Aclidinium bromide inhalation lyophilized preparation and preparation method thereof

Abstract

The present invention discloses an aclidinium bromide inhalation lyophilized agent and a preparation method thereof. The present invention provides an aclidinium bromide lyophilized agent, comprising an active ingredient aclidinium bromide, a pH buffer solution, and an osmotic pressure regulator; and also provides a preparation method of the lyophilized agent. The aclidinium bromide lyophilized agent provided by the present invention does not contain a preservative, has good stability, reliable quality, and good safety. The preparation method of the present invention solves the problem that the powder inhalation dosage form is not suitable for infants and young children who do not have the ability of autonomous inhalation and patients with active breathing difficulties. The preparation method of the aclidinium bromide lyophilized agent is simple to operate and easy to industrialize.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical compositions, and in particular to an aclidinium bromide inhalation lyophilized preparation and a preparation method thereof. Background Art

[0002] Chronic obstructive pulmonary disease (COPD) has become a serious public health problem due to its large number of patients, high mortality rate, and heavy socioeconomic burden. COPD is currently the fourth leading cause of death worldwide, and by 2020 COPD will rank fifth in the world's economic burden of disease. In China, COPD is also an important chronic respiratory disease that seriously endangers people's health. Pulmonary inhalation administration can directly deliver drugs to the bronchi and lungs, which can significantly reduce the oral dosage and reduce the side effects of drugs while improving the therapeutic effect. Therefore, pulmonary administration is the preferred route of administration for COPD treatment.

[0003] The chemical name of aclidinium bromide is 4-(2-hydroxy-2,2-di(thiophen-2-yl)acetoxy)-1-(3-phenoxypropyl)quinulin-1-ammonium bromide; the molecular formula is C26H30BrNO4S2; the molecular weight is 564.56, it is a white or off-white powder; the melting point is 224-229°C; it is very slightly soluble in water, and the structure is as follows:

[0004]

[0005] Aclidinium bromide is a long-acting inhaled anticholinergic drug that can act on M3 receptors for a long time and on M2 receptors for a short time. Therefore, it has high selectivity for cholinergic M3 receptors and is a muscarinic M3 receptor antagonist. When inhaled, aclidinium bromide can inhibit the effect of acetylcholine on muscarinic receptors of airway smooth muscle, thereby inhibiting the contraction of airway smooth muscle and causing bronchial dilation, thereby significantly improving the patient's respiratory condition.

[0006] The raw material aclidinium bromide is poorly soluble. Currently, there is no aclidinium bromide inhalation solution on the domestic market. Overseas, all products are powder inhalers. However, the disadvantage of this powder inhaler is that it is not suitable for infants and children who are unable to inhale independently and patients with active breathing difficulties.

[0007] In order to solve the above technical problems, the present invention provides an inhalation type lyophilized agent, which is added with a solvent to form a solution containing 0.1 mg per 1 ml, and enters the lungs with the patient's breathing for treatment. The preparation of the invention has the characteristics of rapid absorption, high bioavailability, and no gastrointestinal side effects and irritation. Summary of the invention

[0008] In view of the problems existing in the prior art, an aclidinium bromide inhalation lyophilized agent and a preparation method thereof are proposed in the present invention to overcome the above problems or at least partially solve the above problems.

[0009] In order to achieve the above object, the present invention adopts the following technical solutions:

[0010] According to one aspect of the present invention, a lyophilized aclidinium bromide inhalation preparation is provided, wherein a single dose of the lyophilized preparation comprises 0.2-0.6 mg of aclidinium bromide, 30-35 mg of an osmotic pressure regulator and a pH buffer solution, wherein the amount of the pH buffer solution is such that the pH value of the inhalation solution after the lyophilized preparation is reconstituted is 2.5-4.0.

[0011] Preferably, a single dose of the lyophilized agent contains 0.2-0.5 mg of aclidinium bromide, 32-35 mg of an osmotic pressure regulator and a pH buffer solution, and the amount of the pH buffer solution is such that the pH value of the inhalation solution after the lyophilized agent is reconstituted is 2.5-3.0.

