High-quality ebastine hydrochloride oral solution and preparation method thereof
By adjusting the dissolution and mixing order of ebastin oral solution, the inaccurate volume concentration caused by foam production in the existing process is solved, and a high-quality, clear and transparent oral solution preparation is achieved, avoiding the use of defoaming agents , improve product quality and production efficiency.
Patent Information
- Application Number
- CN202411264010.6
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-09-10
- Publication Date
- 2024-12-10
AI Technical Summary
In the existing oral solution preparation process of ebastin, a large amount of foam is generated after mixing the main component solution with sorbitol, resulting in inaccurate volume and unstable product quality. The use of existing defoamers increases process complexity and impurities. Content affects product quality.
In a specific order of dissolution and mixing of materials, firstly mix ebastin hydrochloride, glycerin, polyoxyethylene (40) hydrogenated castor oil and anise brain at a specific temperature to form an M1 solution; then sodium hydroxybenzene and hydroxyl Sodium styrene is mixed to form an M3 solution. Finally, the M3 solution is added to the M1 solution at a specific temperature, and the M2 solution of sorbitol and sucralose is slowly added, the pH value is adjusted and filtered to avoid foam generation.
The solution system is fully defoamed, the accuracy of the quantitative process and the clarity and transparency of the product are ensured, the introduction of defoaming agents is avoided, and the quality and production cost of ebastin hydrochloride oral solution is improved.
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Abstract
Description
Technical Field
[0001] The present invention relates to the technical field of oral preparation preparation technology, and in particular to a high-quality ebastine hydrochloride oral solution and a preparation method thereof. Background Art
[0002] Ebastine, chemical name 1-(4-tert-butylphenyl)-4-[4-(diphenylmethoxy)-1-piperidinyl]-1-butanone, is an organic compound with the chemical formula C 32 H 39 NO2 is clinically used for allergic diseases, including allergic rhinitis in children, perennial rhinitis in adults, seasonal rhinitis, hay fever and chronic urticaria.
[0003] One of the main dosage forms of Ebastine is an oral solution. In the existing process of preparing oral solutions, a large amount of foam will be generated, especially after the main component solution is mixed with sorbitol, which will quickly overflow the feeding port, resulting in inaccurate addition of materials in the constant volume link during the preparation process, and the final content of the main component is unstable. To solve the above problems, the prior art has made certain explorations. For example, the invention patent with document number CN105687128B discloses an Ebastine oral liquid preparation and a preparation method thereof, which adds a certain amount of defoaming agent to the oral liquid formula, wherein the defoaming agent selects methyl silicone oil; the document number CN117180186A discloses an Ebastine oral solution and a preparation method thereof. The technical solution further adds a defoaming agent while solving the problem of Ebastine's poor solubility, and the defoaming agent selects methyl silicone oil. The addition of additional defoaming agents increases the complexity of product raw materials and processes to a certain extent, which is not conducive to industrial expansion of production. And the defoaming agent is an impurity relative to the main component. Adding a defoaming agent to the oral solution is not conducive to the improvement of product quality.
[0004] In addition, a certain amount of simethicone emulsion can be added to the existing prescription for defoaming treatment to overcome the above-mentioned problems of foam generation and volume setting. Simethicone is a mixture of dimethicone and silicon dioxide, commonly used in non-ionic surfactants, and is a silicone defoamer with both defoaming and defoaming effects (CN115754171A; CN118526455A). Simethicone emulsion can also be used to add to ebastine oral solution to play a defoaming effect, but the ingredients in simethicone emulsion are complex, which will affect the clarity of the solution (especially the opalescence phenomenon) and the determination of impurity content. It is urgent to develop an improved method for preparing ebastine oral solution to effectively prevent the generation of a large amount of foam during the solution preparation process (to ensure that the solution is accurately set to volume), and to ensure that the prepared oral solution is clear and transparent, without opalescence, and does not affect the determination of impurities (for example, without using raw materials such as simethicone emulsion). Summary of the invention
[0005] The present invention is intended to provide a method for preparing a high-quality ebastine hydrochloride oral solution, so as to solve the technical problem that it is difficult to ensure that a large amount of foam is not generated during the preparation process of the ebastine oral solution without introducing a simethicone emulsion and the like, which will quickly overflow from the feeding port.
