Revivenacin inhalation solution and preparation method thereof

Abstract

The invention relates to a revienacin inhalation solution and a preparation method thereof. The revienacin inhalation solution comprises revienacin, a stabilizing agent, a buffering agent and water for injection, wherein the stabilizer is disodium edetate and propylene glycol, and the mass volume ratio of the disodium edetate to the propylene glycol is (0.05-0.1) g: (50-300) ml. The revivin inhalation solution can effectively delay degradation of revivin under the high-temperature condition, the long-term stability of a preparation under the high-temperature condition is guaranteed, the preparation prescription and the preparation process are simple and easy to operate, and the revivin inhalation solution is suitable for large-scale industrial production.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulation technology, and in particular to a revinapine inhalation solution and its preparation method. Background Technology

[0002] Revinalcin is a long-acting muscarinic antagonist (LAMA) administered once daily for the maintenance treatment of chronic obstructive pulmonary disease. The structural formula of Revinalcin is as follows:

[0003]

[0004] Its molecular structure contains several unstable groups: 1) Aryl carbamates: relatively sensitive to base-induced / acid-induced hydrolysis, especially under alkaline conditions; high temperature and high humidity can accelerate the cleavage, generating corresponding aniline / alcohol fragments; 2) Tertiary amine sites: readily undergo metal / peroxide-catalyzed N-oxidation in solution, and may also participate in autocatalytic cleavage under alkaline conditions; 3) Aromatic biphenyls: sensitive to ultraviolet light, and may undergo photo-oxidation / photo-rearrangement; 4) Amides: tertiary amides and terminal amides are generally stable, but will slowly hydrolyze under strong base / strong acid or high temperature.

[0005] Chinese patent CN119112787A discloses a refennaxine soft spray and its preparation method, comprising refennaxine, a pH adjuster, a stabilizer, and a solvent. The stabilizers are PVP and sodium gluconate. In the formulation, PVP and sodium gluconate mainly play a role in adjusting osmotic pressure and solution viscosity, and do not help the chemical stability of the API, nor have a significant impact on the long-term stability of the formulation.

[0006] Chinese patent CN117771222A discloses a refennax inhalation spray and its preparation method, comprising refennax or its trihydrate or a pharmaceutically acceptable salt thereof, an osmotic pressure regulator, a pH regulator, an antibacterial agent, a stabilizer, and a solvent. The antibacterial agent is chlorobutanol, and the stabilizer is PVP. In addition to the stabilizers and pH regulators commonly used in sprays, this patent also adds an antibacterial agent, which may increase the burden on the lungs. The use of PVP as a stabilizer mainly serves to adjust the viscosity of the solution and has little impact on the long-term stability of the formulation under high temperature conditions.

[0007] Chinese patent CN118750472A discloses a refennaxine inhalation solution and its preparation method, comprising refennaxine, a buffer, a stabilizer, and a solvent. The stabilizer is at least one of sodium gluconate, L-fucose, and acetylcysteine. However, these stabilizers have little effect on the chemical stability of the API and cannot improve the long-term stability of the formulation under high temperature conditions.

[0008] In existing technologies, stabilizers primarily function to adjust osmotic pressure and solution viscosity, offering no benefit to the chemical stability of APIs. Even at the end of the stability period, total impurities remain as high as approximately 1%, thus necessitating further improvements in the long-term stability of formulations. Summary of the Invention

[0009] The purpose of this invention is to overcome the shortcomings of the prior art and provide a revinapine inhalation solution that can delay the degradation of revinapine under high temperature conditions and ensure the long-term stability of the formulation under high temperature conditions.

[0010] This invention is achieved through the following technical solution:

[0011] A revinapine inhalation solution, the inhalation solution comprising revinapine, a stabilizer, a buffer, and water for injection; wherein the stabilizer is disodium edetate and propylene glycol, and the mass-to-volume ratio of disodium edetate and propylene glycol is 0.05-0.1g:50-300ml.

[0012] Preferably, the mass ratio of the stabilizer to the buffer is 16-120:1.

[0013] Preferably, the buffer is citric acid and sodium citrate.

[0014] Preferably, the mass ratio of citric acid to sodium citrate is 1:2.8-4.6.

[0015] Preferably, each 1000 ml of the inhalation solution contains: 0.05-0.07 g of revinnacin, 0.5-0.7 g of citric acid, 2.0-2.3 g of sodium citrate, 50-300 ml of propylene glycol, 0.05-0.1 g of disodium edetate, and the remainder is water for injection.

[0016] Preferably, the pH value of the solution is 4.5-5.5.

[0017] A method for preparing the above-described revinapine inhalation solution includes the following steps:

[0018] S1. Add 80%-90% of the prescribed amount of water for injection to the mixing tank and pretreat it;

[0019] S2. Add buffer and stabilizer to the pretreated water for injection, stir to dissolve, and finally add revinapine, stir until dissolved, and add water for injection to make up the volume to obtain the drug solution.

