CN111840256A - Atomized inhalant and preparation method thereof - Google Patents
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Abstract
The invention discloses an aerosol inhalant and a preparation method thereof, and the components of the aerosol inhalant comprise active ingredients of umeclidinium bromide and vilanterotriacetic acid salt, a solubilizer, a bacteriostatic agent and a solution carrier. In addition, the invention also discloses a pharmaceutical composition. The active ingredients of the aerosol inhalant, namely the umeclidinium bromide and the vilanterotriptan acetate, are good in stability, and do not contain a propellant, and the prepared aerosol inhalant has small particle size and is beneficial to lung absorption of the medicine. The aerosol inhalant has simple production process and good repeatability, and is suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to an aerosol inhalation and a preparation method thereof.
Background
WUDIDIUM Bromide is white powder, has molecular weight of 508.5, and molecular formula of C29H34NO2Br, slightly soluble in water, of the formula:
the Vilanthionate is white powder, has molecular weight of 774.8, molecular formula of C24H33Cl2NO5. C20H1O2, is almost insoluble in water, and has the following structural formula:
the FDA in the united states approved the use of vilanterol hydrobromide vilanterol inhalation powder from the company glatiramer in 12 months of 2013 for once daily oral inhalation for the maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease. Dry powder inhalers can suffer from moisture in the drug powder during storage and use, and in the case of multi-dose DPIs, uniformity of dose content can occur (DDCU problem). The invention changes the formulation of inhaled powder into inhalation solution, and changes the administration device of powder aerosol into Soft Mist inhalation device (Soft Mist Inhaler) inhaled through oral cavity, ultrasonic vibration sieve atomization device and air compression atomization device, which is more beneficial to the deposition of medicine in lung.
The inhalation solution does not contain a propellant, and is prepared by dissolving umeclidinium bromide and vilanterol triphenoxyacetate in a mixed solvent of ethanol containing tween-80 and purified water, and adding a metal chelating agent, namely disodium edetate and a bacteriostatic agent. The preparation is suitable for inhalation administration of umeclidinium bromide and vilanterotriacetic acid, and is suitable for maintaining and treating airflow obstruction of patients with chronic obstructive pulmonary disease.
Disclosure of Invention
The invention aims to provide an aerosol inhalant which comprises the following components: (a) the active ingredients of the tolnaftate and the tolnaftate, (b) a solubilizer, (c) a bacteriostatic agent and (d) a solution carrier.
The solubilizer is one or more of tween-80, poloxamer, polyoxyethylene castor oil derivatives, polyethylene glycols, SolutolHS 15 and polyvinylpyrrolidone.
The bacteriostatic agent is one or more of benzalkonium chloride, benzoic acid and sodium benzoate.
The solution carrier is one or a mixture of more of distilled water, ethanol, phosphate buffered saline, balanced salt solution and saline, preferably one or a mixture of two of distilled water and ethanol.
The mass median aerodynamic diameter MMAD of the particle size of the aerosol inhalant is less than 10 microns.
The distribution range of the particle size of the aerosol inhalation is uniform, and the particle size D of the aerosol inhalation50Are all less than 10 microns.
The aerosol inhalant of the present invention may further comprise a pharmaceutically acceptable stabilizer selected from one or a mixture of more of edetate disodium dihydrate, edetate disodium, anhydrous citric acid, and anhydrous citric acid.
In practical application, the aerosol inhalant of the present invention is equipped with an atomization device, and the atomization device includes a Soft Mist inhalation device (Soft Mist Inhaler), an Ultrasonic vibrating screen atomizer (Ultrasonic vibrating mesh atomizer), and a Compressed air atomizer (Compressed air atomizer). A soft mist inhalation device is preferred, more preferably a soft mist inhalation device as disclosed in US patent publication No. US 20190030268.
The content of the active ingredient umeclidinium bromide is 15 mg-63 mg/100ml, preferably 15-50 mg/100ml, and more preferably 15-45 mg/100 ml.
The content of the active component of the vilanterotriptan acetate is 8 mg-33 mg/100ml, preferably 8-30 mg/100ml, and more preferably 10-30 mg/100 ml.
The content of the solubilizer is 20 mg-180 mg/100ml, preferably 20-100 mg/100ml, and more preferably 20-80 mg/100 ml.
The content of the bacteriostatic agent is 20 mg-30 mg/100ml, preferably 20-28 mg/100ml, and more preferably 20-25 mg/100 ml.
