Pharmaceutical composition for treating chronic obstructive pulmonary disease and preparation method thereof

Abstract

The invention relates to a pharmaceutical composition for treating chronic obstructive pulmonary disease and a preparation method thereof, in particular to a pharmaceutical composition containing salmeterol, tiotropium bromide and budesonide. The salmeterol, the tiotropium bromide and the budesonide are combined for use, so that a synergistic effect can be exerted, the treatment effect is enhanced, and the pharmaceutical composition has relatively high safety and relatively low adverse reaction occurrence rate and is worthy of wide popularization and application. According to the invention, by controlling the crystal form of tiotropium bromide and the particle sizes and crystal forms of salmeterol, tiotropium bromide, budesonide and the carrier, the medicinal aluminum foil, the polyvinyl chloride solid medicinal hard sheet and the polyamide / aluminum cold-formed solid medicinal composite hard sheet are used for packaging, so that the delivery dose uniformity and the fine particle dose of the medicine are optimized. According to the method, a specific medicine powder inhalation device is adopted, medicine inhaled into the powder inhalation exists in a micronized mode, no propellant or liquid carrier is needed, and a patient can directly inhale medicine particles into the lung through the inhalation action. As the lung surface area is large and the blood supply is rich, the medicine can be quickly absorbed and takes effect, and is especially suitable for relieving acute symptoms.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations and relates to a pharmaceutical composition for treating chronic obstructive pulmonary disease and a preparation method thereof. Background Art

[0002] Tiotropium bromide is a commonly used antiasthmatic drug in clinical practice. It is suitable for the maintenance treatment of dyspnea in patients with COPD. It is a specific and selective anticholinergic drug with a rapid onset and long duration of action. It can effectively inhibit smooth muscle M3 receptors, promote bronchial dilation, improve lung function, and relieve patients' symptoms such as dyspnea and hypoxia.

[0003] Salmeterol is a long-acting β2 receptor agonist that can inhibit the synthesis and release of inflammatory mediators in lung cells, reduce lung inflammatory response, reduce airway hyperresponsiveness, relax respiratory smooth muscle, and at the same time inhibit the release of inflammatory mediators by inflammatory cells such as basophil degranulation, thereby reducing inflammatory damage to bronchial epithelial cells.

[0004] Budesonide, as a glucocorticoid with high binding affinity to the glucocorticoid receptor, can significantly constrict the tiny blood vessels in the lungs, reduce the exudation of inflammatory substances, and effectively inhibit respiratory inflammatory reactions and glandular secretions, thereby quickly relieving patients' symptoms such as cough and wheezing; at the same time, it inhibits the release of allergic transmitters and reduces their activity, thereby reducing airway hyperresponsiveness.

[0005] Studies have shown that the combined use of any two of tiotropium, salmeterol and budesonide is more effective in treating COPD than single medication. Among them, the combined use of tiotropium and salmeterol can dilate the bronchi through different pathways, improve bronchial smooth muscle function, improve lung function, and block the generation of inflammatory cells, improve airway hyperresponsiveness, and thus effectively control the disease; tiotropium combined with budesonide can dilate the bronchi and reduce inflammation, exert a synergistic effect to more effectively control symptoms, and reduce the frequency of acute attacks of COPD. Long-term use helps improve lung function and quality of life; budesonide controls inflammation, and salmeterol dilates the bronchi. The combination of the two can more effectively control symptoms, significantly reduce the frequency and severity of acute exacerbations of COPD, increase FEV1 (forced expiratory volume in one second), improve ventilation function, and effectively relieve symptoms such as dyspnea. Tiotropium, salmeterol and budesonide treat COPD through different mechanisms of action. The combined use of the three can not only further exert a synergistic effect to dilate the bronchi and improve lung function, but also reduce acute exacerbations and more effectively control symptoms.

