Pharmaceutical assembly comprising formoterol fumarate inhalation solution and use thereof
阅读说明：本技术 包含富马酸福莫特罗吸入溶液的药物组件及其用途 (Pharmaceutical assembly comprising formoterol fumarate inhalation solution and use thereof ) 是由 金方 郦旻 邓炜 连晓培 黄娟 俞雄 于 2021-09-28 设计创作，主要内容包括：本发明涉及一种包含富马酸福莫特罗吸入溶液的药物组件及其用途,该药物组件包括：(a)富马酸福莫特罗吸入溶液；和(b)与所述富马酸福莫特罗吸入溶液配合使用的振动筛雾化器；所述振动筛雾化器的雾化功率以阶梯式递减方式由10瓦递减至0瓦,所述富马酸福莫特罗吸入溶液的雾滴粒径为：D-(10)为0.5μm～1.5μm,D-(50)为2.5μm～4.5μm,D-(90)为6.0μm～12.0μm；空气动力学粒径小于5.39μm的粒子占所述富马酸福莫特罗吸入溶液的质量百分比不小于30%。本发明的药物组件达到了较好的临床治疗慢阻肺的效果,同时所使用的振动筛雾化器具有残留药液体积小、使用方便、便于携带、噪音小的优势。(The present invention relates to a pharmaceutical assembly comprising a formoterol fumarate inhalation solution and the use thereof, the pharmaceutical assembly comprising: (a) formoterol fumarate inhalation solution; and (b) a vibrating screen atomizer for use in conjunction with the formoterol fumarate inhalation solution; the atomization power of the vibrating screen atomizer is reduced to 0 watt from 10 watts in a step-type decreasing mode, and the particle size of the formoterol fumarate inhalation solution is as follows: d 10 0.5 to 1.5 μm, D 50 2.5 to 4.5 μm, D 90 6.0-12.0 μm; the mass percentage of particles with aerodynamic particle size less than 5.39 μm in the formoterol fumarate inhalation solution is not less than 30%. The medicine component of the inventionThe vibrating screen atomizer has the advantages of small volume of residual liquid medicine, convenient use, portability and low noise.)
1. Use of a pharmaceutical assembly comprising an inhaled solution of formoterol fumarate in the manufacture of a medicament for the treatment of chronic obstructive pulmonary disease,
wherein the pharmaceutical assembly comprising formoterol fumarate inhalation solution comprises:
(a) formoterol fumarate inhalation solution; and
(b) a vibrating screen atomizer used in cooperation with the formoterol fumarate inhalation solution;
the atomization power of the vibrating screen atomizer is reduced to 0 watt from 10 watts in a step-type decreasing mode, and the particle size of the formoterol fumarate inhalation solution is as follows: d100.5 to 1.5 μm, D502.5 to 4.5 μm, D906.0 to 12.0 μm.
2. Use according to claim 1, wherein the atomizing power of the vibrating screen atomizer is as follows: 10-8 watts in 0-1 minute; 8-7 watts in 1-2 minutes; the 2 nd to 9 th minutes are 7 to 0W.
3. Use according to claim 1, wherein the formoterol fumarate inhalation solution has a droplet size of: d100.8 to 1.2 μm, D502.5 to 3.2 μm, D90Is 7.0 μm to 9.0 μm.
4. Use according to claim 1, wherein the central area of the metal mesh of the vibrating screen atomizer has 1000-1400 micropores.
5. The use according to claim 4, wherein the number of micropores having a diameter of 3.2 to 4.0 μm is not less than 80% of the total number of micropores.
6. Use according to claim 4 or 5, wherein the cross-section of the micro-holes in the vibrating screen atomizer are distributed in a step-like manner, and the taper is 30-50 degrees.
