A kind of revenacin inhalation solution and preparation method

Abstract

The present invention provides a refenacin inhalation solution and a preparation method thereof, wherein the refenacin inhalation solution comprises refenacin at a concentration of 130-180 μg / ml, a buffer stabilizer at a concentration of 5-18 mM, a stabilizer at a concentration of 1.8-3.2 g / L, and a solvent, and the solution pH is 4.9-5.2, and the stabilizer is at least one of sodium gluconate, L-fucose, and acetylcysteine. The present invention can significantly improve the stability of the refenacin inhalation solution under ultrasonic atomization, has good storage stability, and has a better lung deposition rate effect; the preparation process is simple to operate and has low production cost, and is easy to industrialize.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and in particular to a revenacin inhalation solution and a preparation method thereof. Background Art

[0002] Chronic obstructive pulmonary disease (COPD) is a common chronic disease characterized by chronic bronchitis and / or emphysema with airflow obstruction, which can further develop into cor pulmonale and respiratory failure. With the worsening of environmental pollution and population aging, the number of COPD patients has increased year by year. By 2020, COPD ranked third in the global disease impact. Currently, clinical drugs mainly include long-acting β2-receptor agonists (LABA), long-acting anticholinergic drugs (LAMA) and steroid hormones, all of which are administered locally in the lungs, with good efficacy and safety.

[0003] Refenacin is a long-acting muscarinic antagonist that inhibits the tracheal contraction caused by the release of acetylcholine from parasympathetic nerve terminals by binding to the M3 muscarinic receptors on bronchial smooth muscle. The current commercially available product is a refenacin solution for inhalation, with the trade name Yupelri, with a specification of 3ml: 175μg. It needs to be nebulized for 8 minutes each time and the lung deposition rate is only 10% to 20%. To this end, the Chinese patent application number 202311654702.7 discloses a refenacin inhalation spray and a preparation method thereof, including the active ingredient refenacin or its trihydrate or a pharmaceutically acceptable salt thereof, an osmotic pressure regulator, a buffer stabilizer, an antibacterial agent, a stabilizer and a solvent; in the inhalation spray, the active ingredient content is 0.04% to 0.8%, the antibacterial agent content is 0.2% to 0.5%, and the stabilizer content is 0.2% to 0.5%, based on the mass volume ratio. This solution can significantly increase the lung deposition rate and shorten the nebulization time, but crystallization may occur if left at 5°C for more than 10 days, resulting in large fluctuations in the final efficacy; and the inhalation of inorganic ions contained in the osmotic pressure regulator in the prescription will increase the burden on the lungs.

[0004] In view of this, the present invention is proposed. Summary of the invention

[0005] The problem solved by the present invention is that the existing refenacin inhalation solution is degraded under ultrasonic atomization conditions; another problem solved by the present invention is that the existing refenacin inhalation solution has a low lung deposition rate and a low active ingredient concentration, resulting in a long atomization time.

[0006] To solve the above problems, the present invention provides a refenacin inhalation solution, which comprises refenacin with a concentration of 130-180 μg / ml, a buffer stabilizer with a concentration of 5-18 mM, a stabilizer with a concentration of 1.8-3.2 g / L and a solvent, the solution pH is 4.9-5.2, and the stabilizer is sodium gluconate and / or L-fucose.

[0007] Preferably, the stabilizer is composed of acetylcysteine, sodium gluconate, and L-fucose in a weight ratio of 1:2-4:0.2-0.8. Preferably, the stabilizer is composed of acetylcysteine, sodium gluconate, and L-fucose in a weight ratio of 1:2.2-3.8:0.3-0.7 or 1:2.5-3.5:0.4-0.6 or 1:2.8-3.2:0.4-0.6. Preferably, the stabilizer is composed of sodium gluconate and L-fucose in a weight ratio of 1:3:0.5.

[0008] Preferably, the inhalation solution further comprises a pH adjuster, and the pH adjuster is hydrochloric acid or sodium hydroxide.

[0009] Preferably, the solvent is selected from one of drinking water, purified water or water for injection. Preferably, the buffer stabilizer is composed of citric acid and sodium citrate. The applicant found that, completely different from other buffer systems, by using citric acid and sodium citrate, especially controlling the total concentration of citric acid and sodium citrate within 5mM to 18mM, not only can the pH value of the inhaled solution be stabilized at 4.9 to 5.2, but also the influence of impurities and environmental factors in the API on the preparation can be effectively reduced, so that the drug is stable during storage and the growth rate of related substances is slowed down.

