A liraglutide-containing microneedle composition with improved stability and its application.

Abstract

The present invention provides a composition for producing liraglutide-containing microneedles, which contains liraglutide as an active ingredient, does not denature the active ingredient during production, and maintains stability after production, and liraglutide-containing microneedles with improved stability produced from this composition. The composition for producing microneedles according to the present invention uses a specific combination of a biodegradable polymer, a stabilizer, and an antioxidant to prevent the denaturation of the active ingredient, liraglutide, during microneedle production, and maintains the stability of liraglutide after microneedle production.

Description

Technical Field

[0001] The present invention relates to a composition for liraglutide-containing microneedles with improved stability and its use. More specifically, it relates to a composition for liraglutide-containing microneedles that contains liraglutide as an active ingredient, has no denaturation of the active ingredient during production, and maintains stability after production, and to liraglutide-containing microneedles with improved stability produced from this composition.

Background Art

[0002] Liraglutide is a human GLP (glucagon like peptide)-1 analog that binds to and activates the GLP-1 receptor, has the effect of increasing glucose-dependent insulin secretion and suppressing inappropriate glucagon secretion, and is used as a therapeutic agent for type 2 diabetes and obesity. Liraglutide is sold under the product names Victoza for type 2 diabetes and Saxenda for obesity.

[0003] Currently, liraglutide is only used as a subcutaneous injection, which has the annoyance of disinfecting the injection site and injecting at a fixed time every day and the concern of secondary infection, and has the drawback that repeated injections may cause pain, bleeding, rash, and swelling at the injection site. In the case of self-injection agents, the patient himself / herself has to inject, so the compliance with taking medicine decreases due to fear and rejection, and the treatment effect also decreases accordingly.

[0004] In order to improve such problems, some attempts have been made to formulate it as microneedles, but a manufacturing method of microneedles containing liraglutide (Korean Patent Publication No. 10-2022-0151995) that does not bounce back from the skin surface layer, does not break or bend, and shortens the drug manufacturing time and is suitable for mass production has been disclosed.

[0005] On the other hand, liraglutide has low stability and is prone to denaturation due to various factors during the manufacturing process as a microneedle formulation, and its activity may also decrease due to denaturation during storage after manufacturing.

[0006] Therefore, there is a need to develop liraglutide-containing microneedles in which denaturation of liraglutide is prevented during manufacturing, thus maintaining its activity, and denaturation is also prevented during storage after manufacturing, resulting in improved stability. [Overview of the project] [Problems that the invention aims to solve]

[0007] To address the requirements of the prior art, the inventors conducted continuous research and, as a result, confirmed that liraglutide-containing microneedles manufactured using a specific combination of biodegradable polymer, stabilizer, and antioxidant surprisingly prevented denaturation of liraglutide during manufacturing, maintaining its activity, and also prevented denaturation during storage after manufacturing, improving stability. This led to the completion of the present invention.

[0008] Therefore, the object of the present invention is to provide a liraglutide-containing microneedle manufacturing composition with improved stability.

[0009] Another object of the present invention is to provide liraglutide-containing microneedles with improved stability produced from the above composition.

[0010] Another object of the present invention is to provide a microneedle patch for transdermal delivery of liraglutide, which includes the microneedles. [Means for solving the problem]

[0011] To achieve the aforementioned objective of the present invention, a liraglutide-containing microneedle manufacturing composition with improved stability is provided.

[0012] The present invention provides a liraglutide-containing microneedle manufacturing composition with improved stability, comprising liraglutide, a biodegradable polymer, a stabilizer, an antioxidant, and a solvent.

[0013] Liraglutide has the structure of chemical formula 1 and is a human GLP (glucagon-like peptide)-1 analog that binds to and activates the GLP-1 receptor, increasing glucose-dependent insulin secretion and suppressing inappropriate glucagon secretion. It is used in the treatment of type 2 diabetes and obesity.

[0014] [ka] In the compositions of the present invention, the biodegradable polymer is one that can be naturally biodegraded in the body and excreted from the body. At least one selected from the group consisting of hyaluronic acid or a salt thereof and carboxymethyl cellulose (CMC) can be used, with hyaluronic acid or a salt thereof being most preferably used. Compared with other types of biodegradable polymers, compositions for manufacturing microneedles containing these biodegradable polymers can prevent the denaturation of liraglutide and improve stability during microneedle manufacturing and storage.

[0015] In the composition of the present invention, the biodegradable polymer may be included in an amount of 10% to 20% by weight relative to the total composition (100% by weight).

