Dry-powder inhalable pharmaceutical composition and preparation method therefor

Abstract

Disclosed is a dry-powder inhalable pharmaceutical composition, comprising an active ingredient and a first pharmaceutically acceptable excipient. The active ingredient comprises sildenafil or a pharmaceutically acceptable salt thereof. The first pharmaceutically acceptable excipient comprises an amino acid, a phospholipid, polylactic acid, a polylactic acid copolymer, a sugar alcohol, or a combination thereof. Some embodiments of the present invention further provide a method for preparing the dry-powder inhalable pharmaceutical composition. The dry-powder inhalable pharmaceutical composition can improve the aerosol properties, meet the requirements of inhalation administration, and further reduce the onset time.

Description

[0001] FIELD OF THE INVENTION The present invention relates to a dry powder inhalation pharmaceutical composition and a method for preparing the same. Specifically, the present invention relates to a pharmaceutical composition comprising sildenafil or a pharmaceutically acceptable salt thereof. BACKGROUND Sildenafil (Sildenafil), 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, sildenafil is traditionally administered orally. However, because sildenafil 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 sildenafil to increase the onset of sildenafil'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 sildenafil or a pharmaceutically acceptable salt thereof. The first pharmaceutically acceptable excipient comprises an amino acid, a phospholipid, polylactic acid, a polylactic acid copolymer, a sugar alcohol, 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 100%, the weight percentage of the active ingredient is 1% to 99%, and the weight percentage of the amino acid is 1%. In some embodiments, the amino acid includes glycine, alanine, valine, leucine, isoleucine, phenylalanine, tryptophan, tyrosine, aspartic acid, histidine, asparagine, glutamic acid, lysine, leucine, 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 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 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 calculated 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 calculated 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) oIn 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 sugar alcohol is 1% to 50%. In some embodiments, the sugar alcohol comprises mannitol. In 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, elongated strips, 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 invention 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 sildenafil 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 phospholipid, polylactic acid, a poly(hydroxybenzoic acid) copolymer, a sugar alcohol, 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 agent. BRIEF DESCRIPTION OF THE DRAWINGS The above 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 image of sildenafil before spray drying. FIG3 shows an electron microscopic image of microparticles in which the sildenafil was mixed with leucine before spray drying. FIG4 shows an electron microscopic image of microparticles in which the sildenafil was mixed with distearoylphosphatidylcholine (DSPC) before spray drying. FIG5 shows the results of a dynamic moisture sorption test on a dry powder obtained by spray drying DSPC as the first pharmaceutically acceptable excipient and blending it with sildenafil at a weight ratio of 95:5. Figure 6 shows microparticles under an electron microscope, in which sildenafil was mixed with poly(lactic-co-glycolic acid, PLGA) before spray drying. Figure 7 shows microparticles under an electron microscope, in which sildenafil was mixed with mannitol before spray drying. Figure 8 compares the aerosol properties of the "Sil alone" group, the "Sil + leucine" group, and the "Sil + leucine + sucrose" 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 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 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 item or a plurality of items. 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 sildenafil or a pharmaceutically acceptable salt thereof, 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 are pharmacologically inactive and have various uses and functions used in pharmaceutical compositions. The primary objective of the present invention is to provide a dry powder inhalable pharmaceutical composition having a smaller particle size and a specific shape, thereby improving the aerosol properties (or aerodynamics, such as increasing the fine particle fraction (FPF)) of the pharmaceutical composition to meet the requirements of inhalation administration and reduce 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 invention is presented, comprising steps S110, S120, S130, and S140. It should be emphasized that By mixing a first pharmaceutically acceptable excipient with sildenafil 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 sildenafil 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 parathion, 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 phospholipid, polylactic acid, a polylactic acid copolymer, a sugar alcohol, or a combination thereof. In some embodiments, The first pharmaceutically acceptable excipient may also optionally include a polysaccharide. 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 comprises ethanol, methanol, dichloromethane, ethyl acetate, acetonitrile, acetone, dimethyl parathione, 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, fumaric acid, methionine, arginine, serine, threonine, cysteic acid, 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 includes dipalmitoyl phosphatidylcholine (DPPC), distearoyl phosphatidylcholine (DSPC), or a combination thereof. It is worth emphasizing that the use of DSPC as the first pharmaceutically acceptable excipient can also reduce crystallization and achieve better preservation effects. In some embodiments, the polylactic acid copolymer comprises polylactic acid-glycolic acid (PLGA). In some embodiments, the sugar alcohol comprises mannitol. 