Pharmaceutical formulation of erdosteine and preparation method therefor

Abstract

A pharmaceutical formulation of erdosteine, comprising multiple drug microparticles, wherein the multiple drug microparticles are designed as an inhalable dosage form. The multiple drug microparticles comprise: an active ingredient and a first excipient. The active ingredient comprises erdosteine or a pharmaceutically acceptable salt thereof. The first excipient is mixed with the active ingredient. The multiple drug microparticles are substantially spherical in shape, and 90% of the multiple drug microparticles have a particle size of 12 microns or less.

Description

[0001] Pharmaceutical preparation of erdosteine and method of preparing the same Technical field The present invention relates to a pharmaceutical preparation of erdosteine as an active ingredient and a method of preparing the same. Background Art Erdosteine is a mucolytic agent that is mainly used for the treatment of sputum with high viscosity that is not easily expectorated in acute or chronic bronchitis, obstructive pulmonary disease, and the like. Erdosteine and its metabolites in vivo break disulfide bonds of mucin in bronchial secretions, change the composition and rheological properties of the secretions, reduce the viscosity of sputum, and improve inhibited respiratory function, thereby being useful for the treatment of various inflammations of the respiratory tract. Currently, erdosteine is used in the form of a tablet, such as erdosteine capsules and erdosteine dispersible tablets. However, oral administration is degraded in the stomach and intestines, and suffers from a first-pass effect in the gastrointestinal tract and a first-pass elimination effect in the liver, which reduces the amount of the original drug that enters the blood circulation. The drug is metabolized by enzymes in the mucosa of the gastrointestinal tract or the liver before it enters the blood circulation, which affects the efficacy of the drug, reduces the amount of the drug that reaches the systemic circulation and the blood concentration, and lowers the bioavailability. In view of the above problems, the present invention provides a pharmaceutical preparation of erdosteine and a method of preparing the same, which is inhaled in the form of fine powder to directly deliver the drug to the lungs to take effect. Some embodiments of the present invention provide a pharmaceutical preparation of erdosteine, comprising: a plurality of drug microparticles, the plurality of drug microparticles being in the form of an inhalant, wherein the plurality of drug microparticles comprises: an active ingredient and a first excipient. The active ingredient comprises erdosteine or a pharmaceutically acceptable salt thereof. The first excipient is mixed with the active ingredient. The plurality of drug microparticles is in a shape close to a sphere, and 90% of the plurality of drug microparticles has a particle size of 12 micrometers or less. In some embodiments, in the pharmaceutical preparation of erdosteine, the weight percentage of the plurality of drug microparticles is 1% to 99% based on 100%, and the weight percentage of the erdosteine or the pharmaceutically acceptable salt thereof is 1% to 99% based on 100%. In some embodiments, in the pharmaceutical preparation of erdosteine, the weight percentage of the plurality of drug microparticles is 0.1% to 99% based on 100%, and the weight percentage of the first excipient is 0.1% to 99% based on 100%. In some embodiments, in the pharmaceutical preparation of erdosteine, the first excipient comprises: a fatty acid, a phospholipid, a polylactic acid, a polysaccharide, hyaluronic acid, lactose, mannitol, or a combination thereof.In some embodiments, in the pharmaceutical preparation of erdosteine, the weight percentage of the plurality of drug microparticles is 1% to 50% of the total 100% weight percentage of amino acids; the weight percentage of phospholipids is 0.1% to 20%; the weight percentage of polyacids is 0.1% to 30%; the weight percentage of polysaccharides is 0.1% to 20%; the weight percentage of hyaluronic acid is 1% to 99%; the weight percentage of lactose is 1% to 99%; or the weight percentage of mannitol is 1% to 99%. In some embodiments, in the pharmaceutical preparation of erdosteine, the amino acids comprise glycine, alanine, valine, leucine, isoleucine, phenylalanine, tryptophan, tyrosine, aspartic acid, histidine, asparagine, glutamic acid, lysine, arginine, methionine, arginine, serine, threonine, cysteine, proline, or a combination thereof. In some embodiments, in the pharmaceutical preparation of erdosteine, the phospholipids comprise diphosphatidyl choline, distearoyl phosphatidyl choline, or a combination thereof. In some embodiments, in the pharmaceutical preparation of erdosteine, the polysaccharides comprise chitosan, chitosan glutamate, chitosan hydrochloride, or a combination thereof. In some embodiments, in the pharmaceutical preparation of erdosteine, 90% of the plurality of drug microparticles have a particle size of less than 5 microns. In some embodiments, in the pharmaceutical preparation of erdosteine, 50% of the plurality of drug microparticles have a particle size of 2 microns to 3 microns. In some embodiments, in the pharmaceutical preparation of erdosteine, 10% of the plurality of drug microparticles have a particle size of less than 2 microns. In some embodiments, the pharmaceutical preparation of erdosteine further comprises a capsule, an aluminum blister, or a drug reservoir, wherein the plurality of drug microparticles is contained in the capsule, the aluminum blister, or the drug reservoir. In some embodiments, the pharmaceutical preparation of erdosteine further comprises a second excipient mixed with the plurality of drug microparticles. In some embodiments, in the pharmaceutical preparation of erdosteine, the second excipient is lactose, mannitol, or a combination thereof. In some embodiments, in the pharmaceutical preparation of erdosteine, the weight percentage of the mixture of the plurality of drug microparticles and the second excipient is 0.005% to 40% of the total 100% weight percentage. In some embodiments, the pharmaceutical preparation of erdosteine further comprises a flavoring agent mixed with the plurality of drug microparticles. In some embodiments, in the pharmaceutical preparation of erdosteine, the plurality of drug microparticles is a solid sphere, a hollow sphere, a solid polyhedron, a golf ball, or a red blood cell.Some embodiments of the present application provide a method of preparing a pharmaceutical formulation of erdosteine, comprising: dissolving an active ingredient in a first solvent to form a first solution, wherein the active ingredient comprises erdosteine or a pharmaceutically acceptable salt thereof; dissolving a first excipient in a second solvent to form a second