Composition for manufacturing microarray comprising semaglutide, and microarray manufactured using same composition

Abstract

The present invention relates to a composition for manufacturing a microarray comprising semaglutide as an active ingredient, a microarray manufactured using the composition, a method for manufacturing the microarray, and an assembly comprising the microarray. The microarray of the present invention has excellent stability allowing storage and transportation at room temperature and exhibits pharmacokinetic characteristics similar to those of subcutaneous injection.

Description

A composition for manufacturing a microarray comprising semaglutide, and a microarray manufactured with said composition

[0001] The present invention relates to a composition for manufacturing a microarray comprising semaglutide as an active ingredient, a microarray manufactured using said composition, a method for manufacturing a microarray, and an assembly comprising a microarray. The microarray of the present invention has excellent stability that allows for storage and transport at room temperature and has pharmacokinetic characteristics similar to those of a subcutaneous injection.

[0002]

[0003] Research on microarrays as a means of drug delivery is underway. Microarrays are being developed as a means to deliver active ingredients through a target's skin.

[0004] Semaglutide is known to be effective in treating type 2 diabetes and obesity, and has been primarily used as an oral or injectable formulation. Parenteral administration may be preferable to oral administration due to various factors, such as enzymatic degradation in the gastrointestinal tract and intestinal mucosa, insufficient absorption in the intestinal mucosa, and first-pass metabolism in the liver. As an injectable, semaglutide has been commercialized in a pre-filled syringe formulation administered once a week. However, the pre-filled syringe formulation has disadvantages, such as the burden of refrigerated storage, bleeding, infection, and fear of injections.

[0005] The inventors have completed the present invention as a result of repeated research aimed at developing a microarray capable of rapid absorption of semaglutide with pharmacokinetic characteristics identical to those of subcutaneous injection, while being convenient to handle due to room temperature distribution and enabling cost reduction by using a small amount of active ingredient, and compensating for the disadvantages of pre-filled syringe formulations by eliminating pain during administration.

[0006]

[0007] [Prior Art Literature]

[0008] [Patent Literature]

[0009] (Patent Document 0001) Korean Registered Patent No. 10-2553293

[0010] (Patent Document 0002) U.S. Registered Patent No. 10,828,478 B2

[0011]

[0012] The present invention is to provide a composition for manufacturing a microarray that can rapidly absorb an active ingredient and has stability at room temperature, comprising semaglutide or a pharmaceutically acceptable salt thereof as an active ingredient and a biodegradable polymer as a matrix component.

[0013] In addition, the present invention aims to provide a microarray assembly comprising a microarray manufactured from the above composition and a mold used to manufacture the microarray.

[0014] In addition, the present invention aims to provide a method for manufacturing a microarray comprising semaglutide or a pharmaceutically acceptable salt thereof only at the tip portion.

[0015]

[0016] The present invention relates to a composition for manufacturing a microarray comprising semaglutide or a pharmaceutically acceptable salt thereof and a biodegradable polymer, wherein the microarray comprises a tip portion and a base portion, and the composition of the tip portion of the microarray comprises the biodegradable polymer in a weight ratio of 0.02 to 1.1 with respect to the semaglutide or a pharmaceutically acceptable salt thereof.

[0017] In addition, the leading edge composition of the microarray in the present invention may include a biodegradable polymer in a weight ratio of 0.02 to 1.0 with respect to semaglutide or a pharmaceutically acceptable salt thereof.

[0018] In addition, the leading edge composition of the microarray in the present invention may include a biodegradable polymer in a weight ratio of 0.02 to 0.91 with respect to semaglutide or a pharmaceutically acceptable salt thereof.

[0019] In the present invention, the tip refers to the pointed end of the microarray, and the base refers to the part that supports the tip of the microarray from below.

