Dry powder inhalation type pharmaceutical composition and preparation method thereof
Through dry powder inhalation pharmaceutical composition, combined with avanafil and pharmaceutically acceptable excipients, microparticles are formed, which solves the problem of slow onset time for traditional oral administration of avanafil, and achieves the effect of rapid onset and efficient inhalation.
Patent Information
- Application Number
- CN202411541067.6
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Priority Date
- 2023-11-01
- Filing Date
- 2024-10-31
- Publication Date
- 2025-05-06
AI Technical Summary
The traditional oral administration of avanafil limits its onset time and cannot quickly achieve blood circulation.
Through the dry powder inhalation pharmaceutical composition, avanafil or its pharmaceutically acceptable salt is used as the active ingredient, combined with amino acids, glycans, phospholipids, polylactic acid, polylactic acid copolymers, etc. as pharmaceutically acceptable excipients, to form particles of 50 nanometers to 10 microns, improving the characteristics of the aerosol and onset time.
It achieves rapid onset of avanafil, improves its concentration in the blood and inhalation efficiency, and meets the needs of rapid onset of effect.
Smart Images
Figure CN119925314A_ABST
Abstract
Description
Technical Field
[0001] The present invention relates to a dry powder inhalation pharmaceutical composition and a preparation method thereof. Specifically, the present invention relates to a pharmaceutical composition comprising avanafil or a pharmaceutically acceptable salt thereof. Background Art
[0002] Avanafil (Ava), a phosphodiesterase type 5 (PDE5) inhibitor, is mainly used to treat male penile dysfunction (ED) and is one of the mainstream drugs for the treatment of ED. At present, Avanafil is traditionally administered orally. However, since Avanafil needs to be absorbed through the gastrointestinal tract before it can reach the blood circulation, oral administration limits the onset time.
[0003] Therefore, a problem to be solved is how to provide a dry powder inhalation-type pharmaceutical composition containing avanafil to increase the onset time of avanafil. Summary of the invention
[0004] In one aspect of the present invention, a dry powder inhalation 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.
[0005] 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 first pharmaceutically acceptable excipient is 1% to 99%.
[0006] 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% to 99%.
[0007] In some embodiments, the amino acids include glycine, alanine, valine, leucine, isoleucine, phenylalanine, tryptophan, tyrosine, aspartic acid, histidine, asparagine, glutamic acid, lysine, glutamate, methionine, arginine, serine, threonine, cysteine, proline, or a combination thereof.
[0008] 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 polysaccharide is 1% to 99%.
[0009] In some embodiments, the polysaccharide includes chitosan, chitosan salt, hyaluronic acid, or a combination thereof.
[0010] 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 phospholipid is 1% to 50%.
[0011] In some embodiments, the phospholipid comprises dipalmitoylphosphatidylcholine (DPPC), distearoyl phosphatidyl choline (DSPC), or a combination thereof.
[0012] 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 polylactic acid is 1% to 50%.
[0013] 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 polylactic acid copolymer is 1% to 50%.
[0014] In some embodiments, the polylactic acid copolymer comprises poly(lactic-co-glycolic acid) .
[0015] In some embodiments, the active ingredient and the first pharmaceutically acceptable excipient form microparticles having a particle size of 50 nanometers to 10 micrometers.
[0016] In some embodiments, the microparticles are in the shape of solid spheres, hollow spheres, solid polyhedrons, or a combination thereof.
[0017] In some embodiments, the pharmaceutical composition further includes a second pharmaceutically acceptable excipient that is different from the first pharmaceutically acceptable excipient.
[0018] In some embodiments, when the weight of the pharmaceutical composition is 100%, the total weight percentage of the active ingredient and the first pharmaceutically acceptable excipient is 0.005% to 30%, and the weight percentage of the second pharmaceutically acceptable excipient is 70% to 99.995%.
[0019] In some embodiments, the second pharmaceutically acceptable excipient comprises lactose, mannitol, or a combination thereof.
[0020] In another aspect of the present invention, a method for preparing a dry powder inhalable pharmaceutical composition is provided, 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 spray drying the mixed solution to form microparticles.
[0021] 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.
[0022] 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%.
[0023] 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.
[0024] In some embodiments, spray drying the mixed liquor is performed at an outlet temperature of 35°C to 110°C.
[0025] In some embodiments, the method further comprises mixing the microparticles with a second pharmaceutically acceptable excipient different from the first pharmaceutically acceptable excipient.