solution; mixing the first solution and the second solution to form a mixed solution; and spray drying the mixed solution to produce a plurality of pharmaceutical microparticles, wherein 90% of the plurality of pharmaceutical microparticles have a particle size of 12 microns or less. In some embodiments, in the method of preparing a pharmaceutical formulation of erdosteine, the first excipient comprises an amino acid, a phospholipid, a polylactic acid, a polysaccharide, hyaluronic acid, lactose, mannitol, or a combination thereof. In some embodiments, in the method of preparing a pharmaceutical formulation of erdosteine, the first solvent and the second solvent comprise: water, ethanol, methanol, dichloromethane, ethyl acetate, ethyl ether, acetone, dimethyl sulfoxide, or a combination thereof. In some embodiments, in the method of preparing a pharmaceutical formulation of erdosteine, in the mixed solution, the total concentration of the active ingredient and the first excipient is less than 5% weight by volume percentage (w / v%) based on 100% of the mixed solution. oIn some embodiments, in the method of preparing a pharmaceutical preparation of erdosteine, the weight percentage of the plurality of pharmaceutical microparticles is 1% to 99% of 100% based on the weight percentage of erdosteine or a pharmaceutically acceptable salt thereof. In some embodiments, in the method of preparing a pharmaceutical preparation of erdosteine, the weight percentage of the first excipient is 0.1% to 99% of 100% based on the weight percentage of the plurality of pharmaceutical microparticles. In some embodiments, in the method of preparing a pharmaceutical preparation of erdosteine, the mixing weight ratio of the first solution to the second solution in the mixed solution is 1:50 to 99:50. In some embodiments, in the method of preparing a pharmaceutical preparation of erdosteine, the temperature of the spray drying outlet is 60°C to 120°C when the mixed solution is spray dried to obtain the plurality of pharmaceutical microparticles. In some embodiments, the method of preparing a pharmaceutical preparation of erdosteine further comprises mixing the plurality of pharmaceutical microparticles with a second excipient. In some embodiments, the method of preparing a pharmaceutical preparation of erdosteine further comprises mixing the plurality of pharmaceutical microparticles with a flavoring agent. BRIEF DESCRIPTION OF DRAWINGS The above and other objects, features, advantages and embodiments of the present application will become more apparent to those skilled in the art from the following detailed description taken in conjunction with the accompanying drawings. FIG. 1 is an electron microscope image of erdosteine active ingredient particles. FIG. 2 is a flowchart illustrating a method of preparing a pharmaceutical preparation of erdosteine according to some embodiments of the present application. FIG. 3 is a particle size distribution graph of a pharmaceutical preparation of erdosteine according to an embodiment. FIG. 4 is an electron microscope image of a pharmaceutical preparation of erdosteine according to an embodiment. FIG. 5 is a particle size distribution graph of a pharmaceutical preparation of erdosteine according to an embodiment. FIG. 6 is an electron microscope image of a pharmaceutical preparation of erdosteine according to an embodiment. FIG. 7 is a particle size distribution graph of a pharmaceutical preparation of erdosteine according to an embodiment. FIG. 8 is an electron microscope image of a pharmaceutical preparation of erdosteine according to an embodiment. FIG. 9 is a particle size distribution graph of a pharmaceutical preparation of erdosteine according to an embodiment. FIG. 10 is an electron microscope image of a pharmaceutical preparation of erdosteine according to an embodiment. FIG. 11 is a plot of the flight characteristics of a pharmaceutical powder detected using a next-generation impactor according to an embodiment. DETAILED DESCRIPTION In order to describe the present application in detail, embodiments and specific examples of the present application are described in an exemplary manner. However, these are not the only forms of specific embodiments to implement or use the present application. The embodiments disclosed herein can be combined with each other in an advantageous manner or replaced with other embodiments, and other embodiments can be added to an embodiment without further description. In the following description, many specific details are described in detail to provide a sufficient understanding of the following embodiments.However, embodiments of the present application can be practiced without these specific details. While the following described describes a particular sequence or order of operations or steps, alternatives (e.g., steps performed in a different order, steps performed concurrently, etc.) can be used by those skilled in the art depending on the particular situation. Moreover, not all of the activities or elements described are required, which can be utilized from the minimum number of steps / elements by practicing the present application. Additionally, it should be understood that each element or step in the processes described herein can comprise one or more sub-steps or actions. Unless otherwise indicated, the terms "a" or "an" are taken to mean one or more, i.e., for one or more elements, and the terms "coupled" or "connected" are used broadly and encompass both direct and indirect coupling, connections, and the like. Further, "drug" or "active ingredient" as used herein refers to erdosteine or pharmaceutically acceptable salts thereof, including but not limited to salts, esters, complexes, chelates, clathrates, racemates, or enantiomers, etc. "Excipient" or "pharmaceutically acceptable excipient" as used herein refers to a pharmaceutical additive that has no pharmacological activity and has different purposes and functions for use in pharmaceutical compositions. The main object of the present application is to provide a pharmaceutical preparation of erdosteine in dry powder inhalation form having a small particle size and a specific shape, to produce a mucolytic agent solid composition using a spray drying method, to modify the particle size by this technique, to achieve a better lung distribution and therapeutic effect in a specific ratio combination, to meet the requirements of inhalation administration, and to reduce the onset time of the drug. Further, the drugs currently on the market for the treatment of mucus or sputum secretion are administered to the lungs by inhalation using a nebulizer. However, nebulizers are often large and less mobile devices, and the actual dose administered is less accurately controlled. The pharmaceutical preparation of erdosteine provided by the embodiments of the present application is an inhalation preparation in