The content of the stabilizer is 11 mg-22 mg/100ml, preferably 11-20 mg/100ml, and more preferably 11-18 mg/100 ml.
The term "aerosolized inhalant" or "nebulizer" as used in the present specification refers to a formulation that is administered by a nebulizing device. The atomization device includes, but is not limited to, a Soft Mist inhalation device (Soft Mist Inhaler), an Ultrasonic vibrating screen atomizer (Ultrasonic vibrating mesh atomizer), and a Compressed air atomizer (Compressed air atomizer).
The term "ultrasonic vibration sieve atomization device" used in the present specification means a stainless steel screen having a diameter of about 3 to 5 μm, which is formed with a conical shape having a cone bottom facing the page. When this liquid with the conical microsieves is subjected to ultrasonic vibration, the liquid is sent out, and a large amount of mist droplets are generated.
The term "air compression atomizing device" used in the present specification means a device mainly composed of two parts of a compressed air source and an atomizer. The compressed gas is suddenly decompressed after passing through the narrow opening at a high speed, negative pressure is generated locally, liquid sucked into the container by the siphon action generated by the negative pressure of another small pipe beside the airflow outlet is discharged, and when the liquid meets high-pressure airflow, the liquid is collided and cracked into small aerosol particles.
The term "soft mist inhaler" as used in the present specification means that a metered quantity of liquid medicine is forced under pressure out of a nozzle system to form two colliding high velocity jets that form a mist of relatively small particles. The soft mist inhalation device has low mist spraying speed, generates soft mist and does not generate strong impact on the back part of the throat.
The term "Soft Mist Inhaler" or "Soft Mist" as used in the present specification refers to an inhalation formulation administered by Soft Mist inhalation device (Soft Mist Inhaler).
The term "aerosol inhalant" or "aerosol" as used in the present specification includes, but is not limited to, "soft aerosol inhalant" or "soft aerosol".
The invention also provides a preparation method of the atomized inhalant, which comprises the following steps:
step (1): weighing bacteriostatic agent and solubilizer, and dissolving the bacteriostatic agent and the solubilizer in a transferred volumetric flask by using a solution carrier for three times;
step (2): adding active ingredients of umeclidinium bromide and vilanterol trithionate, and dissolving with ultrasound;
and (3): adding a proper amount of pure water for dissolving, then performing ultrasonic dissolution, and fixing the volume by using the pure water.
Further, the solution carrier in the step (1) is ethanol.
Further, the time of the ultrasound in the step (2) is 1-15 minutes.
Further, the time of the ultrasound in the step (3) is 1-15 minutes.
It is another object of the present invention to provide an aerosolized inhaled pharmaceutical composition solution comprising: the preparation method comprises the following steps of (a) active ingredients of umeclidinium and vilanterotriacetic acid salt, (b) a solubilizer, (c) a bacteriostatic agent and (d) a solution carrier.
Preferably, the pharmaceutical composition can be prepared into an aerosol.
Preferably, the pharmaceutical composition is prepared into a pulmonary administration preparation.
The application of the aerosol inhalation in preparing the medicine for treating the respiratory system diseases comprises the following steps: acute and chronic bronchitis, pneumonia, cerebrovascular disease complicated with dropsy pneumonia, bronchiectasis, lung abscess, chronic obstructive pulmonary diseases, pulmonary fungal infection, pulmonary tuberculosis, acute sinusitis, chronic sinusitis, and sinusitis operation inflammation.
The invention has the beneficial effects that: the active ingredients of the aerosol inhalant, namely the umeclidinium bromide and the vilanterotriptan acetate, are good in stability, and do not contain a propellant, and the prepared aerosol inhalant has small particle size and is beneficial to lung absorption of the medicine. The medicine can directly reach the target point, has quick effect, can exert local effect, and has high bioavailability. The aerosol inhalant has simple production process and good repeatability, and is suitable for industrial production.
Drawings
Figure 1 is a graph of the aerodynamic particle size distribution of vilanterotriptan acetate in an aerosolized inhaler according to example 5 of the present invention.
Figure 2 is a graph of the aerodynamic particle size distribution of umeclidinium bromide in an aerosolized inhalant according to example 5 of the present invention.
FIG. 3 is a graph showing the droplet size distribution of example 3 of the present invention measured after spraying using a soft mist inhaler.
Fig. 4 is a graph showing the distribution of the diameters of the droplets obtained from sample 3 of example 6 of the present invention after spraying the droplets using an air compression atomizing device.