[0006] In order to achieve the above object, the present invention adopts the following technical scheme:
[0007] A method for preparing high-quality ebastine hydrochloride oral solution comprises the following steps performed in sequence:
[0008] S1: Add ebastine hydrochloride, glycerol, polyoxyethylene (40) hydrogenated castor oil and anethole into water, then add lactic acid and stir until dissolved to obtain M1 solution;
[0009] Sorbitol and sucralose were added to water and stirred until dissolved to obtain M2 solution;
[0010] Sodium methylparaben and sodium propylparaben were added into water and stirred until dissolved to obtain M3 solution;
[0011] S2: Add M3 solution to M1 solution, then add M2 solution, stir after adding, and finally cool to room temperature to obtain a mixed solution;
[0012] S3: Adjust the pH value of the mixed solution, and then add the remaining amount of water to obtain the intermediate of ebastine hydrochloride oral solution.
[0013] Furthermore, in S1, stirring is performed at 40°C to 50°C until dissolved to obtain an M1 solution.
[0014] Furthermore, in S1, the water used to prepare the M1 solution is 35% to 45% of the formula amount; the water used to prepare the M2 solution is 35% to 45% of the formula amount; and the water used to prepare the M3 solution is 5% to 10% of the formula amount.
[0015] Further, in step S2, the M3 solution is added to the M1 solution at 40°C to 50°C and stirred at 20 to 30 rpm, and then the M2 solution is added.
[0016] Furthermore, in S2, the M2 solution is added at a rate of 300 ml to 400 ml / min.
[0017] Furthermore, in S2, the stirring time after the addition is 30 to 60 minutes.
[0018] Furthermore, in S3, the pH value of the mixed solution is adjusted to 3.9 to 4.2.
[0019] Further, in S3, the crude product of ebastine hydrochloride oral solution is filtered using a 0.45 μm filter membrane, and the finished product is obtained after canning.
[0020] Furthermore, in the ebastine hydrochloride oral solution, the concentration of ebastine is 0.095-0.105% (w / v), the concentration of polyoxyethylene (40) hydrogenated castor oil is 2-3% (w / v), the concentration of glycerol is 15-25% (w / v), the concentration of sucralose is 0.1-0.3% (w / v), the concentration of anethole is 0.015-0.030% (w / v), the concentration of sorbitol is 5-10% (w / v), the concentration of methylparaben sodium is 0.10-0.15% (w / v), the concentration of propylparaben sodium is 0.01-0.0.05% (w / v), and the concentration of lactic acid is 0.2-0.6% (w / v).
[0021] The present invention also provides an ebastine hydrochloride oral solution prepared by a preparation method of a high-quality ebastine hydrochloride oral solution.
[0022] The principle and beneficial effects of this technical solution are:
[0023] The ebastine hydrochloride oral solution of the technical solution achieves sufficient defoaming of the solution system and reduces the deviation between the effective components in the finished product and the theoretical value by adjusting the order of dissolving and mixing materials without using a defoaming agent. The solution first dissolves ebastine hydrochloride, glycerol, polyoxyethylene (40) hydrogenated castor oil and anethole at a specific temperature to obtain an M1 solution; sorbitol and sucralose are mixed and dissolved to obtain an M2 solution; sodium methylparaben and sodium propylparaben are mixed and dissolved to obtain an M3 solution; in the process of mixing the M1 solution, the M2 solution and the M3 solution, a specific ambient temperature is used, and the M3 solution and the M1 solution are first mixed, and then the M2 solution is added dropwise. The above-mentioned operation method can ensure that almost no foam is generated during the mixing process, ensure the accuracy of the quantitative process, avoid the loss of effective components due to the generation of foam, and also avoid the introduction of other redundant components (such as defoaming agents), thereby improving the quality of the ebastine hydrochloride oral solution and reducing the production cost. DETAILED DESCRIPTION
[0024] The following examples are only used to more clearly illustrate the technical solutions of the present invention, and are therefore only used as examples, and cannot be used to limit the scope of protection of the present invention. The specific embodiments listed in the present invention are only examples of the present invention, and the present invention is not limited to the specific embodiments described below. For those skilled in the art, any equivalent modifications and substitutions to the embodiments described below are also within the scope of the present invention. Therefore, equal transformations and modifications made without departing from the spirit and scope of the present invention should be included in the scope of the present invention. In order to better illustrate the present invention, numerous specific details are given in the specific embodiments below. Those skilled in the art should understand that the present invention can also be implemented without certain specific details. In other embodiments, methods, means, equipment and steps well known to those skilled in the art are not described in detail in order to highlight the purport of the present invention.
