Dry powder inhalation type pharmaceutical composition and preparation method thereof

Abstract

A dry powder inhalation type pharmaceutical composition comprises an active ingredient and a first pharmaceutically acceptable excipient. The active component comprises vardenafil or a pharmaceutically acceptable salt thereof. The first pharmaceutically acceptable excipient comprises amino acid, glycan, phospholipid, polylactic acid, polylactic acid copolymer or a combination thereof. Some embodiments of the present invention also provide methods of preparing dry powder inhalation pharmaceutical compositions. The dry powder inhalation type pharmaceutical composition can improve the aerogel characteristic, meets the inhalation administration requirement, and further reduces the onset time.

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 vardenafil or a pharmaceutically acceptable salt thereof. Background Art

[0002] Vardenafil (Var), 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. Currently, vardenafil is traditionally administered orally. However, since vardenafil needs to be absorbed through the gastrointestinal tract before reaching 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 vardenafil to increase the onset time of vardenafil. 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 vardenafil 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 amino acid is 1% to 50%.

[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 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 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 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 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 6 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 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 inhalation pharmaceutical composition is provided, comprising: dissolving an active ingredient in a first solvent to form a first solution, wherein the active ingredient includes vardenafil 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, in the step of spray-drying the mixed solution, the ultrasonic atomization percentage of the mixed solution is 25% to 85%.

[0026] In some embodiments, the method further comprises mixing the microparticles with a second pharmaceutically acceptable excipient different from the first pharmaceutically acceptable excipient.

[0027] 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.

[0028] 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.

[0029] In some embodiments, the method further comprises mixing the microparticles with a flavoring agent. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] 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.

[0031] Figure 1A flow chart is shown of a method for preparing a dry powder inhalable pharmaceutical composition according to some embodiments of the present invention.

[0032] Figure 2A as well as Figure 2B The non-spray-dried vardenafil and microparticles are shown under electron microscope. Figure 2B The vardenafil in the mixture was mixed with leucine before spray drying.

[0033] Figure 3 An electron microscope view of microparticles showing vardenafil mixed with hyaluronic acid prior to spray drying.

[0034] Figure 4A as well as Figure 4B Particles are shown under an electron microscope. Figure 4A The vardenafil was mixed with dipalmitoyl phosphatidylcholine (DPPC) before spray drying. Figure 4B The vardenafil was mixed with distearoyl phosphatidyl choline (DSPC) before spray drying.

[0035] Figure 5 An electron microscopic view of microparticles in which vardenafil was mixed with poly(lactic-co-glycolic acid, PLGA) before spray drying is shown.

[0036] Figure 6 The aerosol properties of the “Var only” group, the “Var+DSPC” group, and the “Var+DSPC+Lac” group detected using the Next Generation Impactor (NGI) are shown. DETAILED DESCRIPTION

[0037] In order to describe the present invention 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 specific embodiments of the present invention. The embodiments disclosed by the present invention 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.

[0038] Although a series of operations or steps are described below to illustrate the method disclosed by the present invention, the order of operations or steps should not be interpreted as limitation. 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 in the present invention may include multiple sub-steps or actions.

[0039] In the present invention, unless otherwise specified herein, "a", "an" and "the" may represent a single or multiple. It should also be understood that "comprising", "including", "having" and similar terms in the present invention represent 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.

[0040] In the present invention, "drug" or "active ingredient" refers to vardenafil or its pharmaceutically acceptable salt, including but not limited to salts, esters, complexes, chelates, caged compounds, racemates, or mirror image isomers.

[0041] In the present invention, "pharmaceutically acceptable excipient" refers to a pharmaceutical additive that has no pharmacological activity and has different uses and functions and is used in a pharmaceutical composition.

[0042] 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.

[0043] 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 vardenafil 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.

[0044] First, referring to step S110 , an active ingredient is dissolved in a first solvent to form a first solution, wherein the active ingredient includes vardenafil or a pharmaceutically acceptable salt thereof.

[0045] 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.

[0046] 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.

[0047] 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.

[0048] 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).

[0049] Referring to step S130 , the first solution and the second solution are mixed to form a mixed solution.

[0050] 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.

[0051] Please refer to step S140, spray drying the mixed liquid to form microparticles.

[0052] In some embodiments, the spray drying of the mixed solution 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 shape. If the outlet temperature is too high, the structure of the active ingredient or pharmaceutically acceptable excipient may change, affecting its function. In some embodiments, in the step of spray drying the mixed solution, the ultrasonic atomization percentage of the mixed solution is 25% to 85%, such as 25%, 40%, 55%, 70%, 85% or any value between any intervals of the above values.

[0053] 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.

[0054] 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.

[0055] In some embodiments, the second pharmaceutically acceptable excipient comprises lactose, mannitol, or a combination thereof.

