Pharmaceutical Inhalation Aerosol and Preparation Method Therefor

Abstract

A pharmaceutical inhalation aerosol and a preparation method therefor. The preparation method comprises the following steps: (1) mixing glycopyrronium bromide coarse powder with indacaterol fine powder, or glycopyrronium bromide coarse powder with indacaterol coarse powder, or glycopyrronium bromide fine powder with indacaterol coarse powder in proportion to obtain a glycopyrronium bromide and indacaterol mixture; (2) micronizing, by a crushing device under pressure, the glycopyrronium bromide and indacaterol mixture prepared in step (1) to obtain a micronized glycopyrronium bromide and indacaterol mixture; and (3) adding the micronized glycopyrronium bromide and indacaterol mixture prepared in step (2) to an aluminum can, performing valve sealing, and filling with a propellant. In the glycopyrronium bromide/indacaterol compound inhalation aerosol prepared by the method, the effective deposition rate of glycopyrronium bromide is significantly improved, and the degree of co-deposition of glycopyrronium bromide and indacaterol is high. The prepared inhalation aerosol is convenient to carry and low in price, has higher medication compliance compared with an inhalation powder aerosol, and is more widely used than a nebulizer.

Claims

1. A preparation method of pharmaceutical inhalation aerosol, wherein it comprises the following steps: (1) mixing glycopyrronium bromide coarse powder with indacaterol fine powder, or glycopyrronium bromide coarse powder with indacaterol coarse powder, or glycopyrronium bromide fine powder with indacaterol coarse powder at a ratio to obtain a glycopyrronium bromide and indacaterol mixture; (2) micronizing, by a crushing device under pressure, the glycopyrronium bromide and indacaterol mixture prepared in step (1) to obtain a micronized glycopyrronium bromide and indacaterol mixture; and (3) adding the micronized glycopyrronium bromide and indacaterol mixture prepared in step (2) to an aluminum can, performing valve sealing, and filling with a propellant.

2. The method of claim 1, wherein in the step (1), the ratio is 5:1 to 1:5 by mass.

3. The method of claim 2, wherein the ratio is 1:1 to 1:5 by mass.

4. The method of claim 1, wherein in the step (2), the pressure of the micronization is 4-10 bar.

5. The method of claim 4, wherein in the step (2), the pressure of the micronization is 8-10 bar.

6. The method of claim 1, wherein in the step (2), the feed rate of the glycopyrronium bromide and indacaterol mixture is 0.5-1.0 g/min.

7. The method of claim 6, wherein in the step (2), the feed rate of the glycopyrronium bromide and indacaterol mixture is 0.5 g/min.

8. The method of claim 1, wherein in the step (2), the crushing device is a ball mill, a jet mill, a high-pressure homogenizer, or a spray dryer.

9. The method of claim 1, wherein in the step (3), the propellant is one of HFA 134a, HFA 227, HFA 152.

10. The method of claim 1, wherein in the step (3), the propellant is a mixture of HFA 134a, HFA 227, and HFA 152.

11. The method of claim 1, wherein in the step (2), the particle size D90 distribution range of the micronized glycopyrronium bromide and indacaterol mixture is 2.86 μm to 4.18 μm, the D50 distribution range is 1.42 μm to 1.86 μm, and the D10 distribution range is 0.58 μm to 0.66 μm.

12. The method of claim 11, wherein the particle size D90 distribution range of the micronized glycopyrronium bromide and indacaterol mixture is 2.86 μm to 3.58 μm, the D50 distribution range is 1.42 μm to 1.68 μm, and the D10 distribution range is 0.58 μm to 0.62 μm.

13. The method of claim 12, wherein the particle size D90 distribution range of the micronized glycopyrronium bromide and indacaterol mixture is 2.86 μm to 3.40 μm, the D50 distribution range is 1.42 μm to 1.53 μm, and the D10 distribution range is 0.58 μm to 0.61 μm.

14. The method of claim 1, wherein in the step (1), the ratio is 1:5 by mass; and in the step (2), the pressure of the micronization is 10 bar.

15. A pharmaceutical inhalation aerosol prepared according to the method of claim 1, wherein it comprises glycopyrronium bromide, indacaterol, and a propellant.

16. The pharmaceutical inhalation aerosol of claim 15, wherein the FPF range of the glycopyrronium bromide is 35% to 60%, and the FPF range of the indacaterol is 35% to 65%.