[0026] In some embodiments, the second pharmaceutically acceptable excipient comprises a first size population, a second size population, or a combination thereof, wherein the volume-based particle size distribution of the first size population is different from the volume-based particle size distribution of the second size population.
[0027] In some embodiments, the D50 particle size of the first size population is between 5 microns and 50 microns, and the D50 particle size of the second size population is between 30 microns and 125 microns.
[0028] In some embodiments, the method further comprises mixing the microparticles with a flavoring agent. BRIEF DESCRIPTION OF THE DRAWINGS
[0029] The above and other objects, features, advantages and embodiments of the present invention may be more fully understood by reading the following detailed description of the embodiments with reference to the accompanying drawings.
[0030] Figure 1 A flow chart is shown of a method for preparing a dry powder inhalable pharmaceutical composition according to some embodiments of the present invention.
[0031] Figure 2 Electron microscopy of avanafil before spray drying.
[0032] Figure 3A Electron microscopy of microparticles showing avanafil mixed with leucine before spray drying.
[0033] Figure 3B Electron microscopy shows microparticles in which avanafil was mixed with methionine before spray drying.
[0034] Figure 4 Electron microscopy of microparticles showing avanafil mixed with hyaluronic acid before spray drying.
[0035] Figure 5 Electron microscopy shows microparticles in which avanafil was mixed with distearoyl phosphatidyl choline (DSPC) before spray drying.
[0036] Figure 6 Electron microscopy shows microparticles in which avanafil was mixed with poly(lactic-co-glycolic acid, PLGA) before spray drying.
[0037] Figure 7 A graph comparing the aerosol properties of the “Ava only” group, the “Ava+leucine” group, and the “Ava+leucine+lactose” group detected using the Next Generation Impactor (NGI) is shown. DETAILED DESCRIPTION
[0038] In order to describe the present disclosure in detail and completely, the implementation and specific embodiments of the present invention are given by exemplary description, but these are not the only forms of implementing or using the specific embodiments of the present disclosure. The embodiments disclosed herein can be combined or replaced with each other in an advantageous manner, and other embodiments can be added to an embodiment without further description. In the following description, many specific details will be described in detail so that the reader fully understands the following embodiments. However, embodiments of the present invention can be put into practice without these specific details.
[0039] Although a series of operations or steps are described below to illustrate the method disclosed herein, the order of operations or steps should not be construed as limiting. For example, some operations or steps can be performed in different orders and / or performed simultaneously with other steps. In addition, not all operations, steps and / or features shown are necessary to realize embodiments of the present invention. In addition, each operation or step described herein may include multiple sub-steps or actions.
[0040] In this document, unless otherwise specified, "a", "an" and "the" may refer to a single or multiple. It should also be understood that "comprising", "including", "having" and similar terms in this document refer to the described features, regions, integers, steps, operations, components and / or components, but do not exclude other features, regions, integers, steps, operations, elements, components and / or groups.
[0041] As used herein, "drug" or "active ingredient" refers to avanafil or a pharmaceutically acceptable salt thereof, including but not limited to salts, esters, complexes, chelates, caged compounds, racemates, or mirror image isomers.
[0042] As used herein, "pharmaceutically acceptable excipient" refers to a pharmaceutical additive that has no pharmacological activity and has various uses and functions and is used in a pharmaceutical composition.
[0043] The main purpose of the present invention is to provide a dry powder inhalable pharmaceutical composition with a smaller particle size and a specific shape, thereby improving the aerosol property or aerodynamics (e.g., increasing the fine particle fraction (FPF)) of the pharmaceutical composition to meet the requirements of inhalation administration and reduce the onset time.
[0044] Please refer to Figure 1 , presenting a flow chart of a method 100 for preparing a dry powder inhalation pharmaceutical composition in some embodiments of the present invention, comprising step S110, step S120, step S130 and step S140. It should be emphasized that by mixing the first pharmaceutically acceptable excipient and avanafil in the mixed solution, and then spray-drying the mixed solution, the shape and particle size of the microparticles can be regulated (including but not limited to the shape being spherical or polyhedral, and the particle size of different batches being more consistent), thereby improving the aerosol properties and onset time of the microparticles.
[0045] First, referring to step S110 , an 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.
[0046] In some embodiments, the first solution includes a first organic solvent to more easily dissolve 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.