FIG. 5 is a graph showing the particle size distribution of the mist droplets obtained after sample 3 of example 6 of the present invention was sprayed using a vibrating screen atomizer.
FIG. 6 is a graph showing the droplet size distribution of example 4 of the present invention measured after spraying using a soft mist inhaler.
Fig. 7 is a graph showing the particle size distribution of the droplets obtained from sample 4 of example 6 of the present invention after spraying using an air compression atomizer.
FIG. 8 is a graph showing the particle size distribution of the mist droplets obtained after sample 4 of example 6 of the present invention was sprayed using a vibrating screen atomizer.
FIG. 9 is a graph showing the droplet size distribution of example 5 of the present invention measured after spraying using a soft mist inhaler.
FIG. 10 is a graph showing the particle size distribution of the droplets obtained from sample 5 of example 6 of the present invention after spraying using an air compression atomizer.
FIG. 11 is a graph showing the particle size distribution of the mist droplets obtained after sample 5 of example 6 of the present invention was sprayed using a vibrating screen atomizer.
Detailed Description
The invention is further illustrated by the following examples. It should be understood that these examples are only for the purpose of the present invention and are not intended to limit the scope of the present invention. Unless defined or indicated otherwise, the scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.
Example 1
Preparation of sample 1 and sample 2 inhalation solutions: 50% benzalkonium chloride and Tween-80 in the amount shown in the prescription in Table 1 are weighed by a weighing bottle, dissolved and transferred into a weighed 100ml volumetric flask in three times by using 95% ethanol in the amount shown in the table 1, and then umeclidinium bromide and vilanterotriptan acetate in the amount shown in the table 1 are added for ultrasonic dissolution. And adding a prescription amount of edetate disodium dihydrate dissolved by a proper amount of pure water, dissolving by ultrasonic waves, and fixing the volume to 100ml by using the pure water. Samples 1 and 2 were clear solutions and the results are shown in Table 2, indicating that both umeclidinium bromide and vilanterite were completely dissolved in the dilute ethanol solution containing Tween-80.
Table 1 prescription of inhalation solutions for sample 1 and sample 2
| Composition (I) | |
|
| Umeclidinium Bromide | 21mg | 21mg |
| Retention acetate salt | 11mg | 11mg |
| Edetate disodium dihydrate | 11mg | 22mg |
| Tween-80 | 20mg | 20mg |
| 50% benzalkonium chloride | 20mg | 20mg |
| 95% ethanol | 16g | 16g |
| Purified water | The volume is fixed to 100ml | The volume is fixed to 100ml |
TABLE 2 measurement results of the content of the imbibed solutions of sample 1 and sample 2
Example 2
50% benzalkonium chloride and Tween-80 in the amounts specified in Table 3 were weighed in weighing bottles, dissolved in 95% ethanol in the amounts specified in Table 3 three times and transferred to weighed 100ml volumetric flasks, and umeclidinium bromide and vilanterotriptan acetate in the amounts specified in Table 3 were added and dissolved by ultrasound. And adding a prescription amount of edetate disodium dihydrate dissolved by a proper amount of pure water, performing ultrasonic dissolution, and fixing the volume to 100ml by using the pure water. Sample 3, sample 4 and sample 5 were clear solutions and the results of the measurements are shown in Table 4, indicating that both umeclidinium bromide and vilanterotriptan acetate were completely dissolved in the dilute ethanol solution containing Tween-80.
Table 3 prescription for inhalation solutions for sample 3, sample 4 and sample 5
TABLE 4 measurement results of the content of the imbibed solutions of sample 3, sample 4 and sample 5
Example 3
50% benzalkonium chloride and Tween-80 in the amount shown in the prescription in Table 5 are weighed by a weighing bottle, dissolved and transferred into a weighed 100ml volumetric flask in three times by 95% ethanol in the amount shown in the prescription in Table 5, and then added with umeclidinium bromide and vilanterotriptan acetate in the amount shown in the prescription in Table 5 for ultrasonic dissolution. Adding a prescription amount of edetate disodium dihydrate dissolved by a proper amount of pure water, dissolving by ultrasonic wave, and fixing the volume to 100ml by using the pure water. Sample 3, sample 4 and sample 5 were all clear solutions and the results of the content measurements are shown in table 6.
