Rafenasin inhalation solution composition and preparation method thereof
By using buffer pairs and specific preparation methods, the problem of poor stability of ravenacin inhalation solution under light conditions is solved, achieving higher stability and safety, while reducing production costs.
Patent Information
- Application Number
- CN202510208162.2
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-02-25
- Publication Date
- 2025-05-13
AI Technical Summary
The existing ravenacin inhalation solution has poor stability under light conditions, especially after using stainless steel containers to dispense liquid, and there is a risk of microbial safety when commercially available products do not adopt sterilization process.
A more stable ravenacin inhalation solution is prepared by using a composition of ravenacin, a buffer pair (composed of acidic compounds such as phosphoric acid, acetic acid, boric acid, and their sodium salts), sodium chloride, hydrochloric acid or sodium hydroxide and water through specific preparation methods including stirring, filtration and humid heat sterilization processes.
It improves the stability of the inhaled solution of rafenacin, makes it tolerate excessive killing and sterilization, is more safe, and reduces production costs.
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Figure CN119970688A_ABST
Abstract
Description
Technical Field
[0001] The present invention relates to the technical field of pharmaceutical preparations, and in particular to a more stable refenacin inhalation solution composition and a preparation method thereof. Background Art
[0002] Revefacin inhalation solution is used for the maintenance treatment of chronic obstructive pulmonary disease. The current commercially available product is Revefacin inhalation solution produced by Mylan Pharmaceuticals in the United States, with the trade name Yupelri, the specification is 3ml:175μg, the packaging material is a low-density polyethylene bottle, the prescription composition is citric acid, sodium citrate, sodium chloride, hydrochloric acid or sodium hydroxide (for pH adjustment), and aseptic filling technology is used.
[0003] The study found that the stability of the above composition is poor under light conditions, and the stability is even worse after using stainless steel containers for liquid preparation. In addition, the inhalation solution specified in the Chinese Pharmacopoeia is a sterile preparation. According to the sterilization decision tree, the overkilling process should be the first choice, but the commercially available products do not use the sterilization process, which poses a microbial safety risk. Summary of the invention
[0004] The main purpose of the present invention is to provide a revfenacin inhalation solution composition and a preparation method thereof, aiming to solve the technical problem that in the prior art, non-metallic containers are required when producing revfenacin inhalation solution, resulting in poor stability of the preparation.
[0005] To achieve the above object, the present invention provides a refenacin inhalation solution composition, which is prepared from the following components: refenacin, buffer, sodium chloride, hydrochloric acid or sodium hydroxide, and water; Wherein, the acidic compound of the buffer pair is one or more of phosphoric acid, acetic acid, boric acid, gallic acid, cysteine, glycolic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, maleic acid, and benzoic acid.
[0006] Optionally, the molar concentration of the acidic compound of the buffer pair in the revenacin inhalation solution is 0.02-0.05 mol / L.
[0007] Optionally, the alkaline compound of the buffer pair is a sodium salt of an acidic compound, and the molar concentration of the sodium salt in the revenacin inhalation solution is 0.05-0.1 mol / L.
[0008] Optionally, the acidic compound of the buffer pair is one or more of boric acid, gallic acid, cysteine, glycolic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, maleic acid, and benzoic acid.
[0009] Optionally, the acidic compound of the buffer pair is one or more of gallic acid, cysteine, glycolic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, and maleic acid.
[0010] Optionally, the acidic compound of the buffer pair is one or more of succinic acid, fumaric acid, malic acid, tartaric acid, and maleic acid.
[0011] The present invention also provides a method for preparing the above-mentioned revenacin inhalation solution, which comprises the following steps: Take 80% of the prescribed amount of water for injection, add the prescribed amount of buffer and sodium chloride, and stir until completely dissolved to obtain the first solution; Adding a prescribed amount of refenacin to the first solution and stirring to dissolve the solution to obtain a second solution; Add hydrochloric acid or sodium hydroxide to the second solution to adjust the pH value to 4-6 to obtain a third solution; Add water to the third solution to the prescribed amount, and filter multiple times to obtain a filtrate; The filtrate is sealed in a polypropylene plastic ampoule or a glass ampoule and sterilized by a wet heat sterilization process to obtain a refenacin inhalation solution product.
