Pharmaceutical component containing etimicin sulfate solution and application thereof

Abstract

The invention discloses a medicine assembly containing an etimicin sulfate solution and application of the medicine assembly. The medicine assembly comprises (a) the etimicin sulfate solution; the vibrating screen atomizer is used in cooperation with the etimicin sulfate solution; 1500-2200 micropores are formed in the central area of an atomizing sheet of the vibrating screen atomizer; the diameter of each micropore is 2.2 microns to 3.8 microns; wherein the vibration frequency of the vibrating screen atomizer is 90-120KHZ; the sections of the micropores in the vibrating screen atomizer are distributed in a step shape, and the taper is 18 degrees. The nebulizer is matched with the etimicin sulfate inhalation solution for use, so that the administration efficiency of the etimicin sulfate inhalation solution is improved, and the medicine can safely reach an effective treatment concentration in the lung. In addition, the form can improve the amount of delivered medicine, can deposit a large amount of medicine in terminal bronchus and pulmonary alveoli, increases the proportion of fine fog drops reaching the lung, shortens the atomization time, and reduces the volume of medicine liquid residues.

Description

Technical Field

[0001] This invention relates to a pharmaceutical component comprising etimicin sulfate solution and its application. Background Technology

[0002] Bronchiectasis (BDE) is a recurrent purulent infection caused by various etiologies, leading to repeated damage and / or obstruction of small and medium-sized bronchi. This results in the destruction of the bronchial wall structure, causing abnormal and persistent dilation of the bronchi. Clinical manifestations include chronic cough, copious sputum production and / or intermittent hemoptysis, with or without shortness of breath and respiratory failure, ranging in severity. In my country, the number of BDE patients is large, and the prevalence is increasing year by year. Studies show that the prevalence of BDE in people over 40 years of age in my country is 1.2% (135 / 10811), and the prevalence increases with age. However, due to insufficient awareness and lack of attention from patients; common symptoms leading to easy misdiagnosis and missed diagnosis; and the lack of simple, accurate, and non-invasive screening methods (such as HRCT and high-resolution CT) in primary hospitals, BDE is often treated as COPD, and the actual prevalence should be much higher than this figure. The increasing number of BDE patients each year has brought a huge medical and economic burden to society. From 2013 to 2017, the average number of outpatient visits and hospitalizations per year for adult bronchiectasis patients in China was approximately 2.0 and 1.2 respectively. The average total cost and hospitalization cost per person increased by 2.18 times and 1.83 times respectively. The average total cost per person per year for bronchiectasis patients increased from US$3,537.83 in 2013 to US$7,696.54 in 2017, and the average hospitalization cost per person per year increased from US$5,959.50 in 2013 to US$10,917.07 in 2017.

[0003] Bronchiectasis Severity Index (BSI) and E-FACED can be used to assess the severity of bronchiectasis, and both consider *Pseudomonas aeruginosa* as an important factor in risk and prognosis assessment. The isolation rate of *P. aeruginosa* is highest among bronchiectasis patients in my country, approximately 30%. The adverse effects of *P. aeruginosa* on bronchiectasis patients are multifaceted, including inflammation levels (local and systemic), lung function impairment, acute exacerbations, decreased quality of life, and increased mortality. Therefore, antimicrobial therapy is particularly important for bronchiectasis patients. Numerous studies both domestically and internationally have confirmed the efficacy and safety of inhaled antimicrobial drugs in treating bronchiectasis, especially in patients with *P. aeruginosa* colonization, demonstrating its promising therapeutic potential.

[0004] Aminoglycoside antibiotics are among the earliest antibiotics used to treat bacterial infections. They possess a structure consisting of aminoglycosides and aminocyclic alcohols. As bactericidal agents operating in the stationary phase, aminoglycoside antibiotics exhibit concentration-dependent bactericidal activity, particularly against Gram-negative bacteria (including Pseudomonas aeruginosa), demonstrating broad in vitro antibacterial activity and a significant post-antibiotic effect (PAE). Their antibacterial activity is enhanced in alkaline environments. Aminoglycoside antibiotics achieve their bactericidal effect by inhibiting bacterial protein synthesis and disrupting the integrity of the cytoplasmic membrane. Being cationic, aminoglycoside antibiotics first bind to anionic compounds on the bacterial surface. The interaction between the cations and anions increases bacterial surface permeability, allowing some aminoglycoside molecules to penetrate into the periplasmic space. Subsequently, a small number of antibiotic molecules reach the cytoplasm with the participation of the functional electron transport system, binding to the 16S RNA of the bacterial 30S ribosome subunit. This alteration of the ribosome structure leads to changes in all subsequent protein synthesis processes (including initiation, elongation, and termination). Reading errors in mRNA lead to the synthesis of abnormal proteins. The insertion of these abnormal proteins disrupts the integrity of the cell membrane, which enhances the penetration of aminoglycoside drugs. A large number of aminoglycoside molecules enter the cell, ultimately leading to cell death.

[0005] Etimicin sulfate is a third-generation aminoglycoside antibiotic independently developed in my country, modified from the C1a component of gentamicin. It has been used clinically for nearly 20 years since its market launch in 1999. Compared with other aminoglycosides, it has similar antibacterial activity, but its incidence of adverse reactions such as nephrotoxicity, ototoxicity, and neuromuscular blocking is significantly lower. Post-marketing safety studies showed that the incidence of ototoxicity with etimicin was 0.15% (4 / 2634), and the incidence of nephrotoxicity was 0.19% (5 / 2634), approaching the incidence of rare adverse reactions. Aminoglycosides may cause adverse reactions such as ototoxicity, nephrotoxicity, and neuromuscular blocking. Ototoxicity includes vestibular dysfunction and damage to the cochlear auditory nerve. The incidence of vestibular toxicity, in descending order, is kanamycin, streptomycin, sisomicin, amikacin, gentamicin, tobramycin, and netilmicin; the incidence of hearing (cochlear) toxicity, in descending order, is kanamycin, amikacin, sisomicin, gentamicin, tobramycin, and netilmicin; the severity of kidney damage, in descending order, is kanamycin, gentamicin, tobramycin, amikacin, and netilmicin. Etimicin has a similar chemical structure to netilmicin, and its otonephrotoxicity is the lowest among aminoglycoside antibiotics.

