A kind of simethicone emulsion and preparation method thereof

Abstract

The invention discloses a simethicone emulsion and a preparation method thereof, and belongs to the technical field of pharmaceutical preparations. The simethicone emulsion of the invention contains: simethicone, behenic acid glyceryl, lauroyl polyoxyethylene glyceride, a sweetener, a buffer, an electrolyte, an antibacterial agent, a tackifier and a flavoring agent, and the pH value is 4.8-5.2. The preparation method of the invention comprises: mixing simethicone with behenic acid glyceryl to prepare an oil phase, adding water to lauroyl polyoxyethylene glyceride to prepare an aqueous phase; mixing the remaining raw materials with water to prepare an additional liquid; adding the aqueous phase to the oil phase to prepare an emulsified solution, and then adding the emulsified solution to the additional liquid, adjusting the pH value to 4.8-5.2, and adding water to the volume. The method of the invention adjusts the pH after the emulsified solution and the additional solution are fused, so that the pH of the prepared simethicone emulsion is stable, and a stable pH value can still be maintained under long-term or high-temperature conditions. The simethicone emulsion of the invention has good compliance.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations, and in particular relates to a simethicone emulsion and a preparation method thereof. Background Art

[0002] Simethicone is a mixture of dimethicone (containing 90.5-99.0%) and silicon dioxide (containing 4.0-7.0%). It is a stable non-ionic surfactant that can change the surface tension of bubbles in the chyme and mucus in the digestive tract, causing them to decompose and release gas. It can be clinically used to treat discomfort caused by excessive gas accumulation in the gastrointestinal tract, and to assist in abdominal imaging examinations.

[0003] The simethicone emulsion currently on the market in China is an original imported product from Berlin-Chemie AG in Germany, with the trade name Espumisan (Percy ). The import registration standard JX20140233 stipulates that simethicone emulsion is a stable emulsion with a viscosity of 90-150mpa.s and no stratification during centrifugation, but the standard does not restrict the emulsion preparation method and particle size.

[0004] Patent CN101229187A is a patent of the original product company, which discloses a simethicone emulsion with polyethylene glycol stearate / palmitate and glyceride as emulsifiers and hydroxypropyl cellulose as a thickener, and discloses a preparation method: prepare the simethicone emulsion according to the formula, first stir and dissolve sorbic acid, sodium cyclamate, and sodium saccharin in purified water, then add hydroxypropyl cellulose to dissolve it, filter the dissolved solution, and finally mix it evenly with the simethicone emulsion and essence to obtain a simethicone emulsion with an emulsion particle size of 10 to 50 nm.

[0005] Patent CN116421559A discloses a stable simethicone emulsion and a preparation method thereof, wherein simethicone, emulsifier polyoxyl 40 stearate and glyceryl monostearate are stirred at 70-80°C until melted to obtain an oil phase. Purified water, carbomer, sorbic acid and a pH regulator are stirred until uniform to obtain an aqueous phase. Finally, the aqueous phase is added to the oil phase, stirred and mixed, and high shear emulsification and homogenization are performed at a speed of 7200-13000rpm for 30-60min to obtain a simethicone emulsion. The patent clarifies the preparation process for preparing the simethicone emulsion, but the applicant found that the simethicone emulsion obtained by the preparation method has the problem of pH value and sorbic acid instability.

[0006] Therefore, providing a simethicone emulsion with good stability and compliance has become a technical problem to be solved urgently by those skilled in the art. Summary of the invention

[0007] The object of the present invention is to provide a simethicone emulsion and a preparation method thereof. The simethicone emulsion has good stability, good taste and fragrance, and improves patient compliance.

[0008] To achieve the above purpose, the present invention adopts the following technical solutions:

[0009] The invention discloses a simethicone emulsion, wherein each 1 ml of the simethicone emulsion contains the following ingredients: 40 mg of simethicone, 3.0-3.4 mg of glyceryl behenate, 3.8-4.0 mg of lauroyl polyoxyethylene glyceride, 69-71 mg of a sweetener, 2.0-2.4 mg of a buffer, 0.6-0.8 mg of an electrolyte, 0.4-0.6 mg of an antibacterial agent, 3.0-3.2 mg of a viscosity enhancer, and 0.01-0.03 mg of a flavoring agent. The pH value of the simethicone emulsion is 4.8-5.2.