[0012] Preferably, the pH buffer solution comprises a first buffer and a second buffer. When the first buffer is citric acid, the second buffer is sodium citrate. When the first buffer is disodium hydrogen phosphate, the second buffer is hydrochloric acid.

[0013] Preferably, a single dose of the lyophilized agent contains 0.2-0.6 mg of aclidinium bromide, 30-35 mg of an osmotic pressure regulator, 3-16 mg of citric acid and sodium citrate, wherein the sodium citrate is used to adjust the pH value of the inhalation solution after the lyophilized agent is reconstituted to 2.5-4.0.

[0014] Preferably, a single dose of the lyophilized agent contains 0.2-0.6 mg of aclidinium bromide, 30-35 mg of an osmotic pressure regulator, 4-20 mg of disodium hydrogen phosphate and hydrochloric acid, wherein the hydrochloric acid is used to adjust the pH value of the inhalation solution after the lyophilized agent is reconstituted to 2.5-4.0.

[0015] Preferably, the osmotic pressure regulator is sodium chloride.

[0016] Preferably, the steps include:

[0017] Preparation of solution: dissolving the first buffer, aclidinium bromide and osmotic pressure regulator in a solvent to form solution a after all are dissolved; adding the second buffer to adjust the pH value to 2.5-4.0 to form solution b; filtering and sterilizing solution b, and filling it into a single-dose packaging container to obtain solution c; wherein the solvent is water for injection, preferably 80% water for injection, and the temperature of the preparation process is controlled at 20°C-30°C;

[0018] Freeze drying: pre-freeze solution c, sublimate it, and then freeze dry it. After freeze drying, increase the pressure, open the box, and roll the lid.

[0019] Preferably, the specific process of freeze-drying is:

[0020] The first stage of pre-freezing: the room temperature is uniformly reduced to -50°C within 1-2.5 hours and kept warm for 1 hour;

[0021] The second stage: within 1-2.5 hours, the temperature rises from -50℃ to -15℃ at a constant speed, and within 1-2 hours, the temperature drops from -15℃ to -50℃ at a constant speed;

[0022] The third stage: within 1-2.5 hours, the temperature rises from -50℃ to -15℃ at a constant speed, and within 1-2 hours, the temperature drops from -15℃ to -50℃ at a constant speed;

[0023] Sublimation vacuum -50℃ to -10℃, a total of 18-20h;

[0024] Dry and vacuum dry at -10℃ and raise the temperature to 25℃ for 4-6h.

[0025] It should be noted that the prescription content and composition of the aclidinium bromide inhalation lyophilized agent of the present invention are determined based on the properties of aclidinium bromide being easily hydrolyzed and sensitive to acid, alkali, light, and oxidation, and the prescription is obtained by investigation and research from the perspectives of pH value range, stabilizer, pH buffer system and concentration, dosage of osmotic pressure regulator, and concentration of the main drug aclidinium bromide. The detailed research contents are as follows:

[0026] 1. Investigation on the stability of raw material solution

[0027] The stability of the raw material aqueous solution was measured, and the results are shown in Table 1. Table 1,

[0028]

[0029] From the results in Table 1, it can be seen that the aqueous solution of aclidinium bromide raw material is unstable and degrades by about 4% in 12 hours at room temperature (about 25°C).

[0030] 2. Investigation of pH range

[0031] 2.1. Sample batch number

[0032] 190701-1~190701-6.

[0033] 2.2 Preparation process

[0034] Add 160 ml of water for injection into a beaker, add aclidinium bromide and dissolve it to form solution 1. At room temperature, use dilute hydrochloric acid or sodium hydroxide to adjust the pH value of solution 1 to 3.0, 4.0, 5.0, 6.0, 7.0, and 8.0, respectively. Add water to the full amount, filter with a 0.22 μm water membrane, and fill in a low-density polyethylene (LDPE) bottle with a filling volume of 5 ml. In addition, the pH value of the aqueous solution of the main drug of aclidinium bromide is close to neutral. During the preparation process, it was found that when the pH value was adjusted with sodium hydroxide, the pH value was unstable and had a downward trend. It is speculated that the hydrolysis of aclidinium bromide may be catalyzed under alkaline conditions. After being kept at room temperature for 5 days, the measurement results of solution 1 are shown in Table 2. Table 2,

