Inhalant composition

Abstract

The present invention relates to an inhalation composition comprising a GLP-1 analogue and a transport carrier. The inhalation composition has high stability due to containing a small amount of impurities while having a high effective particle delivery capacity relative to the content of the composition, and has excellent flowability and fillability. In addition, the inhalation composition according to the present invention has high bioavailability compared to oral preparations due to delivering peptides directly to the lungs, and thus can reduce manufacturing costs by reducing the required dosage compared to oral preparations.

Description

Inhalant composition

[0001] The present invention relates to an inhalable composition comprising a GLP-1 analogue and a transport carrier. The inhalable composition of the present invention has a high effective particle delivery amount relative to the content, a low amount of generated flexible substances, and thus has high stability, and excellent flowability and fillability.

[0002] In the case of peptides, injections account for the majority of administration routes. This is because, when administered via routes other than injection, bioavailability is reduced due to factors such as enzymatic degradation and difficulty in absorption. However, injections have the disadvantage of causing pain and making them difficult for the general public to use without proper training.

[0003] Existing oral medications have low bioavailability due to enzymatic breakdown and peptide digestion within the digestive tract, as well as difficulties in lipid permeation. This necessitates the use of excessive amounts of active ingredients during manufacturing. This, in turn, increases manufacturing costs.

[0004] Accordingly, inhalation formulations that do not cause pain and have high bioavailability can be considered, but much research is needed to develop formulations that have high effective particle delivery and excellent stability.

[0005] The present invention aims to provide an inhalable composition comprising a GLP-1 analogue having a large effective particle delivery amount and excellent stability, and a transport carrier.

[0006] In addition, the present invention aims to provide a method for producing the above inhalable composition.

[0007] However, the technical problems to be solved by the present invention are not limited to the problems mentioned above, and other problems not mentioned can be clearly understood by those skilled in the art from the description below.

[0008] To achieve the above object of the present invention, the present invention provides an inhalation composition comprising a GLP-1 analogue, a first transport carrier, and a second transport carrier.

[0009] In the present invention, the GLP-1 analogue may be at least one selected from the group consisting of semaglutide, exendin-4, CA-exendin-4 (Imidazoacetyl-exendin-4), DA-exendin-4 (Desaminohistidyl-exendin-4), HY-exendin-4 (beta-hydroxy imidazopropoinyl-exendin-4), CX-exendin-4 betacarboxyimidazopropionyl-exendin-4), DM-exendin-4 (Dimethyl-histidyl-exendin-4), lixisenatide, liraglutide, dulaglutide, and albiglutide, but is not limited thereto.

[0010] Preferably, in the present invention, the GLP-1 analogue may be semaglutide.

[0011] The above semaglutide may be a peptide in which the 8th alanine in GLP-1 is substituted with 2-aminoisobutyric acid, the 34th lysine is substituted with arginine, and the 26th lysine is acylated with stearic diacid, but is not limited thereto. In addition, the semaglutide in the present invention may be a natural or artificially synthesized peptide.

[0012] In one embodiment of the present invention, the GLP-1 analogue may be undifferentiated.

[0013] In one embodiment of the present invention, the inhalable composition of the present invention comprises a micronized GLP-1 analogue and a third transport carrier.

[0014] The undifferentiated GLP-1 analogue of the present invention has an improved effective particle delivery amount compared to a non-undifferentiated GLP-1 analogue and has excellent bioavailability and stability.

[0015] Preferably, in the present invention, differentiation can be performed by freeze-drying.

[0016] Peptides, such as GLP-1 analogues, are susceptible to heat, which can cause aggregation and decreased stability. Due to these issues, many peptide or protein preparations currently on the market are stored under refrigerated conditions.

[0017] The GLP-1 analogue of the present invention has the characteristics of minimizing protein or peptide damage, preventing aggregation, and improving stability by performing lyophilization.

[0018] In one embodiment of the present invention, the inhalable composition of the present invention comprises a lyophilized product of a GLP-1 analogue, a first transport carrier, and a second transport carrier.

