3 mg / 0.75 cm³. 2 .

[0096] Example 6

[0097] The ratio of raw materials and excipients in the smegglutinin dissolving microneedle composition in this example is shown in Table 6 below, where the drug-excipient ratio is 1:2.

[0098] Table 6. Raw material and excipient ratio of the smegglutinin microneedle composition

[0099] Based on the raw material and excipient ratios in Table 6, prepare the smegglutinin dissolving microneedles according to the following steps:

[0100] (1) Preparation of microneedle matrix solution

[0101] Add the prescribed amount of polyethylene glycol 400 to a centrifuge tube, then add the prescribed amount of water for injection, stir to dissolve, add the prescribed amount of smegglutinin, stir to dissolve, then add the prescribed amount of Bletilla striata polysaccharide to the centrifuge tube, stir to dissolve, and finally add the prescribed amount of polyvinylpyrrolidone (K90), stir until completely dissolved, place in a centrifuge, and centrifuge at 5000 rpm and 4°C for 3 minutes to remove air bubbles.

[0102] (2) Preparation of microneedle composition

[0103] 100 μL of the prepared matrix solution was added dropwise to the unit mold using a dispensing gun, spread evenly, and then the mold was subjected to negative pressure at room temperature until no solution remained on the mold surface. The microneedles were then allowed to dry naturally at room temperature before demolding. The theoretical drug content of the dissolved microneedles obtained in Example 6 was 3 mg / 0.75 cm³. 2 .

[0104] Example 7

[0105] The ratio of raw materials and excipients in the smegglutinin dissolving microneedle composition in this example is shown in Table 7 below, where the drug-excipient ratio is 3:2.

[0106] Table 7. Raw material and excipient ratios for the Smegglutinin microneedle composition.

[0107] Based on the raw material and excipient ratios in Table 7, prepare the smegglutinin dissolving microneedles according to the following steps:

[0108] (1) Preparation of microneedle matrix solution

[0109] Add the prescribed amount of Span 60 to a centrifuge tube, then add the prescribed amount of water for injection, stir to dissolve, add the prescribed amount of Smegglutinin, stir to dissolve, then add the prescribed amount of polyglutamic acid to the centrifuge tube, stir to dissolve, and finally add the prescribed amount of hyaluronic acid 400,000, stir until completely dissolved, place in a centrifuge, and centrifuge at 5000 rpm and 4°C for 3 minutes to remove air bubbles.

[0110] (2) Preparation of microneedle composition

[0111] 100 μL of the prepared matrix solution was added dropwise to the unit mold using a dispensing gun, spread evenly, and then the mold was subjected to negative pressure at room temperature until no solution remained on the mold surface. The microneedles were then allowed to dry naturally at room temperature before demolding. The theoretical drug content of the dissolved microneedles obtained in Example 7 was 3 mg / 0.75 cm³. 2 .

[0112] Example 8

[0113] The ratio of raw materials and excipients in the semaglutide dissolving microneedle composition in this example is shown in Table 8 below, where the drug-excipient ratio is 2:1.

[0114] Table 8. Raw material and excipient ratio of the smegglutinin microneedle composition

[0115] According to the raw material and excipient ratio in Table 8, prepare the smegglutinin dissolving microneedles according to the following steps:

[0116] (1) Preparation of microneedle matrix solution

[0117] Add the prescribed amount of glycerol to a centrifuge tube, then add the prescribed amount of water for injection, stir to dissolve, add the prescribed amount of smegglutinin, stir to dissolve, then add the prescribed amount of sucrose and 70,000 units of dextran to the centrifuge tube, stir to dissolve, finally add the prescribed amount of 80,000 units of hyaluronic acid, stir until completely dissolved, place in a centrifuge, centrifuge at 5000 rpm and 4°C for 3 minutes to remove air bubbles.

[0118] (2) Preparation of microneedle composition

[0119] 40 μL of the prepared matrix solution was added dropwise to the unit mold using a dispensing gun, spread evenly, and then the mold was subjected to negative pressure at room temperature until no solution remained on the mold surface. The microneedles were then allowed to dry naturally at room temperature before demolding. The theoretical drug content of the dissolved microneedles obtained in Example 8 was 3.2 mg / 0.75 cm³. 2 .

