Inhalation composition

Abstract

The present invention relates to an inhalation composition comprising a GLP-1 analogue and a transport carrier. The inhalation composition has content stability and thermal stability while having a high effective particle delivery amount relative to content. In addition, the inhalable composition of the present invention directly delivers the peptide to the lungs, and thus has a bioavailability higher than that of oral agents. Therefore, manufacturing costs can be lowered through a reduction in required administration amount compared to that of oral agents.

Description

Inhalant composition

[0001] 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 amount relative to the content while also having content stability and thermal stability.

[0002] Peptide drugs are primarily administered via invasive routes, such as intravenous (IV) or subcutaneous (SC) injections. However, these methods require needle insertion into the skin, which carries risks such as pain, bleeding, infection, and swelling. Furthermore, they are difficult for the general public to use without proper training. Furthermore, most biological products, such as peptide drugs, require refrigeration, increasing costs during distribution and storage, and raising concerns about quality deterioration during transport.

[0003] In the case of existing oral medications, drug absorption is significantly limited by various physicochemical and biological barriers, such as enzymatic degradation in the gastrointestinal tract, highly acidic pH, mucus, and absorption barriers. Furthermore, orally absorbed drugs exhibit very low bioavailability due to first-pass metabolism in the liver. Consequently, expensive peptide active ingredients must be administered in excessive amounts, increasing manufacturing costs.

[0004] Accordingly, an inhalation formulation that does not cause pain and has high bioavailability can be considered, but much research is needed to develop a formulation that has a high effective particle delivery rate and excellent stability.

[0005] The present invention aims to provide an inhalation composition comprising a GLP-1 analogue having a large effective particle delivery amount and excellent content stability and thermal 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] In order to achieve the above object of the present invention, the present invention provides an inhalation composition comprising 1) a spray-dried product comprising a GLP-1 analogue; 2) a first transport carrier; and 3) a second transport carrier, wherein the spray-dried product further comprises at least one of a third transport carrier, a stabilizer, or both the third transport carrier and the stabilizer.

[0009] In the present invention, the GLP-1 (Glucagon-like peptide 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 imidazopropionyl-exendin-4), CX-exendin-4 (beta-carboxyimidazopropionyl-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 the present invention, the spray-dried product is characterized in that the GLP-1 analogue has a micronized characteristic through the spray-drying process.

[0013] In one embodiment of the present invention, the GLP-1 analogue included in the spray-dried product may be an undifferentiated GLP-1 analogue.

[0014] 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.

[0015] In one embodiment of the present invention, the inhalable composition of the present invention comprises a micronized GLP-1 analogue and a stabilizer.

[0016] In one embodiment of the present invention, the inhalable composition of the present invention comprises a micronized GLP-1 analogue, a third transport carrier, and a stabilizer.

[0017] 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.

[0018] Peptides such as GLP-1 analogues are susceptible to heat, which can cause aggregation and decreased stability. Because of this problem, many peptide or protein preparations currently on the market are stored under refrigerated conditions.

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

[0020] The GLP-1 analogue of the present invention has the characteristics of maintaining content and improving stability by inhibiting the formation of aggregates, even when performing a raw material micronization process such as spray drying using heat.

[0021] In one embodiment of the present invention, the inhalable composition of the present invention comprises a spray-dried product comprising 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 inhalable composition of the present invention comprises a spray-dried product containing a GLP-1 analogue and a stabilizer, a first transport carrier, and a second transport carrier.

[0023] In one embodiment of the present invention, the inhalable composition of the present invention comprises a spray-dried product comprising a GLP-1 analogue, a third transport carrier, and a stabilizer, a first transport carrier, and a second transport carrier.

