A semaglutide peptide soluble microneedle patch, and a preparation method and use thereof

Abstract

The present application relates to a soluble microneedle patch of semaglutide and a preparation method and use thereof. The soluble microneedle patch of semaglutide comprises a drug-loaded needle tip layer and a back plate layer; the drug-loaded needle tip layer comprises semaglutide and a needle tip layer matrix material; the weight percentage of the semaglutide is 85% to 92% and the weight percentage of the needle tip layer matrix material is 8% to 15% based on the total weight of the drug-loaded needle tip layer being 100%; and the needle tip layer matrix material is hyaluronic acid or a salt thereof. The soluble microneedle patch of semaglutide has excellent needle type, superior mechanical strength and skin puncture performance, high safety, fast drug release and penetration rate, and excellent drug utilization rate and bioavailability; the preparation method is simple, controllable, and suitable for large-scale production. In addition, the soluble microneedle patch of semaglutide is convenient and quick to administer, has high patient compliance, and has a broad clinical application prospect.

Description

Technical Field

[0001] This invention relates to the field of biomedicine, and in particular to a smegglutinin soluble microneedle patch, its preparation method, and its uses. Background Technology

[0002] Smegglutide is a long-acting glucagon-like peptide-1 (GLP-1) receptor agonist with the molecular formula C. 187 H 291 N 45 O 59 With a molecular weight of 4113.57754, it is based on the natural human GLP-1 molecule, by replacing the 8th amino acid (alanine → α-aminobutyric acid) and the 34th amino acid (lysine → arginine), while the lysine at the 26th position is linked to C via a spacer group. 18 The fatty acid diacid side chain retains up to 94% homology with the GLP-1 amino acid sequence. Through modification of the human GLP-1 molecule, smegglutide has achieved resistance to dipeptidyl peptidase-4 (DPP-4) degradation, tight binding to albumin, a significantly prolonged half-life in vivo, allowing for once-weekly dosing, and exhibits good safety. Smegglutide has broad therapeutic effects; clinical studies have shown good efficacy in treating type I or II diabetes, obesity, cardiovascular risk or disease, diabetic nephropathy, Alzheimer's disease, intermittent claudication, non-alcoholic steatohepatitis, stroke, myocardial infarction, polycystic ovary syndrome, heart failure with preserved ejection fraction, peripheral artery disease, ischemic stroke, nicotine addiction (smoking cessation), asthma, alcohol addiction, liver fibrosis, uterine diseases, and liver diseases.

[0003] Currently, semaglutide is available in both injectable and oral tablet forms. Injectable administration causes significant pain and has low patient compliance, while oral administration has extremely low bioavailability, only 0.9-1.2%.

[0004] Soluble microneedles, as a novel transdermal drug delivery technology, can alleviate pain associated with injections and avoid the first-pass effect and adverse gastrointestinal reactions. By arranging micron-sized microneedles on a patch, the microneedle tips pierce the stratum corneum of the skin, opening channels for transdermal drug delivery and facilitating drug transport. Soluble microneedles are mostly prepared from biocompatible, low-toxicity, highly malleable, and low-cost soluble or biodegradable polymers and carbohydrates. However, due to the large molecular weight of smegglutinin, it tends to remain in the epidermal layer after microneedle administration and is difficult to enter the bloodstream, resulting in low bioavailability.

[0005] Several methods have been reported to attempt to improve the bioavailability of semaglutide microneedles. Chinese patent CN114470170B discloses a semaglutide-soluble microneedle composition and its preparation method. It discloses that hyaluronic acid is an important component of the skin's extracellular matrix, and its function in the tissue matrix is ​​to restrict the diffusion of water and other extracellular substances, including drugs. This patent addresses the problem of low bioavailability of semaglutide microneedles due to the large molecular weight of semaglutide making it difficult to penetrate the bloodstream, thus causing it to remain within the epidermal layer.

[0006] To address the technical problem of semaglutide's strong binding force in the subcutaneous tissue after microneedle administration, which hinders its entry into the bloodstream and results in low bioavailability, Chinese patent CN114272511B employs the addition of amino acids as a penetration enhancer to improve the release and penetration rate of semaglutide in the skin, thereby increasing the concentration of the drug entering the bloodstream.

[0007] Chinese patent CN112274633B describes the preparation of smegglutide microneedles by mixing smegglutide with specific types of penetration-enhancing components, small molecule protective agents, and macromolecular backbone materials in a certain amount in an aqueous solution containing a pH buffer. Through the rational combination of each component, the resulting smegglutide microneedle patch has good mechanical strength, while improving the penetration rate of smegglutide in the skin and accelerating the diffusion of smegglutide into the blood in the skin tissue, thereby improving its absorption and utilization rate.