[0025] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those of ordinary skill in the art. Unless otherwise specified, the units used in this specification are international standard units, and the numerical values and numerical ranges appearing in the present invention should be understood to include inevitable systematic errors in industrial production. Unless otherwise specified, the experimental methods used in the following implementations are all conventional methods; the materials, reagents or instruments used without indicating the manufacturer are all reagents and materials available from commercial channels. Those without indicating specific conditions in the examples are all carried out according to conventional conditions or conditions recommended by the manufacturer. At the same time, the present invention does not limit the source of the raw materials used. Unless otherwise specified, the raw materials used in the present invention are all common commercial products in the field of this technology.
[0026] It should be noted that the raw material compositions used in the following examples are uniformly described in Table 1:
[0027] Table 1: Raw material composition (Ebastine hydrochloride oral solution)
[0028] Name of raw materials and auxiliary materials Percentage (w / v) Ebastine (hydrochloride) 0.095～0.105％ Polyoxyethylene (40) hydrogenated castor oil 2～3％ glycerin 15～25％ Sucralose 0.1～0.3％ Anethole 0.015～0.030％ Sorbitol 5～10％ Sodium Methylparaben 0.10～0.15％ Sodium Propylparaben 0.01～0.05％ lactic acid 0.2～0.6％ Sodium hydroxide Appropriate amount (for adjusting pH value) Purified water Add to 100 parts (v)
[0029] The percentage (w / v) of ebastine (hydrochloride) is 0.095-0.105%, which means that every 100 mL of the solution contains 0.095-0.105 g of solute, and the mass of the solute is calculated as ebastine hydrochloride.
[0030] The preparation process is roughly as follows:
[0031] (1) Preparation of M1 solution: Weigh ebastine hydrochloride, glycerol, polyoxyethylene (40) hydrogenated castor oil, and anethole, add 35-45% (preferably 40%) of the preparation batch of purified water, add lactic acid, and stir at 40°C to 50°C to completely dissolve the raw materials.
[0032] (2) Preparation of M2 solution: Take sorbitol and sucralose, add 5-45% (preferably 40%) of the preparation batch of purified water, stir and dissolve.
[0033] (3) Preparation of M3 solution: Take sodium methylparaben and sodium propylparaben, add 5-10% (preferably 5%) of the preparation batch of purified water, stir and dissolve.
[0034] (4) Solution mixing: Take M3 solution, add it to M1 solution under stirring condition (speed of 20-30 rpm, stirring M1 solution), maintain 40°C-50°C, and slowly add M2 solution (dropping speed of 300-400 mL / min) to the above solution under stirring condition (stirring the mixed solution of M1 and M3), always maintain the temperature of the solution between 40°C and 50°C. After the addition, stir and mix for 30-60 minutes to reduce the temperature of the solution to room temperature.
[0035] (5) pH adjustment: While stirring, adjust the pH of the solution to 3.9-4.2 with 4% (w / w) sodium hydroxide solution.
[0036] (6) Quantification: Add the remaining amount of room temperature purified water to the target batch mark and stir to mix evenly.
[0037] (7) Filtration and filling: Filter through a 0.45 μm filter membrane and fill into brown soda-lime glass bottles (120 ml / bottle).