7. The use according to claim 1, wherein the vibrating screen atomizer has a vibration frequency of 110-160 KHz.
8. Use according to claim 1, wherein the vibrating screen atomizer has an atomization rate of 0.13 to 0.22 ml/min.
9. Use according to claim 8, wherein the vibrating screen atomizer has an atomization rate of 0.13 to 0.16 ml/min.
10. Use according to claim 1, wherein the vibrating screen atomizer has a current of 1A, ± 2%; the voltage is 5V +/-2%.
11. Use according to claim 1, wherein the formoterol fumarate inhalation solution comprises formoterol in an amount of 0.0005% to 0.002% (w/v), sodium chloride in an amount of 0.7% to 0.9%, and a pH of 4.0 to 6.0.
12. A pharmaceutical assembly comprising a formoterol fumarate inhalation solution, the pharmaceutical assembly comprising:
(a) formoterol fumarate inhalation solution; and
(b) a vibrating screen atomizer used in cooperation with the formoterol fumarate inhalation solution;
the atomization power of the vibrating screen atomizer is reduced to 0 watt from 10 watts in a step-type decreasing mode, and the particle size of the formoterol fumarate inhalation solution is as follows: d100.5 to 1.5 μm, D502.5 to 4.5 μm, D906.0 to 12.0 μm.
13. The medication assembly of claim 12 wherein the vibratory screen nebulizer has a nebulizing power as follows: 10-8 watts in 0-1 minute; 8-7 watts in 1-2 minutes; the 2 nd to 9 th minutes are 7 to 0W.
14. The medication module of claim 12 wherein the enrichment isThe particle size of the droplets of the formoterol maleate inhalation solution was: d100.8 to 1.2 μm, D502.5 to 3.2 μm, D90Is 7.0 μm to 9.0 μm.
15. The drug assembly of claim 12, wherein the vibrating screen atomizer has a central region of the metal mesh having 1000 and 1400 pores.
16. The drug module according to claim 15, wherein the number of micropores having a diameter of 3.2 to 4.0 μm is not less than 80% of the total number of micropores.
17. The drug assembly of claim 15 or 16, wherein the cross-section of the micro-holes in the vibrating screen atomizer are stepped with a taper of 30-50 degrees.
18. The drug assembly of claim 12, wherein the vibrating screen nebulizer has a vibrating frequency of 110-160 KHz.
19. The drug assembly of claim 12, wherein the vibrating screen nebulizer has a nebulization rate of 0.13 to 0.22 ml/min.
20. The drug assembly of claim 19, wherein the vibrating screen nebulizer has a nebulization rate of 0.13 to 0.16 ml/min.
21. The drug assembly of claim 12, wherein the vibrating screen nebulizer has a current of 1A, ± 2%; the voltage is 5V +/-2%.
22. The pharmaceutical assembly according to claim 12, wherein the formoterol fumarate inhalation solution comprises formoterol in an amount of 0.0005% to 0.002% (w/v), sodium chloride in an amount of 0.7% to 0.9%, and a pH of 4.0 to 6.0.
Technical Field
The invention relates to the technical field of medical treatment, in particular to a drug assembly containing formoterol fumarate inhalation solution and application thereof.
Background
Chronic obstructive pulmonary disease (COPD, chronic obstructive pulmonary disease for short) is a common disease and frequently encountered disease which seriously harm human health, seriously affects the life quality of patients, has high fatality rate and brings heavy economic burden to patients and families. The aerosol inhalation treatment of the chronic obstructive pulmonary disease causes great difficulty in clinical tests due to special sick people and special administration modes or devices. Research shows that the random control population which accords with the slow obstructive pulmonary disease only accounts for 7.2 percent of the total screening population; the correct use of the inhalation device and method of operation is critical to the efficacy of the treatment.
Formoterol is an anilide derived from adrenaline, is a selective β 2-adrenergic receptor agonist, expands the bronchi by agonizing an adrenergic receptor, and also inhibits mast cells from releasing histamine to lower the hyperresponsiveness of the airways. The effect lasts for a long time, the curative effect starts to appear only 1 to 3 minutes after the inhalation, and the effect of bronchiectasis can obviously last for 12 hours. In addition, formoterol has high respiratory tract selectivity, an anti-allergic reaction effect and a pulmonary edema inhibition effect, and the treatment effectiveness of chronic obstructive pulmonary diseases such as bronchial asthma is remarkably improved.