the form of a dry powder, which can be more conveniently administered, the amount administered can be more easily controlled, and the preservation of the drug is more advantageous. In addition, it is possible to increase the proportion of drug particles delivered to the lower respiratory tract or deep lung. The pharmaceutical preparation of erdosteine provided by the embodiments of the present application can be used for diseases, symptoms, and / or disorders associated with mucus or sputum secretion, or symptoms, inflammation, infection, or hypersensitivity of the respiratory system. In the embodiments, the particle size of the drug particles is adjusted by adjusting the concentration of the mixed solution of the drug and the excipient, the solution ratio, and the outlet temperature at which the drug particles are produced by spray drying. Referring to FIG. 1, an electron microscope image of erdosteine active ingredient particles is shown. It can be seen that the particles formed by the erdosteine active ingredient are large in size and irregular in shape.Referring to FIG. 2, a flow chart of a method for preparing a pharmaceutical formulation of erdosteine in some embodiments of the present application is shown. The method 100 includes a step S110, a step S120, a step S130, and a step S140. It is emphasized that the shape and size of the drug microparticles can be controlled by mixing the first excipient with erdosteine or a pharmaceutically acceptable salt thereof in a mixed solution, and then spray-drying the mixed solution, thus improving the aerogel properties and onset time of the drug microparticles. First, referring to the step S110, the active ingredient, including erdosteine or a pharmaceutically acceptable salt thereof, is dissolved in a first solvent to form a first solution. In some embodiments, the first solvent includes water, ethanol, methanol, dichloromethane, ethyl acetate, ethylene cyanide, acetone, dimethyl sulfoxide, or a combination thereof, to facilitate the dissolution of erdosteine or a pharmaceutically acceptable salt thereof. Referring to the step S120, the first excipient is dissolved in a second solvent to form a second solution. In some embodiments, the first excipient is a pharmaceutically acceptable excipient, including an amino acid, a phospholipid, a polylactic acid, a polysaccharide, hyaluronic acid, lactose, mannitol, or a combination thereof. In some embodiments, the second solvent includes water, ethanol, methanol, dichloromethane, ethyl acetate, ethylene cyanide, acetone, dimethyl sulfoxide, or a combination thereof, to dissolve the first excipient. In some embodiments, the amino acid used in the first excipient includes glycine, alanine, leucine, isoleucine, phenylalanine, tryptophan, tyrosine, aspartic acid, histidine, asparagine, glutamic acid, lysine, glutamine, methionine, arginine, serine, threonine, cysteine, proline, or a combination thereof. In some embodiments, the polysaccharide used in the first excipient includes chitosan, chitosan glutamate, chitosan hydrochloride, or a combination thereof. In some embodiments, the phospholipid used in the first excipient includes dipalmitoyl phosphatidyl choline (DPPC), distearoyl phosphatidyl choline (DSPC), or a combination thereof. In some embodiments, the polylactic acid used in the first excipient includes polylactic acid (PLA), poly(lactic-co-glycolic acid (PLGA), or a combination thereof. Referring to the step S130, the first solution and the second solution are mixed to form a mixed solution.In some embodiments, the total concentration of the active ingredient and the excipient is less than 5 weight volume % (w / v %), such as 0.5 w / v %, 1 w / v %, 1.5 w / v %, 2 w / v %, 2.5 w / v %, 3 w / v %, 3.5 w / v %, 4 w / v %, 4.5 w / v %, or any value between any of the aforementioned values, when the weight of the mixed solution is taken as 100%. In some embodiments, the total concentration of the active ingredient and the excipient is 0.2 w / v % to 3 w / v %. If the weight volume percentage is too low, the yield of spray drying is limited. If the weight volume percentage is too high, the mixed solution can not be uniform and too viscous to be spray dried, resulting in limited efficiency of spray drying. In some embodiments, the weight ratio of the edotecavin or a pharmaceutically acceptable salt thereof to the first excipient in the mixed solution is 1 : 1 to 199: 1, such as 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 of the aforementioned values. If the weight ratio is too low, the content of the active ingredient contained in the drug microparticles is limited after spray drying. If the weight ratio is too high, the aerosol properties are weakened because the properties of the drug microparticles are difficult to be controlled by the excipient. Please refer to step S140, the mixed solution is spray dried to prepare drug microparticles. In some embodiments, the temperature of the spray drying outlet of the equipment used when the mixed solution is spray dried to prepare the drug microparticles is 60 °C to 120 °C, such as 60 °C, 65 °C, 70 °C, 75 °C, 80 °C, 85 °C, 90 °C, 95 °C, 100 °C, 110 °C, 120 °C, or any value between any of the aforementioned values. If the temperature of the spray drying outlet is too low, the droplets sprayed are too large, the particle size of the particles after spray drying tends to be large, and the shape of the particles after spray drying will be difficult to maintain spherical. If the temperature of the spray drying outlet is too high, the structure of the active ingredient or the excipient can be changed, affecting its function.In some embodiments, the drug microparticles can be loaded into capsules, aluminum foil blisters, or drug storage tanks in a dry powder inhaler device for inhalation by an individual in need thereof. In some embodiments, the method 100 further comprises mixing the drug microparticles with a second excipient, the first excipient being different from the second excipient. The second excipient is a pharmaceutically acceptable excipient. It is noted that the addition of the second excipient improves the aerosol properties, extends the flight distance of the drug microparticles, and improves the distribution of the drug microparticles in the lungs after inhalation administration. In some embodiments, the second excipient comprises lactose, mannitol, or a combination thereof. In some embodiments, the second excipient is lactose microparticles, mannitol microparticles, or a combination thereof. In some embodiments, the method 100 further comprises mixing the drug microparticles with a flavoring agent (e.g., menthol, lemon, strawberry, orange, etc. natural flavoring) in an amount less than 1% by weight to reduce bitterness during inhalation. In some embodiments, a pharmaceutical formulation of an edotecavin for dry powder inhalation is provided, comprising: an active ingredient; and a first excipient. The active ingredient comprises edotecavin or a pharmaceutically acceptable salt thereof. The first excipient comprises an amino acid, a phospholipid, a polylactic acid, a polysaccharide, a hyaluronic acid, lactose, mannitol, or a combination thereof. By using the first excipient, the shape and particle size of the spray-dried pharmaceutical composition can be controlled to improve the aerosol properties of the pharmaceutical composition. In some embodiments, the active ingredient comprises edotecavin or a pharmaceutically acceptable salt thereof in an amount of 1% to 99% by weight (e.g., 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or any value between any of the aforementioned values). Furthermore, the first excipient is in an amount of 0.1% to 99% by weight (e.g., 0.1%, 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or any value between any of the aforementioned values). If the active ingredient is in too low an amount or the first excipient is in too high an amount, the amount of active ingredient provided by a particular unit of the pharmaceutical formulation of edotecavin is limited. If the active ingredient is in too high an amount or the first excipient is in too low an amount, the aerosol properties of the pharmaceutical formulation of edotecavin are diminished.In some embodiments, when the weight of the microparticle is taken as 100%, and the first excipient uses an amino acid, 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 of the aforementioned values). If the weight percentage of the amino acid is too high, the active ingredient that a particular unit of the pharmaceutical formulation of erdosteine can provide is limited. If the weight percentage of the amino acid is too low, the aerosol characteristics of the pharmaceutical formulation of erdosteine are weakened. In some embodiments, when the weight of the pharmaceutical microparticle is taken as 100%, and the first excipient uses a phospholipid, the weight percentage of the phospholipid is 1% to 20% (e.g., 1%, 5%, 10%, 15%, 20%, or any value between any of the aforementioned values). If the weight percentage of the phospholipid is too high, the active ingredient that a particular unit of the pharmaceutical formulation of erdosteine can provide is limited. If the weight percentage of the phospholipid is too low, the aerosol characteristics of the pharmaceutical formulation of erdosteine are weakened. In some embodiments, when the weight of the pharmaceutical microparticle is taken as 100%, and the first excipient uses a polylactic acid, e.g., polylactic acid (PLA), polylactic acid copolymer (PLGA), the weight percentage of the polylactic acid is 0.1% to 30% (e.g., 0.1%, 1%, 5%, 10%, 15%, 20%, 30%, or any value between any of the aforementioned values). If the weight percentage of the polylactic acid is too high, the active ingredient that a particular unit of the pharmaceutical formulation of erdosteine can provide is limited. If the weight percentage of the polylactic acid is too low, the aerosol characteristics of the pharmaceutical formulation of erdosteine are weakened. In some embodiments, when the weight of the pharmaceutical microparticle is taken as 100%, and the first excipient uses a polysaccharide, the weight percentage of the polysaccharide is 0.1% to 20% (e.g., 0.1%, 1%, 5%, 10%, 15%, 20%, or any value between any of the aforementioned values). If the weight percentage of the polysaccharide is too high, the active ingredient that a particular unit of the pharmaceutical formulation of erdosteine can provide is limited. If the weight percentage of the polysaccharide is too low, the aerosol characteristics of the pharmaceutical formulation of erdosteine are weakened. In some embodiments, when the weight of the pharmaceutical microparticle is taken as 100%, and the first excipient uses hyaluronic acid, lactose, or mannitol, the weight percentage of the hyaluronic acid, lactose, or mannitol is 1% to 99% (e.g., 0.1%, 1%, 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or any value between any of the aforementioned values). If the weight percentage of the hyaluronic acid, lactose, or mannitol is too high, the active ingredient that a particular unit of the pharmaceutical formulation of erdosteine can provide is limited.If the weight percentage of hyaluronic acid, lactose or mannitol is too low, the aerosol properties of the pharmaceutical formulation of uredostatin are diminished. In some embodiments, the active ingredient and the first excipient form pharmaceutical microparticles having a particle size of about 50 nm to about 15 microns, for example 50 nm, 100 nm, 500 nm, 1 micron, 2 microns, 3 microns, 4 microns, 5 microns, 6 microns, 8 microns, 10 microns, 12 microns, 14 microns, 15 microns, or any value between any of the aforementioned values. Notably, the particle size of the pharmaceutical microparticles is smaller than the particle size of the particles formed from uredostatin or a pharmaceutically acceptable salt thereof without spray drying. Thus, the requirement for pharmaceutical particles that can be inhaled into the lungs is satisfied. In some embodiments, 90% of the pharmaceutical microparticles have a particle size of less than 12 microns, for example less than 12 microns, 10 microns, 8 microns, 6 microns, 5 microns. In some embodiments, 50% of the pharmaceutical microparticles have a particle size of less than 5 microns, for example less than 2 microns or 3 microns. In some embodiments, 10% of the pharmaceutical microparticles have a particle size of less than 3 microns, for example less than 2 microns. In some embodiments, the pharmaceutical microparticles formed have a shape that is close to spherical, for example a solid sphere, a hollow sphere, a solid polyhedron, a golf ball, or a red blood cell, or a combination thereof. The size and shape of such pharmaceutical microparticles can enhance the flight distance of the pharmaceutical microparticles, and enhance the distribution of the pharmaceutical microparticles in the lungs when the dry powder pharmaceutical is inhaled by a recipient. In some embodiments, the pharmaceutical formulation of uredostatin further comprises a second excipient different from the first excipient, for example lactose, mannitol or a combination thereof. The addition of the second excipient can further enhance the flight distance of the pharmaceutical microparticles, and enhance the distribution of the pharmaceutical microparticles in the lungs when administered. In some embodiments, the pharmaceutical formulation of uredostatin further comprises other pharmaceutically acceptable excipients for modulating specific properties, for example air dynamics or taste, etc. It should be understood that the above embodiments and the following examples are provided for illustration, not for limitation. Based on the