Ipratropium bromide solution for inhalation and preparation method thereof

Abstract

The invention relates to the technical field of pharmaceutical preparations, in particular to an ipratropium bromide solution for inhalation and a preparation method of the ipratropium bromide solution. The preparation method of the ipratropium bromide solution for inhalation comprises the following steps: dissolving sodium chloride in water for injection, regulating the pH value to 3.1-3.5 by adopting a citric acid-sodium citrate buffer system, then adding a composite surfactant, finally adding ipratropium bromide, stirring, dissolving, fixing the volume, filtering and sterilizing, thereby obtaining the ipratropium bromide solution for inhalation. The composite surfactant is a mixture of polysorbate 20, polysorbate 60 and polysorbate 80. The ipratropium bromide solution for inhalation has excellent stability, can be stored for a long time without deterioration, has relatively excellent atomization performance, and can meet the requirements of various patients.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical preparations, and in particular to an ipratropium bromide solution for inhalation and a preparation method thereof. Background Art

[0002] Respiratory diseases are common and frequently occurring diseases that endanger people's health, and their incidence rate ranks first among many diseases in any age group.

[0003] Ipratropium bromide is a bronchodilator, which is 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 for patients who cannot tolerate such drugs due to muscle tremors and tachycardia caused by beta-receptor agonists.

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

[0005] However, the method of adding stabilizers and other pharmaceutical excipients to improve stability will increase the risk of drug safety. Summary of the invention

[0006] In view of this, the object of the present invention is to provide an ipratropium bromide solution for inhalation and a preparation method thereof, so as to provide an ipratropium bromide solution for inhalation with high stability and high drug safety.

[0007] Based on the above purpose, the present invention provides a preparation method of ipratropium bromide solution for inhalation, comprising the following steps: adding sodium chloride to water for injection, stirring and dissolving, then adding citric acid-sodium citrate buffer solution until the pH reaches 3.1-3.5, then adding a composite surfactant, stirring and dispersing evenly, and finally adding ipratropium bromide, stirring and dissolving, and then adding water for injection to obtain ipratropium bromide liquid; filtering the obtained ipratropium bromide liquid and filling it into a brown glass ampoule bottle, sterilizing, and obtaining the ipratropium bromide solution for inhalation; The composite surfactant is prepared by mixing polysorbate 20, polysorbate 60 and polysorbate 80 in a weight ratio of 1:1:1.

[0008] Preferably, the temperature of the stirring and dissolving is 20-24° C., and the rotation speed is 400-450 rpm.

[0009] Preferably, the amount of sodium chloride added is 0.8%-1% (w / v).

[0010] Preferably, the added amount of the complex surfactant is 0.003%-0.005% (w / v).

[0011] Preferably, the added amount of ipratropium bromide is 0.02%-0.025% (w / v).

[0012] Preferably, the filtration is performed using a PVDF filter membrane.

[0013] Preferably, the sterilization method is constant temperature sterilization at 121° C. for 12 minutes.

[0014] Furthermore, the present invention also provides an ipratropium bromide solution for inhalation, wherein the ipratropium bromide solution for inhalation is prepared according to the above-mentioned method for preparing the ipratropium bromide solution for inhalation.

[0015] 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.

[0016] Beneficial effects of the present invention: The ipratropium bromide solution for inhalation of the present invention can quickly disperse drug molecules, inhibit oxidation / hydrolysis, and adapt to temperature fluctuations by mixing polysorbate 20, polysorbate 60, and polysorbate 80, thereby further improving the stability of the solution.

[0017] The ipratropium bromide solution for inhalation of the present invention can significantly reduce the surface tension of the solution by mixing polysorbate 20, polysorbate 60 and polysorbate 80, promote the rupture of the liquid film in the initial stage of atomization, and inhibit the formation of large droplets during the atomization process, so that the atomized particles are distributed more evenly, thereby improving the atomization performance of the ipratropium bromide solution. DETAILED DESCRIPTION

[0018] In order to make the objectives, technical solutions and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with specific embodiments.