[0020] In the present invention, the biodegradable polymer refers to a polymer that can take the form of a microneedle while dissolving upon skin penetration and can secure the strength required upon skin penetration. Specifically, it may include, but is not limited to, hyaluronic acid (HA), polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), carboxymethylcellulose, collagen, chitosan, chondroitin, hydroxyethyl cellulose, polylactic glycolic acid, gelatin, etc.

[0021] In addition, the biodegradable polymer of the present invention may preferably be one or more selected from the group consisting of polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), and hyaluronic acid (HA).

[0022] Additionally, in the present invention, the base of the microarray may not contain semaglutide or a pharmaceutically acceptable salt thereof.

[0023] In the present invention, when measured with Ametek Brookfield’s DVNext Rheometer RV CP (CPA-40Z 0.8˚ / 2.4CM CP SPINDLE ASSEMBLY), when the torque is 20 to 50% and the RPM is 10 to 50, the leading edge composition may have a viscosity of 30 to 300 cP, and preferably may have a viscosity of 30 to 200 cP.

[0024] Here, the viscometer used for viscosity measurement in the present invention is a rheometer that measures the viscoelasticity of a sample by loading the sample between a rotatable upper cone and a fixed lower plate. The "torque" mentioned in relation to the viscosity measurement test is the force that rotates the rotatable component (cone or plate) in contact from the top to measure the viscoelasticity of the sample in the viscoelasticity measuring equipment, and "RPM" refers to the speed at which it is rotated.

[0025] The present invention relates to a microarray assembly comprising the microarray and a mold used in manufacturing the microarray. Here, the microarray and the mold may have a form that is not separable.

[0026] In the microarray assembly of the present invention, an adhesive may be attached to the base of the microarray.

[0027] In addition, the microarray assembly of the present invention can be sealed in an aluminum packaging material for storage and transport.

[0028] In addition, the microarray assembly of the present invention can maintain a semaglutide content of 90% or more when stored for 28 days at room temperature conditions of 25 ± 2 ℃ and relative humidity of 65 ± 5%.

[0029] In addition, the microarray assembly of the present invention can maintain a semaglutide content of 90% or more when stored for 28 days under accelerated conditions of 40 ± 2 ℃ and relative humidity of 75 ± 5%.

[0030] The microarray of the present invention may have a relative bioavailability of 30% or more compared to subcutaneous injection, and preferably 50% or more.

[0031] The present invention provides a method for manufacturing a microarray, comprising the steps of: injecting a tip composition containing semaglutide and a biodegradable polymer into an intaglio portion of a mold; drying the injected tip composition; injecting a base composition into the upper portion of the dried tip; and drying the base composition, wherein the biodegradable polymer is included in a weight ratio of 0.02 to 1.1 with respect to semaglutide or a pharmaceutically acceptable salt thereof in the tip composition of the microarray.

[0032] In the present invention, the leading edge composition of the microarray may include a biodegradable polymer in a weight ratio of 0.02 to 1.0 with respect to semaglutide or a pharmaceutically acceptable salt thereof.

[0033] Additionally, in the present invention, the leading edge composition of the microarray may contain a biodegradable polymer in a weight ratio of 0.02 to 0.91 with respect to semaglutide or a pharmaceutically acceptable salt thereof. In the present invention, the base composition of the microarray may not contain semaglutide or a pharmaceutically acceptable salt thereof.

[0034] Additionally, in the manufacture of the microarray, the drying step may be performed in a pressurized chamber. During the drying step, air may be injected through the inlet of the pressurized chamber and discharged through the outlet. Preferably, the injection and discharge of air may occur simultaneously.

[0035] In the manufacture of the microarray of the present invention, the pressure of the pressurized chamber may be 1.5 bar or higher.

[0036] In addition, the manufacturing of the microarray according to the present invention may further include a step of packaging without separating the manufactured microarray and the mold.

[0037] In the present invention, the mold can be manufactured using an injection molding technique.

[0038]

[0039] The microarray of the present invention has excellent moldability and has the advantage of containing semaglutide, which is an active ingredient, or a pharmaceutically acceptable salt thereof, only at the leading edge, and containing the active ingredient at a high content of up to 50 times compared to the biodegradable polymer that is the matrix material.

