Dry powder inhalation preparation containing formoterol and tiotropium bromide composition and preparation method of dry powder inhalation preparation

Abstract

The present invention relates to a dry powder composition for an inhalation formulation comprising formoterol or a pharmaceutically acceptable salt thereof, a tiotropium bromide anhydride and a pharmaceutically acceptable carrier. The synthesis methods of the formoterol and the tiotropium bromide are respectively realized through specific chemical reaction steps, and finally high-purity active ingredients are obtained. The weight ratio of the active ingredients to the carrier in the composition is 1: (1-15): (50-50000), and the carrier can be selected from lactose, cane sugar, mannitol or amino acid and the like. The preparation method comprises the following steps: micronizing, mixing, filling into hollow capsules, and finally preparing a finished product through aluminum-plastic packaging. The composition disclosed by the invention has good chemical stability and high inhalation efficiency, can be kept for more than two years at normal temperature, and is accurately and uniformly administered in a targeted lung through a dry powder inhalation device, so that formoterol and tiotropium bromide synergistically play a role in relaxing bronchial smooth muscles, and clinical requirements are met.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and in particular to an inhalation dry powder preparation containing a formoterol and tiotropium bromide composition and a preparation method thereof. Background Art

[0002] Chronic obstructive pulmonary disease (COPD) and asthma are common chronic respiratory diseases that seriously impact patients' quality of life. Formoterol is a long-acting β2-adrenergic receptor agonist (LABA) that effectively relaxes bronchial smooth muscle and relieves airway obstruction. Tiotropium bromide is a long-acting anticholinergic (LAMA) that further relaxes the bronchi by inhibiting the action of acetylcholine.

[0003] The combined use of these two drugs has been clinically shown to significantly improve lung function and quality of life in patients with COPD and asthma. Pharmacodynamic experiments disclosed in CN105125542A demonstrate that tiotropium bromide and formoterol have a synergistic, additive effect, producing a faster and more potent bronchodilator effect. It has been discovered that combining formoterol, or a salt or solvate thereof, with a tiotropium salt can provide unexpected therapeutic benefits, particularly synergistic therapeutic benefits, in the treatment of inflammatory or obstructive airway diseases.

[0004] Currently, several inhalation formulations containing formoterol and tiotropium are available on the market, such as dry powder inhalers (DPIs) and nebulizers. However, these existing formulations still have limitations in terms of drug stability, inhalation efficiency, and patient compliance. For example, the physicochemical properties of dry powder inhalers, such as drug particle size distribution, dispersibility, and flowability, directly influence the drug's pulmonary deposition rate and therapeutic efficacy. Furthermore, existing preparation methods may be complex, costly, and subject to drug degradation, limiting their widespread clinical application.

[0005] Therefore, the development of a novel inhalation dry powder preparation containing a combination of formoterol and tiotropium salt, which has excellent drug stability, high inhalation efficiency and good patient compliance, has become an important research direction in the current field of pharmaceutical preparations.

[0006] CN107496388A discloses a powdered preparation containing a combination of formoterol and tiotropium salt and a preparation method thereof. The weight percentage of particles of formoterol or its pharmaceutically acceptable salt and tiotropium salt with an aerodynamic particle size of less than 5 μm is not less than 30%, and the FPF can be significantly improved. However, there is a lack of research on the control of raw materials and impurities.

[0007] Currently, patents in this field often mention the combination of the above two types of drugs and their efficacy, but lack research on impurities in active ingredients and preparations. It is well known that the active ingredient tiotropium bromide is easily hydrolyzed when exposed to moisture at room temperature, producing impurities that affect its activity, especially its monohydrate, which has poor stability.

[0008] Currently, there is a lack of research in this field into commercial production environments, key technologies for delivering a fixed dose of each active ingredient to the active site, and particularly key technologies suitable for industrial production. It is well known to those skilled in the art that in pharmaceutical compositions containing two or more active substances for inhalation, ensuring effective delivery of all active ingredients is extremely difficult due to interactions between excipients and the active ingredients, as well as between the active ingredients themselves.

[0009] The purpose of the present invention is to overcome the above shortcomings, rationally design the prescription process of inhalation powder aerosols, strictly control the environmental humidity of industrial production, study the impurities of active substances, and study the key technical indicators of various aspects such as the fine particle fraction, delivery metering uniformity and stability of commercial production batches of preparations, so as to ensure that the set dose of each active ingredient reaches the effective site, exerts a synergistic effect, and meets clinical needs. Summary of the Invention

[0010] In order to overcome the defects of the prior art and meet the needs of the art, the purpose of the present invention is to provide a dry powder composition for oral inhalation administration containing formoterol or a pharmaceutically acceptable salt thereof and tiotropium bromide anhydrate. The prepared dry powder composition has good chemical stability and can maintain a shelf life of more than two years at room temperature. It can be accurately and uniformly administered to the lungs through a dry powder inhalation device, so that the two active ingredients can synergistically exert the effect of relaxing bronchial smooth muscle.

[0011] The present invention adopts the following technical solutions to solve the problem:

[0012] The invention provides an inhalable dry powder composition of medicine, which consists of formoterol or a pharmaceutically acceptable salt thereof, anhydrous tiotropium bromide and a pharmaceutically acceptable carrier.

[0013] The invention is characterized in that suitable pharmaceutically acceptable salts of formoterol include inorganic acid salts or organic acid salts known in the art, and formoterol fumarate is particularly preferred.

[0014] The formoterol is prepared by brominating 4-benzyloxy-3-nitroacetophenone to obtain 4-benzyloxy-3-nitrobromoacetophenone, which is then reduced with sodium borohydride to obtain 1-(4-benzyloxy-3-nitro)phenyl oxirane, which is then coupled with N-(4-methoxyphenyl-2-methylethyl)benzylamine to produce intermediate 5; intermediate 5 is reduced to obtain intermediate 6; intermediate 6 is acylated to obtain intermediate 7; and intermediate 7 is hydrogenated to obtain formoterol.

[0015] The suitable pharmaceutically acceptable salt of formoterol is prepared by a salt-forming reaction of formoterol to generate a crude product; and then the crude product is refined to obtain the suitable pharmaceutically acceptable salt of formoterol.

[0016] Through a large number of studies and experiments, it was found that the stability of tiotropium bromide anhydrate at room temperature is significantly better than that of tiotropium bromide monohydrate, and the tiotropium bromide is tiotropium bromide anhydrate.

