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 sildenafil or a pharmaceutically acceptable salt thereof. The first pharmaceutically acceptable excipient comprises amino acid, phospholipid, polylactic acid, polylactic acid copolymer, sugar alcohol 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 sildenafil or a pharmaceutically acceptable salt thereof. Background Art

[0002] Sildenafil (Sil), 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, sildenafil is traditionally administered orally. However, since sildenafil 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 sildenafil to increase the onset time of sildenafil. 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 sildenafil or a pharmaceutically acceptable salt thereof. The first pharmaceutically acceptable excipient comprises an amino acid, a phospholipid, polylactic acid, a polylactic acid copolymer, a sugar alcohol or a combination thereof.

[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 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 active ingredient is 1% to 99%, and the weight percentage of the phospholipid is 1% to 50%.

[0009] In some embodiments, the phospholipid comprises dipalmitoylphosphatidylcholine (DPPC), distearoyl phosphatidyl choline (DSPC), 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 polylactic acid is 1% to 50%.

[0011] 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%.

[0012] In some embodiments, the polylactic acid copolymer comprises poly(lactic-co-glycolic acid) .

[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 sugar alcohol is 1% to 50%.

[0014] In some embodiments, the sugar alcohol comprises mannitol.

[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, elongated strips, 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 inhalation pharmaceutical composition is provided, comprising: dissolving an active ingredient in a first solvent to form a first solution, wherein the active ingredient includes sildenafil or a pharmaceutically acceptable salt thereof; dissolving a first pharmaceutically acceptable excipient in a second solvent to form a second solution, wherein the first pharmaceutically acceptable excipient includes an amino acid, a phospholipid, polylactic acid, a polylactic acid copolymer, a sugar alcohol or a combination thereof; mixing the first solution and the second solution to form a mixed solution; and spray drying the mixed solution to form microparticles.

[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 microscopic view of non-spray-dried sildenafil.

[0032] Figure 3 Electron microscopy of microparticles in which sildenafil was mixed with leucine before spray drying.

[0033] Figure 4 Electron microscopy of microparticles in which sildenafil was mixed with distearoyl phosphatidyl choline (DSPC) before spray drying.

[0034] Figure 5 The result graph of the dynamic moisture adsorption test on the dry powder is presented, wherein the micro powder is obtained by spray drying by using DSPC as the first pharmaceutically acceptable excipient and blending it with sildenafil in a weight ratio of 95:5.

[0035] Figure 6 Electron microscopy shows microparticles in which sildenafil was mixed with poly(lactic-co-glycolic acid, PLGA) before spray drying.

[0036] Figure 7 Electron microscopy shows microparticles in which sildenafil was mixed with mannitol before spray drying.

[0037] Figure 8 A graph comparing the aerosol properties of the “Sil only” group, the “Sil+leucine” group, and the “Sil+leucine+lactose” group detected using the Next Generation Impactor (NGI) is presented. DETAILED DESCRIPTION

[0038] In order to describe the present invention in detail and completely, the implementation and specific embodiments of the present invention are given with exemplary descriptions, but these are not the only forms of implementing or using specific embodiments of the present invention. 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, elements 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 sildenafil 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 sildenafil 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 sildenafil 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] Please refer to step S120, dissolving the first pharmaceutically acceptable excipient in the second solvent to form a second solution, wherein the first pharmaceutically acceptable excipient includes amino acids, phospholipids, polylactic acid, polylactic acid copolymers, sugar alcohols or combinations thereof. In some embodiments, the first pharmaceutically acceptable excipient may also include polysaccharides.

[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. It is worth emphasizing that the use of DSPC as the first pharmaceutically acceptable excipient can also reduce the crystallization situation and achieve a better preservation effect. In some embodiments, the polylactic acid copolymer comprises polylactic-co-glycolic acid (PLGA). In some embodiments, the sugar alcohol comprises mannitol.

[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 shape. 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 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.

[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 sildenafil or a pharmaceutically acceptable salt thereof. The first pharmaceutically acceptable excipient comprises an amino acid, a phospholipid, polylactic acid, a polylactic acid copolymer, a sugar alcohol or a combination thereof (or optionally comprising a polysaccharide).

[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 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.

[0065] In some embodiments, the first pharmaceutically acceptable excipient may optionally include polysaccharides, and when the weight of the active ingredient and the first pharmaceutically acceptable excipient is 100%, the weight percentage of the polysaccharides 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 polysaccharides 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 polysaccharides 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, when the weight of the active ingredient and the first pharmaceutically acceptable excipient is 100%, the weight percentage of the sugar alcohol (mannitol) is 1% to 50% (e.g., 1%, 5%, 10%, 15%, 20%, 30%, 40%, 50% or any value between any intervals of the above values). If the weight percentage of the sugar alcohol 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 sugar alcohol is too low, the aerosol properties of the pharmaceutical composition are weakened.

