CN107233311B - Atomizing agent with arformoterol and glycopyrronium bromide as active ingredients and preparation method thereof - Google Patents
Atomizing agent with arformoterol and glycopyrronium bromide as active ingredients and preparation method thereof Download PDFInfo
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Abstract
The invention relates to an atomizing agent with arformoterol and glycopyrronium bromide as active ingredients and a preparation method thereof. The invention also relates to the use of glycopyrronium bromide for increasing the stability of aqueous solutions of arformoterol. According to the invention, the physical stability of the arformoterol is improved by adopting the glycopyrronium bromide, and the arformoterol can generate a pharmacological synergistic effect, so that the local treatment effect of the lung is improved.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to an atomizing agent with arformoterol and glycopyrronium bromide as active ingredients and a preparation method thereof. The invention also relates to the use of glycopyrronium bromide for increasing the stability of aqueous solutions of arformoterol.
Background
In recent years, the incidence and mortality of chronic respiratory diseases have increased significantly due to air pollution, smoking, aging population and other factors. Common Chronic respiratory diseases include Chronic Obstructive Pulmonary Disease (COPD), bronchial asthma, pulmonary infection, lung cancer, and the like. The incidence rate of the chronic obstructive pulmonary disease is 8.2 percent in China and 14 percent in the United states. Chronic obstructive pulmonary disease is characterized by chronic progressive airflow obstruction, and mainly includes chronic bronchitis and chronic obstructive emphysema, and symptoms of the chronic obstructive pulmonary disease include cough, expectoration, short breath or dyspnea, wheezing, chest distress, etc. As a respiratory disease with extremely high disability and fatality rate, chronic pulmonary heart disease, right heart failure, respiratory failure, sleep disordered breathing and the like are often caused by slow lung obstruction, the life quality of a patient is seriously influenced, and the life safety of the patient is harmed.
In view of the specificity of the disease, COPD patients need to take medicines for a long time. The long-acting preparation is helpful for reducing the times of medication, improving the compliance of patients and improving the quality of life.
In terms of drug selection, the beta receptor agonist has a great improvement effect on the chronic obstructive pulmonary disease. They activate adenylate cyclase, catalyze intracellular Adenosine triphosphate (ATP, Adenosine triphosphate), activate protein kinase A, increase Na+、K+、Ca2+Exchange inside and outside cells, reduce free Ca inside cells2 +Thereby relaxing and relaxing the smooth muscle of the bronchus and playing the role of relieving asthma. And simultaneously can reduce the release of allergic mediators from cells, particularly mast cells.
Arformoterol, also known as (R, R) -formoterol, is a single optical isomer of racemic formoterol and has the structural formula shown below. Arformoterol long-acting beta2Receptor agonists, are clinically useful in the treatment of chronic pulmonary obstruction. Currently marketed formoterol contains two configurations, R and S, S. The research shows that the biological activity of the arformoterol ((R, R) -formoterol) is more than 1000 times of that of the (S, S) -formoterol configuration, and the arformoterol does not have the side effect that the (S, S) -formoterol strengthens acetylcholine to cause bronchoconstriction reaction.
The commercial product of arformoterol abroad is an inhalation liquid under the trade name Brovana, but the stability of the solution is poor (HPLC assay for arformoterol in dry powder inhalants, muxu huaxi pharma journal, 2011.03). CN 1333682 a (entitled "storable formoterol-containing active substance concentrate") teaches that formoterol is not sufficiently stable to be stored in solution so that the pharmaceutical quality of the formulation during long-term storage cannot be ensured, and that formoterol is therefore restricted to powder administration for inhalation therapy. In this regard, CN 1333682 a provides a concentrate in the form of a liquid or suspension containing a formoterol active. However, the concentration of the active substance in the concentrate is so high that the corresponding solution or suspension is not available for inhalation for therapeutic use without dilution.