[0047] Referring to step S120 , a first pharmaceutically acceptable excipient is dissolved in a second solvent to form a second solution, wherein the first pharmaceutically acceptable excipient includes amino acids, polysaccharides, phospholipids, polylactic acid, polylactic acid copolymers or a combination thereof.
[0048] In some embodiments, the second solution includes a second organic solvent or water to dissolve the active ingredient more easily. In some embodiments, the second organic solvent includes ethanol, methanol, dichloromethane, ethyl acetate, acetonitrile, acetone, dimethyl sulfoxide or a combination thereof. In some embodiments, the second solution is the same as the first solution.
[0049] In some embodiments, the amino acid comprises glycine, alanine, valine, leucine, isoleucine, phenylalanine, tryptophan, tyrosine, aspartic acid, histidine, asparagine, glutamic acid, lysine, glutamic acid, methionine, arginine, serine, threonine, cysteine, proline or a combination thereof. In some embodiments, the polysaccharide comprises chitosan, chitosan salt, hyaluronic acid or a combination thereof. In some embodiments, the phospholipid comprises dipalmitoyl phosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC) or a combination thereof. In some embodiments, the polylactic acid copolymer comprises polylactic acid-glycolic acid (PLGA).
[0050] Referring to step S130 , the first solution and the second solution are mixed to form a mixed solution.
[0051] 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%, such as 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 uneven 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 content of the active ingredient contained in the microparticles after spray drying is limited. If the weight ratio is too high, the aerosol properties are weakened because the microparticles are difficult to be regulated by the first pharmaceutically acceptable excipient.
[0052] Please refer to step S140, spray drying the mixed liquid to form microparticles.
[0053] In some embodiments, the spray-dried mixture is performed at an outlet temperature of 35°C to 110°C, such as 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 between any intervals of the above 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 in a spherical or polyhedral shape, and tends to be irregular. If the outlet temperature is too high, the structure of the active ingredient or the pharmaceutically acceptable excipient may change, thereby affecting its function.
[0054] In some embodiments, the microparticles can be loaded into capsules, aluminum foil blister, and drug storage tank in a dry powder inhaler device for inhalation by an individual in need thereof.
[0055] In some embodiments, method 100 further comprises mixing the microparticles with a second pharmaceutically acceptable excipient different from the first pharmaceutically acceptable excipient. It is worth noting that the addition of the second pharmaceutically acceptable excipient improves the aerosol properties, extends the flight distance of the microparticles, and increases the distribution ratio of the microparticles in the lungs after inhalation administration.
[0056] In some embodiments, the second pharmaceutically acceptable excipient comprises lactose, mannitol, or a combination thereof.
[0057] In some embodiments, the second pharmaceutically acceptable excipient includes 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 microns to 50 microns (5 microns, 10 microns, 20 microns, 30 microns, 40 microns, 50 microns, or any value between any intervals of the above values), and the D50 particle size of the second size group is 30 microns to 125 microns (30 microns, 40 microns, 50 microns, 60 microns, 70 microns, 80 microns, 90 microns, 100 microns, 110 microns, 125 microns, or any value between any intervals of the above values).
[0058] In some embodiments, the weight ratio of the second pharmaceutically acceptable excipient to the microparticle is 70:30 to 99.995:0.005, such as 70:30, 80:20, 90:10, 99.995:0.005, or any value between any intervals of the above values. 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 of the aerosol properties is limited.
[0059] In some embodiments, method 100 further includes mixing the microparticles with a flavoring agent (e.g., menthol or a natural flavoring agent such as lemon, strawberry, orange, etc.), wherein the weight percentage of the flavoring agent is less than 1% (e.g., 0.1%, 0.5%, 1%, or any value between any intervals of the above values) to reduce the bitter taste during inhalation. In one embodiment, mixing the microparticles with a weight percentage of 1% of the flavoring agent has a better effect on reducing the bitter taste.
[0060] In some embodiments, a dry powder inhalation 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.
[0061] By using the first pharmaceutically acceptable excipient, the shape and particle size of the spray-dried pharmaceutical composition can be regulated to improve the aerosol properties of the pharmaceutical composition (including but not limited to a shape presenting a specific regular form such as a sphere or polyhedron, and a more consistent particle size in different batches).
[0062] In some embodiments, the viscosity of the first pharmaceutically acceptable excipient is less than 3 dL / g, for example, 0.1 dL / g to 3 dL / g. If the viscosity is too high, the first pharmaceutically acceptable excipient is difficult to spray dry, and the particle size of the microparticles is too large to meet the requirements of inhalation administration.