[0070] 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.

[0071] In some embodiments, the microparticles are in the shape of solid spheres, hollow spheres, solid polyhedrons, elongated strips, or a combination thereof. These microparticle shapes can increase the flight distance of the microparticles and increase the distribution ratio of the microparticles in the lungs during administration.

[0072] 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.

[0073] 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.

[0074] In some embodiments, the pharmaceutical composition further comprises a third pharmaceutically acceptable excipient for modulating specific properties, such as modulating aerodynamics or taste.

[0075] 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.

[0076] In order to clarify the dry powder inhalation pharmaceutical composition and its preparation method, several examples and efficacy tests are provided in sequence below.

[0077] Example 1 - Preparation method and physical properties of dry powder inhalation pharmaceutical composition

[0078] 1. The first pharmaceutically acceptable excipient added before spray drying

[0079] (1) Amino Acids

[0080] Step a: Sildenafil 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.

[0081] Table 1

[0082]

[0083] Step b: spray drying the mixed solution obtained in step a at an outlet temperature of 100° C. to form microparticles.

[0084] 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 it is selected for subsequent physical property observation.

[0085] The shape of particles

[0086] The appearance of sildenafil or microparticles in different preparation steps was observed under an electron microscope. The results are shown in Figure 2 as well as Figure 3 ,in Figure 2 The sildenafil 200 in the step was observed before step b (without spray drying), Figure 3 The microparticles 300 in FIG. 1 are observed after step b (after spray drying).

[0087] Figure 2 The shape of sildenafil 200 before step b (without spray drying) is irregular. Figure 3 The shape of the spray-dried microparticles 300 (after spray drying) is a smooth spherical shape.

[0088] Particle size

[0089] 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.

[0090] Table 2

[0091]

[0092] 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.

[0093] As can be seen from Table 2, more than 90% of the microparticles have a particle size of less than 6 μm, and D50 is only 2 to 3 μm, which is smaller than sildenafil that has not been spray-dried (the sildenafil value is omitted in Table 2).

[0094] Active ingredient uniformity test

[0095] The micropowder obtained by spray drying (the weight ratio of sildenafil to leucine during preparation was 88:12) was subjected to 10 sildenafil content analyses, and the results showed that the average weight percentage of the active ingredient in the micropowder was 81.08%, the coefficient of variance was 8.2%, and the standard deviation was 0.06672. That is, when sildenafil is prepared as micropowder by combining it with the first pharmaceutically acceptable excipient (leucine in this experiment), sildenafil can maintain good content uniformity.

[0096] (2) Phospholipids

[0097] Sildenafil and DPPC (molecular weight (Mw) = 744 g / mol), sildenafil and DPSC (Mw = 790 g / mol) were dissolved in ethanol, respectively, and then the two were mixed with each other through a three-fluid nozzle according to the formulation of Table 3, and spray-dried at an outlet temperature of 90° C. to form microparticles.

[0098] Table 3

[0099]

[0100] Compared with other conditions in Table 3, 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.

[0101] The shape of particles

[0102] The appearance of the spray-dried microparticles (DPSC as the first pharmaceutically acceptable excipient) was observed under an electron microscope. Figure 4 .

[0103] Figure 4 It is shown that the shape of the particle 300 is spherical or polyhedral (eg, golf ball shape).

[0104] Particle size

[0105] The particle sizes (D10, D50, D90 and D100) of the microparticles obtained by mixing sildenafil and DPPC were analyzed through three repeated tests, and the results are summarized in Table 4.

[0106] Table 4 (addition of DPPC)

[0107]

[0108] The particle sizes (D10, D50, D90 and D100) of the microparticles obtained by mixing sildenafil and DSPC are summarized in Table 5.

[0109] Table 5 (Add DSPC)

[0110]

[0111] It can be observed during the process that the particle size of the microparticles is generally less than 5 μm, which is smaller than the sildenafil that has not been spray-dried (the sildenafil values ​​are omitted in Tables 4 and 5).

[0112] Active ingredient uniformity test

[0113] The micropowder obtained by spray drying (the weight ratio of sildenafil to DSPC during preparation was 95:5) was subjected to 10 sildenafil content analyses. The results showed that the average weight percentage of the active ingredient in the micropowder was 98.08%, the coefficient of variance was 1.6%, and the standard deviation was 0.01582. That is, when sildenafil is prepared as micropowder by combining it with the first pharmaceutically acceptable excipient (DSPC in this experiment), sildenafil can maintain good content uniformity.