17. The pharmaceutical inhalation aerosol of claim 16, wherein the FPF range of the glycopyrronium bromide is 45% to 60%, and the FPF range of the indacaterol is 40% to 60%.

18. The pharmaceutical inhalation aerosol of claim 17, wherein the FPF range of the glycopyrronium bromide is 55% to 60%, and the FPF range of the indacaterol is 55% to 60%.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0045] FIG. 1A shows the Anderson cascade impactor test results of an aerosol prepared by pulverizing glycopyrronium bromide coarse powder and indacaterol maleate coarse powder at a ratio of 5:1 with a jet mill;

[0046] FIG. 1B shows the Anderson cascade impactor test results of an aerosol prepared by pulverizing glycopyrronium bromide coarse powder and indacaterol maleate coarse powder at a ratio of 1:1 with a jet mill;

[0047] FIG. 1C shows the Anderson cascade impactor test results of an aerosol prepared by pulverizing glycopyrronium bromide coarse powder and indacaterol maleate coarse powder at a ratio of 1:5 with a jet mill;

[0048] FIG. 2A shows the Anderson cascade impactor test results of an aerosol prepared by pulverizing glycopyrronium bromide coarse powder and indacaterol maleate fine powder at a ratio of 5:1 with a jet mill;

[0049] FIG. 2B shows the Anderson cascade impactor test results of an aerosol prepared by pulverizing glycopyrronium bromide coarse powder and indacaterol maleate fine powder at a ratio of 1:1 with a jet mill;

[0050] FIG. 2C shows the Anderson cascade impactor test results of an aerosol prepared by pulverizing glycopyrronium bromide coarse powder and indacaterol maleate fine powder at a ratio of 1:5 with a jet mill;

[0051] FIG. 3A shows the Anderson cascade impactor test results of an aerosol prepared by pulverizing glycopyrronium bromide fine powder and indacaterol maleate coarse powder at a ratio of 5:1 with a jet mill;

[0052] FIG. 3B shows the Anderson cascade impactor test results of an aerosol prepared by pulverizing glycopyrronium bromide fine powder and indacaterol maleate coarse powder at a ratio of 1:1 with a jet mill;

[0053] FIG. 3C shows the Anderson cascade impactor test results of an aerosol prepared by pulverizing glycopyrronium bromide fine powder and indacaterol maleate coarse powder at a ratio of 1:5 with a jet mill;

[0054] FIG. 4A shows the Anderson cascade impactor test results of an aerosol prepared by pulverizing glycopyrronium bromide coarse powder and indacaterol maleate coarse powder at a ratio of 1:1 with a jet mill at a pressure of 10 bar;

[0055] FIG. 4B shows the. Anderson cascade impactor test results of an aerosol prepared by pulverizing glycopyrronium bromide coarse powder and indacaterol maleate coarse powder at a ratio of 1:1 with a jet mill at a pressure of 8 bar;

[0056] FIG. 4C shows the Anderson cascade impactor test results of an aerosol prepared by pulverizing glycopyrronium bromide coarse powder and indacaterol maleate coarse powder at a ratio of 1:1 with a jet mill at a pressure of 4 bar;

[0057] FIG. 4D shows the Anderson cascade impactor test results of an aerosol prepared by pulverizing glycopyrronium bromide coarse powder and indacaterol maleate coarse powder at a ratio of 1:1 with a jet mill at a pressure of 3 bar;

[0058] FIG. 4E shows the Anderson cascade impactor test results of an aerosol prepared by pulverizing glycopyrronium bromide coarse powder and indacaterol maleate coarse powder at a ratio of 1:1 with a jet mill at a pressure of 2 bar;

[0059] FIG. 5 shows the Anderson cascade impactor test results of a compound aerosol prepared from micronized glycopyrronium bromide powder and micronized indacaterol maleate powder.

DETAILED DESCRIPTION OF THE INVENTION

[0060] In conjunction with the drawings and the preferred embodiments of the present invention, the following further describes the technical means adopted by the present invention to achieve the intended purpose of the invention.

[0061] Experimental equipment: jet mill: Micron JETMILL Lab ultra-fine powder jet mill; High performance liquid chromatography (HPLC) instrument: Waters 2695.