description, those skilled in the art will clearly understand that various changes and modifications can be made within the scope of the present application. In order to make the dry powder inhaled uredostatin pharmaceutical formulation and its preparation method more clear, several examples and tests are provided below.In some embodiments, the solvent that can be used is water, ethanol, methanol, dichloromethane, ethyl acetate, ethyl ether, acetone, DMSO, or a combination thereof. Step B: Both the first solution and the second solution are mixed with each other in a specific ratio to form a solution. In some embodiments, a possible mixing ratio is that the ratio of erdosteine to amino acid is 1-50:99-50 (w / w), for example 1:99 (w / w), 20:80 (w / w), or 50:50 (w / w). oIn some embodiments, the ratio of edoxaban to amino acid is 20:80 (w / w). In some embodiments, the total concentration of edoxaban and amino acid is 0.2% to 3% w / v, for example, 1.5% w / v, i.e., 15 g of solute (edoxaban and amino acid) per 100 ml of solution. Step C: The mixed solution is spray dried using a particle spray dryer to produce the drug microparticles. In some embodiments, the spray drying is performed at a spray drying outlet temperature of 70°C to 110°C. In some embodiments, the spray drying is performed at a spray drying outlet temperature of 100°C. Figure 3 shows a particle size distribution of the drug microparticles formed from edoxaban and leucine. The drug microparticles have a small size, with a D90 particle size (particle size of the top 90% of the microparticles) of 6.51 μm, a D50 particle size (particle size of the top 50%) of 2.26 μm, and a D10 particle size (particle size of the top 10%) of 1.05 μm. Figure 4 shows an electron microscope image of the drug microparticles formed from edoxaban and leucine. The drug microparticles have a spherical shape. Comparing Figures 3 and 1, the spherical drug microparticles formed from edoxaban and leucine have a better aerodynamic structure than the irregular shape of the pure edoxaban active ingredient particles, which can meet the requirements for particle size for pulmonary administration. The shape can help the drug microparticles to fly a longer distance in the lungs.In some embodiments, a possible mixing ratio is erdosteine: polysaccharide = 20-80: 80~20 (w / w), for example, a mixing ratio of erdosteine: polysaccharide (chitosan hydrochloride) is 20:80 (w / w) > 50:50 (w / w) > or 80:20 (w / w). In some embodiments, a preferable ratio of erdosteine: polysaccharide is 50:50 (w / w). In some embodiments, the total concentration of erdosteine and polysaccharide is 0.5 w / v% to 3 w / v%, for example, 1.5 w / v%. Step C: After the mixed solution is filtered with filter paper, spray drying is performed using a spray dryer with a three-fluid nozzle to obtain drug microparticles. In some embodiments, the spray drying outlet temperature is 60°C to 100°C. In some embodiments, a preferable spray drying outlet temperature is 80°C. FIG. 5 shows a particle size distribution diagram of drug microparticles formed by erdosteine and chitosan, and it can be seen that drug microparticles with small sizes are formed, in which the particle size of D90 drug microparticles is 1 (12 microns, the particle size of D50 drug microparticles is 5.78 microns, and the particle size of D10 drug microparticles is 1.94 microns. FIG. 6 shows an electron microscope image of drug microparticles formed by erdosteine and chitosan. It can be seen that the shape of the obtained drug microparticles is similar to a circle or a sphere. Therefore, the drug microparticles formed by erdosteine and chitosan can meet the particle size requirements for pulmonary administration, and this shape can help the drug microparticles to fly a long distance in the lungs.In some embodiments, a possible mixing ratio is 10-90 : 90-10 (w / w) of erdosteine: phospholipid, for example, a mixing ratio of 10:90 (w / w) > 50:50 (w / w), or 90:10 (w / w) of erdosteine: phospholipid. In some embodiments, a preferable mixing ratio of erdosteine: phospholipid is 50:50 (w / w). In some embodiments, the total concentration of erdosteine and phospholipid is 0.5 w / v % to 3 w / v %, for example, 1.5 w / v %. Step C: The mixed solution is spray-dried using a spray dryer with a three-fluid nozzle to obtain drug microparticles. In some embodiments, the spray-drying outlet temperature is 80°C to 100°C. In some embodiments, a preferable spray-drying outlet temperature is 90°C. Figure 7 shows a particle size distribution graph of drug microparticles formed from erdosteine and phospholipid, and it can be seen that drug microparticles with small sizes are formed, in which the particle size of D90 drug microparticles is 4.59 microns, the particle size of D50 drug microparticles is 2.42 microns, and the particle size of D10 drug microparticles is 1.21 microns. Figure 8 shows an electron microscope image of drug microparticles formed from erdosteine and phospholipid. It can be seen that the shape of the obtained drug microparticles is similar to a circular sphere. Therefore, the drug microparticles formed from erdosteine and phospholipid can meet the particle size requirements for pulmonary administration, and this shape can help the drug microparticles to fly a long distance in the lungs.In some embodiments, the mixture ratio of erdosteine: hyaluronic acid is 5-95:95-5 (w / w), for example, the mixture ratio of erdosteine: hyaluronic acid is 5:95 (w / w), 50:50 (w / w), or 95:5 (w / w). In some embodiments, the mixture ratio of erdosteine: hyaluronic acid is preferably 50:50 (w / w). In some embodiments, the total concentration of erdosteine and hyaluronic acid is 0.5-2 w / v%, for example, 1 w / v%. Step C: After the mixed solution is filtered through filter paper, spray drying is performed using a spray dryer to obtain drug microparticles. In some embodiments, the outlet temperature of the spray dryer is 80-120°C. In some embodiments, the outlet temperature of the spray dryer is preferably 100°C. Figure 9 shows the particle size distribution of the drug microparticles formed from erdosteine and hyaluronic acid. As shown, drug microparticles with small sizes are formed, wherein the particle size of the D90 drug microparticles is 9.37 microns, the particle size of the D50 drug microparticles is 2.77 microns, and the particle size of the D10 drug microparticles is 1.06 microns. Figure 10 shows the electron microscope image of the drug microparticles formed from erdosteine and hyaluronic acid. As shown, the shape of the obtained drug microparticles is close to a circle, similar to a red blood cell. Thus, the drug microparticles formed from erdosteine and hyaluronic acid can meet the particle size requirements for pulmonary administration, and the shape can help the drug microparticles to fly a long distance in the lungs. In some embodiments, the erdosteine