[0017] The anhydrous tiotropium bromide is subjected to an ester exchange reaction between 2,2-dithienylglycolic acid methyl ester and scopolamine to obtain 2,2-dithienylglycolic acid scopolamine; the liquid is acidified with dilute hydrochloric acid, the liquid is washed with toluene, and the liquid is alkalized with sodium carbonate acid solution; the liquid is then extracted with dichloromethane, washed three times with purified water, dried and filtered after adding anhydrous sodium sulfate, and then recrystallized with acetonitrile, filtered and dried to obtain 2,2-dithienylglycolic acid scopolamine; 2,2-dithienylglycolic acid scopolamine is added with acetonitrile and dichloromethane solvents to undergo a methylation and bromination reaction with methyl bromide at low temperature, and filtered under reduced pressure to obtain crude tiotropium bromide; crude tiotropium bromide is synthesized from methyl bromide; the crude tiotropium bromide is decolorized by heating with activated carbon, filtered, cooled for crystallization, and then recrystallized with acetonitrile-methanol, and dried under reduced pressure and vacuum to obtain anhydrous tiotropium bromide.

[0018] The schematic diagram of the ester exchange reaction between 2,2-dithienyl glycolic acid methyl ester and scopolol to obtain intermediate III is shown in FIG. Figure 1 .

[0019] The intermediate III is reacted with methyl bromide to obtain crude tiotropium bromide. Figure 2 .

[0020] The pharmaceutically acceptable carrier can be selected from one or more of lactose, sucrose, mannitol, and amino acids, wherein the amino acids include glycine, alanine, valine, leucine, isoleucine, methionine (methionine), proline, tryptophan, serine, tyrosine, cysteine, phenylalanine, asparagine, glutamine, threonine, aspartic acid, glutamic acid, lysine, arginine, and histidine; glycine is particularly preferred.

[0021] The preparation method of the dry powder composition of the present invention comprises the following steps:

[0022] Step 1) Synthesis of Formoterol: 4-benzyloxy-3-nitroacetophenone is brominated to obtain 4-benzyloxy-3-nitrobromoacetophenone, which is then reduced with sodium borohydride to obtain 1-(4-benzyloxy-3-nitro)phenyloxirane, which is then coupled with N-(4-methoxyphenyl-2-methylethyl)benzylamine to produce intermediate 5. Intermediate 5 is reduced to obtain intermediate 6. Intermediate 6 is acylated to obtain intermediate 7. Intermediate 7 is hydrogenated to obtain formoterol.

[0023] Step 2) Formoterol reacts with an acid to obtain a crude pharmaceutically acceptable salt of formoterol; the crude product is decolorized by heating with activated carbon, filtered, cooled for crystallization, and then recrystallized from acetonitrile-methanol, and dried under reduced pressure to obtain a finished pharmaceutically acceptable salt of formoterol.

[0024] Step 3) Synthesis of Tiotropium Bromide Anhydrate: In an anhydrous and oxygen-free box, control the temperature to ≤15°C; evacuate the reaction flask, fill it with nitrogen, and then add 2,2-dithienyl glycolic acid methyl ester, scopolamine, anhydrous toluene, and sodium metal tablets; after the addition is completed, heat and vacuum are turned on, and the liquid temperature is controlled to 70-78°C for reaction; the reaction solution is acidified by dilute hydrochloric acid, washed with toluene, and alkalized with sodium carbonate acid solution; then the solution is extracted with dichloromethane, washed three times with purified water, and anhydrous 2,2-diphenyl glycolate is added. The product is dried over sodium sulfate and filtered, and then recrystallized through acetonitrile. After filtration and drying, 2,2-dithienylglycolic acid scopolamine is obtained; 2,2-dithienylglycolic acid scopolamine is added to acetonitrile and dichloromethane solvent to react with methyl bromide at low temperature through methylation and bromination, and the product is filtered under reduced pressure to obtain crude tiotropium bromide; crude tiotropium bromide is synthesized from methyl bromide; the crude tiotropium bromide is decolorized by heating with activated carbon, filtered, cooled and crystallized, and then recrystallized from acetonitrile-methanol, and dried under reduced pressure and vacuum to obtain anhydrous tiotropium bromide.

[0025] The tiotropium bromide is tested according to the European Pharmacopoeia EP5, (1) impurity A: ≤0.15%; (2) impurity B: ≤0.10%; (3) impurity C: ≤0.1%; (4) impurity D: ≤0.1%; (5) impurity E: ≤0.1%; (6) impurity F: ≤0.1%; (7) single unknown impurity: ≤0.10%, total impurities ≤0.3%.

[0026] Step 4) Micronization of formoterol or its pharmaceutically acceptable salt: Control the humidity of the operating environment to 25-45%, preferably 30%. Micronization can be performed by air flow milling, high-speed grinding, or ball milling. The particle size after milling is D 90 (μm) 5-10, D 50 (μm) 1-5.

[0027] The air flow pulverization needs to control the dew point of the pulverizing gas source pressure to be lower than -40°C.

[0028] Step 5) Micronization of Tiotropium Bromide Anhydrate: Control the humidity of the operating environment to 25-45%, preferably 30%. Micronization can be performed by air flow milling, high-speed grinding, or ball milling. The particle size after milling is D 90 (μm) 5-10, D 50 (μm) 1-5.

[0029] Step 6) Detecting the particle size of the ultrafine powder of formoterol or its pharmaceutically acceptable salt, the ultrafine powder of tiotropium bromide anhydrate, and the ultrafine powder of a pharmaceutically acceptable carrier. If the particle size is qualified, weigh the powder according to the prescribed amount for later use.

[0030] The air flow pulverization needs to control the dew point of the pulverizing gas source pressure to be lower than -40°C.

[0031] Step 7) Preparation of a pharmaceutically acceptable carrier: Control the operating environment humidity to 25-45%, preferably 30%. ≥90% of the pharmaceutically acceptable carrier crystals that cannot pass through an 80-mesh sieve are passed through a hammer mill equipped with a 0.2 mm screen to crush and collect a pharmaceutically acceptable carrier powder. The pharmaceutically acceptable carrier powder is then placed in an ultrasonic vibrating sieve equipped with a 60-150 μm screen and ultrasonically sieved to obtain a pharmaceutically acceptable carrier fine powder having a D90 (μm) of 50-300 and a D50 (μm) of 20-80.

[0032] In step 7, commercially available inhaled lactose, inhaled glycine, or inhaled mannitol that meets the particle size control requirements can be purchased instead.

[0033] Step 8) Controlling the humidity of the operating environment to 25-45%, preferably 30%, the formoterol or a pharmaceutically acceptable salt thereof, tiotropium bromide anhydrate, and a pharmaceutically acceptable carrier are mixed by one or more of sieving mixing, V-shaped mixing, three-dimensional mixing, shear mixing, and the like, preferably shear mixing.

[0034] The composition is mixed, and the weight ratio of formoterol or a pharmaceutically acceptable salt thereof: tiotropium bromide anhydrate: pharmaceutically acceptable carrier is 1:1-15:50-50000, preferably 1:4:550.