[0006] The known disclosed triple medication methods include the combined use of tiotropium inhaler and budesonide formoterol inhaler; the combined use of budesonide suspension, salbutamol hydrochloride and tiotropium inhaler; the combined treatment of budesonide suspension and terbutaline sulfate nebulizer, combined with the use of tiotropium powder inhaler, and the combined use of tiotropium inhalation powder inhaler and salmeterol fluticasone inhalation powder inhaler. The above triple medication methods are all the combined use of two or more drug preparations. Although they have significant clinical advantages, they also have some shortcomings and challenges. On the one hand, the risk of drug interactions and the incidence of adverse reactions are increased. At the same time, the combined use of different preparations usually requires patients to use multiple inhalation devices, and the use methods of each device may be different, which increases the complexity of medication. The frequency of medication of different drugs may be different, which can easily lead to patients missing or taking them by mistake, and reduce patient compliance. In addition, confusion may occur during the use of inhalation devices for different drugs, leading to medication errors; the dosage adjustment of combined use of different preparations is complicated, which may limit the optimization of treatment. The cost of long-term treatment may be high and there is potential for drug resistance.

[0007] Therefore, it is necessary to provide a composition and a preparation method thereof with simpler process, lower cost, easier industrialization, and easier administration for patients, which can not only ensure the stability of the composition, but also increase the delivery behavior of the three active ingredients, and at the same time make up for the shortcomings of the combined use of different drug preparations. Summary of the invention

[0008] The first purpose of the present invention is to provide a drug for treating chronic obstructive pulmonary disease, characterized in that it is composed of salmeterol, tiotropium bromide, budesonide, and a carrier. The composition contains tiotropium bromide crystals, the crystals have stable crystal form and uniform particle size distribution, and the pharmaceutical composition composed of the crystals, salmeterol, budesonide, and a pharmaceutically acceptable carrier has a more significant therapeutic effect.

[0009] The second object of the present invention is to provide a method for preparing the composition, using a special dry powder inhalation device, and the patient inhales the atomized drug into the lungs. The efficacy of inhaled powder inhalers and the incidence of adverse drug reactions are closely related to the drug dose and the deposition site of the drug in the respiratory tract. The mixing uniformity RSD is ≤5%, and the unit uniformity of the controlled dose (calculated by tiotropium bromide) is RSD ≤6%. Generally speaking, drug particles with an aerodynamic particle size greater than 5μm are mainly deposited in the throat through inertial impact, and can reach the gastrointestinal tract with swallowing, and then absorbed into the systemic circulation; particles with a particle size of 0.5μm to 5μm enter the lungs with gravity sedimentation, of which particles of 3 to 5μm are mainly distributed in the central area of ​​the lungs (such as the trachea and bronchi), and particles less than 3μm can be delivered more deeply to the peripheral area of ​​the lungs (such as respiratory bronchioles, alveolar ducts and alveolar sacs). Drugs with a particle size less than 5μm are considered to be inhalable doses, which can bind to receptors in the lungs to produce therapeutic effects. During in vitro studies of inhaled powders, drug particles with an aerodynamic size of less than 5 μm are usually defined as fine particle dose (FPD) to characterize the deposition quality of the drug in the lungs, and the proportion of fine particle dose to delivered dose is defined as fine particle fraction (FPF) to characterize the effective deposition efficiency of the drug.

[0010] To achieve the first objective of the present invention, the present invention adopts the following technical solution:

[0011] A pharmaceutical composition for treating chronic obstructive pulmonary disease, comprising salmeterol, tiotropium bromide, budesonide, and a carrier, wherein the composition contains tiotropium bromide crystals, the crystals are stable, and the mass ratio of each component is as follows 1) or 2) or 3)

[0012] 1) 1 part of tiotropium bromide, 2.78 parts of salmeterol, 4.44 parts of budesonide, and 769.56 parts of carrier;

[0013] 2) 1 part of tiotropium bromide, 2.78 parts of salmeterol, 8.89 parts of budesonide, and 765.11 parts of carrier;

[0014] 3) 1 part of tiotropium bromide, 2.78 parts of salmeterol, 17.78 parts of budesonide, and 756.22 parts of carrier;

[0015] The tiotropium bromide raw material is a stable crystal form. Using XRD powder diffraction measurement, the XRD powder diffraction patterns of three batches of raw materials (batch numbers: Y240102, Y240105, and Y240108) have consistent X-ray diffraction angles, indicating that the crystal form is consistent, indicating that the raw material synthesis process is stable, and the crystal form will not change during the storage of the raw material. The characteristic peaks in the diffraction pattern are 11.342, 13.537°, 14.178°, 14.700°, 15.301°, 15.977°, 16.320°, 16.979°, 17.903°, 18.599°, 19.098°, 19.462°, 20.443°, 21.762°, 22.599°, 23.260°, 24.037°, 26.979°, 27.903°, 28.599°, 29.098°, 2 ...5 °, 24.400°, 25.297°, 26.237°, 27.261°, 28.082°, 28.437°, 29.977°, 30.920°, 31.820°, 32.360°, 33.016°, 33.501°, 34.824°, 35.603°, 36.441°, 36.801°, 38.797°, 39.345°.

