Antibiotic pharmaceutical composition for inhalation and preparation method thereof
By preparing antibiotic drug compositions, the problems of inaccurate drug preparation and poor stability have been solved, enabling precise treatment of lung infections and reducing systemic reactions. These compositions are suitable for nebulized inhalation administration of lung infections.
Patent Information
- Application Number
- CN202511369405.7
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-09-24
- Publication Date
- 2025-12-12
AI Technical Summary
Current treatments for lung infections often involve inaccurate dosages, large concentration errors, poor drug stability, and excessive excipients, leading to systemic adverse reactions and drug resistance.
This product utilizes an antibiotic drug composition, including an antibiotic, an osmotic pressure regulator, an alcohol compound, and a pH adjuster. By precisely formulating it into a solution, it avoids the use of traditional stabilizers, ensuring drug stability and dosage accuracy, and is suitable for nebulized inhalation administration.
It improves drug delivery rate and effective delivery percentage, reduces systemic adverse reactions, enables precision treatment, and is suitable for patients with dysphagia or lung infections requiring long-term treatment.
Smart Images
Figure CN121102182A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of pharmaceutical preparation technology, specifically to an inhaled antibiotic composition and its preparation method. Background Technology
[0002] Pulmonary infection is a common complication of lung diseases such as chronic obstructive pulmonary disease, cystic fibrosis, and pneumoconiosis. It is caused by various pathogens, such as bacteria, viruses, and fungi, infecting the trachea, bronchi, and lung parenchyma. Bacteria are the main pathogens causing pulmonary infections, including Acinetobacter baumannii, Pseudomonas aeruginosa, Streptococcus pneumoniae, and Staphylococcus aureus. Among them, Pseudomonas aeruginosa (PA) is one of the most prevalent bacteria causing pulmonary infections, with a detection rate as high as 40.4% in the spectrum of pathogens causing pulmonary infections. PA is also highly susceptible to multidrug resistance, making treatment difficult, with a high mortality rate and high costs.
[0003] Currently, the main clinical treatments for lung infections include injectable and oral antibiotics. Both injectable and oral administration are systemic routes of administration, which can easily lead to numerous systemic adverse reactions. Furthermore, patients with refractory lung infections require long-term use of broad-spectrum antibiotics, which can cause drug resistance in pathogens and interfere with beneficial bacteria in the gut and other parts of the body.
[0004] The unique structure of the human respiratory system gives inhaled medications a significant advantage over other drug delivery systems in the treatment of lung infections. Firstly, the lungs have a large surface area, a thin alveolar epithelial cell layer, and a rich capillary network, resulting in a significantly lower effective dose after inhalation compared to injection. Secondly, inhaled medications avoid the first-pass effect of the gastrointestinal tract, offering advantages such as direct targeting of the lesion, rapid onset of action, and fewer systemic adverse reactions. Inhaled medications are now widely used in the clinical treatment of lung diseases such as bronchial asthma, chronic obstructive pulmonary disease, pneumonia, and cystic fibrosis.
[0005] For the treatment of lung infections and ICU-related infections caused by pan-drug-resistant bacteria, traditional intravenous administration is often ineffective in some patients. Therefore, nebulized inhalation has become an important supplementary route of administration for these patients. Polymyxin B has potent antibacterial activity against Gram-negative bacteria, such as *Pseudomonas aeruginosa* and *Acinetobacter baumannii*, and has been used in the aforementioned cases. However, current treatment regimens typically involve temporary dissolution before clinical use, which can lead to inaccurate dosage and concentration errors, altering the drug's physical properties and causing microbial contamination, potentially resulting in secondary infections.
[0006] Existing polymyxin inhalation liquid formulations mostly use sodium metabisulfite or disodium EDTA as stabilizers. Because inhaled medications come into direct contact with the human respiratory tract, inhalation in sensitive individuals may trigger asthma, gastrointestinal discomfort, and liver and kidney burden. Therefore, the use of such excipients should be minimized. Based on these issues, there is an urgent need to develop an inhaled polymyxin B sulfate composition that is simple in formulation, does not contain stabilizers, and ensures drug stability. This would allow for stable drug preparation, direct nebulization, and accurate dosage. Summary of the Invention
[0007] The purpose of this invention is to provide an inhaled antibiotic drug composition and its preparation method, so as to solve the shortcomings of the prior art, such as inaccurate dosage of drug solution preparation, large concentration error, poor drug stability, and excessive excipients.
[0008] To achieve the above objectives, the present invention provides the following technical solution: an inhaled antibiotic drug composition, wherein the raw materials, by weight, include: 1-20 parts of antibiotic drug, 1-3 parts of osmotic pressure regulator, 0-30 parts of alcohol compound, 0.1-50 parts of pH regulator, and 1-250 parts of solvent.
[0009] Furthermore, the pH adjuster is at least one of hydrochloric acid, sulfuric acid, sodium hydroxide, citric acid, sodium citrate, disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium phosphate, and phosphoric acid.
[0010] Furthermore, the antibiotic is at least one of polymyxin B, polymyxin E, amikacin, meropenem, vancomycin, azithromycin, levofloxacin, clindamycin, and doxycycline.
[0011] Furthermore, the osmotic pressure regulator is at least one of sodium chloride, mannitol, sorbitol, and glucose; the concentration of the osmotic pressure regulator is 0.1% to 2.0% (w / v).
[0012] Furthermore, the solvent is ultrapure water or a mixed solution of ultrapure water and an alcohol compound.
[0013] Further, the alcohol compound is at least one of anhydrous ethanol, glycerol, propylene glycol, and polyethylene glycol; the concentration of the alcohol compound is 10 mg / ml to 500 mg / ml.
[0014] Further, the polymyxin B is polymyxin B sulfate, and the concentration of polymyxin B sulfate is 0.5% to 10.0% (w / v).