[0062] Reagent Source: glycopyrronium bromide was purchased from Harman Finochem Ltd, India; indacaterol maleate was purchased from Inke, Italy; and HFA 134a was purchased from (Japan) Mexichem.

[0063] Prescription amounts of glycopyrronium bromide and indacaterol maleate were added to an aluminum can, valve-sealed, and filled with propellant, HFA-134a. After being inverted for 2 days, it was tested according to 0951, volume IV general rules of the Pharmacopoeia of the People's Republic of China 2015 Edition. The sum of the deposition from the stage plate 3 to the filter membrane is the Fine Particle Dose (FPD). The FPD (less than 5 μm) divided by the total amount collected by the Anderson cascade impactor (Total Dose, TD) is the Fine Particle Fraction (FPF).

[0064] Experimental Method

[0065] Micronized powders were precisely weighed and placed in a 14 mL fluorocarbon polymerization (FCP)-coated aluminum can, valve-sealed, filled, ultrasonicated for 10 minutes, and then kept for 2 days for Anderson cascade impactor testing. It was tested according to 0951 device 2, volume IV general rules of the Pharmacopoeia of the People's Republic of China 2015 Edition. The relative humidity of the test environment should be 45% to 55%. The flow rate was adjusted to 28.3±1.5 liters per minute. Take 1 bottle of this product, shake it sufficiently, and discard 4 sprays. Wipe the mouthpiece with ethanol, dry it sufficiently, turn on the vacuum pump, shake for 5 seconds (note that shake for 5 seconds before each spray and the interval between sprays is 30 seconds), insert the product into the adapter, and spray once immediately. After removing the aluminum can and the driver, shake for 5 seconds, reinsert into the adapter, and immediately spray the second time. Repeat this process until the completion of 10 sprays. After the last spray, wait 1 minute, then remove the aluminum can and driver, turn off the vacuum pump, and remove the device. The various plates of the Anderson impactor were washed with a specific ratio of methanol aqueous solution, and the content of the drugs deposited on each plate was determined by HPLC.

EXAMPLE 1

[0066] 1.0 g glycopyrronium bromide coarse powder and 0.2 g indacaterol maleate coarse powder (5:1) were weighed and mixed manually for 10 minutes, then the mixture was added to a jet mill, and micronized at a pressure of 8 bar. The micronized API was sealed and stored until use. 24 mg of the glycopyrronium bromide/indacaterol maleate mixture was weighed, and placed in a 14 mL FCP-coated aluminum can, valve-sealed, filled, ultrasonicated for 10 minutes, and then kept for 2 days for testing. The ACI test method is as described above. The Anderson cascade impactor test results are shown in FIG. 1A.

[0067] 0.5 g glycopyrronium bromide coarse powder and 0.5 g indacaterol maleate coarse powder (1:1) were weighed and mixed manually for 10 minutes, then the mixture was added to a jet mill, and micronized at a pressure of 8 bar. The micronized API was sealed and stored until use. 24 mg of the glycopyrronium bromide/indacaterol maleate mixture was weighed, placed in a 14 mL FCP-coated aluminum can, valve-sealed, filled, ultrasonicated for 10 minutes, and then kept for 2 days for testing. The Anderson cascade impactor test results are shown in FIG. 1B.

[0068] 0.2 g glycopyrronium bromide coarse powder and 1.0 g indacaterol maleate coarse powder (1:5) were weighed and mixed manually for 10 minutes, then the mixture was added to a jet mill, and micronized at a pressure of 8 bar. The micronized API was sealed and stored until use. 30 mg of the glycopyrronium bromide/indacaterol maleate mixture was weighed, and placed in a 14 mL FCP-coated aluminum can, valve-sealed, filled, ultrasonicated for 10 minutes, and then kept for 2 days for testing. The Anderson cascade impactor test results are shown in FIG. 1C.