[0120] Comparative Example 1

[0121] The ratio of raw materials and excipients in the semaglutide dissolving microneedle composition in this example is shown in Table 9 below, where the drug-excipient ratio is 1:1. There are no small molecule fast-dissolving materials in this comparative example.

[0122] Table 9. Raw material and excipient ratios for the Smegglutinin microneedle composition.

[0123] According to the raw material and excipient ratio in Table 9, prepare the smegglutinin dissolving microneedles following these steps:

[0124] (1) Preparation of microneedle matrix solution

[0125] Add the prescribed amount of Tween 80 to a centrifuge tube, then add the prescribed amount of water for injection, stir to dissolve, add the prescribed amount of Smegglutinin, stir to dissolve, then add the prescribed amounts of hyaluronic acid (240,000 units) and hyaluronic acid (800,000 units), stir until completely dissolved, place in a centrifuge, centrifuge at 5000 rpm and 4°C for 3 minutes to remove air bubbles.

[0126] (2) Preparation of microneedle composition

[0127] 75 μL of the prepared matrix solution was transferred using a dispensing gun and dropped onto the unit mold, spreading it evenly. The mold was then subjected to negative pressure at room temperature until no solution remained on the surface. After the microneedles were allowed to dry naturally at room temperature, they were demolded. The theoretical drug content of the dissolved microneedles was 3 mg / 0.75 cm³. 2 .

[0128] (3) The formula contains only macromolecular framework materials and active ingredients, without the addition of small molecule materials. After the matrix liquid dries, the microneedles are found to be extremely thin after the film is peeled off, and the tip of the needle is incomplete, with some material remaining in the mold.

[0129] Comparative Example 2

[0130] The ratio of raw materials and excipients in the semaglutide dissolving microneedle composition in this example is shown in Table 10 below, where the drug-excipient ratio is 1:1. There are no macromolecular backbone materials in this comparative example.

[0131] Table 10. Raw material and excipient ratios for the smegglutinin microneedle composition

[0132] According to the raw material and excipient ratio in Table 10, prepare the smegglutinin dissolving microneedles following these steps:

[0133] (1) Preparation of microneedle matrix solution

[0134] Add the prescribed amount of Tween 80 to a centrifuge tube, then add the prescribed amount of water for injection, stir to dissolve, add the prescribed amount of Smeglucopyranoside, stir to dissolve, then add the prescribed amount of sodium betacyclodextrin and dextran (70,000 units), stir until completely dissolved, place in a centrifuge, centrifuge at 5000 rpm and 4°C for 3 minutes to remove air bubbles.

[0135] (2) Preparation of microneedle composition

[0136] 50 μL of the prepared matrix solution was added dropwise to the unit mold using a dispensing gun and spread evenly. The mold was then subjected to negative pressure at room temperature until no solution remained on the surface. After the microneedles were allowed to dry naturally at room temperature, they were demolded. The theoretical drug content of the dissolved microneedles was 3 mg / 0.75 cm³. 2 .

[0137] (3) The formula does not contain macromolecular framework materials, but only active ingredients and small molecule fast-dissolving materials. After the matrix liquid dries, the microneedle patch on the mold cracks and cannot be completely peeled off.

[0138] Comparative Example 3

[0139] The ratio of raw materials and excipients in the smegglutinin dissolving microneedle composition in this example is shown in Table 11 below, where the drug-excipient ratio is 1:20.

[0140] Table 11. Raw material and excipient ratios of the smegglutinin microneedle composition

[0141] According to the raw material and excipient ratio in Table 11, prepare smegglutinin dissolving microneedles according to the following steps:

[0142] (1) Preparation of microneedle matrix solution

[0143] Add the prescribed amount of Tween 80 to a centrifuge tube, then add the prescribed amount of water for injection, stir to dissolve, add the prescribed amount of Smeglucopyranoside, stir to dissolve, then add the prescribed amount of sodium betacyclodextrin and dextran (70,000 units) to the centrifuge tube, stir to dissolve, and finally add the prescribed amount of hyaluronic acid (240,000 units), stir until completely dissolved, place in a centrifuge, and centrifuge at 5000 rpm and 4°C for 3 minutes to remove air bubbles.