[0010] Preferably, the inhalation solution further comprises a penetration enhancer in an amount of 1.5-3.0%. The inhalation solution further comprises a penetration enhancer in an amount of 1.8-2.7% or 1.5-2.5%. Preferably, the content of the penetration enhancer is 2.5%. Preferably, the penetration enhancer is any one of phospholipids, rhamnolipids, octyl maltoside, and threonine.

[0011] The present invention also provides a preparation method of refenacin inhalation solution, comprising the following steps: S1, adding 80-90% of injection water to a prescribed amount of buffer stabilizer and stirring until completely dissolved, then adding a prescribed amount of stabilizer and refenacin and stirring to dissolve for 15-30 minutes; S2, adding the remaining amount of injection water after nitrogen filling, and adjusting the pH value to 4.96-5.12 with hydrochloric acid and sodium hydroxide; S3, sequentially coarse filtering through a 0.45 μm filter membrane and fine filtering through a 0.22 μm filter membrane to obtain a filtrate; S4, packaging the filtrate obtained in S3 by a blowing-sealing-filling integrated process to obtain the filtrate.

[0012] Preferably, step S1 comprises: S11, heating 80-90% of the water for injection to 48-54°C, then adding the prescribed amount of buffer stabilizer and stirring until completely dissolved; S12, adding L-fucose and stirring to dissolve, then adding refenacin and stirring for 25-40min, then adding the remaining raw materials and nitrogen filling, and then slowly cooling to room temperature at a rate of 4-6°C / h. Due to the low solubility of refenacin, the dissolution time at room temperature is long and the amount of residual oxygen in the inhaled solution increases, resulting in poor long-term storage stability; the applicant unexpectedly found that when L-fucose was added first and then refenacin, the dissolution rate of refenacin at high temperature was accelerated, probably because refenacin combined with L-fucose to form hydrogen bonds; and when the heating temperature was further increased, the impurity content would increase and affect the quality and safety of the final product.

[0013] Compared with the prior art, the refenacin inhalation solution and preparation method described in the embodiments of the present invention have the following beneficial effects: 1) the applicant unexpectedly discovered that refenacin is degraded under ultrasonic atomization mode; by optimizing the stabilizer, the stabilizer formed by acetylcysteine, sodium gluconate and L-fucose in proportion can significantly improve the stability of the refenacin inhalation solution under ultrasonic atomization; 2) by adding a specific penetration enhancer, the lung deposition rate of the inhalation solution can be significantly increased without causing adverse reactions; 3) by the addition sequence of the preparation method of the present invention and controlling the temperature of the solvent in the preparation process, the content of impurities in the solution preparation can be well reduced; the operation is simple and the production cost is low, and it is easy to industrialize. DETAILED DESCRIPTION

[0014] In order to make the above-mentioned objects, features and advantages of the present invention more obvious and easy to understand, the specific embodiments of the present invention are described in detail below. The technical features in the embodiments of the present invention can be combined with each other without conflict.

[0015] The experimental methods in the following examples without specifying specific conditions are usually carried out under conventional conditions or under conditions recommended by the manufacturer. Unless otherwise specified, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art.

[0016] As the world's first once-daily inhaled lung-selective long-acting anticholinergic drug, revifenacin can significantly increase FEV1 and has good overall tolerability. It is currently one of the first choice drugs for the treatment of COPD. Although the inhalation spray has a small dosage volume and a significantly higher lung deposition rate, the inhalation solution is currently the only marketed dosage form of revifenacin because crystallization may occur after being placed at low temperatures for 10 days, resulting in product instability and large fluctuations in efficacy. In addition, revifenacin has poor water solubility, and how to increase the concentration of revifenacin and improve its stability is a research and development focus. The single nebulization time of the commercially available product Yupelri is 8 minutes, and there are no reports on the stability of revifenacin in the ultrasonic nebulization process; and the spray usually uses the pressure of a manual pump to spray the drug solution into a mist, which does not involve an ultrasonic nebulization process at all. To this end, the applicant proposes the following technical solution:

[0017] Example 1

[0018] A refenacin inhalation solution is composed of the following raw materials:

[0019]

[0020] Prepared by the following method:

[0021] S1. Take 90% of the water for injection and add the prescribed amount of buffer stabilizer and stir until completely dissolved; S2. Add the prescribed amount of stabilizer and revenacin to the above solution and stir to dissolve for 30 minutes. After nitrogen filling, add the remaining amount of water for injection and adjust the pH value to 4.96 with hydrochloric acid and sodium hydroxide; S3. Coarse filter through a 0.45μm filter membrane and fine filter through a 0.22μm filter membrane in sequence to obtain a filtrate; S4. Use a blowing-sealing-filling integrated process to package the filtrate obtained in S3.

[0022] Example 2

[0023] A refenacin inhalation solution is composed of the following raw materials:

[0024]

[0025]

[0026] Prepared by the following method:

[0027] S1. Heat 85% of the water for injection to 55°C, then add the prescribed amount of buffer stabilizer and stir until completely dissolved; S2. Add the prescribed amount of stabilizer and revenacin to the above solution and stir to dissolve for 25 minutes. After nitrogen filling, slowly cool to room temperature at a rate of 6°C / h, add the remaining amount of water for injection, and then adjust the pH value to 5.05 with hydrochloric acid and sodium hydroxide; S3. Coarse filter through a 0.45μm filter membrane and fine filter through a 0.22μm filter membrane in sequence to obtain a filtrate; S4. Use a blow-seal-fill integrated process to package the filtrate obtained in S3.

[0028] Example 3

[0029] A refenacin inhalation solution is composed of the following raw materials:

[0030]

[0031] Prepared by the following method:

[0032] S1. Heat 95% of the water for injection to 53°C, then add the prescribed amount of buffer stabilizer and stir until completely dissolved; S2. Add the prescribed amount of L-fucose to the above solution and stir to dissolve, then add the prescribed amount of revenacin and sodium gluconate and continue stirring for 15 minutes. After nitrogen filling, slowly cool to room temperature at a rate of 5.5°C / h, add the remaining amount of water for injection, and then adjust the pH value to 5.12 with hydrochloric acid and sodium hydroxide;

[0033] S3, coarse filtration through a 0.45 μm filter membrane and fine filtration through a 0.22 μm filter membrane in sequence to obtain a filtrate; S4, packaging the filtrate obtained in S3 using a blowing-sealing-filling integrated process to obtain the product.

[0034] Example 4

[0035] A refenacin inhalation solution is composed of the following raw materials:

[0036]

[0037] Prepared by the following method:

[0038] S1. Heat 95% of the water for injection to 48°C, then add the prescribed amount of buffer stabilizer and stir until completely dissolved; S2. Add the prescribed amount of L-fucose to the above solution and stir to dissolve, then add the prescribed amount of revenacin and sodium gluconate and stir to dissolve for 30 minutes, slowly cool to room temperature at a rate of 5.5°C / h after nitrogen filling, add the remaining amount of water for injection to the required volume; S3. Coarse filter through a 0.45μm filter membrane and fine filter through a 0.22μm filter membrane in sequence to obtain a filtrate; S4. Use the blow-seal-fill integrated process to package the filtrate obtained in S3.

[0039] Example 5

[0040] A refenacin inhalation solution is composed of the following raw materials:

[0041]

[0042] Prepared by the following method:

[0043] S1. Heat 90% of the water for injection to 52°C, then add the prescribed amount of buffer stabilizer and stir until completely dissolved; S2. Add the prescribed amount of L-fucose to the above solution and stir to dissolve, then add the prescribed amount of revenacin, sodium gluconate and acetylcysteine ​​and stir to dissolve for 30 minutes, slowly cool to room temperature at a rate of 4.8°C / h after nitrogen filling, add the remaining amount of water for injection to the required volume; S3. Coarse filter through a 0.45μm filter membrane and fine filter through a 0.22μm filter membrane in sequence to obtain a filtrate; S4. Package the filtrate obtained in S3 using a blow-seal-fill integrated process to obtain the result.