TABLE-US-00003 TABLE 3 The Anderson cascade impactor test results of glycopyrronium bromide coarse powder and indacaterol maleate coarse powder after being co-micronized by a jet mill at a pressure of 8 bar FPF of FPF of glycopyrronium indacaterol Formulation bromide (%) maleate (%) glycopyrronium bromide + 47.55 49.80 indacaterol maleate (5:1) glycopyrronium bromide + 54.03 56.11 indacaterol maleate (1:1) glycopyrronium bromide + 58.03 59.71 indacaterol maleate (1:5)

[0069] It can be seen from Table 3 that at a pressure of 8 bar, the FPFs of glycopyrronium bromide and indacaterol maleate are 47.55% and 49.8% respectively when the ratio of glycopyrronium bromide/indacaterol maleate reaches 5:1; the FPFs of glycopyrronium bromide and indacaterol maleate are 54.03% and 56.11% respectively when the ratio increases to 1:1; and the FPFs of glycopyrronium bromide and indacaterol maleate are 58.03% and 59.71% respectively when the ratio increases to 1:5. As the proportion of glycopyrronium bromide decreases, the dispersibility of glycopyrronium bromide is significantly improved, and the Fine Particle Fraction is increased.

[0070] The Anderson test results in FIGS. 1A-1C show that for the aerosols prepared by co-micronizing glycopyrronium bromide coarse powder/indacaterol maleate coarse powder at different ratios with a jet mill at a pressure of 8 bar, the degree of co-deposition of glycopyrronium bromide and indacaterol maleate is very high.

EXAMPLE 2

[0071] 1.5 g glycopyrronium bromide coarse powder and 0.3 g indacaterol maleate fine powder (5:1) were weighed and mixed manually for 10 minutes, then the mixture was added to a jet mill, and micronized at a pressure of 8 bar. The micronized API was sealed and stored until use. 24 mg of the glycopyrronium bromide/indacaterol maleate mixture was weighed, and placed in a 14 mL FCP-coated aluminum can, valve-sealed, filled, ultrasonicated for 10 minutes, and then kept for 2 days for testing. The Anderson cascade impactor test results are shown in FIG. 2A.

[0072] 0.5 g glycopyrronium bromide coarse powder and 0.5 g indacaterol maleate fine powder (1:1) were weighed and mixed manually for 10 minutes, then the mixture was added to a jet mill, and micronized at a pressure of 8 bar. The micronized API was sealed and stored until use. 24 mg of the glycopyrronium bromide/indacaterol maleate mixture was weighed, and placed in a 14 mL FCP-coated aluminum can, valve-sealed, filled, ultrasonicated for 10 minutes, and then kept for 2 days for testing. The Anderson cascade impactor test results are shown in FIG. 2B.

[0073] 0.2 g glycopyrronium bromide coarse powder and 1.0 g indacaterol maleate fine powder (1:5) were weighed and mixed manually for 10 minutes, then the mixture was added to a jet mill, and micronized at a pressure of 8 bar. The micronized API was sealed and stored until use. 30 mg of the glycopyrronium bromide/indacaterol maleate mixture was weighed, and placed in a 14 mL FCP-coated aluminum can, valve-sealed, filled, ultrasonicated for 10 minutes, and then kept for 2 days for testing. The Anderson cascade impactor test results are shown in FIG. 2C.

TABLE-US-00004 TABLE 4 The Anderson cascade impactor test results of glycopyrronium bromide coarse powder and indacaterol maleate fine powder after being co-micronized by a jet mill at a pressure of 8 bar FPF of glycopyrronium FPF of indacaterol Formulation bromide (%) maleate (%) glycopyrronium bromide + 44.88 47.98 indacaterol maleate (5:1) glycopyrronium bromide + 52.77 55.38 indacaterol maleate (1:1) glycopyrronium bromide + 54.45 56.90 indacaterol maleate (1:5)

[0074] As shown in Table 4, as the proportion of glycopyrronium bromide decreases, the dispersibility of glycopyrronium bromide is significantly improved, and the Fine Particle Fraction is increased from 44.88% to 54.45%.

[0075] The Anderson test results in FIGS. 2A-2C show that for the aerosols prepared by co-micronizing glycopyrronium bromide coarse powder/indacaterol maleate fine powder at different ratios with a jet mill at a pressure of 8 bar, the degree of co-deposition of glycopyrronium bromide and indacaterol maleate is very high.

EXAMPLE 3

[0076] 1.5 g glycopyrronium bromide fine powder and 0.3 g indacaterol maleate coarse powder (5:1) were weighed and mixed manually for 10 minutes, then the mixture was added to a jet mill, and micronized at a pressure of 8 bar. The micronized API was sealed and stored until use. 24 mg of the glycopyrronium bromide/indacaterol maleate mixture was weighed, and placed in a 14 mL FCP-coated aluminum can, valve-sealed, filled, ultrasonicated for 10 minutes, and then kept for 2 days for testing. The Anderson cascade impactor test results are shown in FIG. 3A.