[0016] In the composition of the present invention, the stabilizer plays a role in contributing to stability during microneedle production, and at least one selected from the group consisting of xylitol and trehalose can be used. Compared to other types of stabilizers, the microneedle production composition containing the stabilizer can ensure stable microneedle production while simultaneously preventing denaturation of liraglutide during microneedle production and storage, thereby improving stability.

[0017] In the composition of the present invention, the stabilizer may be included in an amount of 3% to 10% by weight relative to the total composition.

[0018] In the composition of the present invention, the antioxidant can be at least one selected from the group consisting of DPG (Dipotassium glycyrrhizinate) and EDTA. Compared to other types of antioxidants, the composition for manufacturing microneedles containing the antioxidant can prevent the denaturation of liraglutide and improve stability during microneedle manufacturing and storage.

[0019] In the composition of the present invention, the antioxidant may be present in proportion to the weight of liraglutide, i.e., in a weight ratio of liraglutide to antioxidant of 1:0.3 to 5.

[0020] In the composition of the present invention, liraglutide may be present in an amount of 0.1% to 2.0% by weight relative to the whole composition.

[0021] In the composition of the present invention, the solvent is water, preferably purified water (deionized water), or potassium phosphate buffer (PPB).

[0022] The composition of the present invention may further contain a pH adjusting agent as needed. Any one of those commonly used in microneedle manufacturing, such as NaOH, can be used as the pH adjusting agent. The composition of the present invention has a pH of 7.5 to 8.7, preferably 7.8 to 8.4.

[0023] Furthermore, the composition of the present invention may further contain, if necessary, plasticizers, surfactants, preservatives, etc., that are commonly used in the manufacture of microneedles.

[0024] In accordance with another object of the present invention, the present invention provides liraglutide-containing microneedles with improved stability produced with the above composition.

[0025] The microneedles of the present invention can include a needle portion protruding in one direction and a matrix layer supporting the needle portion. The needle portion has a shape that easily penetrates the skin. The shape of the needle portion of the microneedles according to the present invention can be conical, pyramidal, spherical, truncated, wedge-shaped, blade-shaped, etc., but these must all be shapes that can penetrate the skin. The length of the needle portion is 500 to 1000 μm, preferably 750 μm. The matrix layer has a thickness of 0.1 to 1 mm, preferably 0.1 to 0.3 mm. The needle portion of the microneedles of the present invention can be manufactured so as to be separated from the matrix layer when inserted into the skin if necessary. The composition according to the present invention can be used for manufacturing the needle portion and matrix layer of the microneedles, but if necessary, the matrix layer can also be manufactured from other materials. Therefore, in the microneedles of the present invention, liraglutide can be uniformly distributed in the needle portion and the matrix layer, or liraglutide may be distributed only in the needle portion.

[0026] The microneedles of the present invention are soluble microneedles that release liraglutide while being decomposed in vivo.

[0027] The microneedles of the present invention can be manufactured using a mold. According to another object of the present invention, there is provided a microneedle patch for transdermal delivery of liraglutide containing the microneedles.

[0028] In the microneedle patch of the present invention, an adhesive layer is laminated on one side of the matrix layer, and the microneedle patch can be used by attaching it to the skin. The microneedle patch can also include a protective film on the adhesive layer.

[0029] The microneedle patch for transdermal delivery of liraglutide of the present invention can be used for the treatment and improvement of obesity and for the treatment and improvement of type 2 diabetes.

Effects of the Invention

[0030] The microneedle manufacturing composition according to the present invention uses a specific combination of a biodegradable polymer, a stabilizer, and an antioxidant to prevent the denaturation of liraglutide, the active ingredient, during microneedle manufacturing, and to maintain the stability of liraglutide even after microneedle manufacturing.

[0031] The microneedle according to the present invention is a liraglutide-containing microneedle in which denaturation of liraglutide is prevented during manufacturing, thus maintaining its activity, and denaturation is also prevented during storage after manufacturing, resulting in improved stability.

[0032] The transdermal microneedle patch according to the present invention has improved stability of the active ingredient liraglutide and is useful for the treatment and improvement of obesity and type 2 diabetes. [Brief explanation of the drawing]

[0033] [Figure 1] Figure 1 is a graph showing the results of stability analysis using biodegradable polymers. [Figure 2] Figure 2 is a graph showing the results of the stability analysis using stabilizers. [Figure 3] Figure 3 is a photograph of the microneedle according to the present invention. [Figure 4] Figure 4 is a graph showing the stability analysis results of the microneedle according to the present invention. [Modes for carrying out the invention]

[0034] The following describes the structure and effects of the present invention in more detail through specific examples to aid in understanding the present invention. However, the following examples are merely illustrative to make the present invention clearer, and the scope of the present invention is not limited by the following examples.

