Dry powder inhalable pharmaceutical composition and preparation method therefor

Abstract

A dry powder inhalable pharmaceutical composition, comprising an active ingredient and a first pharmaceutically acceptable excipient. The active ingredient comprises tadalafil or a pharmaceutically acceptable salt thereof. The first pharmaceutically acceptable excipient comprises an amino acid, a glycan, a phospholipid, a polylactic acid, a polylactic acid copolymer, or a combination thereof. Some embodiments of the present invention can also provide a method for preparing the dry powder inhalable pharmaceutical composition. The dry powder inhalable pharmaceutical composition can improve the characteristics of the aerogel and meet the requirements of inhalation and administration, thereby reducing the onset time.

Description

[0001] i Dry Powder Inhalation Pharmaceutical Composition and Preparation Method Thereof TECHNICAL FIELD The present invention relates to a dry powder inhalation pharmaceutical composition and a preparation method thereof. Specifically, the present invention relates to a pharmaceutical composition comprising tadalafil or a pharmaceutically acceptable salt thereof. BACKGROUND ART Tadalafil (Tad), a phosphodiesterase type 5 (PDE5) inhibitor, is primarily used to treat male erectile dysfunction (ED) and is one of the current mainstream drugs for treating ED. Currently, tadalafil is traditionally administered orally. However, because tadalafil must be absorbed through the gastrointestinal tract before reaching the blood circulation, oral administration is not recommended. Therefore, the problem to be solved is how to provide a dry powder inhalable pharmaceutical composition containing tadalafil to increase the onset of tadalafil's effect. SUMMARY OF THE INVENTION In one aspect of the present invention, a dry powder inhalable pharmaceutical composition is provided, comprising: an active ingredient and a first pharmaceutically acceptable excipient. The active ingredient comprises tadalafil or a pharmaceutically acceptable salt thereof. The first pharmaceutically acceptable excipient comprises an amino acid, a polysaccharide, a phospholipid, polylactic acid, a polylactic acid copolymer, or a combination thereof. In some embodiments, when the weight of the active ingredient and the first pharmaceutically acceptable excipient is taken as 100%, the weight percentage of the active ingredient is 1% to 99%, and the weight percentage of the first pharmaceutically acceptable excipient is 1% to 99%. In some embodiments, when the weight of the active ingredient and the first pharmaceutically acceptable excipient is taken as 100%, the weight percentage of the active ingredient is 1% to 99%, and the weight percentage of the amino acid is 1% to 99%. In some embodiments, the amino acids include ganic acid, alanine, satinine, leucine, isoleucine, phenylalanine, tryptophan, tyrosine, aspartic acid, histidine, asparagine, glutamic acid, lysine, nosine, threonine, methionine, arginine, serine, threonine, cysteine, proline, or a combination thereof. In some embodiments, when the weight of the active ingredient and the first pharmaceutically acceptable excipient is taken as 100%, the weight percentage of the active ingredient is 1% to 99%, and the weight percentage of the polysaccharide is 1% to 99%. In some embodiments, the polysaccharide includes chitosan, chitosan salt, chitosan glutamate, hyaluronic acid, or a combination thereof. In some embodiments, when the weight of the active ingredient and the first pharmaceutically acceptable excipient is taken as 100%, the weight percentage of the active ingredient is 1% to 99%, and the weight percentage of the phospholipid is 1% to 99%. In some embodiments, the phospholipid includes dipalmitoyl phosphatidylcholine (DPPC), distearoyl phosphatidylcholine (DSPC), or a combination thereof.In some embodiments, when the weight of the active ingredient and the first pharmaceutically acceptable excipient is taken as 100%, the weight percentage of the active ingredient is 1% to 99%, and the weight percentage of the polylactic acid is 1% to 50%. In some embodiments, when the weight of the active ingredient and the first pharmaceutically acceptable excipient is taken as 100%, the weight percentage of the active ingredient is 1% to 99%, and the weight percentage of the polylactic acid copolymer is 1% to 50%. In some embodiments, the polylactic acid copolymer comprises poly(lactic-co-glycolic acid). In some embodiments, the active ingredient and the first pharmaceutically acceptable excipient form microparticles having a particle size of 50 nanometers to 10 microns. In some embodiments, the microparticles are solid spheres, hollow spheres, solid polyhedrons, or combinations thereof. In some embodiments, the pharmaceutical composition further comprises a second pharmaceutically acceptable excipient different from the first pharmaceutically acceptable excipient. In some embodiments, when the weight of the pharmaceutical composition is 100%, the total weight percentage of the active ingredient and the first pharmaceutically acceptable excipient is 0.005% to 30%, and the weight percentage of the second pharmaceutically acceptable excipient is 70% to 99.995%. In some embodiments, the second pharmaceutically acceptable excipient comprises lactose, mannitol, or a combination thereof. Another aspect of the present invention provides a method for preparing a dry powder inhalable pharmaceutical composition, comprising: dissolving the active ingredient in a first solvent to form a first solution, wherein the active ingredient comprises tadalafil or a pharmaceutically acceptable salt thereof; dissolving the first pharmaceutically acceptable excipient in a second solvent to form a second solution, wherein the first pharmaceutically acceptable excipient comprises an amino acid, a polysaccharide, a phospholipid, polylactic acid, a polylactic acid copolymer, or a combination thereof; mixing the first solution and the second solution to form a mixed solution; and spray drying the mixed solution to form microparticles. In some embodiments, the first solvent comprises a first organic solvent, and the second solvent comprises a second organic solvent, water, or a combination thereof. In some embodiments, the weight percentage of the active ingredient and the first pharmaceutically acceptable excipient is 0.5% to 3%, based on 100% by weight of the mixture. In some embodiments, the weight ratio of the active ingredient to the first pharmaceutically acceptable excipient in the mixture is 0.01:1 to 199:1. In some embodiments, spray drying the mixture is performed at an