[0035] Step 9) The mixed composition is loaded into gelatin hollow capsules or hypromellose capsules by quantitative cannula filling or vacuum drum filling, preferably hypromellose capsules, with a filling amount of 5 to 35 mg.

[0036] Step 10) The filled capsules are packaged in aluminum-plastic (aluminum) packaging to prepare commercially available packaging products.

[0037] The capsule content composition is administered by oral inhalation using an inhalation device and delivered to the lungs, preferably using a powder mist inhalation device CN219423486U disclosed by Nanchang Hongyi Pharmaceutical Co., Ltd.

[0038] The beneficial effects of the present invention are:

[0039] The mixed powder of the composition of the present invention has good filling fluidity, generates less static electricity, has excellent delivery performance after filling, has good chemical stability, and is suitable for industrial production.

[0040] Currently, tiotropium bromide has the problem of hydrolysis at room temperature. The present invention can maintain the total impurity content at room temperature under accelerated conditions within 90 days without increasing by more than 0.5%, and the active ingredient content without decreasing by more than 3%.

[0041] The FPF of the most popular inhalation powders currently on the market (such as Seretide, Spiriva, and Symbicort) is between 15% and 20%, resulting in low effective deposition and a continuous decline in FPF over shelf life. The process of this invention achieves a better FPF, ensuring uniform delivery of both active ingredients and a stable FPF over shelf life. BRIEF DESCRIPTION OF THE DRAWINGS

[0042] Attachment Figure 1 This is a schematic diagram of the ester exchange reaction between methyl 2,2-dithienylglycolate and scopolol to obtain intermediate III.

[0043] Attachment Figure 2 This is a schematic diagram of the synthesis of crude tiotropium bromide by intermediate III and methyl bromide.

[0044] Attachment Figure 3 This is the HPLC detection spectrum of formoterol fumarate related substances.

[0045] Attachment Figure 4 This is the HPLC detection spectrum of related substances of anhydrous tiotropium bromide. DETAILED DESCRIPTION

[0046] The present invention will be further described in detail below with reference to specific examples. The examples are provided only to illustrate the present invention, but not to limit the scope of the present invention.

[0047] The experimental methods in the following examples where specific conditions are not specified are generally performed under conventional conditions or conditions recommended by the manufacturer. Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art.

[0048] In addition, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention. The preferred implementation methods and materials described herein are for demonstration purposes only.

[0049] Unless otherwise specified, all fine particle quantity and delivery uniformity tests were conducted using a powder mist inhalation device (CN219423486U) published by Nanchang Hongyi Pharmaceutical Co., Ltd.

[0050] Example 1: Synthesis of Formoterol Fumarate

[0051] Formoterol fumarate is obtained through a seven-step reaction, and the impurities can be controlled below the limit of the Chinese Pharmacopoeia. It also meets the requirements of the European Pharmacopoeia (EP10.0) and the United States Pharmacopoeia (USP2023). The total impurity content of formoterol fumarate should be less than 0.1%.

[0052] Synthesis of 4-benzyloxy-3-nitroacetophenone by condensation reaction: Under nitrogen protection, various raw materials were added to a reaction flask, refluxed for 6 hours, and then cooled and filtered to obtain a yellow solid.

[0053] Synthesis of 4-benzyloxy-3-nitrobromoacetophenone by bromination reaction: 4-benzyloxy-3-nitroacetophenone was dissolved in chloroform, bromine solution in chloroform was added dropwise, the reaction was carried out for 10 hours, and a white solid was obtained by filtration.

[0054] Synthesis of 1-(4-benzyloxy-3-nitro)phenyl oxirane by sodium borohydride reduction reaction: 4-benzyloxy-3-nitrobromoacetophenone was mixed with NaBH4, K2CO3 and methanol and reacted at room temperature for 2 hours. After concentration, a light yellow solid was obtained, which was then treated to obtain a white powder.

[0055] Synthesis of N-(4-methoxyphenyl-2-methylethyl)benzylamine by reductive amination: Sodium triacetoxyborohydride, 1,2-dichloroethane, p-methoxyphenylacetone, and benzylamine were mixed and reacted at room temperature for 8 hours. After concentration, a reddish-brown oil was obtained.

[0056] Synthesis of intermediate 5 by coupling reaction: 1-(4-benzyloxy-3-nitro)phenyloxirane and N-(4-methoxyphenyl-2-methylethyl)benzylamine were added to a microwave reactor at a power of 400 W. The reaction was carried out for 10 minutes to obtain a reddish-brown colloidal solid crude product as intermediate 5.

[0057] Synthesis of intermediate 6 by iron powder reduction reaction: Intermediate 5 was mixed with activated reduced iron powder, chloroform, methanol and hydrochloric acid, refluxed for 5 hours, cooled and filtered to obtain a black-red oil.

[0058] Acylation reaction to synthesize intermediate 7: Mix intermediate 6 with chloroform, formic acid, and acetic anhydride, stir at room temperature for 4 hours, concentrate, add methanol, sodium carbonate, and water, and stir for 5 hours to obtain a reddish-brown gum. Reaction name: Hydrogenation reaction to synthesize formoterol: Mix intermediate 7 with 10% Pd / C and anhydrous methanol, introduce hydrogen, stir at room temperature for 12 hours, filter, and concentrate to obtain a pale yellow solid.

[0059] Synthesis of formoterol fumarate dihydrate: Mix formoterol with ethanol, add isopropanol solution of fumaric acid, stir at room temperature for 2 hours, concentrate, add ethanol and petroleum ether, refrigerate for 2 hours, and filter to obtain crude formoterol fumarate dihydrate.

[0060] Add about 100g of crude product and about 240ml of 50% methanol solution, install a reflux pipe to pass cooling water, heat to 60-65℃ and stir until dissolved, add about 18g of activated carbon, stir and reflux at 60-65℃ to decolorize for 0.5h.

[0061] Preheat a stainless steel funnel filter with three layers of filter paper to approximately 80°C in a drying oven, attach it to a glass filtration flask, quickly pour in the decolorizing solution, and filter under reduced pressure. Wash twice with approximately 50 ml of acetonitrile-methanol solution (9:1), and drain thoroughly.

[0062] Place a stainless steel funnel filter with three layers of filter paper on a glass filtration flask, pour in the crystallization solution, and filter under reduced pressure. Wash the crystals twice with approximately 300 ml of a 9:1 acetonitrile-methanol solution at or below 0°C, then drain to dryness. Recrystallize the wet product.

