Compositions for enhanced stability liraglutide-containing microneedles and uses thereof

Abstract

The present invention provides a composition for manufacturing a liraglutide-containing microneedle, which contains liraglutide as an active ingredient, does not undergo denaturation during manufacturing, and maintains stability even after manufacturing, and a liraglutide-containing microneedle having enhanced stability manufactured using the same. The composition for manufacturing a liraglutide-containing microneedle according to the present invention uses a specific combination of a biodegradable polymer, a stabilizer, and an antioxidant, prevents the active ingredient liraglutide from denaturating during the manufacturing of a microneedle, and ensures that the stability of liraglutide is maintained after the manufacturing of a microneedle.

Description

Technical Field

[0001] The present invention relates to a composition of liraglutide-containing microneedles for enhanced stability and its uses, and more particularly to a composition for manufacturing liraglutide-containing microneedles and the liraglutide-containing microneedles with enhanced stability manufactured using the composition. The composition contains liraglutide as an active ingredient, and the active ingredient does not denature during the manufacturing process, and the composition also maintains stability even after manufacturing. Background Art

[0002] Liraglutide is a human glucagon-like peptide (GLP)-1 analogue that binds to and activates the GLP-1 receptor, thereby increasing glucose-dependent insulin secretion and inhibiting inappropriate glucagon secretion. It is used for the treatment of type 2 diabetes and obesity. Liraglutide is sold under the brand name Victoza for the treatment of type 2 diabetes and under the brand name Saxenda for the treatment of obesity.

[0003] Currently, liraglutide is only used as a subcutaneous injection, which has the inconvenience of having to disinfect the injection site and inject at a fixed time every day, and there is also a problem of secondary infection. In addition, repeated injections may cause pain, bleeding, rash and swelling at the injection site. In the case of drugs that can be self-injected, patients have to administer the injection themselves, which can lead to fear and aversion, thus reducing drug compliance and consequently reducing the therapeutic effect.

[0004] To solve these problems, attempts have been made to formulate liraglutide into microneedles. However, only a manufacturing method of liraglutide-containing microneedles that does not bounce off the skin surface, does not break or bend, and can be mass-produced by shortening the drug manufacturing time has been disclosed (Korean Patent Application Publication No. 10-2022-0151995).

[0005] Meanwhile, liraglutide has poor stability and is easily denatured by various factors during the microneedle manufacturing process, and its activity also decreases due to denaturation during storage after manufacturing.

[0006] Therefore, there is a need to develop liraglutide-containing microneedles that prevent liraglutide from denaturing during manufacturing to maintain its activity and prevent liraglutide from denaturing during storage after manufacturing to enhance its stability. Summary of the Invention

[0007] Technical Problem to be Solved

[0008] In order to meet the needs of the prior art, the inventors of the present invention continued their research and found that liraglutide-containing microneedles manufactured using a specific combination of a biodegradable polymer, a stabilizer and an antioxidant unexpectedly prevent liraglutide from denaturing during manufacturing to maintain its activity, and prevent liraglutide from denaturing during storage after manufacturing to enhance its stability, thereby completing the present invention.

[0009] Therefore, an object of the present invention is to provide a composition for manufacturing micro - needles containing liraglutide with enhanced stability.

[0010] Another object of the present invention is to provide micro - needles containing liraglutide with enhanced stability manufactured using the composition.

[0011] Another object of the present invention is to provide a micro - needle patch for transdermal delivery of liraglutide containing the micro - needles.

[0012] Technical solution

[0013] To achieve the object of the present invention, the present invention provides a composition for manufacturing micro - needles containing liraglutide with enhanced stability.

[0014] The composition for manufacturing micro - needles containing liraglutide with enhanced stability according to the present invention comprises liraglutide, a biodegradable polymer, a stabilizer, an antioxidant, and a solvent.

[0015] Liraglutide has the structure of formula 1, is a human glucagon - like peptide (GLP) - 1 analogue, which binds to and activates the GLP - 1 receptor, thereby increasing glucose - dependent insulin secretion and inhibiting inappropriate glucagon secretion, and is used for the treatment of type 2 diabetes and obesity:

[0016]

[0017] (Formula 1)

[0018] In the present invention, the biodegradable polymer is a polymer that can be naturally degraded in the body, and can be at least one selected from the group consisting of hyaluronic acid or its salts and carboxymethyl cellulose (CMC), and most preferably hyaluronic acid or its salts. Compared with other types of biodegradable polymers, the composition for manufacturing micro - needles containing these biodegradable polymers can prevent liraglutide from denaturing during micro - needle manufacturing and storage, thereby improving stability.

[0019] In the composition of the present invention, based on the total amount of the composition (100 wt%), the content of the biodegradable polymer can be 10 wt% to 20 wt%.

