Liraglutide-containing composition for microneedles with improved stability and use thereof

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 liraglutide-containing composition for microneedles with improved stability and its use, and more particularly to a liraglutide-containing composition for microneedles that contains liraglutide as an active ingredient, does not denature the active ingredient during production, and maintains stability even after production, and to liraglutide-containing microneedles with improved stability produced from this composition. [Background technology]

[0002] Liraglutide 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, and is used as a drug for treating type 2 diabetes and obesity. Liraglutide is sold under the brand names Victoza for type 2 diabetes and Saxenda for obesity.

[0003] Currently, liraglutide is only available as a subcutaneous injection, which requires the patient to disinfect the injection site at a fixed time each day, which is inconvenient, and raises concerns about secondary infection. Repeated injections can also cause pain, bleeding, rashes, and swelling at the injection site. In the case of self-injected formulations, patients must inject themselves, which can lead to fear and refusal, resulting in reduced compliance and a corresponding decrease in therapeutic efficacy.

[0004] To address these issues, some attempts have been made to formulate the drug as a microneedle, and a method for manufacturing microneedles containing liraglutide that do not bounce off the surface layer of the skin, do not break or bend, and shorten the drug manufacturing time, making them suitable for mass production, has been disclosed (Korean Patent Publication No. 10-2022-0151995).

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

[0006] Therefore, there is a demand for the development of liraglutide-containing microneedles that prevent liraglutide from degenerating during production, thereby maintaining its activity, and that also prevent denaturation during storage after production, thereby improving stability. Summary of the Invention [Problem to be solved by the invention]

[0007] In response to this, the inventors have conducted continuous research to meet the demands of the conventional technology, and as a result have surprisingly found that liraglutide-containing microneedles manufactured using a specific combination of a biodegradable polymer, a stabilizer, and an antioxidant prevent liraglutide from degrading during manufacture, maintaining its activity, and also prevent liraglutide from degrading during storage after manufacture, improving stability, thereby completing the present invention.

[0008] Therefore, an object of the present invention is to provide a liraglutide-containing composition for producing microneedles with improved stability.

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

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

[0011] In order to achieve the above object of the present invention, a composition for producing liraglutide-containing microneedles with improved stability is provided.

[0012] The composition for producing liraglutide-containing microneedles with improved stability of the present invention comprises 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 analogue that binds to and activates the GLP-1 receptor, increasing glucose-dependent insulin secretion and suppressing inappropriate glucagon secretion. It is used to treat type 2 diabetes and obesity:

[0014] [ka] In the composition of the present invention, the biodegradable polymer is one that can be naturally biodegraded in the body and excreted outside the body, and at least one selected from the group consisting of hyaluronic acid or its salt and carboxymethyl cellulose (CMC) can be used, and hyaluronic acid or its salt is most preferably used. Compared to other types of biodegradable polymers, compositions for producing microneedles containing these biodegradable polymers can prevent the denaturation of liraglutide during microneedle production and storage, thereby improving stability.

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

[0016] The stabilizer in the composition of the present invention contributes to stability during microneedle fabrication, and can be at least one selected from the group consisting of xylitol and trehalose. Compared to other types of stabilizers, a composition for fabricating microneedles containing this stabilizer can ensure stable microneedle fabrication and also prevent liraglutide from denaturing during microneedle fabrication and storage, thereby improving stability.

[0017] The stabilizer may be contained in the composition of the present invention in an amount of 3% to 10% by weight based on the total weight of the 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 producing microneedles containing the antioxidant can prevent the denaturation of liraglutide during microneedle production and storage, thereby improving stability.

[0019] In the composition of the present invention, the antioxidant may be contained relative to the weight of liraglutide, ie, the weight ratio of liraglutide:antioxidant may be 1:0.3 to 5.

[0020] In the composition of the present invention, liraglutide may be contained in an amount of 0.1% to 2.0% by weight based on the total weight of the composition.

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

[0022] The composition of the present invention may further contain a pH adjuster as needed. The pH adjuster may be any one of those commonly used in microneedle production, such as NaOH. 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, as needed, a plasticizer, a surfactant, a preservative, etc. that are commonly used in the production of microneedles.

[0024] In accordance with another object of the present invention, the present invention provides liraglutide-containing microneedles with improved stability, which are prepared from the composition.