outlet temperature of 35°C to 110°C. In some embodiments, the method further comprises mixing the microparticles with a second pharmaceutically acceptable excipient different from the first pharmaceutically acceptable excipient.In some embodiments, the second pharmaceutically acceptable excipient comprises a first size group, a second size group, or a combination thereof, wherein the volume-based particle size distribution of the first size group is different from the volume-based particle size distribution of the second size group. In some embodiments, the D50 particle size of the first size group is between 5 and 50 microns, and the D50 particle size of the second size group is between 30 and 125 microns. In some embodiments, the method further comprises mixing the microparticles with a flavoring. BRIEF DESCRIPTION OF THE DRAWINGS The foregoing and other objects, features, advantages, and embodiments of the present invention will be more fully understood by reading the following detailed description of the embodiments with reference to the accompanying drawings. FIG1 depicts a flow chart of a method for preparing a dry powder inhalable pharmaceutical composition according to some embodiments of the present invention. FIG2 shows an electron microscopic view of tadalafil before spray drying. FIG3 shows an electron microscopic view of microparticles in which the tadalafil is mixed with leucine before spray drying. FIG4A shows an electron microscopic view of microparticles in which the tadalafil is mixed with chitosan phosphate before spray drying. Figure 4B shows microparticles under an electron microscope, where tadalafil was mixed with hyaluronic acid before spray drying. Figure 5 shows microparticles under an electron microscope, where tadalafil was mixed with distearoylphosphatidylcholine (DSPC) before spray drying. Figure 6 compares the aerosol properties of the "Tad only" group, the "Tad + leucine" group, and the "Tad + leucine + lactose" group, as detected using a Next Generation Impactor (NGI). DETAILED DESCRIPTION OF THE INVENTION To describe the present invention in detail and completely, exemplary embodiments and implementations of the present invention are provided, but these are not the only ways to implement or use the embodiments of the present invention. The embodiments disclosed herein may be combined or substituted with each other in advantageous ways, and other embodiments may be added to an embodiment without further description. In the following description, many specific details are described in detail to provide the reader with a thorough understanding of the following embodiments. However, the embodiments of the present invention can be practiced without these specific details. Although a series of operations or steps are described below to illustrate the methods disclosed herein, the order of the operations or steps should not be construed as limiting. For example, certain operations or steps may be performed in a different order and / or concurrently with other steps. Furthermore, not all illustrated operations, steps, and / or features are required to implement embodiments of the present invention. Furthermore, each operation or step described herein may include multiple sub-steps or actions.As used herein, unless otherwise specified, "a," "an," and "the" may refer to a single or multiple entity. It should also be understood that "comprising," "including," "having," and similar terms herein refer to the described features, regions, integers, steps, operations, elements, and / or components, but do not exclude other features, regions, integers, steps, operations, elements, components, and / or groups. As used herein, "drug" or "active ingredient" refers to tadalafil or a pharmaceutically acceptable salt thereof, including but not limited to salts, esters, complexes, chelates, caged compounds, racemates, and enantiomers. As used herein, "pharmaceutically acceptable excipient" refers to a pharmaceutical additive that is pharmacologically inactive and has various uses and functions but is used in a pharmaceutical composition. The primary objective of the present invention is to provide a dry powder inhalable pharmaceutical composition with a smaller particle size and a specific shape, thereby improving the pharmaceutical composition's aerosol properties or aerodynamics (e.g., increasing the fine particle fraction (FPF)) to meet inhalation administration requirements and reduce onset time. Referring to FIG1 , a flow chart illustrating a method 100 for preparing a dry powder inhalable pharmaceutical composition according to some embodiments of the present invention is presented, comprising steps S110, S120, S130, and S140. It should be emphasized that by mixing a first pharmaceutically acceptable excipient and tadalafil in a mixed solution and then spray-drying the mixed solution, the shape and size of the microparticles can be manipulated (including but not limited to spherical or polyhedral shapes and more consistent particle sizes across batches), thereby improving the microparticles' aerosol properties and onset time. First, referring to step S110, an active ingredient is dissolved in a first solvent to form a first solution, wherein the active ingredient comprises tadalafil or a pharmaceutically acceptable salt thereof. In some embodiments, the first solution includes a first organic solvent to facilitate dissolution of the active ingredient, such as ethanol, methanol, dichloromethane, ethyl acetate, acetonitrile, acetone, dimethyl sulfide, or a combination thereof. In some other embodiments, the first solution includes water. Referring to step S120, a first pharmaceutically acceptable excipient is dissolved in a second solvent to form a second solution, wherein the first pharmaceutically acceptable excipient includes an amino acid, a polysaccharide, a phospholipid, polylactic acid, a polylactic acid copolymer, or a combination thereof. In some embodiments, the second solution includes a second organic solvent or water to facilitate dissolution of the active ingredient. In some embodiments, the second organic solvent includes ethanol, methanol, dichloromethane, ethyl acetate, acetonitrile, acetone, dimethyl sulfide, or a combination thereof.In some embodiments, the second solution is the same as the first solution. In some embodiments, the amino acids include glycine, alanine, satinine, leucine, isoleucine, phenylalanine, tryptophan, tyrosine, aspartic acid, histidine, asparagine, glutamic acid, lysine, succinylcholine, methionine, arginine, serine, threonine, cysteine, proline, or a combination thereof. In some embodiments, the polysaccharide