[0006] Inhalation therapy is an important treatment for respiratory diseases. Nebulized inhalation delivers medication directly to the respiratory tract and lungs, offering advantages such as rapid onset of action, high local drug concentration, low dosage, convenient application, and minimal systemic absorption and adverse reactions. While aminoglycosides have poor lung penetration after intravenous administration, inhalation results in high concentrations in the alveolar epithelial lining fluid (ELF) and low systemic exposure. Nebulized etimicin sulfate achieves significantly higher proximal airway concentrations than other routes of administration. As a concentration-dependent antibiotic, inhalation leads to a higher AUC / MIC in the lungs, enhancing its bactericidal effect. This allows for higher concentrations within the airways with minimal systemic absorption, minimizing systemic side effects and preventing the development of drug-resistant bacteria.

[0007] Currently, commonly used nebulizers include jet nebulizers, which mainly consist of an air compressor and a nebulizer. Based on the Bernoulli principle, compressed gas delivered by a compressor pump or tubing source creates a localized negative pressure zone when it passes through the narrow nozzle of a venturi tube. This pressure forces the fluid to be ejected from the internal baffles of the nebulizer, where it splashes and forms a mist of droplets that are expelled from the trachea. However, jet nebulizers have drawbacks such as low drug delivery volume, high noise levels, large residual drug volume, long nebulization time, low patient compliance, requirement for AC power, need for a compressor, and large size, making them inconvenient to carry. Furthermore, antibiotic treatment is affected by the drug concentration at the site of infection. A limitation when using a jet nebulizer to nebulize etimicin sulfate nebulized solution is the residual drug level; a large amount of drug can remain in the nebulizer, affecting the amount of drug reaching the lungs. Summary of the Invention

[0008] The technical problem this invention aims to solve is to overcome the shortcomings of existing jet nebulizers, such as low drug delivery volume, high noise, large residual drug volume, long nebulization time, low patient compliance, requirement for AC power, need for a compressor, and large and inconvenient size. Furthermore, antibiotic treatment is affected by the drug concentration at the site of infection. A limitation of using a jet nebulizer to nebulize etimicin sulfate inhalation solution is the residual drug volume; a large amount of drug remains in the nebulizer, affecting the amount of drug reaching the lungs. This invention provides a drug component containing etimicin sulfate solution and its application.

[0009] The present invention solves the above-mentioned technical problems through the following technical solution:

[0010] This invention discloses a pharmaceutical component comprising etimicin sulfate solution, the pharmaceutical component comprising:

[0011] (a) etimicin sulfate solution; and

[0012] (b) A vibrating screen atomizer used in conjunction with the etimicin sulfate solution;

[0013] The central area of ​​the atomizing plate of the vibrating screen atomizer has 1500-2200 micropores;

[0014] The diameter of the micropores is 2.2 μm-3.8 μm;

[0015] The vibration frequency of the vibrating screen atomizer is 90-120 kHz;

[0016] The cross-section of the micropores in the vibrating screen atomizer is stepped, with a taper of 18 degrees.

[0017] Preferably, the central region of the atomizing plate of the vibrating screen atomizer has 1800-2200 micropores.

[0018] Preferably, the current of the vibrating screen atomizer is no more than 400mA;

[0019] And / or, the voltage of the vibrating screen atomizer is 5V±10%;

[0020] And / or, the atomization rate of the vibrating screen atomizer is not less than 0.29 mL / min.

[0021] Preferably, the diameter of the micropores is 2.5μm-3.5μm, more preferably 2.7μm-3.3μm, and even more preferably 2.8μm-3.3μm;

[0022] And / or, the vibration frequency of the vibrating screen atomizer is 90-115 kHz, preferably 100-113 kHz.

[0023] Preferably, the etimicin sulfate solution is solution 1 or solution 2 of the following:

[0024] Solution 1: It consists of etimicin sulfate, osmotic pressure regulator, pH regulator and water;

[0025] in,

[0026] The osmotic pressure of the etimicin sulfate solution is 150-550 mOsmol / kg;

[0027] The pH of the etimicin sulfate solution is 4.0-8.5;

[0028] Solution 2: It consists of etimicin sulfate, an osmotic pressure regulator, and water;

[0029] The osmotic pressure of the etimicin sulfate solution is 150-550 mOsmol / kg.

[0030] Preferably, it satisfies one or more of the following conditions:

[0031] (1) In the solutions 1 and 2, the molecular formula of etimicin sulfate is (C21H43N5O7)2·5H2SO4;

[0032] (2) In solutions 1 and 2, the mass fraction of etimicin sulfate is 59.0%-66.0%;

[0033] (3) In the solutions 1 and 2, the mass fraction of free water in the etimicin sulfate is 0% to 10%;

[0034] (4) In the solutions 1 and 2, the mass-volume ratio of etimicin, the active ingredient in etimicin sulfate, to the water can be 50 mg / ml-100 mg / ml, for example, 50 mg / ml or 75 mg / ml.

[0035] (5) In solutions 1 and 2, the osmotic pressure regulator is glucose or sodium chloride;

[0036] (6) In the solutions 1 and 2, when the osmotic pressure regulator is sodium chloride, the mass ratio of the osmotic pressure regulator to the water can be 0.2%-0.9%, preferably 0.2%-0.5%, more preferably 0.2%, 0.3% or 0.5%, and most preferably 0.3%;

[0037] (7) In the solutions 1 and 2, when the osmotic pressure regulator is sodium chloride, the mass-volume ratio of the osmotic pressure regulator to the water can be 2 mg / mL-9 mg / mL, preferably 2 mg / mL-5 mg / mL, more preferably 2 mg / mL, 3 mg / mL or 5 mg / mL, and most preferably 3 mg / mL.