The key to the inhalation formulation for the pharmaceutically active ingredient to reach the affected area and exert therapeutic effect depends on the size of the spray particle diameter. The size of the spray particles is determined by the formulation recipe and the parameters of the atomizer.
Chinese patent application CN101548943A discloses that formoterol inhalation solution is administered by an air compression nebulizer, the nebulizing device is connected to a compressor by a pipeline, the compressor ejects pressurized air or oxygen at high speed through liquid medicine, the liquid formoterol formulation is converted into aerosol and administered to a patient, and the patient inhales the formed aerosol into the lungs through a mask, mouthpiece or other mouthpiece. When the atomizer is used for administration, the atomizer has the defects of wide droplet size distribution, large range of geometric standard deviation, large volume, inconvenience in carrying, high noise, high energy consumption, large volume of residual liquid medicine, prolonged treatment time, reduced compliance and the like.
Therefore, there is a need to develop a combination product suitable for formoterol aerosol inhalation solutions.
Disclosure of Invention
In order to overcome the disadvantages of the prior art, the present invention provides a pharmaceutical assembly comprising an inhalation solution of formoterol fumarate and uses thereof. The formoterol fumarate inhalation solution is matched with the vibrating screen atomizer for use, so that the effects of small residual volume of liquid medicine, short atomization time, no obvious temperature rise in the atomization process, small administration volume, high atomization efficiency and the like are achieved, and the chronic obstructive pulmonary disease can be more effectively treated.
In order to achieve the purpose of the invention, the technical scheme adopted by the invention is as follows:
in one aspect, the invention provides the use of a pharmaceutical assembly comprising an inhaled solution of formoterol fumarate in the manufacture of a medicament for the treatment of chronic obstructive pulmonary disease,
wherein the pharmaceutical assembly comprising formoterol fumarate inhalation solution comprises:
(a) formoterol fumarate inhalation solution; and
(b) a vibrating screen atomizer used in cooperation with the formoterol fumarate inhalation solution;
the atomization power of the vibrating screen atomizer is reduced to 0 watt from 10 watts in a step-type decreasing mode, and the formoterol fumarate inhales the fog of the solutionThe particle size of the drops is: d100.5 to 1.5 μm, D502.5 to 4.5 μm, D906.0 to 12.0 μm.
Preferably, the mass percentage of particles with aerodynamic particle size less than 5.39 μm in the formoterol fumarate inhalation solution is not less than 30%.
Preferably, the atomizing power of the vibrating screen atomizer is as follows: 10-8 watts in 0-1 minute; 8-7 watts in 1-2 minutes; the 2 nd to 9 th minutes are 7 to 0W.
Preferably, the formoterol fumarate inhalation solution has a droplet size of: d100.8 to 1.2 μm, D502.5 to 3.2 μm, D90Is 7.0 μm to 9.0 μm.
Preferably, the central area of the metal mesh of the vibrating screen atomizer has 1000-1400 micropores.
Preferably, the number of micropores having a diameter of 3.2 to 4.0 μm is not less than 80% of the total number of micropores.
Preferably, the cross section of the micropores in the vibrating screen atomizer is distributed in a step shape, and the taper is 30-50 degrees.
Preferably, the vibration frequency of the vibrating screen atomizer is 110-160 KHz.
Preferably, the atomization rate of the vibrating screen atomizer is 0.13-0.22 ml/min, and further, the atomization rate of the vibrating screen atomizer is 0.13-0.16 ml/min.
Preferably, the current of the vibrating screen atomizer is 1A, ± 2%; the voltage is 5V +/-2%.
Preferably, in the formoterol fumarate inhalation solution, the content of formoterol is 0.0005-0.002% (w/v), the content of sodium chloride is 0.7-0.9%, and the pH value is 4.0-6.0.