includes chitosan, a chitosan salt, a chitosan succinate salt, hyaluronic acid, or a combination thereof. In some embodiments, the phospholipid includes dipalmitoyl phosphatidylcholine (DPPC), distearoyl phosphatidylcholine (DSPC), or a combination thereof. In some embodiments, the polylactic acid copolymer includes polylactic-co-glycolic acid (PLGA). Referring to step S130, the first solution and the second solution are mixed to form a mixed solution. In some embodiments, when the weight of the mixed solution is 100%, the weight percentage of the active ingredient and the first pharmaceutically acceptable excipient is 0.5% to 3%, for example, 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, or any value between any intervals of the above values. If the weight percentage is too low, the yield of spray drying is limited. If the weight percentage is too high, the mixed solution may be inhomogeneous and too viscous to be spray dried, resulting in limited efficiency of spray drying. In some embodiments, the weight ratio of the active ingredient to the first pharmaceutically acceptable excipient in the mixed solution is 0.01:1 to 199:1, for example, 0.01:1, 0.1:1, 1:1, 10:1. The weight ratio may be 1:1, 20:1, 30:1, 40:1, 50:1, 60:1, 70:1, 80:1, 90:1, 100:1, 110:1, 120:1, 130:1, 140:1, 150:1, 160:1, 170:1, 180:1, 190:1, 199:1, or any value within any range thereof. If the weight ratio is too low, the content of the active ingredient in the microparticles after spray drying is limited. If the weight ratio is too high, the microparticles are difficult to control with the first pharmaceutically acceptable excipient, and the aerosol properties are weakened. See step S140, spray drying the mixed solution to form microparticles.In some embodiments, the spray-drying mixture is performed at an outlet temperature of 35°C to 110°C, for example, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, 80°C, 85°C, 90°C, 95°C, 100°C, 110°C, or any value in between these ranges. If the outlet temperature is too low, the sprayed droplets are too large, the particle size of the spray-dried particles tends to be larger, and the shape of the spray-dried particles tends to be irregular, making it difficult to maintain a spherical or polyhedral shape. If the outlet temperature is too high, the structure of the active ingredient or pharmaceutically acceptable excipient may change, thereby affecting their function. In some embodiments, the microparticles can be enclosed in capsules, aluminum foil blister packs, and drug storage tanks within a dry powder inhaler device for inhalation by individuals in need thereof. In some embodiments, method 100 further comprises mixing the microparticles with a second pharmaceutically acceptable excipient different from the first pharmaceutically acceptable excipient. Notably, the addition of the second pharmaceutically acceptable excipient improves aerosol properties, increases the flight distance of the microparticles, and increases the distribution of the microparticles in the lungs following inhalation administration. In some embodiments, the second pharmaceutically acceptable excipient comprises lactose, mannitol, or a combination thereof. In some embodiments, the second pharmaceutically acceptable excipient comprises a first size group, a second size group, or a combination thereof, wherein the volume-based particle size distribution of the first size group is different from the volume-based particle size distribution of the second size group. In some embodiments, the D50 particle size of the first size population is between 5 μm and 50 μm (5 μm, 10 μm, 20 μm, 30 μm, 40 μm, 50 μm, or any value between any intervals thereof), and the D50 particle size of the second size population is between 30 μm and 125 μm (30 μm, 40 μm, 50 μm, 60 μm, 70 μm, 80 μm, 90 μm, 100 μm, 110 μm, 125 μm, or any value between any intervals thereof). In some embodiments, the weight ratio of the second pharmaceutically acceptable excipient to the microparticles is between 70:30 and 99.995:0.005, for example, 70:30, 80:20, 90:10, 99.995:0.005, or any value between any intervals thereof. If the weight ratio of the second pharmaceutically acceptable excipient is too high, the active ingredient that can be provided per specific unit of the pharmaceutical composition is limited.If the weight ratio of the second pharmaceutically acceptable excipient is too low, the improvement in aerosol properties is limited. In some embodiments, method 100 further comprises mixing the microparticles with a flavoring (e.g., menthol or natural flavors such as lemon, strawberry, or orange), wherein the weight percentage of the flavoring is less than 1% (e.g., 0.1%, 0.5%, 1%, or any value within these ranges) to reduce bitterness during inhalation. In one embodiment, mixing the microparticles with a 1% weight percentage of the flavoring has a better effect in reducing bitterness. In some embodiments, a dry powder inhalable pharmaceutical composition is provided, comprising: an active ingredient and a first pharmaceutically acceptable excipient. The active ingredient comprises tadalafil or a pharmaceutically acceptable salt thereof. The first pharmaceutically acceptable excipient comprises an amino acid, a polysaccharide, a phospholipid, polylactic acid, a polylactic acid copolymer, or a combination thereof. By using a first pharmaceutically acceptable excipient, the shape and particle size of the spray-dried pharmaceutical composition can be controlled to improve the aerosol properties of the pharmaceutical composition (including but not limited to achieving a specific regular shape such as a sphere or polyhedron, and more consistent particle size across batches). In some embodiments, the viscosity of the first pharmaceutically acceptable excipient is less than 3 dL / g, for example, 0.1 dL / g to 3 dL / g. If the viscosity is too high, the first pharmaceutically acceptable excipient will be difficult to spray dry, and the particle size of the microparticles will be too large to meet the requirements for inhalation administration. In some embodiments, when the weight of the active ingredient and the first pharmaceutically acceptable excipient is taken as 100%, the weight percentage of the active ingredient is 1% to 99% (e.g., 1%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or any value in between), and the weight percentage of the first pharmaceutically acceptable excipient is 1% to 99% (e.g., 1%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or any value in between). If the weight percentage of the active ingredient is too low or the weight percentage of the first pharmaceutically acceptable