[0038] (8) The osmotic pressure of the solutions 1 and 2 is 260 mOsmol / kg, 286 mOsmol / kg, 314 mOsmol / kg or 348 mOsmol / kg, preferably 286 mOsmol / kg;

[0039] (9) The oxygen content of solutions 1 and 2 is 0.2 ppm to 2.0 ppm;

[0040] Preferably, nitrogen gas is introduced into solutions 1 and 2 to obtain an etimicin sulfate solution with an oxygen content of 0.2 ppm to 2.0 ppm;

[0041] (10) In the solutions 1 and 2, the water is water for injection;

[0042] (11) In the solution 1, the pH adjuster is sodium hydroxide or hydrochloric acid;

[0043] (12) The pH of the solution 1 is 5.0-8.0, preferably 5.0-6.0;

[0044] (13) Solution 1 and Solution 2 shall be stored away from light.

[0045] Preferably, it satisfies one or more of the following conditions:

[0046] (1) Solution 1 is as shown in any of the following formulations:

[0047] Prescription 1: Etimicin sulfate solution: concentration of etimicin 75 mg / mL, sodium chloride concentration 3 mg / mL, pH adjuster: NaOH, pH: 6.0, solvent: water, oxygen content less than 0.2 ppm;

[0048] Prescription 2: Etimicin sulfate solution: concentration of etimicin 75 mg / mL, sodium chloride concentration 3 mg / mL, pH adjuster: NaOH, pH: 6.0, solvent: water;

[0049] Prescription 3: Etimicin sulfate solution: concentration of etimicin 75 mg / mL, sodium chloride concentration 3 mg / mL, pH adjuster: NaOH, pH: 5.0, solvent: water, oxygen content less than 0.2 ppm;

[0050] Prescription 4: Etimicin sulfate solution: concentration of etimicin 50 mg / mL, sodium chloride concentration 9 mg / mL, pH adjuster: NaOH, pH: 5.8, solvent: water, oxygen content less than 0.2 ppm;

[0051] (2) The formulation of solution 2 is as follows: etimicin concentration in etimicin sulfate solution: 75 mg / mL, sodium chloride concentration: 3 mg / mL, solvent: water, oxygen content less than 0.2 ppm.

[0052] Preferably, the etimicin sulfate solution is prepared by method 1 or method 2:

[0053] Method 1: It includes the following steps: dissolving etimicin sulfate, an osmotic pressure regulator, and a pH regulator in water;

[0054] Method 2: It includes the following steps: dissolving etimicin sulfate and an osmotic pressure regulator in water.

[0055] Preferably, it satisfies one or more of the following conditions:

[0056] (1) The method 1 includes the following steps: at 20-30℃, the osmotic pressure regulator and the etimicin sulfate are dissolved in part of water, then the pH regulator is added, and finally water is added to make up the volume, and the solution is filtered to obtain the etimicin sulfate solution.

[0057] The filtration device is, for example, a PVDF filter membrane or a PES filter cartridge;

[0058] The pore size of the PVDF filter membrane is, for example, 0.22 μm;

[0059] The pore size of the PES filter element is, for example, 0.2 μm;

[0060] (2) The method 1 includes the following steps: nitrogen gas is introduced into the etimicin sulfate solution to obtain an etimicin sulfate solution with an oxygen content of 0.2ppm-2.0ppm; the time for introducing nitrogen gas can be 10-20min, for example 10min, 15min or 20min;

[0061] (3) The method 1 may further include a packaging step, wherein the packaging step may involve injecting 2.0 ml of etimicin sulfate solution into an ampoule using a syringe, sealing the ampoule, pressing to check for leaks, and filling it with nitrogen-filled aluminum-plastic packaging.

[0062] The ampoule is a low-density polyethylene ampoule.

[0063] (4) The method 1 may further include a packaging step, wherein the packaging step may be an integrated filling process using a filling machine in a million-level environment, with a filling volume of 2.0 ml and nitrogen-filled aluminum-plastic packaging; wherein the filling machine is a blow-fill-seal three-in-one filling machine.

[0064] (5) The method 2 includes the following steps: at 20-30℃, the osmotic pressure regulator and the etimicin sulfate are dissolved in water and the volume is adjusted, and the solution is filtered to obtain etimicin sulfate solution;

[0065] The filtration device is, for example, a PVDF filter membrane or a PES filter cartridge;

[0066] The pore size of the PVDF filter membrane is, for example, 0.22 μm;

[0067] The pore size of the PES filter element is, for example, 0.2 μm;

[0068] (6) Method 2 may further include the following steps: nitrogen gas is introduced into the etimicin sulfate solution to obtain an etimicin sulfate solution with an oxygen content of 0.2ppm-2.0ppm;

[0069] The nitrogen filling time can be 10-20 minutes, for example, 10 minutes, 15 minutes or 20 minutes;

[0070] (7) The preparation method of etimicin sulfate solution may further include a packaging step, wherein the packaging step may involve injecting 2.0 ml of etimicin sulfate solution into an ampoule using a syringe, sealing the ampoule, pressing to check for leaks, and filling it with nitrogen-filled aluminum-plastic packaging.

[0071] The ampoule is a low-density polyethylene ampoule.

[0072] (8) The preparation method of the etimicin sulfate solution may further include a packaging step, wherein the packaging step may be an integrated filling process using a filling machine in a million-level environment, with a filling volume of 2.0 ml and nitrogen-filled aluminum-plastic packaging.

[0073] The filling machine is a three-in-one filling machine that combines blowing, filling, and sealing.

[0074] This invention provides the use of the above-mentioned pharmaceutical component containing etimicin sulfate solution in the preparation of pharmaceutical products for treating respiratory tract infections.

[0075] In this invention, "PES" refers to polyethersulfone.

[0076] "PVDF" refers to polyvinylidene fluoride.

[0077] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0078] The reagents and raw materials used in this invention are all commercially available.

[0079] The positive and progressive effects of this invention are as follows:

[0080] Using a nebulizer in conjunction with etimicin sulfate inhalation solution improves the drug delivery efficiency, helping the drug safely reach effective therapeutic concentrations in the lungs. Furthermore, this method increases the amount of drug delivered, allowing for greater deposition in the terminal bronchioles and alveoli, increasing the proportion of fine droplets reaching the lungs, shortening nebulization time, reducing residual drug volume, and offering greater portability to meet the needs of patients in various usage scenarios.