[0063] The wet recrystallized product was dried in a vacuum drying oven at 40°C -0.08 MPa (vacuum) for 2 h, turning the product over once. The temperature was then raised to 80°C -0.08 MPa (vacuum) and dried for 16 h, turning the product over once after drying at 80°C for about 2 h to obtain the finished formoterol fumarate, weighing approximately 48.0 g.

[0064] According to the test of formoterol fumarate in Part 2 of the "Chinese Pharmacopoeia (2020 Edition)", all test standards are qualified and qualified products are ready for use.

[0065] Determination of related substances in formoterol fumarate by HPLC: Using the European Pharmacopoeia (EP5) liquid chromatography conditions, the formoterol fumarate sample was analyzed and determined at a wavelength of 214 nm. Only impurity B was detected, and the normalized total impurity was 0.04%. Figure 3 .

[0066] Example 2: Synthesis of Tiotropium Bromide Anhydrate

[0067] In an anhydrous and oxygen-free chamber, maintain the temperature at ≤15°C. Evacuate a 3000ml four-necked reaction flask and fill it with nitrogen to atmospheric pressure. While maintaining nitrogen pressure at 1-2 L / min (nitrogen protection), add 100g of methyl 2,2-dithienylglycolate, 164g of scopolol, 1600ml of anhydrous toluene, and approximately 7.2g of sodium metal flakes.

[0068] Start stirring until it forms a vortex, start heating, start vacuum, control the liquid temperature to 70-78°C and the vacuum to -0.06-0.08Mpa to carry out the reaction, remove the methanol generated by the reaction in time, and distill the dripping toluene methanol distillate.

[0069] Add an appropriate amount of anhydrous toluene from the dropping funnel, maintaining a roughly balanced droplet volume. Raise the temperature to 65°C and time the reaction. A vigorous reaction with abundant bubbles should occur within 1 hour. The reaction should be complete in approximately 6 hours. Switch to an ice-water bath and cool to room temperature with stirring under reduced pressure.

[0070] Take the toluene reaction solution and slowly add it to 2400ml of 5% hydrochloric acid solution while stirring until the endpoint pH is 1-2. Pour the acidified solution into a 5000ml glass separatory funnel, shake well, and let it stand to separate the layers. Let it stand for approximately 20 minutes (approximately 20 minutes) until the layers are clear. Discharge the lower acidic aqueous solution through the drain valve. Pour the acidic aqueous solution into a 5000ml glass separatory funnel, add 730ml of toluene, shake well, and let it stand for approximately 10 minutes until the layers are clear. Discharge the lower acidic aqueous solution through the drain valve and wash twice more using the same method (a total of three washes). Slowly add 3000ml of saturated sodium carbonate solution to the container containing the acidic aqueous solution until the endpoint pH is 9-10. This will produce the alkaline solution.

[0071] Add 1130ml of the alkalized solution to the dichloromethane solution and stir until clear. Pour the solution into a 10,000ml glass separatory funnel, shake well, and allow to stand for approximately 5 minutes until the layers separate. Discard the dichloromethane extract from the lower layer through the drain valve. Extract the upper aqueous layer twice more using the same method (for a total of three extractions). Collect the dichloromethane extracts and combine them with the first extract.

[0072] Add 500ml of purified water to the dichloromethane extract, shake well, and let stand for about 5 minutes until the layers are clear. Discard the lower layer of dichloromethane extract through the drain valve. Wash the dichloromethane extract twice more using the same method (a total of 3 washes).

[0073] Add about 1300g of anhydrous sodium sulfate to the container containing dichloromethane solution, seal it and let it stand for dehydration and drying for 14 hours.

[0074] Place approximately 428 ml of acetonitrile in a rotary evaporator flask and dissolve in a water bath at approximately 80°C. Filter under reduced pressure using a stainless steel funnel filter with 4 layers (2-4 layers) of filter paper. Wash the crystallized filter cake twice with approximately 286 ml of acetonitrile at ≤0°C and drain.

[0075] Take the wet product and dry it in a vacuum drying oven at 40℃ and -0.08MP (vacuum) for 2 hours, turning the material over once. Then heat it to 80℃ and dry it at -0.08MP (vacuum) for 8 hours to obtain 2,2-dithienylglycolic acid scopolamine, weighing about 97.5g.

[0076] To a rotary evaporator, add approximately 96 g of scopolamine 2,2-dithienylglycolate and approximately 960 ml of a 1:1:1 acetonitrile-dichloromethane solution. Set the evaporator to approximately 40°C and rotate until dissolved. Remove the rotary evaporator, add a magnetic stir bar, seal, and cool from -20°C to 0°C or less.

[0077] Quickly pour approximately 139 g of sealed methyl bromide (≤ 0°C) into a solution of acetonitrile-dichloromethane (1:1.1) in a rotary evaporator. Immediately seal with a rubber stopper and tape. Place the solution in the sealed rotary evaporator in a water bath on a magnetic stirrer, stirring to form a vortex. Incubate at 25°C for 48 hours.

[0078] Take the rotary evaporation bottle and use a stainless steel filter equipped with 2 layers of medium-speed filter paper to filter under reduced pressure to obtain the mother liquor of the synthetic crude product.

[0079] Add about 120g of crude mother liquor, add about 240ml of 50% methanol solution, install a reflux pipe to pass cooling water, heat at 60-65℃ and stir until dissolved, add about 18g of activated carbon, stir and reflux at 60-65℃ to decolorize for 0.5h.

[0080] Preheat a stainless steel funnel filter with two layers of filter paper to approximately 80°C in a drying oven, attach it to a glass filtration flask, quickly pour in the decolorizing solution, and filter under reduced pressure. Wash twice with approximately 48 ml of acetonitrile-methanol solution (9:1), and drain thoroughly.

[0081] Place a stainless steel funnel filter with two layers of filter paper on a glass filtration flask, pour in the crystallization solution, and filter under reduced pressure. Wash the crystals twice with approximately 240 ml of a 9:1 acetonitrile-methanol solution at or below 0°C, then drain to dryness. Recrystallize the wet product.

[0082] Take the recrystallized wet product and dry it in a vacuum drying oven at 40°C -0.08MP (vacuum) for 2 hours, turning the material once. Then heat it to 105°C -0.08MP (vacuum) and dry it for 16 hours. Turn the material once after drying at 105°C for about 2 hours to obtain the finished product of tiotropium bromide anhydrate, weighing about 60.0g.

[0083] The finished product is sampled, tested and vacuum packed.

[0084] The finished product of tiotropium bromide anhydrate was tested using the liquid chromatography conditions in accordance with the British Pharmacopoeia (BP) 2020 edition, Volume II, page 1152: (1) Impurity A: 0.13%; (2) Impurity B: Not detected; (3) Impurity C: Not detected; (4) Impurity D: Not detected; (5) Impurity E: Not detected; (6) Impurity F: Not detected; (7) Single unknown impurity: Not detected. Figure 4 .