[0015] Furthermore, the pH value of the composition is 3.5 to 6.5; the osmotic pressure is 250 to 350 mOsmol / kg.
[0016] This invention also discloses a method for preparing an inhaled antibiotic drug composition, specifically comprising the following steps:
[0017] S1. Add an osmotic pressure regulator to a beaker containing solvent, stir, and obtain solution one after the solid particles dissolve.
[0018] S2. Add polymyxin B sulfate to solution one to obtain a mixed solution;
[0019] S3. Adjust the pH of the mixture using a pH adjuster, transfer it to a volumetric flask and bring it to the mark, then filter it through a 0.22µm filter membrane for sterilization to obtain the combined drug solution.
[0020] The present invention also discloses the use of an inhaled antibiotic composition in the preparation of an inhaled pharmaceutical formulation for treating bacterial pulmonary infections.
[0021] Compared with the prior art, the inhaled antibiotic drug composition and its preparation method provided by the present invention have the following beneficial effects:
[0022] (1) This invention prepares antibiotic drugs into solutions and combines them with nebulizers. By optimizing the formulation, the surface tension of the drug solution is reduced, which significantly improves the drug delivery rate, total delivery amount and effective delivery percentage during nebulized inhalation, ensuring that more drugs reach the lung infection lesions and achieve precision treatment. At the same time, it bypasses the first-pass effect, improves local bioavailability and reduces the risk of dose-dependent toxicity.
[0023] (2) The inhaled polymyxin B sulfate and its composition provided by the present invention have simple components and do not require the addition of traditional stabilizers (such as sodium metabisulfite and EDTA), while ensuring the stability of the drug and avoiding the potential toxicity of stabilizers.
[0024] (3) Inhalation administration acts directly on the lungs, which is more convenient and can significantly reduce the distribution of antibiotics in non-target organs, thereby reducing systemic adverse reactions such as nephrotoxicity and ototoxicity. It is especially suitable for patients with lung infections who have difficulty swallowing or require long-term treatment, and significantly improves medication adherence. Attached Figure Description
[0025] To more clearly illustrate the technical solutions in the embodiments of this application or the prior art, the drawings used in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments recorded in this invention. For those skilled in the art, other drawings can be obtained based on these drawings.
[0026] Figure 1 This invention provides a flowchart of a method for preparing an inhaled antibiotic drug composition. Detailed Implementation
[0027] To enable those skilled in the art to better understand the technical solution of the present invention, the present invention will be further described in detail below with reference to the accompanying drawings.
[0028] Example 1:
[0029] Please see Figure 1 An inhaled antibiotic drug composition, wherein the raw materials, by weight, include: 1-20 parts of antibiotic drug, 1-3 parts of osmotic pressure regulator, 0-30 parts of alcohol compound, 0.1-50 parts of pH regulator, and 1-250 parts of solvent.
[0030] The pH adjuster is at least one of hydrochloric acid, sulfuric acid, sodium hydroxide, citric acid, sodium citrate, disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium phosphate, and phosphoric acid.
[0031] The antibiotic is at least one of polymyxin B, polymyxin E, amikacin, meropenem, vancomycin, azithromycin, levofloxacin, clindamycin, or doxycycline.
[0032] The osmotic pressure regulator is at least one of sodium chloride, mannitol, sorbitol, and glucose; the concentration of the osmotic pressure regulator is 0.1% to 2.0% (w / v).
[0033] The solvent is ultrapure water or a mixed solution of ultrapure water and alcohol compounds.
[0034] The alcohol compound is at least one of anhydrous ethanol, glycerol, propylene glycol, and polyethylene glycol; the concentration of the alcohol compound is 10 mg / ml to 500 mg / ml.
[0035] Polymyxin B is polymyxin B sulfate, and the concentration of polymyxin B sulfate is 0.5% to 10.0% (w / v).
[0036] The composition has a pH of 3.5–6.5 and an osmotic pressure of 250–350 mOsmol / kg.
[0037] The specific implementation method is as follows: the pH adjuster is sulfuric acid or sodium hydroxide; the antibiotic is polymyxin B sulfate with a concentration of 0.5% to 10.0% (w / v); the osmotic pressure adjuster is sodium chloride with a concentration of 0.1% to 2.0% (w / v); the solvent is ultrapure water; the pH value of the composition is 3.5; and the osmotic pressure is 292 mOsmol / kg.
[0038] This invention also discloses a method for preparing an inhaled antibiotic drug composition, specifically comprising the following steps:
[0039] S1. Add 2.0g of sodium chloride to a beaker containing an appropriate amount of ultrapure water, stir, and obtain solution one after the solid particles dissolve.
[0040] S2. Add 7.5g of polymyxin B sulfate to solution one to obtain a mixed solution;
[0041] S3. Adjust the pH of the mixture to 3.5 using sulfuric acid / sodium hydroxide, transfer it to a 250ml volumetric flask and bring it to the mark. Then filter it through a 0.22um filter membrane for sterilization to obtain the combined drug solution.
[0042] The present invention also discloses the use of an inhaled antibiotic composition in the preparation of an inhaled pharmaceutical formulation for treating bacterial pulmonary infections.
[0043] The drug solution prepared according to the above method is administered via nebulization. This drug solution is compatible with any suitable nebulizer, including jet nebulizers, ultrasonic nebulizers, and vibrating sieve nebulizers. Representative jet nebulizers include, but are not limited to, those described above. JET atomizer (Vectura, Chippenham, UK) (Trudell Medical International, London, Ontario, Canada), (Westmed INC, Tucson, AZ, USA), InnoSpire Mini Compressor (Philips Healthcare, Andover, MA, USA), NEBU (Salter Labs, Arvin, CA, USA), and Sprint (PAR I, Starnberg, Germany), S-jet atomizers (PARI, Midlothian, VA, USA). Representative ultrasonic atomizers include, but are not limited to, MINIBREEZET MULTRASonic (Mabis, Waukegan, IL, USA) and FLPY™ (Convexity Scientific, Westport, CT, USA). Representative vibrating screen atomizers include, but are not limited to, those with... Solo (Aerogen, Chicago, IL, USA), (PARI, Starnberg, Germany) etc.
