A kind of refenacin soft mist and preparation method thereof

Abstract

The invention provides a refenacin soft mist and a preparation method thereof, belonging to the technical field of pharmaceutical preparations. The refenacin soft mist comprises refenacin, a pH regulator, a stabilizer and a solvent, wherein the weight ratio of refenacin to the stabilizer is 2-4:1-5, and the stabilizer is PVP and sodium gluconate. The refenacin soft mist of the invention has good stability, a high fine particle fraction and a high delivery efficiency, and the preparation method is simple and easy to promote.

Description

Technical Field

[0001] The invention provides a revenacin soft mist and a preparation method thereof, belonging to the technical field of pharmaceutical preparations. Background Art

[0002] Revenacin is a long-acting muscarinic antagonist used for the maintenance treatment of patients with chronic obstructive pulmonary disease (COPD). It is administered via inhalation solution spray and can improve lung function, reduce clinical symptoms of COPD, and prevent further exacerbations of the disease.

[0003] The inhaled refenacin solution developed by Mylan is called Yupelri and has a specification of 3ml:175μg. The inhaled refenacin solution is a nebulized inhalation solution, which is nebulized by a jet nebulizer commonly used on the market and then inhaled orally. It is administered once a day, and each time the nebulization needs to be continued for 8 minutes and the delivery efficiency is low.

[0004] Chinese patent CN117205186A discloses a revenacin inhalation spray and a preparation method thereof. The proportion of fine particles smaller than 5 μm formed by the inhalation spray after atomization by a spray device is not less than 10%, and the particle size distribution of the spray droplets is uniform. However, in the stability test experiment, the impurity content is relatively high.

[0005] Chinese patent CN117771222B discloses a refenacin inhalation spray and a preparation method thereof, comprising an active ingredient refenacin or its trihydrate or a pharmaceutically acceptable salt thereof, an osmotic pressure regulator, a pH regulator, an antibacterial agent, a stabilizer and a solvent; wherein when the antibacterial agent is chlorobutanol, the pH regulator is citric acid or sodium citrate, and the stabilizer is PVP, the atomization time of the patent is short, but crystallization will occur if placed at 5°C for more than 10 days. In addition to the stabilizer and pH regulator commonly used in sprays, an antibacterial agent is also added, which may increase the burden on the lungs. Summary of the invention

[0006] In view of the problems existing in the prior art, the present invention provides a revenacin soft mist and a preparation method thereof, which has good stability, high fine particle fraction, high delivery efficiency and a simple preparation method that is easy to promote.

[0007] To achieve the above purpose, the technical solution adopted by the present invention is as follows:

[0008] On the one hand, the present invention provides a refenacin soft mist, comprising refenacin, a pH regulator, a stabilizer and a solvent; the weight ratio of the refenacin to the stabilizer is: 2-4:1-5; the stabilizer is PVP and sodium gluconate.

[0009] Specifically, the refenacin is refenacin or a pharmaceutically acceptable salt thereof.

[0010] Specifically, the refenacin soft mist comprises the following components by weight percentage: 0.2%-0.7% refenacin, 0.8%-2.5% pH adjuster, 0.5%-0.65% stabilizer and the remainder of solvent.

[0011] Preferably, the refenacin soft mist comprises the following components by weight percentage: 0.3%-0.6% refenacin, 0.9%-1.5% pH adjuster, 0.5%-0.65% stabilizer and the remainder solvent.

[0012] Specifically, the weight ratio of PVP to sodium gluconate is 1-6:2.

[0013] Preferably, the weight ratio of PVP to sodium gluconate is 2-3:1.

[0014] Preferably, the weight ratio of PVP to sodium gluconate is 3:1.

[0015] Specifically, the pH adjuster is one or more of disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium citrate, citric acid, sodium acetate and acetic acid.

[0016] Preferably, the pH adjuster is sodium citrate and citric acid.

[0017] Specifically, the solvent is water for injection.

[0018] Specifically, the pH value of the revenacin soft mist is 4-5.

[0019] Specifically, the particle size of the fine particles formed during aerosol administration is 1-8 μm.

[0020] In a second aspect, the present invention provides a method for preparing a refenacin soft mist, characterized in that it comprises the following steps:

[0021] (1) dissolving the stabilizer in part of the solvent to obtain solution 1;

[0022] (2) adding revenacin to the solution 1 of step (1) to obtain a solution 2;

[0023] (3) adding a pH adjuster to solution 2 of step (2) to adjust the pH value;

[0024] (4) Add the remaining solvent, filter, sterilize, and seal.

[0025] Specifically, the filter membrane used for filtration is 0.22 μm;

[0026] Specifically, the partial solvent in step (1) is 80%-90% by volume of the solvent.

[0027] Specifically, the pH value in step (3) is 4-5.

[0028] The beneficial effects of the present invention are:

[0029] (1) The present invention adjusts the ratio of refenacin to the stabilizer and the type and ratio of the stabilizer itself to make the refenacin soft mist have good stability and less impurities during storage.