[0012] Optionally, in the step of adding hydrochloric acid or sodium hydroxide to the second solution to adjust the pH value to 4-6 to obtain the third solution, the pH value of the third solution is 4.5-5.5.
[0013] Optionally, in the step of adding hydrochloric acid or sodium hydroxide to the second solution to adjust the pH value to 4-6 to obtain the third solution, the pH value of the third solution is 4.8-5.2.
[0014] Optionally, in the step of adding hydrochloric acid or sodium hydroxide to the second solution to adjust the pH value to 4-6 to obtain the third solution, the pH value of the third solution is 5.
[0015] Optionally, in the step of adding water to the third solution to a prescribed amount and filtering the solution multiple times to obtain a filtrate, the solution is coarsely filtered through a 0.45 μm filter membrane and finely filtered through a 0.22 μm filter membrane to obtain a filtrate; Optionally, the filtrate is sealed in a polypropylene plastic ampoule or a glass ampoule and sterilized by a moist heat sterilization process to obtain the revenacin inhalation solution product, wherein the parameters of the moist heat sterilization process are sterilization at 121° C. for 15 minutes.
[0016] In the technical solution of the present invention, the composition uses a buffer pair other than citric acid, which improves the stability of the solution, can withstand excessive killing and sterilization, has higher safety, and lowers the production cost. BRIEF DESCRIPTION OF THE DRAWINGS
[0017] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on the structures shown in these drawings without paying creative work.
[0018] Figure 1 The present invention is a schematic flow chart of an embodiment of a method for preparing a revenacin inhalation solution provided by the present invention.
[0019] The realization of the purpose, functional features and advantages of the present invention will be further explained in conjunction with embodiments and with reference to the accompanying drawings. DETAILED DESCRIPTION
[0020] To make the purpose, technical solution and advantages of the embodiments of the present invention clearer, the technical solution in the embodiments of the present invention will be described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them.
[0021] It should be noted that, in the embodiments, those without specifying specific conditions are carried out according to normal conditions or conditions recommended by the manufacturer. Those without specifying the manufacturer of reagents or instruments used are conventional products that can be purchased commercially. In addition, the meaning of "and / or" appearing in the full text includes three parallel schemes, and "A and / or B" is taken as an example, including schemes A, B, or A and B that meet the same time. In addition, the technical schemes between the various embodiments can be combined with each other, but must be based on the ability of ordinary technicians in the field to achieve. When the combination of the technical schemes is contradictory or cannot be achieved, it should be considered that the combination of such technical schemes does not exist, and is not within the scope of protection required by the present invention. Based on the embodiments in the present invention, all other embodiments obtained by ordinary technicians in the field without making creative work, all belong to the scope of protection of the present invention.
[0022] The stability of revenacin inhalation solution is poor under light conditions, and the stability is even worse after using stainless steel containers for preparation. In addition, the inhalation solution stipulated in the Chinese Pharmacopoeia is a sterile preparation. According to the sterilization decision tree, the overkilling process should be the first choice, but the commercially available products do not use the sterilization process, which poses a microbial safety risk.
[0023] In view of this, the present invention proposes a refenacin inhalation solution composition, which is prepared from the following components: refenacin, a buffer pair, sodium chloride, hydrochloric acid or sodium hydroxide, and water. Among them, the acidic compound of the buffer pair is one or more of phosphoric acid, acetic acid, boric acid, gallic acid, cysteine, glycolic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, maleic acid, and benzoic acid, and its molar concentration in the refenacin inhalation solution is 0.02~0.05mol / L; the alkaline compound of the buffer pair is the sodium salt of the above acid, and the molar concentration of the sodium salt in the refenacin inhalation solution is 0.05~0.1mol / L. Preferably, the acidic compound of the buffer pair is one or more of phosphoric acid, acetic acid, boric acid, gallic acid, cysteine, glycolic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, and maleic acid. More preferably, the acidic compound of the buffer pair is one or more of succinic acid, fumaric acid, malic acid, tartaric acid, and maleic acid.