[0063] 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 active ingredient that can be provided by a specific unit of the pharmaceutical composition is limited. If the weight percentage of the active ingredient is too high or the weight percentage of the first pharmaceutically acceptable excipient is too low, the aerosol properties of the pharmaceutical composition are weakened.
[0064] In some embodiments, when the weight of the active ingredient and the first pharmaceutically acceptable excipient is 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 between any intervals of the above values). If the weight percentage of the amino acid is too high, the active ingredient that can be provided by a specific unit of the pharmaceutical composition is limited. If the weight percentage of the amino acid is too low, the aerosol properties of the pharmaceutical composition are weakened.
[0065] In some embodiments, when the weight of the active ingredient and the first pharmaceutically acceptable excipient is 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 between any intervals of the above values). If the weight percentage of the polysaccharide is too high, the active ingredient that can be provided by a specific unit of the pharmaceutical composition is limited. If the weight percentage of the polysaccharide is too low, the aerosol properties of the pharmaceutical composition are weakened.
[0066] In some embodiments, when the weight of the active ingredient and the first pharmaceutically acceptable excipient is 100%, the weight percentage of the phospholipid is 1% to 50% (e.g., 1%, 5%, 10%, 15%, 20%, 30%, 40%, 50% or any value between any intervals of the above values). If the weight percentage of the phospholipid is too high, the active ingredient that can be provided by a specific unit of the pharmaceutical composition is limited. If the weight percentage of the phospholipid is too low, the aerosol properties of the pharmaceutical composition are weakened.
[0067] In some embodiments, when the weight of the active ingredient and the first pharmaceutically acceptable excipient is 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 between any intervals of the above values). If the weight percentage of PLA is too high, the active ingredient that can be provided by a specific unit of the pharmaceutical composition is limited. If the weight percentage of PLA is too low, the aerosol properties of the pharmaceutical composition are weakened.
[0068] In some embodiments, when the weight of the active ingredient and the first pharmaceutically acceptable excipient is 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 between any intervals of the above values). If the weight percentage of the polylactic acid copolymer is too high, the active ingredient that can be provided by a specific unit of the pharmaceutical composition is limited. If the weight percentage of the polylactic acid copolymer is too low, the aerosol properties of the pharmaceutical composition are weakened.
[0069] In some embodiments, the active ingredient and the first pharmaceutically acceptable excipient form microparticles having a particle size of 50 nanometers to 10 micrometers, such as 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 between any intervals of the above values. It is worth noting that the particle size of the microparticles is smaller than the active ingredient that has not been spray dried. Therefore, the particle size requirement for inhalation into the lungs is met.
[0070] In some embodiments, the microparticles are in the shape of solid spheres, hollow spheres, solid polyhedrons, or a combination thereof. The shapes of these microparticles can increase the flight distance of the microparticles and increase the distribution ratio of the microparticles in the lungs when administered.
[0071] In some embodiments, the pharmaceutical composition further comprises a second pharmaceutically acceptable excipient different from the first pharmaceutically acceptable excipient, such as lactose, mannitol, or a combination thereof. The addition of the second pharmaceutically acceptable excipient can further increase the flight distance of the microparticles and increase the distribution ratio of the microparticles in the lungs when administered.
[0072] In some embodiments, when the weight of the pharmaceutical composition is 100%, the weight percentage of the second pharmaceutically acceptable excipient is 70% to 99.995%, such as 70%, 80%, 90%, 95%, 99.995% or any value between any intervals of the above values. If the weight percentage of the second pharmaceutically acceptable excipient is too high, the active ingredient that can be provided by a specific unit of the pharmaceutical composition is limited. If the weight percentage of the second pharmaceutically acceptable excipient is too low, the aerosol properties of the pharmaceutical composition are weakened. In some embodiments, when the weight of the pharmaceutical composition is 100% and when the pharmaceutical composition contains the second pharmaceutically acceptable excipient, the total weight percentage of the active ingredient and the first pharmaceutically acceptable excipient is 0.005% to 30% (e.g., 0.005%, 0.01%, 0.1%, 1%, 10%, 20%, 30% or any value between any intervals of the above 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 in between any intervals of the above values.
[0073] In some embodiments, the pharmaceutical composition further comprises a third pharmaceutically acceptable excipient for modulating specific properties, such as modulating aerodynamics or taste.