[0035] Manufacturing Example 1: Production of a composition for manufacturing microneedles using biodegradable polymers. To select biodegradable polymers suitable for the production of liraglutide-containing microneedles with improved stability, compositions for microneedle production were prepared using the biodegradable polymers shown in Table 1, manufactured in film form (thin film), and tested for stability.

[0036] [Table 1] Specifically, liraglutide and biodegradable polymer were weighed into 1 ml of purified water (Deionized water; DW) as shown in Table 1, placed in a cup tube, dissolved for 5 minutes using a shaking mixer, and then dried in a dryer at 25°C for 24 hours. The solvent was then completely evaporated using an evaporator under nitrogen to produce a film (thickness 50-100 μm) that could simulate microneedles. The produced films were subjected to stability analysis immediately after production and after being stored for 1 week in a constant temperature and humidity stability chamber at 25°C under 60% accelerated conditions.

[0037] Specifically, for the stability analysis, the entire volume of each film sample was added to 5 ml of a dilution solvent (a 1:1 mixed solvent of Phosphate buffer solution pH 3.5 and 78% Acetonitrile), mixed by shaking, and then quantitative analysis of liraglutide was performed using the HPLC method under the conditions shown in Table 2 below. The results are shown in Table 3 and Figure 1. [Table 2]

[0038] [Table 3] As shown in Table 3 and Figure 1, when hyaluronic acid and CMC were used as biodegradable polymers, it was confirmed that the denaturation of liraglutide was prevented immediately after film manufacturing and after one week of storage, resulting in improved stability. When alginic acid and PVP were used as biodegradable polymers, some denaturation of liraglutide was observed immediately after manufacturing and after one week of storage. Therefore, it can be confirmed that hyaluronic acid and CMC are suitable as biodegradable polymers for liraglutide-containing microneedles, with hyaluronic acid being the most suitable in particular.

[0039] Manufacturing Example 2: Manufacturing of compositions for microneedle production with different stabilizers To select stabilizers suitable for the production of liraglutide-containing microneedles with improved stability, compositions for microneedle production were prepared with the compositions shown in Table 4, and manufactured in film form (thin film) using the same method as in Production Example 1. Stability analysis was then performed using the same method as in Production Example 1.

[0040] [Table 4] The results are shown in Table 5 and Figure 2.

[0041] [Table 5] As shown in Table 5 and Figure 2, when trehalose and xylitol were used as stabilizers, the denaturation of liraglutide was prevented immediately after film manufacturing and after one week of storage, resulting in improved stability. When glycerin or GH-815 (a mixture of propanediol, caprylyl glycerin, and ethylhexylglycerin) were used as stabilizers, denaturation of liraglutide appeared to progress after one week of storage. Therefore, trehalose and xylitol are suitable stabilizers for liraglutide-containing microneedles.

[0042] Manufacturing Example 3: Manufacturing of compositions for manufacturing microneedles with different antioxidants To select antioxidants suitable for the production of liraglutide-containing microneedles with improved stability, hyaluronic acid was used as a biodegradable polymer. Compositions for the production of microneedles with different antioxidant compositions were prepared as shown in Table 6, and these were manufactured in film form (thin film) using the same method as in Production Example 1. Stability analysis was then performed using the same method as in Production Example 1.

[0043] [Table 6] The results are shown in Table 7.

[0044] [Table 7] As shown in Table 7, when EDTA and DPG (Dipotassium glycyrrhizinate) were used as antioxidants, it was confirmed that the denaturation of liraglutide was prevented immediately after film manufacturing and after one week of storage, resulting in improved stability. When BHA (Butylated hydroxyanisole) or BHT (Butylated hydroxytoluene) were used as antioxidants, some denaturation of liraglutide was observed immediately after manufacturing and after one week of storage. Therefore, it can be confirmed that EDTA and DPG are suitable antioxidants for liraglutide-containing microneedles.

[0045] Manufacturing Example 4: Manufacturing of liraglutide-containing microneedles <Manufacturing of compositions for microneedle production> A composition for manufacturing microneedles was prepared with the composition shown in Table 8:

[0046] [Table 8] Specifically, in the compositions of Examples 1 to 4, DPG or EDTA was placed in a conical tube, then purified water or potassium phosphate buffer (PPB) and a 0.1 M NaOH aqueous solution were vortexed for 10 minutes and mixed. This solution was then added to the tube and vortexed for 10 minutes. Xylitol or trehalose was then added and vortexed for 5 minutes, followed by liraglutide and vortexing for 5 minutes. Finally, sodium hyaluronic acid (HA) was added and vortexed for 30 minutes to complete the composition. The pH of the produced composition was approximately 7.8 to 8.4.