[0038] Example 1
[0039] The formula of ebastine hydrochloride is: ebastine 0.1% (w / v), polyoxyethylene (40) hydrogenated castor oil 2.5% (w / v), glycerin 20% (w / v), sucralose 0.2% (w / v), anethole 0.02% (w / v), sorbitol 8% (w / v), methylparaben sodium 0.12% (w / v), propylparaben sodium 0.03% (w / v), lactic acid 0.4% (w / v); pH 3.9-4.2.
[0040] The preparation process is as follows:
[0041] (1) Preparation of M1 solution: Weigh ebastine hydrochloride, glycerol, polyoxyethylene (40) hydrogenated castor oil, and anethole, add 40% of the purified water of the preparation batch, add lactic acid, and stir at 45°C to completely dissolve the raw materials. This step can obtain a clear M1 solution without precipitation.
[0042] (2) Preparation of M2 solution: Take sorbitol and sucralose, add 40% of the purified water of the preparation batch, stir and dissolve.
[0043] (3) Preparation of M3 solution: Take sodium methylparaben and sodium propylparaben, add 5% of the preparation batch of purified water, stir and dissolve.
[0044] (4) Solution mixing: Take M3 solution and add it to M1 solution under stirring (speed 25 rpm), maintaining 45°C. Then, slowly add M2 solution to the above solution under stirring (dropping speed 350 ml / min), always maintaining the temperature of the solution at about 45°C. After the addition, stir and mix for 45 minutes, and allow the temperature of the solution to drop to room temperature.
[0045] (5) pH adjustment: The pH of the solution was adjusted to within the range of 3.9 to 4.2 using 4% (w / w) sodium hydroxide solution while stirring.
[0046] (6) Quantification: Add room temperature purified water to the target batch mark and stir to mix evenly.
[0047] (7) Filtration and filling: Filter through a 0.45 μm filter membrane and fill into brown soda-lime glass bottles (120 ml / bottle, 120 mg / bottle) to obtain the finished product.
[0048] Example 2
[0049] The formula of ebastine hydrochloride is: ebastine 0.095% (w / v), polyoxyethylene (40) hydrogenated castor oil 2% (w / v), glycerin 15% (w / v), sucralose 0.1% (w / v), anethole 0.015% (w / v), sorbitol 5% (w / v), methylparaben sodium 0.10% (w / v), propylparaben sodium 0.01% (w / v), lactic acid 0.2% (w / v); pH 3.9-4.2.
[0050] The preparation process is as follows:
[0051] (1) Preparation of M1 solution: Weigh ebastine hydrochloride, glycerol, polyoxyethylene (40) hydrogenated castor oil, and anethole, add 40% of the batch of purified water, add lactic acid, and stir at 40°C to completely dissolve the raw materials.
[0052] (2) Preparation of M2 solution: Take sorbitol and sucralose, add 40% of the purified water of the preparation batch, stir and dissolve.
[0053] (3) Preparation of M3 solution: Take sodium methylparaben and sodium propylparaben, add 5% of the preparation batch of purified water, stir and dissolve.
[0054] (4) Solution mixing: Take M3 solution and add it to M1 solution under stirring (speed of 20 rpm), maintaining at 40°C. Then, slowly add M2 solution to the above solution under stirring (dropping speed of 300 ml / min), always maintaining the temperature of the solution at about 40°C. After the addition, stir and mix for 30 minutes to cool the solution to room temperature.
[0055] (5) pH adjustment: While stirring, adjust the solution to pH 3.9-4.2 with 4% (w / w) sodium hydroxide solution.
[0056] (6) Quantification: Add room temperature purified water to the target batch mark and stir to mix evenly.
[0057] (7) Filtration and filling: Filter through a 0.45 μm filter membrane and fill into brown soda-lime glass bottles (120 ml / bottle, 120 mg / bottle) to obtain the finished product.
[0058] Example 3
[0059] The formula of ebastine hydrochloride is: ebastine 0.105% (w / v), polyoxyethylene (40) hydrogenated castor oil 3% (w / v), glycerin 25% (w / v), sucralose 0.3% (w / v), anethole 0.030% (w / v), sorbitol 10% (w / v), methylparaben sodium 0.15% (w / v), propylparaben sodium 0.0.05% (w / v), lactic acid 0.6% (w / v), pH 3.9-4.2.
