Inhalable composition and preparation method thereof

Abstract

This invention relates to an inhalation composition comprising a GLP-1 analog and a delivery carrier, wherein the inhalation composition has a high effective particle delivery rate relative to content, while also exhibiting content stability and thermal stability. Furthermore, the inhalation composition of this invention can directly deliver peptides to the lungs, thus exhibiting higher bioavailability compared to oral formulations, thereby reducing manufacturing costs by decreasing the required dosage compared to oral formulations.

Description

[Technical Field]

[0001] The present invention relates to an inhalation composition comprising a GLP-1 analog and a delivery carrier, wherein the inhalation composition has a high effective particle delivery amount relative to the content, and also has content stability and thermal stability. [Previous Technology]

[0002] Peptide drugs are primarily administered via invasive routes such as intravenous (IV) or subcutaneous (SC). However, these methods have drawbacks, including the need to insert a needle into the skin, which carries risks of pain, bleeding, infection, and swelling, and makes them difficult for the general public to use without training. Furthermore, most biopharmaceuticals, including peptides, require refrigerated storage, increasing costs during distribution and storage, and raising concerns about quality degradation during transport.

[0003] Regarding existing oral formulations, drug absorption is greatly limited by various physicochemical and biological barriers such as enzymatic hydrolysis in the gastrointestinal tract, strong acidic pH, mucous membranes, and absorption barriers. Orally absorbed drugs often exhibit very low bioavailability due to first-pass metabolism in the liver. This necessitates the use of excessive amounts of high-priced peptide main components, thus increasing the manufacturing cost.

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

[0005] The purpose of this invention is to provide an inhalation composition comprising a GLP-1 analog and a delivery carrier, which has a high effective particle delivery rate and excellent content stability and thermal stability.

[0006] In addition, an object of the present invention is to provide a method for preparing the inhalation composition.

[0007] However, the technical problem to be solved by the present invention is not limited to the problems mentioned above. Those skilled in the art can clearly understand other problems not mentioned from the following description.

[0008] In order to achieve the above-mentioned objective of the present invention, the present invention provides an inhalation composition comprising: 1) a spray-dried material containing a GLP-1 analog; 2) a first delivery carrier; and 3) a second delivery carrier, wherein the spray-dried material further comprises at least one of a third delivery carrier and a stabilizer, or both a third delivery carrier and a stabilizer.

[0009] In this invention, the GLP-1 (Glucagon-like peptide 1) analogue may be selected from semaglutide, exendin-4, CA-exendin-4 (imidazoacetyl-exendin-4), DA-exendin-4 (deaminohistidyl-exendin-4), HY-exendin-4 (β-hydroxyimidazoacetyl-exendin-4). The group consisting of one or more of the following, but not limited to: imidazopropionyl-exendin-4, CX-histidyl-exendin-4 (β-carboxyimidazopropionyl-exendin-4), DM-histidyl-exendin-4 (Dimethyl-histidyl-exendin-4), lixisenatide, liraglutide, dulaglutide, and albiglutide.

[0010] Preferably, in this invention, the GLP-1 analogue can be smegglutinin.

[0011] The smegglutinin may be a peptide in which the alanine at position 8 of GLP-1 is replaced by 2-aminoisobutyric acid, the lysine at position 34 is replaced by arginine, and the lysine at position 26 is acetic acid-modified with stearic diacid, but is not limited thereto. Furthermore, in this invention, the smegglutinin may be a naturally occurring or synthetically produced peptide.

[0012] The present invention is characterized in that the spray-dried material has the property of micronization of GLP-1 analogs through a spray drying process.

[0013] As an implementation example of the present invention, the GLP-1 analog contained in the spray-dried product may be a micronized GLP-1 analog.

[0014] As an example of the present invention, the inhalation composition of the present invention comprises a micronized GLP-1 analog and a third delivery carrier.

[0015] As an example of the present invention, the inhalation composition of the present invention comprises a micronized GLP-1 analog and a stabilizer.

[0016] As an example of the present invention, the inhalation composition of the present invention comprises a micronized GLP-1 analog, a third delivery carrier and a stabilizer.

[0017] Compared with unmicronized GLP-1 analogs, the micronized GLP-1 analogs of the present invention have improved effective particle delivery and excellent bioavailability and stability.

[0018] GLP-1 analogues and other peptides are susceptible to heat, which can cause aggregation and reduced stability. Due to these issues, many commercially available peptide or protein preparations are currently stored under refrigeration.