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, 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 above values.If the weight ratio is too low, the active ingredient content 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 mixture to form microparticles. In some embodiments, spray drying the 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 within 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 spray-dried particles will have difficulty maintaining a spherical shape. If the outlet temperature is too high, the structure of the active ingredient or pharmaceutically acceptable excipient may change, affecting its functionality. In some embodiments, the microparticles can be encapsulated in a capsule, aluminum foil blister, or drug storage tank within 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 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 group is 5 μm to 50 μm (5 μm, 10 μm, 20 μm, 30 μm, 40 μm, 50 μm, or any value between the above values), and the D50 particle size of the second size group is 30 μm to 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 the above values).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 within these ranges. If the weight ratio of the second pharmaceutically acceptable excipient is too high, the amount of 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 comprises mixing the microparticles with a flavoring (e.g., menthol or a natural flavoring 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 is more effective 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 includes sildenafil or a pharmaceutically acceptable salt thereof. The first pharmaceutically acceptable excipient includes an amino acid, a phospholipid, polylactic acid, a polylactic acid copolymer, a sugar alcohol, or a combination thereof (or optionally includes a polysaccharide). The use of the first pharmaceutically acceptable excipient can control the shape and particle size of the spray-dried pharmaceutical composition 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 deciliter / g, for example, 0.1 deciliter / g to 3 deciliter / 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 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 between any intervals of the above values), 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 between any intervals of the above values).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 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 amino acid 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 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 weakened. In some embodiments, the first pharmaceutically acceptable excipient may optionally include a polysaccharide. 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). 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 1% to 50% (e.g., 1%, 5%, 10%, 15%, 20%, 30%, 40%, 50%, or any value in between). 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 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 within these ranges). If the weight percentage of the polylactic acid copolymer is too high, the 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, when the weight of the active ingredient and the first pharmaceutically acceptable excipient is taken as 100%, the weight percentage of the sugar alcohol (mannitol) is 1% to 50% (e.g., 1%, 5%, 10%, 15%, 20%, 30%, 40%, 50%, or any value within these ranges). If the weight percentage of the sugar alcohol is too high, the active ingredient that can be provided per unit of the pharmaceutical composition is limited. If the weight percentage of the sugar alcohol is too low, the aerosol properties of the pharmaceutical composition may be 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 within these ranges. 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, elongated strips, or combinations thereof. These microparticle shapes can increase their flight distance and, upon administration, improve their distribution in the lungs. In some embodiments, the pharmaceutical composition further comprises a second pharmaceutically acceptable excipient different from the first pharmaceutically acceptable excipient, for example, sucrose, 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 99995%, for example, 70%, 80%, 90%, 95%, 99995%, 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 provided 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 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. Add the first pharmaceutically acceptable excipient (1) amino acid before spray drying Step a: Dissolve sildenafil in ethanol and leucine in water, respectively, and then mix the two 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 weight ratio of 95:5 and a concentration of 1.5% exhibited smaller particle size and a more spherical shape, and were therefore selected for subsequent physical property observations. The appearance of sildenafil or microparticles prepared at different steps was observed under an electron microscope. The results are shown in Figures 2 and 3 . The sildenafil 200 in Figure 2 was observed before step b (unspray-dried), while the microparticles 300 in Figure 3 were observed after step b (spray-dried). Figure 2 shows that the sildenafil 200 before step b (unspray-dried) had an irregular shape. Figure 3 shows that the microparticles 300 after spray drying (spray-dried) were smooth and spherical. The particle size was analyzed by three repetitive tests (DIO, D50, D90 and D100), and the results are summarized in Table 2. Table 2 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. D100 represents the particle size corresponding to the 100% cumulative frequency. As shown in Table 2, over 90% of the microparticles have a particle size less than 6 μm, while D50 is only 2 to 3 μm, smaller than that of unspray-dried sildenafil (sildenafil values ​​are omitted in Table 2). Active ingredient uniformity testing: 10 analyses of sildenafil content were performed on the spray-dried micropowder (prepared with a weight ratio of sildenafil to leucine of 88:12). The results showed an average weight percentage of the active ingredient in the micropowder of 81.08%, a coefficient of variation of 8.2%, and a standard deviation of 0.06672. That is, when sildenafil is combined with a first pharmaceutically acceptable excipient (leucine in this experiment) and prepared into a micronized powder, sildenafil can maintain good content uniformity.