[0060] The preparation process is as follows:
[0061] (1) Preparation of M1 solution: Weigh ebastine hydrochloride, glycerol, polyoxyethylene (40) hydrogenated castor oil, and anethole, add 40% of the batch of purified water, add lactic acid, and stir at 50°C to completely dissolve the raw materials.
[0062] (2) Preparation of M2 solution: Take sorbitol and sucralose, add 40% of the purified water of the preparation batch, stir and dissolve.
[0063] (3) Preparation of M3 solution: Take sodium methylparaben and sodium propylparaben, add 5% of the preparation batch of purified water, stir and dissolve.
[0064] (4) Solution mixing: Take M3 solution and add it to M1 solution under stirring (speed 30 rpm), maintaining 40°C to 50°C. Then, slowly add M2 solution to the above solution under stirring (dropping speed 400 ml / min), always maintaining the temperature of the solution at 50°C. After the addition, stir and mix for 60 minutes to cool the solution to room temperature.
[0065] (5) pH adjustment: While stirring, adjust the pH of the solution to 3.9-4.2 with 4% (w / w) sodium hydroxide solution.
[0066] (6) Quantification: Add room temperature purified water to the target batch mark and stir to mix evenly.
[0067] (7) Filtration and filling: Filter through a 0.45 μm filter membrane and fill into brown soda-lime glass bottles (120 ml / bottle, 120 mg / bottle) to obtain the finished product.
[0068] Comparative Example 1
[0069] This comparative example is basically the same as Example 1, except that step (4) is:
[0070] Take the M2 solution, and slowly add it to the M1 solution (dropping speed 350 ml / min) under stirring and 45°C. Keeping 45°C, add the M3 solution to the above solution under stirring (speed 20 rpm). After the addition, stir for 45 minutes to cool the solution to room temperature. The other operations are the same as in Example 1 to prepare the finished product.
[0071] This comparative experiment found that this operation would result in a large amount of foam being generated during the mixing process of step (4), and the foam would overflow from the feeding port.
[0072] Comparative Example 2
[0073] This comparative example is basically the same as Example 1, except that step (4) is:
[0074] Take M3 and M2 solutions, add them to M1 solution at the same time under stirring (speed 20 rpm), keep 45°C during the process, and the dropping speed of M3 and M2 solutions is 350ml / min. After the addition, stir for 45 minutes to cool the solution temperature to room temperature. Other operations are the same as in Example 1 to prepare the finished product.
[0075] This comparative experiment found that this operation would result in a large amount of foam being generated during the mixing process of step (4), and the foam would overflow from the feeding port.
[0076] Comparative Example 3
[0077] The formula of this comparative example is basically the same as that of Example 1, but the preparation method is changed, as follows:
[0078] 80% of the purified water of the preparation batch is added, and ebastine hydrochloride, glycerin, polyoxyethylene (40) hydrogenated castor oil, anethole, lactic acid, sorbitol, sucralose, sodium methylparaben and sodium propylparaben are added in sequence (all solutes are added at the same time), fully stirred, and the above mixing operation is performed in an environment of 45° C., and then the pH value is adjusted to 3.9-4.2, water is added to make up to the set value, and after filtering and packaging, the finished product is prepared.
[0079] This comparative experiment found that this operation method will cause the main component to fail to completely dissolve during the mixing process of all materials, and a large amount of foam will be generated, overflowing the feeding port, making it difficult to accurately determine the volume in the subsequent water addition step, and due to the overflow of foam, a certain amount of solute (including the effective ingredient Ebastine Hydrochloride) will be lost.
[0080] Comparative Example 4
[0081] The formula of this comparative example is basically the same as that of Example 1, but the preparation method is changed, as follows:
[0082] Preparation of M1 solution: Weigh ebastine hydrochloride, glycerin, polyoxyethylene (40) hydrogenated castor oil, anethole, sodium methylparaben and sodium propylparaben, add 45% of the preparation batch of purified water, add lactic acid, and stir thoroughly at 45°C.