[0024] In one embodiment of the present invention, the concentration of the spray solution before spray drying of the spray-dried product in the present invention may be 0.5 to 15% w / v, preferably 0.5 to 10% w / v, 0.5 to 7% w / v, 0.5 to 5% w / v, and most preferably 1 to 5% w / v, based on the solid content (solute). In the present invention, if the concentration of the spray solution before spray drying is 5% w / v or more based on the solid content (solute), a problem of a decrease in the amount of effective particles may occur. On the other hand, if the concentration is less than 0.5% w / v, not only the time required to obtain solid particles may excessively increase, but also the particle size of the solid content may become small to the nanometer level, so that a significant amount of the solid content may escape through exhalation immediately after inhalation of the solid content, resulting in a quality characteristic of a lowered inhalation delivery efficiency. In addition, a problem of a lower productivity may occur because the production yield may drop below 30%.

[0025] In addition, in one embodiment of the present invention, the concentration of the spray solution containing the GLP-1 analogue in the present invention may be 0.5 mg / mL to 100 mg / mL, preferably 0.5 mg / mL to 70 mg / mL, 0.5 mg / mL to 50 mg / mL, 0.5 mg / mL to 30 mg / mL, 0.5 mg / mL to 15 mg / mL based on the GLP-1 analogue.

[0026] The solvent used in the preparation of the spray solution in the present invention 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, distilled water or an aqueous ethanol solution, but is not limited thereto.

[0027] 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.

[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 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.

[0029] 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.

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

[0031] In one embodiment of the present invention, the lactose or mannitol may be included in the composition of the present invention in an amount of 0.5 to 25 mg.

[0032] In one embodiment of the present invention, the first transport carrier 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%, or 35 to 75 wt%.

[0033] In one embodiment of the present invention, the first transport carrier 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%, or 200 to 1600 wt%, but is not limited thereto.

[0034] 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.

[0035] In one embodiment of the present invention, the second transport carrier 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 inhalable composition of the present invention, but is not limited thereto.

[0036] Preferably, in the present invention, the third transport carrier may be mannitol or trehalose.

[0037] In one embodiment of the present invention, the mannitol or trehalose may be included in the composition of the present invention in an amount of 0.5 to 6 mg.

[0038] In one embodiment of the present invention, the third transport carrier 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%.

[0039] In one embodiment of the present invention, the stabilizer may be an amino acid.

[0040] Preferably, in the present invention, the stabilizer may be at least one selected from glycine and leucine.

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

[0042] In one embodiment of the present invention, the glycine and leucine may each independently be included in an amount of 10 to 90 wt% based on the weight of the GLP-1 analogue, and may also be included in an amount of 10 to 80 wt%, 10 to 70 wt%, or 20 to 60 wt%.

[0043] In one embodiment of the present invention, the first transport carrier has an average particle size (X 90 ) is 30 to 300 μm and the second transport carrier has an average particle size (X 90 ) may be 2 to 50 μm or less.

[0044] 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.

[0045] In one embodiment of the present invention, the composition may further include an active agent.

[0046] 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.

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

[0048] In the above manufacturing method, the GLP-1 analogue, spray drying, first transport carrier, second transport carrier, third transport carrier, and stabilizer are as described above.

[0049] In the present invention, the first step is a step of spray-drying and micronizing the GLP-1 analogue, and the concentration of the spray solution containing the GLP-1 analogue before spray-drying may be 0.5 to 15% w / v, preferably 0.5 to 10% w / v, 0.5 to 7% w / v, 0.5 to 10% w / v, and most preferably 1 to 5% w / v, based on the solid content (solute). In addition, the concentration of the spray solution containing the GLP-1 analogue before spray-drying may be 0.5 mg / mL to 100 mg / mL, preferably 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 based on the GLP-1 analogue.

[0050] The solvent used in the spray solution of the present invention 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.

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

[0052] 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).

[0053] In one embodiment of the present invention, the capsule may contain HPMC (Hydroxypropyl methylcellulose).