drug microparticles prepared by the foregoing steps can be packaged in a dry powder inhaler dosage form such as a capsule, an aluminum blister, a drug reservoir, etc., or can be mixed with lactose or mannitol with an appropriate particle size in an appropriate ratio and then packaged in a dry powder inhaler dosage form such as a capsule, an aluminum blister, a drug reservoir, etc. In some embodiments, the erdosteine drug microparticles are mixed with second excipient microparticles, such as lactose microparticles or mannitol microparticles. In some embodiments, the particle size of the second excipient microparticles is larger than that of the erdosteine drug microparticles. The function of the second excipient is to act as a carrier to carry the erdosteine drug microparticles to help pass through the oropharynx. In some embodiments, the second excipient microparticles with a certain particle size range are mixed with the erdosteine drug microparticles, for example, the D50 of the second excipient microparticles is less than 60 microns (for example, the D50 is 5-50 microns or 5-60 microns), and the D90 is less than 100 microns (for example, the D90 is 20-80 microns or 20-100 microns). Alternatively, the D50 of the second excipient microparticles is less than 130 microns (for example, the D50 is 30-125 microns), and the D90 is less than 300 microns (for example, the D90 is 50-300 microns).In other embodiments, the second excipient microparticles of multiple particle size ranges can be mixed with the eprosartan drug microparticles, for example, the second excipient microparticles contain first type microparticles and second type microparticles. The second excipient microparticles of two particle size ranges can provide better effect of helping the eprosartan drug microparticles pass through the oropharynx. The first type microparticles have a D50 of less than 60 microns (e.g., a D50 of 5 to 50 microns or 5 to 60 microns) and a D90 of less than 100 microns (e.g., a D90 of 20 to 80 microns or 20 to 100 microns); the second type microparticles have a D50 of less than 130 microns (e.g., a D50 of 30 to 125 microns) and a D90 of less than 300 microns (e.g., a D90 of 50 to 300 microns). See Table 1 and Table 2 below, which show the mixing ratios of the second excipient microparticles added. The eprosartan drug microparticles are the drug microparticles of the aforementioned eprosartan or pharmaceutically acceptable salt thereof and the first excipient. Table 1 shows the eprosartan drug microparticles mixed with two different particle size ranges of lactose monohydrate. Table 2 shows the eprosartan drug microparticles mixed with two different particle size ranges of mannitol. Table 2 In some embodiments, the ingredients in the proportions of Table 1 or Table 2 above are mixed in a high speed mixer at a speed of 500 rpm to 2000 rpm, depending on the amount of mixture, to mix uniformly. An appropriate amount of the mixture (e.g., 10 mg to 100 mg) is then loaded into a capsule, an aluminum foil blister, a medicine reservoir, or a similar dry powder inhaler device. In some embodiments, the drug particles are mixed with lactose or mannitol of an appropriate particle size, so that the mixture formed can increase the fine particle fraction of the drug particles in the lung and enhance the therapeutic effect. In some embodiments, a next generation impactor (NGI) can be used to measure the in vitro deposition of different levels to evaluate the flight effect of the drug powder. The main method for in vitro aerodynamic particle size analysis of dry powder inhalers is the cascade impactor (CI) method, which is currently the pharmacopoeia method for evaluating inhalation preparations. Such devices mainly use a next generation impactor. The measurement principle of the next generation impactor is that in a suitable air flow, drug particles of different sizes and inertias are collected by different levels of collection trays. Suitable collection liquid is used to extract the active ingredients in each collection tray, and suitable detection means is used to detect the content, so as to obtain the drug content and particle size distribution corresponding to each level and other data. Particles with larger aerodynamic diameters are easily deposited in the induction port (IP), pre-separator (PSP), and earlier levels due to inertia, and particles with smaller aerodynamic diameters fly farther and are deposited in later levels. The main evaluation parameter is the fine particle fraction (FPF), which is the percentage of the cumulative deposition content with an aerodynamic particle size of less than 5 pans to the total output content, reflecting the effective deposition rate of the drug in the lung. Referring to FIG. 11, the flight characteristics of the drug powder detected using a next generation impactor according to an embodiment are shown.The particles tested were particles of the active ingredient of erdosteine (API), particles of erdosteine and leucine (first excipient) (API + Leu), and a mixture of particles of erdosteine and leucine (first excipient) and lactose (second excipient) (API + Leu + Lac). As shown in Fig. 11, the particles of erdosteine and leucine (API + Leu) and the mixture of particles of erdosteine and leucine and lactose (API + Leu + Lac) were distributed with a higher retention in the 5th, 6thand 7thstages of the NGI device, indicating a longer flight distance. That is, the particles of erdosteine and leucine (API + Leu) and the mixture of particles of erdosteine and leucine and lactose (API + Leu + Lac) had a higher amount in the later stages than the particles of the active ingredient of erdosteine (API). The in vitro nebulization parameters FPF (fme particle fraction), the fine particle fraction of the preparation, and the proportion of particles having a particle size of less than 5 μm were calculated. The higher the FPF content, the higher the proportion of the drug distributed in the lungs. The FPF calculated for the particles of erdosteine and leucine (API + Leu) and the mixture of particles of erdosteine and leucine and lactose (API + Leu + Lac) was significantly higher than that of the simple compound powder (API) having a similar particle size shown in Fig. 11. Thus, the particles of erdosteine (containing erdosteine or a pharmaceutically acceptable salt thereof and a first excipient) and the mixture of particles of erdosteine and a second excipient according to the embodiments of the present application can achieve a longer flight distance, which is advantageous for a higher distribution of the drug particles in the lungs when administered by inhalation. Although the present application has been described in detail according to certain embodiments, other embodiments are also possible. Thus, the spirit and scope of the appended claims should not be limited to the embodiments described herein.