TABLE 5 prescription for inhalation solutions for sample 6, sample 7 and sample 8
| Composition (I) | Sample No. 6 | |
Sample 8 |
| Umeclidinium Bromide | 21mg | 21mg | 21mg |
| Retention acetate salt | 11mg | 11mg | 11mg |
| Edetate disodium dihydrate | 11mg | 11mg | 11mg |
| 50% benzalkonium chloride | 20mg | 20mg | 20mg |
| Tween-80 | 30mg | 30mg | 30mg |
| 95% ethanol | 16g | 20g | 24g |
| Adding water to | 100ml | 100ml | 100ml |
TABLE 6 determination of the content of the imbibed solutions of sample 6, sample 7 and sample 8
Example 4
Preparation of sample 6 and sample 7 inhalation solutions: 50% benzalkonium chloride and Tween-80 in the amounts specified in Table 7 were weighed in weighing bottles, dissolved in 95% ethanol in the amount specified in Table 1 three times and transferred to weighed 100ml volumetric flasks, and umeclidinium bromide and vilanterotriptan acetate in the amounts specified in Table 7 were added and dissolved by ultrasound. And adding a prescription amount of edetate disodium dihydrate dissolved by a proper amount of pure water, dissolving by ultrasonic waves, and fixing the volume to 100ml by using the pure water. Sample 6 and sample 7 were both clear solutions.
TABLE 7 prescription for inhalation solutions for sample 6 and sample 7
| Composition (I) | Sample No. 6 | |
| Umeclidinium Bromide | 15mg | 63mg |
| Retention acetate salt | 8mg | 33mg |
| Edetate disodium dihydrate | 11mg | 11mg |
| Poloxamers | 40mg | 180mg |
| 50% benzalkonium chloride | 20mg | 20mg |
| 95% ethanol | 20g | 20g |
| Purified water | The volume is fixed to 100ml | The volume is fixed to 100ml |
Example 5
When a soft mist inhalation device is used, a sample 3 is administrated by the soft mist inhalation device, 30 microliters (one dose per 4 rams, and a new Generation impactor NGI (Next Generation Impactor)) is used to measure the aerodynamic particle size distribution of the umeatropium bromide retinate acetate inhalation solution at 30L/min, the specific steps are that a silicone oil coating is added into each collection disc, the coating is evenly coated on the surface of each disc, NGI is built according to the requirements of the instrument device, NGI, a filter, a flowmeter and a vacuum pump are sequentially arranged from left to right, the flow rate is adjusted to 30L/min, the NGI is put into a refrigerator at 5 ℃ for 2 hours and then taken out, after the NGI is connected with a pump, the power supply of the pump is turned on, the flow rate adjusting knob on the pump is adjusted to make the flow rate reach 30L/min, the device is inserted and continuously pumped for 8 seconds per 5 seconds, each stop for 5 seconds. Removing adapter and throat part, sealing one end of throat part with sealing membrane, pouring 50ml diluent, sealing the other end of throat part, shaking the whole throat part carefully, collecting solution in beaker, cleaning adapter with the solution, filtering with 0.45 μm microporous membrane, and sampling 1ml solution. Washing the collecting plates with the diluent for three times respectively, fixing the volume to a 10ml volumetric flask, filtering with a 0.45 mu m microporous filter membrane, and taking 1ml for sample injection. Finally, 9 samples of T, 1, 2, 3, 4, 5, 6, 7 and MOC are obtained. The results show that: sample 3 both components had mass median aerodynamic diameter MMAD less than 10 microns and geometric standard deviation GSD less than 5% measured after spraying (table 8).
TABLE 8 aerodynamic particle size distribution determination of Updium Bromide Vilanter inhalation solution
Example 6
After the samples 3, 4 and 5 were sprayed with a soft spray inhaler, an air compression atomizer and a vibrating screen atomizer, respectively, the particle size distribution of the droplets was measured using a real-time particle analyzer SprayTec (STP 5313, malvern instruments ltd, uk), and the measurement results are shown in table 9, which indicated that: after spraying 3 samples using different inhalation devices D50Are all less than 10 microns and have a relatively more uniform particle size distribution as measured using a soft mist inhaler.
TABLE 9 results of particle size distribution (μm) of droplets measured after spraying using different inhalation devices
Although the present invention has been described with reference to the preferred embodiments, it is not intended to be limited thereto. Those skilled in the art can make numerous changes and modifications to the disclosed embodiments, or modify equivalent embodiments without departing from the scope of the invention. Therefore, any simple modification, equivalent change and modification made to the above embodiments according to the technical essence of the present invention should fall within the protection scope of the technical solution of the present invention, unless departing from the contents of the technical solution of the present invention.