[0085] Only impurity A was detected in anhydrous tiotropium bromide, accounting for 0.13% of the total impurities.

[0086] Example 3: Micronization of Formoterol Fumarate

[0087] The formoterol fumarate prepared in Example 1 was ground using a DecJet 30 jet mill. Compressed air with a dew point temperature below -40°C and a gas source pressure greater than 12 bar was connected. The Venturi pressure was adjusted to 11 bar and the rotary pressure to 10 bar. The feed rate was controlled to be 0.5 g per minute for grinding. The ground material was collected in a drying bottle for later use.

[0088] Example 4: Micronization of Tiotropium Bromide Anhydrate

[0089] The anhydrous tiotropium bromide of Example 2 was pulverized using a DecJet 30 airflow mill with compressed air having a dew point temperature below -40°C (-41.3°C indicated on the meter) and a gas source pressure greater than 12 bar. The Venturi pressure was adjusted to 11 bar and the rotary pressure to 10 bar. The feed rate was controlled to be 0.5 g per minute and the pulverized product was collected in a drying bottle for later use.

[0090] Example 5: Preparation of glycine carrier:

[0091] Control the operating environment humidity at 35±5%;

[0092] A Quadro U5c hammer mill was used with the main cutter head speed set at 8000 rpm and the feed rate set at 25 rpm. A 0.2 mm sieve was installed and glycine (for injection) with ≥90% of the material failing to pass through an 80-mesh sieve was added to the hammer mill to obtain glycine fine powder (to be screened).

[0093] A 90 μm sieve was installed on a RUSSELL Finex Separator grading sieve, glycine micropowder (to be sieved) was added, and the sieve underflow was collected to obtain glycine micropowder.

[0094] Glycine micropowder D10 (μm) 5; D50 (μm) 26; D90 (μm) 76.

[0095] Example 6: Lactose carrier preparation:

[0096] Control the operating environment humidity at 35±5%

[0097] The D10 of lactose SV001 is 139, the D50 is 226, and the D90 is 312.

[0098] A Quadro U5c hammer mill was used with the main cutter head speed set at 8000 rpm and the feeding speed set at 25 rpm. A 0.2 mm sieve was installed and lactose SV001 was added to the hammer mill to obtain lactose SV001 powder (to be sieved).

[0099] Use a Russell Finex Separator grading sieve equipped with a 90 μm sieve, add lactose SV001 micropowder (to be sieved), sieve and collect the sieve underflow to obtain lactose SV001 micropowder, and vacuum pack it for later use.

[0100] The D10 of lactose SV001 micropowder is 5; D50 is 22; and D90 is 61.

[0101] Lactose L100 is commercially available inhaled lactose with a D10 of 58, a D50 of 132, and a D90 of 214, and is vacuum-packed.

[0102] Lactose L200 is commercially available inhaled lactose with a D10 of 9, a D50 of 72, and a D90 of 149, and is vacuum-packed.

[0103] Lactose L201 is commercially available inhaled lactose with a D10 of 3, a D50 of 22, and a D90 of 59, and is vacuum-packed.

[0104] The particle sizes are shown in Table 1.

[0105] Table 1: Particle size table of Example 5 and Example 6

[0106] Material Name <![CDATA[D 10 (μm)]]> <![CDATA[D 50 (μm)]]> <![CDATA[D 90 (μm)]]> Glycine Micropowder 5 26 76 Lactose SV001 micro powder 5 22 61 Lactose L100 58 132 214 Lactose L200 9 72 149 Lactose L201 3 22 59

[0107] Example 7:

[0108] Steps

[0109] The formoterol fumarate of Example 1, the anhydrous tiotropium bromide of Example 3, and the ultrafine glycine powder of Example 5 were weighed and set aside to obtain Prescription 1, as shown in Table 2.

[0110] Taking into account the production loss of the pilot scale, the feed amount of formoterol fumarate and tiotropium bromide anhydrate was increased by 5%.

[0111] Table 2: Prescription 1, each 5mg inhalation contains 18μg of anhydrous tiotropium bromide and 4.5μg of formoterol fumarate

[0112] Element Single pill dosage Total dosage of 50,000 tablets (g) Formoterol fumarate 4.5 μg 0.236 g Tiotropium bromide anhydrate 18 μg 0.945 g Glycine ultrafine powder 4.9775 mg 248.875 g total 5 mg 250.056 g

[0113] Before use, formoterol fumarate, tiotropium bromide anhydrate, and glycine ultrafine powder were manually sieved through a 100-mesh sieve in a water-free box (control the operating environment humidity to ≤20%) to destroy agglomerates in the package.

[0114] The operating environment humidity was controlled at 30±5%, 1 / 3 of the prescribed weight of glycine ultrafine powder was placed in a high shear mixer and mixed at a low speed of 100 rpm for 30 seconds, formoterol fumarate, tiotropium bromide anhydrate, and 2 / 3 of the prescribed weight of glycine ultrafine powder were added to the high shear mixer, the mixture was mixed at a high speed of 1500 rpm for 3 minutes, and then mixed at a low speed for 60 seconds before discharging to obtain a formoterol fumarate tiotropium bromide composition.

[0115] The humidity of the operating environment was controlled at 35±5%, and the composition was loaded into empty gelatin capsules (manufacturer: Suzhou Capsule Co., Ltd.; specification: 3#; batch number: 12888616) by Hanhui vacuum drum filling.

[0116] The filled composition was aluminum-plastic packaged by a Hualian DPH380 aluminum-plastic blister packaging machine within 6 hours at a heat sealing temperature of 130°C.

[0117] The aluminum-plastic composite is packaged into a finished product by manual simulation, and the packaging environment temperature is ≤30°C.

[0118] Example 8:

[0119] Formoterol fumarate of Example 1, tiotropium bromide anhydrate of Example 3, and glycine ultrafine powder of Example 5 were weighed and prepared to prepare Prescription 1, and the capsules were filled with hypromellose capsules according to the following process.

[0120] Steps:

[0121] The formoterol fumarate of Example 1, the anhydrous tiotropium bromide of Example 3, and the ultrafine glycine powder of Example 5 were weighed and set aside to obtain Prescription 2, as shown in Table 3.

[0122] Taking into account the production loss of the pilot scale, the feed amount of formoterol fumarate and tiotropium bromide anhydrate was increased by 5%.