[0003] (2) Phospholipid sildenafil and DPPC (molecular weight (Mw) = 744 g / mol), sildenafil and DPSC (Mw = 790 g / mol) were dissolved in ethanol, respectively. Then, the two were mixed with each other through a three-fluid nozzle according to the formulation in Table 3 and spray-dried at an outlet temperature of 90°C to form microparticles. Table 3 Compared to the other conditions listed in Table 3, the microparticles prepared using a weight ratio of 95:5 and a concentration of 2% 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 (DPSC as the first pharmaceutically acceptable excipient) was observed under an electron microscope. The results are shown in Figure 4. Figure 4 shows that the microparticles 300 exhibited spherical or polyhedral shapes (e.g., golf ball-shaped). The particle size of the microparticles obtained by mixing sildenafil and DPPC was analyzed using three reproducible tests.

[0004] (DIO, D50, D90 and D100), and the results are summarized in Table 4. Table 4 (addition of DPPC) The particle sizes (D10, D50, D90, and D100) of the mixed particles are summarized in Table 50 (with DSPC added). During the process, it was observed that the particle size of the microparticles was generally less than 5 microns, smaller than that of sildenafil without spray drying (sildenafil values ​​are omitted in Tables 4 and 5). The active ingredient uniformity test involved 10 sildenafil content analyses of the spray-dried micropowder (prepared with a 95:5 weight ratio of sildenafil to DSPC). The results showed an average weight percentage of the active ingredient in the micropowder of 98.08%, a coefficient of variation of 1.6%, and a standard deviation of 0.01582. This indicates that when sildenafil is prepared as a micropowder in combination with the first pharmaceutically acceptable excipient (DSPC in this experiment), good sildenafil content uniformity is maintained. To compare the storage stability of the microparticles under the aforementioned preparation conditions, dynamic moisture sorption testing was conducted using continuous gravimetric analysis. Under isothermal conditions, samples were exposed to a relative humidity environment created at atmospheric pressure. A balance automatically recorded the sample weight as a function of relative humidity and time, thereby studying the adsorption and desorption rates of moisture in the microparticles. The results are shown in Figure 5 (Result Graph 400). Figure 5 shows that the micropowders prepared using DSPC as the first pharmaceutically acceptable excipient and spray-dried with sildenafil (the weight ratio of sildenafil to DSPC during preparation was 95:5) exhibited excellent stability, with the microparticles only beginning to recrystallize at a relative humidity of 90%. Compared to microparticles prepared using existing dry powders or other first pharmaceutically acceptable excipients (which typically begin to recrystallize at 40%), the use of DSPC as the first pharmaceutically acceptable excipient reduced crystallization and exhibited better storage properties.