[0008] However, because microneedles pierce the stratum corneum of the skin during use, they can disrupt the skin's natural barrier function to some extent. Furthermore, the addition of penetration enhancers and other additives can easily cause skin irritation and other safety issues, posing a particularly high risk to individuals with sensitive skin. In addition, microneedles need sufficient mechanical strength to pierce the skin. To prepare smegglutide microneedles with sufficient mechanical strength, the aforementioned existing patents all incorporate a large amount of macromolecular framework materials into the needle body.

[0009] Chinese patent application CN118453547A also relates to a semaglutide soluble microneedle composition. It discloses that the macromolecular backbone material helps maintain the integrity of the microneedles without hindering drug release, while the small-molecule rapidly dissolving material enables rapid drug delivery. The combination of these two materials creates microneedles with a high loading of active ingredients and sufficient mechanical strength to penetrate the skin. Furthermore, this patent argues that when the delivered drug is a macromolecular drug, the dosage delivered by layered microneedles is usually limited, failing to achieve good bioequivalence with existing dosage forms. Therefore, it employs an integrated microneedle, which also results in lower drug utilization.

[0010] Therefore, there is a need to develop a semaglutide soluble microneedle patch with good mechanical strength and skin punctureability, as well as improved safety, drug utilization and bioavailability to meet market demand. Summary of the Invention

[0011] To address the aforementioned technical problems, this invention provides a semaglutide soluble microneedle patch, its preparation method, and its uses. The semaglutide soluble microneedle patch exhibits good mechanical strength and skin puncture resistance, high safety, high drug permeability, and excellent drug utilization and bioavailability.

[0012] To solve the above-mentioned technical problems, the present invention provides the following technical solution: The first aspect of this invention provides a semaglutide soluble microneedle patch, comprising a drug-loaded needle tip layer and a backing layer; wherein the drug-loaded needle tip layer comprises semaglutide and a needle tip layer matrix material; based on the total weight of the drug-loaded needle tip layer as 100%, the weight percentage of semaglutide is 85%~92%, and the weight percentage of the needle tip layer matrix material is 8%~15%; the needle tip layer matrix material is hyaluronic acid or a salt thereof; Preferably, the hyaluronic acid salt is sodium hyaluronate.

[0013] Preferably, based on the total weight of the drug-loaded needle tip layer as 100%, the weight percentage of the smegglutinin is 88% to 92%, and the weight percentage of the needle tip layer matrix material is 8% to 12%.

[0014] Preferably, the needle tip matrix material is hyaluronic acid or its salt with a molecular weight of 4k to 8k; More preferably, the needle tip matrix material is hyaluronic acid or its salt with a molecular weight of 4k to 6k; More preferably, the needle tip matrix material is sodium hyaluronate with a molecular weight of 4k to 8k; More preferably, the needle tip matrix material is sodium hyaluronate with a molecular weight of 4k, 5k, 6k, 7k or 8k.

[0015] Preferably, the backsheet layer is made of a backsheet layer solution containing a backsheet material.

[0016] Preferably, the backing material is hyaluronic acid or a salt thereof; More preferably, the backing material is hyaluronic acid or its salt with a molecular weight of 2w to 6w; More preferably, the backplate material is sodium hyaluronate with a molecular weight of 3w to 5w.

[0017] Preferably, the drug loading of the microneedles in the smegglutinin soluble microneedle patch is 0.25 mg / cm³.2 ~ 5 mg / cm 2 .

[0018] A second aspect of the present invention provides a method for preparing the semaglutide soluble microneedle patch described in the first aspect of the present invention, comprising the following steps: S1: Inject the needle tip solution containing smegglutinin and needle tip matrix material into the mold to obtain the drug-loaded needle tip layer; S2: Inject a backplate layer solution containing backplate material into a mold above the drug-loaded needle tip layer obtained in step S1, and demold to obtain the smegglutinin soluble microneedle patch. Preferably, in step S1, before injecting the needle tip layer solution into the mold, a step of stirring and / or centrifugation is further included; Preferably, in step S1, when the needle tip layer solution is injected into the mold, a vacuum is drawn under the mold; Preferably, in step S1, after the step of injecting the needle tip layer solution into the mold, a drying step is further included; more preferably, the drying is carried out at 15~45°C, and even more preferably, the drying is carried out at room temperature; Preferably, in step S2, before injecting the backing layer solution into the mold, a step of stirring and / or centrifugation is further included; Preferably, in step S2, when the backsheet layer solution is injected into the mold, a vacuum is drawn below the mold; Preferably, in step S2, after injecting the backing layer solution into the mold, a drying step is further included; more preferably, the drying is carried out at 15~45°C, and even more preferably, the drying is carried out at room temperature.