[0044] Example 2:
[0045] Please see Figure 1 This embodiment provides a technical solution based on Embodiment 1:
[0046] An inhaled antibiotic composition comprises, by weight: 1-20 parts of antibiotic drug, 1-3 parts of osmotic pressure regulator, 0-30 parts of alcohol compound, 0.1-50 parts of pH regulator, and 1-250 parts of solvent.
[0047] The specific implementation method is as follows: the pH adjuster is sulfuric acid or sodium hydroxide; the antibiotic is polymyxin B sulfate with a concentration of 0.5% to 10.0% (w / v); the osmotic pressure adjuster is sodium chloride with a concentration of 0.1% to 2.0% (w / v); the solvent is ultrapure water; the pH value of the composition is 4.0; and the osmotic pressure is 294 mOsmol / kg.
[0048] This invention also discloses a method for preparing an inhaled antibiotic drug composition, specifically comprising the following steps:
[0049] S1. Add 2.0g of sodium chloride to a beaker containing an appropriate amount of ultrapure water, stir, and obtain solution one after the solid particles dissolve.
[0050] S2. Add 7.5g of polymyxin B sulfate to solution one to obtain a mixed solution;
[0051] S3. Adjust the pH of the mixture to 4.0 using sulfuric acid / sodium hydroxide, transfer it to a 250ml volumetric flask and bring it to the mark. Then filter it through a 0.22um filter membrane for sterilization to obtain the combined drug solution.
[0052] The present invention also discloses the use of an inhaled antibiotic composition in the preparation of an inhaled pharmaceutical formulation for treating bacterial pulmonary infections.
[0053] Example 3:
[0054] Please see Figure 1 This embodiment provides a technical solution based on Embodiment 1:
[0055] An inhaled antibiotic composition comprises, by weight: 1-20 parts of antibiotic drug, 1-3 parts of osmotic pressure regulator, 0-30 parts of alcohol compound, 0.1-50 parts of pH regulator, and 1-250 parts of solvent.
[0056] The specific implementation method is as follows: the pH adjuster is sulfuric acid or sodium hydroxide; the antibiotic is polymyxin B sulfate with a concentration of 0.5% to 10.0% (w / v); the osmotic pressure adjuster is sodium chloride with a concentration of 0.1% to 2.0% (w / v); the solvent is ultrapure water; the pH value of the composition is 4.5; and the osmotic pressure is 289 mOsmol / kg.
[0057] This invention also discloses a method for preparing an inhaled antibiotic drug composition, specifically comprising the following steps:
[0058] S1. Add 2.0g of sodium chloride to a beaker containing an appropriate amount of ultrapure water, stir, and obtain solution one after the solid particles dissolve.
[0059] S2. Add 7.5g of polymyxin B sulfate to solution one to obtain a mixed solution;
[0060] S3. Adjust the pH of the mixture to 4.5 using sulfuric acid / sodium hydroxide, transfer it to a 250ml volumetric flask and bring it to the mark. Then filter it through a 0.22um filter membrane for sterilization to obtain the combined drug solution.
[0061] The present invention also discloses the use of an inhaled antibiotic composition in the preparation of an inhaled pharmaceutical formulation for treating bacterial pulmonary infections.
[0062] Example 4:
[0063] Please see Figure 1 This embodiment provides a technical solution based on Embodiment 1:
[0064] An inhaled antibiotic composition comprises, by weight: 1-20 parts of antibiotic drug, 1-3 parts of osmotic pressure regulator, 0-30 parts of alcohol compound, 0.1-50 parts of pH regulator, and 1-250 parts of solvent.
[0065] The specific implementation method is as follows: the pH adjuster is sulfuric acid or sodium hydroxide; the antibiotic is polymyxin B sulfate with a concentration of 0.5% to 10.0% (w / v); the osmotic pressure adjuster is sodium chloride with a concentration of 0.1% to 2.0% (w / v); the solvent is ultrapure water; the pH value of the composition is 5.0; and the osmotic pressure is 290 mOsmol / kg.
[0066] This invention also discloses a method for preparing an inhaled antibiotic drug composition, specifically comprising the following steps:
[0067] S1. Add 2.0g of sodium chloride to a beaker containing an appropriate amount of ultrapure water, stir, and obtain solution one after the solid particles dissolve.
[0068] S2. Add 7.5g of polymyxin B sulfate to solution one to obtain a mixed solution;
[0069] S3. Adjust the pH of the mixture to 5.0 using sulfuric acid / sodium hydroxide, transfer it to a 250ml volumetric flask and bring it to the mark. Then filter it through a 0.22um filter membrane for sterilization to obtain the combined drug solution.
[0070] The present invention also discloses the use of an inhaled antibiotic composition in the preparation of an inhaled pharmaceutical formulation for treating bacterial pulmonary infections.
[0071] Example 5:
[0072] Please see Figure 1 This embodiment provides a technical solution based on Embodiment 1:
[0073] An inhaled antibiotic composition comprises, by weight: 1-20 parts of antibiotic drug, 1-3 parts of osmotic pressure regulator, 0-30 parts of alcohol compound, 0.1-50 parts of pH regulator, and 1-250 parts of solvent.
[0074] The specific implementation method is as follows: the pH adjuster is sulfuric acid or sodium hydroxide; the antibiotic is polymyxin B sulfate with a concentration of 0.5% to 10.0% (w / v); the osmotic pressure adjuster is sodium chloride with a concentration of 0.1% to 2.0% (w / v); the solvent is ultrapure water; the pH value of the composition is 5.5; and the osmotic pressure is 292 mOsmol / kg.