[0016] According to the aforementioned pharmaceutical composition, wherein the tiotropium bromide raw material is prepared by the following method:

[0017] 1) Add 1 part of intermediate I, 1.5-1.9 parts of intermediate II, 4-16 parts of anhydrous toluene, and 5-10 parts of metal sodium flakes to the reaction flask. Control the liquid temperature to 65-78°C, vacuum--0.05--0.09Mpa to react, and the reaction is completed for 5-7h. The reaction solution is cooled to room temperature, added to hydrochloric acid solution to adjust the pH to ≤3 to acidify the salt, washed with toluene to obtain an acid solution; sodium carbonate solution is added to the acid solution to pH 9-10 to obtain an alkaline solution; the alkaline solution is extracted and separated with 8-11 parts of dichloromethane for 3 times; 11-14 parts of anhydrous sodium sulfate are added to the dichloromethane extract, and the extract is left to stand for dehydration and drying for ≥8h, filtered; the filtrate is evaporated to dryness under reduced pressure to obtain a crude intermediate III; the crude product is refined twice with acetonitrile, cooled and crystallized to obtain a wet product, and vacuum dried to obtain intermediate III.

[0018] 2) Dissolve the intermediate III with acetonitrile-dichloromethane (1:1.1) solution, quickly pour in methyl bromide, seal the reaction bottle, react at 15-35°C for 30-48h, filter the reaction solution, wash the filter cake with acetonitrile:dichloromethane (1:1.1) solution, and drain to obtain the wet crude tiotropium bromide; vacuum dry to obtain the crude tiotropium bromide.

[0019] 3) Add water to the crude product of tiotropium bromide, heat to ≥80℃ until dissolved, add EDTA-2Na and activated carbon, decolorize by rotation at 80-100℃ for 0.5h, filter, wash the activated carbon filter cake with hot water ≥80℃ and drain, stir the filtrate in an ice water bath for crystallization for about 1-2h; filter to obtain a primary recrystallization wet product; take the primary recrystallization wet product, add acetonitrile-methanol solution (9:1), heat to 70-80℃ until dissolved, add activated carbon, decolorize by rotation at 70-80℃ for 0.5h, filter, wash the activated carbon filter cake with acetonitrile-methanol solution (9:1) and drain. Add isopropyl ether to the filtrate and crystallize at room temperature for about 0.5h. Filter, wash the filter cake with isopropyl ether, drain to obtain a secondary recrystallization wet product, vacuum dry to obtain tiotropium bromide raw material.

[0020] The particle size of the salmeterol is D90 of 1 to 10 um, preferably D90 of 5 um;

[0021] The particle size of tiotropium bromide is D90 of 1 to 10 um, preferably D90 of 5 um;

[0022] The particle size of the budesonide is D90 of 1 to 10 um, preferably D90 of 5 um;

[0023] The particle size of the ultrafine powder of the carrier is D90 of 7 to 15 um, preferably D90 of 10 um;

[0024] The particle size of the carrier powder is D90 of 55-75um, preferably D90 of 63um;

[0025] The ratio of the raw material ultrafine powder (including salmeterol ultrafine powder, tiotropium bromide ultrafine powder, budesonide ultrafine powder) to the carrier ultrafine powder is 1:2-10, and the preferred ratio of the carrier ultrafine powder to the carrier micropowder is 1:6;

[0026] The carrier is one of lactose, sucrose, mannitol, erythritol, xylitol, gum arabic, and amino acids, or a mixture of two of them; the preferred carrier is glycine and lactose.

[0027] 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.

[0028] The glycine crystal form is one of the α crystal form and the γ crystal form or a mixture of the two; the preferred glycine crystal form is the α crystal form.