[0019] Preferably, the solvent of the needle tip layer solution is selected from one or more of water, methanol, ethanol, isopropanol, propylene glycol, glycerol, dimethyl sulfoxide (DMSO), N,N-dimethylacetamide (DMA), and N-methylpyrrolidone (NMP); Preferably, the solvent of the backsheet layer solution is selected from one or more of water, methanol, ethanol, isopropanol, propylene glycol, glycerol, dimethyl sulfoxide (DMSO), N,N-dimethylacetamide (DMA), and N-methylpyrrolidone (NMP).

[0020] The third aspect of this invention provides the use of the smegglutide soluble microneedle patch described in the first aspect of this invention or the smegglutide soluble microneedle patch prepared by the preparation method described in the second aspect of this invention for the treatment and / or prevention of type I or type II diabetes, obesity, cardiovascular risk or disease, diabetic nephropathy, Alzheimer's disease, intermittent claudication, non-alcoholic steatohepatitis, stroke, myocardial infarction, polycystic ovary syndrome, heart failure with preserved ejection fraction, peripheral artery disease, ischemic stroke, nicotine addiction (smoking cessation), asthma, alcohol addiction, liver fibrosis, uterine disease, and / or liver disease.

[0021] Compared with the prior art, the beneficial effects of the present invention are as follows: This invention provides a semaglutide soluble microneedle patch, its preparation method, and its uses. The semaglutide soluble microneedle patch exhibits excellent needle shape, superior mechanical strength and skin puncture performance, high safety, rapid drug release and penetration rate, and high drug permeability, resulting in excellent drug utilization and bioavailability. Its preparation method is simple, highly controllable, and suitable for large-scale production. Furthermore, the semaglutide soluble microneedle patch offers convenient and rapid administration, high patient compliance, and broad clinical application prospects. Attached Figure Description

[0022] The accompanying drawings, which are included to provide a further understanding of this application and form part of this application, illustrate exemplary embodiments and are used to explain this application, but do not constitute an undue limitation of this application. In the drawings: Figure 1 This is a micronail morphology diagram of the smegglutinin soluble microneedle patch of Example 3 of the present invention under a microscope.

[0023] Figure 2 Blood drug concentration-time curves for subcutaneous administration of smegglutide injection to Bama miniature pigs and transdermal administration of the smegglutide soluble microneedle patch of Example 3 of the present invention. Detailed Implementation

[0024] To make the technical solution and beneficial effects of the present invention more apparent and understandable, a detailed description is provided below by listing specific embodiments. The accompanying drawings are not necessarily drawn to scale, and local features may be enlarged or reduced to more clearly show the details of the local features. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments that do not specify specific conditions are generally performed under conventional experimental conditions. Unless otherwise specified, all reagents and raw materials used in this invention are commercially available.

[0025] In the following description, numerous specific details are set forth in order to provide a more thorough understanding of this application. However, it will be apparent to those skilled in the art that this application can be practiced without one or more of these details. In other instances, to avoid confusion with this application, some technical features well-known in the art have not been described; that is, not all features of actual embodiments are described herein, nor are well-known functions and steps described in detail.

[0026] The terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of this application. When used herein, the singular forms “a,” “an,” and “the” are also intended to include the plural forms unless the context clearly indicates otherwise. It should also be understood that the terms “comprising” and / or “including,” when used in this specification, identify the presence of the stated features, integers, steps, operations, elements, and / or components, but do not exclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and / or groups. When used herein, the term “and / or” includes any and all combinations of the associated listed items.

[0027] To fully understand this application, detailed steps and structures will be presented in the following description to illustrate the technical solution of this application. Preferred embodiments of this application are described in detail below; however, in addition to these detailed descriptions, this application may have other implementation methods.

[0028] Unless otherwise defined, the technical and scientific terms used in this application have the same meanings as those in the technical and scientific field to which this application pertains.

[0029] Unless otherwise specified, the techniques or conditions described in the following embodiments are generally performed in accordance with conventional techniques or conditions described in the literature in this field, or in accordance with the product manual and the manufacturer's recommendations. All numerical ranges in the following embodiments include endpoint values.

[0030] The term "soluble microneedle patch" as used in this invention refers to a transdermal drug delivery system comprising a backplate and needles, wherein, after being applied to the skin of a human or animal for a period of time, at least a portion of the drug-containing needles can dissolve and release the drug into the human or animal body.

[0031] As used in this invention, the term "backplate" refers to a thin, flat support sheet used to fix the needle body, which comes into contact with the skin surface after the microneedle patch is applied to the skin.

[0032] As used in this invention, the term "needle body" refers to a micron-sized array of needles extending vertically from one side of the "backplate" for piercing the skin surface.

[0033] The term "integrated microneedle patch" as used in this invention refers to a microneedle in which the backplate and the needle body are integrally formed from the same material, and both the backplate and the needle body contain active pharmaceutical ingredients.