[0123] Table 3: Prescription 2, each 5mg inhalation contains 18μg of anhydrous tiotropium bromide and 4.5μg of formoterol fumarate

[0124] Element Single pill dosage Total dosage of 50,000 tablets (g) Formoterol fumarate 4.5 μg 0.236 g Tiotropium bromide anhydrate 18 μg 0.945 g Glycine ultrafine powder 4.9775 mg 248.875 g total 5 mg 250.056 g

[0125] Before use, formoterol fumarate, tiotropium bromide anhydrate, and glycine ultrafine powder were manually sieved through a 100-mesh sieve in a water-free box (control the operating environment humidity to ≤20%) to destroy agglomerates in the package.

[0126] The operating environment humidity was controlled at 30±5%, 1 / 3 of the prescribed weight of glycine ultrafine powder was placed in a high shear mixer and mixed at a low speed of 100 rpm for 30 seconds, formoterol fumarate, tiotropium bromide anhydrate, and 2 / 3 of the prescribed weight of glycine ultrafine powder were added to the high shear mixer, the mixture was mixed at a high speed of 1500 rpm for 3 minutes, and then mixed at a low speed for 60 seconds before discharging to obtain a formoterol fumarate tiotropium bromide composition.

[0127] The humidity of the operating environment was controlled at 35±5%, and the composition was loaded into a hypromellose capsule (manufacturer: Suzhou Capsule Co., Ltd.; specification: 3#; batch number: 12887345) by Hanhui vacuum drum filling.

[0128] The filled composition was aluminum-plastic packaged by a Hualian DPH380 aluminum-plastic blister packaging machine within 6 hours at a heat sealing temperature of 130°C.

[0129] The aluminum-plastic composite is packaged into a finished product by manual simulation, and the packaging environment temperature is ≤30°C.

[0130] Example 9:

[0131] Steps

[0132] The formoterol fumarate of Example 1, the anhydrous tiotropium bromide of Example 3, and the lactose SV001 micropowder of Example 6 were weighed and used to obtain Prescription 3, as shown in Table 4.

[0133] Table 4: Prescription 3, each 5mg inhalation contains 18μg of anhydrous tiotropium bromide and 4.5μg of formoterol fumarate

[0134] Element Single pill dosage Total dosage of 50,000 tablets (g) Formoterol fumarate 4.5 μg 0.236 g Tiotropium bromide anhydrate 18 μg 0.945 g Lactose SV001 micro powder 4.9775 mg 248.875 g total 5 mg 250.056 g

[0135] Before use, formoterol fumarate, tiotropium bromide anhydrate, and lactose SV001 micropowder were manually sieved through a 100-mesh sieve in a water-free box (control the operating environment humidity to ≤20%) to destroy agglomerates in the package.

[0136] The operating environment humidity was controlled at 30±5%, 1 / 3 of the prescription weight of lactose SV001 micropowder was placed in a high shear mixer and mixed at a low speed of 100 rpm for 30 seconds, formoterol fumarate, tiotropium bromide anhydrate, and 2 / 3 of the prescription weight of lactose SV001 micropowder were put into the high shear mixer, and the mixture was mixed at a high speed of 1500 rpm for 3 minutes, and then mixed at a low speed for 60 seconds to obtain a formoterol fumarate tiotropium bromide anhydrate composition.

[0137] The humidity of the operating environment was controlled at 35±5%, and the composition was loaded into empty gelatin capsules (manufacturer: Suzhou Capsule Co., Ltd.; specification: 3#; batch number: 12888616) by Hanhui vacuum drum filling.

[0138] The filled composition was aluminum-plastic packaged by a Hualian DPH380 aluminum-plastic blister packaging machine within 6 hours at a heat sealing temperature of 130°C.

[0139] The aluminum-plastic composite is packaged into a finished product by manual simulation, and the packaging environment temperature is ≤30°C.

[0140] Example 10: The formoterol fumarate of Example 1, the anhydrous tiotropium bromide of Example 3, and lactose L100 were weighed to obtain Prescription 4, as shown in Table 5.

[0141] Table 5: Prescription 4, 5 mg per inhalation, containing 18 μg of anhydrous tiotropium bromide and 4.5 μg of formoterol fumarate

[0142] Element Single pill dosage Total dosage of 50,000 tablets (g) Formoterol fumarate 4.5 μg 0.236 g Tiotropium bromide anhydrate 18 μg 0.945 g Lactose L100 4.9775 mg 248.875 g total 5 mg 250.056 g

[0143] Before use, formoterol fumarate, tiotropium bromide anhydrate, and lactose L100 were manually sieved through a 100-mesh sieve in a water-free box (the operating environment humidity was controlled to be ≤20%) to destroy agglomerates in the package.

[0144] The operating environment humidity was controlled at 30±5%, 1 / 3 of the prescription weight of lactose L100 was placed in a high shear mixer and mixed at a low speed of 100 rpm for 30 seconds, formoterol fumarate, tiotropium bromide anhydrate, and 2 / 3 of the prescription weight of lactose L100 were put into the high shear mixer, the mixture was mixed at a high speed of 1500 rpm for 3 minutes, and then mixed at a low speed for 60 seconds before discharging to obtain a formoterol fumarate tiotropium bromide composition.

[0145] The humidity of the operating environment was controlled at 35±5%, and the composition was loaded into empty gelatin capsules (manufacturer: Suzhou Capsule Co., Ltd.; specification: 3#; batch number: 12888616) by Hanhui vacuum drum filling.

[0146] The filled composition was aluminum-plastic packaged by a Hualian DPH380 aluminum-plastic blister packaging machine within 6 hours at a heat sealing temperature of 130°C.

[0147] The aluminum-plastic composite is packaged into a finished product by manual simulation, and the packaging environment temperature is ≤30°C.

[0148] Example 11: The formoterol fumarate of Example 1, the anhydrous tiotropium bromide of Example 3, and lactose L200 were weighed to obtain Prescription 5, as shown in Table 6.

[0149] Table 6: Prescription 5, each 5mg inhalation contains 18μg of anhydrous tiotropium bromide and 4.5μg of formoterol fumarate

[0150] Element Single pill dosage Total dosage of 50,000 tablets (g) (including 5% API loss) Formoterol fumarate 4.5 μg 0.236 g Tiotropium bromide anhydrate 18 μg 0.945 g Lactose L200 4.9775 mg 248.875 g total 5 mg 250.056 g

[0151] Before use, formoterol fumarate, tiotropium bromide anhydrate, and lactose L200 were manually sieved through a 100-mesh sieve in a water-free box (the operating environment humidity was controlled to be ≤20%) to destroy agglomerates in the package.

[0152] The operating environment humidity was controlled at 30±5%, 1 / 3 of the prescription weight of lactose L200 was placed in a high shear mixer and mixed at a low speed of 100 rpm for 30 seconds, formoterol fumarate, tiotropium bromide anhydrate, and 2 / 3 of the prescription weight of lactose L200 were put into the high shear mixer, and the mixture was mixed at a high speed of 1500 rpm for 3 minutes, and then mixed at a low speed for 60 seconds to obtain a formoterol fumarate anhydrate composition.