In another aspect, the present invention provides a pharmaceutical assembly comprising a formoterol fumarate inhalation solution, the pharmaceutical assembly comprising:
(a) formoterol fumarate inhalation solution; and
(b) a vibrating screen atomizer used in cooperation with the formoterol fumarate inhalation solution;
the atomization power of the vibrating screen atomizer is reduced to 0 watt from 10 watts in a step-type decreasing mode, and the particle size of the formoterol fumarate inhalation solution is as follows: d100.5 to 1.5 μm, D502.5 to 4.5 μm, D906.0 to 12.0 μm.
Preferably, the mass percentage of particles with aerodynamic particle size less than 5.39 μm in the formoterol fumarate inhalation solution is not less than 30%.
Preferably, the atomizing power of the vibrating screen atomizer is as follows: 10-8 watts in 0-1 minute; 8-7 watts in 1-2 minutes; the 2 nd to 9 th minutes are 7 to 0W.
Preferably, the formoterol fumarate inhalation solution has a droplet size of: d100.8 to 1.2 μm, D502.5 to 3.2 μm, D90Is 7.0 μm to 9.0 μm.
For inhalation formulations, clinical efficacy depends on the ability of the drug to penetrate the respiratory tract. In order to permeate the surrounding area, the particle size of the drug is required to be within a certain range. In addition to the therapeutic purpose, the side effects of the drug need to be taken into account, and in this regard, the size of the drug particles is also an important factor. In general, larger particles deposited in the upper respiratory tract may be rapidly removed from the lungs by mucociliary clearance, while the drug may be absorbed systemically, leading to potential side effects. The same problem may occur with too small particles of the drug, for example, as the drug may penetrate deep into the lungs, which may result in higher systemic exposure, which also increases the undesirable systemic effects of the drug. Therefore, controlling the particle size of the drug in an inhalation formulation while exerting a therapeutic effect is one of the most critical factors. The invention controls the particle size of the fogdrop of the formoterol fumarate inhalation solution as follows: d100.5 to 1.5 μm, D502.5 to 4.5 μm, D906.0 to 12.0 μm, preferably D100.8 to 1.2 μm, D502.5 to 3.2 μm, D90The particle size is 7.0-9.0 μm, so that the clinical treatment effect can be achieved, and the side effect can be reduced.
Preferably, the central area of the metal mesh of the vibrating screen atomizer has 1000-1400 micropores.
Preferably, the number of micropores having a diameter of 3.2 to 4.0 μm is not less than 80% of the total number of micropores.
Preferably, the cross section of the micropores in the vibrating screen atomizer is distributed in a step shape, and the taper is 30-50 degrees.
Preferably, the vibration frequency of the vibrating screen atomizer is 110-160 KHz.
Preferably, the atomization rate of the vibrating screen atomizer is 0.13-0.22 ml/min, and further, the atomization rate of the vibrating screen atomizer is 0.13-0.16 ml/min.
Preferably, the current of the vibrating screen atomizer is 1A, ± 2%; the voltage is 5V +/-2%.
The vibrating screen atomizer used in the present invention forms droplets by minute ultrasonic vibration and a mesh type spray head structure by vibrating a vibrator up and down to squeeze out a chemical liquid from holes of a nozzle type mesh type spray head. The structure of the vibrating screen atomizer used in the present invention can be referred to as described in CN 111569200A.
Preferably, in the formoterol fumarate inhalation solution, the content of formoterol is 0.0005-0.002% (w/v), the content of sodium chloride is 0.7-0.9%, and the pH value is 4.0-6.0.
Compared with the prior art, the invention has the beneficial effects that:
the formoterol inhalation solution is administrated by a vibrating screen atomizer, wherein the atomizing power, the micropore diameter, the micropore quantity, the micropore taper and the vibration frequency of an atomizing screen sheet in the atomizer, and the fogdrop particle size parameter (D) of the formoterol inhalation solution10\D50\D90) As a whole, the preparation characteristics and the clinical use effect of the product are influenced, and the medicine component has the advantages of small volume of residual liquid medicine, convenience in use, portability and low noise, and has a good effect of clinically treating chronic obstructive pulmonary disease.