[0019] As a micronization process for peptide drugs as described above, spray freeze drying can be used, but it requires liquid nitrogen or a low-temperature environment, and freeze drying requires considerable maintenance costs and has low productivity due to the long drying time.

[0020] The GLP-1 analogue of the present invention has the following characteristics: even when the raw material is micronized by a process such as hot spray drying, the content can be maintained, the formation of aggregates can be suppressed, and thus the stability can be improved.

[0021] As an example of the present invention, the inhalation composition of the present invention comprises a spray-dried material containing a GLP-1 analog and a third delivery carrier, a first delivery carrier, and a second delivery carrier.

[0022] As an example of the present invention, the inhalation composition of the present invention comprises a spray-dried product containing a GLP-1 analog and a stabilizer, a first delivery carrier and a second delivery carrier.

[0023] As an example of the present invention, the inhalation composition of the present invention comprises a spray-dried product containing a GLP-1 analog, a third delivery carrier and a stabilizer, a first delivery carrier and a second delivery carrier.

[0024] As an implementation example of the present invention, in this invention, based on the solids (solute), the concentration of the spray solution before spray drying of the spray-dried product can be from 0.5% w / v to 15% w / v, preferably from 0.5% w / v to 10% w / v, 0.5% w / v to 7% w / v, 0.5% w / v to 5% w / v, and most preferably from 1% w / v to 5% w / v. In this invention, based on the solids (solute), when the concentration of the spray solution before spray drying is 5% w / v or higher, the effective particle quantity may decrease. Conversely, when the concentration is less than 0.5% w / v, the time to obtain solid particles increases excessively, and the solid particle size decreases to the nanometer level, causing a large amount of solid to escape through exhalation immediately after inhalation, resulting in a quality characteristic of reduced inhalation delivery efficiency. In addition, the production yield will drop to below 30%, resulting in a problem of reduced productivity.

[0025] In addition, as an implementation example of the present invention, the concentration of the spray solution containing the GLP-1 analogue can be from 0.5 mg / mL to 100 mg / mL, preferably from 0.5 mg / mL to 70 mg / mL, 0.5 mg / mL to 50 mg / mL, 0.5 mg / mL to 30 mg / mL, or 0.5 mg / mL to 15 mg / mL.

[0026] In this invention, the solvent used to prepare the spray solution may be selected from known solvents (such as polar protic solvents, nonpolar protic solvents, polar aprotic solvents, nonpolar aprotic solvents) or combinations thereof, and the solvent may be, for example, distilled water or an aqueous solution of ethanol, but is not limited thereto.

[0027] As an implementation example of the present invention, the first transport carrier, the second transport carrier and the third transport carrier may each be independently selected from one or more of the group consisting of monosaccharides, disaccharides, polysaccharides, polyols and their hydrates.

[0028] As an implementation example of the present invention, the first transport carrier, the second transport carrier, or the third transport carrier may each be independently selected from one or more of the group consisting of monosaccharides including glucose or arabinose, disaccharides including lactose, maltose, trehalose, or sucrose, polysaccharides including starch, dextrin, or dextran, polyols including sorbitol, mannitol, or xylitol, and their hydrates.

[0029] As an implementation example of the present invention, the first transport carrier, the second transport carrier or the third transport carrier may each be independently selected from one or more of the group consisting of lactose, micronized lactose, mannitol and their hydrates.

[0030] Preferably, in this invention, the first transport carrier can be lactose or mannitol, and the second transport carrier can be micronized lactose.

[0031] As an example of the present invention, the composition of the present invention may contain 0.5 mg to 25 mg of the lactose or mannitol.

[0032] As an implementation example of the present invention, the composition may contain 20% to 90% by weight of the first transport carrier, or 25% to 85% by weight, 30% to 80% by weight or 35% to 75% by weight, based on the total weight of the composition.

[0033] As an implementation example of the present invention, based on the weight of the GLP-1 analogue, the first transport carrier may contain 100% to 3100% by weight, or 150% to 2100% by weight or 200% to 1600% by weight, but is not limited thereto.

[0034] In addition, as an implementation example of the present invention, the composition of the present invention may contain 0.1 mg to 5 mg of the micronized lactose.