[0010] In some embodiments of the present invention, each 1 ml of simethicone emulsion contains the following ingredients: 40 mg of simethicone, 3.2 mg of glyceryl behenate, 3.9 mg of lauroyl polyoxyethylene glyceride, 70.15 mg of sweetener, 2.2 mg of buffer, 0.7 mg of electrolyte, 0.5 mg of antibacterial agent, 3.1 mg of viscosity enhancer, and 0.02 mg of flavoring agent.

[0011] In some embodiments of the present invention, the sweetener comprises a non-crystalline sorbitol solution and acesulfame potassium; the non-crystalline sorbitol content in the non-crystalline sorbitol solution is 0.2-0.4 mg / ml;

[0012] Preferably, each 30 mL of simethicone emulsion contains 69.5-70.5 mg of non-crystalline sorbitol solution, more preferably 70 mg; 0.14-0.16 mg of acesulfame potassium, more preferably 0.15 mg;

[0013] or / and the buffer comprises sodium citrate;

[0014] or / and the electrolyte comprises sodium chloride;

[0015] or / and the antibacterial agent includes sorbic acid;

[0016] or / and the viscosity increasing agent comprises microcrystalline cellulose-sodium carboxymethyl cellulose;

[0017] Or / and flavoring agents include banana flavor.

[0018] The present invention discloses a method for preparing a simethicone emulsion, comprising the following steps:

[0019] The oil phase is prepared by mixing simethicone and behenic acid glyceryl, and water is added to lauroyl polyoxyethylene glyceride to prepare an aqueous phase; the remaining raw materials are mixed with water to prepare an additional liquid; the aqueous phase is added to the oil phase to prepare an emulsified solution, and the emulsified solution is added to the additional liquid, the pH value is adjusted to 4.8-5.2, water is added to make up the volume, and the mixture is stirred evenly to obtain the simethicone emulsion.

[0020] In some embodiments of the present invention, when preparing the oil phase, a prescribed amount of simethicone is placed in a container, and a prescribed amount of behenic acid glyceryl is added, heated and stirred until completely melted, stirred, heated to 75.0° C. to 85.0° C., and kept warm to obtain the oil phase;

[0021] Preferably, the stirring speed is 80-120 rpm; more preferably 100 rpm.

[0022] In some embodiments of the present invention, when preparing the aqueous phase, water is placed in a container, a prescribed amount of lauroyl polyoxyethylene glyceride is added, stirred, heated to 75.0° C. to 85.0° C., and kept warm to obtain the aqueous phase;

[0023] Preferably, in the aqueous phase, the mass ratio of lauroyl polyoxyethylene glyceride to water is 3.9:30-40; more preferably 3.9:35;

[0024] Preferably, the stirring speed is 80-120 rpm; more preferably 100 rpm.

[0025] In some embodiments of the present invention, when preparing the additional liquid, water is added to a container, heated to 75.0°C to 85.0°C, a prescribed amount of an antibacterial agent is added, and after stirring evenly, a sweetener, an electrolyte and a buffer are added, the temperature is lowered, and a viscosity enhancer is added under stirring conditions, and after adding water to a fixed volume, stirring is continued, and then the additional liquid is allowed to stand for at least 12 hours, and then a flavoring agent is added and stirred to obtain the additional liquid;

[0026] Preferably, after adding the antibacterial agent, stirring is performed at 80 to 120 rpm for 10 to 60 min; more preferably, stirring is performed at 100 rpm for 30 min;

[0027] Preferably, the temperature is lowered to below 30.0°C;

[0028] Preferably, add microcrystalline cellulose-sodium carboxymethyl cellulose under stirring at 80-120 rpm, add purified water to make the weight constant, and continue stirring for 0.5-4 hours;

[0029] Preferably, a flavoring agent is added, the stirring speed is 20-60 rpm, and the stirring time is not less than 3 hours.

[0030] In some embodiments of the present invention, when preparing the emulsified solution, the water phase is added to the oil phase, stirred, and the pipeline of the liquid preparation tank is opened for shearing to obtain the emulsified solution;

[0031] Preferably, the water phase is added to the oil phase while hot and stirred for 10 to 20 minutes, more preferably 15 minutes;

[0032] Preferably, the stirring speed during shearing is 4500-5500 rpm, more preferably 5000 rpm;

[0033] Preferably, the shearing time is 10 to 20 min; more preferably 15 min.

[0034] In some embodiments of the present invention, the emulsified solution is added to the external liquid, stirred, and then a sodium hydroxide solution or a hydrochloric acid solution is added to adjust the pH value to 4.8 to 5.2;

[0035] Preferably, the emulsified solution is added to the external liquid and stirred at 800-1200 rpm for 5-15 min; more preferably, the stirring time is 10 min at 1000 rpm.