[0034] The term "layered microneedle patch" as used in this invention refers to a microneedle patch comprising at least two layers in the direction of the needle body, wherein each layer is made of a material containing different components. Common examples include the needle body and the backing plate being made of materials containing different components, or the needle body itself comprising at least two layers, each of which is made of a material containing different components.

[0035] The term "drug-loaded microneedle patch" as used in this invention refers to a microneedle patch in which the active pharmaceutical ingredient (API) is present at the tip of the microneedle body. The portion of the microneedle patch in which the API is added is called the "drug-loaded tip layer," and the portion containing the backing plate is called the "backing plate layer." In a preferred embodiment of this invention, no API is added to the tip of the needle body or to the backing plate. In this case, the entire portion of the needle body near the backing plate, excluding the drug-loaded tip layer, is referred to as the "backing plate layer." Even when no API is added to the backing plate layer, the backing plate layer may contain trace amounts of API due to factors such as drug diffusion during the preparation process. Such cases are all included within the scope of this invention.

[0036] The inventors of this invention unexpectedly discovered during extensive research that, contrary to the teachings of the prior art, the presence of either macromolecular framework materials or small molecule rapidly dissolving materials in the tip layer formulation of microneedle patches does not promote rapid drug release; on the contrary, it hinders drug release, especially when the content of macromolecular framework materials and small molecule rapidly dissolving materials is high.

[0037] Furthermore, high levels of macromolecular framework materials and rapidly dissolving small molecules are not essential for the microneedles of semaglutide microneedle patches to meet the requirements for shaping and mechanical strength. When the semaglutide content is increased to a certain level, only a small amount of needle tip matrix material is needed to prepare microneedles with complete needle shape and mechanical strength meeting the puncture requirements.

[0038] Furthermore, with the high semaglutide content of this invention, the drug release and penetration into the bloodstream are faster, resulting in higher drug permeability and bioavailability. Based on this, drug-loaded microneedle patches can be prepared to meet the required delivery dosage, improving drug utilization. Moreover, the needle-tip drug delivery method allows for the delivery of more drug to deeper areas under the skin, avoiding semaglutide retention in the epidermal layer. This invention achieves rapid penetration of semaglutide into the bloodstream without the need for penetration enhancers or other additives, resulting in a simple formulation and high safety.

[0039] The first aspect of this invention provides a semaglutide soluble microneedle patch, comprising a drug-loaded needle tip layer and a backing plate layer; wherein the drug-loaded needle tip layer comprises semaglutide and a needle tip layer matrix material; based on the total weight of the drug-loaded needle tip layer as 100%, the weight percentage of semaglutide is 85%~92%, and the weight percentage of the needle tip layer matrix material is 8%~15%; the needle tip layer matrix material is hyaluronic acid or a salt thereof.

[0040] In some embodiments, the hyaluronic acid salt is sodium hyaluronate.

[0041] At the above-mentioned concentrations, the needle tip layer prepared by mixing smegglutinin with the needle tip layer matrix material exhibits good formability and excellent mechanical strength.

[0042] In some embodiments, based on the total weight of the drug-loaded needle tip layer as 100%, the weight percentage of the smegglutinin is 88% to 92%, and the weight percentage of the needle tip layer matrix material is 8% to 12%. For example, the weight percentage of the smegglutinin may be 88%, 88.1%, 88.2%, 88.3%, 88.4%, 88.5%, 88.6%, 88.7%, 88.8%, 88.9%, 89%, 89.1%, 89.2%, 89.3%, 89.4%, 89.5%, 89.6%, 89.7%, 89.8%, 89.9%, 90%, 90.1%, 90.2%, 90.3%, 90.4%, 90.5%, 90.6%, 90.7%, 90.8%, 90.9%, 91%, 91.1%, 91.2%, 91.3%, 91.4%, 91.5%, 91.6%, 91.7%, 91.8%, 91.9%, 92%, or any of the above ranges. The weight percentage of the needle tip matrix material can be 12%, 11.9%, 11.8%, 11.7%, 11.6%, 11.5%, 11.4%, 11.3%, 11.2%, 11.1%, 11%, 10.9%, 10.8%, 10.7%, 10.6%, 10.5%, 10.4%, 10.3%, 10.2%, 10.1%, 10%, 9.9%, 9.8%, 9.7%, 9.6%, 9.5%, 9.4%, 9.3%, 9.2%, 9.1%, 9%, 8.9%, 8.8%, 8.7%, 8.6%, 8.5%, 8.4%, 8.3%, 8.2%, 8.1%, 8%, or any decimal or integer value within the above range.

[0043] In some embodiments, the needle tip matrix material is hyaluronic acid or its salt with a molecular weight of 4k to 8k.

[0044] In some embodiments, the needle tip matrix material is hyaluronic acid or its salt with a molecular weight of 4k to 6k.

[0045] In some embodiments, the needle tip matrix material is sodium hyaluronate with a molecular weight of 4k to 8k.