[0074] It should be understood that the above-mentioned embodiments and the following examples are provided for illustration rather than limitation. According to the description, it is clear to those skilled in the art that various changes and modifications can be made within the scope of the present invention.
[0075] In order to clarify the dry powder inhalation pharmaceutical composition and its preparation method, several examples and efficacy tests are provided in sequence below.
[0076] Example 1 - Preparation method and physical properties of dry powder inhalation pharmaceutical composition
[0077] 1. The first pharmaceutically acceptable excipient added before spray drying
[0078] (1) Amino Acids
[0079] Step a: Avanafil is dissolved in ethanol, and leucine or methionine is dissolved in water, respectively, and then the two (avanafil solution and amino acid solution) are mixed with each other according to the formula of Table 1.
[0080] Table 1
[0081]
[0082] Step b: spray drying the mixed solution obtained in step a at an outlet temperature of 80° C. to form microparticles.
[0083] Compared with other conditions in Table 1, the particles prepared by the weight ratio of 20:80 and the concentration of 2.0% have smaller particle size and more spherical shape, so they are selected for subsequent physical property observations.
[0084] The shape of particles
[0085] The appearance of avanafil or microparticles in different preparation steps was observed under an electron microscope. The results are shown in Figure 2 , Figure 3A as well as Figure 3B ,in Figure 2 The sildenafil in the mixture was observed before step b (without spray drying), Figure 3A as well as Figure 3B The particles in the sample are observed after the step (spray drying), Figure 3A It is a microparticle obtained by spray drying sildenafil and leucine. Figure 3B It is microparticles obtained by spray drying sildenafil and methionine.
[0086] Figure 2 The sildenafil 200 before step b (without spray drying) is in the shape of irregular blocks. Figure 3A (Leucine added) and Figure 3B (methionine added) presents the shape of microparticles 300 (after spray drying) as spheres or polyhedrons (such as golf ball shapes, i.e. solid polyhedrons with multiple grooves on the surface). Compared with sildenafil 200 ( Figure 2 ) of irregular blocks, particles 300( Figure 3A as well as Figure 3B ) are relatively consistent in shape.
[0087] Particle size
[0088] The particle sizes (D10, D50, and D90) of the microparticles were analyzed after three repeated tests, and the results are summarized in Table 2A (leucine added) and Table 2B (methionine added).
[0089] Table 2A (Leucine Addition)
[0090]
[0091] Note: D10 refers to the particle size corresponding to 10% cumulative frequency. D50 refers to the particle size corresponding to 50% cumulative frequency. D90 refers to the particle size corresponding to 90% cumulative frequency.
[0092] As can be seen from Table 2A, more than 90% of the microparticles have a particle size of less than 5 microns, and D50 is only 2 to 3 microns, which is smaller than avanafil that has not been spray-dried (the avanafil value is omitted in Table 2A).
[0093] Table 2B (methionine added)
[0094]
[0095] As can be seen from Table 2B, more than 90% of the microparticles have a particle size of less than 5 microns, and D50 is only 2 to 3 microns, which is smaller than avanafil that has not been spray-dried (the avanafil value is omitted in Table 2B).
[0096] (2) Polysaccharides
[0097] 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.
[0098] Table 3
[0099]
[0100] Step b: spray drying the mixed solution obtained in step a at an outlet temperature of 85° C. to form microparticles.
[0101] Compared with other conditions in Table 3, the microparticles prepared by the weight ratio of 50:50 and the concentration of 2.0% have smaller particle size, more spherical shape, and are more stable during storage. Therefore, the microparticles prepared by the weight ratio of 50:50 and the concentration of 2.0% were selected for subsequent physical property observations.
[0102] The shape of particles
[0103] 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 .
[0104] Figure 4 The particle 300 is spherical (e.g., a red blood cell) or polyhedral (e.g., a golf ball). Compared to the sildenafil 200 that has not been spray dried (see Figure 2 ) is an irregular block, while the shape of the particles 300 is relatively consistent.
[0105] Particle size
[0106] The particle sizes (D10, D50, and D90) of the microparticles were analyzed through three repeated tests, and the results are summarized in Table 4.
[0107] Table 4
[0108]
[0109] It can be observed during the process that the particle size of the microparticles is less than 8.0 μm, which is smaller than avanafil without spray drying (not shown in Table 4).