[0054] The present invention relates to an inhalable composition comprising a GLP-1 analogue and a transport carrier, wherein the inhalable composition has a high fine particle fraction (FPF) relative to the content, thereby providing high efficiency of effective particle delivery to the lungs, and has high content stability and thermal stability due to low generation of degradation products (impurities), and has excellent flowability and fillability. In addition, the inhalable composition of the present invention directly delivers the peptide to the lungs, thereby providing higher bioavailability than oral agents, and thus reducing the required dosage compared to oral agents, thereby reducing manufacturing costs.

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

[0056] Figure 2 is a graph showing the total emitted dose and fine particle fraction according to the micronization process (spray drying, freeze drying, bead mill, jet mill).

[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.

[0058] 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.

[0059]

[0060] Example

[0061] Experimental Example 1: Particle Microanalysis

[0062] In order to micronize the raw material, semaglutide was weighed according to the content and solution concentration presented in Table 1 below (Example 1-5), dissolved in a solvent (purified water) (Examples 2 and 3), and spray-dried, freeze-dried, bead milled, or jet-milled according to the conditions presented in Table 2 below to prepare Example 1-5. Thereafter, the degree of micronization and particle properties of Example 1-5 were confirmed using a scanning electron microscope (SEM).

[0063]

[0064]

[0065] Images taken by SEM are shown in Figs. 1(a) to 1(e). Fig. 1(a) is a scanning electron microscope image showing semaglutide before micronization (Example 1), Fig. 1(b) is a scanning electron microscope image showing semaglutide after spray drying (Example 2), Fig. 1(c) is a scanning electron microscope image showing semaglutide after freeze drying (Example 3), Fig. 1(d) is a scanning electron microscope image showing semaglutide after bead milling (Example 4), and Fig. 1(e) is a scanning electron microscope image showing semaglutide after jet milling (Example 5).

[0066] As a result, the most suitable size of particles that can adhere to the lungs could be obtained through spray drying, and most particle sizes were uniformly obtained with a size of 3 μm or less (Fig. 1(d)). When freeze-dried, the active ingredient was micronized into needle shapes, and the size was widely distributed from 3 μm to 80 μm (Fig. 1(c)). When particles were micronized through bead milling, similar to freeze-drying, the particle sizes were widely distributed from 3 μm or less to 80 μm (Fig. 1(d)). Jet milling produced a uniform particle size with most particle sizes ranging from 8 μm to 10 μm (Fig. 1(e)). An attempt was made to increase the pressure during jet milling to reduce the particle size, but due to the sheet-like nature of the raw material, it was not fed into the grinding chamber but scattered upwards, making it impossible to further reduce the particle size. Therefore, considering that the particle size that can adhere to the lungs is 1 μm or more and 5 μm or less, it was confirmed that jet milling is not suitable for producing effective particles for lung delivery.

[0067]

[0068] Experimental Example 2: Evaluation of Effective Particle Delivery Amount by Differentiation Process

[0069] According to the compositions presented in Table 3 below, semaglutide alone or semaglutide and the third transport carrier (mannitol or micronized lactose) were weighed and dissolved in a solvent (distilled water) to prepare a 1% w / v solution (Example 6) and a 0.2% w / v solution (Example 7), which were then micronized according to the conditions presented in Table 2. The milling process was performed to micronize immediately in a powder state. Then, the micronized raw material and the first transport carrier (lactose), the second transport carrier (micronized lactose), and the lubricant (magnesium stearate) were sieved three times using a 100 mesh, mixed, and then filled into a #3 hard capsule with an HPMC base.

[0070]

[0071] Manufactured 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 lung area, the particle size distribution was measured for 2.4 seconds at a flow rate of 100 L / min using a Next Generation Impactor (NGI) (Copley). The particle distribution of 5 μm or less in size was set and evaluated as the effective particle dose.