[0046] In some embodiments, the needle tip matrix material is sodium hyaluronate with a molecular weight of 4k, 5k, 6k, 7k, or 8k, or any decimal or integer value within the above range.

[0047] The inventors of this invention have discovered through research that hyaluronic acid or its salts have a small inhibitory effect on the release and penetration of semaglutide. Specifically, compared to high molecular weight hyaluronic acid or its salts, low molecular weight hyaluronic acid or its salts have an even smaller inhibitory effect on the release and penetration of semaglutide. Therefore, this invention preferably uses low molecular weight hyaluronic acid or its salts as the needle tip matrix material. This allows for rapid release of semaglutide and improves the drug penetration rate, thereby enhancing the drug utilization and bioavailability of semaglutide.

[0048] In some embodiments, the backsheet layer is made of a backsheet layer solution containing a backsheet material.

[0049] In some embodiments, the backsheet material is hyaluronic acid or a salt thereof.

[0050] In some embodiments, the backsheet material is hyaluronic acid or its salt with a molecular weight of 2w to 6w.

[0051] In some embodiments, the backsheet material is hyaluronic acid or its salt with a molecular weight of 4w to 6w.

[0052] In some embodiments, the backsheet material is sodium hyaluronate with a molecular weight of 3w to 5w.

[0053] In some embodiments, the backsheet material is sodium hyaluronate with a molecular weight of 5w.

[0054] In some embodiments, the drug loading of the microneedles in the semaglutide soluble microneedle patch is 0.25 mg / cm³. 2 ~ 5 mg / cm 2 For example, 0.25 mg / cm 2 0.5 mg / cm 2 0.75 mg / cm 2 1 mg / cm 2 1.25 mg / cm 2 1.5 mg / cm 2 1.75 mg / cm 2 2 mg / cm 22.25 mg / cm 2 2.5 mg / cm 2 2.75 mg / cm 2 3 mg / cm 2 3.25 mg / cm 2 3.5 mg / cm 2 3.75 mg / cm 2 4 mg / cm 2 4.25 mg / cm 2 4.5 mg / cm 2 4.75 mg / cm 2 5 mg / cm 2 Or any decimal or integer value within the above range.

[0055] A second aspect of the present invention provides a method for preparing the semaglutide soluble microneedle patch described in the first aspect of the present invention, comprising the following steps: S1: Inject the needle tip solution containing smegglutinin and needle tip matrix material into the mold to obtain the drug-loaded needle tip layer; S2: Inject a backplate layer solution containing backplate material into a mold above the drug-loaded needle tip layer obtained in step S1, and demold to obtain the smegglutinin soluble microneedle patch.

[0056] In some embodiments, the solvent of the needle tip layer solution is selected from one or more of water, methanol, ethanol, isopropanol, propylene glycol, glycerol, dimethyl sulfoxide (DMSO), N,N-dimethylacetamide (DMA), and N-methylpyrrolidone (NMP).

[0057] In some embodiments, the solvent for the needle tip layer solution is selected from water.

[0058] In some embodiments, the solvent of the backsheet layer solution is selected from one or more of water, methanol, ethanol, isopropanol, propylene glycol, glycerol, dimethyl sulfoxide (DMSO), N,N-dimethylacetamide (DMA), and N-methylpyrrolidone (NMP).

[0059] In some embodiments, the solvent for the backsheet layer solution is selected from water.

[0060] In some embodiments, the backsheet layer solution is composed of 10% to 25% backsheet material and 75% to 90% water, with the total weight of the backsheet layer solution being 100%.

[0061] In some embodiments, the backsheet layer solution is composed of 25% backsheet material and 75% water, with the total weight of the backsheet layer solution being 100%.

[0062] In some embodiments, step S1, before injecting the needle tip layer solution into the mold, further includes steps such as stirring and / or centrifugation.

[0063] In some embodiments, in step S1, when the needle tip layer solution is injected into the mold, a vacuum is drawn under the mold.

[0064] In some embodiments, step S1, after the step of injecting the needle tip layer solution into the mold, further includes a drying step.

[0065] In some embodiments, the drying is carried out at 15-45°C, more preferably at room temperature.

[0066] In some embodiments, step S2, before injecting the backing layer solution into the mold, further includes steps such as stirring and / or centrifugation.

[0067] In some embodiments, in step S2, when the backsheet layer solution is injected into the mold, a vacuum is drawn under the mold.

[0068] In some embodiments, step S2, after injecting the backing layer solution into the mold, further includes a drying step.

[0069] In some embodiments, the drying is carried out at 15-45°C, more preferably at room temperature.

