An inhalation ipratropium bromide solution and its preparation method

Abstract

This invention relates to the field of pharmaceutical formulation technology, specifically to an inhaled ipratropium bromide solution and its preparation method. The inhaled ipratropium bromide solution of this invention is prepared by dissolving sodium chloride in water for injection, adjusting the pH to 3.1-3.5 using a citrate-sodium citrate buffer system, adding a composite surfactant, and finally adding ipratropium bromide. The mixture is stirred to dissolve, diluted to volume, filtered, and sterilized. The composite surfactant is a mixture of polysorbate 20, polysorbate 60, and polysorbate 80. The inhaled ipratropium bromide solution of this invention exhibits excellent stability, can be stored for extended periods without deterioration, and has superior nebulization performance, meeting the needs of various patients.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulation technology, and in particular to an inhaled ipratropium bromide solution and its preparation method. Background Technology

[0002] Respiratory diseases are common and frequently occurring illnesses that endanger people's health, and their incidence rate ranks first among many diseases in any age group. (No decrease.)

[0003] Ipratropium bromide is a bronchodilator, mainly used clinically to relieve bronchospasm and wheezing symptoms caused by chronic obstructive pulmonary disease; it can also be used to prevent and treat asthma, especially suitable for patients who cannot tolerate such drugs due to muscle tremors and tachycardia caused by β-receptor agonists.

[0004] Patent document CN106667975A discloses a method for preparing an inhalation ipratropium bromide solution, wherein the inhalation solution contains a main component, a stabilizer, an isotonic agent, a pH adjuster, and water for injection.

[0005] However, using methods such as adding stabilizers and other pharmaceutical excipients to improve stability can increase the risk to medication safety. Summary of the Invention

[0006] In view of this, the purpose of this invention is to provide an inhaled ipratropium bromide solution and its preparation method, so as to provide an inhaled ipratropium bromide solution with high stability and high drug safety.

[0007] To achieve the above objectives, the present invention provides a method for preparing an inhaled ipratropium bromide solution comprising the following steps: adding sodium chloride to water for injection and stirring to dissolve; then adding a citrate-sodium citrate buffer solution until the pH reaches 3.1-3.5; then adding a composite surfactant and stirring to disperse evenly; finally adding ipratropium bromide and stirring to dissolve; and then adding water for injection to obtain an ipratropium bromide solution; filtering the obtained ipratropium bromide solution and filling it into brown glass ampoules, sterilizing the ampoules to obtain an inhaled ipratropium bromide solution.

[0008] The composite surfactant is a mixture of polysorbate 20, polysorbate 60 and polysorbate 80 in a weight ratio of 1:1:1.

[0009] Preferably, the stirring and dissolving temperature is 20-24℃ and the stirring speed is 400-450 rpm.

[0010] Preferably, the amount of sodium chloride added is 0.8%-1% (w / v).

[0011] Preferably, the amount of the composite surfactant added is 0.003%-0.005% (w / v).

[0012] Preferably, the amount of ipratropium bromide added is 0.02%-0.025% (w / v).

[0013] Preferably, the filtration is performed using a PVDF filter membrane.

[0014] Preferably, the sterilization method is constant temperature sterilization at 121°C for 12 minutes.

[0015] Furthermore, the present invention also provides an ipratropium bromide solution for inhalation, which is prepared according to the above-described preparation method of ipratropium bromide solution for inhalation.

[0016] Furthermore, each 1 ml of ipratropium bromide solution contains 0.2-0.25 mg of ipratropium bromide, 8-10 mg of sodium chloride, and a pH of 3.1-3.5.

[0017] The beneficial effects of the present invention: The ipratropium bromide inhalation solution of the present invention, by mixing polysorbate 20, polysorbate 60 and polysorbate 80, can rapidly disperse drug molecules, inhibit oxidation / hydrolysis and adapt to temperature fluctuations, thereby further improving the stability of the solution.

[0018] The ipratropium bromide inhalation solution of the present invention, by mixing polysorbate 20, polysorbate 60 and polysorbate 80, can significantly reduce the surface tension of the solution, promote the rupture of the liquid film in the early stage of atomization and inhibit the formation of large droplets during atomization, so as to make the atomized particles more uniformly distributed and thus improve the atomization performance of the ipratropium bromide solution. Detailed Implementation

[0019] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to specific embodiments.

[0020] Example 1: An ipratropium bromide solution for inhalation, the specific preparation steps are as follows:

[0021] (1) Add 8g of sodium chloride to 600ml of water for injection and stir at 400rpm at 20℃ to dissolve. Then add citrate-sodium citrate buffer solution until pH reaches 3.1. Then add 0.01g of polysorbate 20, 0.01g of polysorbate 60 and 0.01g of polysorbate 80 and stir to disperse evenly. Finally add 0.2g of ipratropium bromide and stir to dissolve. Then add water for injection to make up to 1000ml to obtain ipratropium bromide solution.