[0020] In the present invention, the stabilizer is used to assist in the stability during the micro - needle manufacturing process, and can be at least one selected from the group consisting of xylitol and trehalose. Compared with other types of stabilizers, the composition for manufacturing micro - needles containing these stabilizers can stably manufacture micro - needles while preventing liraglutide from denaturing during micro - needle manufacturing and storage to enhance stability.

[0021] In the present invention, based on the total amount of the composition, the content of the stabilizer can be 3 wt% to 10 wt%.

[0022] In the present invention, the antioxidant can be at least one selected from the group consisting of dipotassium glycyrrhizinate (DPG) and EDTA. Compared with other types of antioxidants, the composition for manufacturing microneedles containing these antioxidants can prevent the denaturation of liraglutide during the manufacturing and storage of microneedles, so as to enhance stability.

[0023] In the composition of the present invention, the content of the antioxidant relative to the weight of liraglutide can be such that the weight ratio of liraglutide: antioxidant is 1:0.3 to 5.

[0024] In the composition of the present invention, based on the total amount of the composition, the content of liraglutide can be 0.1 wt% to 2.0 wt%.

[0025] In the composition of the present invention, the solvent is water, preferably deionized water, or potassium phosphate buffer (PPB).

[0026] The composition of the present invention may further contain a pH regulator as needed. The pH regulator can be any one commonly used in microneedle manufacturing, such as NaOH. The pH value of the composition of the present invention is 7.5 to 8.7, preferably 7.8 to 8.4.

[0027] The composition of the present invention may further contain plasticizers, surfactants, preservatives, etc. commonly used in microneedle manufacturing as needed.

[0028] According to another object of the present invention, the present invention provides liraglutide-containing microneedles with enhanced stability manufactured using the composition according to the present invention.

[0029] The microneedles of the present invention may include a needle portion protruding in one direction and a cushion layer supporting the needle portion. The needle portion has a shape suitable for penetrating the skin. The shape of the needle portion of the microneedles according to the present invention can be conical, pyramidal, spherical, frustum-shaped, wedge-shaped, blade-shaped, etc., all of which have a shape capable of penetrating the skin. The length of the needle portion is 500 to 1000 μm, preferably 750 μm. The thickness of the cushion layer is 0.1 to 1 mm, preferably 0.1 to 0.3 mm. If necessary, the needle portion of the microneedles of the present invention can be manufactured to be separated from the cushion layer when inserted into the skin. The composition according to the present invention can be used to manufacture the needle portion and the cushion layer of the microneedles, and if necessary, the cushion layer can be made of different materials. Therefore, in the microneedles of the present invention, liraglutide can be uniformly distributed in the needle portion and the cushion layer, or liraglutide can be distributed only in the needle portion.

[0030] The microneedles of the present invention are dissolvable microneedles that degrade in vivo while releasing liraglutide.

[0031] The microneedles of the present invention can be manufactured using a mold.

[0032] According to another object of the present invention, there is provided a microneedle patch for transdermal delivery of liraglutide, which comprises the microneedles according to the present invention.

[0033] The microneedle patch of the present invention has an adhesive layer laminated to one side of a backing layer, which enables the microneedle patch to be applied to the skin. The microneedle patch may further include a protective film on the adhesive layer.

[0034] The microneedle patch for transdermal delivery of liraglutide according to the present invention can be used for treating and improving obesity and treating and improving type 2 diabetes.

[0035] Advantageous Effects

[0036] 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 active ingredient liraglutide from denaturing during the manufacturing of microneedles and to maintain the stability of liraglutide after the microneedles are manufactured.

[0037] The microneedles according to the present invention are liraglutide-containing microneedles with enhanced stability, which prevent liraglutide from denaturing during manufacturing to maintain its activity and prevent liraglutide from denaturing during storage after manufacturing.

[0038] The microneedle patch for transdermal delivery of liraglutide according to the present invention enhances the stability of the active ingredient liraglutide and can be used for treating and improving obesity and treating and improving type 2 diabetes. Brief Description of the Drawings

[0039] Figure 1 is a graph showing the results of stability analysis of each biodegradable polymer used.

[0040] Figure 2 is a graph showing the results of stability analysis of each stabilizer used.

[0041] Figure 3 is a photograph of the microneedles according to the present invention.

[0042] Figure 4 is a graph showing the results of stability analysis of the microneedles according to the present invention. Detailed Description of the Invention

[0043] The present invention will be described in more detail below with reference to the following examples. However, the following examples are only for the purpose of illustrating the present invention, and thus the scope of the present invention is not limited thereto.

[0044] Preparation Example 1: Preparation of a composition for manufacturing microneedles using various biodegradable polymers

[0045] In order to select a biodegradable polymer suitable for manufacturing liraglutide-containing microneedles with enhanced stability, compositions for manufacturing microneedles were prepared using each of the biodegradable polymers shown in Table 1, made into films, and subjected to stability tests.

