Inhalable pharmaceutical composition and method

Abstract

A dry powder inhalable pharmaceutical composition, comprising an active ingredient and a first pharmaceutically acceptable excipient. The active ingredient comprises avanafil 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 disclosure also provide a method for preparing a 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] TECHNICAL FIELD The present disclosure relates to a dry powder inhalable pharmaceutical composition and a method for preparing the same. Specifically, the present disclosure relates to a pharmaceutical composition comprising avanafil or a pharmaceutically acceptable salt thereof. BACKGROUND Avanafil (Avanafil), a phosphodiesterase type 5 (PDE5) inhibitor, is primarily used to treat male erectile dysfunction (ED) and is one of the current mainstream drugs for ED. Currently, avanafil is traditionally administered orally. However, because avanafil must be absorbed through the gastrointestinal tract before reaching the bloodstream, oral administration is difficult. Therefore, the problem to be solved is how to provide a dry powder inhalable pharmaceutical composition containing avanafil to increase the onset of avanafil's effect. SUMMARY OF THE INVENTION In one aspect of the present disclosure, a dry powder inhalable pharmaceutical composition is provided, comprising: an active ingredient and a first pharmaceutically acceptable excipient. The active ingredient comprises avanafil 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 acid includes glycine, alanine, valine, leucine, isoleucine, phenylalanine, tryptophan, tyrosine, aspartic acid, histidine, asparagine, glutamic acid, lysine, hydroxysuccinyl 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, hyaluronic acid, or a combination thereof. In some embodiments, when the weight of the active ingredient and the first pharmaceutically acceptable excipient is calculated as 100%, the weight percentage of the active ingredient is 1% to 99%, and the weight percentage of the phospholipid is 1% to 50%. In some embodiments, the phospholipid comprises 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 calculated as 100%, the weight percentage of the active ingredient is 1% to 99%, and the weight percentage of polylactic acid is 1% to 50%. oIn some embodiments, 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%. o In some embodiments, the polylactic acid copolymer comprises poly(lactic-co-glycolic acid) oIn some embodiments, the active ingredient and the first pharmaceutically acceptable excipient form microparticles having a particle size of 50 nanometers to 10 micrometers. In some embodiments, the microparticles are solid spheres, hollow spheres, solid polyhedrons, or a combination 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 taken as 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 99995%. In some embodiments, the second pharmaceutically acceptable excipient comprises lactose, mannitol, or a combination thereof. Another aspect of the present disclosure provides a method for preparing a dry powder inhalable pharmaceutical composition, comprising: dissolving an active ingredient in a first solvent to form a first solution, wherein the active ingredient comprises avanafil 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 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 mixed solution. 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. 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 μm and 50 μm, and the D50 particle size of the second size group is between 30 μm and 125 μm. 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 disclosure will be more fully understood by reading the following detailed description of the embodiments with reference to the accompanying drawings.Figure 1 depicts a flow chart illustrating a method for preparing a dry powder inhalable pharmaceutical composition according to some embodiments of the present disclosure. Figure 2 shows an electron microscopic image of avanafil before spray drying. Figure 3A shows an electron microscopic image of microparticles in which avanafil is mixed with leucine before spray drying. Figure 3B shows an electron microscopic image of microparticles in which avanafil is mixed with methionine before spray drying. Figure 4 shows an electron microscopic image of microparticles in which avanafil is mixed with hyaluronic acid before spray drying. Figure 5 shows an electron microscopic image of microparticles in which avanafil is mixed with distearoylphosphatidylcholine (DSPC) before spray drying. FIG6 shows microparticles under an electron microscope, in which avanafil was mixed with poly(lactic-co-glycolic acid, PLGA) before spray drying. FIG7 shows a comparison of the aerosol properties of the "Ava only" group, the "Ava + Leucine" group, and the "Ava + Leucine + Lactose" group detected using a Next Generation Impactor (NGI). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS To describe the present disclosure in detail and completely, exemplary embodiments and implementations of the present disclosure are provided, but these are not the only ways to implement or use the embodiments of the present disclosure. 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 will be described in detail to provide the reader with a full understanding of the following embodiments. However, the embodiments of the present disclosure may 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 disclosure. Furthermore, each operation or step described herein may include multiple sub-steps or actions. Throughout this document, unless otherwise indicated, "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, components, and / or elements, but do not exclude other features, regions, integers, steps, operations, elements, components, and / or groups.As used herein, "drug" or "active ingredient" refers to avanafil or its pharmaceutically acceptable salts, including but not limited to salts, esters, complexes, chelates, caged compounds, racemates, or enantiomers. As used herein, "pharmaceutically acceptable excipients" refer to pharmaceutical additives that lack pharmacological activity and have various uses and functions used in pharmaceutical compositions. The primary objective of the present disclosure is to provide dry powder inhalable pharmaceutical compositions with relatively small particle sizes and specific shapes, thereby improving the aerosol properties (e.g., increasing the fine particle fraction (FPF)) of the pharmaceutical compositions to meet the requirements of inhalation administration and reducing the onset of action. Referring to FIG. 1 , a