[0019] In one embodiment of the present invention, the inhalable composition of the present invention comprises a lyophilized product of a GLP-1 analogue alone, a first transport carrier, and a second transport carrier.

[0020] In one embodiment of the present invention, the micronization may be performed by additionally including a third transport carrier in addition to the GLP-1 analogue. That is, the micronized composition of the GLP-1 analogue in the present invention may include the active ingredient, the GLP-1 analogue, alone or together with the third transport carrier.

[0021] In one embodiment of the present invention, the inhalable composition of the present invention comprises a lyophilized product of a GLP-1 analogue and a third transport carrier, a first transport carrier, and a second transport carrier.

[0022] In one embodiment of the present invention, the differentiation in the present invention is performed by lyophilization, and the concentration of the solution containing the GLP-1 analogue before lyophilization may be 150 to 900 μg / mL, preferably 250 to 750 μg / mL, 300 to 700 μg / mL, 350 to 650 μg / mL, 400 to 700 μg / mL, or 450 to 550 μg / mL based on the GLP-1 analogue.

[0023] Additionally, preferably, the concentration of the solution containing the GLP-1 analogue before lyophilization may be 250 to 500 μg / mL based on the GLP-1 analogue.

[0024] In one embodiment of the present invention, the solution containing the GLP-1 analogue before lyophilization in the present invention may contain 2000 to 4000 times the weight of the GLP-1 analogue as a solvent.

[0025] The solvent may be selected from known solvents, such as, for example, polar protic, non-polar protic, polar aprotic, non-polar aprotic solvents, or combinations thereof, and the solvent may be, for example, but is not limited to, water.

[0026] In one embodiment of the present invention, the first transport carrier, the second transport carrier, and the third transport carrier may each independently be at least one selected from the group consisting of monosaccharides, disaccharides, polysaccharides, polyalcohols, and hydrates thereof.

[0027] In one embodiment of the present invention, the first transport carrier, the second transport carrier, or the third transport carrier may each independently be at least one selected from the group consisting of a monosaccharide including glucose or arabinose; a disaccharide including lactose, maltose, trehalose, or sucrose; a polysaccharide including starch, dextrin, or dextran; a polyalcohol including sorbitol, mannitol, or xylitol, and hydrates thereof.

[0028] In one embodiment of the present invention, the first transport carrier, the second transport carrier, or the third transport carrier may each independently be at least one selected from the group consisting of lactose, powdered lactose, mannitol, and hydrates thereof.

[0029] Preferably, in the present invention, the first transport carrier may be lactose and the second transport carrier may be powdered lactose.

[0030] In one embodiment of the present invention, the lactose may be included in the composition of the present invention in an amount of 0.5 to 25 mg.

[0031] In one embodiment of the present invention, the lactose may be included in an amount of 20 to 90 wt% based on the total weight of the composition, and may also be included in an amount of 25 to 85 wt%, 30 to 80 wt%, 35 to 75 wt%, 35 to 60 wt%, 35 to 55 wt%, 35 to 50 wt%, or 35 to 45 wt%.

[0032] In one embodiment of the present invention, the lactose may be included in an amount of 100 to 3100 wt% based on the weight of the GLP-1 analogue, and may also be included in an amount of 150 to 2100 wt%, 200 to 1600 wt%, 250 to 1100 wt%, 300 to 600 wt%, 300 to 500 wt%, 300 to 400 wt%, or 300 to 350 wt%, but is not limited thereto.

[0033] Additionally, in one embodiment of the present invention, the micronized milk sugar may be included in the composition of the present invention in an amount of 0.1 to 5 mg.

[0034] In one embodiment of the present invention, the micronized milk sugar may be included in an amount of 5 to 15 wt%, 6 to 14 wt%, 7 to 13 wt%, 8 to 12 wt%, or 9 to 11 wt% based on the total weight of the inhalation composition of the present invention, but is not limited thereto.

[0035] Preferably, in the present invention, the third transport carrier may be mannitol.

[0036] In one embodiment of the present invention, the mannitol may be included in the composition of the present invention in an amount of 0.5 to 6 mg.