[0029] To achieve the second objective of the present invention, a method for preparing a pharmaceutical composition for treating chronic obstructive pulmonary disease comprises the following steps:

[0030] S1, air flow pulverizing an appropriate amount of salmeterol to obtain salmeterol ultrafine powder 1;

[0031] S2, air flow pulverizing an appropriate amount of tiotropium bromide to obtain tiotropium bromide ultrafine powder 2;

[0032] S3, air flow pulverizing an appropriate amount of budesonide to obtain budesonide ultrafine powder 3;

[0033] S4, crushing an appropriate amount of carrier to obtain carrier powder 4;

[0034] S5, air flow pulverizing a small amount of the carrier fine powder obtained in step S4 to obtain carrier ultrafine powder 5;

[0035] S6, adding the remaining carrier powder obtained in step S4 into a high shear mixer and mixing at a low speed to obtain premixed powder 6;

[0036] S7, adding the carrier ultrafine powder obtained in step S5 and the mixed powder obtained in step S6 into a high shear mixer for high-speed mixing to obtain premixed powder 7;

[0037] S8, adding the mixed powder obtained in step S7 and the ultrafine powder obtained in steps S1, S2 and S3 into a high shear mixer for high-speed mixing to obtain a total mixed powder;

[0038] S9, filling the total mixed powder obtained in step S8 to obtain tiotropium bromide / salmeterol / budesonide capsules.

[0039] S10, packaging the capsules obtained in step S9 with medicinal aluminum foil, polyvinyl chloride solid medicinal hard sheet, or polyamide / aluminum cold-formed solid medicinal composite hard sheet.

[0040] S11. The tiotropium bromide / salmeterol / budesonide capsule product obtained in step S10 is administered using a special powder inhaler of Nanchang Hongyi Pharmaceutical Co., Ltd.

[0041] The air flow crushing conditions in step S1 are a rotation pressure of 5 bar to 6 bar and a Venturi pressure of 6 bar to 7 bar.

[0042] The air flow crushing conditions in step S2 are a rotation pressure of 5 bar to 6 bar and a Venturi pressure of 6 bar to 7 bar.

[0043] The air flow crushing conditions in step S3 are a rotation pressure of 5 bar to 6 bar and a Venturi pressure of 6 bar to 7 bar.

[0044] The crushing conditions in step S4 are as follows: a crushing speed of 3000 to 10000 rpm, a feeding speed of 10 to 30 RPM, and a screen of 0.2 to 0.315 mm.

[0045] The air flow pulverization conditions in step S5 are as follows: a rotation pressure of 0.4-0.6 MPa, a venturi pressure of 0.6-0.7 MPa, and a feeding motor of 10-30 rpm.

[0046] The mixing conditions in step S6 are a stirring speed of 100 to 500 rpm and a mixing time of 20 to 50 seconds.

[0047] The mixing conditions in step S7 are a stirring speed of 500 to 1200 rpm and a mixing time of 30 to 90 seconds.

[0048] The mixing conditions in step S8 are a stirring speed of 800 to 1500 rpm and a mixing time of 10 to 14 minutes.

[0049] The filling condition in step S9 is a filling speed of 10,000 to 50,000 grains per hour.

[0050] The packaging conditions in step S10 are: molding temperature: 120±20°C, heat sealing temperature 1: 150±20°C, heat sealing temperature 2: 150±20°C.

[0051] The tiotropium bromide / salmeterol / budesonide capsule prepared by the method of the present invention has good deposition quality in the lungs and can effectively achieve a therapeutic effect. In vitro research experiments on inhaled powder aerosols show that the fine drug particle fraction FPF (%) is greater than 10%, which can effectively meet the lung deposition requirements, and the fine particle dosage of the composition is consistent with that of the control preparation. BRIEF DESCRIPTION OF THE DRAWINGS

[0052] Attached Figure 1 These are the X-ray diffraction patterns of three batches of tiotropium bromide raw materials. DETAILED DESCRIPTION

[0053] The following are specific embodiments of the present invention, and the embodiments are intended to further describe the present invention rather than to limit the present invention.