[0030] (2) The present invention adjusts the ratio of revifenacin to the stabilizer and the type and ratio of the stabilizer itself to make the revifenacin soft mist have a high fine particle fraction and a high delivery efficiency. DETAILED DESCRIPTION

[0031] In order to make the purpose, technical scheme and advantages of the present invention more clearly understood, the present invention is described by the following specific embodiments, but is by no means limited thereto. The following are preferred embodiments of the present invention, which are only used to describe the present invention and cannot be understood as limiting the present invention. It should be pointed out that any modification, equivalent substitution and improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

[0032] 1. Examples and Comparative Examples

[0033] Preparation steps:

[0034] (1) Dissolve the stabilizer in 80% solvent;

[0035] (2) adding revenacin to the solution of step (1);

[0036] (3) adding a pH adjuster to the solution of step (2) until the pH of the solution is 4-5;

[0037] (4) Add the remaining solvent, filter, sterilize, and seal.

[0038] The compositions of Examples 1-3 and Comparative Examples 1-5 are shown in Table 1.

[0039] Table 1

[0040]

[0041] 2. Stability Test

[0042] Examples 1-3, Comparative Examples 1-5 and purchased Yupelri refenacin solution (hereinafter referred to as Yupelri) were placed at 60° C. for 10 days, and their impurity contents were tested.

[0043] Examples 1-3, Comparative Examples 1-5 and Yupelri were placed at 5° C. for 10 days to observe whether crystallization occurred.

[0044] The stability test results are shown in Table 2.

[0045] Table 2

[0046]

[0047] The weight ratio of revenacin and stabilizer in Comparative Example 1 is not within the scope of protection of the present application, and its stability is poor, the total impurity content increases, and it is easy to crystallize at low temperature. Comparative Examples 2-3 only use one stabilizer, and its stability is poor, the total impurity content increases, and it is easy to crystallize at low temperature. The weight ratio of PVP and sodium gluconate in Comparative Example 4 is not within the scope of protection of the present application, and its stability is poor, the total impurity content increases, and it is easy to crystallize at low temperature. Comparative Example 5 uses L-fucose and gluconic acid as stabilizers, and its stability is poor, the total impurity content increases, and it is easy to crystallize at low temperature. Although the stability of the commercially available preparation Yupelri is worse than that of the comparative example, it is not as good as Examples 1-3 of the present invention.

[0048] Examples 1-3 are within the scope of the present invention, have good stability, have little total impurities when placed at 60° C. for 10 days, and do not crystallize at low temperatures.

[0049] 3. Atomization index detection

[0050] The APSD of Examples 1-3, Comparative Examples 1-5 and Yupelri were tested. Referring to Part IV of the 2020 edition of the Chinese Pharmacopoeia, the aerodynamic characteristics of fine particles of inhaled preparations (General Rule 0951) were measured using a new generation cascade impactor (NGI) to simulate the structure of the human respiratory tract, and the fine particle fraction (FPF) and delivery efficiency were examined. The results are shown in Table 3.

[0051] Table 3

[0052]

[0053] The weight ratio of revenacin and stabilizer in Comparative Example 1 is not within the scope of protection of the present application, and its fine particle fraction is low and the delivery efficiency is low. Comparative Examples 2-3 only use one stabilizer, and its fine particle fraction is low and the delivery efficiency is low. The weight ratio of PVP and sodium gluconate in Comparative Example 4 is not within the scope of protection of the present application, and its fine particle fraction is low and the delivery efficiency is low. Comparative Example 5 uses other types of stabilizers in combination with sodium gluconate, but its fine particle fraction is low and the delivery efficiency is low. The fine particle fraction and delivery efficiency of the commercially available preparation Yupelri are not much different from those of the comparative examples, and the effect is not as good as that of Examples 1-3 of the present invention.

[0054] Examples 1-3 are within the scope of the present invention, having high fine particle fractions and high delivery efficiency.

[0055] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions of the technical solution of the present invention by ordinary technicians in this field do not deviate from the essence and scope of the technical solution of the present invention.

Claims

1. A refenacin soft spray, characterized in that: including refenacin, a pH adjuster, a stabilizer and a solvent; The weight ratio of revenacin to the stabilizer is: 2-4:1-5; The stabilizers are PVP and sodium gluconate; The refenacin soft mist comprises the following components, measured by weight percentage: 0.2%-0.7% refenacin, 0.8%-2.5% pH regulator, 0.5%-0.65% stabilizer and the remainder of solvent; The weight ratio of PVP to sodium gluconate is 1-6:2; The pH value of the refenacin soft mist is 4-5.

2. The refenacin soft spray according to claim 1, characterized in that The refenacin is refenacin or a pharmaceutically acceptable salt thereof.

3. The refenacin soft spray according to claim 1, characterized in that The invention comprises the following components by weight percentage: 0.3%-0.6% of refenacin, 0.9%-1.5% of a pH regulator, 0.5%-0.65% of a stabilizer and the remainder of a solvent.

4. The refenacin soft spray according to claim 1, characterized in that The pH regulator is one or more of sodium dihydrogen phosphate, sodium citrate, citric acid, sodium acetate and acetic acid; The solvent is water for injection.

5. The refenacin soft spray according to claim 1, characterized in that: The particle size of the fine particles formed during aerosol administration is 1-8μm.

6. The method for preparing the revenacin soft mist according to any one of claims 1 to 5, characterized in that: The steps include: (1) dissolving the stabilizer in part of the solvent to obtain solution 1; (2) adding revenacin to the solution 1 of step (1) to obtain a solution 2; (3) adding a pH adjuster to solution 2 of step (2) to adjust the pH value; (4) Add the remaining solvent, filter, sterilize, and seal.

7. The preparation method according to claim 6, characterized in that: The partial solvent in step (1) is 80%-90% by volume of the solvent.

8. The preparation method according to claim 6, characterized in that: The pH value of step (3) is 4-5.

Images