[0024] The present invention also provides a method for preparing the above-mentioned revenacin inhalation solution, combining Figure 1 A schematic flow chart of an embodiment of a method for preparing a revenacin inhalation solution is provided, which comprises the following steps.
[0025] Step S10, taking 80% of the prescribed amount of water for injection, adding the prescribed amount of buffer solution and sodium chloride and stirring until completely dissolved to obtain a first solution.
[0026] In this embodiment, the injection water needs to be cooled to room temperature, and the buffer pair is a buffer pair, and one or more of phosphoric acid, acetic acid, boric acid, gallic acid, cysteine, glycolic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, maleic acid, and benzoic acid are selected.
[0027] Step S20, adding a prescribed amount of revenacin to the first solution and stirring to dissolve, to obtain a second solution.
[0028] Step S30, adding hydrochloric acid or sodium hydroxide to the second solution to adjust the pH value to 4-6 to obtain a third solution.
[0029] In this embodiment, the pH value is preferably adjusted to 4.5-5.5, more preferably adjusted to 4.8-5.2, and particularly preferably adjusted to 5.0.
[0030] Step S40, adding water to the third solution to a prescribed amount, and filtering the solution multiple times to obtain a filtrate.
[0031] In this embodiment, the filtrate was filtered through a 0.45 μm filter membrane and then filtered through a 0.22 μm filter membrane to obtain a filtrate. Step S50, filling the filtrate into a polypropylene plastic ampoule or a glass ampoule, and sterilizing it by a moist heat sterilization process to obtain a refenacin inhalation solution product.
[0032] In this embodiment, the parameters of the moist heat sterilization process are sterilization at 121° C. for 15 minutes.
[0033] In the technical solution of the present invention, the composition uses a buffer pair, which improves the stability of the solution, can withstand excessive killing and sterilization, and is safer. At the same time, citric acid is not used, which will not corrode steel pipes, and stainless steel pipes can be used for production, which has lower production costs.
[0034] The technical solution of the present invention is further described in detail below in conjunction with specific embodiments and drawings. It should be understood that the following embodiments are only used to explain the present invention and are not used to limit the present invention. Example 1
[0035] Take 32 mL of water for injection, add 165 mg of succinic acid, 486 mg of sodium succinate and 500 mg of sodium chloride, stir until completely dissolved, continue to add 120 mg of refenasin to the solution and stir to dissolve, then add an appropriate amount of hydrochloric acid or sodium hydroxide to the solution to adjust the pH value to 5.0, continue to add water for injection to the solution, fix the volume to 40 mL, and filter the solution through a 0.45 μm filter membrane and a 0.22 μm filter membrane to obtain a filtrate; the filtrate is sealed in a polypropylene plastic ampoule, and sterilized at 121°C for 15 minutes by a wet heat sterilization process to obtain a refenasin inhalation solution product. Example 2
[0036] Take 32 mL of water for injection, add 162 mg of fumaric acid, 414 mg of monosodium fumarate and 500 mg of sodium chloride, stir until completely dissolved, continue to add 120 mg of revenacin to the solution and stir to dissolve, then add an appropriate amount of hydrochloric acid or sodium hydroxide to the solution to adjust the pH value to 5.0, continue to add water for injection to the solution, fix the volume to 40 mL, and filter the solution through a 0.45 μm filter membrane and a 0.22 μm filter membrane to obtain a filtrate; the filtrate is sealed in a polypropylene plastic ampoule, and sterilized at 121°C for 15 minutes by a wet heat sterilization process to obtain a revenacin inhalation solution product. Example 3