[0035]

[0036] 2.3 Results Analysis

[0037] As shown in Table 2, when the pH value is in the range of 3.0 to 5.0, the pH value is relatively stable, but aclidinium bromide degrades faster; when the pH value is adjusted to 7.0 to 8.0, the pH value decreases more, and the related substances of aclidinium bromide increase more, which confirms the speculation that the hydrolysis of aclidinium bromide is accelerated under alkaline conditions.

[0038] 3. Examining the pH range under buffer system conditions

[0039] 3.1. Sample batch number

[0040] 190704-1~190704-6.

[0041] 3.2 Preparation process

[0042] At room temperature, add 80% water for injection into a beaker, add citric acid-sodium citrate solution, adjust the pH value to 3.0, 4.0, 5.0, 6.0, and 7.0, then add the main drug and osmotic pressure regulator in turn, stir to dissolve, filter with 0.22μm water membrane, and fill in LDPE bottle with a filling volume of 5ml. Measure each prescription at 0 day, 30 days, 6℃±2℃, 25℃-40%RH, and the measurement results are shown in Table 3. Table 3,

[0043]

[0044]

[0045] 3.3 Results Analysis

[0046] From the results in Table 3, it can be seen that when the pH value of the citric acid-sodium citrate buffer system is 3.0-6.0, the pH value is relatively stable under the conditions of 6℃±2℃, 25℃-40%RH for 5 days, and there is no significant difference in properties and color; the related substances increase with the increase of the pH value of the buffer system, so the pH value of the buffer system is reduced to 2.5 to further investigate more stable pH conditions.

[0047] 3.4. Sample batch number

[0048] 190901-1~190901-3.

[0049] 3.5 Preparation process

[0050] Add 80% injection water to a beaker at room temperature, the temperature is 20℃-30℃, add citric acid, main drug and sodium chloride in turn, stir while adding to dissolve, add sodium citrate to adjust the pH value to 2.5, 2.8, 3.0 respectively, then add water to the full amount, filter with 0.22μ filter membrane, fill in LDPE bottle, fill volume 5ml, the results are shown in Table 4. Table 4,

[0051]

[0052]

[0053] 3.6 Results Analysis

[0054] From the results in Table 4, it can be seen that when the pH value of the citric acid-sodium citrate buffer system is 2.5-2.8, the pH value of the prescription is stable for 10 days under the conditions of 6℃±2℃ and 25℃-40%RH, and there is no significant difference in properties and color; the related substances increase with the increase of the pH value of the buffer system, and the buffer system is most stable at a pH of 2.5.

[0055] Three prescriptions with main drug concentrations of 0.4 mg / ml, 0.2 mg / ml and 0.1 mg / ml were prepared respectively, and the stability of the prescriptions at different main drug concentrations was investigated.

[0056] 4.1. Sample batch number

[0057] 190805-1~190805-3.

[0058] 4.2 Preparation process

[0059] The results of the main drug prescriptions with different concentrations at 0 days, 30 days, 6℃±2℃, 25℃-40% relative humidity (RH) are shown in Table 5. Table 5:

[0060]

[0061]

[0062] 4.3 Results Analysis

[0063] From the results in Table 5, it can be seen that there was no significant difference in the properties, pH value, color and related substances of the main drug at different concentrations at 30 days.

[0064] 5. Investigation of the type and concentration of buffer system

[0065] Study on the concentration of citric acid-sodium citrate buffer system

[0066] 5.1. Sample batch number

[0067] 191101-1~191101-3.