Muscarinic acetylcholine receptor antagonists are able to inhibit their action by blocking the binding of acetylcholine to the receptor. Glycopyrronium Bromide (Glycopyrronium Bromide) is a novel anticholinergic agent with the structural formula shown below. Glycopyrrolate can powerfully and selectively block M3 receptors (muscarinic receptors), can generate more lasting bronchoprotective and bronchodilatory effects, and has quick response and the bronchodilatory effect lasts for more than 24 hours. Glycopyrrolate has a faster onset of action than tiotropium bromide by about 3-5 times, and is well tolerated as compared to tiotropium bromide. However, glycopyrrolate cannot be mixed with basic drugs, ester groups are easily hydrolyzed when the pH is greater than 6, and highly polarized amino groups in glycopyrrolate limit the permeation of glycopyrrolate through lipid membranes, so that the glycopyrrolate is not favorable for binding with lung cell membrane surface receptors to exert drug effects, and the exertion of the drug effects of glycopyrrolate is limited to a certain extent.
WO2016/170518 a1 discloses a pharmaceutical composition comprising arformoterol or a salt thereof and glycopyrronium bromide in the form of a suspension or solution comprising a propellant for administration as an aerosol.
US2011/0150782 a1 discloses an aerosol suitable for administration to COPD patients by means of a pressurized doser, comprising glycopyrronium bromide and formoterol.
US2011/0150784 a1 and CN 102665678 disclose aerosols comprising glycopyrronium chloride and formoterol, wherein the propellant is Hydrofluoroalkane (HFA).
WO2013/021199 a2 discloses a pharmaceutical composition of two classes of pharmacologically active ingredients for COPD, in particular using co-crystal technology.
CN 104257610 discloses a process for the preparation of carrier particles for inhalable dry powders, as well as carrier particles obtainable by said process and powder pharmaceutical formulations thereof, comprising formoterol or glycopyrronium bromide.
The literature, Aclidinium bromide and formoterol a fixed-dose combination in COPD, pooloanalysis of symptoms and exa-base from six-month, multicentre, randomised studios (ACLIFORM and AUGMENT), discloses a fixed-dose combination of Aclidinium bromide and formoterol fumarate, with an emphasis on investigating the pharmacological indicators of this combination.
At present, most of the medicament dosage forms for treating chronic obstructive pulmonary disease in the market are dry powder or aerosol. However, due to the particularity of the aerosol, the requirement on the patient compliance during the administration process is high, professional medical staff are required to guide the administration mode and require the patient to inhale synchronously, otherwise the treatment effect is greatly influenced, and especially for the old and the children with weak receptivity, the administration effect is possibly not ideal. In addition, the aerosol or dry powder dosage form requires the patient to inhale and hold breath, which affects the lung function of the patient suffering from lung diseases, and it is difficult to achieve the air flow rate required for the drug of the dosage form to exert the ideal drug effect.
Furthermore, EP 1157689 and CN 102665679 mention that formoterol fumarate aerosols are relatively unstable and degrade significantly under high temperature, high humidity conditions.
In addition, animal experiments show that the incidence of lung cancer is significantly increased after long-term administration of insulin dry powder. Although it is not yet certain whether it is caused by a drug, it is also caused by the dosage form itself for pulmonary administration (retrospective analysis of the treggio insulin dry powder inhalant Exubera document [ J ] south pharmaceutical, 2009:7 (10)).
In contrast, the nebulizer does not require a micronization step, avoiding possible negative effects; the special cooperation of the patient is not needed, the operation is simpler, and the normal breathing state is kept, so that the problem of uncoordinated breathing starting is avoided; and can also avoid the problems of incompatibility of the propellant in the medicament and the aerosol, and the like.
However, the aqueous solution of arformoterol is relatively unstable, for example, arformoterol tartrate undergoes significant degradation under acid, alkali, high temperature, light and oxidation conditions, and significant degradation products are generated. Therefore, there are few nebulizers in the prior art that involve arformoterol, which nebulizers use water as a solvent.
In view of this, there is a need to develop a simple to operate, use-stable nebuliser for arformoterol.
Disclosure of Invention
In order to solve the problems of poor stability and easy degradation of arformoterol in an aqueous solution, the invention aims to provide a nebulant which takes arformoterol and glycopyrronium bromide as active ingredients and water as a solvent.
Further, the arformoterol in the nebulant of the present invention is present in the form of a salt, including but not limited to tartrate, fumarate, hydrochloride, sulphate, besylate, succinate, preferably tartrate.
Further, the molar ratio of arformoterol to glycopyrronium bromide in the nebuliser of the invention is from 1:10 to 10:1, preferably 1: 2.
Furthermore, the amount of arformoterol in the nebuliser of the invention is from 0.17 to 22.98. mu.g/mL, preferably 7.66. mu.g/mL.