[0047] <Microneedle Manufacturing> The compositions prepared as described above were loaded into silicone recessed molds engraved with microneedle shapes. After loading, the molds were placed in a desiccator, and the pressure was reduced to -0.04 MPa for 5 minutes. Then, the molds were ventilated, and any resulting air bubbles were removed using an air gun. The silicone molds were then placed in a hot air dryer and dried at 30°C for 2 hours. The finished microneedles were then separated from the silicone molds using tweezers to produce the microneedles. Photographs of the produced microneedles are shown in Figure 3.

[0048] If necessary, the recovered microneedles can be made into patches by attaching a colloidal band or similar material to the back surface to improve their usability.

[0049] As shown in Figure 3, it can be confirmed that microneedles are well formed when the compositions of Examples 1 to 4 are used.

[0050] The microneedles produced with the compositions of Examples 1-4 also possessed sufficient strength for skin penetration.

[0051] Test Example 1: Drug Stability Analysis of Microneedles Stability analysis was performed on each of the microneedles from Examples 1 to 4 produced in Manufacturing Example 4 using the same method as in Manufacturing Example 1, and the results are shown in Table 9 and Figure 4.

[0052] [Table 9] As shown in Table 9 and Figure 4, the microneedles of Examples 1 to 3, manufactured with a composition containing hyaluronic acid as a biodegradable polymer, xylitol or trehalose as a stabilizer, and DPG as an antioxidant, showed excellent stability immediately after manufacture, with liraglutide denaturation prevented, and excellent stability was maintained even after one week of storage. Similarly, the microneedles of Example 4, manufactured with a composition containing EDTA as an antioxidant, showed excellent stability after one week of storage, with liraglutide denaturation prevented. Therefore, it can be confirmed that the stability of liraglutide-containing microneedles is improved only when a specific combination of the biodegradable polymer, stabilizer, and antioxidant according to the present invention is included.

Claims

1. A liraglutide-containing microneedle manufacturing composition with improved stability, The composition comprises liraglutide, a biodegradable polymer, a stabilizer, an antioxidant, and a solvent. The biodegradable polymer is at least one selected from the group consisting of hyaluronic acid or a salt thereof. The stabilizer is at least one selected from the group consisting of xylitol and trehalose. The antioxidant is at least one selected from the group consisting of DPG (Dipotassium glycyrrhizinate) and EDTA. The solvent is water or potassium phosphate buffer. The liraglutide is present in an amount of 0.1% to 2.0% by weight relative to the whole composition. The biodegradable polymer is included in the composition in an amount of 10% to 20% by weight of the whole composition. The stabilizer is included in the composition in an amount of 3% to 10% by weight, The aforementioned antioxidant is characterized in that it is included in a composition for manufacturing microneedles in a weight ratio of liraglutide to antioxidant of 1:0.3 to 5.

2. The liraglutide-containing microneedle manufacturing composition with improved stability, characterized in that the biodegradable polymer is hyaluronic acid or a salt thereof, according to Claim 1.

3. The liraglutide-containing microneedle manufacturing composition with improved stability, characterized in that the stabilizer is xylitol, according to Claim 1.

4. The liraglutide-containing microneedle manufacturing composition with improved stability, characterized in that the antioxidant is DPG according to Claim 1.

5. The composition for manufacturing liraglutide-containing microneedles with improved stability, characterized in that the biodegradable polymer is hyaluronic acid or a salt thereof, the stabilizer is xylitol, and the antioxidant is DPG.

6. The liraglutide-containing microneedle manufacturing composition with improved stability, characterized in that the biodegradable polymer is hyaluronic acid or a salt thereof, the stabilizer is trehalose, and the antioxidant is DPG.

7. A liraglutide-containing microneedle with improved stability comprising the composition according to Claim 1, The microneedle is characterized by comprising a needle portion protruding in one direction and a matrix layer supporting the needle portion.

8. The liraglutide-containing microneedle according to claim 7, characterized in that the needle portion can be separated from the matrix layer when inserted into the skin, thereby improving stability.

9. A microneedle patch for transdermal delivery of liraglutide, comprising the microneedle according to claim 7.

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