[0037] In one embodiment of the present invention, the mannitol may be included in an amount of 150 to 900 wt% based on the weight of the GLP-1 analogue, and may also be included in an amount of 200 to 800 wt%, 200 to 700 wt%, 250 to 600 wt%, 250 to 500 wt%, 250 to 400 wt%, or 250 to 300 wt%.

[0038] In one embodiment of the present invention, the first transport carrier may have an average particle size (X90) of 30 to 150 μm, and the second transport carrier may have an average particle size (X90) of 2 to 50 μm or less.

[0039] In one embodiment of the present invention, the inhalation composition may have an effective particle size of 5 μm or less in an amount of 20% or more based on the total weight of the composition when evaluating particle size distribution for 2.4 seconds at a flow rate of 100 L / min.

[0040] In one embodiment of the present invention, the composition may further include an active agent.

[0041] In one embodiment of the present invention, the active agent may be any active agent known in the art, and is not particularly limited as long as it does not impede the desired effect of the inhalable composition of the present invention. For example, the active agent may include, but is not limited to, one or more selected from the group consisting of stearic acid, magnesium stearate, silicon dioxide, talc, sucrose fatty acid ester, hydrogenated vegetable oil, high-melting point wax, glyceryl fatty acid ester, glycerol dibehenate, and any combination thereof.

[0042]

[0043] In addition, the present invention provides a method for preparing an inhalation composition, comprising a first step of lyophilizing a GLP-1 analogue; and a second step of mixing the lyophilized product prepared in the first step with a first transport carrier and a second transport carrier.

[0044] In one embodiment of the present invention, the freeze-drying in the first step may be performed by additionally including a third transport carrier.

[0045] In the above manufacturing method, the GLP-1 analogue, lyophilization, first transport carrier, second transport carrier, and third transport carrier are as described above.

[0046] The first step is a step of lyophilizing and micronizing the GLP-1 analogue, and the concentration of the solution containing the GLP-1 analogue before lyophilization may be 150 to 900 μg / mL, preferably 250 to 750 μg / mL, 300 to 700 μg / mL, 350 to 650 μg / mL, 400 to 700 μg / mL, or 450 to 550 μg / mL based on the GLP-1 analogue.

[0047] Additionally, the solution containing the GLP-1 analogue in the first step may contain 2000 to 4000 times the weight of the GLP-1 analogue as a solvent.

[0048] The solvent may be selected from known solvents, such as, for example, polar protic, non-polar protic, polar aprotic, non-polar aprotic solvents, or combinations thereof, and the solvent may be, for example, water, but is not limited thereto.

[0049] The present invention provides a capsule comprising the above composition.

[0050] In one embodiment of the present invention, the capsule comprises any suitable container for a drug, and may contain, for example, gelatin, polyethylene, or HPMC (Hydroxypropyl methylcellulose).

[0051] In one embodiment of the present invention, the capsule may contain HPMC (Hydroxypropyl methylcellulose).

[0052] The present invention relates to an inhalable composition comprising a GLP-1 analogue and a transport carrier, wherein the inhalable composition has a high effective particle delivery rate relative to the content while generating a low amount of volatile substances, thereby exhibiting high stability and excellent flowability and fillability. In addition, the inhalable composition of the present invention directly delivers the peptide to the lungs, thereby exhibiting higher bioavailability than oral agents, and thus reducing the required dosage compared to oral agents, thereby lowering manufacturing costs.

[0053] Figure 1 is a schematic diagram of the manufacturing method.

[0054] Figure 2 shows the Next Generation Impactor (Copley) test device used for particle size distribution testing.

[0055] Figure 3 is a graph showing particle size distribution according to mannitol content ratio (MP: Mouthpiece adaptor, Throat: Induction port, PS: Pre-separator, 1-7: stage 1-7, MOC: Micro-orifice collector, hereinafter the same).

[0056] Figure 4 is a graph showing the particle size distribution according to the concentration of the freeze-dried solution based on the main component.

[0057] Figure 5 is a graph showing particle size distribution according to the content ratio of micronized milk sugar.