[0075] This invention also discloses a method for preparing an inhaled antibiotic drug composition, specifically comprising the following steps:
[0076] S1. Add 2.0g of sodium chloride to a beaker containing an appropriate amount of ultrapure water, stir, and obtain solution one after the solid particles dissolve.
[0077] S2. Add 7.5g of polymyxin B sulfate to solution one to obtain a mixed solution;
[0078] S3. Adjust the pH of the mixture to 5.5 using sulfuric acid / sodium hydroxide, transfer it to a 250ml volumetric flask and bring it to the mark. Then filter it through a 0.22um filter membrane for sterilization to obtain the combined drug solution.
[0079] The present invention also discloses the use of an inhaled antibiotic composition in the preparation of an inhaled pharmaceutical formulation for treating bacterial pulmonary infections.
[0080] Example 6:
[0081] Please see Figure 1 This embodiment provides a technical solution based on Embodiment 1:
[0082] An inhaled antibiotic composition comprises, by weight: 1-20 parts of antibiotic drug, 1-3 parts of osmotic pressure regulator, 0-30 parts of alcohol compound, 0.1-50 parts of pH regulator, and 1-250 parts of solvent.
[0083] The specific implementation method is as follows: the pH adjuster is sulfuric acid or sodium hydroxide; the antibiotic is polymyxin B sulfate with a concentration of 0.5% to 10.0% (w / v); the osmotic pressure adjuster is sodium chloride with a concentration of 0.1% to 2.0% (w / v); the solvent is ultrapure water; the pH value of the composition is 6.0; and the osmotic pressure is 290 mOsmol / kg.
[0084] This invention also discloses a method for preparing an inhaled antibiotic drug composition, specifically comprising the following steps:
[0085] S1. Add 2.0g of sodium chloride to a beaker containing an appropriate amount of ultrapure water, stir, and obtain solution one after the solid particles dissolve.
[0086] S2. Add 7.5g of polymyxin B sulfate to solution one to obtain a mixed solution;
[0087] S3. Adjust the pH of the mixture to 6.0 using sulfuric acid / sodium hydroxide, transfer it to a 250ml volumetric flask and bring it to the mark. Then filter it through a 0.22um filter membrane for sterilization to obtain the combined drug solution.
[0088] The present invention also discloses the use of an inhaled antibiotic composition in the preparation of an inhaled pharmaceutical formulation for treating bacterial pulmonary infections.
[0089] Example 7:
[0090] Please see Figure 1 This embodiment provides a technical solution based on Embodiment 1:
[0091] An inhaled antibiotic composition comprises, by weight: 1-20 parts of antibiotic drug, 1-3 parts of osmotic pressure regulator, 0-30 parts of alcohol compound, 0.1-50 parts of pH regulator, and 1-250 parts of solvent.
[0092] The specific implementation method is as follows: the pH adjuster is sulfuric acid or sodium hydroxide; the antibiotic is polymyxin B sulfate with a concentration of 0.5% to 10.0% (w / v); the osmotic pressure adjuster is sodium chloride with a concentration of 0.1% to 2.0% (w / v); the solvent is ultrapure water; the pH value of the composition is 6.5; and the osmotic pressure is 293 mOsmol / kg.
[0093] This invention also discloses a method for preparing an inhaled antibiotic drug composition, specifically comprising the following steps:
[0094] S1. Add 2.0g of sodium chloride to a beaker containing an appropriate amount of ultrapure water, stir, and obtain solution one after the solid particles dissolve.
[0095] S2. Add 7.5g of polymyxin B sulfate to solution one to obtain a mixed solution;
[0096] S3. Adjust the pH of the mixture to 6.5 using sulfuric acid / sodium hydroxide, transfer it to a 250ml volumetric flask and bring it to the mark. Then filter it through a 0.22um filter membrane for sterilization to obtain the combined drug solution.
[0097] The present invention also discloses the use of an inhaled antibiotic composition in the preparation of an inhaled pharmaceutical formulation for treating bacterial pulmonary infections.
[0098] Tables 1 to 3 examine the stability of the drug solutions of Examples 1 to 7 at different pH values. The formulation of the drug solutions of Examples 1 to 7 is shown in Table 1.
[0099] Table 2 shows the test results of the drug solutions of Examples 1 to 7 on day 0. As can be seen from the results in Table 2, there is no significant difference in osmotic pressure and related impurities of the drug solutions with different pH values on day 0.
[0100] Table 3 shows the test results of the drug compositions from Examples 1 to 7 after being placed at 25°C for 3 months. As can be seen from Table 3, the properties, pH value, and osmolar concentration of the drug compositions at different pH values did not change significantly; the increase in impurities was small, with the drug composition sample at pH 5.0 showing the lowest total impurities. This indicates that, under the condition that other substances are in the same proportion, the drug composition at pH 5.0 has the best stability.
[0101] Table 1. Proportions of drug solutions for different pH values
[0102]
[0103] Table 2. Detection results of drug solutions with different pH values on day 0.
[0104]
[0105]
[0106] Note: " / " indicates that it was not detected.
[0107] Table 3. Results of stability study of drug solutions with different pH values after 3 months at 25°C.
[0108]
[0109] Note: " / " indicates that it was not detected.
[0110] Example 8:
[0111] Please see Figure 1 This embodiment provides a technical solution based on embodiment four:
[0112] An inhaled antibiotic composition comprises, by weight: 1-20 parts of antibiotic drug, 1-3 parts of osmotic pressure regulator, 0-30 parts of alcohol compound, 0.1-50 parts of pH regulator, and 1-250 parts of solvent.
[0113] The specific implementation method is as follows: the pH adjuster is citric acid / sodium citrate; the antibiotic is polymyxin B sulfate with a concentration of 0.5% to 10.0% (w / v); the osmotic pressure adjuster is sodium chloride with a concentration of 0.1% to 2.0% (w / v); the solvent is ultrapure water; the pH value of the composition is 5.0; and the osmotic pressure is 287 mOsmol / kg.