flow chart illustrating a method 100 for preparing a dry powder inhalable pharmaceutical composition according to some embodiments of the present disclosure is presented, comprising steps S110, S120, S130, and S140. It should be emphasized that by mixing a first pharmaceutically acceptable excipient with avanafil 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 size across batches), thereby improving the aerosol properties and onset time of the microparticles. First, referring to step S110, the active ingredient is dissolved in a first solvent to form a first solution, wherein the active ingredient includes avanafil 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 sulfoxide, or a combination thereof. In some other embodiments, the first solution includes water. Referring to step S120, the 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 more easily dissolve the active ingredient. In some embodiments, the second organic solvent includes ethanol, methanol, dichloromethane, ethyl acetate, acetonitrile, acetone, dimethyl sulfone, or a combination thereof. In some embodiments, the second solution is the same as the first solution.In some embodiments, the amino acid comprises glycine, alanine, satinine, leucine, isoleucine, phenylalanine, tryptophan, tyrosine, aspartic acid, histidine, asparagine, glutamic acid, lysine, succinylamino acid, methionine, arginine, serine, threonine, cysteine, proline, or a combination thereof. In some embodiments, the polysaccharide comprises chitosan, a chitosan salt, hyaluronic acid, or a combination thereof. In some embodiments, the phospholipid comprises dipalmitoyl phosphatidylcholine (DPPC), distearoyl phosphatidylcholine (DSPC), or a combination thereof. In some embodiments, the polylactic acid copolymer includes poly(lactic-co-glycolic acid, PLGA). See 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 spray drying efficiency. 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, spray drying the mixed solution is performed at an outlet temperature of 35°C to 110°C.The outlet temperature may be 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 within any range of the foregoing values. 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 will be difficult to maintain as a sphere or polyhedron, tending to be irregular. If the outlet temperature is too high, the structure of the active ingredient or pharmaceutically acceptable excipient may change, affecting its function. In some embodiments, the microparticles can be loaded into a capsule, aluminum foil blister, or drug storage tank in a dry powder inhaler device for inhalation by individuals in need. 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 ratio 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 by a 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 includes mixing the microparticles with a flavoring agent (e.g., menthol or natural flavorings such as lemon, strawberry, or orange), wherein the flavoring agent comprises less than 1% by weight (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 flavoring agent at a 1% weight percentage has a greater effect on 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 avanafil 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. The use of the first pharmaceutically acceptable excipient allows for the control of the shape and particle size of the spray-dried pharmaceutical composition to improve its aerosol properties (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 deciliters / gram, for example, 0.1 deciliters / gram to 3 deciliters / gram. If the viscosity is too high, the first pharmaceutically acceptable excipient may be difficult to spray-dry, and the particle size of the microparticles may 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 number 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 number 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 per 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 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 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 amino acids 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 amino acids 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 polysaccharide 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 these values). If the weight percentage of the polysaccharide 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 polysaccharide 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 phospholipid is between 1% and 50% (e.g., 1%, 5%, 10%, 15%, 20%, 30%, 40%, 50%, or any value within these ranges). If the weight percentage of the phospholipid 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 phospholipid 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 (PLA) is between 1% and 50% (e.g., 1%, 5%, 10%, 15%, 20%, 30%, 40%, 50%, or any value within these ranges). 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 micrometers, for example, 50 nanometers, 100 nanometers, 500 nanometers, 1 micrometer, 2 micrometers, 3 micrometers, 4 micrometers, 5 micrometers, 6 micrometers, 7 micrometers, 8 micrometers, 9 micrometers, 10 micrometers, 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 includes a second pharmaceutically acceptable excipient different from the first pharmaceutically acceptable excipient, for example, lactose, mannitol, or a combination thereof. The addition of a second pharmaceutically acceptable excipient can further increase the flight distance of the microparticles and improve their distribution ratio 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 ranges. If the weight percentage of the second pharmaceutically acceptable excipient is too high, the amount of active ingredient that can be delivered per 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 a 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 between any intervals of the aforementioned values. In some embodiments, the pharmaceutical composition further comprises a third pharmaceutically acceptable excipient for regulating specific properties, such as aerodynamics or taste.It should be understood that the aforementioned embodiments and the following examples are provided for illustrative purposes only and are not intended to be limiting. Based on the description, those skilled in the art will readily appreciate that various variations and modifications can be made within the scope of this disclosure. To clarify the dry powder inhalable pharmaceutical composition and its preparation method, several examples and efficacy tests are provided below. Example 1 - Preparation Method and Physical Properties of the Dry Powder Inhalable Pharmaceutical Composition.