[0144] (2) Preparation of microneedle composition

[0145] 500 μL of the prepared matrix solution was added dropwise to the unit mold using a dispensing gun, spread evenly, and then the mold was subjected to negative pressure at room temperature until no solution remained on the surface. The microneedles were then allowed to air dry at room temperature before demolding. The theoretical drug content of the dissolved microneedles was 3 mg / 0.75 cm³. 2 .

[0146] (3) Figure 2 shows the thickness of the microneedle basement membrane in Example 1 (Figure 2(A)) and Comparative Example 3 (Figure 2(B)). The thickness of the microneedle basement membrane in Example 1 is only 31 μm, while the thickness of the microneedle basement membrane in Comparative Example 3 reaches 117 μm.

[0147] Microneedle puncture and solubility test

[0148] Take the fresh pork skin that has been stored in a -80℃ freezer and cut out several pieces, each about 2cm in size. 2 Pigskin was prepared and dried with lint-free paper, then laid out on a table with the stratum corneum facing upwards. Using the microneedles from Example 2, with the needle body facing the stratum corneum, the microneedle patch was pressed with a handheld LCD watch at a force of 4 kg for 20 seconds. The patch was then removed after 0 minutes and 3 minutes. Two drops of trypan blue solution were added to the pigskin after the patch was removed at 0 minutes. After standing for one hour, excess dye solution was wiped off, and the patch was photographed under a stereomicroscope, as shown in Figure 3(A). Clearly visible pinholes were observed on the pigskin, and the array was relatively complete, indicating that the microneedles had sufficient mechanical strength to penetrate the stratum corneum. The patch removed at 3 minutes was photographed under a microscope, as shown in Figure 3(B). The microneedle body had completely dissolved, indicating that the drug had been fully delivered into the skin. If the application time is extended, the drug can continue to be delivered into the skin based on the concentration gradient.

[0149] Microneedle delivery dose test

[0150] (1) Using isolated pig skin as a test receptor

[0151] Cut multiple 2cm pieces 2 Fresh pigskin was collected and dried with lint-free paper. The microneedles of Examples 1 and 3 were positioned with the needle body facing the keratin layer of the pigskin. A handheld LCD screen was used to press the microneedles with a force of 4 kg for 20 seconds. The pigskin with the patch was then transferred to an agarose gel. Three replicates were made at each time point. The patches were removed at 1, 3, 6, and 15 hours and collected in centrifuge tubes. An appropriate amount of 0.01 M PBS solution (pH = 7.4) was added to the centrifuge tubes, and the mixture was vortexed at 1000 rpm for 30 minutes to completely dissolve the residual patch. The solution was filtered through a 0.22 μm filter membrane, and the drug content of the residual microneedles was analyzed using high-performance liquid chromatography (HPLC) to calculate the delivery dose.

[0152] The delivery dose is calculated as: drug content in the patch - residual drug content in the microneedles.

[0153] Table 12 Delivery dose of microneedle patches applied to pigskin at different times in Example 1 and Comparative Example 3

[0154] As shown in Table 12, Example 1 achieved a drug delivery of 1.41 mg of smegglutide to the skin 15 hours after microneedle application, while Comparative Example 3 delivered a lower dose, only 0.221 mg. This indicates that a thinner microneedle basement membrane is more conducive to drug delivery.

[0155] (2) Using volunteers as test subjects

[0156] Multiple volunteers were selected and used the microneedle patches described in Examples 2-4. The microneedle body was positioned with the patch facing the back of the hand. A handheld LCD screen was used to press the microneedle with a force of 4 kg for 20 seconds. The patch was then removed directly after 15 hours and collected in centrifuge tubes. An appropriate amount of 0.01M PBS solution (pH = 7.4) was added to the centrifuge tubes, and the mixture was vortexed at 1000 rpm for 30 minutes to completely dissolve any remaining patch. The solution was filtered through a 0.22 μm filter membrane, and the drug content of the remaining microneedles was analyzed using high-performance liquid chromatography (HPLC) to calculate the delivery dose.

[0157] Table 13 Delivery dose of microneedle patches applied to the back of the hand in Examples 2-8, 15 hours after application.