[0114] This invention also discloses a method for preparing an inhaled antibiotic drug composition, specifically comprising the following steps:
[0115] S1. Add 2.2g of sodium chloride to a beaker containing an appropriate amount of ultrapure water, stir, and obtain solution one after the solid particles dissolve.
[0116] S2. Add 1.2g of polymyxin B sulfate to solution one to obtain a mixed solution;
[0117] S3. Adjust the pH of the mixture to 5.0 using citric acid / sodium citrate, transfer it to a 250ml volumetric flask and bring it to the mark. Then filter it through a 0.22um filter membrane for sterilization to obtain the combined drug solution.
[0118] The present invention also discloses the use of an inhaled antibiotic composition in the preparation of an inhaled pharmaceutical formulation for treating bacterial pulmonary infections.
[0119] Example 9:
[0120] Please see Figure 1 This embodiment provides a technical solution based on embodiment four:
[0121] An inhaled antibiotic composition comprises, by weight: 1-20 parts of antibiotic drug, 1-3 parts of osmotic pressure regulator, 0-30 parts of alcohol compound, 0.1-50 parts of pH regulator, and 1-250 parts of solvent.
[0122] The specific implementation method is as follows: the pH adjuster is citric acid / sodium citrate; the antibiotic is polymyxin B sulfate with a concentration of 0.5% to 10.0% (w / v); the osmotic pressure adjuster is sodium chloride with a concentration of 0.1% to 2.0% (w / v); the solvent is ultrapure water; the pH value of the composition is 5.0; and the osmotic pressure is 290 mOsmol / kg.
[0123] This invention also discloses a method for preparing an inhaled antibiotic drug composition, specifically comprising the following steps:
[0124] S1. Add 2.1g of sodium chloride to a beaker containing an appropriate amount of ultrapure water, stir, and obtain solution one after the solid particles dissolve.
[0125] S2. Add 2.5g of polymyxin B sulfate to solution one to obtain a mixed solution;
[0126] S3. Adjust the pH of the mixture to 5.0 using citric acid / sodium citrate, transfer it to a 250ml volumetric flask and bring it to the mark. Then filter it through a 0.22um filter membrane for sterilization to obtain the combined drug solution.
[0127] The present invention also discloses the use of an inhaled antibiotic composition in the preparation of an inhaled pharmaceutical formulation for treating bacterial pulmonary infections.
[0128] Example 10:
[0129] Please see Figure 1 This embodiment provides a technical solution based on embodiment four:
[0130] An inhaled antibiotic composition comprises, by weight: 1-20 parts of antibiotic drug, 1-3 parts of osmotic pressure regulator, 0-30 parts of alcohol compound, 0.1-50 parts of pH regulator, and 1-250 parts of solvent.
[0131] The specific implementation method is as follows: the pH adjuster is citric acid / sodium citrate; the antibiotic is polymyxin B sulfate with a concentration of 0.5% to 10.0% (w / v); the osmotic pressure adjuster is sodium chloride with a concentration of 0.1% to 2.0% (w / v); the solvent is ultrapure water; the pH value of the composition is 5.0; and the osmotic pressure is 288 mOsmol / kg.
[0132] This invention also discloses a method for preparing an inhaled antibiotic drug composition, specifically comprising the following steps:
[0133] S1. Add 1.9g of sodium chloride to a beaker containing an appropriate amount of ultrapure water, stir, and obtain solution one after the solid particles dissolve.
[0134] S2. Add 7.5g of polymyxin B sulfate to solution one to obtain a mixed solution;
[0135] S3. Adjust the pH of the mixture to 5.0 using citric acid / sodium citrate, transfer it to a 250ml volumetric flask and bring it to the mark. Then filter it through a 0.22um filter membrane for sterilization to obtain the combined drug solution.
[0136] The present invention also discloses the use of an inhaled antibiotic composition in the preparation of an inhaled pharmaceutical formulation for treating bacterial pulmonary infections.
[0137] Example 11:
[0138] Please see Figure 1 This embodiment provides a technical solution based on embodiment four:
[0139] An inhaled antibiotic composition comprises, by weight: 1-20 parts of antibiotic drug, 1-3 parts of osmotic pressure regulator, 0-30 parts of alcohol compound, 0.1-50 parts of pH regulator, and 1-250 parts of solvent.
[0140] The specific implementation method is as follows: the pH adjuster is citric acid / sodium citrate; the antibiotic is polymyxin B sulfate with a concentration of 0.5% to 10.0% (w / v); the osmotic pressure adjuster is sodium chloride with a concentration of 0.1% to 2.0% (w / v); the solvent is ultrapure water; the pH value of the composition is 5.0; and the osmotic pressure is 292 mOsmol / kg.
[0141] This invention also discloses a method for preparing an inhaled antibiotic drug composition, specifically comprising the following steps:
[0142] S1. Add 1.7g of sodium chloride to a beaker containing an appropriate amount of ultrapure water, stir, and obtain solution one after the solid particles dissolve.
[0143] S2. Add 12.5g of polymyxin B sulfate to solution one to obtain a mixed solution;
[0144] S3. Adjust the pH of the mixture to 5.0 using citric acid / sodium citrate, transfer it to a 250ml volumetric flask and bring it to the mark. Then filter it through a 0.22um filter membrane for sterilization to obtain the combined drug solution.
[0145] The present invention also discloses the use of an inhaled antibiotic composition in the preparation of an inhaled pharmaceutical formulation for treating bacterial pulmonary infections.
[0146] Example 12:
[0147] Please see Figure 1 This embodiment provides a technical solution based on embodiment four:
[0148] An inhaled antibiotic composition comprises, by weight: 1-20 parts of antibiotic drug, 1-3 parts of osmotic pressure regulator, 0-30 parts of alcohol compound, 0.1-50 parts of pH regulator, and 1-250 parts of solvent.