[0068] 5.2 Preparation process

[0069] At room temperature, add 80% of the injection water in the beaker, the system temperature is 20℃~30℃, add the prescribed amount of citric acid (191101-1 batch: 0.02mol / L, 191101-2 batch: 0.01mol / L, 191101-3 batch: 0.005mol / L), main drug and sodium chloride in turn, stir while adding to dissolve, add sodium citrate (190902-1 batch: 0.24mmol / L, 190902-2 batch: 0.01mmol / L, 190902-3 batch: not added) to adjust the pH value to 2.5, then add water to the full amount, filter with 0.22μ filter membrane, fill in low-density polyethylene (LDPE) bottle, fill 4ml. 0 days, 30 days and 2℃-8℃, 25℃-40%RH conditions, the results are shown in Table 6. Table 6,

[0070]

[0071]

[0072] Phosphate buffer system

[0073] 5.3. Sample batch number

[0074] 191203-1~191203-3.

[0075] 5.4 Preparation process

[0076] Add 80% injection water in a beaker at room temperature, the system temperature is 20℃~30℃, add the prescribed amount of disodium hydrogen phosphate (191203-1 batch: 0.1%, 191203-2 batch: 0.3%, 191203-3 batch: 0.5%), the main drug and sodium chloride in turn, stir while adding to dissolve, add hydrochloric acid to adjust the pH value to 2.5, then add water to the full amount, filter with a 0.22μ filter membrane, fill in LDPE bottles, fill 4ml. 0 days, 30 days and 2℃-8℃, 25℃-40%RH conditions, the results are shown in Table 7. Table 7,

[0077]

[0078] 5.5 Results Analysis

[0079] From the results in Tables 6 and 7, it can be seen that there is no significant difference in the properties, pH value, and color of the prescriptions under the two buffer system conditions. The growth rate of related substances in the citrate buffer system is slightly slower than that in the phosphate buffer system, and the citrate buffer system is preferred. There is no significant difference in the properties, pH value, color, and related substances of the prescriptions with different concentrations of citrate buffer systems.

[0080] 6. Whether to add stabilizer in the prescription

[0081] 6.1. Sample batch number

[0082] 190901-3~190901-6.

[0083] 6.2 Preparation process

[0084] Using citric acid-sodium citrate with a pH value of 3.0 as the buffer system, the effects of disodium edetate, sodium metabisulfite and no stabilizer on the stability of the prescription were investigated. At room temperature, add 80% of the prepared injection water into a beaker at a temperature of 20°C to 30°C, and add the prescribed amount of citric acid, stabilizer (disodium edetate and / or sodium metabisulfite), main drug and sodium chloride in sequence, stirring while adding to dissolve, add sodium citrate to adjust the pH value to 3.0, then add water to the full amount, filter with a 0.22μ filter membrane, and fill in an LDPE bottle with a filling volume of 5ml. Each prescription was measured at 0 days, 5 days and 6℃±2℃, 25℃-40% relative humidity (RH), 10 days and 6℃±2℃, 25℃-40% RH. The measurement results are shown in Table 8. Table 8,

[0085]

[0086]

[0087] 6.3 Results Analysis

[0088] From the results in Table 8, it can be seen that there is no significant difference in properties, pH value and color of different stabilizer prescriptions under the conditions of 6℃±2℃, 25℃-40%RH for 10 days; the growth rate of related substances is the slowest when no stabilizer is added, so it is chosen not to add stabilizer.

[0089] 7. Investigation on whether the prescription requires nitrogen protection

[0090] 7.1. Sample batch number

[0091] 191206~191207.

[0092] 7.2 Preparation process

[0093] The stability of the full nitrogen-filled prescription was investigated using 0.03% edetate disodium as a stabilizer, 0.1% sodium metabisulfite as an antioxidant, citric acid-sodium citrate as a buffer, and 0.75% sodium chloride as an osmotic pressure regulator. The full nitrogen-filled prescription and the non-nitrogen-filled prescription were compared at 0 days, 5 days and 6℃±2℃, 25℃-40% relative humidity (RH), 10 days and 6℃±2℃, 25℃-40% RH, and 2 months and 6℃±2℃, 25℃-40% RH. The results are shown in Table 9. Table 9,

[0094]

[0095]

[0096] 7.3 Results Analysis

[0097] From the results in Table 9, it can be seen that there is no significant difference in the properties, pH value, color, and related substances of the nitrogen-filled samples under refrigerated conditions and those of the non-nitrogen-filled samples. The growth rate of related substances in the non-nitrogen-filled samples under 25℃-40%RH conditions is slower, so the process without nitrogen filling was finally selected.