[0114] Storage stability

[0115] Based on the above preparation conditions, in order to compare the storage stability of the microparticles, a dynamic moisture adsorption test was performed using a continuous gravimetric analysis method. Under isothermal conditions, the samples were exposed to a relative humidity environment created under normal pressure, and the balance was allowed to automatically record the curve of sample weight changes with relative humidity and time, thereby studying the adsorption and desorption ratio of moisture in the microparticles. The results are shown in Figure 5 (Result graph 400).

[0116] Figure 5 The results show that the micropowder obtained by spray drying DSPC as the first pharmaceutically acceptable excipient and blending it with sildenafil (the weight ratio of sildenafil to DSPC during preparation is 95:5) has excellent stability, and the microparticles begin to recrystallize at a relative humidity of 90%. Compared with microparticles prepared from existing dry powders or other first pharmaceutically acceptable excipients (usually recrystallize at 40%), the use of DSPC as the first pharmaceutically acceptable excipient can reduce the crystallization and has a better preservation effect.

[0117] (3) Polylactic acid or polylactic acid copolymer

[0118] Step a: Sildenafil and polylactic acid-glycolic acid (PLGA) with a viscosity of 0.16 dL / g to 0.24 dL / g were dissolved in acetone respectively, and then the two were mixed with each other through a three-fluid nozzle according to the formulation of Table 6, and spray-dried at an outlet temperature of 90° C. to form microparticles.

[0119] Table 6

[0120]

[0121] Compared with other conditions in Table 6, the microparticles prepared by the weight ratio of 95:5 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.

[0122] The shape of particles

[0123] The appearance of the microparticles was observed under an electron microscope (PLGA was used as the first pharmaceutically acceptable excipient). Figure 6 .

[0124] Figure 6 It is shown that the shape of the particle 300 is spherical, hollow spherical or polyhedral (such as golf ball shape).

[0125] Particle size

[0126] After three repeated tests, the particle sizes (D10, D50, D90 and D100) of the microparticles were analyzed and the results are summarized in Table 7.

[0127] Table 7

[0128]

[0129] It can be observed during the process that the particle size of the microparticles is less than 6 μm, which is smaller than the sildenafil that has not been spray-dried (the sildenafil value is omitted in Table 7).

[0130] Active ingredient uniformity test

[0131] The micropowder obtained by spray drying (the weight ratio of sildenafil to PLGA during preparation was 95:5) was subjected to 10 sildenafil content analyses. The results showed that the average weight percentage of the active ingredient in the micropowder was 96.2%, the coefficient of variance was 1.8%, and the standard deviation was 0.01725. That is, when sildenafil is prepared as micropowder by combining it with the first pharmaceutically acceptable excipient (PLGA in this experiment), sildenafil can maintain good content uniformity.

[0132] (4) Sugar alcohol

[0133] Step a: Sildenafil is dissolved in ethanol, and mannitol is dissolved in water or 60% ethanol aqueous solution. Then the two are mixed with each other through a three-fluid nozzle according to the formula in Table 8, and spray-dried at an outlet temperature of 100°C to form microparticles. Through the selection of the three-fluid nozzle, the sildenafil solution and the mannitol solution can enter from different channels respectively, and then with the assistance of the gas flow, they are mixed into a small, uniform jet inside the nozzle and then spray-dried. Compared with the existing two-fluid nozzle, when different solvents are used in the spray drying process, the selection of a three-fluid nozzle can better control the particle size and mixing uniformity.

[0134] Table 8

[0135]

[0136] Compared with other conditions in Table 8, the microparticles prepared by the weight ratio of 90:10 and the concentration of 1.0% have a smaller particle size and a more regular and uniform shape, so they are selected for subsequent physical property observations.

[0137] The shape of particles

[0138] The appearance of the microparticles was observed under an electron microscope (mannitol was used as the first pharmaceutically acceptable excipient). Figure 7 .

[0139] Figure 7 The shape of the microparticle 300 is spherical, polyhedral (such as golf ball or red blood cell), or a long dendrite formed by agglomeration of several spheres.

[0140] Particle size

[0141] After three repeated tests, the particle sizes (D10, D50, D90 and D100) of the microparticles were analyzed and the results are summarized in Table 9.

[0142] Table 9

[0143]

[0144] It can be observed during the process that the particle size of the microparticles is less than 6 μm, which is smaller than the sildenafil that has not been spray-dried (the sildenafil value is omitted in Table 9).

[0145] Active ingredient uniformity test

[0146] The micropowder obtained by spray drying (the weight ratio of sildenafil to mannitol during preparation was 90:10) was subjected to 10 sildenafil content analysis. The results showed that the average weight percentage of the active ingredient in the micropowder was 90%, the coefficient of variance was 5.8%, and the standard deviation was 0.05254. That is, when sildenafil is combined with the first pharmaceutically acceptable excipient (mannitol in this experiment) to prepare micropowder, sildenafil can maintain good content uniformity, and the weight percentage of the active ingredient in the finished microparticles is basically consistent with the weight percentage before spray drying.