[0035] As an example of the present invention, based on the total weight of the inhalation composition of the present invention, it may contain 5% to 15% by weight, 6% to 14% by weight, 7% to 13% by weight, 8% to 12% by weight, or 9% to 11% by weight of the second delivery carrier, but is not limited thereto.

[0036] Preferably, in this invention, the third delivery carrier can be mannitol or trehalose.

[0037] As an example of the present invention, the composition of the present invention may contain 0.5 mg to 6 mg of the mannitol or trehalose.

[0038] As an implementation example of the present invention, based on the weight of the GLP-1 analogue, the third transport carrier may contain 150% to 900% by weight, or may contain 200% to 800% by weight, 200% to 700% by weight, 250% to 600% by weight, 250% to 500% by weight, 250% to 400% by weight, or 250% to 300% by weight.

[0039] As an example of the present invention, the stabilizer may be an amino acid.

[0040] Preferably, in this invention, the stabilizer may be selected from one or more of glycine and leucine.

[0041] More preferably, in this invention, the stabilizer may be leucine.

[0042] As an implementation example of the present invention, based on the weight of the GLP-1 analogue, each may independently contain 10% to 90% by weight of the glycine and leucine, or may contain 10% to 80% by weight, 10% to 70% by weight, or 20% to 60% by weight of the glycine and leucine.

[0043] As an implementation example of the present invention, the average particle size (X90) of the first transport carrier can be from 30 μm to 300 μm, and the average particle size (X90) of the second transport carrier can be from 2 μm to less than 50 μm.

[0044] As an implementation example of the present invention, when the particle size distribution is evaluated for 2.4 seconds at a flow rate of 100 L / min, the amount of effective particles smaller than 5 μm in the inhalation composition can be 20% or more, based on the total weight of the composition.

[0045] As an embodiment of the present invention, the composition may further include a lubricant.

[0046] As one embodiment of the present invention, the lubricant can be any lubricant known in the art, as long as it does not interfere with the intended effect of the inhalation composition of the present invention, and is not particularly limited thereto. For example, the lubricant may include one or more of the group consisting of stearic acid, magnesium stearate, silicon dioxide, talc, sucrose fatty acid esters, hydrogenated vegetable oils, high-melting-point waxes, glycerol fatty acid esters, glyceryl disorbate, and any combination thereof, but is not limited thereto.

[0047] In addition, the present invention provides a method for preparing an inhalation composition, the method comprising: a first step of spray drying a GLP-1 analogue together with a third delivery carrier, or a stabilizer, or both a third delivery carrier and a stabilizer; and a second step of mixing the spray-dried product prepared in the first step with a first delivery carrier and a second delivery carrier.

[0048] In the preparation method, the GLP-1 analog, spray drying, first delivery carrier, second delivery carrier, third delivery carrier and stabilizer are as described above.

[0049] In this invention, the first step is a micronization step achieved by spray drying of GLP-1 analogs. Based on the solid (solute) content, the concentration of the spray solution containing GLP-1 analogs before spray drying can be from 0.5% w / v to 15% w / v, preferably from 0.5% w / v to 10% w / v, 0.5% w / v to 7% w / v, 0.5% w / v to 5% w / v, and most preferably from 1% w / v to 5% w / v. Furthermore, based on the GLP-1 analog, the concentration of the spray solution containing GLP-1 analogs before spray drying can be from 0.5 mg / mL to 100 mg / mL, preferably from 0.5 mg / mL to 70 mg / mL, 0.5 mg / mL to 50 mg / mL, 0.5 mg / mL to 30 mg / mL, and 0.5 mL to 15 mg / mL.

[0050] The solvent used in the spray solution of the present invention may be selected from known solvents (such as polar protic solvents, nonpolar protic solvents, polar aprotic solvents, nonpolar aprotic solvents) or combinations thereof, for example, the solvent may be water, but is not limited thereto.

[0051] The present invention provides a capsule comprising the composition.

[0052] As an implementation example of the present invention, the capsule may include any suitable container for pharmaceuticals, for example, which may contain gelatin, polyethylene or hydroxypropyl methylcellulose (HPMC).

[0053] As an implementation example of the present invention, the capsule may contain hydroxypropyl methylcellulose (HPMC).