[0036] In some embodiments of the present invention, after adjusting the pH value, purified water is added to make up the volume, and stirring is continued at a stirring speed of 60-100 rpm for 15-60 min; preferably, the stirring speed is 80 rpm for 30 min.

[0037] Compared with the prior art, the present invention has the following beneficial effects:

[0038] 1. The present invention innovatively provides a preparation process for preparing simethicone emulsion using a water-soluble emulsifier (lauroyl polyoxyethylene glyceride). The existing technology for preparing simethicone emulsion mostly uses a composite oil-soluble emulsifier, and does not consider the use of a water-soluble emulsifier.

[0039] The present invention adopts water-soluble emulsifier and purified water to prepare the water phase, the mass ratio of lauroyl polyoxyethylene glyceride to water is 3.9:30-40, and the amount of purified water is small. Contrary to the configuration conditions of sorbic acid solution, when sorbic acid is prepared into solution, the amount of water required is large. Therefore, if sorbic acid is added during the configuration process of the water phase, the sorbic acid will not be fully dissolved. In view of this, the present invention proposes to configure the additional liquid separately, and configure the auxiliary materials such as pH regulator, viscosity enhancer, sweetener, etc. together, which solves the problem of water phase preparation without adding process steps; and, since the dissolution temperature of sorbic acid is relatively high, it is also easier to control the sorbic acid content by configuring the additional solution separately.

[0040] 2. In the present invention, the additional liquid is added after emulsification, so that the sorbic acid in the prepared emulsion is more stable and the pH value is more stable, which is more conducive to long-term storage.

[0041] 3. The present invention adopts microcrystalline cellulose-sodium carboxymethyl cellulose as a thickener, which has lower viscosity than carbomer and shorter preparation time. Selecting microcrystalline cellulose-sodium carboxymethyl cellulose as a thickener can further shorten the entire process time of simethicone emulsion. BRIEF DESCRIPTION OF THE DRAWINGS

[0042] Attached Figure 1 It is a process flow chart of the present invention. DETAILED DESCRIPTION

[0043] In order to make the purpose, technical scheme and advantages of the embodiments of the present invention clearer, the technical scheme in the embodiments of the present invention will be described clearly and completely below. If the specific conditions are not specified in the embodiments, the conditions recommended by the conventional conditions or reagent providers are used. If the manufacturer is not specified for the reagents or instruments used, they are all conventional products that can be purchased commercially.

[0044] Example 1

[0045] This embodiment discloses a method for preparing the simethicone emulsion of the present invention, and its process flow is as shown in the attached Figure 1 The prescription of this embodiment is as follows:

[0046] Table 1 Prescription of Example 1

[0047]

[0048] The content of non-crystalline sorbitol in the non-crystalline sorbitol solution is 0.3 mg / ml.

[0049] The preparation method of this embodiment is as follows:

[0050] 1. Weighing:

[0051] Weigh each material according to the prescription list and set aside.

[0052] 2. Liquid preparation

[0053] (1) Preparation of external liquid: Add 500g of purified water to the liquid preparation tank, heat to 75.0℃~85.0℃, add sorbic acid, start stirring, stir at 80rpm, and stir for 30min. Add weighed non-crystalline sorbitol solution, sodium chloride, acesulfame potassium and sodium citrate. Start cooling, and stop cooling when the solution temperature drops below 30.0℃. Add microcrystalline cellulose-sodium carboxymethyl cellulose at a stirring speed of 100rpm, and add purified water to weigh to 680g. Stir for about 2 hours and then stop stirring. Let it stand overnight for at least 12 hours. Add banana flavor, start stirring, stir at 40rpm, and stir for 3 hours. Set aside.

[0054] (2) Preparation of oil phase: Place the weighed simethicone in a stainless steel barrel, add behenic acid glyceryl, heat and stir using an induction cooker until completely melted, then transfer to a liquid preparation tank, stir at 100 rpm and heat to 75.0°C~85.0°C for insulation. This is the oil phase and is ready for use.

[0055] (3) Preparation of aqueous phase: Add the prescribed amount of purified water and lauroyl polyoxyethylene glyceride into the liquid preparation tank, start stirring at a speed of 100 rpm, and heat to 75.0°C~85.0°C to keep warm, i.e., the aqueous phase, for later use.