[0149] The specific implementation method is as follows: the pH adjuster is citric acid / sodium citrate; the antibiotic is polymyxin B sulfate with a concentration of 0.5% to 10.0% (w / v); the osmotic pressure adjuster is sodium chloride with a concentration of 0.1% to 2.0% (w / v); the solvent is ultrapure water; the pH value of the composition is 5.0; and the osmotic pressure is 291 mOsmol / kg.
[0150] This invention also discloses a method for preparing an inhaled antibiotic drug composition, specifically comprising the following steps:
[0151] S1. Add 1.4g of sodium chloride to a beaker containing an appropriate amount of ultrapure water, stir, and obtain solution one after the solid particles dissolve.
[0152] S2. Add 18.8g of polymyxin B sulfate to solution one to obtain a mixed solution;
[0153] S3. Adjust the pH of the mixture to 5.0 using citric acid / sodium citrate, transfer it to a 250ml volumetric flask and bring it to the mark. Then filter it through a 0.22um filter membrane for sterilization to obtain the combined drug solution.
[0154] The present invention also discloses the use of an inhaled antibiotic composition in the preparation of an inhaled pharmaceutical formulation for treating bacterial pulmonary infections.
[0155] Tables 4 to 6 examine the stability of the drug solutions of Examples 8 to 12 at different concentrations of active pharmaceutical ingredients. The formulation of the drug solutions of Examples 8 to 12 is shown in Table 4.
[0156] Table 5 shows the test results of the drug compositions of Examples 8 to 12 on day 0. As can be seen from the results in Table 5, there was no significant difference in the relevant impurities of the drug compositions with different concentrations of raw materials on day 0.
[0157] Table 6 shows the test results of the drug compositions of Examples 8 to 12 after being placed at 25°C for 1 month. As can be seen from the results in Table 6, there were no significant changes in the properties, pH value, and osmotic pressure molar concentration of the drug compositions with different concentrations of raw materials; the impurities increased only slightly, indicating that the drug compositions with different concentrations of raw materials can maintain their stability.
[0158] Table 4. Composition ratio of drug solution for different raw material concentrations
[0159]
[0160] Table 5. Detection results of drug solutions with different raw material concentrations on day 0.
[0161] Note: " / " indicates that it was not detected.
[0162] Table 6. Results of the stability study of the drug solutions with different raw material concentrations after one month at 25°C.
[0163] Note: " / " indicates that it was not detected.
[0164] Example 13:
[0165] Please see Figure 1 This embodiment provides a technical solution based on embodiment four:
[0166] An inhaled antibiotic composition comprises, by weight: 1-20 parts of antibiotic drug, 1-3 parts of osmotic pressure regulator, 0-30 parts of alcohol compound, 0.1-50 parts of pH regulator, and 1-250 parts of solvent.
[0167] The specific implementation method is as follows: the pH adjuster is sulfuric acid; the antibiotic is polymyxin B sulfate with a concentration of 0.5% to 10.0% (w / v); the osmotic pressure adjuster is sodium chloride with a concentration of 0.1% to 2.0% (w / v); the solvent is ultrapure water or a mixed solution of ultrapure water and an alcohol compound; the alcohol compound is at least one of anhydrous ethanol, glycerol, and propylene glycol; the pH value of the composition is 5.0; and the osmotic pressure is 294 mOsmol / kg.
[0168] This invention also discloses a method for preparing an inhaled antibiotic drug composition, specifically comprising the following steps:
[0169] S1. Add 0.08g of anhydrous ethanol and 2.0g of sodium chloride to a beaker containing an appropriate amount of ultrapure water, stir, and obtain solution one after the solid particles dissolve.
[0170] S2. Add 7.5g of polymyxin B sulfate to solution one to obtain a mixed solution;
[0171] S3. Adjust the pH of the mixture to 5.0 using sulfuric acid, transfer it to a 250ml volumetric flask and bring it to the mark. Then filter it through a 0.22um filter membrane for sterilization to obtain the combined drug solution.
[0172] The present invention also discloses the use of an inhaled antibiotic composition in the preparation of an inhaled pharmaceutical formulation for treating bacterial pulmonary infections.
[0173] Example 14:
[0174] Please see Figure 1 This embodiment provides a technical solution based on embodiment four:
[0175] An inhaled antibiotic composition comprises, by weight: 1-20 parts of antibiotic drug, 1-3 parts of osmotic pressure regulator, 0-30 parts of alcohol compound, 0.1-50 parts of pH regulator, and 1-250 parts of solvent.
[0176] The specific implementation method is as follows: the pH adjuster is sulfuric acid; the antibiotic is polymyxin B sulfate with a concentration of 0.5% to 10.0% (w / v); the osmotic pressure adjuster is sodium chloride with a concentration of 0.1% to 2.0% (w / v); the solvent is ultrapure water or a mixed solution of ultrapure water and an alcohol compound; the alcohol compound is at least one of anhydrous ethanol, glycerol, and propylene glycol; the pH value of the composition is 5.0; and the osmotic pressure is 293 mOsmol / kg.
[0177] This invention also discloses a method for preparing an inhaled antibiotic drug composition, specifically comprising the following steps:
[0178] S1. Add 25g of propylene glycol and 1.0g of sodium chloride to a beaker containing an appropriate amount of ultrapure water, stir, and obtain solution one after the solid particles dissolve.
[0179] S2. Add 7.5g of polymyxin B sulfate to solution one to obtain a mixed solution;
[0180] S3. Adjust the pH of the mixture to 5.0 using sulfuric acid, transfer it to a 250ml volumetric flask and bring it to the mark. Then filter it through a 0.22um filter membrane for sterilization to obtain the combined drug solution.
[0181] The present invention also discloses the use of an inhaled antibiotic composition in the preparation of an inhaled pharmaceutical formulation for treating bacterial pulmonary infections.