[0044] Example 6

[0045] A refenacin inhalation solution is composed of the following raw materials:

[0046]

[0047]

[0048] Prepared by the following method:

[0049] S1. Heat 88% of the water for injection to 51°C, then add the prescribed amount of buffer stabilizer and stir until completely dissolved; S2. Add the prescribed amount of L-fucose to the above solution and stir to dissolve, then add the prescribed amount of revenacin, sodium gluconate and acetylcysteine ​​and stir to dissolve for 45 minutes, slowly cool to room temperature at a rate of 4.5°C / h after nitrogen filling, add the remaining amount of water for injection to the required volume; S3. Coarse filter through a 0.45μm filter membrane and fine filter through a 0.22μm filter membrane in sequence to obtain a filtrate; S4. Package the filtrate obtained in S3 using a blow-seal-fill integrated process to obtain the result.

[0050] Comparative Example 1

[0051] Commercially available product, trade name Yupelri.

[0052] Comparative Example 2

[0053] The revenacin inhalation solution was prepared by the method of Example 1 in Publication No. CN11777122A.

[0054] Comparative Example 3

[0055] The same preparation process as in Example 1 was used, the only difference being that the concentration of the buffer stabilizer was 40 mM.

[0056] Experimental Example 1 Stabilizer Screening

[0057] In the experiment, the applicant connected the outlet of the ultrasonic nebulizer with the chamber by a pipe to perform constant volume ultrasonic nebulization, and unexpectedly found that the total impurity content in the commercially available refenacin inhalation solution increased significantly after a long period of ultrasonic nebulization (power 2500KHz), and the results are shown in Table 1. The specific detection method of the total impurity content of refenacin is the existing technology.

[0058] Table 1 Ultrasonic atomization stability results

[0059] time 0min 20min 40min 60min 90min Total impurity content% 0.12 0.15 0.17 0.25 0.36

[0060] To this end, the applicant screened stabilizers to improve the stability of revenacin under ultrasonic atomization, and used the prescription dosage and production process of Example 1 and the stabilizers in Table 2 to prepare the inhalation solution. The total impurity content was detected after ultrasonic atomization for 90 minutes under the same conditions.

[0061] Table 2 Effect of stabilizer on ultrasonic atomization

[0062] type Total impurity content% type Total impurity content% Sodium Gluconate 0.19 Vitamin C 0.35 L-fucose 0.23 Edetate Disodium 0.31 Sodium Thiosulfate 0.41 Acetylcysteine 0.27 Sodium sulfite 0.33 Sodium bisulfite 0.34

[0063] Currently, there are three commonly used nebulizers: jet nebulizer, vibrating mesh nebulizer and ultrasonic nebulizer. For ultrasonic nebulizer, not all stabilizers can improve the stability of refenacin under ultrasonic nebulization. Only sodium gluconate and L-fucose can effectively control the total impurity content in the inhaled solution within 90 minutes of ultrasonic nebulization, and effectively improve the stability of refenacin under ultrasonic nebulization.

[0064] On this basis, the applicant studied the stability of inhalation solutions of L-fucose and sodium gluconate alone and in combination under ultrasonic atomization, adopted the prescription dosage and production process of Example 1, used the stabilizer in Table 3 to prepare inhalation solutions P1-P5, and detected relevant impurities during ultrasonic atomization for 90 minutes.

[0065] Table 3 Effect of stabilizers on the stability of inhalation solutions

[0066]

[0067]

[0068] It can be seen from Table 3 that when the weight ratio of acetylcysteine, sodium gluconate and L-fucose is 1:3:0.5, the stability of the revenacin inhalation solution under ultrasonic atomization conditions is optimal.

[0069] Experimental Example 2 Study on atomization performance

[0070] The applicant prepared an inhalation solution using the penetration enhancer in Table 4 based on the prescription and preparation process of Examples 1 and 2, respectively. The penetration enhancer in the inhalation solution was 0.25%. After being assembled with the inhalation device, the aerodynamic particle size distribution (APSD) of the spray droplets was tested by simulating the human respiratory tract structure using a new generation cascade impactor (NGI) according to the method for determining the aerodynamic characteristics of fine particles of inhalation preparations in Part IV 0951 of the 2020 edition of the Chinese Pharmacopoeia, and approximately evaluating the deposition efficiency of drug particles in the lungs.