[0110] (3) Phospholipids
[0111] Avanafil and DPPC (molecular weight (Mw) = 744 g / mol), and avanafil and DPSC (Mw = 790 g / mol) were dissolved in ethanol, respectively, and then the two were mixed with each other according to the formula in Table 5.
[0112] Table 5
[0113]
[0114] Step b: spray drying the mixed solution obtained in step a at an outlet temperature of 70° C. to form microparticles.
[0115] Compared with other conditions in Table 5, the microparticles prepared by the weight ratio of 80:20 and the concentration of 2% have a smaller particle size and a more spherical shape, so they are selected for subsequent physical property observations.
[0116] The shape of particles
[0117] The appearance of the spray-dried microparticles (DPSC as the first pharmaceutically acceptable excipient) was observed under an electron microscope. Figure 5 .
[0118] Figure 5 The particle 300 is spherical or polyhedral (eg, golf ball-shaped). Compared with the sildenafil 200 that has not been spray dried (see Figure 2 ) is an irregular block, while the shape of the particles 300 is relatively consistent.
[0119] Particle size
[0120] The particle sizes (D10, D50, and D90) of the microparticles obtained by mixing avanafil and DSPC were analyzed through three repeated tests, and the results are summarized in Table 6.
[0121] Table 6 (Add DSPC)
[0122]
[0123] It can be observed during the process that the particle size of the microparticles is generally less than 7 microns, which is smaller than that of avanafil that has not been spray-dried (the avanafil value is omitted in Table 5).
[0124] (4) Polylactic acid or polylactic acid copolymer
[0125] Step a: Avanafil and polylactic acid-glycolic acid (PLGA) having a viscosity of 0.16 dL / g to 0.24 dL / g were dissolved in acetone respectively, and then the two were mixed with each other according to the formulation of Table 7.
[0126] Table 7
[0127]
[0128] Compared with other conditions in Table 7, the microparticles prepared by the weight ratio of 80:20 and the concentration of 2.0% have a smaller particle size and a more spherical shape, so they are selected for subsequent physical property observations.
[0129] The shape of particles
[0130] The appearance of the microparticles was observed under an electron microscope (PLGA was used as the first pharmaceutically acceptable excipient). Figure 6 .
[0131] Figure 6 The shape of the microparticles 300 is spherical. Compared with the sildenafil 200 (see Figure 2 ) is an irregular block, while the shape of the particles 300 is relatively consistent.
[0132] Particle size
[0133] The particle sizes (D10, D50, and D90) of the microparticles were analyzed through three repeated tests, and the results are summarized in Table 8.
[0134] Table 8
[0135]
[0136] It can be observed during the process that the particle size of the microparticles is less than 8 microns, which is smaller than that of avanafil that has not been spray-dried (the value of avanafil is omitted in Table 8).
[0137] 2. Add a second pharmaceutically acceptable excipient after spray drying
[0138] Lactose with two particle sizes was added to a high shear mixer and mixed with the microparticles obtained in step 1.(2). The microparticles used DPSC as the first pharmaceutically acceptable excipient, and the weight ratio was 80:20 and the concentration was 2%. The mixing ratio of the second pharmaceutically acceptable excipient (lactose) to the microparticles was obtained according to Table 9.
[0139] Table 9
[0140]
[0141] Aerosol properties
[0142] In order 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, microparticles of the "Ava only" group, the "Ava + leucine" group, and the "Ava + leucine + lactose" group were provided for detecting aerosol properties, and the aerosol properties were detected according to the Next Generation Impactor (NGI) (brand: Copley Scientific, equipment name: Model 170) in a cascade impaction (CI) at an airflow rate of 60 L / min. The "Ava only" group was prepared by directly spray-drying avanafil, the "Ava+Leucine" group was prepared by adding a first pharmaceutically acceptable excipient (leucine) before spray-drying (selecting the preferred conditions in Table 1, the weight ratio of avanafil to leucine was 20:80, and the concentration of the mixture was 2.0%), and the "Ava+Leucine+Lactose" group was prepared by adding a first pharmaceutically acceptable excipient (leucine) before spray-drying and adding a second pharmaceutically acceptable excipient (lactose) after spray-drying (the preparation ratio is similar to the above-mentioned point 2).
[0143] Please refer to the results Figure 7 And Table 10 (data compiled from Figure 7 ), the fine particle fraction (FPF) is the percentage of the cumulative deposition content of particles smaller than 5 microns to the total output particle content, reflecting the effective deposition rate of particles in the lungs.