excipient is too high, the amount of active ingredient that can be provided in a specific unit of the pharmaceutical composition is limited. If the weight percentage of the active ingredient is too high or the weight percentage of the first pharmaceutically acceptable excipient is too low, the aerosol properties of the pharmaceutical composition may be weakened.In some embodiments, when the weight of the active ingredient and the first pharmaceutically acceptable excipient is taken as 100%, the weight percentage of the amino acid is 1% to 99% (e.g., 1%, 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 99%, or any value in between). If the weight percentage of the amino acid is too high, the amount of active ingredient that can be provided per unit of the pharmaceutical composition is limited. If the weight percentage of the amino acid is too low, the aerosol properties of the pharmaceutical composition are impaired. In some embodiments, when the weight of the active ingredient and the first pharmaceutically acceptable excipient is taken as 100%, the weight percentage of the glycan is 1% to 99% (e.g., 1%, 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 60%, 90%, 95%, 99%, or any value in between). If the weight percentage of polysaccharides is too high, the amount of active ingredient that can be provided per unit of the pharmaceutical composition is limited. If the weight percentage of polysaccharides is too low, the aerosol properties of the pharmaceutical composition are weakened. In some embodiments, when the weight of the active ingredient and the first pharmaceutically acceptable excipient is taken as 100%, the weight percentage of phospholipids is 1% to 99% (e.g., 1%, 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or any value in between these values). If the weight percentage of phospholipids is too high, the amount of active ingredient that can be provided per unit of the pharmaceutical composition is limited. If the weight percentage of phospholipids is too low, the aerosol properties of the pharmaceutical composition are weakened. In some embodiments, when the weight of the active ingredient and the first pharmaceutically acceptable excipient is taken as 100%, the weight percentage of polylactic acid (PLA) is 1% to 50% (e.g., 1%, 5%, 10%, 15%, 20%, 30%, 40%, 50%, or any value in between). If the weight percentage of PLA is too high, the amount of active ingredient that can be provided per unit of the pharmaceutical composition is limited. If the weight percentage of PLA is too low, the aerosol properties of the pharmaceutical composition are weakened. In some embodiments, when the weight of the active ingredient and the first pharmaceutically acceptable excipient is taken as 100%, the weight percentage of the polylactic acid copolymer (e.g., PLGA) is 1% to 50% (e.g., 1%, 5%, 10%, 15%, 20%, 30%, 40%, 50%, or any value in between).If the weight percentage of the polylactic acid copolymer is too high, the amount of active ingredient that can be provided per unit of the pharmaceutical composition is limited. If the weight percentage of the polylactic acid copolymer is too low, the aerosol properties of the pharmaceutical composition are weakened. In some embodiments, the active ingredient and the first pharmaceutically acceptable excipient form microparticles having a particle size between 50 nanometers and 10 microns, for example, 50 nanometers, 100 nanometers, 500 nanometers, 1 micron, 2 microns, 3 microns, 4 microns, 5 microns, 6 microns, 7 microns, 8 microns, 9 microns, 10 microns, or any value in between these values. Notably, the particle size of the microparticles is smaller than that of the unspray-dried active ingredient. Therefore, the particle size requirement for inhalation into the lungs is met. In some embodiments, the microparticles are solid spheres, hollow spheres, solid polyhedrons, or combinations thereof. These microparticle shapes can increase the flight distance of the microparticles and, upon administration, improve the distribution ratio of the microparticles in the lungs. In some embodiments, the pharmaceutical composition further comprises a second pharmaceutically acceptable excipient different from the first pharmaceutically acceptable excipient, such as lactose, mannitol, or a combination thereof. The addition of the second pharmaceutically acceptable excipient can further increase the flight distance of the microparticles and improve the distribution ratio of the microparticles in the lungs upon administration. In some embodiments, when the weight of the pharmaceutical composition is taken as 100%, the weight percentage of the second pharmaceutically acceptable excipient is 70% to 99.995%, for example, 70%, 80%, 90%, 95%, 99.995%, or any value in between these values. If the weight percentage of the second pharmaceutically acceptable excipient is too high, the active ingredient that can be provided by a specific unit of the pharmaceutical composition is limited. If the weight percentage of the second pharmaceutically acceptable excipient is too low, the aerosol properties of the pharmaceutical composition are weakened.In some embodiments, when the weight of the pharmaceutical composition is 100% and when the pharmaceutical composition contains the second pharmaceutically acceptable excipient, the total weight percentage of the active ingredient and the first pharmaceutically acceptable excipient is 0.005% to 30% (e.g., 0.005%, 0.01%, 0.1%, 1%, 10%, 20%, 30%, or any number between any intervals of the foregoing values), and the weight ratio of the active ingredient to the first pharmaceutically acceptable excipient is 0.01:1 to 199:1, for example, 0.01:1, 0.1:1, 1:1, 10:1, 20:1, 30:1, 40:1, 50:1, 60:1, 70:1, 80:1, 90:1, 100:1, 110:1, 120:1, 130:1, 140:1, 150:1, 160:1, 170:1, 180:1, 190:1, 199:1, or any value within any range of the aforementioned values. In some embodiments, the pharmaceutical composition further includes a third pharmaceutically acceptable excipient for regulating specific properties, such as aerodynamics or taste. It should be understood that the above embodiments and the following examples are provided for illustrative purposes only and are not intended to be limiting. Based on the description, it will be apparent to those skilled in the art that various variations and modifications can be made within the scope of the present invention. To clarify the dry powder inhalable pharmaceutical composition and its preparation method, several examples and efficacy tests are provided below in order. Example 1 - Preparation Method and Physical Properties of Dry Powder Inhalable Pharmaceutical Composition.