[0054] Example 1. Preparation of Stable Crystalline Form of Tiotropium Bromide API

[0055] 1) Add 1 part of intermediate I, 1.5-1.9 parts of intermediate II, 4-16 parts of anhydrous toluene, and 5-10 parts of metal sodium flakes to the reaction flask. Control the liquid temperature to 65-78°C, vacuum--0.05--0.09Mpa to react, and the reaction is completed for 5-7h. The reaction solution is cooled to room temperature, added to hydrochloric acid solution to adjust the pH to ≤3 to acidify the salt, washed with toluene to obtain an acid solution; sodium carbonate solution is added to the acid solution to pH 9-10 to obtain an alkaline solution; the alkaline solution is extracted and separated with 8-11 parts of dichloromethane for 3 times; 11-14 parts of anhydrous sodium sulfate are added to the dichloromethane extract, and the extract is left to stand for dehydration and drying for ≥8h, filtered; the filtrate is evaporated to dryness under reduced pressure to obtain a crude intermediate III; the crude product is refined twice with acetonitrile, cooled and crystallized to obtain a wet product, and vacuum dried to obtain intermediate III.

[0056] 2) Dissolve the intermediate III with acetonitrile-dichloromethane (1:1.1) solution, quickly pour in methyl bromide, seal the reaction bottle, react at 15-35°C for 30-48h, filter the reaction solution, wash the filter cake with acetonitrile:dichloromethane (1:1.1) solution, and drain to obtain the wet crude tiotropium bromide; vacuum dry to obtain the crude tiotropium bromide.

[0057] 3) Add water to the crude product of tiotropium bromide, heat to ≥80℃ until dissolved, add EDTA-2Na and activated carbon, decolorize by rotation at 80-100℃ for 0.5h, filter, wash the activated carbon filter cake with hot water ≥80℃ and drain, stir the filtrate in an ice water bath for crystallization for about 1-2h; filter to obtain a primary recrystallization wet product; take the primary recrystallization wet product, add acetonitrile-methanol solution (9:1), heat to 70-80℃ until dissolved, add activated carbon, decolorize by rotation at 70-80℃ for 0.5h, filter, wash the activated carbon filter cake with acetonitrile-methanol solution (9:1) and drain. Add isopropyl ether to the filtrate and crystallize at room temperature for about 0.5h. Filter, wash the filter cake with isopropyl ether, drain to obtain a secondary recrystallization wet product, vacuum dry to obtain tiotropium bromide raw material.

[0058] The obtained tiotropium bromide crystal form has the same X-ray diffraction angle in the XRD powder diffraction patterns of three batches of raw materials (batch numbers: Y240102, Y240105, and Y240108), indicating that the crystal form is consistent, indicating that the raw material synthesis process is stable, and the crystal form will not change during the storage of the raw material. The characteristic peaks in the diffraction pattern obtained by XRD powder diffraction measurement are 11.342, 13.537°, 14.178°, 14.700°, 15.301°, 15.977°, 16.320°, 16.979°, 17.903°, 18.599°, 19.098°, 19.462°, 20.443°, 21.762°, 22.599°, 23.260°, 2 4.037°, 24.400°, 25.297°, 26.237°, 27.261°, 28.082°, 28.437°, 29.977°, 30.920°, 31.820°, 32.360°, 33.016°, 33.501°, 34.824°, 35.603°, 36.441°, 36.801°, 38.797°, 39.345°, e.g. Figure 1 shown.

[0059] [Example 1] The formulation composition of tiotropium bromide / salmeterol / budesonide capsules (specifications 18 μg / 50 μg / 80 μg) (see Table 1).

[0060] Table 1 Composition of Tiotropium / Salmeterol / Budesonide Capsules Prescription

[0061]

[0062] The inhalation preparation process was adopted, using batch Y240102 of tiotropium bromide API, and the process is shown in Table 2.

[0063] Table 2 Inhalation preparation process steps

[0064]

[0065]

[0066] [Example 2] The formulation composition of tiotropium bromide / salmeterol / budesonide capsules (specifications 18 μg / 50 μg / 160 μg) (see Table 3).

[0067] Table 3 Composition of Tiotropium / Salmeterol / Budesonide Capsule Prescription

[0068]

[0069] The inhalation preparation process was adopted, using batch Y240102 of tiotropium bromide API, and the process is shown in Table 4.

[0070] Table 4 Inhalation preparation process steps

[0071]

[0072]

[0073] [Example 3] The formulation composition of tiotropium bromide / salmeterol / budesonide capsules (specifications 18 μg / 50 μg / 320 μg) (see Table 5).