[0040] Due to these advantages, the microarray of the present invention rapidly absorbs active ingredients, providing excellent efficacy with a small dose and reducing side effects. Furthermore, since it possesses pharmacokinetic characteristics similar to those of subcutaneous injection, it can be applied to subjects for whom oral or injectable formulations are difficult to administer.

[0041] Furthermore, since the microarray of the present invention has excellent stability at room temperature, it is easy to transport and store. In addition, by eliminating the process of separately separating the mold used in the manufacturing process of the microarray, the method for manufacturing the microarray of the present invention has a manufacturing process that is highly suitable for mass production.

[0042]

[0043] FIG. 1 illustrates the filling and drying of the tip composition for the mold (100).

[0044] FIG. 2 illustrates the filling and drying of the base composition for the mold (100).

[0045] Figure 3 is a photograph of the microarray of Example 5.

[0046] Figure 4 is a photograph of the microarray of Example 1.

[0047] Figure 5 is a photograph of a microarray in which the weight ratio of the biodegradable polymer to semaglutide is 0.01 (Comparative Example 2).

[0048] Figure 6 is a photograph of a microarray in which the weight ratio of the biodegradable polymer to the semaglutide is 1.2 (Comparative Example 3).

[0049] Figure 7 shows the state in which a microarray is formed in a mold and then packaged without separating the microarray from the mold.

[0050] Figure 8 is a graph showing the results of the stability evaluation test under room temperature conditions.

[0051] Figure 9 is a graph showing the results of the stability evaluation test under accelerated conditions.

[0052] Figure 10 is a graph showing the plasma concentration of semaglutide in the microarray of Comparative Example 1 and subcutaneous injection (control group).

[0053] Figure 11 is a graph showing the plasma concentration of semaglutide in the microarray of Example 4 and subcutaneous injection (control group).

[0054] Figure 12 is a graph showing the plasma concentration of semaglutide in the microarray of Example 5 and subcutaneous injection (control group).

[0055] Figure 13 is a graph showing the plasma concentration of semaglutide in the microarrays and subcutaneous injection (control group) of Examples 10, 11, and 12.

[0056]

[0057] Hereinafter, embodiments and examples of the present invention will be described in detail with reference to the attached drawings so that those skilled in the art can easily implement the present invention. However, the present invention may be embodied in various forms and is not limited to the embodiments and examples described herein.

[0058] Throughout this specification, when a part is described as "comprising" a certain component, this means that, unless specifically stated otherwise, it does not exclude other components but may include additional components.

[0059] The present invention is to be explained in more detail through the following examples, but the following examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

[0060]

[0061] [Preparation Example 1]

[0062] Preparation of a composition for microarray manufacturing:

[0063]

[0064] In order to ensure that the active ingredient semaglutide or a pharmaceutically acceptable salt thereof is contained only in the tip portion of the microarray, the tip portion composition and the base portion composition of the microarray were prepared, respectively, by the following method. To manufacture the microarray by molding, the tip portion composition was filled into the pointed tip portion located at the bottom of the mold, and the base portion composition was filled into the top of the tip portion composition.

[0065]

[0066] (1) Preparation of the advanced part composition

[0067]

[0068] After adding semaglutide, a biodegradable polymer, sodium chloride, disodium phosphate dihydrate, glycerin, and purified water, the mixture was stirred with a magnetic stirrer at 400 rpm for 1 hour until completely dissolved. The compositions of the microarray tips of Comparative Example 1 and Examples 1 to 12 were prepared by mixing in the amounts (weight%) shown in Tables 1 to 3 below.