[0037] Take 32 mL of water for injection, add 187 mg of malic acid, 561 mg of sodium malate and 500 mg of sodium chloride, stir until completely dissolved, continue to add 120 mg of refenasin to the solution and stir to dissolve, then add an appropriate amount of hydrochloric acid or sodium hydroxide to the solution to adjust the pH value to 5.0, continue to add water for injection to the solution, fix the volume to 40 mL, and filter the solution through a 0.45 μm filter membrane and a 0.22 μm filter membrane to obtain a filtrate; the filtrate is sealed in a polypropylene plastic ampoule, and sterilized at 121°C for 15 minutes through a wet heat sterilization process to obtain a refenasin inhalation solution product. Example 4
[0038] Take 32 mL of water for injection, add 136 mg of gallic acid, 384 mg of sodium gallate and 500 mg of sodium chloride, stir until completely dissolved, continue to add 120 mg of refenasin to the solution and stir to dissolve, then add an appropriate amount of hydrochloric acid or sodium hydroxide to the solution to adjust the pH value to 5.0, continue to add water for injection to the solution, fix the volume to 40 mL, and filter the solution through a 0.45 μm filter membrane and a 0.22 μm filter membrane to obtain a filtrate; the filtrate is sealed in a polypropylene plastic ampoule, and sterilized at 121°C for 15 minutes through a wet heat sterilization process to obtain a refenasin inhalation solution product. Example 5
[0039] Take 32 mL of water for injection, add 210 mg of tartaric acid, 582 mg of sodium tartrate and 500 mg of sodium chloride, stir until completely dissolved, continue to add 120 mg of revenacin to the solution and stir to dissolve, then add an appropriate amount of hydrochloric acid or sodium hydroxide to the solution to adjust the pH value to 5.0, continue to add water for injection to the solution, fix the volume to 40 mL, and filter the solution through a 0.45 μm filter membrane and a 0.22 μm filter membrane to obtain a filtrate; the filtrate is sealed in a polypropylene plastic ampoule, and sterilized at 121°C for 15 minutes by a wet heat sterilization process to obtain a revenacin inhalation solution product. Example 6
[0040] Take 32 mL of water for injection, add 244 mg of benzoic acid, 576 mg of sodium benzoate and 500 mg of sodium chloride, stir until completely dissolved, continue to add 120 mg of refenasin to the solution and stir to dissolve, then add an appropriate amount of hydrochloric acid or sodium hydroxide to the solution to adjust the pH value to 5.0, continue to add water for injection to the solution, fix the volume to 40 mL, and filter the solution through a 0.45 μm filter membrane and a 0.22 μm filter membrane to obtain a filtrate; the filtrate is sealed in a polypropylene plastic ampoule, and sterilized at 121°C for 15 minutes by a wet heat sterilization process to obtain a refenasin inhalation solution product. Comparative Example 1
[0041] Take 32 mL of water for injection, add 120 mg of citric acid, 240 mg of sodium citrate and 500 mg of sodium chloride, stir until completely dissolved, continue to add 120 mg of refenasin to the solution and stir to dissolve, then add an appropriate amount of hydrochloric acid or sodium hydroxide to the solution to adjust the pH value to 5.0, continue to add water for injection to the solution, fix the volume to 40 mL, and successively filter the solution through a 0.45 μm filter membrane and a 0.22 μm filter membrane to obtain a filtrate; the filtrate is sealed in a polypropylene plastic ampoule to obtain a refenasin inhalation solution product.
[0042] Stability test The products of Examples 1-5 and the product of Comparative Example 1 were placed under light conditions (25°C ± 2°C, RH 60% ± 5%) for 30 days, and samples were taken on the 0th, 10th, 20th and 30th days to test their properties, acidity, solution clarity and related substances. The experimental results are shown in the following table.