[0153] The humidity of the operating environment was controlled at 35±5%, and the composition was loaded into empty gelatin capsules (manufacturer: Suzhou Capsule Co., Ltd.; specification: 3#; batch number: 12888616) by Hanhui vacuum drum filling.

[0154] The filled composition was aluminum-plastic packaged by a Hualian DPH380 aluminum-plastic blister packaging machine within 6 hours at a heat sealing temperature of 130°C.

[0155] The aluminum-plastic composite is packaged into a finished product by manual simulation, and the packaging environment temperature is ≤30°C.

[0156] Example 12: The formoterol fumarate of Example 1, the anhydrous tiotropium bromide of Example 3, and inhalation lactose L201 were weighed and prepared to obtain Prescription 6, as shown in Table 7.

[0157] Table 7: Prescription 6, each 5mg inhalation contains 18μg of anhydrous tiotropium bromide and 4.5μg of formoterol fumarate

[0158] Element Single pill dosage Total dosage of 50,000 tablets (g) (including 5% API loss) Formoterol fumarate 4.5 μg 0.236 g Tiotropium bromide anhydrate 18 μg 0.945 g Lactose L201 4.9775 mg 248.875 g total 5 mg 250.056 g

[0159] Before use, formoterol fumarate, tiotropium bromide anhydrate, and lactose L201 were manually sieved through a 100-mesh sieve in a water-free box (control the operating environment humidity to ≤20%) to destroy agglomerates in the package.

[0160] The operating environment humidity was controlled at 30±5%, 1 / 3 of the prescription weight of lactose L201 was placed in a high shear mixer and mixed at a low speed of 100 rpm for 30 seconds, formoterol fumarate, tiotropium bromide anhydrate, and 2 / 3 of the prescription weight of lactose L201 were put into the high shear mixer, and the mixture was mixed at a high speed of 1500 rpm for 3 minutes, and then mixed at a low speed for 60 seconds before discharging to obtain a formoterol fumarate tiotropium bromide composition.

[0161] The humidity of the operating environment was controlled at 35±5%, and the composition was loaded into empty gelatin capsules (manufacturer: Suzhou Capsule Co., Ltd.; specification: 3#; batch number: 12888616) by Hanhui vacuum drum filling.

[0162] The filled composition was aluminum-plastic packaged by a Hualian DPH380 aluminum-plastic blister packaging machine within 6 hours at a heat sealing temperature of 130°C.

[0163] The aluminum-plastic composite is packaged into a finished product by manual simulation, and the packaging environment temperature is ≤30°C.

[0164] Example 13: The formoterol fumarate of Example 1, the anhydrous tiotropium bromide of Example 3, inhalation lactose L100 and lactose L200 were weighed to obtain prescription 7, as shown in Table 8.

[0165] Table 8: Prescription 7, 20 mg per inhalation, containing 18 μg of anhydrous tiotropium bromide and 4.5 μg of formoterol fumarate

[0166] Element Single pill dosage Total dosage of 50,000 tablets (g) (including 5% API loss) Tiotropium bromide anhydrate 18 μg 0.945 g Formoterol fumarate 4.5 μg 0.236 g Lactose L100 4.28 mg 214.0 g Lactose L200 15.70 mg 785.0 g total 20 mg 788.68 g

[0167] Before use, formoterol fumarate, tiotropium bromide anhydrous, lactose L100, and lactose L200 were manually sieved through a 100-mesh sieve in a water-free box (control the operating environment humidity ≤ 20%) to destroy agglomerates in the package.

[0168] The operating environment humidity is controlled at 30±5%, 1 / 3 of the prescription weight of lactose L100 and 1 / 3 of the prescription weight of lactose L200 are placed in a high shear mixer and mixed at a low speed of 100 rpm for 30 seconds, formoterol fumarate, tiotropium bromide anhydrate, 2 / 3 of the prescription weight of lactose L100, and 2 / 3 of the prescription weight of lactose L200 are put into the high shear mixer, the mixture is mixed at a high speed of 1500 rpm for 3 minutes, and then mixed at a low speed for 60 seconds to obtain a formoterol fumarate tiotropium bromide anhydrate composition.

[0169] The humidity of the operating environment was controlled at 35±5%, and the composition was loaded into empty gelatin capsules (manufacturer: Suzhou Capsule Co., Ltd.; specification: 3#; batch number: 12888616) by Hanhui vacuum drum filling.

[0170] The filled composition was aluminum-plastic packaged by a Hualian DPH380 aluminum-plastic blister packaging machine within 6 hours at a heat sealing temperature of 130°C.

[0171] The aluminum-plastic composite is packaged into a finished product by manual simulation, and the packaging environment temperature is ≤30°C.

[0172] Example 14: Fine Particle Fraction of Composition

[0173] The inhalation powder aerosol test method was used using device 3 in the "Determination of Aerodynamic Characteristics of Fine Particles of Inhalation Preparations" 0951 of the "Chinese Pharmacopoeia (2020 Edition)", see Table 9.

[0174] Table 9: Fine particle fractions of tiotropium bromide and formoterol

[0175] prescription Tiotropium bromide (%) Formoterol (%) Prescription 1 40.25 31.94 Prescription 2 42.21 29.45 Prescription 3 35.47 31.08 Prescription 4 30.15 28.35 Prescription 5 31.33 27.48 Prescription 6 34.68 24.37

[0176] Example 15: Delivery Dosage Uniformity of Composition

[0177] The two active ingredients, tiotropium bromide and formoterol, were tested using the inhalation powder delivery dose uniformity test method in 0111 inhalation preparations of the "Chinese Pharmacopoeia (2020 Edition)", see Table 10.

[0178] Table 10: Tiotropium and Formoterol Delivery Dosage Uniformity

[0179] prescription Tiotropium bromide (%) Formoterol (%) Prescription 1 88.2 88.5 Prescription 2 86.5 88.4 Prescription 3 91.7 95.2 Prescription 4 92.3 93.9 Prescription 5 87.1 87.4 Prescription 6 86.3 85.7

[0180] Example 16: Total impurities of the composition

[0181] The total impurities of tiotropium bromide were determined by HPLC using the liquid chromatography conditions on page 1152 of Volume II of the British Pharmacopoeia (BP) 2020 edition.

[0182] The total impurities of formoterol were determined by HPLC using the European Pharmacopoeia (EP5) liquid chromatography conditions, as shown in Tables 11 and 12.