The inventor finds in research that when the formoterol inhalation solution is used with a vibrating screen atomizer having specific parameters, the final therapeutic effect of the product is influenced by the formula ratio, the particle size distribution, the vibration frequency of the vibrating screen atomizer, the number of the atomizing micropores and the diameter of the atomizing micropores in the preparation product. Thus, in the present application, the parameters of the formoterol inhalation solution and the vibrating screen nebulizer were controlled in a coordinated manner, and clinical studies showed that patients using the drug combination of the present invention had a significant improvement in forced expiratory volume at 1 second (FEV 1) compared to placebo, with a statistically significant difference between the two groups (P < 0.05).
Drawings
Fig. 1 is a graph of the atomization power of a vibrating screen atomizer over time (mode 1);
fig. 2 is a graph of the atomization power of a vibrating screen atomizer over time (mode 2).
Detailed Description
To make the objects, technical solutions and advantages of the present invention clearer, the technical solutions of the present invention will be clearly and completely described below with reference to the accompanying drawings, and it is obvious that the described embodiments are only exemplary and do not represent all technical solutions of the present application. All other technical solutions obtained by a person skilled in the art without any creative effort based on the embodiments of the present invention belong to the protection scope of the present invention.
In the following examples, the nebulizer assay method is as follows:
the data were measured using a laser particle sizer (Sympatec GmbH) whose principle is light scattering.
The effective inhalation amount of the drug was collected by a cascade impactor having 7 stages and 1 micropore collector, and the effective inhalation amount of the collected drug was measured by high performance liquid chromatography.
The cascade impactor is connected with the L-shaped throat pipe and placed in an environment at 5 ℃ for 90 minutes, the effective inhalation amount of the medicine is tested within 5 minutes after the medicine is taken out, atomized particles with the cut-off particle size of less than 5 mu m are collected and then are measured by high performance liquid chromatography.
Unless otherwise stated, the atomizing power of the vibrating screen atomizer used in the following examples is: 10-8 watts in 0-1 minute; 8-7 watts in 1-2 minutes; the 2 nd to 9 th minutes are 7 to 0W. The trend of the atomization power over time can be selected in either of two ways: mode 1 — as shown in fig. 1; mode 2-as shown in fig. 2. In which the atomizing power of examples 1 to 6 was varied with time as shown in FIG. 1, and the atomizing power of example 7 and application example 1 was varied with time as shown in FIG. 2. It should be noted that these two ways are examples, but the present invention is not limited to these two ways.
Unless otherwise stated, the atomization rate of the vibrating screen atomizer used in the following examples is 0.13-0.16 ml/min, the vibration frequency is 110-160KHz, the current is 1A, and the voltage is 5V. The construction of the vibrating screen atomizer used in the following examples is described in patent CN111610261A, unless otherwise specified.
Unless otherwise specified, the formoterol aerosol inhalation solutions used in the following examples were formulated as follows: formoterol fumarate (0.001%, w/v), sodium chloride (0.85%, w/v), citric acid (0.027%, w/v), sodium citrate (0.08%, w/v), water for injection, pH = 5.0.
Example 1
The metal mesh sheets with different punching numbers and the same micropore diameter are selected to be applied to the same type of vibrating screen atomizer, and the influence of the atomization effect when the metal mesh sheets are applied to formoterol inhalation solution is detected, and the result is shown in table 1.
Example 2
The metal mesh sheets with different micropore diameters but the same number of punched holes are selected to be applied to the vibrating screen atomizer with the same vibration frequency, and the influence of the metal mesh sheets applied to the atomization effect of the formoterol inhalation solution is detected, and the result is shown in table 2.
Practice ofExample 3
When the same type of vibrating screen atomizer of the metal mesh with the same parameters is inspected, and the proportion of the number of micropores with the aperture of 3.2-4.0 mu m to the total number of micropores is different, the vibrating screen atomizer is applied to the influence of the atomization effect of the formoterol inhalation solution, and the result is shown in table 3.