[0072] After coating Stage #1 and MOC with 100 μL of Glycerol / Brij35 adhesive, Stages #2 to #7 with 50 μL, and then adding 10 mL of diluted solution to the pre-separator to prepare for the test. One capsule was placed in a DPI inhaler (pressure drop value / L / min: 0.0191 to 0.0247), punched, and aspirated at a flow rate of 100 L / min for 2.4 seconds, which was repeated 4 times (3 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. The effective particle delivery amount was analyzed by analyzing the content of the inhalation composition prepared with the composition of the above example, and then expressed as the delivery amount per content (FPF) by calculating it using the following equation:

[0073] FPF (Fine Particle Fraction)(%) = FPD (Fine Particle Dose)(%) / ED (Emitted Dose)(%) x 100

[0074] The content-to-delivery ratio (%) is shown in Table 4 and Fig. 2 below. Through repeated experiments, the content-to-delivery ratio (%) for each batch of each example was obtained, and the average value thereof is shown.

[0075]

[0076] As shown in Table 4 and Figure 2 above, the total delivery amount of the main ingredient according to the process was 76.6% to 84.0%, and among them, the delivery amount per content of the composition was significantly higher at 77.3% when using the spray drying process. From these results, it was confirmed that the delivery amount per content was superior when spray drying was applied than when freeze drying was applied for the same formulation.

[0077] For bead mills and jet mills, the total delivery was 76.6% and 81.5%, respectively, but the effective particle delivery was low at 33.8% and 13.4%, indicating that it was difficult to secure a fine particle fraction for lung deposition.

[0078] Through this, it was confirmed that the spray drying process is the best process in terms of lung delivery efficiency and particle stability of the GLP-1 analogue-based inhalation composition.

[0079]

[0080] Experimental Example 3: Accelerated stability test for each process

[0081] According to Experimental Example 1, the particle size and shape were obtained differently depending on each process. To evaluate the stability by process, the content stability of semaglutide of the examples stored for two weeks under accelerated stability conditions (40°C, 75% RH) was evaluated.

[0082] For each example, semaglutide alone or semaglutide and the third transport carrier (mannitol) were weighed according to the composition in Table 5 below, dissolved in a solvent (distilled water) to prepare a 1% w / v solution (Examples 2 and 6) and 0.2% w / v (Example 7), and then micronized according to the conditions described in Table 2. The milling process was performed to micronize immediately in a powder state. Then, the micronized raw material, the first transport carrier (lactose), the second transport carrier (micronized lactose), and the lubricant (magnesium stearate) were sieved three times using a 100 mesh, mixed, and then filled into a #3 hard capsule with an HPMC base.

[0083]

[0084] The capsules of the manufactured examples were stored under accelerated conditions (40°C, 75% RH) and the content (%) after two weeks was analyzed by HPLC. The results are shown in Table 6 below.

[0085]

[0086] As shown in Table 6 above, the content of the non-micronized raw material itself (Example 1) was confirmed to be approximately 94.1% after 2 weeks of acceleration compared to the initial content, and the spray-dried product of the raw material alone (Example 2) also maintained 93.1% of the content after 2 weeks, showing a stability equivalent to that of the non-micronized raw material. Peptides are generally known to be vulnerable to heat, so it may be considered that the spray-drying process in which heat is applied may not be suitable. However, through this experimental example, the heat stability of the active ingredient after spray-drying was confirmed, and from this, the applicability of the spray-drying process to GLP-1 analogues was confirmed.

[0087] In addition, in the examples formulated through a mixing process to improve chargeability, first, in the case of bead milling (Example 8), it showed stability at a level equivalent to that of Examples 1 and 2 that were not formulated at 93.8%, and in the case of spray drying (Example 6), it showed stability at a significant level at 88.2%, and in the case of freeze drying (Example 7), it showed stability at 90.7%.

[0088] On the other hand, in the case of Example 10, which was micronized using the jet milling process, the content significantly decreased to 78.0% after two weeks, confirming a significant decrease in stability. This confirmed that the jet milling process can have a detrimental effect on the stability of the drug, and demonstrated that the micronization method of raw materials using spray drying, freeze drying, and bead milling is more suitable than the jet milling method in maintaining the stability of the drug.