[0002] 1. The first pharmaceutically acceptable excipient added before spray drying

[0003] (1) Amino acid step a: Tadalafil was dissolved in ethanol and leucine was dissolved in water, and then the two were mixed with each other according to the formula in Table 1. Table 1 Step b: The mixed solution obtained in step a was spray-dried at an outlet temperature of 100°C to form microparticles. Compared to the other conditions listed in Table 1, the microparticles prepared using a 50:50 weight ratio and a 2.0% concentration exhibited smaller and more spherical particle sizes, and were therefore selected for subsequent physical property observations. The appearance of tadalafil or microparticles prepared at different steps was observed under an electron microscope. The results are shown in Figures 2 and 3. The tadalafil in Figure 2 was observed before step b (without spray drying), while the microparticles in Figure 3 were observed after step b (with spray drying). These microparticles are obtained by spray-drying tadalafil and leucine. Figure 2 shows that the tadalafil 200 before step b (without spray drying) exhibits irregular shapes, agglomeration, and large variations in particle size. Figure 3 shows that the microparticles 300 (after spray drying) are spherical or polyhedral (e.g., golf ball-shaped, i.e., solid polyhedrons with multiple grooves on their surfaces). Compared to the irregular shape of unspray-dried tadalafil 200 (Figure 2), the microparticles 300 (Figure 3) exhibit a more consistent shape. Particle size was analyzed three times through repeated testing (D10, D50, and D90), and the results are summarized in Table 2 (Leucine Added). Table 2 (Leucine Added) Note: D10 represents the particle size corresponding to a cumulative frequency of 10%. D50 represents the particle size corresponding to a cumulative frequency of 50%. D90 represents the particle size corresponding to a cumulative frequency of 90%. As shown in Table 2, over 90% of the microparticles have a particle size less than 7 μm, while D50 is only 3 to 4 μm, smaller than that of unspray-dried tadalafil (the tadalafil value is omitted in Table 2).