[0005] (3) Polylactic acid or polylactic acid copolymer Step a: Sildenafil and polylactic acid-glycolic acid (PLGA) with a viscosity of 0.16 dl / g to 0.24 dl / g were dissolved in acetone, and then the two were mixed with each other through a three-fluid nozzle according to the formulation of Table 6 and spray-dried at an outlet temperature of 90 °C to form microparticles. Table 6 Compared to the other conditions listed in Table 6, the microparticles prepared using a weight ratio of 95:5 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 exhibited spherical, hollow spherical, or polyhedral shapes (e.g., golf ball-shaped). Particle size: The particle size (D10, D50, D90, and D100) was analyzed through three repeated tests, and the results are summarized in Table 7. Table 7 During the process, it was observed that the particle size of the microparticles was less than 6 microns, smaller than that of sildenafil without spray drying (sildenafil values ​​are omitted in Table 7). The spray-dried micropowder (prepared with a weight ratio of sildenafil to PLGA of 95:5) was analyzed for sildenafil content 10 times. The results showed that the average weight percentage of the active ingredient in the micropowder was 96.2%, the coefficient of variation was 1.8%, and the standard deviation was 0.01725. This indicates that when sildenafil is combined with the first pharmaceutically acceptable excipient (PLGA in this experiment) to form a micropowder, sildenafil maintains good content uniformity.

[0006] (4) Sugar alcohol step a: Sildenafil is dissolved in ethanol, and mannitol is dissolved in water or 60% ethanol aqueous solution. Then the two are mixed with each other through a three-fluid nozzle according to the formula in Table 8, and spray-dried at an outlet temperature of 100°C to form microparticles. By selecting a three-fluid nozzle, the sildenafil solution and the mannitol solution can enter from different channels respectively, and then, with the assistance of gas flow, they are mixed into small, uniform jets inside the nozzle and then spray-dried. Compared with the existing two-fluid nozzle, when different solvents are used in the spray drying process, the selection of a three-fluid nozzle can better control the particle size and mixing uniformity. Table 8 Compared to the other conditions listed in Table 8, the microparticles prepared using a weight ratio of 90:10 and a concentration of 1.0% exhibited smaller particle size and more regular and uniform shape, and were therefore selected for subsequent physical property observations. Microparticle shape: The appearance of the microparticles was observed under an electron microscope (mannitol was used as the first pharmaceutically acceptable excipient). The results are shown in Figure 7. Figure 7 shows that the microparticles 300 exhibited spherical, polyhedral (e.g., golf ball or red blood cell) shapes, or long, dendritic shapes formed by the aggregation of several spheres. Particle size (D10, D50, D90, and D100) was analyzed through three repetitive tests, and the results are summarized in Table 9. Table 9 During the process, it was observed that the particle size of the microparticles was less than 6 microns, smaller than that of sildenafil before spray drying (sildenafil values ​​are omitted in Table 9). The active ingredient uniformity test involved 10 sildenafil content analyses of the spray-dried micropowder (prepared with a 90:10 weight ratio of sildenafil to mannitol). The results showed an average weight percentage of the active ingredient in the micropowder of 90%, a coefficient of variation of 5.8%, and a standard deviation of 0.05254. This indicates that when sildenafil is combined with the first pharmaceutically acceptable excipient (mannitol in this experiment) to form a micropowder, sildenafil maintains good content uniformity, and the weight percentage of the active ingredient in the finished micropowder is substantially consistent with the weight percentage before spray drying.