Furthermore, glycopyrronium bromide is used in the nebulant according to the invention in an amount of 0.4-54. mu.g/mL, preferably 18. mu.g/mL.
In a preferred embodiment of the invention, the arformoterol in the nebulant according to the invention is present in the form of the tartrate salt, wherein the arformoterol tartrate is present in an amount of from 0.25 to 33 mug/mL, preferably 11 mug/mL.
In a preferred embodiment of the present invention, the atomizing agent of the present invention further comprises a nonionic surfactant.
Further, the nonionic surfactant in the nebulant of the present invention includes, but is not limited to, tween, span, polyol, poloxamer, preferably tween 80.
Furthermore, the amount of the nonionic surfactant in the atomizing agent of the present invention is 50 to 400mg/L, preferably 100 mg/L.
In a preferred embodiment of the invention, the nebulant of the invention further comprises a pH buffer.
Further, the pH buffer solution in the atomizing agent comprises acetic acid-sodium acetate, phosphoric acid-sodium phosphate and citric acid-sodium citrate, preferably citric acid-sodium citrate.
In a preferred embodiment of the invention, the pH of the nebulant according to the invention is from 4.0 to 6.0, preferably 4.5.
In a preferred embodiment of the present invention, the atomizing agent of the present invention further comprises an osmotic pressure regulator.
Further, the osmotic pressure regulator in the aerosol of the present invention includes sodium chloride, glucose, propylene glycol, glycerin, preferably sodium chloride.
Further, the amount of the osmotic pressure regulator in the aerosol of the present invention is 8-10mg/mL, preferably 9 mg/mL.
In a preferred embodiment of the present invention, the atomizing agent of the present invention further comprises a complexing agent.
Further, the complexing agent in the atomizing agent of the invention is EDTA or salt thereof, preferably EDTA-2 Na.
Furthermore, the amount of the complexing agent in the atomizing agent of the present invention is 50 to 500mg/L, preferably 300 mg/L.
The invention also provides a method for preparing the atomizing agent, which comprises the following steps:
dissolving an osmotic pressure regulator in water with a proper volume, stirring and dissolving, adding arformoterol tartrate and glycopyrronium bromide, stirring and dissolving, adding water to full volume, and adding a pH buffer solution to regulate the pH value to obtain the compound preparation.
In a preferred embodiment of the present invention, the method for preparing the atomizing agent comprises:
dissolving an osmotic pressure regulator and a complexing agent in water with a proper volume, stirring and dissolving, adding arformoterol tartrate and glycopyrronium bromide, and stirring until the arformoterol tartrate and the glycopyrronium bromide are dissolved; adding water with proper volume into the nonionic surfactant, standing until the water is uniformly dispersed, adding the mixture into the solution, fully stirring, adding water to full volume, and adding a pH buffer solution to adjust the pH value to obtain the water-soluble nonionic surfactant.
The invention also provides the use of a combination of arformoterol and glycopyrronium bromide in the manufacture of a nebulant for the treatment of chronic respiratory diseases.
In a preferred embodiment of the invention, the chronic respiratory disease comprises chronic obstructive pulmonary disease, bronchial asthma, lung infection.
The inventor surprisingly found that the addition of glycopyrronium bromide to the nebulant of the invention not only enhances the stability of arformoterol from the viewpoint of physicochemical properties, but also has a synergistic effect on the pharmacology, which contributes to the improvement of the therapeutic effect of arformoterol.
The atomizing agent of the invention takes water as solvent, does not need dilution, and can directly utilize technologies such as air compression, ultrasonic atomization, vibrating screen and the like to realize atomization administration.
In addition, the non-ionic surfactant is added into the atomizing agent, so that the defect that glycopyrronium bromide is difficult to enter alveolar cells due to strong polarity is overcome, the appropriate non-ionic surfactant is selected to prolong the retention time of the lung and promote the lung absorption of the medicament, and further, the local treatment effect of the lung is improved. The invention further improves the stability of the arformoterol by selecting a proper pH range and a complexing agent. The osmotic pressure of the atomizing agent is adjusted by adding an osmotic pressure regulator, so that the stimulation to lung tissues is reduced after the atomizing agent is atomized into the lung.
Drawings
FIG. 1 is an HPLC chromatogram of the arformoterol tartrate control solution of example 4.
FIG. 2 is a HPLC chromatogram of arformoterol tartrate in example 4 after degradation under acidic conditions.