[0058] Figure 6 is a graph showing the particle size distribution by type of third transport carrier.

[0059] Figure 7 shows the results showing the appearance of the lyophilized product in the vial. (a) is the appearance of the lyophilized product of semaglutide alone, (b) is the appearance of the lyophilized product of semaglutide and mannitol, and (c) is the appearance of the lyophilized product of semaglutide and sucrose.

[0060] Figure 8 is a graph showing the results of accelerated stability by lactose content, where (a) shows the total amount of flexible substances and (b) shows the oligomer formation ratio.

[0061] In Fig. 9, (a) is a scanning microscope image of semaglutide before freeze-drying, and (b) is a scanning microscope image of semaglutide after freeze-drying.

[0062] Hereinafter, preferred examples are presented to aid in understanding the present invention. However, the following examples are provided solely to facilitate a better understanding of the present invention, and the scope of the present invention is not limited by the examples.

[0063]

[0064] Examples and Comparative Examples

[0065] Semaglutide alone or semaglutide and transport carrier (mannitol, sucrose) were weighed according to the compositions presented in Tables 1 and 2 below, dissolved in a solvent (distilled water), and lyophilized (-80°C, 5 m Torr) for 48 hours. The lyophilized product, transport carrier (lactose, micronized lactose), and lubricant (magnesium stearate) were sieved three times through a 35 mesh, mixed, and then filled into a #3 hard capsule with HPMC as a base.

[0066]

[0067]

[0068]

[0069] Experimental Example 1-1: Evaluation of Effective Particle Volume

[0070] Manufactured examples and comparative examples USP <601> Aerosol performance was evaluated according to INHALATION AND NASAL DRUG PRODUCTS: AEROSOLS, SPRAYS, AND POWDERS—PERFORMANCE QUALITY TESTS. To measure the actual dose delivered to the target area of ​​the lung, the particle size distribution was measured for 2.4 seconds at a flow rate of 100 L / min using the Next Generation Impactor (NGI) (Copley) of Fig. 2, and the amount of particles sized 5 μm or less was set and evaluated as the effective particle amount. After coating 100 μL of Glycerol / Brij35 adhesive for stage #1 and MOC, and 50 μL for stages #2 to #7, 10 mL of diluent was added to the pre-separator to prepare for the test. DPI inhaler (pressure drop value) / L / min: 0.0191 to 0.0247), punch, and suction at a flow rate of 100 L / min for 2.4 seconds, repeating this 4 times (4 caps per test). Afterwards, the sample solution was rinsed with Mouthpiece (10 mL), Throat (20 mL), Pre-separator (50 mL), Stages #1 to #7, and MOC (10 mL), and analyzed using chromatography. Each effective particle amount was calculated by analyzing the content of the inhalation compositions manufactured with the compositions of the examples and comparative examples, and then calculating the effective particle amount per content.

[0071]

[0072] Table 3 above shows the cut-off diameter (μm) by flow rate, and is based on USP <601> Table 3b can be referenced. Based on Table 3 above, the effective particle size of 5 μm or less at a flow rate of 100 L / min refers to the distribution amount from stages #2 to #7 and up to MOC.

[0073]

[0074] Table 4 above shows the pressure drop values ​​of the DPI inhaler used in the examples and comparative examples.

[0075] <Particle size distribution test HPLC analysis conditions>

[0076] Column: A column filled with octylsilylated silica gel for liquid chromatography with a particle size of 5 μm in a stainless steel tube with an inner diameter of approximately 4.6 mm and a length of 150 mm.

[0077] Mobile phase: 0.1% phosphoric acid solution: acetonitrile = 55:45 (v / v)

[0078] Detector: UV spectrophotometer (measuring wavelength 280 nm)

[0079] Temperature: 30 ℃

[0080] Flow rate: 1.0 mL / min

[0081] Injection volume: 50 μL

[0082] The content-to-delivery amount (%) is shown in Table 5 and Figures 3 to 6. Through repeated experiments, the content-to-delivery amount (%) for each batch of each example and comparative example was obtained, and the average value thereof is shown.