[0077] 0.5 g glycopyrronium bromide fine powder and 0.5 g indacaterol maleate coarse powder (1:1) were weighed and mixed manually for 10 minutes, then the mixture was added to a jet mill, and micronized at a pressure of 8 bar. The micronized API was sealed and stored until use. 24 mg of the glycopyrronium bromide/indacaterol maleate mixture was weighed, and placed in a 14 mL FCP-coated aluminum can, valve-sealed, filled, ultrasonicated for 10 minutes, and then kept for 2 days for testing. The Anderson cascade impactor test results are shown in FIG. 3B.

[0078] 0.2 g glycopyrronium bromide fine powder and 1.0 g indacaterol maleate coarse powder (1:5) were weighed and mixed manually for 10 minutes, then the mixture was added to a jet mill, and micronized at a pressure of 8 bar. The micronized API was sealed and stored until use. 30 mg of the glycopyrronium bromide/indacaterol maleate mixture was weighed, and placed in a 14 mL FCP-coated aluminum can, valve-sealed, filled, ultrasonicated for 10 minutes, and then kept for 2 days for testing. The Anderson cascade impactor test results are shown in FIG. 3C.

TABLE-US-00005 TABLE 5 The Anderson cascade impactor test results of glycopyrronium bromide fine powder and indacaterol maleate coarse powder after being co-micronized by a jet mill at a pressure of 8 bar FPF of glycopyrronium FPF of indacaterol Formulation bromide (%) maleate (%) glycopyrronium bromide + 51.30 51.14 indacaterol maleate (5:1) glycopyrronium bromide + 55.91 56.32 indacaterol maleate (1:1) glycopyrronium bromide + 56.90 56.13 indacaterol maleate (1:5)

[0079] As shown in Table 5, as the proportion of glycopyrronium bromide decreases, the dispersibility of glycopyrronium bromide is significantly improved, and the Fine Particle Fraction is increased from 51.30% to 56.90%.

[0080] The Anderson test results in FIGS. 3A-3C show that for the aerosols prepared by co-micronizing glycopyrronium bromide fine powder/indacaterol maleate coarse powder at different ratios with a jet mill at a pressure of 8 bar, the degree of co-deposition of glycopyrronium bromide and indacaterol maleate is very high. Among them, the degree of co-deposition of the two active ingredients in each of the aerosols prepared with the mixture of the ratio of 5:1 and 1:1 is higher than that of the ratio of 1:5. This is mainly because the aerosol prepared from glycopyrronium bromide/indacaterol maleate with a ratio of 1:5 has a relatively large difference in the deposition rates of the two active ingredients on the stage plate 4, while the deposition rates on other plates are very similar.

EXAMPLE 4

[0081] 0.5 g glycopyrronium bromide coarse powder and 0.5 g indacaterol maleate coarse powder (1:1) were weighed and mixed manually for 10 minutes, and micronized at 10 bar. The API was then sealed and stored until use. 16 mg of the glycopyrronium bromide/indacaterol maleate mixture was weighed, and placed in a 14 mL FCP-coated aluminum can, valve-sealed, filled, ultrasonicated for 10 minutes, and then kept for 2 days for testing.

[0082] The pressure of the jet mill was decreased and the above steps were repeated, in order to investigate the effect of pressure (10 bar, 8 bar, 4 bar, 3 bar, 2 bar) on the particle size of the glycopyrronium bromide/indacaterol maleate mixture, the Fine Particle Fraction of glycopyrronium bromide and the degree of co-deposition of the two active ingredients.

TABLE-US-00006 TABLE 6 The particle size test results of the glycopyrronium bromide coarse powder and indacaterol maleate coarse powder mixture Airflow pressure D10 (μm) D50 (μm) D90 (μm) SPAN 10 bar  0.61 1.42 2.86 1.58 8 bar 0.62 1.68 3.58 1.76 4 bar 0.66 1.86 4.18 1.89 3 bar 0.67 2.31 6.35 2.46 2 bar 0.77 3.39 9.05 2.44

[0083] The particle size test results in Table 6 show that as the airflow pressure decreases, the particle size of the mixture increases, and the changes in D50, D90 and SPAN are the most significant.