[0069]

[0070]

[0071]

[0072]

[0073]

[0074]

[0075]

[0076] (2) Preparation of base composition:

[0077]

[0078] After adding a biodegradable polymer, hyaluronic acid, trehalose, ethanol, and purified water, the mixture was stirred using a rotary stirrer at 1000 rpm for 1 hour until completely dissolved. The microarray base compositions of Examples 1 to 12 were prepared by mixing at the content (weight%) of Tables 4 to 6 below.

[0079]

[0080]

[0081]

[0082]

[0083]

[0084]

[0085]

[0086] [Preparation Example 2]

[0087] Microarray manufacturing:

[0088]

[0089] A microarray was prepared using the leading and trailing part compositions of Preparation Example 2, as shown in FIGS. 1 and 2.

[0090] FIG. 1 illustrates the filling and drying of an advanced part composition for a mold (100), and FIG. 2 illustrates the filling and drying of a base part composition for a mold (100). After the filling and drying of the advanced part composition shown in FIG. 1, the filling and drying of the base part composition shown in FIG. 2 were performed to manufacture a microarray.

[0091] The application of the raw material (120) may be performed by applying one or more droplets only to the recessed portion (110) of the mold (100) (in the case of the tip portion composition), or by applying it entirely to the upper surface of the mold (100) where the recessed portion (110) is formed (in the case of the base portion composition). In the step of pressurizing the raw material (120) applied to the recessed portion (110) in the pressurizing chamber (30), the raw material (120) is pressurized using the internal pressure of the pressurizing chamber (30) to fill the raw material (120) into the microstructure (111) of the recessed portion (110). When the pressure chamber (30) is shielded, air is injected through the inlet (31) of the pressure chamber (30) to increase the pressure of the pressure chamber (30). Then, the raw material (120) is subjected to pressure by the gas pressure inside the pressure chamber (30), causing the microbubbles contained in the raw material (120) to naturally detach from the raw material (120) and be removed, and the raw material (120) is filled into the microstructure (111) within the engraved portion (110). At this time, air discharge through the outlet (32) of the pressure chamber (30) is carried out simultaneously to cause an air circulation phenomenon within the pressure chamber (30), thereby allowing the drying of the raw material (120) to be performed simultaneously. In the microarray manufacturing method of the present invention, the pressure and drying processes are performed simultaneously within the pressure chamber (30) on the raw material (120) applied to the engraved portion (110) of the mold (100).

[0092] Meanwhile, the internal pressure of the pressurized chamber (30) may be 1.5 bar or higher, preferably 2 bar or higher. If the internal pressure of the pressurized chamber (30) is less than 1.5 bar, the filling of the raw material (120) into the microstructure (111) within the intaglio part (110) is not smooth, and the microbubbles contained in the raw material (120) do not naturally escape from the raw material (120).

[0093] In addition, it was confirmed that when the internal pressure is 1 bar, microbubbles at the end of the mold are not discharged and remain in the mold, so the polymer material is not filled into the space occupied by the bubbles, and therefore the tip of the microneedle becomes blunt and fails to form the desired shape.

[0094] In the above pressurized drying process, the pressure inside the chamber was increased until it reached 7.5 bar. After reaching 7.5 bar, air was discharged through the air vent pipe so that the pressure inside the pressurized chamber (30) became 6.5 bar. Air flow was maintained inside the chamber while the pressure was maintained at 6.5 bar.

[0095] The tip portion prepared by the above method contains semaglutide, but the base portion does not contain semaglutide. In addition, the weight ratio of the biodegradable polymer to semaglutide in the tip portion of the microarray of the present invention is shown in Table 7 below.

[0096]

[0097]

[0098]

[0099] [Test Example 1]

[0100] Evaluation of the shape of the microarray of the present invention

[0101]

[0102] As a result of verifying the shape of the microarrays of Examples 1 to 12 of the present invention, all of them showed good shapes.