[0083]

[0084] Looking at Table 5 above, i) when the composition was dissolved with a transport carrier (mannitol) and then freeze-dried, the delivery amount was high relative to the content (Examples 1 to 3, Example 5-2), ii) when the solution concentration of the main ingredient before freeze-drying was 150 to 900 μg / mL, the delivery amount was high relative to the content (Example 4, Example 5-1, Comparative Example 1). In addition, iii) when the weight range of the micronized milk sugar was 5 to 15 wt% relative to the total weight of the composition, the delivery amount was high relative to the content (Example 5-1, Comparative Examples 2 and 3), and iv) when mannitol was applied rather than sucrose during freeze-drying, the delivery amount was high relative to the content (Example 8 and Comparative Example 4). This is described in more detail in Experimental Examples 1-2 to 1-5 below.

[0085]

[0086] Experimental Example 1-2: Confirmation of effective particle size according to mannitol content

[0087] In order to confirm the change in effective particle size according to mannitol content, Table 6 was organized below with reference to Tables 1, 2, 4, and 5 above.

[0088]

[0089] Referring to Table 6 and Fig. 3 above, the aerodynamic particle size distribution test results of Examples 1 to 3 and Example 5-2 showed that when mannitol was added during freeze-drying, the delivery amount per content was higher compared to when semaglutide was freeze-dried alone. From this, it was confirmed that the effective particle amount of the composition increased when semaglutide was dissolved together with a transport carrier and then freeze-dried compared to when semaglutide was freeze-dried alone.

[0090]

[0091] Experimental Example 1-3: Confirmation of effective particle size according to main ingredient concentration before freeze-drying

[0092] In order to confirm the change in effective particle size according to the concentration of main ingredient before freeze-drying, Table 7 below was organized with reference to Tables 1, 2, 4, and 5 above.

[0093]

[0094] Referring to Table 7 and FIG. 4 above, the results of the aerodynamic particle size distribution test of Example 4, Example 5-1, and Comparative Example 1 showed excellent delivery amount per content when the concentration of the solution before freeze-drying based on the main component was 150 to 900 μg / mL, but it was confirmed that the delivery amount per content decreased when the concentration of the solution before freeze-drying based on the main component exceeded 900 μg / mL.

[0095]

[0096] Experimental Example 1-4: Confirmation of effective particle size according to the content of micronized lactose

[0097] In order to confirm the change in effective particle size according to the content of micronized milk sugar, Table 8 was organized below with reference to Tables 1, 2, 4, and 5 above.

[0098]

[0099] Referring to Table 8 and FIG. 5 above, the results of the aerodynamic particle size distribution test of Example 5-1 and Comparative Examples 2 and 3 showed a high delivery amount relative to the content when the weight range of the micronized milk sugar relative to the total weight of the composition excluding capsules was 5 to 15 wt%, but it was confirmed that the delivery amount relative to the content decreased when the weight range of the micronized milk sugar relative to the total weight of the composition excluding capsules was less than 5 wt% or exceeded 15 wt%.

[0100]

[0101] Experimental Example 1-5: Confirmation of effective particle size according to freeze-dried sugar

[0102] In order to confirm the change in effective particle size according to the sugar used as the third transport carrier during freeze-drying, Table 9 was organized below with reference to Tables 1, 2, 4, and 5 above.

[0103]

[0104] Referring to Table 9 and Figure 6 above, the particle size distribution test results of Example 8 and Comparative Example 4 confirmed that when mannitol was applied rather than sucrose during freeze-drying, the delivery amount per content was approximately 5.4 times higher.