[0074] Table 5 Composition of Tiotropium / Salmeterol / Budesonide Capsule Prescription

[0075]

[0076] The inhalation preparation process was adopted, using batch Y240102 of tiotropium bromide API, and the process is shown in Table 6.

[0077] Table 6 Inhalation preparation process steps

[0078]

[0079] [Example 4] The formulation composition of tiotropium bromide / salmeterol / budesonide capsules (specifications 18 μg / 50 μg / 80 μg) (see Table 7).

[0080] Table 7 Composition of Tiotropium / Salmeterol / Budesonide Capsule Prescription

[0081]

[0082] The inhalation preparation process was adopted, using batch Y240102 of tiotropium bromide API, and the process is shown in Table 8.

[0083] Table 8 Inhalation preparation process steps

[0084]

[0085]

[0086] [Example 5] The formulation composition of tiotropium bromide / salmeterol / budesonide capsules (specifications 18 μg / 50 μg / 160 μg) (see Table 9).

[0087] Table 9 Composition of Tiotropium / Salmeterol / Budesonide Capsule Prescription

[0088]

[0089] The inhalation preparation process was adopted, using batch Y240102 of tiotropium bromide API, and the process is shown in Table 10.

[0090] Table 10 Inhalation preparation process steps

[0091]

[0092]

[0093] [Example 6] The formulation composition of tiotropium bromide / salmeterol / budesonide capsules (specifications 18 μg / 50 μg / 320 μg) (see Table 11).

[0094] Table 11 Composition of Tiotropium / Salmeterol / Budesonide Capsules Prescription

[0095]

[0096] The inhalation preparation process was adopted, using batch Y240102 of tiotropium bromide raw material, and the process is shown in Table 12.

[0097] Table 12 Inhalation preparation process steps

[0098]

[0099]

[0100] [Example 7] The formulation composition of Tiotropium / Salmeterol / Budesonide Capsules (specifications 18 μg / 50 μg / 80 μg) (see Table 13).

[0101] Table 13 Composition of Tiotropium / Salmeterol / Budesonide Capsules Prescription

[0102]

[0103] The inhalation preparation process was adopted, using batch Y240102 of tiotropium bromide raw materials, and the process is shown in Table 14.

[0104] Table 14 Inhalation preparation process steps

[0105]

[0106]

[0107] [Example 8] The formulation composition of tiotropium bromide / salmeterol / budesonide capsules (specifications 18 μg / 50 μg / 160 μg) (see Table 15).

[0108] Table 15 Composition of Tiotropium / Salmeterol / Budesonide Capsules Prescription

[0109]

[0110] The inhalation preparation process was adopted, using batch Y240102 of tiotropium bromide raw material, and the process is shown in Table 16.

[0111] Table 16 Inhalation preparation process steps

[0112]

[0113] [Example 9] The formulation composition of Tiotropium / Salmeterol / Budesonide Capsules (specifications 18 μg / 50 μg / 320 μg) (see Table 17).

[0114] Table 17 Composition of Tiotropium / Salmeterol / Budesonide Capsules Prescription

[0115]

[0116] The inhalation preparation process was adopted, using batch Y240102 of tiotropium bromide raw materials, and the process is shown in Table 18.

[0117] Table 18 Inhalation preparation process steps

[0118]

[0119]

[0120] [Example 10] The formulation composition of Tiotropium / Salmeterol / Budesonide Capsules (specifications 18 μg / 50 μg / 80 μg) (see Table 19).

[0121] Table 19 Composition of Tiotropium / Salmeterol / Budesonide Capsules Prescription

[0122]

[0123] The inhalation preparation process was adopted, using batch Y240102 of tiotropium bromide raw material, and the process is shown in Table 20.

[0124] Table 20 Inhalation preparation process steps

[0125]

[0126]

[0127] [Example 11] The formulation composition of Tiotropium / Salmeterol / Budesonide Capsules (specifications 18 μg / 50 μg / 160 μg) (see Table 21).

[0128] Table 21 Composition of Tiotropium / Salmeterol / Budesonide Capsules Prescription

[0129]

[0130] The inhalation preparation process was adopted, using batch Y240102 of tiotropium bromide raw material, and the process is shown in Table 22.

[0131] Table 22 Inhalation preparation process steps

[0132]

[0133]

[0134] [Example 12] The formulation composition of Tiotropium / Salmeterol / Budesonide Capsules (specifications 18 μg / 50 μg / 320 μg) (see Table 23).