[0020] S3. Filter the obtained liquid through a filter membrane, fill it into glass ampoules, fill with nitrogen and seal it to obtain the product;

[0021] S4. Sterilize the obtained product in a water bath sterilizer.

[0022] Preferably, in step S1, the pretreatment of the water for injection involves cooling it to 50-60°C and purging it with nitrogen to reduce the dissolved oxygen content to below 1 mg / L.

[0023] Preferably, in step S3, the pore size of the filter membrane is 0.45 μm and 0.22 μm.

[0024] Preferably, in step S3, the filling temperature is 20-30°C.

[0025] Preferably, in step S3, the oxygen content of the headspace portion of the nitrogen-filled ampoule is ≤2%.

[0026] Preferably, in step S4, the temperature of the autoclaving sterilization is 121°C and the sterilization time is 12-15 min.

[0027] Disodium edetate efficiently chelates trace metal ions, interrupting the initiation and propagation of metal / peroxide-catalyzed N-oxidation and free radical chain reactions at tertiary amine sites, thus reducing the probability of oxygen-containing degradation pathways. Propylene glycol, as a co-solvent, lowers the dielectric constant and water activity of the system, reduces the hydrolysis driving force of aryl carbamate groups, and inhibits breakage and transformation at high temperatures. This invention utilizes continuous nitrogen sealing with dissolved oxygen ≤2% for filling and autoclaving at 121°C. Propylene glycol / disodium edetate exhibit a synergistic effect in the low-oxygen, low-metal environment: disodium edetate removes metal / peroxides, while propylene glycol lowers the highly polar aqueous phase, simultaneously restricting multiple potential degradation pathways and resulting in stability exceeding expectations.

[0028] The beneficial effects of this invention are:

[0029] This invention uses disodium edetate and propylene glycol as stabilizers, and limits their mass-to-volume ratio, which can effectively delay the degradation of revinapine under high temperature conditions, ensuring the long-term stability of the formulation under high temperature conditions. Experiments show that revinapine inhalation solution, after being placed at 60°C for 30 days, can control the total impurities to below 0.505%.

[0030] In the preparation method of the present invention, the dissolved oxygen of the drug solution is reduced to below 1 mg / L during the solution preparation stage, thereby eliminating oxidation inside the drug solution. During the filling stage, the oxygen content of the headspace of the ampoule is ≤2%, creating an oxygen-free storage environment for the product and improving the long-term stability of the formulation under high temperature conditions.

[0031] The formulation and preparation process of this invention are simple and easy to operate, and are suitable for large-scale industrial production. Detailed Implementation

[0032] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the embodiments. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0033] Unless otherwise specified in the examples, the procedures should be performed under standard conditions or conditions recommended by the manufacturer. Reagents or instruments whose manufacturers are not specified are all commercially available products.

[0034] Example 1

[0035] Material composition 1000ml dosage Revinapine 0.05g Sodium edetate 0.05g Propylene glycol 50ml Citric acid 0.5g Sodium citrate 2.0g Water for Injection Adjust the volume to 1000ml headspace Nitrogen

[0036] Preparation method:

[0037] Add 80% of the prescribed volume of water for injection to the mixing tank, and continuously cool to 55°C under nitrogen purging. Once the dissolved oxygen level drops below 1 mg / L, add the prescribed volumes of citric acid, sodium citrate, and disodium edetate sequentially, stirring for 10 minutes to dissolve. Then add the prescribed volume of propylene glycol, stirring for 10 minutes to dissolve. Finally, add revinapine, stirring until completely dissolved, and then add water for injection to bring the volume to a final level. Cool the solution to 25°C, filter it through 0.45 μm and 0.22 μm microporous membranes, and fill it into 3 ml borosilicate glass ampoules. Purge with nitrogen to ensure the oxygen content in the headspace of the ampoules is ≤2%, and then flame seal at high temperature. Sterilize the sealed ampoules by autoclaving at 121°C for 12 minutes.

[0038] Example 2

[0039] Material composition 1000ml dosage Revinapine 0.06g Sodium edetate 0.05g Propylene glycol 100ml Citric acid 0.63g Sodium citrate 2.12g Water for Injection Adjust the volume to 1000ml headspace Nitrogen

[0040] Prepared using the following method:

[0041] Add 80% of the prescribed volume of water for injection to the mixing tank, and continuously cool to 55°C under nitrogen purging. Once the dissolved oxygen level drops below 1 mg / L, add the prescribed volumes of citric acid, sodium citrate, and disodium edetate sequentially, stirring for 10 minutes to dissolve. Then add the prescribed volume of propylene glycol, stirring for 10 minutes to dissolve. Finally, add revinapine, stirring until completely dissolved, and then add water for injection to bring the volume to a final level. Cool the solution to 25°C, filter it through 0.45 μm and 0.22 μm microporous membranes, and fill it into 3 ml borosilicate glass ampoules. Purge with nitrogen to ensure the oxygen content in the headspace of the ampoules is ≤2%, and then flame seal at high temperature. Sterilize the sealed ampoules by autoclaving at 121°C for 12 minutes.