[0002] SYMBOL DESCRIPTION

[0003] 100: method S110: step

[0004] S120: step

[0005] S130: step

[0006] S140: step.

Claims

CLAIM 1. A pharmaceutical preparation of erdosteine, comprising: a plurality of drug microparticles, the plurality of drug microparticles being an inhalation dosage form drug, wherein the plurality of drug microparticles comprises: an active ingredient, wherein the active ingredient comprises erdosteine or a pharmaceutically acceptable salt thereof; and a first excipient, mixed with the active ingredient; wherein, The plurality of drug microparticles are approximately spherical in shape, and 90% of the plurality of drug microparticles have a particle size of 12 microns or less.

2. The pharmaceutical preparation of erdosteine according to claim 1, wherein, The weight percentage of the plurality of drug microparticles is 1% to 99% of 100% by weight of the edoxaban or pharmaceutically acceptable salt thereof.

3. The pharmaceutical preparation of erdosteine according to claim 1, wherein, The weight percentage of the plurality of drug microparticles is 0.1% to 99% of 100% by weight of the first excipient.

4. The pharmaceutical preparation of erdosteine according to claim 1, wherein, The first excipient comprises: an amino acid, a phospholipid, a polylactic acid, a polysaccharide, hyaluronic acid, lactose, mannitol, or a combination thereof.