FIG. 3 is a HPLC chromatogram of arformoterol tartrate in example 4 after degradation under basic conditions.
FIG. 4 is a HPLC chromatogram of arformoterol tartrate in example 4 after degradation at high temperature.
FIG. 5 is a HPLC chromatogram of arformoterol tartrate in example 4 after degradation under light irradiation.
FIG. 6 is a HPLC chromatogram of arformoterol tartrate in example 4 after degradation under oxidative conditions.
Detailed Description
The foregoing and other aspects of the invention are apparent from the following more particular description of the invention, as illustrated in the accompanying drawings and described in the detailed description. It will nevertheless be understood by those skilled in the art that no limitation of the scope of the invention is thereby intended.
Examples
The raw material arformoterol tartrate (AF) manufacturer used in the embodiment of the invention is MSN Laboratories Pravate Limited, and the batch number is AFS/C062/3/01; glycopyrronium Bromide (GB) was produced by M/S. HARMAN FINOCHEM LTD, lot number GCP/006/2014-2015.
Example 1 preparation of arformoterol tartrate monol nebulizer and glycopyrronium bromide monol nebulizer
Arformoterol tartrate and glycopyrronium bromide single nebulizer were prepared separately as in table 1.
TABLE 1
The preparation method comprises the following steps:
weighing a prescription amount of sodium chloride, dissolving the sodium chloride in water (about 700ml) with a proper volume, stirring and dissolving, adding the prescription amount of arformoterol tartrate or glycopyrronium bromide, stirring and dissolving, adding water to the full amount, and adding citric acid-sodium citrate buffer solution to adjust the pH value to obtain the sodium chloride-glycopyrronium bromide-sodium citrate sustained-release tablet.
Example 2 preparation of arformoterol tartrate and glycopyrronium bromide compound nebulizer
Arformoterol tartrate and glycopyrronium bromide compound nebulizer was prepared as in table 2.
TABLE 2
The preparation method comprises the following steps:
weighing a prescription amount of sodium chloride, dissolving the sodium chloride in water (about 700ml) with a proper volume, stirring and dissolving, adding the prescription amount of arformoterol tartrate and glycopyrronium bromide, stirring and dissolving, adding water to the full amount, and adding citric acid-sodium citrate buffer solution to adjust the pH value to obtain the sodium chloride-glycopyrronium bromide water-soluble powder.
Example 3 dose consideration of arformoterol tartrate and glycopyrronium bromide in a Compound nebulizer formulation
The compound aerosol of arformoterol tartrate and glycopyrronium bromide in table 3 below was prepared according to the preparation method of example 2.
TABLE 3
Five arformoterol tartrate and glycopyrronium bromide compound atomizing agents prepared according to the table 3 are respectively placed for 1 month under the conditions of 40 +/-2 ℃/75% RH +/-5% RH, and then a sample is taken to determine the content of the main drug (T is used as the content of the main drug)0Content as 100%). The results of the accelerated test at 40 ℃. + -. 2 ℃/75% RH. + -. 5% RH for 1 month are shown in Table 4 below.
TABLE 4
The result shows that in the compound atomizer of arformoterol tartrate and glycopyrronium bromide, the preferable dosage of arformoterol tartrate is 11 mug/mL, and the preferable dosage of glycopyrronium bromide is 18 mug/mL.
Example 4 stability Studies of Arformoterol and glycopyrronium Bromide
The method for measuring the forced degradation of the arformoterol tartrate adopts a high performance liquid chromatograph Agilent1100, and HPLC conditions are as follows:
a chromatographic column: c18 column (150 mm. times.4.6 mm, 5 μm)
Mobile phase: 23.9mmol/L sodium dihydrogen phosphate water solution-acetonitrile, the volume ratio of the sodium dihydrogen phosphate water solution to the acetonitrile is 85:15
Flow rate: 1mL/min
Detection wavelength: 214nm
Column temperature: 40 deg.C
Sample introduction volume: 20 μ l.
The method for measuring the forced degradation of glycopyrronium bromide adopts a high performance liquid chromatograph Agilent1100, and HPLC conditions are as follows:
a chromatographic column: c18 column (150 mm. times.4.6 mm, 5 μm)
Mobile phase: 23.9mmol/L sodium dihydrogen phosphate water solution-acetonitrile, the volume ratio of the sodium dihydrogen phosphate water solution to the acetonitrile is 75:25
Flow rate: 1mL/min
Detection wavelength: 214nm
Column temperature: 40 deg.C
Sample introduction volume: 20 μ l.