[0105]

[0106] Experimental Example 1-6: Confirmation of effective particle amount according to freeze-dried product density

[0107] In addition, in order to compare the correlation between the density of the lyophilized product and the effective particle amount, the appearance of the lyophilized product in a vial of Example 5-2 is shown in Fig. 7 (a), the appearance of the lyophilized product in a vial of Example 8 is shown in Fig. 7 (b), and the appearance of the lyophilized product in a vial of Comparative Example 4 is shown in Fig. 7 (c), respectively. As can be seen from the drawings, the density of the lyophilized product of Example 5-2, in which only the main ingredient was lyophilized, or of Comparative Example 4, in which the main ingredient and sucrose were lyophilized, was confirmed to be higher than the density of the lyophilized product of Example 8, in which the main ingredient and mannitol were lyophilized. Referring to Table 5 above regarding the delivery amount per content along with these results, it was confirmed that a lyophilized product with a high density was disadvantageous in securing an effective particle amount, and a lyophilized product with a low density was advantageous in securing an effective particle amount.

[0108]

[0109] Experimental Example 2: Stability Evaluation

[0110] Flexibility tests and size exclusion chromatography are used as indicators to evaluate the stability of peptides. It can be determined that the larger the size of the flexible material and the higher the oligomer formation rate, the lower the stability of the active ingredient. The effect of lactose on the stability of the composition was evaluated through the accelerated stability test (40°C / 75%RH) of Examples 6 to 8.

[0111] <Flexible test HPLC analysis conditions>

[0112] Column: A column filled with octylsilylated silica gel for liquid chromatography with a particle size of 5 μm in a stainless steel tube with an inner diameter of approximately 4.6 mm and a length of 250 mm.

[0113] Mobile phase A: 0.15% trifluoroacetic acid in 1% acetonitrile

[0114] Mobile phase B: 0.15% trifluoroacetic acid in acetonitrile

[0115] Detector: UV spectrophotometer (measuring wavelength 220 nm)

[0116] Temperature: 50 ℃

[0117] Flow rate: 1.0 mL / min

[0118] Injection volume: 50 μL

[0119] <Size exclusion chromatography HPLC analysis conditions>

[0120] Column: SEC column with particle size of 5 μm in a stainless steel tube with an inner diameter of approximately 8.0 mm and a length of 300 mm.

[0121] Mobile phase: water:acetonitrile:trifluoroacetic acid = 500:500:1 (v / v / v)

[0122] Detector: UV spectrophotometer (measuring wavelength 280 nm)

[0123] Temperature: 30 ℃

[0124] Flow rate: 0.5 mL / min

[0125] Injection volume: 20 μL

[0126] Referring to Figures 8 (a) and 8 (b), the stability test results for Examples 6 to 8 confirmed that the size of the flexible material was small and the oligomer formation rate was also low. Therefore, from the above results, it can be seen that Examples 6 to 8 have excellent stability.

[0127]

[0128] Experimental Example 3: Particle Microanalysis

[0129] After freeze-drying to differentiate the raw material, the degree of differentiation of Example 2 was confirmed using a scanning electron microscope (SEM).

[0130] Fig. 9 (a) is a scanning electron microscope image showing the active ingredient before freeze-drying, and Fig. 9 (b) is a scanning electron microscope image showing the active ingredient after freeze-drying. It can be confirmed that the particle size of the raw material is reduced after freeze-drying.

[0131] Through these results, it can be seen that the amount of effective particles of 5 μm or less for alveolar delivery can be increased by micronizing the raw material through freeze-drying as in the present invention.

[0132]

[0133] Experimental Example 4: Flowability Evaluation

[0134] The flowability of Examples 5-1 and 8 and Comparative Example 5 was evaluated. The flowability of granules or powder has a significant impact on the filling property, and if the flowability (fluidity) of granules or powder is poor, the loading on the dosing disk of the filling equipment may not be uniform, which may cause a decrease in the content uniformity. Specifically, as shown in Table 10, the flowability of Examples 5-1 and 8 and Comparative Example 5 was evaluated using the Hausner ratio.

[0135]

[0136] When the Hausner ratio is 1.6 or higher, the flowability is evaluated as very, very poor. In the case of Comparative Example 5, which does not contain lactose and an activator, the Hausner ratio was 1.92, which corresponds to very, very poor flowability. However, when lactose and an activator were included, it was confirmed that the flowability was improved.

[0137]

[0138] Experimental Example 5: Chargeability Evaluation

[0139] In order to evaluate the fillability of the above Examples 5-1, 8 to 9 and Comparative Examples 5 to 7, the amount of fill in the hard capsule was evaluated.