[0147] 2. Add a second pharmaceutically acceptable excipient after spray drying

[0148] 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 95:5 and the concentration was 2%. The mixing ratio of the second pharmaceutically acceptable excipient (lactose) and sildenafil was obtained according to Table 10.

[0149] Table 10

[0150]

[0151] Aerosol properties

[0152] 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 "Sil only" group (sildenafil only), the "Sil + leucine" group, and the "Sil + leucine + lactose" group were provided for detecting aerosol properties, and the aerosol properties were detected according to the Next Generation Impactor (Next Generation Impactor, NGI) (brand: Copley Scientific, equipment name: Model 170) in a cascade impactor (CI) at an airflow rate of 60 liters / minute. The "Sil only" group was prepared by direct spray drying of sildenafil, the "Sil+Leucine" group was prepared by adding a first pharmaceutically acceptable excipient (leucine) before spray drying, and the "Sil+Leucine+Lactose" group was prepared by adding a first pharmaceutically acceptable excipient (leucine) before spray drying and a second pharmaceutically acceptable excipient (lactose) after spray drying.

[0153] Please refer to the results Figure 8 And Table 11 (data compiled from Figure 8 ), the fine particle fraction (FPF) is the percentage of the cumulative deposition content of particles smaller than 5 microns to the total content of particles output, reflecting the effective deposition rate of particles in the lungs. The results are presented in Figure 8 (Aerosol property comparison diagram 500), wherein the levels from left to right represent the flight distance from near to far.

[0154] Figure 8 It is shown that, compared with the "Sil only" group, the "Sil + Leucine" group and the "Sil + Leucine + Lactose" group have fewer particles distributed in the front layers (e.g., the residual of the capsule to the preseparator (Preseparator) layer) (relatively shorter flight distance), while the distribution of particles in the "Sil + Leucine" group and the "Sil + Leucine + Lactose" group in the subsequent layers is improved, such as the S2 layer to the S8 layer, indicating that a relatively longer flight distance can be achieved. That is, compared with the "Sil only" group, the "Sil + Leucine" group and the "Sil + Leucine + Lactose" group have longer flight distances.

[0155] In addition, it can be observed that the distribution of the particles in the "Sil+Leucine+Lactose" group is improved after the S6 stage (which requires a relatively long flight distance) compared to the "Sil+Leucine" group. That is, the "Sil+Leucine+Lactose" group further exhibits a longer flight distance compared to the "Sil+Leucine" group.

[0156] Table 11

[0157]

[0158] Note: MMAD is the mass median aerodynamic diameter.

[0159] Table 11 shows that, compared with the "Sil only" group, the "Sil+Leucine" group and the "Sil+Leucine+Lactose" group showed higher FPF and smaller MMAD; compared with the "Sil+Leucine" group, the "Sil+Leucine+Lactose" group showed higher FPF and smaller MMAD.

[0160] therefore, Figure 8And Table 11 reveals that the flight distances in the three groups are ranked (long to short) in the following order: (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 sildenafil. 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.

[0161] Next, please return to Figure 3 , Figure 4 , Figure 6 as well as Figure 7 , and together Figure 8 As shown in Table 11, it should be emphasized that when sildenafil 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.

[0162] 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.

[0163]

Explanation of symbols

[0164] 100: Methods

[0165] S110, S120, S130, S140: Step 200: Sildenafil

[0166] 300: Particles

[0167] 400: Result graph

[0168] 500: 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 sildenafil or a pharmaceutically acceptable salt thereof; as well as The first pharmaceutically acceptable excipient includes amino acids, phospholipids, polylactic acid, polylactic acid copolymers, sugar alcohols or a combination thereof.

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

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

4. The pharmaceutical composition 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 phospholipid is 1% to 50%.

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

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

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

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

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

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

12. The pharmaceutical composition according to claim 1, wherein the active ingredient and the first pharmaceutically acceptable excipient form microparticles with a particle size of 50 nanometers to 10 micrometers. 13 . The pharmaceutical composition according to claim 12 , wherein the microparticles are in the shape of solid spheres, hollow spheres, solid polyhedrons, elongated strips or a combination thereof.

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

15. The pharmaceutical composition 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 sildenafil or a pharmaceutically acceptable salt thereof; Dissolving a first pharmaceutically acceptable excipient in a second solvent to form a second solution, wherein the first pharmaceutically acceptable excipient comprises amino acids, polysaccharides, phospholipids, polylactic acid, polylactic acid copolymers, sugar alcohols 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, wherein: Also included is mixing the microparticles with a flavoring agent.

Images