[0183] Table 11: Miscellaneous information of tiotropium and formoterol (Day 0)

[0184] prescription Total impurities of Tiotropium bromide (%) Total impurities in formoterol (%) Prescription 1 0.15 0.05 Prescription 2 0.14 0.05 Prescription 3 0.13 0.06 Prescription 4 0.12 0.05 Prescription 5 0.15 0.06 Prescription 6 0.15 0.05 Prescription 7 0.13 0.06

[0185] Table 12: Total impurities of tiotropium bromide and formoterol (accelerated study for 90 days at a temperature of 40°C ± 2°C and a relative humidity of 75% ± 5%)

[0186] prescription Total impurities of Tiotropium bromide (%) Total impurities in formoterol (%) Prescription 1 0.22 0.07 Prescription 2 0.18 0.07 Prescription 3 0.30 0.07 Prescription 4 0.30 0.06 Prescription 5 0.33 0.08 Prescription 6 0.31 0.06 Prescription 7 0.32 0.07

[0187] Example 17: Stability study of the composition

[0188] Commercially available tiotropium bromide monopreparation, Spiriva, lot number 107147, was purchased as contrast agent 1, and lot number 302249 was purchased as contrast agent 2. The delivery uniformity and fine particle fraction of contrast agents 1 and 2 were tested using the included device. Stability study results are shown in Tables 13, 14, and 15.

[0189] Table 13: Accelerated Stability Study Day 0

[0190]

[0191] Table 14: Accelerated stability study (3 months at 40°C ± 2°C and 75% ± 5% relative humidity)

[0192]

[0193] Table 15: Accelerated stability study (accelerated study for 6 months at a temperature of 40°C ± 2°C and a relative humidity of 75% ± 5%)

[0194]

[0195] Effect evaluation:

[0196] The dry powder composition of the present invention has demonstrated excellent performance in terms of fine particle fraction, delivery metering uniformity, and chemical stability through the practice of commercial production specifications of 50,000 particles. The test results compared with contrast agents 1 and 2 at 0 days, 3 months, and 6 months show that the prescription of the present invention is superior to the contrast agents in terms of fine particle fraction and delivery metering uniformity, and exhibits better stability and consistency in accelerated stability studies. In particular, in terms of impurity control of tiotropium bromide, the problem of easy degradation of tiotropium bromide is solved. In particular, prescriptions 1 and 2 using glycine as a carrier perform outstandingly in various tests and have good application prospects. The preparation process of the present invention is simple and suitable for industrial production and clinical application.

Claims

1. A dry powder composition for inhalation preparation, characterized in that, Comprising formoterol or a pharmaceutically acceptable salt thereof, tiotropium bromide anhydrate and a pharmaceutically acceptable carrier; wherein, The synthesis of formoterol or a pharmaceutically acceptable salt thereof comprises the following steps: a. Using 4-benzyloxy-3-nitroacetophenone as the starting material, bromination reaction is performed to generate 4-benzyloxy-3-nitrobromoacetophenone; b. Reduction with sodium borohydride to produce 1-(4-benzyloxy-3-nitro)phenyl oxirane; c. coupling with N-(4-methoxyphenyl-2-methylethyl)benzylamine to generate intermediate 5; d. Intermediate 5 is subjected to reduction reaction to produce intermediate 6; e. Intermediate 6 is acylated to produce intermediate 7; f intermediate 7 is subjected to hydrogenation reaction to obtain formoterol; g. Formoterol is reacted with an acid to form a salt, decolorized with activated carbon, recrystallized from acetonitrile - methanol and dried under reduced pressure to obtain a pharmaceutically acceptable salt of formoterol; The synthesis of the anhydrate of Tiotropium bromide comprises the following steps: a. 2,2-dithienylglycolic acid methyl ester and scopolamine are subjected to an ester exchange reaction to produce 2,2-dithienylglycolic acid scopolamine; b. Acidification with dilute hydrochloric acid, washing with toluene, alkalization with sodium carbonate, extraction with dichloromethane and purification by recrystallization with acetonitrile; c. The purified 2,2-dithienylglycolic acid scopolamine was subjected to a methylation-bromination reaction with methyl bromide in an acetonitrile-dichloromethane solvent at low temperature to produce crude tiotropium bromide; d. The crude product was decolorized with activated carbon, recrystallized from acetonitrile and methanol, and dried under reduced pressure to give anhydrous tiotropium bromide. The preparation method of the composition comprises: a. Formoterol or a pharmaceutically acceptable salt thereof and tiotropium bromide anhydrate are micronized separately and the operating environment humidity is controlled at 25-45% to meet the requirements of inhalation preparations; b. The micronized active ingredient is mixed with a pharmaceutically acceptable carrier under controlled humidity, and quantitatively filled into hollow capsules, which are then packaged in aluminum-plastic (aluminum) packaging to form the finished product.

2. The dry powder composition according to claim 1, characterized in that The pharmaceutically acceptable salt of formoterol is formoterol fumarate.

3. The dry powder composition according to claim 1, characterized in that The pharmaceutically acceptable carrier can be selected from one or more of lactose, sucrose, mannitol, and amino acids, wherein the amino acids include glycine, alanine, valine, leucine, isoleucine, methionine (methionine), proline, tryptophan, serine, tyrosine, cysteine, phenylalanine, asparagine, glutamine, threonine, aspartic acid, glutamic acid, lysine, arginine, and histidine.

4. The dry powder composition according to claim 1, characterized in that The micronization treatment adopts air flow pulverization, high-speed grinding or ball milling, and the pressure dew point of the pulverization air source is lower than -40°C.

5. The dry powder composition according to claim 1, characterized in that In the mixing step, the weight ratio of formoterol or its pharmaceutically acceptable salt, tiotropium bromide anhydrate and the pharmaceutically acceptable carrier is 1:1-15:50-50000.

6. The dry powder composition according to claim 1, characterized in that The hollow capsules are gelatin hollow capsules or hypromellose capsules, and the filling amount is 5 to 35 mg.

7. The dry powder composition according to claim 1, characterized in that The total impurity content of the tiotropium bromide anhydrate is ≤0.3%, and the single unknown impurity is ≤0.10%.

8. The dry powder composition according to claim 1, characterized in that In an accelerated stability test, the total impurity content of the composition does not increase by more than 0.5% and the active ingredient content does not decrease by more than 3% within 90 days under accelerated conditions.

9. The method for preparing the dry powder composition according to claim 1, characterized in that: The following steps are involved: a. Synthesis and purification of formoterol or a pharmaceutically acceptable salt thereof; b. Synthesis and purification of tiotropium bromide anhydrate; c. Micronization of active ingredients; d. Micronization of pharmaceutically acceptable carriers; e. The active ingredient is mixed with the carrier under controlled humidity; f The mixed composition is quantitatively filled into hollow capsules; g. Aluminum-plastic (aluminum) packaging.

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