5. The pharmaceutical preparation of erdosteine according to claim 4, wherein, The weight percentage of the plurality of drug microparticles is 1% to 50% of 100% by weight of the amino acid; 0.1% to 20% by weight of the phospholipid; 0.1% to 30% by weight of the polylactic acid; 0.1% to 20% by weight of the polysaccharide; 1% to 99% by weight of the hyaluronic acid; 1% to 99% by weight of the sugar-poor; or The weight percentage of the mannitol is 1% to 99% of 100%.

6. The pharmaceutical preparation of erdosteine according to claim 4, wherein, The amino acid comprises: glycine, alanine, serine, leucine, isoleucine, phenylalanine, tryptophan, tyrosine, aspartic acid, histidine, asparagine, glutamic acid, lysine, arginine, methionine, arginine, serine, threonine, cysteine, proline, or a combination thereof.

7. The pharmaceutical formulation of erdosteine according to claim 4, wherein, The phospholipid comprises: dipalmitoyl phosphatidyl choline, distearoyl phosphatidyl choline, or a combination thereof.

8. The pharmaceutical preparation of erdosteine according to claim 4, wherein, The polysaccharide comprises: chitosan, chitosan glutamate, chitosan hydrochloride, or a combination thereof.

9. The pharmaceutical preparation of erdosteine according to claim 1, wherein, 90% of the plurality of drug microparticles have a particle size of less than 5 microns.

10. The pharmaceutical preparation of erdosteine according to claim 1, wherein, 50% of the plurality of drug microparticles have a particle size of 2 microns to 3 microns.

11. The pharmaceutical preparation of erdosteine according to claim 1, wherein, 10% of the plurality of drug microparticles have a particle size of less than 2 microns.

12. The pharmaceutical preparation of edoxaban of claim 1, further comprising: a capsule, an aluminum foil blister, or a drug reservoir, wherein the plurality of drug microparticles are contained in the capsule, the aluminum foil blister, or the drug reservoir.

13. The pharmaceutical preparation of edoxaban of claim 1, further comprising: a second excipient, mixed with the plurality of drug microparticles.

14. The pharmaceutical preparation of erdosteine according to claim 13, wherein, The second excipient is lactose, mannitol, or a combination thereof.

15. The pharmaceutical preparation of erdosteine according to claim 13, wherein, The weight percentage of the mixture of the plurality of drug microparticles and the second excipient is 0.005% to 40% of 100% by weight of the plurality of drug microparticles.

16. The pharmaceutical preparation of edoxaban of claim 1, further comprising: a flavoring agent, mixed with the plurality of drug microparticles.

17. The pharmaceutical preparation of erdosteine according to claim 1, wherein, The plurality of drug microparticles are solid spherical, hollow spherical, solid polyhedral, golf ball-like, or red blood cell-like.

18. A method of preparing a pharmaceutical formulation of erdosteine, comprising: dissolving an active ingredient in a first solvent to form a first solution, wherein the active ingredient comprises erdosteine or a pharmaceutically acceptable salt thereof; dissolving a first excipient in a second solvent to form a second solution; mixing the first solution and the second solution to form a mixed solution; and spray-drying the mixed solution to produce a plurality of pharmaceutical microparticles, wherein 90% of the plurality of pharmaceutical microparticles have a particle size of 12 microns or less.

19. The method of preparing a pharmaceutical preparation of erdosteine according to claim 18, wherein, The first excipient comprises an amino acid, a phospholipid, a polylactic acid, a polysaccharide, hyaluronic acid, lactose, mannitol, or a combination thereof.

20. The method of preparing a pharmaceutical preparation of erdosteine according to claim 18, wherein, The first solvent and the second solvent comprise water, ethanol, methanol, dichloromethane, ethyl acetate, ethyl carbonate, acetone, dimethyl sulfoxide, or a combination thereof.

21. The method of preparing a pharmaceutical preparation of erdosteine according to claim 18, wherein, In the mixed solution, a total concentration of the active ingredient and the first excipient is less than 5% weight by volume percent (w / v%) based on 100% of the mixed solution.

22. The method of preparing a pharmaceutical preparation of erdosteine according to claim 18, wherein, A weight percent of the erdosteine or the pharmaceutically acceptable salt thereof is 1% to 99% based on 100% of the plurality of pharmaceutical microparticles.

23. The method of preparing a pharmaceutical preparation of erdosteine according to claim 18, wherein, A weight percent of the first excipient is 0.1% to 99% based on 100% of the plurality of pharmaceutical microparticles.

24. The method of preparing a pharmaceutical formulation of erdosteine according to claim 18, wherein a mixed weight ratio of the first solution to the second solution in the mixed solution is 1 to 50: 50 to 99. In the spray-drying the mixed solution to produce the plurality of pharmaceutical microparticles, a temperature of a spray-drying outlet is 60°C to 120°C.

25. The method of preparing a pharmaceutical preparation of erdosteine according to claim 18, wherein, 26. The method of preparing a pharmaceutical formulation of erdosteine according to claim 18, further comprising: mixing the plurality of pharmaceutical microparticles with a second excipient.

27. The method of preparing a pharmaceutical formulation of erdosteine according to claim 18, further comprising: mixing the plurality of pharmaceutical microparticles with a flavoring agent. ​

Images