[0043] Table 3-Summary of stability results (experimental data stored at 25℃±2℃, RH60%±5% for 12 months)
[0044] Comparison of Comparative Example 1 with other embodiments shows that with the significant increase in illumination time, the total impurity level in Comparative Example 1 is significantly higher than that in other embodiments; the drug stability deteriorates and the content decreases; the solution becomes turbid and the safety decreases.
[0045] The technical features of the above embodiments may be combined arbitrarily. To make the description concise, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.
[0046] The above embodiments only express several implementation methods of the present application, and the descriptions thereof are relatively specific and detailed, but they cannot be understood as limiting the scope of the invention patent. It should be pointed out that, for a person of ordinary skill in the art, several variations and improvements can be made without departing from the concept of the present application, and these all belong to the protection scope of the present application. Therefore, the protection scope of the patent of the present application shall be subject to the attached claims.
Claims
1. A revenacin inhalation solution, characterized in that: Prepared from the following components: refenacin, buffer, sodium chloride, hydrochloric acid or sodium hydroxide, and water; Wherein, the acidic compound of the buffer pair is one or more of phosphoric acid, acetic acid, boric acid, gallic acid, cysteine, glycolic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, and benzoic acid.
2. The revenacin inhalation solution according to claim 1, characterized in that: The molar concentration of the acidic compound of the buffer pair in the revenacin inhalation solution is 0.02-0.05 mol / L.
3. The revenacin inhalation solution according to claim 1, characterized in that: The alkaline compound of the buffer pair is a sodium salt of an acidic compound, and the molar concentration of the sodium salt in the revenacin inhalation solution is 0.05-0.1 mol / L.
4. The revenacin inhalation solution according to claim 2, characterized in that: The acidic compound of the buffer pair is one or more of gallic acid, cysteine, glycolic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, and benzoic acid.
5. The revenacin inhalation solution according to claim 2, characterized in that: The acidic compound of the buffer pair is one or more of succinic acid, fumaric acid, malic acid and tartaric acid.
6. A method for preparing the revenacin inhalation solution according to any one of claims 1 to 5, characterized in that: The steps include: Take 80% of the prescribed amount of water for injection, add the prescribed amount of buffer and sodium chloride, and stir until completely dissolved to obtain the first solution; Adding a prescribed amount of refenacin to the first solution and stirring to dissolve the solution to obtain a second solution; Add hydrochloric acid or sodium hydroxide to the second solution to adjust the pH value to 4-6 to obtain a third solution; Add water to the third solution to the prescribed amount, and filter multiple times to obtain a filtrate; The filtrate is sealed in a polypropylene plastic ampoule or a glass ampoule and sterilized by a wet heat sterilization process to obtain a refenacin inhalation solution product.
7. The method for preparing the revenacin inhalation solution according to claim 6, characterized in that: In the step of adding hydrochloric acid or sodium hydroxide to the second solution to adjust the pH value to 4-6 to obtain the third solution, the pH value of the third solution is 4.5-5.
5.
8. The method for preparing the revenacin inhalation solution according to claim 6, characterized in that: In the step of adding hydrochloric acid or sodium hydroxide to the second solution to adjust the pH value to 4-6 to obtain the third solution, the pH value of the third solution is 5.
9. The method for preparing the revenacin inhalation solution according to claim 6, characterized in that: In the step of adding water to the third solution to the prescribed amount and filtering for multiple times to obtain the filtrate, the filtrate is obtained by coarse filtration through a 0.45 μm filter membrane and fine filtration through a 0.22 μm filter membrane in sequence.
10. The method for preparing the revenacin inhalation solution according to claim 6, characterized in that: The filtrate is sealed in a polypropylene plastic ampoule or a glass ampoule and sterilized by a moist heat sterilization process to obtain the revenacin inhalation solution product. The parameters of the moist heat sterilization process are sterilization at 121° C. for 15 minutes.