[0144] Figure 7 The (aerogel properties comparison graph 400) shows that, relative to the "Ava only" group, the "Ava+Leucine" group and the "Ava+Leucine+Lactose" group have fewer particles distributed in the front layers (e.g., the residual layer of the capsule to the preseparator layer) (relatively shorter flight distance), and the distribution in the subsequent layers, such as the S3 layer to the S8 layer, indicates that a relatively longer flight distance can be achieved. That is, relative to the "Ava only" group, the "Ava+Leucine" group and the "Ava+Leucine+Lactose" group exhibited a longer flight distance.
[0145] In addition, compared with the "Ava+Leucine" group, it can be observed that the distribution of the particles in the "Ava+Leucine+Lactose" group is improved in the S4 to S8 stages (which require a relatively long flight distance). That is, compared with the "Ava+Leucine" group, the "Ava+Leucine+Lactose" group further exhibited a longer flight distance.
[0146] Table 10
[0147]
[0148] Note: MMAD is the mass median aerodynamic diameter.
[0149] Table 10 shows that the "Ava+Leucine" group and the "Ava+Leucine+Lactose" group showed higher FPF and smaller MMAD compared to the "Ava only" group; the "Ava+Leucine+Lactose" group showed higher FPF and smaller MMAD compared to the "Ava+Leucine" group.
[0150] therefore, Figure 7 And Table 10 reveals that the flight distances in these three groups are ranked (long to short) in the order of (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. That is, according to the above data, microparticles prepared by adding the first pharmaceutically acceptable excipient, or microparticles prepared by adding the first pharmaceutically acceptable excipient and the second pharmaceutically acceptable excipient, achieve a higher distribution ratio in the lungs relative to microparticles prepared by direct spray drying.
[0151] Next, please return to Figure 3A , Figure 3B , Figure 4 , Figure 5 as well as Figure 6 , and together Figure 7 As shown in Table 10, it should also be emphasized that when avanafil is mixed with a 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 of the microparticles in the lungs when administered.
[0152] Although the present invention has been described in detail with reference to certain embodiments, other embodiments are possible. Therefore, the spirit and scope of the appended claims should not be limited to the embodiments described herein.
[0153]
Explanation of symbols
[0154] 100: Methods
[0155] S110, S120, S130, S140: Step 200: Avanafil
[0156] 300: Particles
[0157] 400: Comparison chart of aerosol properties.
Claims
1. A dry powder inhalation pharmaceutical composition, characterized in that: include: An active ingredient, wherein the active ingredient comprises avanafil or a pharmaceutically acceptable salt thereof; as well as The first pharmaceutically acceptable excipient includes amino acids, polysaccharides, phospholipids, polylactic acid, polylactic acid copolymers 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 99%.
4. The pharmaceutical composition of claim 1, wherein the amino acid comprises glycine, alanine, valine, leucine, isoleucine, phenylalanine, tryptophan, tyrosine, aspartic acid, histidine, asparagine, glutamic acid, lysine, glutamine, 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 dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine or a combination thereof.
9. 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%.
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%. 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 of 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 of 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, characterized in that: include: 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 amino acids, polysaccharides, phospholipids, polylactic acid, polylactic acid copolymers 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 of claim 17, wherein the first solvent comprises a first organic solvent, and the second solvent comprises a second organic solvent, water, or a combination thereof.
19. The method according to claim 17, wherein when the weight of the mixed solution is 100%, the weight percentage of the active ingredient and the first pharmaceutically acceptable excipient is 0.5% to 3%.
20. The method according to claim 17, wherein the weight ratio of the active ingredient to the first pharmaceutically acceptable excipient in the mixed solution is 0.01:1 to 199:
1.
21. The method according to claim 17, wherein spray drying the mixed solution is performed at an outlet temperature of 35°C to 110°C.
22. The method according to claim 17, wherein: Also included is mixing the microparticles with a second pharmaceutically acceptable excipient that is different from the first pharmaceutically acceptable excipient.
23. The method of claim 22, wherein the second pharmaceutically acceptable excipient comprises a first size group, a second size group, or a combination thereof, wherein the volume-based particle size distribution of the first size group is different from the volume-based particle size distribution of the second size group.
24. The method of claim 23, wherein the D50 particle size of the first size group is 5 microns to 50 microns, and the D50 particle size of the second size group is 30 microns to 125 microns.
25. The method of claim 17, further comprising mixing the microparticles with a flavoring agent.