[0025] The microneedle of the present invention may include a needle portion protruding in one direction and a matrix layer supporting the needle portion. The needle portion has a shape that facilitates skin penetration. The needle portion of the microneedle of the present invention may be conical, pyramidal, spherical, truncated, wedge-shaped, or blade-shaped, but all shapes must be capable of penetrating the skin. The length of the needle portion is 500 to 1000 μm, preferably 750 μm. The thickness of the matrix layer is 0.1 to 1 mm, preferably 0.1 to 0.3 mm. The needle portion of the microneedle of the present invention may be prepared so as to be separated from the matrix layer upon insertion into the skin, if necessary. The composition of the present invention can be used to prepare the needle portion and matrix layer of the microneedle, but the matrix layer can also be prepared from other materials if necessary. Therefore, in the microneedle of the present invention, liraglutide may be uniformly distributed in the needle portion and matrix layer, or liraglutide may be distributed only in the needle portion.

[0026] The microneedles of the present invention are dissolvable microneedles that release liraglutide while being degraded 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, comprising the microneedles.

[0028] The microneedle patch of the present invention has an adhesive layer laminated on one side of the matrix layer, and can be used by adhering the microneedle patch 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 treating and improving obesity and for treating and improving type 2 diabetes. [Effects of the Invention]

[0030] The composition for manufacturing 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 the manufacturing of microneedles and to maintain the stability of liraglutide even after the manufacturing of microneedles.

[0031] The microneedles according to the present invention are liraglutide-containing microneedles that are prevented from degenerating during production, thereby maintaining activity, and that are also prevented from degenerating during storage after production, thereby improving stability.

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

[0033] [Figure 1] FIG. 1 is a graph showing the results of stability analysis using biodegradable polymers. [Figure 2] FIG. 2 is a graph showing the results of stability analysis using stabilizers. [Figure 3] FIG. 3 is a photograph of a microneedle according to the present invention. [Figure 4] FIG. 4 is a graph showing the stability analysis results of the microneedles according to the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0034] Hereinafter, the present invention will be described in more detail with reference to specific examples to aid in understanding the present invention. However, the following examples are merely illustrative examples for a clearer understanding of the present invention, and the scope of the present invention is not limited to the following examples.

[0035] Preparation Example 1: Preparation of a composition for producing microneedles using a biodegradable polymer In order to select a biodegradable polymer suitable for producing liraglutide-loaded microneedles with improved stability, compositions for producing microneedles for each biodegradable polymer were prepared according to the formulations shown in Table 1, and then fabricated into thin films and tested for stability.

[0036] [Table 1] Specifically, liraglutide and biodegradable polymers were weighed as shown in Table 1 and placed in a cup tube. The mixture was dissolved in a shaker mixer for 5 minutes and then dried in a dryer at 25°C for 24 hours. The solvent was then completely evaporated in an evaporator under nitrogen to produce a film (50-100 μm thick) capable of simulating microneedles. The resulting films were analyzed for stability immediately after production and after one week of storage in a constant temperature and humidity stability chamber at 25°C and 60% accelerated temperature.

[0037] Specifically, the stability analysis was carried out by adding the entire amount of each film sample to 5 ml of dilution solvent (a 1:1 mixture of phosphate buffer solution pH 3.5 and 78% acetonitrile) and shaking the mixture. Liraglutide was then quantitatively analyzed using HPLC under the conditions shown in Table 2 below, and 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 liraglutide denaturation was prevented and stability was improved immediately after film production and after one week of storage. When alginate or PVP was used as the biodegradable polymer, it appeared that some liraglutide denaturation had progressed immediately after production and after one week of storage. Therefore, it can be confirmed that hyaluronic acid and CMC are suitable biodegradable polymers for liraglutide-loaded microneedles, with hyaluronic acid being particularly suitable.

[0039] Preparation Example 2: Preparation of a composition for manufacturing microneedles using a stabilizer In order to select a stabilizer suitable for producing liraglutide-containing microneedles with improved stability, compositions for producing microneedles for each stabilizer were prepared according to the formulations shown in Table 4, and then fabricated into thin films in the same manner as in Preparation Example 1. Stability analysis was then performed in the same manner as in Preparation 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 production and after one week of storage, improving stability. When glycerin or GH-815 (a mixture of propanediol, caprylyl glycol, and ethylhexylglycerin) was used as a stabilizer, the denaturation of liraglutide appeared to progress after one week of storage. Therefore, it can be confirmed that trehalose and xylitol are suitable stabilizers for liraglutide-loaded microneedles.

[0042] Preparation Example 3: Preparation of compositions for manufacturing microneedles using different antioxidants In order to select an antioxidant suitable for producing liraglutide-loaded microneedles with improved stability, hyaluronic acid was used as a biodegradable polymer to prepare compositions for producing microneedles for each antioxidant with the formulations shown in Table 6. These compositions were then fabricated into thin films in the same manner as in Preparation Example 1, and stability analysis was performed in the same manner as in Preparation 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, the denaturation of liraglutide was prevented immediately after film production and after one week of storage, improving stability. When BHA (butylated hydroxyanisole) or BHT (butylated hydroxytoluene) were used as antioxidants, some denaturation of liraglutide occurred immediately after production and after one week of storage. Therefore, it can be confirmed that EDTA and DPG are suitable antioxidants for liraglutide-loaded microneedles.