[0103] FIG. 3 is a photograph of the microarray of Example 5, which has the lowest weight ratio (0.02) of the biodegradable polymer to semaglutide among Examples 1 to 12. FIG. 3A is a top view of the microarray, showing that the composition injected into the mold is pushed into the micro-tip of the mold and that drying is completed in that state. FIG. 3B is a side view of the microarray, showing that the tip of the needle has a pointed shape. FIG. 3C shows the height of the needle, the diameter of the needle base, the diameter of the tip, and the diameter of the upper surface of the base of the microarray. The height of the needle was measured to be 750 μm, the diameter of the needle base to be 600 μm, the diameter of the tip to be 50 μm, and the height of the base to be 100 μm. As shown in FIG. 3C, it can be confirmed that the tip composition is well pushed into the micro-tip of the mold. In FIG. 3C, the structure formed by the apex composition among the apex composition and the base composition is indicated in blue.

[0104] FIG. 4 is a photograph of the microarray of Example 1, which has the lowest weight ratio (0.91) of the biodegraded polymer to semaglutide among Examples 1 to 12. FIG. 4A is a top view of the microarray, showing that the composition injected into the mold has been pushed into the micro-tip of the mold and that drying is completed in that state. FIG. 4B is a side view of the microarray, showing that the tip of the needle has a pointed shape. As shown in FIG. 4C, it can be seen that the tip composition has been pushed well into the micro-tip of the mold. In FIG. 4C, the structure formed by the tip composition among the tip composition and the base composition is indicated in blue.

[0105] Figure 5 is a photograph of a microarray in which the weight ratio of the biodegradable polymer to semaglutide is 0.01 (Comparative Example 2). Figure 5 was taken from the top of the microarray, and it can be seen that many bubbles are generated in the needles and stains are formed as the composition splashes between the needles. That is, when manufacturing the microarray of Comparative Example 2, a scattering phenomenon of the composition (a phenomenon in which the composition splashes upon hitting the mold) was observed when dispensing the composition into the mold.

[0106] Figure 6 is a photograph of a microarray in which the weight ratio of the biodegradable polymer to semaglutide is 1.2 (Comparative Example 3). Figure 6A is a top view of the microarray, showing that the composition injected into the mold is not properly pushed into the micro-tip of the mold, and a large circle is formed at the tip. Figure 6B is a side view of the microarray, showing that the tip of the needle is not pointed but blunt. In Figure 6C, the structure formed by the tip composition among the tip composition and the base composition is indicated in blue. As shown in Figure 6C, it can be seen that the tip composition does not properly reach the micro-tip of the mold, and the distance between the virtual ideal conical tip and the actually molded tip reaches 225 μm.

[0107] From the above test results, it can be seen that in order to manufacture a microarray having an excellent shape, the weight ratio of the biodegradable polymer to the semaglutide in the leading edge composition should be 0.02 to 1.1, preferably 0.02 to 1.0, or more preferably 0.02 to 0.91.

[0108] The microarray of the present invention contains a significantly large amount of semaglutide at the tip. That is, the microarray of the present invention, which contains up to 50 times the amount of semaglutide compared to the biodegradable polymer serving as the matrix of the microarray and has an excellent shape with pointed tips, is an optimal formulation for administering semaglutide to a patient.

[0109] Specifically, when a high concentration of semaglutide is distributed at the tip of the microarray, the amount of semaglutide delivered to the target increases, allowing the drug to exert its effect rapidly on the target and reducing side effects.

[0110]

[0111] [Test Example 2]

[0112] Evaluation of the viscosity of the advanced component composition

[0113]

[0114] In Examples 1 to 12 of the present invention, the viscosity of the leading edge composition was measured. Specifically, the viscosity of the composition was measured using a Brookfield DVNX RV CP Viscometer, and a spin of CPA-40Z 0.8 degrees (viscosity range: 1 - 32,000 cP) was applied. It is a cone-and-plate type viscometer, and after placing the composition on the plate, the shear rate and shear stress were measured by applying rotation after contact with a cone-type spindle.

[0115] The viscosity of the composition, applied torque, and RPM values ​​are shown in Table 8 below, and the temperature at the time of measurement was 25 ℃.