[0081] Etimicin sulfate solution has one or more of the following advantages: a) good stability, long-term storage, no significant increase in solution color and impurities, and meets quality standards; b) low irritation to the lungs; c) when used with appropriate devices, this solution generates an inhalable aerosol, enabling efficient delivery of the drug to the site of infection and exerting its therapeutic effect. Attached Figure Description

[0082] Figure 1 The histopathology of lung tissue after the dosing period is shown (HE, 100×); a is the blank control group, b is the test formulation group 1, c is the test formulation group 2, and d is a magnified view of the edematous tissue in the test formulation group 2.

[0083] Figure 2 The image shows a front view of the atomizing plate of the vibrating screen atomizer.

[0084] Explanation of reference numerals in the attached figures:

[0085] 100 atomizing tablets

[0086] Central Area 1 Detailed Implementation

[0087] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0088] In this invention, "room temperature" refers to 20-30℃.

[0089] etimicin sulfate (C 21 H 43 The structural formula of N5O7)2·5H2SO4 is as follows:

[0090]

[0091] Example 1 (Standard prescription, 75 mg / ml etimicin)

[0092] Table 1 Prescription Table for Example 1

[0093]

[0094] a: Based on the purity and moisture content of the raw material, this is actually equivalent to 15g of etimicin (C) after drying and purification. 21 H 43 (N5O7). b: Due to the change in solution volume, the volume of the prescription was determined by the volume adjustment method, and the actual amount of water added was slightly less than 200 mL.

[0095] The preparation method is as follows:

[0096] 1) Add 70% of the prescribed amount of water for injection (at room temperature);

[0097] 2) Dissolve the prescribed amount of sodium chloride;

[0098] 3) Add the prescribed amount of etimicin sulfate and stir magnetically to dissolve;

[0099] 4) Adjust the pH of the prepared solution to 6.0 using NaOH;

[0100] 5) Add the prescribed amount of water for injection to make up the volume (the pH should not change significantly after making up the volume);

[0101] 6) Passed through a 0.22μm PVDF filter membrane;

[0102] 7) Purge the prepared drug solution with nitrogen until the residual oxygen content is less than 200 ppb (μg / L), for 15 minutes;

[0103] 8) Fill a low-density polyethylene ampoule with nitrogen for 40 seconds;

[0104] 9) Using a disposable syringe, inject approximately 2.0 ml of the prepared medication solution into the low-density polyethylene solution.

[0105] The ampoule is sealed, pressed to check for leaks, and then filled with nitrogen and packaged in an aluminum-plastic composite.

[0106] Example 2 (Drug solution without nitrogen filling, 75 mg / ml etimicin)

[0107] Table 2 Prescription Table for Example 2

[0108]

[0109] a: Based on the purity and moisture content of the raw material, this is actually equivalent to 15g of etimicin (C) after drying and purification. 21 H 43 (N5O7). b: Due to the change in solution volume, the volume of the prescription was determined by the volume adjustment method, and the actual amount of water added was slightly less than 200 mL.

[0110] The preparation method is as follows:

[0111] 1. Add 70% of the prescribed amount of water for injection (at room temperature);

[0112] 2. Dissolve the prescribed amount of sodium chloride;

[0113] 3. Add the prescribed amount of etimicin sulfate and stir magnetically to dissolve;

[0114] 4. Adjust the pH of the prepared solution to 6.0 using NaOH;

[0115] 5. Add the prescribed amount of water for injection to bring the volume to a final level (the pH should not change significantly after leveling).

[0116] 6. Passed through a 0.22μm PVDF filter membrane;

[0117] 7. Purge a low-density polyethylene ampoule with nitrogen for 40 seconds;

[0118] 8. Using a disposable syringe, inject approximately 2.0 ml of the prepared medication into a low-density polyethylene ampoule, seal the ampoule, press to check for leaks, and then fill with nitrogen-filled aluminum-plastic packaging.

[0119] Example 3 (with chelating agent, 75 mg / ml etimicin)

[0120] Table 3 Prescription Table for Example 3

[0121]

[0122] a: Based on the purity and moisture content of the raw material, this is actually equivalent to 15g of etimicin (C) after drying and purification. 21 H 43 (N5O7). b: Due to the change in solution volume, the volume of the prescription was determined by the volume adjustment method, and the actual amount of water added was slightly less than 200 mL.

[0123] The preparation method is as follows:

[0124] 1. Add 70% of the prescribed amount of water for injection (at room temperature);

[0125] 2. Dissolve the prescribed amount of sodium chloride;

[0126] 3. Add the prescribed amount of etimicin sulfate and stir magnetically to dissolve;

[0127] 4. Add the prescribed amount of EDTA to dissolve;

[0128] 5. Adjust the pH of the prepared solution to 6.0 using NaOH;

[0129] 6. Add the prescribed amount of water for injection to bring the volume to a final level (the pH should not change significantly after leveling).

[0130] 7. Passed through a 0.22μm PVDF filter membrane;

[0131] 8. Purge the prepared solution with nitrogen until the residual oxygen content is less than 200 ppb (μg / L), which takes 10-15 minutes;

[0132] 9. Purge a low-density polyethylene ampoule with nitrogen for 40 seconds;

[0133] 10. Using a disposable syringe, inject approximately 2.0 ml of the prepared medication into a low-density polyethylene ampoule, seal the ampoule, press to check for leaks, and then fill with nitrogen-filled aluminum-plastic packaging.

[0134] Example 4 (50 mg / ml etimicin with anhydrous sodium sulfite)

[0135] Table 4 Prescription Table for Example 4

[0136]

[0137] a: Based on the purity and moisture content of the raw material, this is actually equivalent to 5g of etimicin (C) after drying and purification. 21 H43 (N5O7). b: Due to the change in solution volume, the volume of the prescription was determined by the volume adjustment method, and the actual amount of solution added was slightly less than 100 mL.