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

[0003] (1) Amino acid step a: Avanafil is dissolved in ethanol, and leucine or methionine is dissolved in water, and then the two (avanafil solution and amino acid solution) are mixed with each other according to the formula in Table 1. Table 1 Step b: The mixed solution obtained from step a is heated to 80°C. (2) Spray drying was performed to form microparticles. Compared to the other conditions in Table 1, the microparticles prepared with a weight ratio of 20:80 and a concentration of 2.0% had smaller particle size and more spherical shape, so they were selected for subsequent physical property observations. Microparticle Shape The appearance of avanafil or microparticles in different preparation steps was observed under an electron microscope. The results are shown in Figures 2, 3A, and 3B. The sildenafil in Figure 2 was observed before step b (without spray drying), while the microparticles in Figures 3A and 3B were observed after step b (with spray drying). Figure 3A shows microparticles obtained by spray drying sildenafil with leucine, and Figure 3B shows microparticles obtained by spray drying sildenafil with methionine. Figure 2 shows that the sildenafil 200 before step b (without spray drying) is an irregular block. Figures 3A (with leucine added) and 3B (with methionine added) show the shape of microparticles 300 (with spray drying). The microparticles are spherical or polyhedral (e.g., golf ball-shaped, i.e., solid polyhedrons with multiple grooves on their surfaces). Compared to the irregular, blocky shape of unspray-dried sildenafil 200 (Figure 2), the microparticles 300 (Figures 3A and 3B) are relatively uniform in shape. The particle size (D10, D50, and D90) was analyzed through three repetitive tests, and the results are summarized in Table 2A (leucine addition) and Table 2B (methionine addition). Table 2A (leucine addition) Note: D10 represents the particle size corresponding to the 10% cumulative frequency. D50 represents the particle size corresponding to the 50% cumulative frequency. D90 represents the particle size corresponding to the 90% cumulative frequency. As shown in Table 2A, over 90% of the particles have a particle size less than 5 μm, while D50 is only 2 to 3 μm, smaller than that of unspray-dried avanafil (the avanafil values ​​are omitted in Table 2A). Table 2B (methionine added) As shown in Table 2B, more than 90% of the microparticles have a particle size of less than 5 μm, and the D50 is only 2 to 3 μm, which is smaller than that of avanafil that has not been spray-dried (the numerical value of avanafil is omitted in Table 2B).

[0004] (2) Polysaccharide step a: Avanafil is dissolved in ethanol, and hyaluronic acid is dissolved in water or 60% ethanol solution, and then the two are mixed with each other according to the formula in Table 3. Table 3 Step b: The mixed solution obtained from step a is heated to an outlet temperature of 85.degree. (2) Spray drying was performed to form microparticles. Compared to the other conditions in Table 3, the microparticles prepared with a weight ratio of 50:50 and a concentration of 2.0% had a smaller particle size, a more spherical shape, and were more stable during storage. Therefore, the microparticles prepared with a weight ratio of 50:50 and a concentration of 2.0% were selected for subsequent physical property observations. The appearance of the microparticles was observed under an electron microscope (hyaluronic acid was used as a pharmaceutically acceptable excipient). The results are shown in Figure 4. Figure 4 shows that the shapes of the microparticles 300 are spherical (e.g., red blood cells) or polyhedral (e.g., golf balls). Compared to the irregular lumps of sildenafil 200 (see Figure 2) that was not spray-dried, the shapes of the microparticles 300 are relatively consistent. Particle size was analyzed through three repeated tests (D10, D50, and D90), 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 8.0 μm, which was smaller than that of avanafil without spray drying (not shown in Table 4).

[0005] (3) Phospholipids avanafil and DPPC (molecular weight (Mw) = 744 g / mol), avanafil and DPSC (Mw = 790 g / mol) were dissolved in ethanol, 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 70°C (20°F) to form microparticles. Compared to the other conditions listed in Table 5, the microparticles prepared using a weight ratio of 80:20 and a concentration of 2% exhibited smaller particle size and a more spherical shape, and were therefore selected for subsequent physical property observations. The appearance of the spray-dried microparticles (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 ball-shaped). Compared to the irregular, clumpy shape of unspray-dried sildenafil 200 (see Figure 2), the microparticles 300 exhibited relatively consistent shapes. The particle sizes (D10, D50, and D90) of the microparticles obtained by mixing avanafil and DSPC were analyzed through three repetitive tests, and the results are summarized in Table 6. Table 6 (DSPC Addition) During the process, it was observed that the particle size of the microparticles was generally less than 7 μm, which was smaller than that of avanafil that had not been spray-dried (the avanafil value was omitted in Table 5).