[0116]

[0117]

[0118]

[0119] As shown in Table 8 above, the viscosity of the composition with a weight ratio of 0.02 of the biodegradable polymer (Example 5) was 36.46 Pc, and the viscosity of the composition with a content ratio of 0.97 of the biodegradable polymer (Example 1) was 157.6 Pc.

[0120] The viscosity of Comparative Example 3 was 349.9 Pc, and as shown in FIG. 6, it can be seen that if the viscosity of the composition is high, it is difficult to fill the composition into the microstructure inside the mold. In addition, the viscosity of Comparative Example 2 was 20.11 Pc, and as shown in FIG. 5, it can be seen that if the viscosity of the composition is low, the composition does not accumulate in the indented part but scatters due to pressure.

[0121] Therefore, for excellent molding of the microarray, it can be seen that when measured with Ametek Brookfield’s DVNext Rheometer RV CP (CPA-40Z 0.8˚ / 2.4CM CP SPINDLE ASSEMBLY), the torque is 20 to 50% and the RPM is 10 to 50, and the viscosity of the composition is appropriate to have a range of 30 to 300 cP, preferably 30 to 200 cP.

[0122]

[0123] [Test Example 3]

[0124] Stability evaluation of the microarray of the present invention

[0125]

[0126] While conventional microarrays containing semaglutide have required refrigerated storage and transportation to maintain product stability, the microarray of the present invention can be stored and transported at room temperature, and it was confirmed by the following method that the microarray of the present invention possesses stability at room temperature.

[0127] It is common practice to separate the microarray from the mold and package only the microarray after it has been formed in the mold. However, when packaging the microarray after manufacturing according to the present invention, the microarray is packaged as is without separating it from the mold, so that the mold functions as a packaging material for the microarray.

[0128] When packaging the microarray of the present invention, an adhesive patch was attached to the base layer, and a protective layer was added to protect the adhesive layer. Subsequently, the microarray was placed in an aluminum packaging material and sealed.

[0129] Figure 7 shows photographs of the microarray mold before separation and after packaging is complete.

[0130] Stability evaluations under room temperature conditions and under accelerated conditions were performed in the above-mentioned sealed state. The microarray of Example 5 was placed in a chamber maintained at 25 ± 2 ℃ and relative humidity of 65 ± 5%, and evaluated for 28 weeks under room temperature conditions. Quantification was confirmed through HPLC analysis under the conditions shown in Table 9 below.

[0131]

[0132]

[0133]

[0134] The results of the stability evaluation at room temperature above are shown in Table 10 and Figure 8 below.

[0135]

[0136]

[0137]

[0138] As shown in Table 10 above, it was confirmed that the microarray of the present invention has excellent room temperature stability, with the semaglutide content maintained for 28 weeks.

[0139]

[0140] Next, stability evaluation under accelerated conditions was performed. The microarray of Example 5 was placed in a chamber maintained at 40 ± 2 ℃ and relative humidity of 75 ± 5% and evaluated for 28 weeks under accelerated conditions. It was quantified and confirmed through HPLC analysis under the conditions of Table 9 above.

[0141] The results of the stability evaluation under the above acceleration conditions are shown in Table 11 and Figure 9 below.

[0142]

[0143]

[0144]

[0145] As shown in Table 11 above, it was confirmed that the microarray of the present invention maintained the semaglutide content for 28 weeks and had excellent stability even under accelerated conditions.

[0146] In Figures 8 and 9, the x-axis represents the content % relative to the target content.

[0147]

[0148] [Test Example 4]

[0149] Evaluation of Microarray Pharmacokinetic Characteristics

[0150]

[0151] Semaglutide was quantified to prepare a stock solution at a concentration of 1 mg / mL. Working solutions were prepared by diluting the semaglutide in a 50% acetonitrile (0.1% formic acid) solution to concentrations of 100, 300, 500, 5000, 10000, 30000, 100000, and 300000 ng / mL, respectively.