[0083] The preparation of M2 solution is the same as that of Example 1, but M3 solution is not prepared. Take M2 solution, maintain 45°C, and slowly add (dropping speed 350ml / min) to M1 solution under stirring conditions (speed 25 rpm). After the addition, stir for 45 minutes to cool the solution temperature to room temperature. The remaining pH adjustment, quantification, filtration, and filling processes are the same as those of Example 1 to prepare the finished product.
[0084] This comparative experiment found that during the preparation of the M1 solution, even after sufficient stirring, the M1 solution did not dissolve and become clear, and there was always precipitation.
[0085] Comparative Example 5
[0086] The formula of this comparative example is basically the same as that of Example 1, but the preparation method is changed, as follows:
[0087] Preparation of M1 solution: Weigh ebastine hydrochloride, glycerol, polyoxyethylene (40) hydrogenated castor oil, anethole, sorbitol and sucralose, add 80% of the purified water of the preparation batch, add lactic acid, stir at 45°C to completely disperse the raw materials.
[0088] The preparation of M3 solution is the same as that of Example 1, but M2 solution is not prepared. Take M3 solution, keep it at 45°C, add it to M1 solution under stirring (speed 25 rpm), and stir for 45 minutes after the addition to cool the solution to room temperature. The remaining pH adjustment, quantitative determination, filtration, and filling processes are the same as those of Example 1 to obtain a finished product.
[0089] This comparative experiment found that after being left for a short period of time, the M1 solution did not dissolve and became clear, with precipitation at the bottom.
[0090] Comparative Example 6
[0091] The formulation of this comparative example is basically the same as that of Example 1, but the preparation method is changed as follows: the ambient temperature in steps (1) and (4) is 55° C., and the other operation methods are the same as those of Example 1 to obtain the finished product.
[0092] This comparative experiment found that this operation would cause rapid foam generation during the mixing process of step (4), and even cause foam to overflow from the feeding port.
[0093] Comparative Example 7
[0094] The formula of this comparative example is basically the same as that of Example 1, but the preparation method is changed as follows: the ambient temperature in (1) and (4) is 35° C. The remaining operations are the same as those of Example 1. The other operations are the same as those of Example 1 to obtain the finished product.
[0095] This comparative experiment found that after mixing the M1, M2 and M3 solutions, the main component did not dissolve.
[0096] Comparative Example 8
[0097] The formula of this comparative example is basically the same as that of Example 1, but the preparation method is changed as follows: The ambient temperature in (1) and (4) is room temperature. The remaining operations are the same as those of Example 1. The other operations are the same as those of Example 1 to obtain the finished product.
[0098] This comparative experiment found that after mixing the M1, M2 and M3 solutions, the main component did not dissolve.
[0099] Comparative Example 9
[0100] The formula of this comparative example is basically the same as that of Example 1, but the preparation method is changed as follows: in (4), the M2 solution is added to the mixed solution of M1 and M3 at a rate of 500 ml / min, and the remaining operations are the same as those of Example 1 to obtain the finished product.
[0101] Comparative Example 10
[0102] The preparation method is basically the same as that of Example 1, except that in step (4), 0.1% simethicone emulsion is added before M2 is added and mixed.
[0103] The properties of the ebastine hydrochloride oral solution prepared in the embodiment and comparative example and the ebastine content were tested (finished product), and the foam generation during the mixing process was recorded. The experimental results are shown in Table 2. The ebastine content is measured by the labeled content (actual amount / standard amount). The foam generation was observed in the embodiment and comparative examples 1, 2, 6 to 10, after all the materials were mixed. In comparative examples 3 to 5, although the operating steps are different, the foam generation was observed after all the materials were mixed.