[0054] This invention relates to inhalation compositions comprising a GLP-1 analog and a delivery carrier, wherein the inhalation compositions exhibit excellent effective particle delivery (fine particle fraction (FPF) relative to content, high effective particle delivery efficiency to the lungs, low generation of impurities, and therefore high content stability and thermal stability, as well as excellent flowability and filling properties. Furthermore, the inhalation compositions of this invention can directly deliver peptides to the lungs, thus exhibiting higher bioavailability compared to oral formulations, thereby reducing manufacturing costs by reducing the required dosage compared to oral formulations. [Simplified Explanation of the Diagram]

[0055] Part (a) of Figure 1 is a scanning electron microscope image of the active ingredient before micronization (scale bar: 100 μm), Part (b) of Figure 1 is a scanning electron microscope image of the active ingredient after spray drying (scale bar: 5 μm), Part (c) of Figure 1 is a scanning electron microscope image of the active ingredient after freeze drying (scale bar: 100 μm), Part (d) of Figure 1 is a scanning electron microscope image of the active ingredient after bead milling (scale bar: 100 μm), and Part (e) of Figure 1 is a scanning electron microscope image of the active ingredient after jet milling (scale bar: 100 μm).

[0056] Figure 2 is a graph showing the total amount of pulverized material and the effective amount of pulverized material (fine particle fraction) according to the micronization process (spray drying, freeze drying, bead milling, jet milling).

[0057] Figure 3 is a graph showing the total delivery amount and effective particle delivery amount according to the ethanol concentration (0%, 20%, 40%) of the spray solvent.

Implementation Method

[0058] Hereinafter, preferred embodiments are proposed to aid in understanding the present invention. However, the following embodiments are provided only to facilitate a better understanding of the present invention, and the content of the present invention is not limited to the embodiments.

[0058] Example

[0058] Experimental Example 1: Particle Microscopic Analysis

[0059] To micronize the raw materials, smegglutinin (Examples 1-5) was weighed according to the content and solution concentration shown in Table 1 below, dissolved in solvent (pure water) (Examples 2 and 3), and then spray-dried, freeze-dried, bead-milled, or jet-milled according to the conditions shown in Table 2 below, thereby preparing Examples 1-5. Then, the degree of micronization and particle properties of Examples 1-5 were confirmed using a scanning electron microscope (SEM).

[0059]

[0059]

[0060] SEM images are shown in parts (a) to (e) of Figure 1. Part (a) of Figure 1 is a scanning electron microscope image of smegglutinin before micronization (Example 1), part (b) of Figure 1 is a scanning electron microscope image of smegglutinin after spray drying (Example 2), part (c) of Figure 1 is a scanning electron microscope image of smegglutinin after freeze drying (Example 3), part (d) of Figure 1 is a scanning electron microscope image of smegglutinin after bead milling (Example 4), and part (e) of Figure 1 is a scanning electron microscope image of smegglutinin after jet milling (Example 5).

[0061] As a result, spray drying yields particles of the most suitable size for adhesion to the lungs, with most particles having a uniform diameter of less than 3 μm (part (d) of Figure 1). During freeze drying, the active ingredient is micronized into needle-like particles, exhibiting a wide size distribution, ranging from a minimum of 3 μm to a maximum of 80 μm (part (c) of Figure 1). When particle micronization is performed via bead milling, similar to freeze drying, a wide particle size distribution is observed, ranging from a minimum of 3 μm to a maximum of 80 μm (part (d) of Figure 1). The particles obtained by jet milling have a uniform size, with most particles having a size of 8 μm or more and less than 10 μm (part (e) of Figure 1). In an attempt to reduce the particle size, the pressure during jet milling was increased, but due to the sheet-like properties of the raw material, it could not be fed into the grinding chamber and instead dispersed upwards, thus preventing further reduction in particle size. Therefore, considering that the particle size that can adhere to the lungs is greater than 1 μm and less than 5 μm, it can be confirmed that jet milling is not suitable for preparing effective particles for lung delivery.

[0061] Experimental Example 2: Evaluation of Effective Particle Delivery Rate in Various Micronization Processes

[0062] Based on the composition shown in Table 3 below, smegglutinin was weighed separately, or smegglutinin and the third delivery carrier (mannitol or micronized lactose) were weighed and dissolved in a solvent (distilled water) to prepare 1% w / v solutions (Example 6) and 0.2% w / v solutions (Example 7), and then micronized according to the conditions shown in Table 2. As a grinding process, micronization was performed directly in the powder state. Next, the micronized raw material, the first delivery carrier (lactose), the second delivery carrier (micronized lactose), and the lubricant (magnesium stearate) were passed through a 100-mesh sieve three times, mixed, and then filled into HPMC matrix #3 hard capsules.