[0019] Example 1: An ipratropium bromide solution for inhalation, the specific preparation steps are as follows: (1) Add 8 g of sodium chloride to 600 ml of water for injection, stir at 400 rpm at 20°C to dissolve, then add citric acid-sodium citrate buffer solution until the pH reaches 3.1, then add 0.01 g of polysorbate 20, 0.01 g of polysorbate 60 and 0.01 g of polysorbate 80, stir and disperse evenly, finally add 0.2 g of ipratropium bromide, stir and dissolve, then add water for injection to make up to 1000 ml to obtain ipratropium bromide solution; (2) The ipratropium bromide solution was filtered through a 0.22 μm PVDF filter membrane, filled into a brown glass ampoule, and sterilized at 121°C for 12 min to obtain an ipratropium bromide solution for inhalation.

[0020] Example 2: An ipratropium bromide solution for inhalation, the specific preparation steps are as follows: (1) Add 9 g of sodium chloride to 650 ml of water for injection, stir at 430 rpm at 22°C to dissolve, then add citric acid-sodium citrate buffer solution until the pH reaches 3.3, then add 0.015 g of polysorbate 20, 0.015 g of polysorbate 60 and 0.015 g of polysorbate 80, stir and disperse evenly, finally add 0.23 g of ipratropium bromide, stir and dissolve, then add water for injection to make up to 1000 ml to obtain ipratropium bromide solution; (2) The ipratropium bromide solution was filtered through a 0.22 μm PVDF filter membrane, filled into a brown glass ampoule, and sterilized at 121°C for 12 min to obtain an ipratropium bromide solution for inhalation.

[0021] Example 3: An ipratropium bromide solution for inhalation, the specific preparation steps are as follows: (1) Add 10 g of sodium chloride to 700 ml of water for injection, stir and dissolve at 450 rpm at 24°C, then add citric acid-sodium citrate buffer solution until the pH reaches 3.5, then add 0.02 g of polysorbate 20, 0.02 g of polysorbate 60 and 0.02 g of polysorbate 80, stir and disperse evenly, finally add 0.25 g of ipratropium bromide, stir and dissolve, then add water for injection to make up to 1000 ml to obtain ipratropium bromide solution; (2) The ipratropium bromide solution was filtered through a 0.22 μm PVDF filter membrane, filled into a brown glass ampoule, and sterilized at 121°C for 12 min to obtain an ipratropium bromide solution for inhalation.

[0022] Comparative Example 1: An ipratropium bromide solution for inhalation, which differs from Example 2 in that it does not contain polysorbate 80, and the specific preparation steps are as follows: (1) Add 9 g of sodium chloride to 650 ml of water for injection, stir at 430 rpm at 22°C to dissolve, then add citric acid-sodium citrate buffer solution until the pH reaches 3.3, then add 0.015 g of polysorbate 20 and 0.015 g of polysorbate 60, stir and disperse evenly, finally add 0.23 g of ipratropium bromide, stir and dissolve, then add water for injection to make up to 1000 ml to obtain ipratropium bromide solution; (2) The ipratropium bromide solution was filtered through a 0.22 μm PVDF filter membrane, filled into a brown glass ampoule, and sterilized at 121°C for 12 min to obtain an ipratropium bromide solution for inhalation.

[0023] Comparative Example 2: An ipratropium bromide solution for inhalation, which differs from Example 2 in that it does not contain polysorbate 20, and the specific preparation steps are as follows: (1) Add 9 g of sodium chloride to 650 ml of water for injection, stir at 430 rpm at 22°C to dissolve, then add citric acid-sodium citrate buffer solution until the pH reaches 3.3, then add 0.015 g of polysorbate 60 and 0.015 g of polysorbate 80, stir and disperse evenly, finally add 0.23 g of ipratropium bromide, stir and dissolve, then add water for injection to make up to 1000 ml to obtain ipratropium bromide solution; (2) The ipratropium bromide solution was filtered through a 0.22 μm PVDF filter membrane, filled into a brown glass ampoule, and sterilized at 121°C for 12 min to obtain an ipratropium bromide solution for inhalation.