Example 4
Compare shale shaker atomizer and compressed air atomizer atomizing formoterol effect of inhaling solution, the atomizer that accords with this patent requirement is selected for use to the shale shaker atomizer, and the compressed air atomizer selects for use certain import atomizer (pari Turboboy N), and the liquid medicine in the same time of two atomizer atomizing contrasts the effect of dosing of two atomizers, and the result is seen in table 4.
Example 5
Different brands of commercially available vibrating screen atomizers and the vibrating screen atomizer provided by the invention are selected to atomize the formoterol inhalation solution under the same conditions, the atomization effect of the two atomizers is compared, and the test results are shown in tables 5-6.
Example 6
The same parameters of the atomizer are used, different atomization rates are set, the influence of the atomization rates on the atomization effect is examined, and the results are shown in tables 7-8.
Example 7
The process comprises the following steps: adding 100kg of water for injection into the liquid preparation tank, cooling to below 40 ℃, adding the raw and auxiliary materials, and stirring to dissolve completely. Filtering the medicinal liquid with two-stage 0.2 μm filter for sterilization, and aseptically packaging the filtered medicinal liquid in 2ml low density polyethylene bottle.
The fine particle dose is measured by controlling the droplet size of the drug solution.
Fine particle dose: the determination is carried out by adopting an apparatus NGI according to the determination method of the aerodynamic characteristics of the fine particles of the inhaled preparation of 0951 in the four-part general rule of 2020 edition of Chinese pharmacopoeia.
The results of the measurement are shown in the following table 9:
application example 1Clinical use of formoterol fumarate inhalation solutions
The prescription of the medicine is as follows: formoterol fumarate (0.001%, w/v), sodium chloride (0.85%, w/v), citric acid (0.027%, w/v), sodium citrate (0.08%, w/v), water for injection, pH = 5.0.
Control group: physiological saline (0.9%).
The dosage is as follows:
the product is administered by inhalation only, and the recommended dose is one dose (20 μ g) per time, twice a day.
The time interval between twice daily administration is as close to 12 hours as possible, and should be not less than 6 hours.
Instructions for use:
using a matched vibrating screen hole atomizer (the technical parameters are shown in table 10), taking 1 piece of the product during each atomization, unscrewing a bottle cap, squeezing all the liquid medicine into an atomizing cup, opening the atomizer, and inhaling through mouth until complete atomization (no aerosol is generated, generally 9 minutes).
The product is not dilutable, and can be used immediately after unscrewing the cap to avoid contamination, and new unopened medicine should be used each time, and used medicine which is left unused after opening the cap for a long time or damaged medicine should not be used.
Before using the product, please carefully read the information instruction of the patient, understand how to use the product, and follow the instructions of the vibrating screen atomizer.
The project groups were subjected to a multicenter, randomized, double-blind, placebo parallel-controlled clinical study to test the effectiveness and safety of formoterol fumarate inhalation solution nebulization for the treatment of adult chronic obstructive pulmonary disease. 264 chronic obstructive pulmonary disease subjects were enrolled in the study. Subjects completed the screening session and were assessed by the investigator as eligible, randomized to either the experimental or control groups, and entered the treatment session. During the treatment period, formoterol fumarate in solution (20 mug/2 ml/time, 2 times/day) or placebo normal saline (2 ml/time, 2 times/day) was separately administered by aerosol inhalation. The treatment period is 8 weeks, and the continuous administration mode is adopted.
The study mainly adopted one main efficacy endpoint index: change in trough FEV1 from baseline at 56 days post treatment. Wherein the particle diameter of the fogdrop of the formoterol inhalation solution is D10: 0.86 μm, D50: 3.14 μm, D90: 6.98 μm.
The study showed that: the trough of forced expiratory volume at 1 second (FEV 1) on day 56 post-treatment was significantly improved compared to placebo with statistically significant differences (P < 0.05).
The applicant carried out experiments with the atomization power shown in fig. 1, and obtained results similar to those described above.
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