[0062]

[0063] According to the United States Pharmacopeia <601> Inhaled and nasal medication products: aerosols, sprays, and powders - performance quality testing (USP) <601> The aerosol performance of the prepared examples was evaluated using the following aerosol tests: INHALATION AND NASAL DRUG PRODUCTS: AEROSOLS, SPRAYS, AND POWDERS-PERFORMANCE QUALITY TESTS. To determine the actual dose delivered to the lung target site, particle size distribution was measured for 2.4 seconds using a Next Generation Impactor (NGI) (Copley) at a flow rate of 100 L / min, and the distribution of particles smaller than 5 μm was set as the effective particle quantity for evaluation.

[0064] Using glycerol / Brij35 binder, 100 μL was coated on grade #1 and MOC, and 50 μL was coated on grades #2 to #7. Then, 10 mL of diluent was added to the pre-separator for testing. One capsule was placed in a DPI inhaler (pressure drop / L / min: 0.0191 to 0.0247) and punched in. The capsule was inhaled at a flow rate of 100 L / min for 2.4 seconds, and this process was repeated 4 times (3 capsules were tested per test). Next, after rinsing the mouthpiece (10 mL), throat (20 mL), pre-separator (50 mL), grades #1 to #7, and MOC (10 mL), the sample solution was analyzed by chromatography. After analyzing the content of the inhalation composition prepared from the composition of the examples, the effective particle delivery amount was calculated according to the following formula and then expressed as the delivery amount (FPF) relative to the content:

[0065] Fine Particle Fraction (FPF) (%) = Fine Particle Dose (FPD) (%) / Emitted Dose (ED) (%) x 100

[0066] Table 4 and Figure 2 below show the delivery amount (%) relative to the content. Through repeated experiments, the delivery amount (%) relative to the content for each batch of each embodiment was obtained, and their average values ​​are shown.

[0066]

[0067] As shown in Table 4 and Figure 2 above, the total delivery of the main components in the process ranged from 76.6% to 84.0%, with the delivery of the composition relative to content being significantly higher (77.3%) when using the spray drying process. These results confirm that, when using the same ingredients, the delivery of the composition relative to content is superior when using spray drying compared to freeze drying.

[0068] In terms of bead milling and jet milling, the total delivery rates were 76.6% and 81.5%, respectively, but the effective particle delivery rates were low (33.8% and 13.4%), which suggests that it is difficult to ensure the ratio of fine particles deposited in the lungs.

[0069] It can be seen that the spray drying process is the best process in terms of pulmonary delivery efficiency and particle stability of inhalation compositions based on GLP-1 analogs.

[0069] Experimental Example 3: Accelerated Stability Test of Content in Each Process

[0070] According to Experimental Example 1, the particle size and properties obtained from each process were different. In order to evaluate the stability of each process, the smegglutinin of the example stored for 2 weeks under accelerated stability conditions (40°C, 75% relative humidity (RH)) was evaluated for its content stability.

[0071] In each embodiment, according to the composition in Table 5 below, smegglutinin or smegglutinin and the third delivery carrier (mannitol) were weighed separately and dissolved in a solvent (distilled water) to prepare 1% w / v solutions (Examples 2 and 6) and 0.2% w / v solutions (Example 7), and then micronized according to the conditions shown in Table 2. As a grinding process, micronization was performed directly in the powder state. Next, the micronized raw material, the first delivery carrier (lactose), the second delivery carrier (micronized lactose), and the lubricant (magnesium stearate) were passed through a 100-mesh sieve three times, mixed, and then filled into HPMC matrix #3 hard capsules.

[0071]

[0072] The capsules of the prepared examples were stored under accelerated conditions (40°C, 75% relative humidity (RH)) and the content (%) was analyzed by HPLC after two weeks. The results are shown in Table 6 below.

[0072]

[0073] As shown in Table 6 above, the content of the unmicronized raw material (Example 1) was approximately 94.1% after two weeks of accelerated drying compared to the initial content. The spray-dried product of the raw material alone (Example 2) also maintained a content of 93.1% after two weeks, exhibiting the same level of stability as the unmicronized raw material. It is well known that peptides are generally heat-sensitive, and therefore, a heated spray-drying process might be considered unsuitable. However, this experimental example confirmed the thermal stability of the active ingredient after spray drying, thereby confirming the applicability of the spray-drying process to GLP-1 analogs.