[0098] 8. Inspection of feeding sequence

[0099] During the prescription preparation process, it was found that if sodium chloride was added first and the main drug was added later, the main drug could not be completely dissolved within 30 minutes and the dissolution rate slowed down. Therefore, the feeding order was to add the main drug first and then sodium chloride.

[0100] IX. Freeze-drying process investigation

[0101] Freeze drying process:

[0102] Pre-freeze:

[0103] Cool uniformly from room temperature to -50°C within 1-2.5 hours and keep warm for 1 hour.

[0104] The temperature rises uniformly from -50℃ to -15℃ within 1-2.5h, and then decreases uniformly from -15℃ to -50℃ within 1-2h.

[0105] The temperature rises uniformly from -50℃ to -15℃ within 1-2.5h, and then decreases uniformly from -15℃ to -50℃ within 1-2h.

[0106] One sublimation:

[0107] Start vacuuming while heating up, and the temperature rises to -10℃, and the total time is 18-20h

[0108] Analytical drying:

[0109] Continue to evacuate the mixture, raise the temperature to 25°C, and analyze for 4-6 hours.

[0110] Freeze drying is completed, pressure is increased, unpacking is done, and manual stoppering is performed

[0111] The preliminary stability results of the freeze-drying process are shown in Table 10. Table 10,

[0112]

[0113]

[0114] It can be seen from Table 10 that the formulation prepared by freeze-drying process is more stable than the solution, so the freeze-drying process was finally selected as the final process.

[0115] Compared with the prior art, the present invention has the following technical effects:

[0116] 1. The inhalation-type aclidinium bromide lyophilized agent provided by the present invention is suitable for various groups of people, and solves the disadvantage that the commercially available inhalation agents are not suitable for infants and children without autonomous inhalation ability and patients with active breathing difficulties.

[0117] 2. The inhalation type aclidinium bromide lyophilized agent provided by the present invention does not contain preservatives, has good stability, reliable quality and good safety.

[0118] 3. The preparation method of the aclidinium bromide lyophilized agent of the present invention is simple to operate and easy to industrialize. DETAILED DESCRIPTION

[0119] In order to make the objectives, technical solutions and advantages of the present invention more clear, the embodiments of the present invention will be described in further detail below.

[0120] The aclidinium bromide lyophilized preparation for inhalation of the present invention is packaged in single-dose medicine. Single dose refers to the dose of the medicinal active ingredient used for a single inhalation. In this specification, a single dose means 4 mL, and the single-dose dose is adopted to avoid the drawbacks of repeated measurement and repeated dilution preparation caused by large multi-dose packaging, which is easy to breed microorganisms.

[0121] Example 1

[0122] prescription

[0123]

[0124] Prepare the solution: dissolve 1250 mg of citric acid, 25 mg of aclidinium bromide and 3750 mg of sodium chloride in 80% water for injection in sequence, and form solution a1 after all of them are dissolved; add appropriate amount of sodium citrate to adjust the pH value to 2.5, and then add water to 500 ml to form solution b1; filter and sterilize solution b1, and fill it into 15 ml vials to obtain solution c1;

[0125] Freeze-drying: Solution c1 is pre-frozen, sublimated, and freeze-dried.

[0126] The first stage of pre-freezing: the room temperature is uniformly reduced to -50℃ within 1 hour, and kept warm for 1 hour

[0127] The second stage: within 1 hour, the temperature rises from -50℃ to -15℃ at a constant speed, and within 1.5 hours, the temperature drops from -15℃ to -50℃ at a constant speed.

[0128] The third stage: within 1 hour, the temperature rises from -50℃ to -15℃ at a constant speed, and within 1.5 hours, the temperature drops from -15℃ to -50℃ at a constant speed.

[0129] Sublimation vacuum -50℃ to -10℃ at a constant speed for 18h

[0130] Drying and vacuum drying -10℃ to 25℃ at a constant speed for 4h

[0131] After freeze-drying, increase the pressure, open the box, and seal the lid to obtain the aclidinium bromide lyophilized agent for inhalation.