[0158] As shown in Table 13, after 15 hours of microneedle application, volunteers in Examples 2–8 all achieved at least 0.770 mg / 0.75 cm⁻¹. 2 Drug delivery.

[0159] Microneedle mechanical property testing

[0160] Mechanical properties were tested using the semaglutide dissolving microneedles prepared in Example 3. The microneedle patch was fixed to the test platform below a force-stroke tester using pressure-sensitive adhesive, with the needle tips facing upwards and perpendicularly aligned with the mechanical sensor probe above. At the start of the test, the sensor probe moved vertically downwards at a longitudinal speed of 1.1 mm / s, applying a longitudinal force to the microneedle array, with a maximum force of 10 N. The computer simultaneously recorded the curves of the longitudinal force on the microneedles versus the probe's movement distance. The tested patch was placed under a microscope, and the number of microneedles subjected to force was recorded. The obtained data were plotted as a mechanical property curve, as shown in Figure 4. The compressive force of a single microneedle was greater than 0.058 N (the minimum compressive force that can penetrate the skin according to the literature), indicating that the semaglutide dissolving microneedles have sufficient mechanical strength to penetrate the stratum corneum for drug delivery.

[0161] In vitro release test

[0162] In vitro release tests were conducted using the semaglutide dissolution microneedles prepared in Example 4, with three batches repeated. The microneedle patch was fixed to the inner wall of the reciprocating cylinder near the bottom using double-sided tape. The reciprocating cylinder was then placed in a dissolution vessel containing 0.01M PBS phosphate buffer. Release conditions were set as follows: temperature 32±0.5℃, stroke 4cm, flushing volume 10ml, sample volume 3ml, replenishment volume 3ml, valve hold time 2s, sampling advance time 55s, and running speed 25dpm. After start-up, samples were taken at 5, 10, 15, 20, 25, 30, 35, and 40 minutes. The sample solutions were filtered through a 0.22μm filter membrane and analyzed by high-performance liquid chromatography (HPLC). The cumulative release rate at each time point was calculated. The cumulative release curve is shown in Figure 5. After 15 minutes, the cumulative release rate of semaglutide reached over 90%, and after 20 minutes, the cumulative release of semaglutide tended to reach equilibrium. The in vitro release curves of these three batches showed good parallelism, indicating that the smegglutide microneedle formulation has high reproducibility.

[0163] Pharmacokinetic studies

[0164] The smegglutinin dissolving microneedles and injection solution prepared in Example 4 were used for pharmacokinetic studies.

[0165] The microneedles prepared in Example 4 were cut into half-patches and quarter-patches using a scalpel; one patch (3mg / 0.75cm) was then used to cut the microneedles into half-patches and quarter-patches. 2 ), 1 / 2 patch (1.5mg / 0.38cm) 2 ), 1 / 4 patch (0.75mg / 0.19cm) 2These were used as high, medium, and low dose groups, respectively. Pharmacokinetic experiments were conducted using male SD rats weighing 220±20g. Twenty male SD rats were randomly divided into four groups of four rats each, and each group was labeled. One day prior to the experiment, all abdominal hair was removed from the rats and treated with depilatory cream. High, medium, and low microneedle administration groups: After anesthetizing rats with isoflurane, one, half, and one-quarter patches of microneedles were applied to the abdominal skin for 20 seconds, respectively. The rat abdomen was then wrapped with medical tape. After 12 hours, the remaining patches were removed from the skin, collected in centrifuge tubes, and the drug was extracted from the patches using PBS solution. The drug content was analyzed by high-performance liquid chromatography. Subcutaneous injection group: After anesthetizing rats with isoflurane, 0.5 mL of smegglutide solution (0.5 / mL) was injected subcutaneously into the abdomen of each rat using a 1 mL syringe. The dosage was 0.25 mg / rat. Blood samples were collected from the orbital cavity at 1, 3, 6, 8, 12, 24, 48, and 72 hours after drug administration. Rats were briefly anesthetized with isoflurane before each blood collection. Whole blood was collected in EDTAK2 centrifuge tubes, shaken, and centrifuged at 1600 x g for 10 min at 4°C. The supernatant was collected, and the smegglutinin content in the blood samples was analyzed using liquid chromatography-mass spectrometry (LC-MS / MS), and pharmacokinetic curves were plotted.