1. Forced degradation of glycopyrronium bromide
Glycopyrronium bromide (1mg/mL) does not generate obvious degradation substances after 24 hours under the conditions of acid, high temperature and violent oxidation, and can be degraded by about 28 percent after 2 hours under the alkaline condition of 1M NaOH.
2. Forced degradation of arformoterol tartrate
Arformoterol tartrate (1mg/mL) was significantly degraded under acid, alkaline, high temperature, light and oxidation conditions, and significant degradation products were present. See table 5 for details.
TABLE 5
The HPLC profile of the arformoterol tartrate control solution without forced degradation is shown in fig. 1, and the HPLC profile of arformoterol tartrate after degradation under the forced degradation conditions is shown in fig. 2 to 6.
Example 5 comparison of arformoterol tartrate, glycopyrronium bromide single compound nebulizer
The possible interaction between arformoterol tartrate and glycopyrronium bromide was examined by single compound comparison.
Respectively taking the arformoterol tartrate and glycopyrronium bromide compound atomizing agent prepared in the example 2 and the arformoterol tartrate single atomizing agent and the glycopyrronium bromide single atomizing agent prepared in the example 1, placing for 2 months under the conditions of 40 +/-2 ℃/75 RH +/-5% RH, sampling and determining the content of the main drug (using T to measure the content of the main drug)0Content as 100%).
The content detection adopts a high performance liquid chromatograph Waters 2690, and the HPLC conditions are as follows:
a chromatographic column: c18 column (150 mm. times.4.6 mm, 5 μm)
Mobile phase: 23.9mmol/L sodium dihydrogen phosphate water solution-acetonitrile, the volume ratio of the sodium dihydrogen phosphate water solution to the acetonitrile is 75:25
Flow rate: 1mL/min
Detection wavelength: 214nm
Column temperature: 40 deg.C
Sample introduction volume: 20 μ l.
The results of the accelerated test at 40 ℃. + -. 2 ℃/75% RH. + -. 5% RH for 2 months are shown in Table 6 below.
TABLE 6
| AF(％) | GB(％) | |
| Arformoterol tartrate (AF) monotherapy | 10.33 | N/A |
| Glycopyrronium Bromide (GB) single component | N/A | 4.44 |
| Compound of arformoterol tartrate (AF) and Glycopyrronium Bromide (GB) | 29.73 | 10.44 |
The results show that the content of arformoterol tartrate in the arformoterol tartrate single formulation is 10.33%, the content of glycopyrronium bromide in the glycopyrronium bromide single formulation is 4.44%, and the content of arformoterol tartrate and glycopyrronium bromide in the arformoterol tartrate and glycopyrronium bromide compound formulation is 29.73% and 10.44%, respectively. Compared with each single component, the compound has significant difference (P < 0.05). Therefore, compared with the arformoterol tartrate single atomizing agent, the stability of the arformoterol tartrate is remarkably improved by adding the glycopyrronium bromide. From the chemical structure analysis of the two, it is possible that glycopyrronium bromide contains hydroxyl and ester groups in the molecule, and the glycopyrronium bromide can form hydrogen bonds with the hydroxyl, carboxyl and other groups in the arformoterol tartrate, so that the stability of the arformoterol tartrate is enhanced.
Example 6 examination of the influence of pH on the stability of the nebulant according to the invention
Previous forced degradation experiments (example 4) showed that arformoterol tartrate was degraded under acidic conditions. Based on this, compound nebulizers with pH of 4.5, 5.0 and 5.5 were prepared respectively for study.
According to the preparation method of the example 2, the arformoterol tartrate and glycopyrronium bromide compound atomizing agent is prepared according to the raw material dosage of the table 7.
TABLE 7
Three arformoterol tartrate and glycopyrronium bromide compound atomizing agents prepared according to the table 7 are respectively placed for 1 month under the conditions of 40 +/-2 ℃/75% RH +/-5% RH, and the content of the main drug is measured by sampling (T is used0Content as 100%). The results of the accelerated test at 40 ℃. + -. 2 ℃/75% RH. + -. 5% RH for 1 month are shown in Table 8 below.