[0070] The third aspect of this invention provides the use of the smegglutide soluble microneedle patch described in the first aspect of this invention or the smegglutide soluble microneedle patch prepared by the preparation method described in the second aspect of this invention in the preparation of medicaments for the treatment and / or prevention of type I or type II diabetes, obesity, cardiovascular risk or disease, diabetic nephropathy, Alzheimer's disease, intermittent claudication, non-alcoholic steatohepatitis, stroke, myocardial infarction, polycystic ovary syndrome, heart failure with preserved ejection fraction, peripheral artery disease, ischemic stroke, nicotine addiction (smoking cessation), asthma, alcohol addiction, liver fibrosis, uterine diseases, and / or liver diseases.

[0071] The method of the present invention will be described below through specific embodiments. It should be understood that these embodiments are used to illustrate the basic principles, main features and advantages of the present invention, and the present invention is not limited to the scope of the following embodiments. The implementation conditions used in the embodiments can be further adjusted according to specific requirements, and the implementation conditions not specified are usually the conditions in conventional experiments.

[0072] Examples 1 to 11 The microneedle patches of Examples 1 to 11 of this invention were prepared according to the formulations of the tip layer solution and backing plate solution listed in Table 1, following the steps described below (each patch had a drug loading of 1 mg / cm²). 2 ): (1) Weigh each component of the needle tip layer solution according to the prescription in Table 1 and place them in a centrifuge tube. Stir the solution to completely dissolve the matrix material, centrifuge to remove air bubbles, and obtain the needle tip layer solution. Let it stand for later use. (2) Add the needle tip layer solution to the microneedle mold, evacuate the bottom of the mold to allow the solution to enter the cavity of the mold, and place it at room temperature to dry; (3) Weigh each component of the backplate solution according to the prescription in Table 1 and place them in a centrifuge tube. Stir the solution to completely dissolve the matrix material, centrifuge to remove air bubbles, and obtain the backplate solution. Let it stand for later use. (4) Use a continuous pipette to drop the backing layer solution onto the microneedle mold with the prepared needle tip, spread the solution evenly, evacuate the bottom of the mold to allow the solution to enter the cavity of the mold, and place it at room temperature to dry; (5) Remove the microneedle patch from the mold.

[0073] Table 1. Distribution ratio of each group of microneedle patches in Examples 1 to 11

[0074] Microscopic observation of the morphology of the microneedle patches obtained in Examples 1 to 11 revealed that each microneedle patch was intact and undamaged, and the microneedles had sharp tips. An axial force of 15 mN was applied to a single microneedle, and the mechanical strength of the microneedle was evaluated by whether it broke. Its puncture resistance was evaluated by whether the microneedle could puncture the detached pig skin. The results showed that the mechanical strength of the microneedles obtained in Examples 1 to 11 of this invention was appropriate and the puncture resistance was good. Subsequent in vivo patching experiments were conducted on Bama miniature pigs. Figure 1 The image shows the morphology of the smegglutinin microneedle patch obtained in Example 3 of the present invention as observed under a microscope.

[0075] Comparative Examples 1 to 6 Microneedle patches of Comparative Examples 1 to 6 were prepared using the same method as in Examples 1 to 11, according to the formulations of the tip layer solution and backing plate solution listed in Table 2 (each patch had a drug loading of 1 mg / cm²). 2 ): Table 2. Distribution ratio of microneedle patches in each group of Comparative Examples 1 to 6

[0076] Microscopic observation of the microneedle patches obtained in Comparative Examples 1 to 6 revealed that each patch was intact and undamaged, with sharp needle tips. An axial force of 15 mN was applied to each microneedle, and the mechanical strength was evaluated by whether it broke. The puncture resistance was assessed by whether the microneedles could puncture detached pig skin. The results showed that the microneedles obtained in Comparative Example 1 lacked sufficient mechanical strength and could not puncture detached pig skin; while the microneedles obtained in Comparative Examples 2 to 6 possessed sufficient mechanical strength and could puncture detached pig skin. Therefore, the microneedle patches obtained in Comparative Examples 2 to 6 were selected for subsequent in vivo patching experiments on Bama miniature pigs.

[0077] Example 1 This efficacy example evaluates the drug release performance of each microneedle patch by calculating the drug permeability of the microneedle patches applied to Bama miniature pigs in the embodiments and comparative examples of this application, and examines skin irritation by observing the skin condition at the application site.

[0078] Experimental subjects: 8 healthy male Bama miniature pigs, 30 days old, weighing 2.5-3.0 kg.