[0182] Example 15:
[0183] Please see Figure 1 This embodiment provides a technical solution based on embodiment four:
[0184] An inhaled antibiotic composition comprises, by weight: 1-20 parts of antibiotic drug, 1-3 parts of osmotic pressure regulator, 0-30 parts of alcohol compound, 0.1-50 parts of pH regulator, and 1-250 parts of solvent.
[0185] The specific implementation method is as follows: the pH adjuster is sulfuric acid; the antibiotic is polymyxin B sulfate with a concentration of 0.5% to 10.0% (w / v); the osmotic pressure adjuster is sodium chloride with a concentration of 0.1% to 2.0% (w / v); the solvent is ultrapure water or a mixed solution of ultrapure water and an alcohol compound; the alcohol compound is at least one of anhydrous ethanol, glycerol, and propylene glycol; the pH value of the composition is 5.0; and the osmotic pressure is 290 mOsmol / kg.
[0186] This invention also discloses a method for preparing an inhaled antibiotic drug composition, specifically comprising the following steps:
[0187] S1. Add 5g of glycerol and 1.8g of sodium chloride to a beaker containing an appropriate amount of ultrapure water, stir, and obtain solution one after the solid particles dissolve.
[0188] S2. Add 7.5g of polymyxin B sulfate to solution one to obtain a mixed solution;
[0189] S3. Adjust the pH of the mixture to 5.0 using sulfuric acid, transfer it to a 250ml volumetric flask and bring it to the mark. Then filter it through a 0.22um filter membrane for sterilization to obtain the combined drug solution.
[0190] The present invention also discloses the use of an inhaled antibiotic composition in the preparation of an inhaled pharmaceutical formulation for treating bacterial pulmonary infections.
[0191] Example 16:
[0192] Please see Figure 1 This embodiment provides a technical solution based on embodiment four:
[0193] An inhaled antibiotic composition comprises, by weight: 1-20 parts of antibiotic drug, 1-3 parts of osmotic pressure regulator, 0-30 parts of alcohol compound, 0.1-50 parts of pH regulator, and 1-250 parts of solvent.
[0194] The specific implementation method is as follows: the pH adjuster is sulfuric acid; the antibiotic is polymyxin B sulfate with a concentration of 0.5% to 10.0% (w / v); the osmotic pressure adjuster is sodium chloride with a concentration of 0.1% to 2.0% (w / v); the solvent is ultrapure water or a mixed solution of ultrapure water and an alcohol compound; the alcohol compound is at least one of anhydrous ethanol, glycerol, and propylene glycol; the pH value of the composition is 5.0; and the osmotic pressure is 291 mOsmol / kg.
[0195] This invention also discloses a method for preparing an inhaled antibiotic drug composition, specifically comprising the following steps:
[0196] S1. Add 0.08g of anhydrous ethanol, 25g of propylene glycol, and 1.0g of sodium chloride to a beaker containing an appropriate amount of ultrapure water, stir, and obtain solution one after the solid particles dissolve.
[0197] S2. Add 7.5g of polymyxin B sulfate to solution one to obtain a mixed solution;
[0198] S3. Adjust the pH of the mixture to 5.0 using sulfuric acid, transfer it to a 250ml volumetric flask and bring it to the mark. Then filter it through a 0.22um filter membrane for sterilization to obtain the combined drug solution.
[0199] The present invention also discloses the use of an inhaled antibiotic composition in the preparation of an inhaled pharmaceutical formulation for treating bacterial pulmonary infections.
[0200] Example 17:
[0201] Please see Figure 1 This embodiment provides a technical solution based on embodiment four:
[0202] An inhaled antibiotic composition comprises, by weight: 1-20 parts of antibiotic drug, 1-3 parts of osmotic pressure regulator, 0-30 parts of alcohol compound, 0.1-50 parts of pH regulator, and 1-250 parts of solvent.
[0203] The specific implementation method is as follows: the pH adjuster is sulfuric acid; the antibiotic is polymyxin B sulfate with a concentration of 0.5% to 10.0% (w / v); the osmotic pressure adjuster is sodium chloride with a concentration of 0.1% to 2.0% (w / v); the solvent is ultrapure water or a mixed solution of ultrapure water and an alcohol compound; the alcohol compound is at least one of anhydrous ethanol, glycerol, and propylene glycol; the pH value of the composition is 5.0; and the osmotic pressure is 295 mOsmol / kg.
[0204] This invention also discloses a method for preparing an inhaled antibiotic drug composition, specifically comprising the following steps:
[0205] S1. Add 0.08g of anhydrous ethanol, 5g of glycerol, and 1.8g of sodium chloride to a beaker containing an appropriate amount of ultrapure water, stir, and obtain solution one after the solid particles dissolve.
[0206] S2. Add 7.5g of polymyxin B sulfate to solution one to obtain a mixed solution;
[0207] S3. Adjust the pH of the mixture to 5.0 using sulfuric acid, transfer it to a 250ml volumetric flask and bring it to the mark. Then filter it through a 0.22um filter membrane for sterilization to obtain the combined drug solution.
[0208] The present invention also discloses the use of an inhaled antibiotic composition in the preparation of an inhaled pharmaceutical formulation for treating bacterial pulmonary infections.
[0209] Tables 7 to 9 examine the stability, liquid delivery rate, total delivery amount, and delivery percentage of the drug solutions in Examples 13 to 17 after the addition of different alcohol compounds. The formulation of the drug solutions in Examples 13 to 17 is shown in Table 7.
[0210] Tables 8 and 9 show the test results of the compositions of Examples 13 to 17 on day 0 and after being placed at 25°C for 1 month, respectively.