[0004] (2) Polysaccharides

[0005] (2)-1. Chitosan amino acid step a: Tadalafil is dissolved in acetone, and chitosan amino acid (molecular weight (Mw) of chitosan = 5 kilodaltons to 190 kilodaltons) is dissolved in ethanol or acetone. Then, the two are mixed with each other through a three-fluid nozzle according to the formula in Table 3 and spray-dried at an outlet temperature of 80°C to form microparticles. Compared with the existing two-fluid nozzle, when different solvents are used in the spray drying process, the three-fluid nozzle can be used to better control the particle size and mixing uniformity. Table 3 Compared to the other conditions listed in Table 3, the microparticles prepared using a weight ratio of 50:50 and a concentration of 2.0% exhibited smaller particle sizes and more spherical shapes. Therefore, the microparticles prepared using a weight ratio of 50:50 and a concentration of 2.0% were selected for subsequent physical property observations. Microparticle shape was observed under an electron microscope (with chitosan and choline as a pharmaceutically acceptable excipient). The results are shown in Figure 4A. Figure 4A shows that the microparticles 300 are spherical (e.g., red blood cells). Compared to the irregular shape of unspray-dried tadalafil 200 (see Figure 2), the shape of the microparticles 300 is relatively consistent. Particle size (D10, D50, and D90) was analyzed through three repetitive tests, and the results are summarized in Table 4. Table 4 During the process, it was observed that the particle size of the microparticles was less than 7.0 μm, which was smaller than that of tadalafil that had not been spray-dried (not shown in Table 4).

[0006] (2)-2, Hyaluronic acid step a: Tadalafil is dissolved in ethanol, and hyaluronic acid (molecular weight (Mw) = 182.17 g

[0007] / mol) was dissolved in water or 60% ethanol solution, and then the two were mixed with each other according to the formula in Table 5. Table 5 Step b: The mixed solution obtained in step a was spray-dried at an outlet temperature of 100°C to form microparticles. Compared to the other conditions listed in Table 5, microparticles prepared using a weight ratio of 20:80 and a concentration of 1.0% exhibited smaller particle size and a more spherical shape. Therefore, the microparticles prepared using a weight ratio of 20:80 and a concentration of 1.0% were selected for subsequent physical property observations. Microparticle shape: Electron microscopic observations of the microparticles (using hyaluronic acid as a pharmaceutically acceptable excipient) were performed. The results are shown in Figure 4B. Figure 4B shows that the microparticles 300 exhibit spherical shapes (e.g., red blood cells) or polyhedral shapes (e.g., golf balls). Compared to the irregular shapes of unspray-dried tadalafil 200 (see Figure 2), the microparticles 300 exhibited relatively consistent shapes. The particle size was analyzed by repeatability test 3 times (DIO, D50 and D90), and the results are summarized in Table 6. During the process, it was observed that the particle size of the microparticles was less than 7.0 μm, which was smaller than that of tadalafil that had not been spray-dried (not shown in Table 6).

[0008] (3) Phospholipid tadalafil and DPSC (Mw = 790 g / mol) were dissolved in ethanol, and then the two were mixed with each other through a three-fluid nozzle according to the formulation in Table 7 and spray-dried at an outlet temperature of 90°C to form microparticles. Table 7 Compared to the other conditions listed in Table 7, the microparticles prepared using a 50:50 weight ratio and a 2% concentration exhibited smaller particle size and a more spherical shape, and were therefore selected for subsequent physical property analysis. The appearance of the spray-dried microparticles (using DPSC as the first pharmaceutically acceptable excipient) was observed under an electron microscope. The results are shown in Figure 5. Figure 5 shows that the microparticles 300 exhibit spherical or polyhedral shapes (e.g., golf balls). Compared to the irregular shape of the unspray-dried tadalafil 200 (see Figure 2), the microparticles 300 exhibited a relatively consistent shape. The particle size (D10, D50, and D90) of the microparticles obtained by mixing tadalafil and DSPC was analyzed in three repetitive tests, and the results are summarized in Table 8. Table 8 (DSPC Addition) During the process, it was observed that the particle size of the microparticles was generally less than 5 μm, which was smaller than that of tadalafil that had not been spray-dried (the tadalafil value was omitted in Table 8).