[0074] In addition, in the embodiments of formulation by mixing process for improving filling properties, firstly, in the case of bead milling (Example 8), its stability was 93.8%, which was the same level as that of unformulated Examples 1 and 2. In the case of spray drying (Example 6), its stability was 88.2%. In the case of freeze drying (Example 7), its stability was 90.7%, which showed a significant level of stability.

[0075] Conversely, in Example 10, where micronization was achieved through a jet milling process, the content decreased significantly to 78.0% after two weeks, thus confirming a significant decrease in stability. This confirms that the jet milling process may have an adverse effect on drug stability, and demonstrates that micronization methods using raw materials such as spray drying, freeze drying, or bead milling are more suitable than jet milling methods for maintaining drug stability.

[0076] Summarizing the results of Experiments 1 to 3, the spray drying process showed excellent results in terms of particle size, effective particle delivery, and stability, confirming that the spray drying process is suitable for the micronization of GLP-1 analogs.

[0076] Experimental Example 4: Evaluation of peptide aggregates (High Molecular Weight (HMW%))

[0077] Peptides can exhibit physicochemical instability depending on the process conditions. In particular, exposure to high temperature, interface, and dehydration environments may induce the formation of aggregates (HMW species), which may reduce biological activity and induce immunogenicity, which has a significant impact on the quality and safety of the dosage form.

[0078] In order to ensure the stability of the peptide dosage form, quantitative analysis of the content of aggregates (HMW%) was performed.

[0079] Specifically, according to the composition shown in Table 7 below, smegglutinin and the third delivery carrier (mannitol) were weighed, dissolved in a solvent (distilled water) to prepare a solution, and then spray-dried or freeze-dried according to the conditions shown in Table 2, thereby preparing the compositions of Examples 11-13.

[0079]

[0080] The effect of each process on peptide stability was evaluated by analyzing the aggregate content (HMW%) of each prepared example. The results are shown in Table 8 below.

[0080]

[0081] As a result, as shown in Table 8, the HMW% of the spray-dried raw materials of Examples 11 and 12 was approximately 0.1%, which was lower than the HMW% (0.23%) of the freeze-dried raw material of Example 13. This confirms that the spray-drying process can provide dosage form stability at or above the level of freeze-drying, wherein freeze-drying is a well-known representative stabilization process that maintains the aggregation stability of peptides while minimizing thermal and interfacial stresses.

[0082] The thermal stability of the spray drying process was confirmed. Considering the preparation time and preparation cost, the spray drying process was determined as the final application process.

[0082] Experimental Example 5: Accelerated stability test of each ingredient

[0083] In order to evaluate the stability of the inhalation formulation containing the GLP-1 analog of the present invention, the content (%) was analyzed by HPLC after two weeks under accelerated conditions (40°C, 75% relative humidity (RH)).

[0083] Experimental Example 5-1: Accelerated Stability Test of the Third Transport Carrier

[0084] Based on the composition shown in Table 9 below, smegglutinin was weighed separately, or smegglutinin and the third delivery carrier (mannitol or trehalose) were weighed and dissolved in a solvent (distilled water) to prepare a 10% w / v solids solution, which was then micronized according to the conditions shown in Table 2. The micronized raw material, the first delivery carrier (lactose), the second delivery carrier (micronized lactose), and the lubricant (magnesium stearate) were passed through a 100-mesh sieve three times, and the accelerated stability was evaluated after mixing.

[0084]

[0085] The compositions of the various examples prepared were stored under accelerated conditions (40°C, 75% relative humidity (RH)) and the content (%) was analyzed by HPLC after two weeks. The results are shown in Table 10 below.

[0085]

[0086] As shown in Table 10 above, when smegglutide was spray-dried together with a third delivery carrier (mannitol or trehalose), it was confirmed to be good at the two-week acceleration time point, with a content of 91.5% (Example 15) and 90.5% (Example 16).

[0086] Experimental Example 5-2. Accelerated Stability Test of Stabilizer

[0087] As a stabilizer, the stability of the composition by adding amino acids (glycine and leucine) was evaluated. Specifically, according to the composition shown in Table 11 below, smegglutide was weighed alone, or smegglutide and the third delivery carrier (mannitol) and / or stabilizer (glycine and leucine) were weighed and dissolved in a solvent (distilled water) to prepare a 10% w / v solution based on solids, and then micronized according to the conditions shown in Table 2. The micronized raw material, the first delivery carrier (lactose), the second delivery carrier (micronized lactose), and the lubricant (magnesium stearate) were passed through a 100-mesh sieve three times, and after mixing, the accelerated stability was evaluated.