[0135] Table 23 Composition of Tiotropium / Salmeterol / Budesonide Capsules Prescription

[0136]

[0137] The inhalation preparation process was adopted, using batch Y240102 of tiotropium bromide raw material, and the process is shown in Table 24.

[0138] Table 24 Inhalation preparation process steps

[0139]

[0140]

[0141] [Example 13] The formulation composition of Tiotropium / Salmeterol / Budesonide Capsules (specifications 18 μg / 50 μg / 80 μg) (see Table 25).

[0142] Table 25 Composition of Tiotropium / Salmeterol / Budesonide Capsules Prescription

[0143]

[0144] The inhalation preparation process was adopted, using batch Y240102 of tiotropium bromide raw material, and the process is shown in Table 26.

[0145] Table 26 Inhalation preparation process steps

[0146]

[0147] [Example 14] The formulation composition of Tiotropium / Salmeterol / Budesonide Capsules (specifications 18 μg / 50 μg / 160 μg) (see Table 27).

[0148] Table 27 Composition of Tiotropium / Salmeterol / Budesonide Capsules Prescription

[0149]

[0150] The inhalation preparation process was adopted, using batch Y240102 of tiotropium bromide raw material, and the process is shown in Table 28.

[0151] Table 28 Inhalation preparation process steps

[0152]

[0153]

[0154] [Example 15] The formulation composition of Tiotropium / Salmeterol / Budesonide Capsules (specifications 18 μg / 50 μg / 320 μg) (see Table 29).

[0155] Table 29 Composition of Tiotropium / Salmeterol / Budesonide Capsules Prescription

[0156]

[0157] The inhalation preparation process was adopted, using batch Y240102 of tiotropium bromide raw material, and the process is shown in Table 30.

[0158] Table 30 Inhalation preparation process steps

[0159]

[0160]

[0161] Effect evaluation:

[0162] 1) Preparation Example 1 to Preparation Example 12 were tested for content determination (limit requirement: 80.0%-105.0% of the labeled amount of tiotropium bromide, 80.0%-105.0% of the labeled amount of salmeterol, and 80.0%-105.0% of the labeled amount of budesonide); delivery dose uniformity (limit requirement: 80%-120% of the labeled amount of tiotropium bromide, 80%-120% of the labeled amount of salmeterol, and 80%-120% of the labeled amount of budesonide); fine drug particle fraction FPF (%) (limit requirement: tiotropium bromide should not be less than 10% of the labeled amount, salmeterol should not be less than 10% of the labeled amount, and budesonide should not be less than 10% of the labeled amount) and the results all met the requirements. The results are shown in Table 31.

[0163] Table 31 Test results of content, delivery dose uniformity and fine drug particle fraction of formulation examples 1 to 12

[0164]

[0165] 2) Preparation Examples 2, 5, 7, 10, and 13 were subjected to stability studies at accelerated intermediate conditions (25°C ± 2°C / RH 65% ± 5%) in accordance with the 2020 edition of the Chinese Pharmacopoeia Stability Guidelines. The results of the 6-month stability tests were mainly for the content and fine drug particle fraction FPF of the products. The results were good and met the requirements. The results are shown in Table 32.

[0166] Table 32 Accelerated stability study results of formulation examples 2, 5, 7, 10, 13

[0167]

[0168] From the above data, it can be seen that the tiotropium bromide / salmeterol / budesonide capsules prepared by the present invention have a reasonable prescription, a simple preparation process, low cost, are easier to industrialize, and are easier for patients to take. The composition and its preparation method not only ensure the stability of the composition, but also increase the delivery behavior of the three active ingredients, while making up for the shortcomings of the combined use of different drug preparations.