[0046] Table 1

[0047]

[0048] Specifically, 1 ml of deionized water (DW), liraglutide, and a biodegradable polymer (weighed as shown in Table 1) were placed in a cuvette, dissolved using a vortex mixer for 5 minutes, and dried at 25 °C for 24 hours using a dryer. Then, the solvent was completely evaporated using an evaporator under nitrogen to prepare a film (with a thickness of 50 to 100 μm) that could simulate microneedles.

[0049] After preparation, stability analysis was immediately performed on the prepared film, and stability analysis was also performed after storing it for 1 week under accelerated conditions of 25 °C and 60% humidity in a stability chamber with controlled temperature and humidity.

[0050] Specifically, for stability analysis, each film sample was added to 5 ml of a dilution solvent (a 1:1 mixture of phosphate buffer solution with pH 3.5: 78% acetonitrile), shaken well, and then quantitative analysis of liraglutide was performed using HPLC under the conditions shown in Table 2 below. The results are shown in Table 3 and Figure 1 in.

[0051] Table 2

[0052]

[0053] Table 3

[0054]

[0055] As shown in Table 3 and Figure 1 it can be confirmed that the use of hyaluronic acid and CMC in the biodegradable polymer can enhance stability by preventing the denaturation of liraglutide immediately after film preparation and after 1 week of storage. When alginate or PVP was used as the biodegradable polymer, some denaturation of liraglutide was observed immediately after preparation and after 1 week of storage. Therefore, it can be confirmed that hyaluronic acid and CMC are suitable as biodegradable polymers for liraglutide-containing microneedles, and hyaluronic acid is the most suitable.

[0056] Preparation Example 2: Preparation of a composition for manufacturing microneedles using various stabilizers

[0057] To select a stabilizer suitable for manufacturing liraglutide-containing microneedles with enhanced stability, compositions for manufacturing microneedles were prepared using each of the stabilizers shown in Table 4, and the compositions were formed into films in the same manner as in Preparation Example 1, and stability analysis was performed in the same manner as in Preparation Example 1.

[0058] Table 4

[0059]

[0060] The results are shown in Table 5 and Figure 2 as follows.

[0061] Table 5

[0062]

[0063]

[0064] As shown in Table 5 and Figure 2 as follows, it was confirmed that using trehalose and xylitol as stabilizers enhanced the stability by preventing the denaturation of liraglutide immediately after film preparation and after 1-week storage. When using glycerol or GH-815 (a mixture of propylene glycol, caprylyl glycol, and ethylhexylglycerin) as a stabilizer, liraglutide denatured after 1-week storage. Therefore, it was confirmed that trehalose and xylitol are suitable as stabilizers for liraglutide-containing microneedles.

[0065] Preparation Example 3: Preparation of a composition for manufacturing microneedles using various antioxidants

[0066] To select an antioxidant suitable for manufacturing liraglutide-containing microneedles with enhanced stability, hyaluronic acid was used as a biodegradable polymer, and compositions for manufacturing microneedles were prepared together with each of the antioxidants shown in Table 6, and the compositions were formed into films in the same manner as in Preparation Example 1, and stability analysis was performed in the same manner as in Preparation Example 1.

[0067] Table 6

[0068]

[0069]

[0070] The results are shown in Table 7.

[0071] Table 7

[0072]

[0073] As shown in Table 7, it can be confirmed that when EDTA and DPG (dipotassium glycyrrhizinate) are used as antioxidants, the stability is enhanced by preventing the immediate denaturation of liraglutide after film preparation and its denaturation after 1 week of storage. When BHA (butylated hydroxyanisole) or BHT (butylated hydroxytoluene) is used as an antioxidant, some denaturation of liraglutide is observed immediately after preparation and after 1 week of storage. Therefore, it can be confirmed that EDTA and DPG are suitable as antioxidants for liraglutide-containing microneedles.

[0074] Preparation Example 4: Preparation of microneedles containing liraglutide

[0075] <Preparation of the composition for manufacturing microneedles>

[0076] The composition for manufacturing microneedles is prepared according to the composition shown in Table 8:

[0077] Table 8

[0078]

[0079]

[0080] Specifically, for the compositions of Examples 1 to 4, DPG or EDTA is placed in a conical tube, and then the solution prepared by vortex mixing deionized water or potassium phosphate buffer (PPB) and 0.1 M NaOH solution for 10 minutes is added to the tube and vortexed for 10 minutes. Then xylitol or trehalose is added and vortexed for 5 minutes, liraglutide is added and vortexed for 5 minutes, and sodium hyaluronate as hyaluronic acid (HA) is added and vortexed for 30 minutes to complete the composition.