TABLE 8
| AF(％) | GB(％) | |
| Compound aerosol 1(pH4.5) | 48.11 | 15.86 |
| Compound aerosol 2(pH5.0) | 51.64 | 30.32 |
| Compound aerosol 3(pH5.5) | 40.11 | 19.81 |
Stability comparison research of arformoterol tartrate and glycopyrronium bromide compound atomizing agent and arformoterol tartrate single atomizing agent
For comparative studies, arformoterol tartrate single formulations were prepared at pH4.5, 5.0 and 5.5, respectively.
Arformoterol tartrate monol nebulisers were prepared according to the preparation method of example 1 with the raw material amounts of table 9.
TABLE 9
Three arformoterol tartrate single atomizing agents prepared according to the table 9 are respectively placed for 1 month under the conditions of 40 ℃ +/-2 ℃/75% RH +/-5% RH, and then a sample is taken to determine the content of the main drug (T is used as the content of the main drug)0Content as 100%). The results of accelerated test at 40 ℃. + -. 2 ℃/75% RH. + -. 5% RH for 1 month are shown in Table 10 below.
| AF(％) | |
| AF Single-component atomizing agent 1(pH4.5) | 37.11 |
| AF Single-component atomizing agent 2(pH5.0) | 50.04 |
| AF Single-component atomizing agent 3(pH5.5) | 30.60 |
The results show that the compound nebulizer of the invention has higher content of arformoterol tartrate and glycopyrronium bromide (P <0.05) when the pH is 4.5-5.0, namely, the compound nebulizer of the invention is more stable when the pH is 4.5-5.0. On the other hand, regardless of whether the pH of the nebulizer is 4.5, 5.0, or 5.5, the content of arformoterol tartrate in the compound nebulizer was higher than that of arformoterol tartrate in the single nebulizer, which indicates that the addition of glycopyrronium bromide enhances the stability of arformoterol tartrate.
Example 7 examination of the Effect of protective Agents on the stability of Compound nebulizer of the invention
The protecting agents considered in this example are nonionic surfactants and complexing agents.
The arformoterol tartrate and glycopyrronium bromide compound aerosol is prepared according to the raw material dosage of table 11.
TABLE 11
The preparation method comprises the following steps:
weighing and dissolving the sodium chloride and the EDTA-2Na (aiming at the cases of the compound atomizing agents 2 and 4) in the water with proper volume (about 700ml), stirring and dissolving, adding the arformoterol tartrate and the glycopyrronium bromide in the formula amounts, and stirring and dissolving. Adding appropriate amount of water (about 20ml) into Tween 80 (in case of compound atomizing agents 3 and 4), standing until uniform dispersion, adding into the above solution, stirring, adding water to full volume, and adding citric acid-sodium citrate buffer solution to adjust pH.
The four arformoterol tartrate and glycopyrronium bromide compound atomizing agents prepared according to the table 11 are respectively placed for 2 months under the conditions of 40 +/-2 ℃/75% RH +/-5% RH, and the content of the main drug is measured by sampling (T is used as the content of the main drug)0Content as 100%). The results of the accelerated test at 40 ℃. + -. 2 ℃/75% RH. + -. 5% RH for 2 months are shown in Table 12 below.
TABLE 12
| AF(％) | GB(％) | |
| Compound aerosol 1(pH4.5, without EDTA-2Na/Tween 80) | 29.73 | 10.44 |
| Compound aerosol 2(pH4.5, with EDTA-2Na) | 73.34 | 77.58 |
| Compound aerosol 3(pH4.5, with Tween 80) | 45.06 | 28.74 |
| Compound aerosol 4(pH4.5, with EDTA-2Na/Tween 80) | 71.96 | 75.25 |
In addition, four arformoterol tartrate and glycopyrronium bromide compound atomizing agents prepared according to the table 11 are respectively placed for 1 month under the conditions of 40 ℃ plus or minus 2 ℃/75% RH plus or minus 5% RH, and then a sample is taken to determine the content of the main drug (T is used as the content of the main drug)0Content as 100%). The results of accelerated test at 40 ℃. + -. 2 ℃/75% RH. + -. 5% RH for 1 month are shown in Table 13 below.