[0104] Table 2: Test results of solution properties and ebastine content of Examples and Comparative Examples (ebastine content (%) is the average value of 3 batches of samples)
[0105]
[0106] The finished products of the ebastine oral liquid prepared in Examples 1 to 3 are transparent and clear in appearance. After all materials are mixed and without adding simethicone emulsion as a defoaming agent, almost no foam is generated, the loss of the main component is very small, and the ebastine content test results in the finished products are closer to the theoretical value (calculated according to the feed amount). The closer the labeled content is to 100%, the higher the accuracy of the loading amount. The labeled content of Examples 1 to 3 can reach more than 99% and is close to the level of 100%, which meets the ideal expectation.
[0107] The mixing order of M1, M2 and M3 in comparative example 1 is adjusted. M1 and M2 are mixed first, and then M3 is mixed. This will result in a large amount of foam being generated during the mixing process of step (4), and the foam overflows the feeding port (causing some functional ingredients to be taken out of the system, causing losses), and the actual content of Bastin in the final product is reduced. In comparative example 2, M2 and M3 are added to M1 at the same time, which will result in a large amount of foam being generated during the mixing process of step (4), and the foam overflows the feeding port, and the actual content of Bastin in the final product is reduced. Comparative example 3 mixes all materials at the same time, and a large amount of foam is generated during the mixing process, and the foam overflows the feeding port, and the actual content of Bastin in the final product is reduced. It can be seen that the mixing order of M1, M2 and M3 is very critical to whether the mixed materials generate foam. This scheme adopts the method of mixing M3 and M1 first, and then adding M2 dropwise to the above-mentioned mixed solution, which can effectively avoid the generation of foam without adding a defoamer, and avoid the loss of functional ingredients and inaccurate constant volume. In particular, the operation method of comparative example 3 also leads to unsatisfactory clarity of the overall solution system and precipitation. Even in the operation step of preparing the finished product, a 0.45 μm filter membrane is used for filtration, but the finished product after canning still precipitates after being placed for a short time, and the solution is relatively turbid.
[0108] In Comparative Examples 4 and 5, in order to save operating steps, different solutes were tried to be mixed. It was found that adding sorbitol and sucralose to M1, or adding sodium methylparaben and sodium propylparaben, would cause M1 to be unclear and precipitated. Even if all operating steps (including 0.45 μm membrane filtration, etc.) were completed, the oral liquid product obtained still had precipitation after being placed for a short time, and the solution was relatively turbid. In addition, adding sorbitol and sucralose to M1 first (Comparative Example 5) would also cause a large amount of foam to appear during the configuration process. Sodium methylparaben and sodium propylparaben are conventional preservatives. The inventor first discovered that the addition of these ingredients to the overall oral liquid system would significantly affect the content of the functional ingredients in the finished product. If sodium methylparaben and sodium propylparaben were directly mixed with the main component (Comparative Example 4), precipitation would occur in the system, and the content of the main component in the finished product would be significantly reduced, resulting in unsatisfactory finished product quality (both the labeled content and the solution properties did not meet the requirements). Sodium methylparaben, sodium propylparaben and the main ingredient need to be dissolved separately and then mixed to meet the quality requirements of the finished product.
[0109] Comparative Example 6 increases the temperature of material mixing. Too high a temperature will cause the generation of foam, and high temperature will cause the target ingredient to degrade to a certain extent. In the final product, the content of Ebastine is reduced. The material mixing temperature of Comparative Examples 7 and 8 is relatively low, and almost no foam is generated, but the main component is insoluble. Even in the operation steps of preparing the finished product, a 0.45 μm filter membrane is used to filter and remove some insoluble substances, but the finished product after filling still precipitates after being placed for a short time, and the solution is relatively turbid as a whole. And due to the loss of precipitation, the content of the functional ingredients in the finished product is greatly reduced.
[0110] In Comparative Example 9, the droplet acceleration of the M2 solution was too fast, resulting in a large amount of foam generated during the material mixing process. The overflow of the foam caused part of the main component to be lost from the system. Therefore, in the finished product, there was a certain loss of effective ingredients, and the content of the target ingredient Ebastine in the finished product was low.