[0006] (4) Polylactic acid or polylactic acid copolymer Step a: Avanafil and polylactic acid-glycolic acid (PLGA) with a viscosity of 0.16 dl / g to 0.24 dl / g are dissolved in acetone, and then the two are mixed with each other according to the formula of Table 7. Table 7 Compared to the other conditions listed in Table 7, the microparticles prepared using a weight ratio of 80:20 and a concentration of 2.0% exhibited smaller particle size and a more spherical shape, and were therefore selected for subsequent physical property observations. Microparticle shape: The appearance of the microparticles (PLGA as the first pharmaceutically acceptable excipient) was observed under an electron microscope. The results are shown in Figure 6. Figure 6 shows that the microparticles 300 exhibit spherical shape. Compared to the irregular, clumpy shape of unspray-dried sildenafil 200 (see Figure 2), the shape of the microparticles 300 is relatively consistent. Particle size (D10, D50, and D90) was analyzed through three reproducible tests, and the results are summarized in Table 8. Table 8 During the process, it was observed that the particle size of the microparticles was less than 8 μm, which was smaller than that of avanafil that had not been spray-dried (the avanafil value was omitted in Table 8).

[0007] 2. Adding the second pharmaceutically acceptable excipient after spray drying: Add lactose with two particle sizes to a high shear mixer and mix with the microparticles obtained in step 1. (2). The microparticles use DPSC as the first pharmaceutically acceptable excipient, with a weight ratio of 80:20 and a concentration of 2%. The mixing ratio of the second pharmaceutically acceptable excipient (lactose) to the microparticles is 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 "Ava only" group, the "Ava + leucine" group, and the "Ava + 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 (CT) system at an airflow rate of 60 L / min. The "Ava only" group was prepared by direct spray drying of avanafil. The "Ava + Leucine" group was prepared by adding a first pharmaceutically acceptable excipient (leucine) before spray drying (using the preferred conditions in Table 1, with a weight ratio of avanafil to leucine of 20:80 and a mixture concentration of 2.0%). The "Ava + 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 (using similar preparation ratios as described in point 2 above). The results are shown in Figure 7 and Table 10 (data compiled from Figure 7). 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 deposition rate of particles in the lungs. Figure 7 (Aerosol Properties Comparison Graph 400) shows that, compared to the "Ava Only" group, the particles in the "Ava + Leucine" and "Ava + Leucine + Lactose" groups are less distributed in the early stages (e.g., from the capsule residue to the preseparator stage) (relatively short flight distances), while their distribution improves in subsequent stages, such as from S3 to S8, indicating that they can achieve relatively long flight distances. In other words, compared to the "Ava Only" group, the "Ava + Leucine" and "Ava + Leucine + Lactose" groups exhibit longer flight distances. Furthermore, compared to the "Ava + Leucine" group, the "Ava + Leucine + Lactose" group exhibits improved distribution of particles from S4 to S8 (requiring a relatively long flight distance). In other words, compared to the "Ava + Leucine" group, the "Ava + 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 "Ava only" group, the "Ava + Leucine" group and the "Ava + Leucine + Lactose" group showed higher FPF and smaller MMAD; compared with the "Ava + Leucine" group, the "Ava + Leucine + Lactose" group showed higher FPF and smaller MMAD. Therefore, Figure 7 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 avanafil. In other words, the above data demonstrate that, compared to microparticles prepared by direct spray drying, microparticles prepared by adding the first pharmaceutically acceptable excipient, or by adding both the first and second pharmaceutically acceptable excipients, achieve a higher distribution ratio in the lungs. Referring back to Figures 3A, 3B, 4, 5, and 6, and also to Figure 7 and Table 10, it should be emphasized that when avanafil is mixed with the first pharmaceutically acceptable excipient at least before spray drying, the shape of the resulting microparticles enables a longer flight distance and, upon administration, a higher distribution ratio in the lungs. Although this disclosure 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.

[0008]

Explanation of symbols

[0009] 100: Methods

[0010] S110, S120, S130, S140: Step 200: Avanafil

[0011] 300: Particles

[0012] 400: Comparison chart of aerosol properties.

Claims

Claims 1. A dry powder inhalation pharmaceutical composition, comprising: An active ingredient, wherein the active ingredient comprises avanafil 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, satin, leucine, isoleucine, phenylalanine, tryptophan, tyrosine, aspartic acid, histidine, asparagine, glutamic acid, lysine, amino acid, methionine, arginine, serine, 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, 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 50%.

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 avanafil 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 the spray drying of 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, further comprising mixing the particles with a flavoring agent.

Images