Watch 13
| AF(％) | GB(％) | |
| Compound aerosol 1(pH4.5, without EDTA-2Na/Tween 80) | 48.11 | 15.86 |
| Compound aerosol 2(pH4.5, with EDTA-2Na) | 93.36 | 98.5 |
| Compound atomizationAgent 3(pH4.5, with Tween 80) | 69.02 | 60.28 |
| Compound aerosol 4(pH4.5, with EDTA-2Na/Tween 80) | 90.58 | 95.0 |
Stability comparison research of arformoterol tartrate and glycopyrronium bromide compound atomizing agent and arformoterol tartrate single atomizing agent
For comparative studies, arformoterol tartrate monol nebulisers were prepared with the raw material amounts of table 14.
TABLE 14
The preparation method comprises the following steps:
the sodium chloride and EDTA-2Na (in the case of single-component atomizing agents 2 and 4) in the prescribed amounts are weighed and dissolved in water (about 700ml) with a proper volume, and after the sodium chloride and the EDTA-2Na are stirred and dissolved, the arformoterol tartrate in the prescribed amounts is added and stirred until the sodium chloride and the EDTA-2Na are dissolved. Adding appropriate amount of water (about 20ml) into Tween 80 (in case of single-component atomizing agents 3 and 4), standing until uniform dispersion, adding into the above solution, stirring, adding water to full volume, and adding citric acid-sodium citrate buffer solution to adjust pH.
Four arformoterol tartrate single atomizing agents prepared according to the table 14 are respectively placed for 1 month under the conditions of 40 ℃ +/-2 ℃/75% RH +/-5% RH, and then sampling is carried out to determine the content of the main drug (T is used as the content of the main drug)0Content as 100%). The results of the accelerated test at 40 ℃. + -. 2 ℃/75% RH. + -. 5% RH for 1 month are shown in Table 15 below.
| AF(％) | |
| AF Single atomizing agent 1(pH4.5, without EDTA-2Na/Tween 80) | 37.11 |
| AF Single atomizing agent 2(pH4.5, with EDTA-2Na) | 95.94 |
| AF Single atomizing agent 3(pH4.5, with Tween 80) | 60.78 |
| AF Single atomizing agent 4(pH4.5, with EDTA-2Na/Tween 80) | 93.72 |
The results show that when the compound atomizing agent contains the complexing agent or contains the complexing agent and the nonionic surfactant, the content of the arformoterol tartrate and the content of the glycopyrronium bromide are both very high (P < 0.05). On the other hand, the content of the arformoterol tartrate can be improved by adding the glycopyrronium bromide, the stability improvement effect is slightly weaker than that of the arformoterol tartrate by adding the protective agent, but compared with the situation that the stability of the arformoterol tartrate is improved by only adding the protective agent, the glycopyrronium bromide is added, so that the beta receptor is excited, the M receptor is blocked, the pharmacological synergistic effect can be exerted, the airway smooth muscle is synergistically relaxed, and the treatment effect is improved.
Example 8 optimization study of the arformoterol tartrate and glycopyrronium bromide compound nebulizer of the invention
Arformoterol tartrate and glycopyrronium bromide compound nebulizer were prepared as in table 16.
TABLE 16
The preparation method comprises the following steps:
weighing and dissolving the sodium chloride and the EDTA-2Na with the prescription amount in water (about 700ml) with a proper volume, stirring and dissolving, adding the arformoterol tartrate and the glycopyrronium bromide with the prescription amount, and stirring and dissolving; adding appropriate amount of water (about 20ml) into Tween 80, standing to disperse uniformly, adding into the above solution, stirring, adding water to full volume, and adding citric acid-sodium citrate buffer solution to adjust pH.
Placing the prepared arformoterol tartrate and glycopyrronium bromide compound atomizing agent at 4 ℃, 25 +/-2 ℃ and 40 +/-2 ℃ for 2 months, sampling and determining the content of the main drug (by using T)0Content as 100%).
The results of the measurement after leaving at 4 ℃ 25. + -. 2 ℃ and 40. + -. 2 ℃ for 2 months are shown in Table 17 below.
TABLE 17
| AF(％) | GB(％) | |
| 4℃ | 80.07 | 78.43 |
| 25℃±2℃ | 77.49 | 77.39 |
| 40℃±2℃ | 71.96 | 75.25 |
The results show that the compound atomizer of arformoterol tartrate and glycopyrronium bromide has very high content of arformoterol tartrate and glycopyrronium bromide after being placed for 2 months at the temperature of 4 ℃, 25 +/-2 ℃ and 40 +/-2 ℃, and the content of arformoterol tartrate and glycopyrronium bromide is the highest when being placed for 2 months at the temperature of 4 ℃, and is about 80%.