[0111] In Comparative Example 10, a defoaming agent was added, but the defoaming effect was almost the same as that of the embodiment, and the content of ebastine in the finished product was almost the same. However, after the defoaming agent was added, the oral liquid was a solution with a slight opalescence, and impurities were introduced. In the prior art, adding a defoaming agent is an effective means to reduce the generation of foam. However, by adopting the preparation process sequence of this scheme, it is possible to ensure that almost no foam is generated in the system without adding a defoaming agent, fully avoid the introduction of new impurities, and improve the metering accuracy of the effective components of the oral liquid.
[0112] The above is only an embodiment of the present invention, and the common knowledge such as the known specific technical solutions and / or characteristics in the solution is not described in detail here. It should be pointed out that for those skilled in the art, without departing from the technical solution of the present invention, several modifications and improvements can be made, which should also be regarded as the protection scope of the present invention, and these will not affect the effect of the implementation of the present invention and the practicality of the patent. The scope of protection required by this application shall be based on the content of its claims, and the specific implementation methods and other records in the specification can be used to interpret the content of the claims.
Claims
1. A method for preparing high-quality ebastine hydrochloride oral solution, characterized in that: The method includes the following steps in sequence: S1: Add ebastine hydrochloride, glycerol, polyoxyethylene (40) hydrogenated castor oil and anethole into water, then add lactic acid and stir until dissolved to obtain M1 solution; Sorbitol and sucralose were added to water and stirred until dissolved to obtain M2 solution; Sodium methylparaben and sodium propylparaben were added into water and stirred until dissolved to obtain M3 solution; S2: Add M3 solution to M1 solution, then add M2 solution, stir after adding, and finally cool to room temperature to obtain a mixed solution; S3: Adjust the pH value of the mixed solution, and then add the remaining amount of water to obtain ebastine hydrochloride oral solution.
2. The method for preparing a high-quality ebastine hydrochloride oral solution according to claim 1, characterized in that: In S1, stir at 40°C to 50°C until dissolved to obtain M1 solution.
3. The method for preparing a high-quality ebastine hydrochloride oral solution according to claim 2, characterized in that: In S1, the water used to prepare the M1 solution is 35-45% of the formula amount; the water used to prepare the M2 solution is 35-40% of the formula amount; and the water used to prepare the M3 solution is 5-10% of the formula amount.
4. The method for preparing a high-quality ebastine hydrochloride oral solution according to claim 3, characterized in that: In step S2, the M3 solution is added to the M1 solution at 40°C to 50°C and stirred at 20 to 30 rpm, and then the M2 solution is added.
5. The method for preparing a high-quality ebastine hydrochloride oral solution according to claim 4, characterized in that: In S2, the M2 solution is added at a rate of 300 ml to 400 ml / min.
6. The method for preparing a high-quality ebastine hydrochloride oral solution according to claim 5, characterized in that: In S2, the stirring time after the addition is 30 to 60 minutes.
7. The method for preparing a high-quality ebastine hydrochloride oral solution according to claim 6, characterized in that: In S3, the pH value of the mixed solution is adjusted to 3.9-4.
2.
8. The method for preparing a high-quality ebastine hydrochloride oral solution according to claim 7, characterized in that: In S3, the crude product of ebastine hydrochloride oral solution is filtered using a 0.45 μm filter membrane and canned to obtain a finished product.
9. The method for preparing a high-quality ebastine hydrochloride oral solution according to any one of claims 1 to 8, characterized in that: In the ebastine hydrochloride oral solution, the concentration of ebastine is 0.090-0.105% (w / v), the concentration of polyoxyethylene (40) hydrogenated castor oil is 2-3% (w / v), the concentration of glycerol is 15-25% (w / v), the concentration of sucralose is 0.1-0.3% (w / v), the concentration of anethole is 0.015-0.030% (w / v), the concentration of sorbitol is 5-10% (w / v), the concentration of methylparaben sodium is 0.10-0.15% (w / v), the concentration of propylparaben sodium is 0.01-0.0.05% (w / v), and the concentration of lactic acid is 0.2-0.6% (w / v).
10. The ebastine hydrochloride oral solution prepared by the method for preparing a high-quality ebastine hydrochloride oral solution according to claim 9.