[0138] The preparation method is as follows:

[0139] 1. Add 85% of the prescribed amount of 0.9% sodium chloride (w / w) injection (at room temperature);

[0140] 2. Add the prescribed amount of anhydrous sodium sulfite and stir magnetically to dissolve;

[0141] 3. Add the prescribed amount of etimicin sulfate and stir magnetically to dissolve;

[0142] 4. Adjust the pH of the prepared solution to 5.8 using NaOH;

[0143] 5. Add 0.9% sodium chloride (w / w) injection solution to make up to volume (the pH did not change significantly after making up to volume);

[0144] 6. Passed through a 0.22μm PVDF filter membrane;

[0145] 7. Purge the prepared solution with nitrogen until the residual oxygen content is less than 200 ppb (μg / L), which takes 10-15 minutes;

[0146] 8. Purge a low-density polyethylene ampoule with nitrogen for 40 seconds;

[0147] 9. Using a disposable syringe, inject approximately 2.0 ml of the prepared medication into each low-density polyethylene ampoule, seal the ampoule, press to check for leaks, and then fill with nitrogen-filled aluminum-plastic packaging.

[0148] Example 5 (50 mg / ml etimicin)

[0149] Table 5 Prescription Table for Example 5

[0150]

[0151] a: Based on the purity and moisture content of the raw material, this is actually equivalent to 5g of etimicin (C) after drying and purification. 21 H 43 (N5O7). b: Due to the change in solution volume, the volume of the prescription was determined by the volume adjustment method, and the actual amount of solution added was slightly less than 100 mL.

[0152] The preparation method is as follows:

[0153] 1. Add 85% of the prescribed amount of 0.9% sodium chloride (w / w) injection (at room temperature);

[0154] 2. Add the prescribed amount of etimicin sulfate and stir magnetically to dissolve;

[0155] 3. Adjust the pH of the prepared solution to 5.8 using NaOH;

[0156] 4. Add 0.9% sodium chloride (w / w) injection solution to make up to volume (the pH did not change significantly after making up to volume);

[0157] 5. Passed through a 0.22μm PVDF filter membrane;

[0158] 6. Purge the prepared solution with nitrogen until the residual oxygen content is less than 200 ppb (μg / L), which takes 10-15 minutes;

[0159] 7. Purge a low-density polyethylene ampoule with nitrogen for 40 seconds;

[0160] 8. Using a disposable syringe, inject approximately 2.0 ml of the prepared medication into a low-density polyethylene ampoule, seal the ampoule, press to check for leaks, and then fill with nitrogen-filled aluminum-plastic packaging.

[0161] The prepared etimicin sulfate solution was subjected to quality inspection, and its stability was compared between different embodiments under high temperature and light exposure conditions. The high temperature test was conducted by placing the intact packaged sample in a constant temperature and humidity chamber at 60°C, with periodic sampling and testing. The light exposure test was conducted by placing the sample (ampoule packaging) in a light chamber, with periodic sampling and testing, at an illuminance of 4500 lx ± 500 lx, and a total illuminance of not less than 1.2 × 10⁻⁶. 6 lux·hr. Near-ultraviolet energy not less than 200 W·hr / m 2 Samples taken under both conditions were tested for content, total impurities, and colorimetric properties.

[0162] Comparison of results from Examples 1, 2, and 3

[0163] Table 6 Comparison of results from Examples 1, 2, and 3

[0164]

[0165] The determination of content, impurities (related substances), and colorimetric properties shall be carried out in accordance with the determination method under "Etimicin Sulfate Injection" in Part II of the Pharmacopoeia of the People's Republic of China (2020 Edition).

[0166] Comparing Examples 1 and 2, the formulation without nitrogen purging changed color faster under high temperature conditions, while the formulation after nitrogen purging changed color more slowly under high temperature conditions. Comparing Examples 1 and 3, when EDTA was removed, the formulation of Example 1 did not show an increase in total impurities under high temperature and light conditions, and its stability was better.

[0167] Comparison of results from Examples 4 and 5

[0168] Table 7 Comparison of Results from Examples 4 and 5

[0169]

[0170] Comparing Examples 4 and 5, it was found that both formulations were relatively stable under high-temperature conditions. Under light exposure, the formulation with added antioxidants (Example 4) showed less impurity growth than the formulation without antioxidants, but both formulations showed a significant increase in impurities. The comparison of these examples has confirmed that light exposure has a significant impact on stability, and light protection should be considered.

[0171] Comparative Example 1 (Sodium Chloride)

[0172] Compared with Example 1, everything else is the same except that the amount of sodium chloride added in step 3 is reduced to 400 mg.

[0173] Comparative Example 2 (Sodium Chloride)

[0174] Compared with Example 1, everything else is the same except that the amount of sodium chloride added in step 3 is increased to 800 mg.

[0175] Comparative Example 3 (Sodium Chloride)

[0176] Compared with Example 1, everything else is the same except that the amount of sodium chloride added in step 3 is increased to 1000 mg.

[0177] Comparative Example 4 (pH)

[0178] Compared to Example 1, no pH adjuster was added, the pH was slightly higher than 5, and everything else was the same.

[0179] Comparative Example 5 (pH)

[0180] Compared with Example 1, everything else is the same except that sodium hydroxide solution is used in step 4 to adjust the pH value to 7.0.

[0181] Comparative Example 6 (pH)

[0182] Compared with Example 1, everything else is the same except that sodium hydroxide solution is used in step 4 to adjust the pH value to 8.0.

[0183] The prepared etimicin sulfate solution was subjected to quality inspection, and the osmotic pressure of Comparative Examples 1-3 was measured. Comparative Examples 4-6 were placed under high temperature and light conditions. The results of Example 1 were compared and analyzed with those of Comparative Examples 1-6 to determine the content of the patent prescription ingredients.

[0184] Comparison of the results of Example 1 with those of Comparative Examples 1, 2, and 3

[0185] Sodium chloride plays a primary role in formulations as an osmotic pressure regulator.