[0009] 2. Add the second pharmaceutically acceptable excipient after spray drying. Add the lactose with two particle sizes to a high shear mixer and mix with the second pharmaceutically acceptable excipient from the first

[0010] 1. (3) The microparticles obtained in point (3) were mixed. The microparticles were prepared using DPSC as the first pharmaceutically acceptable excipient at a weight ratio of 50:50 and a concentration of 2%. The mixing ratio of the second pharmaceutically acceptable excipient (lactose) to the microparticles was obtained according to Table 9. Table 9 Aerosol Properties To compare the aerosol properties of microparticles prepared by direct spray drying, adding a first pharmaceutically acceptable excipient before spray drying, or adding a first pharmaceutically acceptable excipient before spray drying and adding a second pharmaceutically acceptable excipient after spray drying, microparticles from the "Tad only" group, the "Tad + leucine" group, and the "Tad + leucine + lactose" group were used to measure aerosol properties. Aerosol properties were measured using a Next Generation Impactor (NGI) (Copley Scientific, Model 170) in a cascade impaction (CI) system at an airflow rate of 60 liters / minute. The "Tad only" group was prepared by direct spray drying of tadalafil. The "Tad + Leucine" group was prepared by adding the first pharmaceutically acceptable excipient (leucine) before spray drying (using the preferred conditions in Table 1, a 50:50 weight ratio of tadalafil to leucine, and a mixture concentration of 2.0%). The "Tad + Leucine + Lactose" group was prepared by adding the first pharmaceutically acceptable excipient (leucine) before spray drying and the second pharmaceutically acceptable excipient (lactose) after spray drying (the preparation ratios were similar to those in point 2 above). The results are shown in Figure 6 and Table 10 (data compiled from Figure 6). The fine particle fraction (FPF) is the percentage of the cumulative deposited particles smaller than 5 μm to the total output particles, reflecting the effective particle deposition rate in the lungs. Figure 6 (Aerosol Properties Comparison Graph 400) shows that, compared to the "Tad Only" group, the particles in the "Tad + Leucine" and "Tad + Leucine + Lactose" groups are less distributed in the early layers (e.g., the residual layer of the capsule to the S2 layer) (relatively short flight distances), while the distribution improves in the subsequent layers, such as the S3 to S8 layers, indicating that relatively long flight distances can be achieved. In other words, compared to the "Tad Only" group, the "Tad + Leucine" and "Tad + Leucine + Lactose" groups exhibit longer flight distances. Furthermore, compared to the "Tad + Leucine" group, the particles in the "Tad + Leucine + Lactose" group exhibit improved distribution in the S4 to S7 layers (requiring a relatively long flight distance). In other words, compared to the "Tad + Leucine" group, the "Tad + Leucine + Lactose" group exhibits even longer flight distances. Table 10 Note: MMAD is the mass median aerodynamic diameter. Table 10 shows that, compared with the "Tad only" group, the "Tad + Leucine" group and the "Tad + Leucine + Lactose" group showed higher FPF and smaller MMAD; compared with the "Tad + Leucine" group, the "Tad + Leucine + Lactose" group showed higher FPF and smaller MMAD. Therefore, Figure 6 and Table 10 reveal that the flight distance ranking (long to short) among these three groups is (1) microparticles prepared by adding the first pharmaceutically acceptable excipient before spray drying and adding the second pharmaceutically acceptable excipient after spray drying, (2) microparticles prepared by adding the first pharmaceutically acceptable excipient before spray drying, and (3) microparticles prepared by directly spray drying tadalafil. That is, according to the above data, compared with the microparticles prepared by direct spray drying, the microparticles prepared by adding the first pharmaceutically acceptable excipient have a higher flight distance than the microparticles prepared by direct spray drying. Or, by adding a first pharmaceutically acceptable excipient and a second pharmaceutically acceptable excipient to produce microparticles, a higher distribution ratio in the lungs is achieved. Referring back to Figures 3, 4A, 4B, and 5, and also to Figure 6 and Table 10, it should be emphasized that when tadalafil is mixed with the first pharmaceutically acceptable excipient at least before spray drying, the shape of the resulting microparticles can achieve a longer flight distance and a higher distribution ratio in the lungs upon administration. Although the present invention has been described in detail with reference to certain embodiments, other embodiments are also possible. Therefore, the spirit and scope of the appended claims should not be limited to the embodiments described herein.

[0011]

Explanation of symbols

[0012] 100: Methods

[0013] S110, S120, S130, S140: Steps

[0014] 200: Tadalafil

[0015] 300: Particles

[0016] 400: Comparison chart of aerosol properties.

Claims

Claims 1. A dry powder inhalation pharmaceutical composition, comprising: An active ingredient, wherein the active ingredient comprises tadalafil or a pharmaceutically acceptable salt thereof; and a first pharmaceutically acceptable excipient, including amino acids, polysaccharides, phospholipids, polylactic acid, polylactic acid copolymers or combinations thereof.

2. The pharmaceutical composition according to claim 1, wherein when the weight of the active ingredient and the first pharmaceutically acceptable excipient is 100%, the weight percentage of the active ingredient is 1% to 99%, and the weight percentage of the first pharmaceutically acceptable excipient is 1% to 99%.