Claims (16)
1. A nebulant takes arformoterol and glycopyrronium bromide as active ingredients, water as a solvent, and further comprises a pH buffer solution and an osmotic pressure regulator, wherein the molar ratio of the arformoterol to the glycopyrronium bromide is 1:10-10:1, the dosage of the glycopyrronium bromide is 0.4-54 mu g/mL, the pH value of the nebulant is 4.0-6.0, and the dosage of the osmotic pressure regulator is 8-10 mg/mL.
2. A nebulant according to claim 1 wherein the arformoterol is in the form of a salt comprising the tartrate, fumarate, hydrochloride, sulphate, besylate or succinate salt.
3. A nebulant according to claim 1 or claim 2 wherein the molar ratio of arformoterol to glycopyrronium bromide is 1: 2.
4. A nebulant according to claim 1 or claim 2 wherein the amount of arformoterol is from 0.17 to 22.98 μ g/mL.
5. A nebulant according to claim 4 wherein the amount of arformoterol is 7.66 μ g/mL.
6. A nebulant according to claim 1 or claim 2 wherein the arformoterol is present in the form of the tartrate salt thereof, and wherein the arformoterol tartrate is present in an amount of from 0.25 to 33 μ g/mL.
7. A nebulant according to claim 6 wherein arformoterol tartrate is present in an amount of 11 μ g/mL and the glycopyrronium bromide is present in an amount of 18 μ g/mL.
8. A nebulant according to claim 1 or claim 2 wherein the nebulant further comprises a non-ionic surfactant, wherein the non-ionic surfactant comprises a tween, span, polyol or poloxamer, wherein the amount of non-ionic surfactant is from 50 to 400 mg/L.
9. A nebulant according to claim 8 wherein the non-ionic surfactant is Tween 80 in an amount of 100 mg/L.
10. A nebulant according to claim 1 or claim 2 wherein the pH buffer comprises acetic acid-sodium acetate, phosphoric acid-sodium phosphate or citric acid-sodium citrate.
11. A nebulant according to claim 1 or claim 2 wherein the pH of the nebulant is 4.5.
12. A nebulant according to claim 1 or claim 2 wherein the tonicity modifier comprises sodium chloride, glucose, propylene glycol or glycerol.
13. A nebulant according to claim 12 wherein the amount of tonicity modifier is 9 mg/mL.
14. A nebulant according to claim 1 or claim 2 wherein the nebulant further comprises a complexing agent which is EDTA or a salt thereof, wherein the complexing agent is present in an amount of from 50 to 500 mg/L.
15. A nebulant according to claim 14 wherein the complexing agent is EDTA-2Na in an amount of 300 mg/L.
16. A method of preparing a nebulant according to any one of claims 1 to 15 comprising:
dissolving the osmotic pressure regulator in water with a proper volume, stirring for dissolving, adding arformoterol and glycopyrronium bromide, stirring for dissolving, adding water to full volume, and adding pH buffer solution to regulate pH.
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| CN112972384B (en) * | 2019-12-02 | 2022-03-18 | 长风药业股份有限公司 | Preparation method of glycopyrronium bromide and indacaterol bulk drug micro-powder mixture |
| CN115015459B (en) * | 2022-05-30 | 2023-04-07 | 上海奥科达医药科技股份有限公司 | Method for detecting diastereoisomers in formoterol fumarate inhalation solution |
| CN116298046B (en) * | 2022-05-30 | 2023-11-17 | 上海奥科达医药科技股份有限公司 | Quality control method for diastereoisomers in arformoterol tartrate inhalation solution |
| CN115267024B (en) * | 2022-07-31 | 2023-06-30 | 浙江知一药业有限责任公司 | Pharmaceutical composition for treating respiratory diseases and detection method thereof |
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| CN101657191A (en) * | 2007-04-19 | 2010-02-24 | 奇斯药制品公司 | Use of a composition comprising formoterol and beclomethasone dipropionate for the prevention or treatment of an acute condition of asthma |
| CN102665678A (en) * | 2009-12-23 | 2012-09-12 | 奇斯药制品公司 | Combination therapy for copd |
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