[0024] Comparative Example 3: An ipratropium bromide solution for inhalation, which differs from Example 2 in that it does not contain polysorbate 60, and the specific preparation steps are as follows: (1) Add 9 g of sodium chloride to 650 ml of water for injection, stir at 430 rpm at 22°C to dissolve, then add citric acid-sodium citrate buffer solution until the pH reaches 3.3, then add 0.015 g of polysorbate 20 and 0.015 g of polysorbate 80, stir and disperse evenly, finally add 0.23 g of ipratropium bromide, stir and dissolve, then add water for injection to make up to 1000 ml to obtain ipratropium bromide solution; (2) After filtering the ipratropium bromide solution through a 0.22 μm PVDF filter membrane, fill it into a brown glass ampoule and sterilize it at 121°C for 12 minutes to obtain the ipratropium bromide solution for inhalation. Comparative Example 4: An ipratropium bromide solution for inhalation, which differs from Example 2 in that it does not contain a complex surfactant, and the specific preparation steps are as follows: (1) Add 9 g of sodium chloride to 650 ml of water for injection, stir at 430 rpm at 22°C to dissolve, then add citric acid-sodium citrate buffer solution until the pH reaches 3.3, add 0.23 g of ipratropium bromide, stir to dissolve, and then add water for injection to make up to 1000 ml to obtain ipratropium bromide solution; (2) The ipratropium bromide solution was filtered through a 0.22 μm PVDF filter membrane, filled into a brown glass ampoule, and sterilized at 121°C for 12 min to obtain an ipratropium bromide solution for inhalation.

[0025] Performance Testing Accelerated test: at 40℃ / 75% RH, maintain for 6 months, observe the degradation products, the test results are shown in Table 1; After irradiation at 4500 lux for 10 days, the impurity generation was observed. The test results are shown in Table 1. Atomization performance test: The test items are FPD (%) and MMAD (μm), and the test results are shown in Table 1.

[0026] Table 1 Performance test results

[0027] Data analysis shows that the ipratropium bromide solution for inhalation of the present invention has the characteristics of high stability and high inhalation safety, can adapt to long-term storage, and its high atomization safety can meet the medication needs of various patients.

[0028] It can be seen from Example 2 and Comparative Examples 1, 2, and 3 that the present invention mixes polysorbate 20, polysorbate 60, and polysorbate 80. The strong hydrophilicity of polysorbate 20 can make the short-chain laurate groups form small-volume micelles, thereby quickly dispersing drug molecules. The hydrophobic core of polysorbate 60 is denser and can wrap the hydrophobic groups of ipratropium bromide to inhibit oxidation / hydrolysis. In addition, polysorbate 80 can give the micelles flexibility and adapt to temperature fluctuations, thereby further improving the stability of the solution. At the same time, the high HLB value of polysorbate 20 can significantly reduce the surface tension of the solution, promote the rupture of the liquid film in the early stage of atomization, and the long-chain stearic acid of polysorbate 60 can increase the viscoelasticity of the solution, inhibit the formation of large droplets during atomization, and the unsaturated oleic acid chain of polysorbate 80 can enhance the interfacial fluidity, make the atomized particles more evenly distributed, thereby improving the stability and atomization performance of the ipratropium bromide solution.

[0029] It can be seen from Example 2 and the comparative example that polysorbate 20, polysorbate 60 and polysorbate 80 have a synergistic effect. After mixing, they can not only form a multi-scale micelle network, enhance the drug encapsulation efficiency through hydrophobic chain complementarity, reduce free drug exposure, and thus reduce the risk of degradation, but also form a dynamic adsorption layer at the air-liquid interface, adjust the atomization energy transfer efficiency through the HLB gradient, and improve the lung deposition rate.

[0030] Those skilled in the art should understand that the discussion of any of the above embodiments is merely illustrative and is not intended to imply that the scope of the present invention is limited to these examples. Under the concept of the present invention, the technical features in the above embodiments or different embodiments may be combined, the steps may be implemented in any order, and there are many other variations of the different aspects of the present invention as described above, which are not provided in detail for the sake of simplicity.

Claims

1. A method for preparing an ipratropium bromide solution for inhalation, characterized in that: The following steps are involved: Adding sodium chloride to water for injection, stirring to dissolve, then adding citric acid-sodium citrate buffer solution until the pH reaches 3.1-3.5, then adding a composite surfactant, stirring to disperse evenly, and finally adding ipratropium bromide, 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 a brown glass ampoule, sterilizing, and obtaining an ipratropium bromide solution for inhalation; The composite surfactant is prepared by mixing 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, wherein 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 added amount of the composite surfactant 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 added amount of the ipratropium bromide 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° C. for 12 minutes.

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

7. An ipratropium bromide solution for inhalation, 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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