[0056] 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).

[0057] 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.

[0058] In some embodiments, method 100 further comprises 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.

[0059] 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 vardenafil 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.

[0060] 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 spherical or polyhedral shape, and more consistent particle sizes in different batches).

[0061] 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.

[0062] 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.

[0063] 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 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 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.

[0064] 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.

[0065] 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.

[0066] 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.

[0067] 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.

[0068] In some embodiments, the active ingredient and the first pharmaceutically acceptable excipient form microparticles having a particle size of 50 nanometers to 6 micrometers, such as 50 nanometers, 100 nanometers, 500 nanometers, 1 micrometer, 2 micrometers, 3 micrometers, 4 micrometers, 5 micrometers, 6 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.

[0069] 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.

[0070] 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.

[0071] 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 a second pharmaceutically acceptable excipient, the weight percentage of the active ingredient and the second 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.

[0072] In some embodiments, the pharmaceutical composition further comprises a third pharmaceutically acceptable excipient for modulating specific properties, such as modulating aerodynamics or taste.

[0073] 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.

[0074] In order to clarify the dry powder inhalation pharmaceutical composition and its preparation method, several examples and efficacy tests are provided in sequence below.

[0075] Example 1 - Preparation method and physical properties of dry powder inhalation pharmaceutical composition

[0076] 1. The first pharmaceutically acceptable excipient added before spray drying

[0077] (1) Amino Acids

[0078] Step a: vardenafil is dissolved in ethanol and leucine is dissolved in water respectively, and then the two are mixed with each other according to the formula of Table 1.

[0079] Table 1

[0080]

[0081] Step b: spray drying the mixed solution obtained in step a at an outlet temperature of 80° C. and an atomization ratio of 65% to form microparticles.

[0082] Compared with other conditions in Table 1, the particles prepared by the weight ratio of 95:5 and the concentration of 1.5% have smaller particle size and more spherical shape, so they are selected for subsequent physical property observations.

[0083] The shape of particles

[0084] The appearance of vardenafil or microparticles in different preparation steps was observed under an electron microscope. The results are shown in Figure 2A as well as Figure 2B ,in Figure 2A The vardenafil in the step is observed before step b (without spray drying), Figure 2B The microparticles in are observed after step b (spray drying).

[0085] Figure 2A The shape of vardenafil before step b (without spray drying) is irregular. Figure 2B The particle shape (after spray drying) is spherical or polyhedral (for example, golf ball shape, i.e., a solid polyhedron with a plurality of grooves on the surface).

[0086] Particle size

[0087] The particle sizes (D10, D50, D90 and D100) of the microparticles were analyzed through three repeated tests, and the results are summarized in Table 2.

[0088] Table 2

[0089]

[0090] 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. D100 refers to the particle size corresponding to 100% cumulative frequency.

[0091] It can be observed during the process that the particle size of the microparticles is generally less than 5 μm, which is smaller than that of vardenafil that has not been spray-dried (not shown in Table 2).

[0092] (2) Phospholipids

[0093] Step a: Vardenafil is dissolved in ethanol, and hyaluronic acid is dissolved in water, and then the two are mixed with each other according to the formula of Table 3.

[0094] Table 3

[0095]

[0096] Step b: spray drying the mixed solution obtained in step a at an outlet temperature of 85° C. and an atomization ratio of 65% to form microparticles.

[0097] Compared with other conditions in Table 3, the microparticles prepared by the weight ratio of 99:1 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 99:1 and the concentration of 2.0% were selected for subsequent physical property observations.

[0098] The shape of particles

[0099] The appearance of the particles was observed under an electron microscope (hyaluronic acid was used as a pharmaceutically acceptable excipient). The results are shown in Figure 3 .

[0100] Figure 3 The microparticles are spherical (eg, red blood cells) or polyhedral (eg, golf balls).

[0101] Particle size

[0102] The particle sizes (D10, D50, and D90) of the microparticles were analyzed through three repeated tests, and the results are summarized in Table 4.

[0103] Table 4

[0104]

[0105] It can be observed during the process that the particle size of the microparticles is less than 5.0 μm, which is smaller than that of vardenafil that has not been spray-dried (not shown in Table 4).

[0106] (3) Phospholipids

[0107] Step a: Vardenafil and DPPC (molecular weight (Mw) = 744 g / mol), and Vardenafil 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.

[0108] Table 5

[0109]

[0110] Step b: spray drying the mixed solution obtained in step a at an outlet temperature of 70° C. and an atomization ratio of 65% to form microparticles.

[0111] Compared with other conditions in Table 5, the microparticles prepared by the weight ratio of 95:5 and the concentration of 2% have a smaller particle size and a more spherical shape, so they are selected for subsequent physical property observations.