[0022] (2) After filtering the ipratropium bromide solution through a 0.22 μm PVDF filter membrane, it was filled into brown glass ampoules and sterilized at 121℃ for 12 min to obtain an ipratropium bromide solution for inhalation.

[0023] Example 2: An ipratropium bromide solution for inhalation, the specific preparation steps are as follows:

[0024] (1) Add 9g of sodium chloride to 650ml of water for injection and stir at 430rpm at 22℃ to dissolve. Then add citrate-sodium citrate buffer solution until the pH reaches 3.3. Then add 0.015g of polysorbate 20, 0.015g of polysorbate 60 and 0.015g of polysorbate 80 and stir to disperse evenly. Finally add 0.23g of ipratropium bromide and stir to dissolve. Then add water for injection to make up to 1000ml to obtain ipratropium bromide solution.

[0025] (2) After filtering the ipratropium bromide solution through a 0.22 μm PVDF filter membrane, it was filled into brown glass ampoules and sterilized at 121℃ for 12 min to obtain an ipratropium bromide solution for inhalation.

[0026] Example 3: An ipratropium bromide solution for inhalation, the specific preparation steps are as follows:

[0027] (1) Add 10g of sodium chloride to 700ml of water for injection and stir at 450rpm at 24℃ to dissolve. Then add citrate-sodium citrate buffer solution until the pH reaches 3.5. Then add 0.02g of polysorbate 20, 0.02g of polysorbate 60 and 0.02g of polysorbate 80 and stir to disperse evenly. Finally add 0.25g of ipratropium bromide and stir to dissolve. Then add water for injection to make up to 1000ml to obtain ipratropium bromide solution.

[0028] (2) After filtering the ipratropium bromide solution through a 0.22 μm PVDF filter membrane, it was filled into brown glass ampoules and sterilized at 121℃ for 12 min to obtain an ipratropium bromide solution for inhalation.

[0029] Comparative Example 1: An inhalation ipratropium bromide solution, differing from Example 2 in that it does not contain polysorbate 80. The specific preparation steps are as follows:

[0030] (1) Add 9g of sodium chloride to 650ml of water for injection and stir at 430rpm at 22℃ to dissolve. Then add citrate-sodium citrate buffer solution until the pH reaches 3.3. Then add 0.015g of polysorbate 20 and 0.015g of polysorbate 60 and stir to disperse evenly. Finally add 0.23g of ipratropium bromide and stir to dissolve. Then add water for injection to make up to 1000ml to obtain ipratropium bromide solution.

[0031] (2) After filtering the ipratropium bromide solution through a 0.22 μm PVDF filter membrane, it was filled into brown glass ampoules and sterilized at 121℃ for 12 min to obtain an ipratropium bromide solution for inhalation.

[0032] Comparative Example 2: An inhalation ipratropium bromide solution, differing from Example 2 in that it lacks polysorbate 20. The specific preparation steps are as follows:

[0033] (1) Add 9g of sodium chloride to 650ml of water for injection and stir at 430rpm at 22℃ to dissolve. Then add citrate-sodium citrate buffer solution until the pH reaches 3.3. Then add 0.015g of polysorbate 60 and 0.015g of polysorbate 80 and stir to disperse evenly. Finally add 0.23g of ipratropium bromide and stir to dissolve. Then add water for injection to make up to 1000ml to obtain ipratropium bromide solution.

[0034] (2) After filtering the ipratropium bromide solution through a 0.22 μm PVDF filter membrane, it was filled into brown glass ampoules and sterilized at 121℃ for 12 min to obtain an ipratropium bromide solution for inhalation.

[0035] Comparative Example 3: An inhalation ipratropium bromide solution, differing from Example 2 in that it does not contain polysorbate 60. The specific preparation steps are as follows:

[0036] (1) Add 9g of sodium chloride to 650ml of water for injection and stir at 430rpm at 22℃ to dissolve. Then add citrate-sodium citrate buffer solution until the pH reaches 3.3. Then add 0.015g of polysorbate 20 and 0.015g of polysorbate 80 and stir to disperse evenly. Finally add 0.23g of ipratropium bromide and stir to dissolve. Then add water for injection to make up to 1000ml to obtain ipratropium bromide solution.

[0037] (2) After filtering the ipratropium bromide solution through a 0.22 μm PVDF filter membrane, the solution was filled into brown glass ampoules and sterilized at 121℃ for 12 min to obtain an ipratropium bromide solution for inhalation.

[0038] Comparative Example 4: An ipratropium bromide solution for inhalation, which differs from Example 2 in that it does not contain a complex surfactant. The specific preparation steps are as follows:

[0039] (1) Add 9g of sodium chloride to 650ml of water for injection and stir at 430rpm at 22℃ to dissolve. Then add citrate-sodium citrate buffer solution until pH reaches 3.3. Add 0.23g of ipratropium bromide, stir to dissolve, and then add water for injection to make up to 1000ml to obtain ipratropium bromide solution.