[0081] The pH value of the prepared composition is about 7.8 to 8.4.

[0082] <Preparation of microneedles>

[0083] Each prepared composition is loaded into a silicon female mold engraved with the shape of microneedles. The loaded mold is placed in a dryer, the pressure is reduced to -0.04 MPa and maintained for 5 minutes, then it is ventilated and the generated bubbles are removed with an air gun. Then the mold is placed in a hot air dryer and dried at 30 °C for 2 hours. The completed microneedles are separated from the mold using tweezers to obtain the microneedles. Photographs of the prepared microneedles are taken as Figure 3 shown.

[0084] If necessary, the prepared microneedles can be made into the form of a patch with a colloid strip on the back for more convenient use.

[0085] As Figure 3 shown, it can be seen that when the compositions of Examples 1 to 4 are used, the microneedles are well formed.

[0086] The microneedles prepared with the compositions of Examples 1 to 4 also have sufficient strength to penetrate the skin.

[0087] Test Example 1: Analysis of drug stability in microneedles

[0088] For each of the microneedles of Examples 1 to 4 prepared in Preparation Example 4, stability analysis was carried out in the same manner as in Preparation Example 1, and the results are shown in Table 9 and Figure 4 as follows.

[0089] Table 9

[0090]

[0091]

[0092] As shown in Table 9 and Figure 4 as follows, it can be seen that the microneedles of Examples 1 to 3 prepared with the composition containing hyaluronic acid as a biodegradable polymer, xylitol or trehalose as a stabilizer, and DPG as an antioxidant showed excellent stability, preventing the immediate denaturation of liraglutide after preparation and still maintaining excellent stability after 1 week of storage. It can also be seen that the microneedles of Example 4 prepared with the composition containing EDTA as an antioxidant maintained excellent stability after 1 week of storage, preventing the denaturation of liraglutide.

[0093] Therefore, it can be confirmed that only when a specific combination of the biodegradable polymer, stabilizer, and antioxidant according to the present invention is used, the stability of the liraglutide-containing microneedles is enhanced.

Claims

1. A composition for manufacturing liraglutide-containing microneedles with enhanced stability, Among them, the composition comprising liraglutide, a biodegradable polymer, a stabilizer, an antioxidant, and a solvent, the biodegradable polymer being at least one selected from the group consisting of hyaluronic acid or its salt and carboxymethyl cellulose (CMC), the stabilizer being at least one selected from the group consisting of xylitol and trehalose; and the antioxidant being at least one selected from the group consisting of DPG (dipotassium glycyrrhizinate) and EDTA.

2. The composition for manufacturing a liraglutide-containing microneedle with enhanced stability according to claim 1, wherein, The biodegradable polymer is hyaluronic acid or its salt.

3. The composition for manufacturing the liraglutide-containing microneedles with enhanced stability according to claim 1, wherein, The stabilizer is xylitol.

4. The composition for manufacturing the liraglutide-containing microneedles with enhanced stability according to claim 1, wherein, The antioxidant is DPG.

5. The composition for manufacturing the liraglutide-containing microneedles with enhanced stability according to claim 1, wherein, The biodegradable polymer is hyaluronic acid or its salt, the stabilizer is xylitol, and the antioxidant is DPG.

6. The composition for manufacturing the liraglutide-containing microneedles with enhanced stability according to claim 1, wherein, The biodegradable polymer is hyaluronic acid or its salt, the stabilizer is trehalose, and the antioxidant is DPG.

7. The composition for manufacturing the liraglutide-containing microneedles with enhanced stability according to claim 1, wherein, Based on the total weight of the composition, the content of the biodegradable polymer is 10 wt% to 20 wt%.

8. The composition for manufacturing the liraglutide-containing microneedles with enhanced stability according to claim 1, wherein, Based on the total weight of the composition, the content of the stabilizer is 3 wt% to 10 wt%.

9. The composition for manufacturing liraglutide-containing microneedles with enhanced stability according to claim 1, wherein the content of the antioxidant is such that the weight ratio of liraglutide to the antioxidant is 1:0.3 to 5.

10. A stability-enhanced liraglutide-containing microneedle manufactured using the composition according to claim 1, wherein, The microneedle includes a needle portion protruding in one direction and a backing layer supporting the needle portion.

11. The liraglutide-containing microneedles with enhanced stability according to claim 10, wherein, The needle portion can be separated from the backing layer when inserted into the skin.

12. The liraglutide-containing microneedles with enhanced stability according to claim 10, wherein, The microneedle is manufactured using a mold.

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

14. The microneedle patch for transdermal delivery of liraglutide according to claim 13, wherein, The microneedle patch is used for treating and improving obesity.

15. The microneedle patch for transdermal delivery of liraglutide according to claim 13, wherein, The microneedle patch is used for treating and improving type 2 diabetes.

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