[0089] When the results of Experimental Examples 1 to 3 are summarized, it was confirmed that the spray drying process is a suitable process for micronizing GLP-1 analogues, as it showed excellent results in terms of particle size, effective particle delivery amount, and stability.

[0090]

[0091] Experimental Example 4: Evaluation of Peptide Aggregates (High Molecular Weight, HMW%)

[0092] Peptides can exhibit physical and chemical instability depending on process conditions, and exposure to high temperatures, interfaces, and dehydration environments can induce the formation of aggregates (HMW species). These aggregates can reduce biological activity and induce immunogenicity, significantly affecting the quality and safety of the formulation.

[0093] Accordingly, quantitative analysis of aggregate (HMW%) content was conducted to ensure the stability of the peptide formulation.

[0094] Specifically, semaglutide and the third transport carrier (mannitol) were weighed according to the composition presented in Table 7 below, dissolved in a solvent (distilled water) to prepare a solution, and spray-dried or freeze-dried according to the conditions presented in Table 2 to prepare the compositions of Examples 11-13.

[0095]

[0096] The impact of each process on peptide stability was evaluated by analyzing the aggregate content (HMW%) of each manufactured example. The results are shown in Table 8 below.

[0097]

[0098] 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% of the freeze-dried raw material of Example 13, 0.23%. From this, it was confirmed that the spray-drying process can provide formulation stability equivalent to or greater than that of freeze-drying, which is widely known as a representative stabilization process that can maintain the aggregation stability of peptides while minimizing the heat and interface stress of peptides.

[0099] As the thermal stability of the spray drying process was confirmed, the spray drying process was decided as the final application process considering production aspects such as process time and production cost.

[0100]

[0101] Experimental Example 5: Accelerated Stability Test by Prescription

[0102] To evaluate the stability of the inhalation preparation including the GLP-1 analogue of the present invention, the content (%) after 2 weeks under accelerated conditions (40°C, 75% RH) was analyzed by HPLC.

[0103]

[0104] Experimental Example 5-1. Accelerated Stability Test of the Third Transport Carrier

[0105] Semaglutide alone or semaglutide and a third transport carrier (mannitol or trehalose) were weighed according to the composition presented in Table 9 below, dissolved in a solvent (distilled water), and a solution having a solid content of 10% w / v was prepared, which was micronized according to the conditions presented in Table 2. The micronized raw material, the first transport carrier (lactose), the second transport carrier (micronized lactose), and the lubricant (magnesium stearate) were mixed by sieving them three times using a 100 mesh, and then the accelerated stability was evaluated.

[0106]

[0107] The compositions of each manufactured example were stored under accelerated conditions (40°C, 75% RH) and the content (%) after two weeks was analyzed by HPLC. The results are shown in Table 10 below.

[0108]

[0109] As shown in Table 10 above, when semaglutide was spray-dried together with a third transport carrier (mannitol or trehalose), the content was confirmed to be good at 91.5% (Example 15) and 90.5% (Example 16) at the 2-week acceleration point.

[0110]

[0111] Experimental Example 5-2. Accelerated Stability Test of Stabilizer

[0112] The stability of the composition according to the addition of amino acids (glycine, leucine) as stabilizers was evaluated. Specifically, semaglutide alone or semaglutide and the third transport carrier (mannitol) and / or stabilizer (glycine, leucine) were weighed according to the composition presented in Table 11 below, dissolved in a solvent (distilled water), and a 10% w / v solution based on solids was prepared, which was micronized according to the conditions presented in Table 2. The micronized raw material, the first transport carrier (lactose), the second transport carrier (micronized lactose), and the lubricant (magnesium stearate) were mixed by sieving three times using a 100 mesh, and then the accelerated stability was evaluated.