[0186] Table 8 Comparison of results of Example 1 with Comparative Examples 1, 2, and 3

[0187] serial number Sodium chloride dosage (%, w / w) Osmotic pressure (mOsmol / kg) Comparative Example 1 0.2 260 Example 1 0.3 286 Comparative Example 2 0.4 314 Comparative Example 3 0.5 348

[0188] Comparison of the results of Example 1 with those of Comparative Examples 4, 5, and 6

[0189] Sodium hydroxide, besides ensuring a physiologically suitable pH value for the solution, is also related to the stability of the formulation. In this study, pH values ​​within the range of 5-8 met physiological requirements. The results indicate that the solution exhibits good stability at pH 5-6.

[0190] Table 9 Comparison of results of Example 1 with Comparative Examples 4, 5, and 6

[0191] Example 6: Inhalation irritation after adding anhydrous sodium sulfite to the formulation

[0192] The inhalation irritation of etimicin sulfate was assessed by observing whether local reversible inflammatory reactions such as redness, swelling, congestion, and exudation occurred in the oral mucosa, nasal mucosa, pharynx, trachea, and lungs after rats were exposed to anhydrous sodium sulfite via nebulized inhalation. Healthy SD rats were randomly divided into three groups using a stratified randomization method. The blank control group received nebulized inhalation of 0.9% sodium chloride solution, the test formulation group 1 received nebulized inhalation of the formulation described in Example 1 of this invention, and the test formulation group 2 received nebulized inhalation of the formulation described in Example 1 of this invention with the addition of 0.2% (w / v) anhydrous sodium sulfite. Rats in each group were administered the drug once daily for 60 minutes via oral and nasal exposure towers for 14 consecutive days. One day after the last administration, some rats were sacrificed and dissected, and the remaining rats were allowed to recover for 7 days and were sacrificed and dissected one day after the recovery period ended. After dissection, observe the animal's clinical symptoms and weight changes; perform gross dissection to observe whether there are symptoms such as congestion and edema in the local respiratory mucosa and lung tissue, and determine the level of respiratory mucosal irritation response; take nasal, larynx, trachea, bronchus and lung tissues, fix them and perform histopathological examination.

[0193] No significant abnormalities were observed in the clinical symptoms, body weight, and gross anatomical examination of the mucosa and lung tissue in any of the groups of animals. The respiratory mucosal irritation response score was 0 in all groups. At the end of the dosing period, no pulmonary edema was observed in the test formulation 1 group and the blank control group, while very slight to mild pulmonary edema was observed in the test formulation 2 group (see...). Figure 1 The condition can be reversed after the recovery period. In rats, the concentration of inhaled sodium sulfite aerosol ≥5 mg / m³ is [not specified]. 3 It can induce increased glycoprotein secretion, decreased dry / wet ratio of lung tissue, and pulmonary edema in rats. The concentration of sodium sulfite in the aerosol after nebulized administration of the test formulation 2 was approximately 6 mg / m³. 3 Mild pulmonary edema in rats after inhalation administration was associated with anhydrous sodium sulfite in the inhalation excipient.

[0194] Table 10. Inhalation Dosage of Two Formulated Etimicin Sulfate Nebulized Inhalation Solutions

[0195]

[0196] Example 7:

[0197] like Figure 2 As shown, this embodiment provides a pharmaceutical component comprising etimicin sulfate solution, the pharmaceutical component including:

[0198] (a) etimicin sulfate solution; and

[0199] (b) A vibrating screen atomizer used in conjunction with etimicin sulfate solution;

[0200] The central region 1 of the atomizing plate 100 of the vibrating screen atomizer has 1500-2200 micropores;

[0201] The diameter of the micropores ranges from 2.2 μm to 3.8 μm.

[0202] The vibration frequency of the vibrating screen atomizer is 90-120KHZ;

[0203] The cross-section of the micropores in the vibrating screen atomizer is distributed in a stepped manner with a taper of 18 degrees.

[0204] In practical use, combining the nebulizer with etimicin sulfate inhalation solution improves the drug delivery efficiency of the nebulized etimicin sulfate solution, helping the drug safely reach an effective therapeutic concentration in the lungs. Furthermore, this method increases the amount of drug delivered, allowing for greater deposition in the terminal bronchioles and alveoli, increasing the proportion of fine droplets reaching the lungs, shortening nebulization time, reducing residual drug volume, and providing greater portability to meet the needs of patients in various usage scenarios.

[0205] The central region 1 of the nebulizing plate 100 of the vibrating screen nebulizer has 1800-2200 micropores. Specifically, the number and distribution density of micropores are one of the key factors affecting the nebulization effect. More micropores can increase the surface area of ​​liquid in contact with air, thereby improving nebulization efficiency and speed. The uniform distribution of micropores helps to produce finer and more uniform droplets, which helps the drug deposit in the respiratory tract and lungs, improving the therapeutic effect. In addition, the working principle of the microporous nebulizing plate 100 is to use high-pressure airflow or ultrasonic vibration to make the liquid medium flow at high speed in the micropores and generate strong shear force, breaking it into tiny droplets. By adopting the above method, the proportion of fine droplets reaching the lungs is increased, the nebulization time is shortened, and the residual volume of drug solution is reduced.

[0206] In this embodiment, the current of the vibrating screen atomizer is no greater than 400mA; the voltage of the vibrating screen atomizer is 5V±10%; and the atomization rate of the vibrating screen atomizer is no less than 0.29mL / min.

[0207] In this embodiment, the diameter of the micropores is 2.5μm-3.5μm, preferably 2.7μm-3.3μm, and more preferably 2.8μm-3.3μm; the vibration frequency of the vibrating screen atomizer is 90-115KHZ, preferably 100-113KHZ.

[0208] Example 8:

[0209] In this embodiment, keeping other parameters constant, the effect of different micropore diameters on the atomization effect of etimicin sulfate nebulized inhalation solution was investigated, and the results are shown in the table.

[0210] Table 11 Comparison of atomization performance with different micropore diameters

[0211]

[0212] Among them, the mass median aerodynamic diameter (MMAD) is 50% of the mass distribution below this diameter.

[0213] Fine particle mass (FPD): The mass of drugs with an aerodynamic particle size of less than 5 μm.

[0214] Fine particle fraction FPF = FPD / delivery mass.

[0215] Example 9:

[0216] In this embodiment, keeping other parameters constant, the effect of different perforation numbers on the atomization effect of etimicin sulfate nebulized inhalation solution was investigated, and the results are shown in Table 12.