[0007] 2. Add 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, and the weight ratio and concentration are selected to be 95:5 and 2%. The mixing ratio of the second pharmaceutically acceptable excipient (lactose) and sildenafil is obtained according to Table 10. Table 10 Aerosol Properties To compare the aerosol properties of microparticles prepared by direct spray drying, adding the first pharmaceutically acceptable excipient before spray drying, or adding the first pharmaceutically acceptable excipient before spray drying and adding the second pharmaceutically acceptable excipient after spray drying, the "S11 only" group (sildenafil only),

[0008] The particles of the "S11+leucine" group and the "S11+leucine+lactose" group were provided for detecting the aerosol properties. The aerosol properties were determined based on the next generation impactor in the cascade impaction (CT)

[0009] Detection was performed using a Next Generation Impactor (NGI) (Manufacturer: Copley Scientific, Equipment Name: Model 170) at an airflow rate of 60 liters / minute. The "Sil Only" group was prepared by direct spray drying of sildenafil, the "S11 + Leucine" group was prepared by adding a first pharmaceutically acceptable excipient (leucine) before spray drying, and the "S11 + Leucine + Lactose" group was prepared by adding a first pharmaceutically acceptable excipient (leucine) before spray drying and a second pharmaceutically acceptable excipient (lactose) after spray drying. The results are shown in Figure 8 and Table 11 (data compiled from Figure 8). The fine particle fraction (FPF) is the percentage of the cumulative deposition of particles smaller than 5 microns to the total output particle content, reflecting the effective deposition rate of particles in the lungs. The results are presented in Figure 8 (Aerosol Characteristics Comparison Graph 500), where the layers from left to right represent flight distances from near to far. Figure 8 shows that compared to the "Sil Only" group, the "S11 + Leucine" group and the "S11 + Leucine + Lactose" group have fewer particles distributed in the early layers (e.g., from the capsule residue to the preseparator layer) (resulting in relatively shorter flight distances). However, the "SU + Leucine" group and the "S11 + Leucine + Lactose" group have an improved distribution of particles in the subsequent layers, such as layers S2 to S8, indicating a relatively longer flight distance. That is, compared to the "Sil alone" group, the "SU + Leucine" group and the "SU + Leucine + Lactose" group exhibited longer flight distances. Furthermore, compared to the "S11 + Leucine" group, it was observed that the distribution of particles in the "S11 + Leucine + Lactose" group was improved after the S6 stage (which requires a relatively long flight distance). That is, compared to the "S11 + Leucine" group, the "S11 + Leucine + Lactose" group exhibited a further longer flight distance. Table 11 Table 11 shows that compared with the "Sil only" group, the "S11+leucine" group and the "S11+leucine+lactose" group exhibited higher FPF and smaller MMAD; compared with the "SU+leucine" group, the "SU+leucine+lactose" group exhibited higher FPF and smaller MMADo. Therefore, Figure 8 and Table 11 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 sildenafil. 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 pharmaceutically acceptable excipient and the second pharmaceutically acceptable excipient, achieve a higher distribution ratio in the lungs. Referring back to Figures 3, 4, 6, and 7, and also to Figure 8 and Table 11, it should be emphasized that when sildenafil 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.

[0010]

Explanation of symbols

[0011] 100: Methods

[0012] S110, S120, S130, S140: Steps

[0013] 200: Sildenafil

[0014] 300: Particles

[0015] 400: Result graph

[0016] 500: Comparison chart of aerosol properties.

Claims

Claims 1. A dry powder inhalation pharmaceutical composition, comprising: An active ingredient, wherein the active ingredient comprises sildenafil or a pharmaceutically acceptable salt thereof; and a first pharmaceutically acceptable excipient, comprising cynamic acid, phospholipid, polylactic acid, polylactic acid copolymer, sugar alcohol or a combination 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 50%.

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, tathione, 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 phospholipid is 1% to 50%.

6. The pharmaceutical composition according to claim 1, wherein the phospholipid comprises disalmitoylphosphatidylcholine, distearoylphosphatidylcholine 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 polylactic acid is 1% to 50%.

8. 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 poly(hedral oligomer) copolymer is 1% to 50%.

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

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 sugar alcohol is 1% to 50%.

11. The pharmaceutical composition according to claim 1, wherein the sugar alcohol comprises mannitol.

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, elongated strips 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 sildenafil 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, a sugar alcohol or a combination thereof; The first solution and the second solution are mixed to form a mixed solution; and the mixed solution 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:

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.

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