[0152] Leuprorelin was used as the internal standard (IS) and was prepared by diluting it in a 7:3 = acetonitrile : MeOH solution to a concentration of 10 ng / mL.

[0153] Standard plasma samples for the calibration curve were prepared by adding 5 μL of semaglutide working solution to 45 μL of blank plasma to obtain standard plasma samples with concentrations of 10, 30, 50, 100, 300, 500, 1000, 3000, 10000, and 30000 ng / mL. 200 μL of leuprorelin, an internal standard, was added to 50 μL of the standard plasma samples and vertex mixed for at least 5 minutes. Subsequently, the samples were centrifuged at 13,000 rpm for 10 minutes to re-proteinize them. After centrifugation, approximately 50 μL was transferred to an auto-sampler glass vial and injected into an LC-MS / MS.

[0154] LC-MS / MS was performed using a TQ5500, and a Kinetex C18 column (2.1 x 50 mm, 5 μm, 100 Å) was used. For the mobile phase, A was 0.1% formic acid in purified water and B was 0.1% formic acid in acetonitrile, respectively, and 70% acetonitrile was used as the rinsing solvent. During the analysis, the run time, flow rate, sample injection volume, and column temperature were set to 4 min, 0.4 ml / min, 2 μL, and 40°C, respectively. The changes in LC Gradient conditions over 4 minutes are shown in Table 12 below.

[0155]

[0156]

[0157]

[0158] The m / z of semaglutide was 1029.3 → 135.9, and the m / z of leuprorelin was 605.2 → 249.0. The MS parameters Curtain Gas, Collison Gas, ionSpray Voltage, Temperature, Ion Source Gas 1, Ion Source Gas 2, DP, CE, CXP, and EP were set to 20, 7, 5500, 500, 50, 40, 220, 40, 15, and 10, respectively.

[0159] The results of the PK profile experiment according to the weight ratio of biodegradable polymer in the advanced part composition are shown in Table 13 below.

[0160]

[0161]

[0162]

[0163] As shown in Table 13 above, the relative BA (bioavailability) value in the microarrays of Examples 1 to 12 of the present invention is 50% or higher, while the relative BA value in the microarray of Comparative Example 1 is 19.8%, confirming that the microarray of the present invention has a relative BA that is more than twice as high as that of the microarray of Comparative Example 1.

[0164]

[0165] In addition, the microarrays of Comparative Example 1, Examples 4 and 5, and Examples 10 to 12 were attached to experimental animals, removed after 6 hours, and the content was measured and used as the residual amount, and the results are shown in Table 14 below.

[0166]

[0167]

[0168]

[0169] As shown in Table 14 above, the residual amount of the embodiment of the present invention did not exceed 22%, but the residual amount of Comparative Example 1 was found to be the highest at 53.00%.

[0170] Ultimately, it was confirmed that the microarray of the present invention exhibits high relative BA and low residual amount, and thus has high delivery efficiency of semaglutide, thereby showing high efficacy even with low dose.

[0171]

[0172] [Test Example 5]

[0173] Comparative evaluation of microarrays and injectable formulations

[0174]

[0175] The plasma concentration of semaglutide in the microarray of the present invention and subcutaneous injection was compared and evaluated.

[0176] Specifically, a control group (injectable formulation) for the microarrays of Comparative Example 1 and Examples 4, 5, 10, 11, and 12 was prepared with the composition of Table 15 below. Specifically, an injectable formulation was prepared by adding the semaglutide, disodium phosphate dihydrate, and sodium chloride of Table 15 below to 1 mL of sterile distilled water, and then 200 μL was administered subcutaneously to experimental animals to serve as the control group.