[0140]

[0141] Referring to Table 11, in the case of Comparative Example 5, which did not contain lactose, micronized milk sugar, and a lubricant, the relative deviation of the filling amount was very large at 17.1%, similar to the Hausner ratio result of Experimental Example 4, confirming that the filling property was low. In addition, in the case of Examples 5-1 and 8 to 9, where the content of micronized milk sugar was in the range of 5 to 15 wt% of the total composition weight, the relative deviation was 6% or less, confirming that the filling property was good. In Comparative Examples 6 and 7, where micronized milk sugar was included in an amount of 20 wt% or more, it was confirmed that the relative deviation of the filling amount increased again. In the case of Comparative Example 6, which contained 20 wt% of micronized milk sugar, there was one capsule whose filling amount exceeded 15% of the reference mass. In the case of Comparative Example 7, which contained 30 wt% of micronized milk sugar, there were three capsules whose filling amount exceeded 15% of the reference mass, confirming that the filling was uneven and therefore not suitable for production in terms of filling property.

[0142] From the above results, it was confirmed that the filling property was improved when lactose, powdered milk sugar, and a lubricant were included, and it was confirmed that the filling property was good when the range of powdered milk sugar was 5 wt% or more and 15 wt% or less based on the total weight of the composition.

Claims

1. An inhalation composition comprising a GLP-1 analogue, a first transport carrier and a second transport carrier.

2. In paragraph 1, An inhalation composition wherein the GLP-1 analogue is at least one selected from the group consisting of semaglutide, exendin-4, CA-exendin-4 (Imidazoacetyl-exendin-4), DA-exendin-4 (Desaminohistidyl-exendin-4), HY-exendin-4 (beta-hydroxy imidazopropoinyl-exendin-4), CX-exendin-4 betacarboxyimidazopropionyl-exendin-4), DM-exendin-4 (Dimethyl-histidyl-exendin-4), lixisenatide, liraglutide, dulaglutide, and albiglutide.

3. An inhalation composition according to claim 1, wherein the GLP-1 analogue is undifferentiated.

4. An inhalation composition according to claim 3, wherein the differentiation is performed by freeze-drying.

5. In the third paragraph, the differentiation is performed by lyophilization, and the concentration of the solution containing the GLP-1 analogue before lyophilization is 150 to 900 μg / mL based on the GLP-1 analogue.

6. In the first paragraph, the first transport carrier and the second transport carrier are each independently at least one selected from the group consisting of monosaccharides, disaccharides, polysaccharides, polyalcohols, and hydrates thereof.

7. An inhalation composition according to claim 1, wherein the first transport carrier is lactose and the second transport carrier is micronized lactose.

8. A composition for inhalation according to claim 7, wherein the micronized milk sugar is contained in an amount of 5 to 15 wt% based on the total weight of the composition.

9. An inhalation composition according to claim 3, wherein the differentiation is performed by additionally including a third transport carrier.

10. In the 9th paragraph, the third transport carrier is at least one selected from the group consisting of monosaccharides, disaccharides, polysaccharides, polyalcohols, and hydrates thereof.

11. An inhalation composition according to claim 9, wherein the third transport carrier is mannitol.

12. An inhalation composition according to claim 11, wherein the mannitol is contained in an amount of 150 to 900% by weight based on the weight of the GLP-1 analogue.

13. An inhalation composition according to claim 1, wherein the composition further comprises an active agent.

14. In the first paragraph, the inhalation composition is an inhalation composition in which the amount of particles of 5 μm or less is 20% or more based on the total weight of the composition when evaluating particle size distribution for 2.4 seconds at a flow rate of 100 L / min.

15. The first step of lyophilizing the GLP-1 analogue; and A method for producing an inhalation composition, comprising a second step of mixing the lyophilized product produced in the first step with a first transport carrier and a second transport carrier.

16. A manufacturing method in claim 15, wherein the freeze-drying in the first step is performed by additionally including a third transport carrier.

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