[0079] Hair removal was performed on the back of the Bama miniature pigs at the application site before application. The release film was removed, and the microneedle patches of Examples 1-11 and Comparative Examples 2-6 of this invention were applied to the treated skin, with two patches applied to each sample (each patch being 1 cm thick). 2 Four patches were applied to each pig, pressing firmly for 30 seconds to 1 minute. First, a silicone pad of similar size to the microneedle patch was used to cover it, then adhesive tape was used for further fixation, followed by a backing and self-adhesive bandage. After fixation, the Bama miniature pigs were returned to their cages and allowed to move freely. No abnormalities were observed during the application test, and the microneedle patches were well-fixed. The microneedle patches were removed 24 hours after application, and the drug residue was measured. The drug permeability was calculated (drug permeability = (drug content of patch - drug residue) / drug content of patch), and the average value was taken. Skin irritation at the application site was also observed. The experimental results are shown in Table 3. Table 3 Results of drug penetration rate and skin irritation test

[0080] As shown in Table 3, the microneedle patches of Examples 1-11 of this invention resulted in good skin condition in Bama miniature pigs after application, indicating that the microneedle patches obtained in Examples 1-11 were non-irritating to the skin. The patches of Examples 1-11 of this invention all exhibited good drug permeability, significantly higher than that of the microneedle patches of Comparative Examples 2-6. Furthermore, the experimental results showed that the addition of glycine did not improve drug release performance.

[0081] To accelerate microneedle dissolution and drug release, the art typically involves adding small-molecule, rapidly dissolving materials to accelerate tip disintegration, creating pores in the microneedles to facilitate drug release. However, the inventors of this invention discovered through the aforementioned research that the presence of both macromolecular framework materials such as sodium hyaluronate and small-molecule, rapidly dissolving materials such as dextran and trehalose dihydrate hinders the release of smegglutinin, and the higher the content of these excipients, the greater the hindering effect on smegglutinin release. This invention, by controlling the content of excipients in the needle tip within a certain range, yields microneedles that meet both mechanical strength requirements and good release performance.

[0082] Example 2 1. Drug Information Smegglutinin microneedle patch: Smegglutinin microneedle patch of Example 3 of the present invention.

[0083] Smegglutide injection: Novo Nordisk. Batch number: 202209BAP1, Specification: 3ml / vial / box, Content: 1.34mg / ml.

[0084] 2. Experimental animals Healthy Bama miniature pigs, 30 days old, female, weight: 2.5-3.5kg.

[0085] 3. Dosing regimen Bama miniature pigs were divided into a semaglutide microneedle patch group and a semaglutide injection group. In the microneedle patch group, each Bama miniature pig received a dose of 4 mg (1 mg / patch × 4). Hair was removed from the application site before patching. The microneedle side was applied to the pre-treated skin, the needle tips were pressed firmly into the skin, and the patch was secured with silicone and then wrapped with adhesive tape. The patch was removed after 24 hours. In the semaglutide injection group, each Bama miniature pig received a subcutaneous injection of 1 mg.

[0086] 4. Sample Collection Whole blood samples were collected before administration and at 6, 12, 24, and 48 hours after administration, with approximately 0.4 mL collected at each time point. The samples were placed in blood collection tubes containing EDTA-K2. The whole blood was centrifuged at 2-8 °C, 2000 g, for 10 min within 1 hour of collection. The supernatant was then transferred to a new EP tube with a volume of at least 200 µL. The plasma samples were placed in an ultra-low temperature freezer. After the experiment, the plasma samples were transferred to the biological laboratory and stored in an ultra-low temperature freezer.

[0087] Sample collection follows the relevant SOP (Standard Operating Procedure).

[0088] 5. Biological sample analysis The collected samples were detected using an established and validated LC-MS / MS sample detection method.

[0089] 6. Data Statistics The experimental data were statistically analyzed using WinNonlin software, and pharmacokinetic parameters were calculated. The results are shown in [Figure number missing]. Figure 2 .

[0090] 7. Results After the application of the semaglutide microneedle patch to Bama miniature pigs and the subcutaneous injection of the commercially available control product semaglutide injection to Bama miniature pigs, the time to peak blood concentration (Tmax) in both Bama miniature pigs was 12 hours, indicating that the pharmacokinetic trends of the two administration methods were similar.

[0091] In Bama miniature pigs, after applying four 1mg / patches of the semaglutide microneedle patch of the present invention, the peak plasma concentration (Cmax) was 2751.14 ng / ml. After dose normalization, the theoretical Cmax of a single patch was approximately 687.79 ng / ml, which is close to the Cmax value of Bama miniature pigs after subcutaneous injection of the commercially available control product semaglutide injection. After dose normalization, the relative bioavailability of a single patch compared to subcutaneous injection was approximately 44.45%.

[0092] It should be understood that the above embodiments are exemplary and are not intended to encompass all possible implementations included in the claims. Various modifications and changes can be made to the above embodiments without departing from the scope of this disclosure. Similarly, the various technical features of the above embodiments can be arbitrarily combined to form other embodiments of the present invention that may not be explicitly described. Therefore, the above embodiments only illustrate several implementations of the present invention and do not limit the scope of protection of this patent.