[0177]

[0178]

[0179]

[0180] Figures 10 to 13 show the results of comparing the plasma concentrations of semaglutide of the control group (subcutaneous injection), Comparative Example 1, and Examples 4, 5, 10, 11, and 12. It was confirmed that the plasma concentration of the microarray of Comparative Example 1 was very low compared to the control group. On the other hand, the microarray of the present invention showed a plasma concentration similar to that of the control group, indicating that the microarray of the present invention has pharmacokinetic characteristics similar to those of subcutaneous injection.

Claims

1. A composition for manufacturing a microarray comprising semaglutide or a pharmaceutically acceptable salt thereof and a biodegradable polymer, wherein The microarray includes an advanced portion and a base portion, and The leading edge composition of the microarray comprises a biodegradable polymer in a weight ratio of 0.02 to 1.1 with respect to semaglutide or a pharmaceutically acceptable salt thereof, Composition for manufacturing microarrays by a molding process.

2. A composition for manufacturing a microarray according to claim 1, wherein the leading edge composition of the microarray comprises a biodegradable polymer in a weight ratio of 0.02 to 1.0 with respect to semaglutide or a pharmaceutically acceptable salt thereof.

3. A composition for manufacturing a microarray according to claim 1, wherein the leading edge composition of the microarray comprises a biodegradable polymer in a weight ratio of 0.02 to 0.91 with respect to semaglutide or a pharmaceutically acceptable salt thereof.

4. A composition for manufacturing a microarray according to claim 1, wherein the biodegradable polymer is one or more selected from the group consisting of hyaluronic acid, polyvinylpyrrolidone, polyvinyl alcohol, carboxymethylcellulose, collagen, chitosan, chondroitin, hydroxyethyl cellulose, polylactic glycolic acid, and gelatin.

5. A composition for manufacturing a microarray according to claim 1, wherein the biodegradable polymer is one or more selected from the group consisting of polyvinylpyrrolidone, polyvinyl alcohol, and hyaluronic acid.

6. A composition for manufacturing a microarray according to claim 1, wherein the base of the microarray does not contain semaglutide or a pharmaceutically acceptable salt thereof.

7. In claim 1, the above-mentioned leading edge composition is a composition for manufacturing a microarray having a viscosity of 30 to 200 cP.

8. A microarray assembly comprising a microarray manufactured from a composition for manufacturing a microarray according to any one of claims 1 to 7, and a mold used for manufacturing the microarray.

9. A microarray assembly according to claim 8, wherein the microarray and the mold are in a non-separable form.

10. A step of injecting a tip composition comprising semaglutide and a biodegradable polymer into the recessed portion of the mold; A step of drying the injected tip composition; A step of injecting a base composition into the upper part of a dried tip; and It includes a step of drying the base composition, A biodegradable polymer comprising 0.02 to 1.1 weight ratio with respect to semaglutide or a pharmaceutically acceptable salt thereof in the above-mentioned advanced part composition, A method for manufacturing a microarray by a molding process.

11. A method for manufacturing a microarray according to claim 10, wherein the composition of the leading edge of the microarray comprises a biodegradable polymer in a weight ratio of 0.02 to 1.0 with respect to semaglutide or a pharmaceutically acceptable salt thereof.

12. A method for manufacturing a microarray according to claim 10, wherein the composition of the leading edge of the microarray comprises a biodegradable polymer in a weight ratio of 0.02 to 0.91 with respect to semaglutide or a pharmaceutically acceptable salt thereof.

13. A method for manufacturing a microarray according to claim 10, wherein the biodegradable polymer is one or more selected from the group consisting of hyaluronic acid, polyvinylpyrrolidone, polyvinyl alcohol, carboxymethylcellulose, collagen, chitosan, chondroitin, hydroxyethyl cellulose, polylactic glycolic acid, and gelatin.

14. A method for manufacturing a microarray according to claim 10, wherein the biodegradable polymer is one or more selected from the group consisting of polyvinylpyrrolidone, polyvinyl alcohol, and hyaluronic acid.

15. A method for manufacturing a microarray according to claim 10, wherein the base composition of the microarray does not include semaglutide or a pharmaceutically acceptable salt thereof.

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