Claims (16)
1. An aerosol inhalation comprising the following components: (a) the active ingredients of the tolnaftate and the tolnaftate, (b) a solubilizer, (c) a bacteriostatic agent and (d) a solution carrier.
2. The aerosol inhalation formulation of claim 1, wherein the solubilizer is one or more selected from tween-80, poloxamer, polyoxyethylene castor oil derivatives, polyethylene glycols, Solutol HS 15, and polyvinylpyrrolidone.
3. The aerosol inhalation of claim 1, wherein the bacteriostatic agent is one or more of benzalkonium chloride, benzoic acid, and sodium benzoate.
4. The aerosol inhalant as claimed in claim 1, wherein the solution carrier is one or a mixture of more of distilled water, ethanol, phosphate buffered saline, balanced salt solution, and saline.
5. The aerosolized inhaler of claim 1, further comprising a stabilizer.
6. The aerosol inhalant as claimed in claim 5, wherein the stabilizer is one or a mixture of more of edetate disodium dihydrate, edetate disodium, anhydrous citric acid, and anhydrous citric acid.
7. The aerosol inhalation formulation according to claim 6, wherein the stabilizer is present in an amount of 11 to 22mg/100 ml.
8. The aerosol inhaler of claim 1, further comprising an aerosolization device comprising a soft mist inhalation device, an ultrasonic vibrating screen aerosolization device, an air compression aerosolization device.
9. The aerosol inhalation formulation of claim 1, wherein umeclidinium bromide is present in an amount of 15mg to 63mg/100ml and vilanterotricin acetate is present in an amount of 8mg to 33mg/100 ml.
10. The aerosol inhalation according to claim 1, wherein the content of solubilizer is from 20mg to 180mg/100 ml.
11. The aerosol inhalation according to claim 1, wherein the bacteriostatic agent is present in an amount of 20mg to 30mg per 100 ml.
12. An aerosol inhalation according to claim 1, characterised in that the mass median aerodynamic diameter MMAD of the particle size of the aerosol inhalation is less than 10 microns.
13. An aerosol inhalation according to claim 1, characterised in that the aerosol inhalation has a particle size D50Are all less than 10 microns.
14. A process for the preparation of an aerosolized inhaler according to claim 1, comprising the steps of:
Step (1): weighing bacteriostatic agent and solubilizer, dissolving with solution carrier for three times, and transferring into volumetric flask;
step (2): adding active ingredients of umeclidinium bromide and vilanterol trithionate, and dissolving with ultrasound;
and (3): adding a proper amount of pure water for dissolving, then performing ultrasonic dissolution, and fixing the volume by using the pure water.
15. The process for the preparation of an aerosolized inhaler according to claim 14, wherein the solution carrier in step (1) is ethanol.
16. The process for preparing an aerosol inhalation according to claim 14, wherein the time for the ultrasound in the steps (2) and (3) is 1 to 15 minutes.
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| CN201910357750.7A CN111840256A (en) | 2019-04-29 | 2019-04-29 | Atomized inhalant and preparation method thereof |
| PCT/CN2020/080075 WO2020220855A1 (en) | 2019-04-29 | 2020-03-18 | Atomization inhalant and preparation method therefor |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103347518A (en) * | 2011-02-17 | 2013-10-09 | 奇斯药制品公司 | Liquid propellant-free formulation comprising an antimuscarinic drug |
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| CN105250245A (en) * | 2015-10-15 | 2016-01-20 | 北京神州泰洁生物科技有限公司 | Atomized inhalant for treating respiratory system diseases |
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| CN106943350A (en) * | 2017-03-14 | 2017-07-14 | 上海现代药物制剂工程研究中心有限公司 | Aerosol and preparation method containing muscarinic receptor antagonist and β 2 receptor agonist |
| CN110292559A (en) * | 2018-03-23 | 2019-10-01 | 上海现代药物制剂工程研究中心有限公司 | Umeclidinium aerosol inhalation solution and preparation method thereof |
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- 2019-04-29 CN CN201910357750.7A patent/CN111840256A/en active Pending
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| CN103347518A (en) * | 2011-02-17 | 2013-10-09 | 奇斯药制品公司 | Liquid propellant-free formulation comprising an antimuscarinic drug |
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