Claims

1. A semaglutide-soluble microneedle patch, characterized in that, Including the drug-loaded needle tip layer and the backing plate layer; The drug-loaded needle tip layer comprises smegglutinin and a needle tip layer matrix material; Based on the total weight of the drug-loaded needle tip layer as 100%, the weight percentage of the smegglutinin is 85%~92%, and the weight percentage of the needle tip layer matrix material is 8%~15%. The needle tip matrix material is hyaluronic acid or its salt; Preferably, the hyaluronic acid salt is sodium hyaluronate.

2. The smegglutinin soluble microneedle patch according to claim 1, characterized in that, Based on the total weight of the drug-loaded needle tip layer as 100%, the weight percentage of the smegglutinin is 88%~92%, and the weight percentage of the needle tip layer matrix material is 8%~12%.

3. The smegglutinin soluble microneedle patch according to claim 1 or 2, characterized in that, The needle tip matrix material is hyaluronic acid or its salt with a molecular weight of 4k to 8k; Preferably, the needle tip matrix material is hyaluronic acid or its salt with a molecular weight of 4k to 6k; Preferably, the needle tip matrix material is sodium hyaluronate with a molecular weight of 4k to 8k; Preferably, the needle tip matrix material is sodium hyaluronate with a molecular weight of 4k, 5k, 6k, 7k or 8k.

4. The smegglutinin soluble microneedle patch according to any one of claims 1-3, characterized in that, The backsheet layer is made of a backsheet layer solution containing backsheet material.

5. The smegglutinin soluble microneedle patch according to any one of claims 1-4, characterized in that, The backplate material is hyaluronic acid or its salt; Preferably, the backing material is hyaluronic acid or its salt with a molecular weight of 2w to 6w; More preferably, the backplate material is sodium hyaluronate with a molecular weight of 3w to 5w.

6. The smegglutinin soluble microneedle patch according to any one of claims 1-5, characterized in that, The drug-loaded needle tip layer is prepared from a needle tip layer solution containing smegglutinin and a needle tip layer matrix material; The needle tip layer solution comprises 5% to 15% smegglutinin and 0.5% to 2.6% needle tip layer matrix material, with the total weight of the needle tip layer solution being 100%.

7. The smegglutinin soluble microneedle patch according to any one of claims 1-6, characterized in that, The drug loading of the microneedles in the semaglutide soluble microneedle patch is 0.25 mg / cm³. 2 ~ 5 mg / cm 2 .

8. A method for preparing a smegglutinin soluble microneedle patch according to any one of claims 1-7, characterized in that, The preparation method includes the following steps: S1: Inject the needle tip solution containing smegglutinin and needle tip matrix material into the mold to obtain the drug-loaded needle tip layer; S2: Inject a backplate layer solution containing backplate material into a mold above the drug-loaded needle tip layer obtained in step S1, and demold to obtain the smegglutinin soluble microneedle patch. Preferably, in step S1, before injecting the needle tip layer solution into the mold, a step of stirring and / or centrifugation is further included; Preferably, in step S1, when the needle tip layer solution is injected into the mold, a vacuum is drawn under the mold; Preferably, in step S1, after the step of injecting the needle tip layer solution into the mold, a drying step is further included; more preferably, the drying is carried out at 15~45°C, and even more preferably, the drying is carried out at room temperature; Preferably, in step S2, before injecting the backing layer solution into the mold, a step of stirring and / or centrifugation is further included; Preferably, in step S2, when the backsheet layer solution is injected into the mold, a vacuum is drawn below the mold; Preferably, in step S2, after injecting the backing layer solution into the mold, a drying step is further included; more preferably, the drying is carried out at 15~45°C, and even more preferably, the drying is carried out at room temperature.

9. The preparation method according to claim 8, characterized in that, The solvent of the tip layer solution is selected from one or more of water, methanol, ethanol, isopropanol, propylene glycol, glycerol, dimethyl sulfoxide (DMSO), N,N-dimethylacetamide (DMA), and N-methylpyrrolidone (NMP); the solvent of the backsheet layer solution is selected from one or more of water, methanol, ethanol, isopropanol, propylene glycol, glycerol, dimethyl sulfoxide (DMSO), N,N-dimethylacetamide (DMA), and N-methylpyrrolidone (NMP).

10. The use of the smegglutide soluble microneedle patch according to any one of claims 1-7 or the smegglutide soluble microneedle patch prepared according to the preparation method according to claim 8 or 9 in the preparation of medicaments for the treatment and / or prevention of type I or type II diabetes, obesity, cardiovascular risk or disease, diabetic nephropathy, Alzheimer's disease, intermittent claudication, non-alcoholic steatohepatitis, stroke, myocardial infarction, polycystic ovary syndrome, heart failure with preserved ejection fraction, peripheral artery disease, ischemic stroke, nicotine addiction (smoking cessation), asthma, alcohol addiction, liver fibrosis, uterine diseases, and / or liver diseases.

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