[0132] Example 2

[0133] prescription

[0134]

[0135] Prepare the solution: dissolve 1000 mg of citric acid, 75 mg of aclidinium bromide and 4375 mg of sodium chloride in 80% water for injection in sequence, and form solution a2 after all of them are dissolved; add appropriate amount of sodium citrate to adjust the pH value to 2.8, and then add water to 500 ml to form solution b2; filter and sterilize solution b2, and fill it into 5 ml LDPE bottles to obtain solution c2;

[0136] Freeze-drying: pre-freeze, sublimate, and freeze-dry solution c2.

[0137] The first stage of pre-freezing: the room temperature is uniformly reduced to -50℃ within 2 hours, and kept warm for 1 hour

[0138] The second stage: within 2 hours, the temperature rises from -50℃ to -15℃ at a constant speed, and within 1.5 hours, the temperature drops from -15℃ to -50℃ at a constant speed.

[0139] The third stage: within 2 hours, the temperature rises from -50℃ to -15℃ at a constant speed, and within 1.5 hours, the temperature drops from -15℃ to -50℃ at a constant speed.

[0140] Sublimation vacuum -50℃ to -10℃ at a constant speed for 20h

[0141] Drying and vacuum drying -10℃ to 25℃ at a constant speed for 6h

[0142] After freeze-drying, increase the pressure, open the box, and seal the lid to obtain the aclidinium bromide lyophilized agent for inhalation.

[0143] Example 3

[0144] prescription

[0145]

[0146]

[0147] Prepare the solution: dissolve 875 mg of citric acid, 37.5 mg of aclidinium bromide and 3875 mg of sodium chloride in 80% water for injection in sequence, and form solution a3 after all of them are dissolved; add appropriate amount of sodium citrate to adjust the pH value to 2.6, and then add water to 500 ml to form solution b3; filter and sterilize solution b3, and fill it into 5 ml LDPE bottles to obtain solution c3;

[0148] Freeze-drying: pre-freeze, sublimate, analyze and freeze-dry solution c3.

[0149] The first stage of pre-freezing: the room temperature is uniformly reduced to -50℃ within 2.5 hours, and kept warm for 1 hour

[0150] The second stage: within 2.5 hours, the temperature rises from -50℃ to -15℃ at a constant speed, and within 2 hours, the temperature drops from -15℃ to -50℃ at a constant speed.

[0151] The third stage: within 2.5 hours, the temperature rises from -50℃ to -15℃ at a constant speed, and within 2 hours, the temperature drops from -15℃ to -50℃ at a constant speed.

[0152] Sublimation vacuum -50℃ to -10℃ at a constant speed, a total of 19h

[0153] Drying and vacuum drying -10℃ to 25℃ at a constant speed for 5h

[0154] After freeze-drying, increase the pressure, open the box, and seal the lid to obtain the aclidinium bromide lyophilized agent for inhalation.

[0155] Example 4

[0156] prescription

[0157]

[0158] Prepare the solution: dissolve 2250 mg of disodium hydrogen phosphate, 50 mg of aclidinium bromide and 4125 mg of sodium chloride in 80% water for injection in sequence, and form solution a4 after all of them are dissolved; add appropriate amount of hydrochloric acid to adjust the pH value to 3.5, and then add water to 500 ml to form solution b4; filter and sterilize solution b4, and fill it into 5 ml LDPE bottles to obtain solution c4;

[0159] Freeze-drying: Solution C4 is pre-frozen, sublimated, and freeze-dried.

[0160] The first stage of pre-freezing: the room temperature is uniformly reduced to -50℃ within 1 hour, and kept warm for 1 hour

[0161] The second stage: within 1 hour, the temperature rises from -50℃ to -15℃ at a constant speed, and within 1.5 hours, the temperature drops from -15℃ to -50℃ at a constant speed.

[0162] The third stage: within 1 hour, the temperature rises from -50℃ to -15℃ at a constant speed, and within 1.5 hours, the temperature drops from -15℃ to -50℃ at a constant speed.