[0045] Production Example 4: Production of liraglutide-containing microneedles <Production of composition for producing microneedles> A composition for producing microneedles was prepared according to the composition shown in Table 8:

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

[0047] <Microneedle manufacturing> Each of the prepared compositions was loaded into a silicon recess mold engraved with a microneedle shape. After loading, the mold was placed in a desiccator and vacuumed to -0.04 MPa for 5 minutes, after which ventilation was performed and any air bubbles that had formed were removed using an air gun. The silicon mold was then placed in a hot air dryer and dried at 30°C for 2 hours. The completed microneedles were then separated from the silicon mold using tweezers to produce microneedles. Photographs of the prepared microneedles are shown in Figure 3.

[0048] If necessary, the recovered microneedles can be made into a patch form by attaching a colloid band or the like to the rear surface to enhance usability.

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

[0050] The microneedles made with the compositions of Examples 1 to 4 also had sufficient strength for skin penetration.

[0051] Test Example 1: Drug Stability Analysis of Microneedles The stability of the microneedles of Examples 1 to 4 prepared in Preparation Example 4 was analyzed in the same manner as in Preparation Example 1, and the results are shown in Table 9 and FIG.

[0052] [Table 9] As shown in Table 9 and Figure 4, the microneedles of Examples 1 to 3, which were prepared using a composition containing hyaluronic acid as a biodegradable polymer, xylitol or trehalose as a stabilizer, and DPG as an antioxidant, exhibited excellent stability by preventing liraglutide denaturation immediately after preparation, and maintained excellent stability even after one week of storage. Furthermore, the microneedles of Example 4, which were prepared using a composition containing EDTA as an antioxidant, also exhibited excellent stability by preventing liraglutide denaturation after one week of storage. Therefore, it can be confirmed that the stability of liraglutide-containing microneedles is improved only when the microneedles contain the specific combination of biodegradable polymer, stabilizer, and antioxidant according to the present invention.

Claims

1. A composition for producing liraglutide-containing microneedles 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 and carboxymethylcellulose (CMC); the stabilizer is at least one selected from the group consisting of xylitol and trehalose; The composition for manufacturing microneedles, wherein the antioxidant is at least one selected from the group consisting of DPG (Dipotassium glycyrrhizinate) and EDTA.

2. In paragraph 1, a composition for producing liraglutide-containing microneedles with improved stability, characterized in that the biodegradable polymer is hyaluronic acid or a salt thereof.

3. In paragraph 1, the composition for producing liraglutide-containing microneedles with improved stability is characterized in that the stabilizer is xylitol.

4. In paragraph 1, the composition for producing liraglutide-containing microneedles with improved stability is characterized in that the antioxidant is DPG.

5. In paragraph 1, a composition for producing 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. In paragraph 1, a composition for producing liraglutide-containing microneedles 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. In paragraph 1, the composition for producing liraglutide-containing microneedles with improved stability, characterized in that the biodegradable polymer is contained in an amount of 10% by weight to 20% by weight based on the total weight of the composition.

8. In paragraph 1, the composition for manufacturing liraglutide-containing microneedles with improved stability is characterized in that the stabilizer is contained in an amount of 3% by weight to 10% by weight based on the total composition.

9. In paragraph 1, a composition for manufacturing liraglutide-containing microneedles with improved stability, characterized in that the antioxidant is contained so that the weight ratio of liraglutide to antioxidant is 1:0.3 to 5.

10. A liraglutide-containing microneedle having improved stability, which is manufactured using the composition according to claim 1, The microneedle includes a needle portion protruding in one direction and a matrix layer supporting the needle portion.

11. In item 10, a liraglutide-containing microneedle with improved stability, characterized in that the needle portion can be separated from the matrix layer when inserted into the skin.

12. In item 10, the liraglutide-containing microneedle with improved stability is characterized in that the microneedle is manufactured using a mold.

13. A microneedle patch for transdermal delivery of liraglutide, comprising microneedles according to claim 10.

14. In item 13, the microneedle patch for transdermal delivery of liraglutide is characterized in that the microneedle patch is used for treating and improving obesity.

15. In item 13, the microneedle patch for transdermal delivery of liraglutide is characterized in that the microneedle patch is used for treating and improving type 2 diabetes.

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