[0112] The shape of particles

[0113] The appearance of the spray-dried microparticles (DPPC or DPSC as the first pharmaceutically acceptable excipient) was observed under an electron microscope. Figure 4A as well as Figure 4B . Figure 4A as well as Figure 4B In the form of particles, Figure 4A The vardenafil was mixed with DPPC before spray drying. Figure 4B The vardenafil was mixed with DSPC before spray drying.

[0114] Figure 4A as well as Figure 4B The shape of the particles is spherical or polyhedral (eg, golf ball shape).

[0115] Particle size

[0116] The particle sizes (D10, D50, D90, and D100) of the microparticles obtained by mixing vardenafil with DPPC were analyzed through three repeated tests, and the results are summarized in Table 6.

[0117] Table 6 (add DPPC)

[0118]

[0119] The particle sizes (D10, D50, D90, and D100) of microparticles obtained by mixing vardenafil with DSPC are summarized in Table 7 (DSPC).

[0120] Table 7 (Add DSPC)

[0121]

[0122] It can be observed during the process that the particle size of the microparticles is generally less than 5 μm, which is smaller than that of vardenafil that has not been spray-dried (not shown in Tables 6 and 7).

[0123] (4) Polylactic acid or polylactic acid copolymer

[0124] Step a: Vardenafil and polylactic acid-glycolic acid (PLGA) having a viscosity of 0.16 dL / g to 0.24 dL / g were dissolved in ethanol respectively, and then the two were mixed with each other according to the formulation of Table 8.

[0125] Table 8

[0126]

[0127] Step b: spray drying the mixed solution obtained in step a at an outlet temperature of 45° C. and an atomization ratio of 65% to form microparticles.

[0128] Compared with other conditions in Table 8, the microparticles prepared by the weight ratio of 90:10 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 5 .

[0131] Figure 5 The shape of the particles is spherical or polyhedral (eg, golf ball shape).

[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 9.

[0134] Table 9

[0135]

[0136] It can be observed during the process that the particle size of the microparticles is less than 5 μm, which is smaller than that of vardenafil that has not been spray-dried (not shown in Table 9).

[0137] 2. Add a second pharmaceutically acceptable excipient after spray drying

[0138] Lactose or mannitol

[0139] Lactose or mannitol with two particle sizes is added to a high shear mixer and mixed with the microparticles obtained in point 1. (3). 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 or mannitol) and vardenafil is obtained according to Table 10 (lactose) or Table 11 (mannitol).

[0140] Table 10

[0141]

[0142] Table 11

[0143]

[0144] Aerosol properties

[0145] In order to compare the aerosol properties of microparticles prepared by direct spray drying, adding a first pharmaceutically acceptable excipient before spray drying, or adding a first pharmaceutically acceptable excipient before spray drying and adding a second pharmaceutically acceptable excipient after spray drying, microparticles of the "Var only" group, the "Var+DSPC" group, and the "Var+DSPC+Lac" 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 "Var only" group was prepared by direct spray drying of vardenafil, the "Var+DSPC" group was prepared by adding the first pharmaceutically acceptable excipient (DSPC) before spray drying, and the "Var+DSPC+Lac" group was prepared by adding the first pharmaceutically acceptable excipient (DSPC) before spray drying and the second pharmaceutically acceptable excipient (lactose) after spray drying.

[0146] Please refer to the results Figure 6 And Table 12 (data compiled from Figure 6 ), 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.

[0147] Figure 6 It is shown that, compared with the "Var only" group, the particles of the "Var+DSPC" group and the "Var+DSPC+Lac" group are less distributed in the induction port (IP) stage and the preseparator stage (relatively short flight distance), while the particles of the "Var+DSPC" group and the "Var+DSPC+Lac" group are distributed more in the subsequent stages, such as the S3 stage to the S8 stage, indicating that a relatively long flight distance can be achieved. That is, compared with the "Var only" group, the "Var+DSPC" group and the "Var+DSPC+Lac" group have a longer flight distance.

[0148] In addition, compared with the "Var+DSPC" group, it can be observed that the distribution of particles in the "Var+DSPC+Lac" group is improved in the S4 to S8 order (which requires a relatively long flight distance). That is, compared with the "Var+DSPC" group, the "Var+DSPC+Lac" group further exhibited a longer flight distance.

[0149] Table 12

[0150]

[0151] Note: MMAD is the mass median aerodynamic diameter.

[0152] Table 12 shows that the "Var+DSPC" group and the "Var+DSPC+Lac" group showed higher FPF and smaller MMAD compared with the "Var only" group; the "Var+DSPC+Lac" group showed higher FPF and smaller MMAD compared with the "Var+DSPC" group.

[0153] therefore, Figure 6 And Table 12 reveals that the flight distances in the 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 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 vardenafil. 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.