[0163] Sublimation vacuum -50℃ to -10℃ at a constant speed for 20h

[0164] Drying and vacuum drying -10℃ to 25℃ at a constant speed for 4h

[0165] After freeze-drying, increase the pressure, open the box, and seal the lid to obtain the aclidinium bromide lyophilized agent for inhalation.

[0166] Quality Inspection

[0167] The experimental results of Examples 1-4 are shown in Table 11.

[0168] Table 11,

[0169]

[0170] As shown in Table 11, even if the aclidinium bromide lyophilized agent for inhalation of the present invention is placed for 3 months, the related substances of aclidinium bromide increase slightly, the stability of aclidinium bromide is excellent, and the preparation properties, pH value, color and clarity do not change.

Claims

1. An aclidinium bromide inhalation lyophilized preparation, characterized in that: A single dose of the lyophilized agent contains 0.2-0.6 mg of aclidinium bromide, 30-35 mg of an osmotic pressure regulator, and a pH buffer solution, wherein the pH buffer solution is used in an amount such that the pH value of the inhalation solution after the lyophilized agent is reconstituted is 2.5-4.0; The pH buffer solution comprises a first buffer and a second buffer. When the first buffer is citric acid, the second buffer is sodium citrate. When the first buffer is disodium hydrogen phosphate, the second buffer is hydrochloric acid.

2. The lyophilized agent according to claim 1, characterized in that A single dose of the lyophilized agent contains 0.2-0.5 mg of aclidinium bromide, 32-35 mg of an osmotic pressure regulator and a pH buffer solution. The amount of the pH buffer solution is such that the pH value of the inhalation solution after the lyophilized agent is reconstituted is 2.5-3.

0.

3. The lyophilized agent according to claim 1, characterized in that A single dose of the lyophilized agent contains 0.2-0.6 mg of aclidinium bromide, 30-35 mg of an osmotic pressure regulator, 3-16 mg of citric acid and sodium citrate. The sodium citrate is used to adjust the pH value of the inhalation solution of the lyophilized agent after reconstitution to 2.5-4.

0.

4. The lyophilized agent according to claim 1, characterized in that A single dose of the lyophilized agent contains 0.2-0.6 mg of aclidinium bromide, 30-35 mg of an osmotic pressure regulator, 4-20 mg of disodium hydrogen phosphate and hydrochloric acid. The hydrochloric acid is used to adjust the pH value of the inhalation solution after the lyophilized agent is reconstituted to 2.5-4.

0.

5. The lyophilized agent according to claim 2, characterized in that The osmotic pressure regulator is sodium chloride.

6. The method for preparing the lyophilized agent according to any one of claims 1 to 5, characterized in that: The following steps are involved: Preparation of solution: dissolving the first buffer, aclidinium bromide and osmotic pressure regulator in a solvent in sequence, and forming solution a after all are dissolved; adding the second buffer to adjust the pH value to 2.5-4.0 to form solution b; filtering and sterilizing solution b, and filling it into a single-dose packaging container to obtain solution c; wherein the solvent is water for injection, and the temperature of the preparation process is controlled at 20°C-30°C; Freeze drying: pre-freeze solution c, sublimate it, and then freeze dry it. After freeze drying, increase the pressure, open the box, and roll the lid.

7. The method for preparing the lyophilized agent according to claim 6, characterized in that: The specific process of freeze drying is: The first stage of pre-freezing: the room temperature is uniformly reduced to -50℃ within 1-2.5h, and kept warm for 1h; The second stage: within 1-2.5 hours, the temperature rises from -50℃ to -15℃ at a constant speed, and within 1-2 hours, the temperature drops from -15℃ to -50℃ at a constant speed; The third stage: within 1-2.5 hours, the temperature rises from -50℃ to -15℃ at a constant speed, and within 1-2 hours, the temperature drops from -15℃ to -50℃ at a constant speed; Sublimation vacuum -50℃ to -10℃, a total of 18-20h; Desorption drying, vacuum drying, heating from -10℃ to 25℃, for 4-6h.

Images