[0217] Table 12 Comparison of atomization performance with different numbers of micropores

[0218]

[0219] Among them, the mass median aerodynamic diameter (MMAD) is 50% of the mass distribution below this diameter.

[0220] Fine particle mass (FPD): The mass of drugs with an aerodynamic particle size of less than 5 μm.

[0221] Fine particle fraction FPF = FPD / delivery mass.

[0222] Example 10:

[0223] In this embodiment, keeping other parameters constant, the effect of vibration frequency on the nebulization effect of etimicin sulfate nebulized inhalation solution was investigated, and the results are shown in Table 13.

[0224] Table 13 Comparison of atomization performance at different vibration frequencies

[0225]

[0226]

[0227] Among them, the mass median aerodynamic diameter (MMAD) is 50% of the mass distribution below this diameter.

[0228] Fine particle mass (FPD): The mass of drugs with an aerodynamic particle size of less than 5 μm.

[0229] Fine particle fraction FPF = FPD / delivery mass.

[0230] Example 11:

[0231] In this embodiment, the effects of a vibrating screen nebulizer and a jet nebulizer on nebulizing etimicin sulfate inhalation solution were compared. A vibrating screen nebulizer meeting the requirements of this invention was selected, and a PARI LC Plus nebulizer paired with a PARI TurboBoy air compressor was selected. Both nebulizers nebulized the same volume of medication; the results are shown in Table 14.

[0232] Table 14 Comparison of atomization performance between vibrating screen atomizers and jet atomizers

[0233]

[0234]

[0235] Among them, the mass median aerodynamic diameter (MMAD) is 50% of the mass distribution below this diameter.

[0236] Fine particle mass (FPD): The mass of drugs with an aerodynamic particle size of less than 5 μm.

[0237] Fine particle fraction FPF = FPD / delivery mass.

[0238] Example 12:

[0239] The effects of the vibrating screen nebulizer of this invention and commercially available vibrating screen nebulizers on nebulizing etimicin sulfate inhalation solution were compared. The results of nebulizing the same volume of drug solution with different models of nebulizers are shown in the table.

[0240] Table 15 Comparison of atomization performance between the vibrating screen atomizer of the present invention and commercially available vibrating screen atomizers.

[0241]

[0242]

[0243] Among them, the mass median aerodynamic diameter (MMAD) is 50% of the mass distribution below this diameter.

[0244] Fine particle mass (FPD): The mass of drugs with an aerodynamic particle size of less than 5 μm.

[0245] Fine particle fraction FPF = FPD / delivery mass.

[0246] While specific embodiments of the present invention have been described above, those skilled in the art should understand that these are merely illustrative examples, and the scope of protection of the present invention is defined by the appended claims. Those skilled in the art can make various changes or modifications to these embodiments without departing from the principles and essence of the present invention, but all such changes and modifications fall within the scope of protection of the present invention.

Claims

1. A pharmaceutical assembly comprising a solution of etimicidn sulfate, characterized in that, The medicine assembly comprises: (a) a solution of etimicin sulfate; and (b) a vibrating mesh nebulizer used in cooperation with the solution of etimicin sulfate; The central region of the atomizing sheet of the vibrating mesh nebulizer has 1500-2200 micropores; The diameter of the micropores is 2.2-3.8 μm; The vibrating frequency of the vibrating mesh nebulizer is 90-120 KHZ; The cross section of the micropores in the vibrating mesh nebulizer is in a stepped distribution, and the taper is 18 degrees.

2. The pharmaceutical assembly comprising the solution of etimicin sulfate according to claim 1, characterized in that, The central region of the atomizing sheet of the vibrating mesh nebulizer has 1800-2200 micropores.

3. The pharmaceutical assembly comprising a solution of etimicid sulfate according to any one of claims 1-2, characterized in that, The current of the vibrating mesh nebulizer is not more than 400 mA; And / or, the voltage of the vibrating mesh nebulizer is 5 V ± 10%; And / or, the atomization rate of the vibrating mesh nebulizer is not less than 0.29 mL / min.

4. The pharmaceutical assembly comprising a solution of etimicidn sulfate according to any one of claims 1 to 3, characterized in that, The diameter of the micropores is 2.5-3.5 μm, preferably 2.7-3.3 μm, and more preferably 2.8-3.3 μm; And / or, the vibrating frequency of the vibrating mesh nebulizer is 90-115 KHZ, preferably 100-113 KHZ.

5. The pharmaceutical assembly comprising a solution of etimicidn sulfate according to any one of claims 1 to 4, characterized in that, The solution of etimicin sulfate is solution 1 or solution 2 as follows: Solution 1: which is composed of etimicin sulfate, an osmotic pressure regulator, a pH regulator, and water; The osmotic pressure of the solution of etimicin sulfate is 150-550 mOsmol / kg; The pH of the solution of etimicin sulfate is 4.0-8.5; Solution 2: which is composed of etimicin sulfate, an osmotic pressure regulator, and water; The osmotic pressure of the solution of etimicin sulfate is 150-550 mOsmol / kg. One or more of the following conditions are met:

6. The pharmaceutical assembly comprising the solution of etimicin sulfate according to claim 5, wherein (2) In the solution 1 and solution 2, the mass fraction of etimicin in the etimicin sulfate is 59.0%-66.0%; (1) The formula of the Etitmimi sulfate in the solution 1 and the solution 2 is (C 21 H 43 N5O7)2·5H2SO4; (3) In the solution 1 and solution 2, the mass fraction of free water in the etimicin sulfate is 0%-10%; (4) In the solution 1 and solution 2, the mass-volume ratio of the active ingredient etimicin in the etimicin sulfate to the water can be 50-100 mg / ml, for example 50 mg / ml or 75 mg / ml; (5) In the solution 1 and solution 2, the osmotic pressure regulator is glucose or sodium chloride; (6) In the solution 1 and solution 2, when the osmotic pressure regulator is sodium chloride, the mass ratio of the osmotic pressure regulator to the water can be 0.2%-0.9%, preferably 0.2%-0.5%, further preferably 0.2%, 0.3%, or 0.5%, and most preferably 0.3%; (7) In the solution 1 and solution 2, when the osmotic pressure regulator is sodium chloride, the mass-volume ratio of the osmotic pressure regulator to the water can be 2-9 mg / mL, preferably 2-5 mg / mL, further preferably 2 mg / mL, 3 mg / mL, or 5 mg / mL, and most preferably 3 mg / mL; ​ (8) the osmotic pressure of the solution 1 and the solution 2 is 260 mOsmol / kg, 286 mOsmol / kg, 314 mOsmol / kg or 348 mOsmol / kg, preferably 286 mOsmol / kg; (9) the oxygen content of the solution 1 and the solution 2 is 0.2 ppm-2.0 ppm; Preferably, the solution 1 and the solution 2 are filled with nitrogen to obtain the solution of etimicin sulfate with the oxygen content of 0.2 ppm-2.0 ppm; (10) the water in the solution 1 and the solution 2 is water for injection; (11) the pH adjusting agent in the solution 1 is sodium hydroxide or hydrochloric acid; (12) the pH of the solution 1 is 5.0-8.0, preferably 5.0-6.0; (13) the solution 1 and the solution 2 are stored in the dark.

7. The pharmaceutical assembly comprising the solution of Eritromycin sulfate according to claim 5, characterized in that, One or more of the following conditions are met: (1) the solution 1 is as shown in any of the following formulations: Formulation 1: the concentration of etimicin in the solution of etimicin sulfate is 75 mg / mL, the concentration of sodium chloride is 3 mg / mL, the pH adjusting agent is NaOH, the pH is 6.0, the solvent is water, and the oxygen content is less than 0.2 ppm; Formulation 2: the concentration of etimicin in the solution of etimicin sulfate is 75 mg / mL, the concentration of sodium chloride is 3 mg / mL, the pH adjusting agent is NaOH, the pH is 6.0, the solvent is water; Formulation 3: the concentration of etimicin in the solution of etimicin sulfate is 75 mg / mL, the concentration of sodium chloride is 3 mg / mL, the pH adjusting agent is NaOH, the pH is 5.0, the solvent is water, and the oxygen content is less than 0.2 ppm; Formulation 4: the concentration of etimicin in the solution of etimicin sulfate is 50 mg / mL, the concentration of sodium chloride is 9 mg / mL, the pH adjusting agent is NaOH, the pH is 5.8, the solvent is water, and the oxygen content is less than 0.2 ppm; (2) the formulation of the solution 2 is: the concentration of etimicin in the solution of etimicin sulfate is 75 mg / mL, the concentration of sodium chloride is 3 mg / mL, the solvent is water, and the oxygen content is less than 0.2 ppm.

8. The pharmaceutical assembly comprising the solution of Eritromycin sulfate according to claim 5, characterized in that, The solution of etimicin sulfate is prepared by the following method 1 or method 2: Method 1: comprising the following steps: dissolving etimicin sulfate, an osmotic pressure adjusting agent and a pH adjusting agent in water; Method 2: comprising the following steps: dissolving etimicin sulfate and an osmotic pressure adjusting agent in water.

9. The pharmaceutical assembly comprising the solution of Eritromycin sulfate according to claim 8, characterized in that, One or more of the following conditions are met: (1) the method 1 comprises the following steps: dissolving the osmotic pressure adjusting agent and the etimicin sulfate in part of the water at 20-30℃, then adding the pH adjusting agent, finally adding water to constant volume, and filtering to obtain the solution of etimicin sulfate; The filtering device for the filtration is, for example, a PVDF filter membrane or a PES filter core; The pore size of the PVDF filter membrane is, for example, 0.22 μm; The pore size of the PES filter core is, for example, 0.2 μm; (2) the method 1 comprises the following step: nitrogen is filled into the solution of Eritromycin Sulfate to obtain a solution of Eritromycin Sulfate with oxygen content of 0.2-2.0 ppm; the time for filling nitrogen can be 10-20 min, for example, 10 min, 15 min or 20 min; (3) the method 1 can further comprise a packaging step, which can be injecting 2.0 ml of the solution of Eritromycin Sulfate into an ampoule by using a syringe, sealing, leak detection, nitrogen-filled aluminum plastic packaging; wherein the ampoule is a low-density polyethylene ampoule; (4) the method 1 can further comprise a packaging step, which can be integrated filling by using a filling machine under a million-level environment, with a filling amount of 2.0 ml, nitrogen-filled aluminum plastic packaging; wherein the filling machine is a blow-filling-seal three-in-one filling machine; (5) the method 2 comprises the following steps: the osmotic pressure regulator and the solution of Eritromycin Sulfate are dissolved in water at 20-30℃, and the solution is filtered to obtain a solution of Eritromycin Sulfate; the filtering device for filtering is, for example, a PVDF filter membrane or a PES filter core; the pore size of the PVDF filter membrane is, for example, 0.22 μm; the pore size of the PES filter core is, for example, 0.2 μm; (6) the method 2 can further comprise the following step: nitrogen is filled into the solution of Eritromycin Sulfate to obtain a solution of Eritromycin Sulfate with oxygen content of 0.2-2.0 ppm; the time for filling nitrogen can be 10-20 min, for example, 10 min, 15 min or 20 min; (7) the method for preparing the solution of Eritromycin Sulfate can further comprise a packaging step, which can be injecting 2.0 ml of the solution of Eritromycin Sulfate into an ampoule by using a syringe, sealing, leak detection, nitrogen-filled aluminum plastic packaging; wherein the ampoule is a low-density polyethylene ampoule; (8) the method for preparing the solution of Eritromycin Sulfate can further comprise a packaging step, which can be integrated filling by using a filling machine under a million-level environment, with a filling amount of 2.0 ml, nitrogen-filled aluminum plastic packaging; wherein the filling machine is a blow-filling-seal three-in-one filling machine.

10. Use of a pharmaceutical assembly comprising a solution of Eritromycin Sulfate as claimed in any one of claims 1-9 for the preparation of a pharmaceutical product for treating respiratory tract infection diseases.

Images