[0166] As a control, semaglutide dissolving microneedles were applied to the abdomen of rats to study the pharmacokinetics of semaglutide. The pharmacokinetic curves after administration are shown in Figure 6. It can be seen that the medium-dose microneedle group and the injection group have similar pharmacokinetic behavior, with peak plasma concentrations of 5390 ng / mL and 4038 ng / mL, respectively. 6–8 hours after administration, the peak plasma concentrations of the high-, medium-, and low-dose microneedle groups and the injection group all reached their respective levels. This indicates that microneedle administration can achieve the same effect as the original drug's injection administration. Furthermore, the peak concentrations of the high-, medium-, and low-dose microneedle groups showed a significant dose-dependent relationship.

[0167] The present invention has been described above with reference to the embodiments. It should be understood that the present invention is not limited to the specific embodiments described above. For those skilled in the art, various modifications or variations can be made within the scope of the claims, which do not affect the substantive content of the present invention.

Claims

1. A microneedle composition containing an active ingredient, characterized in that, The microneedle composition comprises an active component, a biodegradable polymer material, and a surfactant, with the balance being a solvent. The active component comprises 1-15% by weight, the biodegradable polymer material comprises 0.1-15% by weight, and the surfactant comprises 0.05-5% by weight, based on the total weight of the microneedle composition. The weight ratio of the active component to the biodegradable polymer material is 5:1 to 1:10; The biodegradable polymer materials include both macromolecular framework materials and small molecule rapidly dissolving materials. The macromolecular framework material includes one or more of hyaluronic acid and sodium alginate; the small molecule rapidly dissolving material includes one or more of water-soluble cyclodextrin, dextran, trehalose, sucrose, polyglutamic acid, pullulan, and Bletilla striata polysaccharide. The weight ratio of the macromolecular framework material to the small molecule rapidly dissolving material is 5:1-1:10; The surfactant is selected from one or more of Tween, Span, propylene glycol, glycerin, and polyethylene glycol; the solvent is water for injection.

2. The microneedle composition according to claim 1, characterized in that, The active component is a GLP-1 receptor agonist polypeptide, specifically liraglutide, semaglutide, dulaglutide, exenatide microspheres, benaglutide, and polyethylene glycol loxenatide.

3. The microneedle composition according to claim 1, characterized in that, The hyaluronic acid has a molecular weight of 80,000 to 800,000; the dextran has a molecular weight of 40,000 or 70,000; and the water-soluble cyclodextrin is selected from one or more of sodium sulfobutyl ether beta-cyclodextrin, methyl beta-cyclodextrin, and hydroxypropyl beta-cyclodextrin.

4. The microneedle composition according to claim 1, characterized in that, The weight ratio of the active component to the biodegradable polymer material is 2:1 to 1:

5.

5. The microneedle composition according to claim 1, characterized in that, The weight ratio of the macromolecular framework material to the small molecule rapidly dissolving material is 3:1 to 1:

2.

6. A soluble microneedle patch, characterized in that, It includes a substrate and a needle on the substrate; the substrate and the needle are made of the same material, including the microneedle composition as described in any one of claims 1-5.

7. The soluble microneedle patch according to claim 6, characterized in that, In the microneedle patch, the film thickness of the substrate is 10-60 μm, and the drug loading of the microneedle patch is greater than or equal to 1 mg / 0.75 cm2.

8. A method for preparing a soluble microneedle patch as described in any one of claims 6-7, characterized in that, The process includes the following steps: dissolving the active component in an aqueous solution containing a surfactant, then adding a biodegradable polymer material and stirring to dissolve it into a solution of the microneedle composition; taking an appropriate amount of the microneedle composition solution, dropping it into a mold, coating it evenly, applying negative pressure, drying it, and removing it from the mold to obtain the soluble microneedle patch.

9. Use of the microneedle composition according to any one of claims 1-5, or the soluble microneedle patch according to any one of claims 6-7, or the soluble microneedle patch prepared by the preparation method according to claim 8 in the preparation of a medicament for treating metabolic-related diseases; wherein the metabolic-related diseases are selected from diabetes, hyperglycemia, and obesity.

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