[0154] Next, please return to Figure 2B , Figure 3 , Figure 4B as well as Figure 5 , and together Figure 6 As shown in Table 12, it should also be emphasized that when vardenafil is mixed with a first pharmaceutically acceptable excipient at least before spray drying, the shape of the obtained microparticles can achieve a longer flight distance and a higher distribution ratio of the microparticles in the lungs when administered.

[0155] Example 2 - Animal Experiment for Comparative Test

[0156] In order to observe the absorption efficiency, Sprague-Dawley rats (SD rats) and dogs were selected as experimental animals. The grouping of the animal experiments was based on Table 13, wherein the microparticles of the "Var+Leu" group were obtained from point 1(1) of Example 1 (weight ratio of 95:5 and concentration of 1.5%), the microparticles of the "Var+PLGA" group were obtained from point 1(4) of Example 1 (weight ratio of 90:10 and concentration of 2%), and the microparticles of the "Var+DSPC" group were obtained from point 1(3) of Example 1 (weight ratio of 95:5 and concentration of 2%).

[0157] Table 13

[0158]

[0159] The specific process of the SD rat group is described below. First, 0.2 ml / rat to 0.3 ml / rat blood samples were collected from the submandibular vein or anterior vena cava of rats in each group before administration and 2 minutes (0.033 hours), 5 minutes (0.083 hours), 10 minutes (0.167 hours), 15 minutes (0.25 hours), 1 hour, 3 hours, 5 hours, 8 hours and 24 hours after administration. The blood samples of each group were mixed with heparin sodium for anticoagulation (at least 40 U of heparin sodium was used to anticoagulate 1 ml of blood). The anticoagulated blood was then centrifuged at 2000 x g for 10 minutes at 4°C, and the centrifuged plasma was collected, and then the centrifuged plasma was transferred to a new tube for analysis or stored at -30°C until analysis.

[0160] The specific procedure of the dog group was basically similar to that of the SD rat group, wherein the main differences between the dog group and the SD rat group were that the blood sample collected from the dog each time was 1 ml / dog, and the dose of the dog group was 0.12 mg vardenafil / kg dog.

[0161] Next, the pharmacokinetic parameters of vardenafil in the blood samples were analyzed and summarized in Tables 14 and 15.

[0162] Table 14

[0163]

[0164] Note 1: t1 / 2 is the half-life of vardenafil in the blood

[0165] Note 2: Cmax is the maximum plasma concentration, and Tmax is the time to reach Cmax.

[0166] Note 3: AUC(0-t) is the area under the concentration-time curve from time zero to time t, where time t represents the last time point at which the concentration in the blood can be measured.

[0167] Note 4: MRT(0-t) is the average residence time of vardenafil in the body.

[0168] Table 14 shows that the test group (Var+Leu), the test group (Var+PLGA), and the test group (Var+DSPC) have shorter Tmax (about 5 minutes to 15 minutes) compared to the original drug (oral (Var)) group (Tmax is 0.85 hours), indicating that less time is required to reach Cmax. That is, the onset time of the test group (inhalation) is faster than that of the original drug group (oral (Var)) (oral administration via gavage).

[0169] In addition, compared with the original drug group (oral (Var)), the test group (Var+Leu), the test group (Var+PLGA), and the test group (Var+DSPC) used a lower required dosage (the dosage of the test group was 1 / 3 of that of the original drug group (oral (Var))), which showed a higher AUC, indicating that the test group can be more easily absorbed and has a better absorption efficiency.

[0170] Table 15

[0171]

[0172] Table 15 shows that after oral administration, the concentration of the active ingredient in the original drug group (oral (Var)) increased significantly until 0.5 hour to 1 hour (about 30 minutes to 60 minutes), but the concentration of each test group increased significantly within 0.033 hours (about 2 minutes) after inhalation, indicating that the test group has a faster onset time.

[0173] 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.

[0174]

Explanation of symbols

[0175] 100: Methods

[0176] S110, S120, S130, S140: steps.

Claims

1. A dry powder inhalation pharmaceutical composition, characterized in that: include: An active ingredient, wherein the active ingredient comprises vardenafil 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 amino acid is 1% to 50%.

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 calculated as 100%, 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 calculated as 100%, 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 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 calculated as 100%, 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 6 micrometers.

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

14. The pharmaceutical composition according to claim 1, wherein Also included is a second pharmaceutically acceptable excipient that is different from the first pharmaceutically acceptable excipient.

15. The pharmaceutical composition according to claim 14, wherein when the weight of the pharmaceutical composition is 100%, the 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 vardenafil 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 in the step of spray drying the mixed solution, the ultrasonic atomization percentage of the mixed solution is 25% to 85%.

23. 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.

24. The method of claim 23, wherein 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.

25. The method of claim 24, 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.

26. The method of claim 17, wherein: Also included is mixing the microparticles with a flavoring agent.

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