[0042] Example 3

[0043] Material composition 1000ml dosage Revinapine 0.07g Sodium edetate 0.1g Propylene glycol 300ml Citric acid 0.7g Sodium citrate 2.3g Water for Injection Adjust the volume to 1000ml headspace Nitrogen

[0044] Prepared using the following method:

[0045] Add 80% of the prescribed volume of water for injection to the mixing tank, and continuously cool to 55°C under nitrogen purging. Once the dissolved oxygen level drops below 1 mg / L, add the prescribed volumes of citric acid, sodium citrate, and disodium edetate sequentially, stirring for 10 minutes to dissolve. Then add the prescribed volume of propylene glycol, stirring for 10 minutes to dissolve. Finally, add revinapine, stirring until completely dissolved, and then add water for injection to bring the volume to a final level. Cool the solution to 25°C, filter it through 0.45 μm and 0.22 μm microporous membranes, and fill it into 3 ml borosilicate glass ampoules. Purge with nitrogen to ensure the oxygen content in the headspace of the ampoules is ≤2%, and then flame seal at high temperature. Sterilize the sealed ampoules by autoclaving at 121°C for 12 minutes.

[0046] Comparative Examples 1-7

[0047] The control group was prepared using the same method, and the formulation is as follows:

[0048]

[0049]

[0050] The influencing factors of the Revinapine inhalation solutions prepared in Examples 1-3 and Comparative Examples 1-7 of this invention were investigated, including high temperature conditions (60℃±2℃), storage for 10 and 30 days, and light conditions (visible light 5500lx±500lx, near-ultraviolet 90μw / cm). 2 After being placed for 10 days, the results of the observation are as follows:

[0051] Results of the investigation in Examples 1-3

[0052]

[0053] Comparative results of Examples 1-7

[0054]

[0055] Results analysis:

[0056] As shown in the table above, the revinapine inhalation solutions prepared in Examples 1-3 of this invention have good stability. Comparative Examples 2 and 3, after being stored at high temperature for 30 days, had total impurities as high as 1.093% and 1.059%, respectively. Comparative Examples 4-6, using PVP and / or sodium gluconate as stabilizers, still had total impurities exceeding 1% after 30 days under high temperature conditions. In Comparative Example 7, the mass-to-volume ratio of disodium edetate to propylene glycol was 0.1 g:400 ml. The increased amount of propylene glycol was detrimental to long-term stability under high temperature conditions; the total impurities after 30 days under high temperature conditions were still close to 1%, which does not meet the storage requirements for clinical drugs.

[0057] This invention effectively delays the degradation of revinnain under high temperature conditions, ensuring the long-term stability of the formulation under high temperature conditions.

[0058] Finally, it should be noted that the above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments or make equivalent substitutions for some of the technical features. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A revinapine inhalation solution, characterized in that, The inhalation solution comprises revinnacin, a stabilizer, a buffer, and water for injection; wherein the stabilizer is disodium edetate and propylene glycol, and the mass-to-volume ratio of disodium edetate and propylene glycol is 0.05-0.1g:50-300ml.

2. The revinapine inhalation solution according to claim 1, characterized in that, The mass ratio of the stabilizer to the buffer is 16-120:

1.

3. The revinapine inhalation solution according to claim 1, characterized in that, The buffer is citric acid and sodium citrate.

4. The revinapine inhalation solution according to claim 3, characterized in that, The mass ratio of citric acid to sodium citrate is 1:2.8-4.

6.

5. A method for preparing the revinapine inhalation solution as described in any one of claims 1-4, characterized in that, Includes the following steps: S1. Add 80%-90% of the prescribed amount of water for injection to the mixing tank and pretreat it; S2. Add buffer and stabilizer to the pretreated water for injection, stir to dissolve, and finally add revinapine, stir until dissolved, and add water for injection to make up the volume to obtain the drug solution. S3. Filter the obtained liquid through a filter membrane, fill it into glass ampoules, fill with nitrogen and seal it to obtain the product; S4. Sterilize the obtained product in a water bath sterilizer.

6. The method for preparing Revinapine inhalation solution according to claim 5, characterized in that, In step S1, the pretreatment of the water for injection involves cooling it to 50-60°C and purging it with nitrogen to reduce the dissolved oxygen content to below 1 mg / L.

7. The method for preparing Revinapine inhalation solution according to claim 5, characterized in that, In step S3, the pore size of the filter membrane is 0.45 μm and 0.22 μm.

8. The method for preparing Revinapine inhalation solution according to claim 5, characterized in that, In step S3, the filling temperature is 20-30℃.

9. The method for preparing Revinaprine inhalation solution according to claim 5, characterized in that, In step S3, the oxygen content of the headspace portion of the nitrogen-filled ampoule is ≤2%.

10. The method for preparing Revinapine inhalation solution according to claim 5, characterized in that, In step S4, the temperature for autoclaving is 121°C and the sterilization time is 12-15 minutes.

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