3. The pharmaceutical composition according to claim 1, wherein when the weight of the active ingredient and the first pharmaceutically acceptable excipient is 100%, the weight percentage of the active ingredient is 1% to 99%, and the weight percentage of the amino acid is 1% to 99%.

4. The pharmaceutical composition according to claim 1, wherein the amino acid comprises glycine, alanine, leucine, isoleucine, phenylalanine, tryptophan, tyrosine, aspartic acid, histidine, asparagine, glutamic acid, lysine, arginine, threonine, cysteine, proline or a combination thereof.

5. The pharmaceutical composition according to claim 1, wherein when the weight of the active ingredient and the first pharmaceutically acceptable excipient is 100%, the weight percentage of the active ingredient is 1% to 99%, and the weight percentage of the polysaccharide is 1% to 99%.

6. The pharmaceutical composition according to claim 1, wherein the polysaccharide comprises chitosan, chitosan salt, chitosan amino acid salt, hyaluronic acid or a combination thereof.

7. The pharmaceutical composition according to claim 1, wherein when the weight of the active ingredient and the first pharmaceutically acceptable excipient is 100%, the weight percentage of the active ingredient is 1% to 99%, and the weight percentage of the phospholipid is 1% to 99%.

8. The pharmaceutical composition according to claim 1, wherein the phospholipid comprises disalmitoylphosphatidylcholine, distearoylphosphatidylcholine or a combination thereof.

9. The pharmaceutical composition according to claim 1, wherein the active ingredient and the first The weight percentage of the pharmaceutically acceptable excipient is 100%, the weight percentage of the active ingredient is 1% to 99%, and the weight percentage of the polylactic acid is 1% to 50%.

10. The pharmaceutical composition according to claim 1, wherein when the weight of the active ingredient and the first pharmaceutically acceptable excipient is 100%, the weight percentage of the active ingredient is 1% to 99%, and the weight percentage of the polylactic acid copolymer is 1% to 50%.

11. The pharmaceutical composition according to claim 1, wherein the polylactic acid copolymer comprises polylactic acid-glycolic acid.

12. The pharmaceutical composition according to claim 1, wherein the active ingredient and the first pharmaceutically acceptable excipient form microparticles with a particle size of 50 nanometers to 10 micrometers.

13. The pharmaceutical composition according to claim 12, wherein the microparticles are in the shape of solid spheres, hollow spheres, solid polyhedrons or a combination thereof.

14. The pharmaceutical composition according to claim 1, wherein Also included is a second pharmaceutically acceptable excipient that is different from the first pharmaceutically acceptable excipient. 15> The pharmaceutical composition according to claim 14, wherein when the weight of the pharmaceutical composition is 100%, the total weight percentage of the active ingredient and the first pharmaceutically acceptable excipient is 0.005% to 30%, and the weight percentage of the second pharmaceutically acceptable excipient is 70% to 99.995%.

16. The pharmaceutical composition according to claim 14, wherein the second pharmaceutically acceptable excipient comprises lactose, mannitol or a combination thereof.

17. A method for preparing a dry powder inhalation pharmaceutical composition, comprising: Dissolving an active ingredient in a first solvent to form a first solution, wherein the active ingredient includes tadalafil or a pharmaceutically acceptable salt thereof; dissolving a first pharmaceutically acceptable excipient in a second solvent to form a second solution, wherein the first pharmaceutically acceptable excipient includes an amino acid, a polysaccharide, a phospholipid, polylactic acid, a polylactic acid copolymer or a combination thereof; mixing the first solution and the second solution to form a mixed solution; and The mixture is spray dried to form microparticles.

18. The method according to claim 17, wherein the first solvent comprises a first organic solvent, and the second solvent comprises a second organic solvent, water or a combination thereof.

19. The method according to claim 17, wherein when the weight of the mixed solution is 100%, the weight percentage of the active ingredient and the first pharmaceutically acceptable excipient is 0.5% to 3%.

20. The method according to claim 17, wherein the weight ratio of the active ingredient to the first pharmaceutically acceptable excipient in the mixed solution is 0.01:1 to 199:

1.

21. The method according to claim 17, wherein spray drying the mixed solution is performed at an outlet temperature of 35°C to 110°C.

22. The method according to claim 17, wherein: Also included is mixing the microparticles with a second pharmaceutically acceptable excipient that is different from the first pharmaceutically acceptable excipient.

23. The method of claim 22, wherein the second pharmaceutically acceptable excipient comprises a first size group, a second size group, or a combination thereof, wherein the volume-based particle size distribution of the first size group is different from the volume-based particle size distribution of the second size group.

24. The method of claim 23, wherein the D50 particle size of the first size group is 5 μm to 50 μm, and the D50 particle size of the second size group is 30 μm to 125 μm.

25. The method according to claim 17, wherein: Also included is mixing the microparticles with a flavoring agent.

Images