[0113]

[0114] The compositions of each manufactured example were stored under accelerated conditions (40°C, 75% RH) and the content (%) after two weeks was analyzed by HPLC. The results are shown in Table 12 below.

[0115]

[0116] As shown in Table 12 above, in the case of Example 17, the content was stable at 88.1% after 2 weeks of acceleration, but the addition of glycine did not significantly improve the content stability. On the other hand, when leucine was added, the content was 100.4% (Example 18) and 95.5% (Example 19) after 2 weeks of acceleration, confirming that the content of the main ingredient was maintained stably compared to Example 15.

[0117] Through this, it was confirmed that leucine is an effective stabilizer that significantly improves the content stability of GLP-1 analogues after spray drying.

[0118]

[0119] Experimental Example 6: Evaluation of effective particle delivery according to ethanol concentration of spray solvent

[0120] Semaglutide and the third transport carrier (mannitol) were weighed according to the compositions presented in Table 13 below, dissolved in a solvent (distilled water or ethanol 20% v / v and 40% v / v) to prepare solutions of each concentration, and micronized according to the conditions presented in Table 2. The micronized raw materials, the first transport carrier (lactose), the second transport carrier (micronized lactose), and the lubricant (magnesium stearate) were sieved three times using a 100 mesh, mixed, and then filled into a #3 hard capsule with an HPMC base. The total emitted dose (TED) and fine particle fraction (FPF) according to the concentration of the organic solvent used in the spray-drying process were measured for the capsules of each manufactured example. The fine particle fraction was expressed as the delivered dose per content (FPF) using the same calculation formula used in Experimental Example 2.

[0121]

[0122] As a result, as shown in Fig. 3, the total transport amount was maintained at a high level of 80% or more in all examples, and the effective particle transport amount also showed a stable value in the range of 73-77%. In particular, the effective particle transport efficiency was maintained without significant decrease even when 20% or 40% ethanol was added compared to the case where 0% ethanol was added. This confirmed that the effect of changes in the organic solvent content on the aerodynamic performance of the composition was limited.

[0123] From these results, the total delivery amount and effective particle delivery amount are stably maintained regardless of changes in the composition of the organic solvent (ethanol 0 to 40%), and therefore the present invention has excellent flexibility in the manufacturing process and industrial applicability.

[0124] The results of these experimental examples confirmed that the process and formulation conditions of the present invention were optimized so that the particle size, dispersibility, and aerodynamic performance of the powder could be secured at a certain level or higher.

Claims

1. 1) Spray-dried product containing a GLP-1 analogue; 2) first transport carrier; and 3) An inhalable composition comprising a second transport carrier, An inhalation composition, wherein the spray-dried product further comprises at least one of a third transport carrier, a stabilizer, or both a third transport carrier and a stabilizer.

2. In the first paragraph, the spray-dried product is an inhalation composition having a GLP-1 analogue having a micronized characteristic through a spray-drying process.

3. 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 imidazopropionyl-exendin-4), CX-exendin-4 (beta-carboxyimidazopropionyl-exendin-4), DM-exendin-4 (Dimethyl-histidyl-exendin-4), lixisenatide, liraglutide, dulaglutide, and albiglutide.

4. In the first paragraph, the concentration of the spray solution before spray drying of the spray-dried product is 0.5 to 15% w / v based on solid content, in an inhalation composition.

5. 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.

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

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

8. An inhalation composition according to claim 1, wherein the third transport carrier is mannitol or trehalose.

9. An inhalation composition according to claim 1, wherein the stabilizer is an amino acid.

10. An inhalation composition according to claim 1, wherein the stabilizer is at least one selected from glycine and leucine.

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

12. A first step of spray-drying a GLP-1 analogue together with a third transport carrier, a stabilizer, or both a third transport carrier and a stabilizer; and A method for producing an inhalation composition, comprising a second step of mixing the spray-dried product produced in the first step with a first transport carrier and a second transport carrier.

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