[0040] (2) After filtering the ipratropium bromide solution through a 0.22 μm PVDF filter membrane, it was filled into brown glass ampoules and sterilized at 121℃ for 12 min to obtain an ipratropium bromide solution for inhalation.

[0041] Performance testing

[0042] Accelerated test: The degradation products were observed after 6 months at 40℃ / 75% RH. The test results are shown in Table 1.

[0043] The impurities were observed after 10 days of illumination at 4500 lux, and the test results are shown in Table 1.

[0044] Atomization performance test:

[0045] The test items were FPD (%) and MMAD (μm), and the test results are shown in Table 1.

[0046] Table 1 Performance Test Results

[0047]

[0048] Data analysis shows that the ipratropium bromide inhalation solution of the present invention has the characteristics of high stability and high inhalation safety, can be adapted to long-term storage, and its high nebulization safety can meet the medication needs of various types of patients.

[0049] As can be seen from Examples 2 and Comparative Examples 1, 2, and 3, this invention, by mixing polysorbate 20, polysorbate 60, and polysorbate 80, achieves the following: the strong hydrophilicity of polysorbate 20 enables short-chain laurate groups to form small-volume micelles, thereby rapidly dispersing drug molecules; the more dense hydrophobic core of polysorbate 60 can encapsulate the hydrophobic groups of ipratropium bromide, inhibiting oxidation / hydrolysis; and polysorbate 80 imparts flexibility to the micelles, adapting to temperature fluctuations, thus further improving the stability of the solution. Simultaneously, the high HLB value of polysorbate 20 significantly reduces the surface tension of the solution, promoting film rupture in the initial stage of atomization; the long-chain stearic acid of polysorbate 60 increases the viscoelasticity of the solution, inhibiting the formation of large droplets during atomization; and the unsaturated oleic acid chains of polysorbate 80 enhance interfacial fluidity, resulting in a more uniform distribution of atomized particles, thereby improving the stability and atomization performance of the ipratropium bromide solution.

[0050] As can be seen from Example 2 and the comparative example, polysorbate 20, polysorbate 60 and polysorbate 80 have a synergistic effect. When mixed, they can not only form a multi-scale micelle network, but also enhance drug encapsulation efficiency through hydrophobic chain complementarity, reduce free drug exposure and thus reduce degradation risk. At the same time, the three can form a dynamic adsorption layer at the gas-liquid interface, which can adjust the atomization energy transfer efficiency through HLB gradient and improve the lung deposition rate.

[0051] Those skilled in the art should understand that the discussion of any of the above embodiments is merely exemplary and is not intended to imply that the scope of the invention is limited to these examples; within the framework of the invention, the technical features of the above embodiments or different embodiments can also be combined, the steps can be implemented in any order, and there are many other variations of the different aspects of the invention as described above, which are not provided in detail for the sake of brevity.

Claims

1. A method for preparing an inhalation ipratropium bromide solution, characterized in that, Includes the following steps: Sodium chloride was added to water for injection and stirred to dissolve. Then, citrate-sodium citrate buffer solution was added until the pH reached 3.1-3.

5. Then, a composite surfactant was added and stirred to disperse evenly. Finally, ipratropium bromide was added and stirred to dissolve. Water for injection was added to obtain ipratropium bromide solution. The obtained ipratropium bromide solution was filtered and filled into brown glass ampoules and sterilized to obtain ipratropium bromide solution for inhalation. The composite surfactant is a mixture of polysorbate 20, polysorbate 60 and polysorbate 80 in a weight ratio of 1:1:

1.

2. The method for preparing ipratropium bromide solution for inhalation according to claim 1, characterized in that, The amount of sodium chloride added is 0.8%-1% (w / v).

3. The method for preparing ipratropium bromide solution for inhalation according to claim 1, characterized in that, The amount of the composite surfactant added is 0.003%-0.006% (w / v).

4. The method for preparing ipratropium bromide solution for inhalation according to claim 1, characterized in that, The amount of ipratropium bromide added is 0.02%-0.025% (w / v).

5. The method for preparing ipratropium bromide solution for inhalation according to claim 1, characterized in that, The sterilization method is constant temperature sterilization at 121℃ for 12 minutes.

6. An ipratropium bromide solution for inhalation, characterized in that, The ipratropium bromide inhalation solution is prepared by the method for preparing ipratropium bromide inhalation solution according to any one of claims 1-5.

7. The ipratropium bromide inhalation solution according to claim 6, characterized in that, Each 1 ml of ipratropium bromide solution contains 0.2-0.25 mg of ipratropium bromide, 8-10 mg of sodium chloride, and a pH of 3.1-3.5.

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