Claims

1. A pharmaceutical composition for treating chronic obstructive pulmonary disease, characterized in that: It is composed of salmeterol, tiotropium bromide, budesonide, and carrier; The salmeterol includes its pharmaceutically acceptable salts, hydrates, etc.; The tiotropium bromide includes its pharmaceutically acceptable salts, hydrates, etc.; The budesonide includes its pharmaceutically acceptable salts, hydrates, etc.; The carrier is one of lactose, sucrose, mannitol, erythritol, xylitol, gum arabic and amino acids or a mixture of two of them; 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; The glycine crystal form is one of the α crystal form and the γ crystal form or a mixture of the two; The tiotropium bromide is a stable crystalline form. The characteristic peaks 2θ in the diffraction pattern measured by XRD powder diffraction are 11.342, 13.537°, 14.178°, 14.700°, 15.301°, 15.977°, 16.320°, 16.979°, 17.903°, 18.599°, 19.098°, 19.462°, 20.443°, 21.762°, 22.599°, 23.260°, 24.037°, 24.400°, 25.297 °, 26.237°, 27.261°, 28.082°, 28.437°, 29.977°, 30.920°, 31.820°, 32.360°, 33.016°, 33.501°, 34.824°, 35.603°, 36.441°, 36.801°, 38.797°, 39.345° display; The particle size of the salmeterol is D90 of 1 to 10 um; The particle size of the tiotropium bromide is D90 1 to 10 um; The particle size of the budesonide is D90 of 1 to 10 um; The carrier ultrafine powder particle size D90 is 7 to 15um; The carrier powder particle size D90 is 55 ~ 75um; The ratio of the raw material ultrafine powder (including salmeterol ultrafine powder, tiotropium bromide ultrafine powder and budesonide ultrafine powder) to the carrier ultrafine powder is 1:2-10.

2. A pharmaceutical composition for treating chronic obstructive pulmonary disease and a preparation method thereof, comprising the following steps: S1, air flow pulverizing an appropriate amount of salmeterol to obtain salmeterol ultrafine powder 1; S2, air flow pulverizing an appropriate amount of tiotropium bromide to obtain tiotropium bromide ultrafine powder 2; S3, air flow pulverizing an appropriate amount of budesonide to obtain budesonide ultrafine powder 3; S4, crushing an appropriate amount of carrier to obtain carrier powder 4; S5, air flow pulverizing a small amount of the carrier fine powder obtained in step S4 to obtain carrier ultrafine powder 5; S6, adding the remaining carrier powder obtained in step S4 into a high shear mixer and mixing at a low speed to obtain premixed powder 6; S7, adding the carrier ultrafine powder obtained in step S5 and the mixed powder obtained in step S6 into a high shear mixer for high-speed mixing to obtain premixed powder 7; S8, adding the mixed powder obtained in step S7 and the ultrafine powder obtained in steps S1, S2 and S3 into a high shear mixer for high-speed mixing to obtain a total mixed powder; S9, filling the total mixed powder obtained in step S8 to obtain tiotropium bromide / salmeterol / budesonide capsules; S10, packaging the capsules obtained in step S9 with medicinal aluminum foil, polyvinyl chloride solid medicinal hard sheet, or polyamide / aluminum cold-formed solid medicinal composite hard sheet; S11, administering the tiotropium bromide / salmeterol / budesonide capsule product obtained in step S10 using a special powder inhaler of Nanchang Hongyi Pharmaceutical Co., Ltd.; The air flow crushing conditions in step S1 are a rotation pressure of 5 bar to 6 bar and a Venturi pressure of 6 bar to 7 bar; The air flow crushing conditions in step S2 are a rotation pressure of 5 bar to 6 bar and a Venturi pressure of 6 bar to 7 bar; The air flow crushing conditions in step S3 are a rotation pressure of 5 bar to 6 bar and a Venturi pressure of 6 bar to 7 bar; The crushing conditions in step S4 are as follows: crushing speed 3000-10000 rpm, feeding speed 10-30 RPM, screen 0.2-0.315 mm; The air flow crushing conditions in step S5 are as follows: a rotation pressure of 0.4-0.6 MPa, a venturi pressure of 0.6-0.7 MPa, and a feeding motor of 10-30 rpm; The mixing conditions of step S6 are a stirring speed of 100 to 500 rpm and a mixing time of 20 to 50 seconds; The mixing conditions in step S7 are a stirring speed of 500 to 1200 rpm and a mixing time of 30 to 90 seconds; The mixing conditions in step S8 are a stirring speed of 800 to 1500 rpm and a mixing time of 10 to 14 minutes; The filling condition of step S9 is a filling speed of 10,000 to 50,000 grains per hour; The packaging conditions in step S10 are: molding temperature: 120±20°C, heat sealing temperature 1: 150±20°C, heat sealing temperature 2: 150±20°C.

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