[0211] As shown in Tables 8 and 9, compared with Example 4, the surface tension of the drug solution with different added alcohols decreased after the addition of propylene glycol, while the delivery rate, total delivery volume, and delivery percentage all increased significantly. The surface tension of the drug solution with the addition of anhydrous ethanol did not change significantly, but the delivery rate, total delivery volume, and delivery percentage all decreased slightly. The surface tension of the drug solution with the addition of glycerin increased, while the delivery rate, total delivery volume, and delivery percentage all decreased significantly. Therefore, reducing the surface tension of the drug solution can improve delivery performance, while increasing the surface tension of the drug solution will decrease its delivery performance.
[0212] Furthermore, compared with Example 4, the properties, pH value, osmotic pressure molar concentration, and related impurities of the drug solutions containing different alcohol compounds in Examples 13 to 17 showed no significant differences after 0 days and 1 month at 25°C, indicating that adding alcohol compounds to the drug solutions does not change their stability.
[0213] Table 7. Samples of pharmaceutical solutions containing different added alcohol compounds.
[0214]
[0215]
[0216] Table 8. Detection results of drug solutions containing different added alcohols on day 0.
[0217]
[0218] Table 9. Test results of drug solutions containing different added alcohols after being stored at 25°C for 1 month.
[0219]
[0220] Example 18:
[0221] The drug solution sample prepared in Example 4 was used to test the delivery rate and total delivery amount of the drug solution. The test method is as follows:
[0222] (1) Experimental setup: A special measuring device equipped with a breathing simulator and a filtration system was used; the breathing simulator can accurately simulate the human breathing curve, the filtration system is equipped with low-resistivity filter paper, and a high-performance liquid chromatograph is used for quantitative analysis of drugs.
[0223] (2) Test conditions and parameters: The test was conducted according to the method for determination of delivery rate and total delivery amount in Appendix 0111 of the General Chapters, Part IV of the Chinese Pharmacopoeia 2025. The steps are as follows:
[0224] First, take 5.0 ml of the sample from Example 4 and add it to the drug storage chamber of the nebulizer, ensuring that the nebulizer nozzle is sealed to the filtration system. Then, start the nebulizer until the drug solution is completely atomized, replacing the filter paper during this period. The delivery rate is calculated as the ratio of the amount of drug collected during the first filter paper replacement to the corresponding nebulization time. Finally, combine all the residual drugs from the filter paper and collection device, elute, and determine the total amount of drug using HPLC, which is the total delivery amount.
[0225] The atomizing devices used included: a jet atomizer (manufacturer model A); and vibrating screen atomizers (manufacturer models B and C). The drug solution from Example 5 was atomized using these atomizers, and the delivery performance was compared. The results are shown in Table 10.
[0226] Table 10 Comparison of atomization performance of atomizers from different manufacturers
[0227]
[0228] The results in Table 10 show that the total delivery volume and delivery percentage of the sample were lower after nebulization by the type A nebulizer. Types B and C nebulizers have the same nebulization principle, and there was no significant difference in the total delivery volume and delivery percentage after nebulization. However, the nebulization time and delivery rate of the type B nebulizer were superior to those of the type C nebulizer, demonstrating good clinical applicability. Therefore, the type B nebulizer is preferred as the nebulization delivery device for the drug solution.
[0229] The foregoing has only described certain exemplary embodiments of the present invention by way of illustration. Undoubtedly, those skilled in the art can modify the described embodiments in various ways without departing from the spirit and scope of the present invention. Therefore, the foregoing drawings and descriptions are illustrative in nature and should not be construed as limiting the scope of protection of the claims of the present invention.
Claims
1. An inhaled antibiotic composition, characterized in that, Its raw materials, by weight, include: 1-20 parts of antibiotic drugs, 1-3 parts of osmotic pressure regulators, 0-30 parts of alcohol compounds, 0.1-50 parts of pH regulators, and 1-250 parts of solvents.
2. The inhaled antibiotic composition according to claim 1, characterized in that, The pH adjuster is at least one of hydrochloric acid, sulfuric acid, sodium hydroxide, citric acid, sodium citrate, disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium phosphate, and phosphoric acid.
3. The inhaled antibiotic composition according to claim 1, characterized in that, The antibiotic is at least one of polymyxin B, polymyxin E, amikacin, meropenem, vancomycin, azithromycin, levofloxacin, clindamycin, and doxycycline.
4. The inhaled antibiotic composition according to claim 1, characterized in that, The osmotic pressure regulator is at least one of sodium chloride, mannitol, sorbitol, and glucose; the concentration of the osmotic pressure regulator is 0.1% to 2.0% (w / v).
5. The inhaled antibiotic composition according to claim 1, characterized in that, The solvent is ultrapure water or a mixed solution of ultrapure water and an alcohol compound.
6. The inhaled antibiotic composition according to claim 5, characterized in that, The alcohol compound is at least one of anhydrous ethanol, glycerol, propylene glycol, and polyethylene glycol; the concentration of the alcohol compound is 10 mg / ml to 500 mg / ml.
7. The inhaled antibiotic composition according to claim 3, characterized in that, The polymyxin B is polymyxin B sulfate, and the concentration of polymyxin B sulfate is 0.5% to 10.0% (w / v).
8. The inhaled antibiotic composition according to claim 1, characterized in that, The composition has a pH of 3.5 to 6.5 and an osmotic pressure of 250 to 350 mOsmol / kg.
9. The inhaled antibiotic composition according to claim 7, characterized in that, Its preparation method specifically includes the following steps: S1. Add an osmotic pressure regulator to a beaker containing solvent, stir, and obtain solution one after the solid particles dissolve. S2. Add polymyxin B sulfate to solution one to obtain a mixed solution; S3. Adjust the pH of the mixture using a pH adjuster, transfer it to a volumetric flask and bring it to the mark, then filter it through a 0.22µm filter membrane for sterilization to obtain the combined drug solution.
10. Use of the composition according to any one of claims 1-8 in the preparation of an inhaled pharmaceutical formulation for treating bacterial pulmonary infections.