[0087]

[0088] The compositions of the various examples prepared were stored under accelerated conditions (40°C, 75% relative humidity (RH)) and the content (%) after two weeks was analyzed by HPLC. The results are shown in Table 12 below.

[0088]

[0089] As shown in Table 12 above, in Example 17, the content was 88.1% after two weeks of acceleration, which is equivalent to a stable level, but it did not show a significant improvement in content stability with the addition of glycine. Conversely, when leucine was added, the content was 100.4% (Example 18) and 95.5% (Example 19) after two weeks of acceleration, confirming that the content of the main component remained stable compared to Example 15.

[0090] This confirms that leucine is an effective stabilizer that can significantly improve the content stability of GLP-1 analogs after spray drying.

[0090] Experimental Example 6: Evaluation of Effective Particle Delivery Rate Based on Ethanol Concentration of Spray Solvent

[0091] Based on the composition shown in Table 13 below, smegglutinin and the third delivery carrier (mannitol) were weighed and dissolved in solvents (distilled water or ethanol (20% v / v and 40% v / v)) to prepare solutions of various concentrations, and then micronized according to the conditions shown in Table 2. The micronized raw materials, the first delivery carrier (lactose), the second delivery carrier (micronized lactose), and the lubricant (magnesium stearate) were passed through a 100-mesh sieve three times, mixed, and filled into HPMC matrix #3 hard capsules. Using the capsules of the various embodiments prepared, the total quantified dose (TED) and the effective particle delivery (fine particle fraction (FPF)) were determined according to the concentration of the organic solvent used in the spray drying process. The effective particle delivery was expressed as delivery (FPF) relative to the content using the same calculation formula as used in Experimental Example 2.

[0091]

[0092] As a result, as shown in Figure 3, in all embodiments, the total delivery rate remained at a high level of over 80%, and the effective particle delivery rate also showed a stable value in the range of 73-77%. In particular, compared with the case of adding 0% ethanol, the effective particle delivery efficiency was still maintained without significant reduction when adding 20% ​​or 40%. This confirms that the change in organic solvent content has a limited effect on the aerodynamic performance of the composition.

[0093] These results show that the total delivery amount and effective particle delivery amount can be maintained stably regardless of changes in the composition of the organic solvent (0-40% ethanol). Therefore, the present invention has excellent flexibility in preparation process and industrial applicability.

[0094] The results of this experiment confirm that the present invention optimizes the process and dosage form conditions to ensure that the microparticle size, dispersibility and aerodynamic properties of the powder reach the specified level or above.

Claims

1. An inhalation composition comprising: 1) a spray-dried material containing a GLP-1 analog; 2) a first delivery carrier; and 3) a second delivery carrier, wherein the inhalation composition is characterized in that the spray-dried material further comprises a third delivery carrier, or a stabilizer, or both a third delivery carrier and a stabilizer, wherein, The GLP-1 analogue is smegglutide; the first delivery carrier is lactose; the second delivery carrier is micronized lactose; the third delivery carrier is mannitol or trehalose; and the stabilizer is one or more selected from glycine and leucine.

2. The inhalation composition as described in claim 1, wherein, The spray-dried material has the characteristic of being micronized through a spray drying process, similar to GLP-1.

3. The inhalation composition as described in claim 1, wherein, Based on the solid content, the concentration of the spray solution before spray drying of the spray-dried material is from 0.5% w / v to 15% w / v.

4. The inhalation composition as claimed in claim 1, wherein, The composition further contains a lubricant.

5. A method for preparing an inhalation composition, wherein, include: The first step involves spray drying the GLP-1 analogue together with a third delivery carrier, or a stabilizer, or both a third delivery carrier and a stabilizer. The second step involves mixing the spray-dried material prepared in the first step with a first delivery carrier and a second delivery carrier, wherein the GLP-1 analog is smegglutinin; the first delivery carrier is lactose; the second delivery carrier is micronized lactose; the third delivery carrier is mannitol or trehalose; and the stabilizer is one or more selected from glycine and leucine.

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