TABLE-US-00007 TABLE 7 The Anderson cascade impactor test results of glycopyrronium bromide coarse powder and indacaterol maleate coarse powder mixture after being co-micronized by a jet mill at different pressures FPF of glycopyrronium FPF of indacaterol maleate Airflow pressure bromide (%) (%) 10 bar  56.31 58.31 8 bar 54.03 56.11 4 bar 46.20 48.13 3 bar 30.04 31.32 2 bar 14.33 12.50

[0084] The particle size test data and the Anderson cascade impactor test data in Table 6 and Table 7 show that as the airflow pressure increases, the particle size decreases, the dispersibility of glycopyrronium bromide increases, and the FPF increases.

[0085] The Anderson cascade impactor test results in FIGS. 4A-4E show that for the aerosols prepared by co-micronizing glycopyrronium bromide coarse powder/indacaterol maleate coarse powder (1:1) with a jet mill at different pressures from 2-10 bar, the degree of co-deposition of glycopyrronium bromide and indacaterol maleate is high. When the airflow pressure is 2 bar or 3 bar, the Fine Particle Fraction of the two active ingredients are very low. Therefore, the pressure of jet-mill micronization is at least 4 bar or more.

COMPARATIVE EXAMPLE 1

[0086] 20 mg micronized glycopyrronium bromide was precisely weighed and placed in a 14 mL FCP-coated aluminum can, valve-sealed, filled, ultrasonicated for 10 minutes, and then kept for 2 days for Anderson cascade impactor testing. The specific steps are shown above.

[0087] 4 mg micronized indacaterol maleate was precisely weighed and placed in a 14 mL FCP-coated aluminum can, valve-sealed, filled, ultrasonicated for 10 minutes, and then kept for 2 days for Anderson cascade impactor testing. The specific steps are shown above.

[0088] 20 mg micronized glycopyrronium bromide and 4 mg micronized indacaterol maleate (5:1) were precisely weighed and mixed manually for 10 minutes. The mixture was then placed in a 14 mL FCP-coated aluminum can, valve-sealed, filled, ultrasonicated for 10 minutes, and then kept for 2 days for Anderson cascade impactor testing. The test results are shown in FIG. 5.

TABLE-US-00008 TABLE 8 The Anderson cascade impactor test results of the inhalation aerosol prepared directly from micronized glycopyrronium bromide powder and indacaterol maleate powder FPF of glycopyrronium FPF of indacaterol Formulation bromide (%) maleate (%) glycopyrronium bromide 25.68 — indacaterol maleate — 45.66 glycopyrronium 28.48 38.50 bromide:indacaterol (5:1)

[0089] As evidenced by the data in Table 8, in the inhalation aerosol prepared directly from micronized glycopyrronium bromide powder and indacaterol maleate powder, the FPF of glycopyrronium bromide has increased from 25.68% of a single formulation to 28.48%, which is only an increase of 3%, and the dispersibility is still very poor. In contrast, the FPF of single indacaterol maleate is 45.66%, and the dispersibility is significantly higher than that of glycopyrronium bromide.

[0090] The Anderson test results in FIG. 5 show that the degree of co-deposition of glycopyrronium bromide and indacaterol maleate is very low. In FIG. 5, the ordinate is the deposition rate of the two active ingredients, and the abscissa is the number of each ACI stage plate.

[0091] The above are only the preferred embodiments of the present application, so that those skilled in the art can understand or implement the invention of the present application. Various modifications and combinations of these embodiments will be obvious to those skilled in the art, and the general principles defined in this document. can be implemented in other embodiments without departing from the spirit or scope of the present application. Therefore, this application will not be limited to the embodiments shown in this document, but should conform to the widest scope consistent with the principles and novel features disclosed in this document.

[0092] The above are only preferred embodiments of the present invention, and do not limit the present invention in any form. Although the present invention has been disclosed as above in preferred embodiments, it is not intended to limit the present invention. Any person familiar with the art, without departing from the scope of the technical solution of the present invention, should be able to use the technical content disclosed above to make some changes or modifications into equivalent embodiments with equivalent changes. Any simple amendments, equivalent changes and modifications made to the above embodiments based on the technical essence of the present invention without departing from the technical solutions of the present invention still fall within the scope of the technical solutions of the present invention.