[0071] Table 4 Effect of penetration enhancers on spray droplets

[0072]

[0073] As can be seen from the above table, surfactants as penetration enhancers can reduce the surface tension of the solution, help reduce the particle size of the droplets after atomization, and even increase the delivery efficiency. When octyl maltoside or rhamnolipid is used as a penetration enhancer, the atomized particle size of the refenacin inhalation solution can be made more uniform and concentrated, and the generated aerosol particles are conducive to the attachment of droplets, effectively improving the lung deposition rate; at the same time, it was unexpectedly found that when octyl maltoside is used in combination with L-fucose, L-fucose can promote the attachment of droplets to the alveoli, avoiding some particles from being exhaled out of the body due to random movement, which can further significantly improve the lung deposition rate of atomized particles.

[0074] On this basis, the applicant was able to optimize the use of octyl maltoside based on Example 2, and the results are shown in Table 5.

[0075] Table 5 Effect of the dosage of octyl maltoside on spray droplets

[0076]

[0077]

[0078] As shown in Table 5, the median particle size of the droplets gradually decreases with the increase of the content of octyl maltoside, while the delivery efficiency and fine particle fraction (FPF) gradually increase with the increase of the content of octyl maltoside. When the content of octyl maltoside is higher than 0.25%, the above indicators basically do not change. Therefore, the content of octyl maltoside is 0.25%.

[0079] The refenacin inhalation solutions prepared in Examples 1-4, the commercially available preparations in Comparative Example 1, and the refenacin spray in Comparative Example 2 were tested for lung deposition rate (FPF). The total impurity content of the preparations was tested after accelerated treatment (40° C., RH 75%) for 6 months. The results are shown in Table 6.

[0080] Table 6 Stability data

[0081]

[0082] It can be seen from the above table that the refenacin inhalation solutions prepared in Examples 1-4 of the present invention have good storage stability, and also have better stability in ultrasonic spray mode, which is significantly better than commercially available preparations; when octyl maltoside is used as a penetration enhancer in Example 4, the aerodynamic particle size distribution (APSD) of the atomized droplets is also significantly better than the commercially available preparation, and the relevant parameters are basically equivalent to those of Comparative Example 2; at the same time, the applicant placed the refenacin inhalation solutions prepared in Examples 1-4 at 4°C for 30 days, and there was no crystallization phenomenon, while Comparative Example 2 had visible foreign matter under the same conditions, and the appearance was unqualified, which could not meet the storage and atomization requirements of clinical drugs.

[0083] Although the present invention is disclosed as above, the present invention is not limited thereto. Any person skilled in the art can make various changes and modifications without departing from the spirit and scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the scope defined by the claims.

Claims

1. A revenacin inhalation solution, characterized in that: The inhalation solution comprises 130-180 μg / ml of revenacin, 5-18 mM of a buffer stabilizer, 1.8-3.2 g / L of a stabilizer and a solvent, the pH of the solution is 4.9-5.2, the stabilizer is at least one of sodium gluconate, L-fucose and acetylcysteine, the solvent is selected from one of drinking water, purified water or water for injection, and the buffer stabilizer consists of citric acid and sodium citrate.

2. The revenacin inhalation solution according to claim 1, characterized in that The stabilizer is composed of acetylcysteine, sodium gluconate and L-fucose in a weight ratio of 1:2-4:0.2-0.

8.

3. The revenacin inhalation solution according to claim 1, characterized in that The inhalation solution further comprises a pH adjuster, and the pH adjuster is hydrochloric acid or sodium hydroxide.

4. The revenacin inhalation solution according to claim 1, characterized in that The inhalation solution further comprises a penetration enhancer at a concentration of 0.25%, wherein the penetration enhancer is any one of phospholipids, rhamnolipids, octyl maltoside, and threonine.

5. The method for preparing the revenacin inhalation solution according to any one of claims 1 to 4, characterized in that: The method comprises the following steps: S1, taking 80-90% of the water for injection, adding the prescribed amount of buffer stabilizer, stirring until completely dissolved, and then adding the prescribed amount of stabilizer and revenacin, stirring and dissolving for 15-30 minutes; S2, adding the remaining amount of water for injection after nitrogen filling, and adjusting the pH value to 4.96-5.12 with hydrochloric acid and sodium hydroxide; S3, sequentially coarse filtering through a 0.45 μm filter membrane and fine filtering through a 0.22 μm filter membrane to obtain a filtrate; S4, adopting a blowing-sealing-filling integrated process to package the filtrate obtained in S3 to obtain the product.

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