[0056] (4) Emulsification: Add the water phase into the oil phase while it is hot, stir for 15 minutes, then start the shear of the liquid preparation tank pipeline (stirring speed 5000 rpm), and stir for 15 minutes to obtain an emulsified solution.

[0057] (5) Mixing the emulsified solution with the external liquid: Add the emulsified solution into the external liquid and increase the stirring speed to 1000 rpm for 10 min.

[0058] (6) pH adjustment: Add sodium hydroxide solution or hydrochloric acid solution to adjust the pH to 5.0.

[0059] (7) Make up the volume: Add purified water to make up to 1 L and continue stirring at 80 rpm for 30 min.

[0060] 3. Bottle washing

[0061] The pharmaceutical bottles should be cleaned, sterilized and dried for later use. The dried pharmaceutical bottles should be free of water marks, stains and foreign matter visible to the naked eye.

[0062] 4. Filling

[0063] After the simethicone emulsion is tested and qualified, the liquid is pumped into the buffer tank, and the test filling and filling volume are adjusted. The volume of each bottle is adjusted to 30ml, and the volume should meet the requirements. Start the filling machine to screw the cap, observe whether the capping is straight and tight, and formal filling is carried out after it meets the requirements.

[0064] 5. Packaging

[0065] Before packing, check the simethicone emulsion to be packaged to see if there are impurities, glass slag, foreign matter, etc. in the bottle. If there are foreign matter, remove them as unqualified products.

[0066] 6. Storage

[0067] After the packaged products are put into cartons, they are sealed with sealing tape, and relevant information is pasted on the outside of the carton. The products are then put into the finished product warehouse.

[0068] Example 2

[0069] In this embodiment, oil-soluble behenic acid glyceryl and water-soluble lauroyl polyoxyethylene glyceride are used as emulsifiers to prepare simethicone emulsion. The preparation method is different from that in Example 1, except that the emulsifiers are different, and the other conditions are the same. The ratio of behenic acid glyceryl and water-soluble lauroyl polyoxyethylene glyceride determines the hydrophilic-lipophilic balance (HLB value) of the system, and the HLB value plays an important role in the stability of the emulsion. Since both emulsifiers are non-ionic emulsifiers, the HLB value after mixing can be calculated according to the formula HLB 12 =W1×HLB1+W2×HLB2, where W1 and W2 represent the mass fractions of the two.

[0070] Therefore, the HLB value of the emulsifier was examined with emulsion stability and defoaming ability as detection indicators, and then the dosage of the two emulsifiers was determined. The results are shown in the table below.

[0071] Table 2 Emulsifier dosage investigation

[0072]

[0073] Among them, the detection method of the stability of the emulsion is: take the product, shake it well, take 10ml and place it in a centrifuge tube, centrifuge it at 2000rpm for 6min, and there should be no stratification.

[0074] Defoaming ability test method: Take two portions of 1.0% Triton X-100 solution without foam, 50 ml each, and carefully inject them into two clean 250 ml stoppered measuring cylinders respectively. Measure 0.4 ml of this product (rinse the measuring vessel with water twice, 2.0 ml each time) and put it into one of the measuring cylinders. Seal the two measuring cylinders tightly, shake them vigorously 5 times, leave them for 1 minute, measure the foam height, divide the height of the reduced foam in the measuring cylinder with emulsion by the height of the foam in the measuring cylinder without emulsion (100%), and calculate the defoaming ability, which should be no less than 80%.

[0075] According to the test results, when the HLB value is 8, the defoaming ability and stability of the obtained emulsion are good, that is, 3.2 mg of glyceryl behenate and 3.9 mg of lauroyl polyoxyethylene glyceride.

[0076] Example 3

[0077] In this example, simethicone emulsions with different pH values ​​were prepared and their stability was investigated. The simethicone emulsion in the test group was prepared according to the method of Example 1, except that the pH value was adjusted differently; the simethicone emulsion in the reference preparation was an original imported product of Berlin-Chemie AG in Germany, which is listed in China, and its trade name is Espumisan®. The quality control of the emulsion production process and the quality control of the delivery process adopt conventional technology. The results of the investigation are shown in the following table:

[0078] Table 3 Results of stability study of simethicone emulsions at different pH values

[0079]

[0080] The properties required are: milky white low-viscosity emulsion with banana fragrance.

[0081] The centrifugal stability requirement is: there should be no stratification after centrifugation at 2000 revolutions per minute for 6 minutes.

[0082] From the above results, it can be seen that the pH of the simethicone emulsion prepared by the method of the present invention is more stable, and the pH value does not change significantly at 40°C and 60°C, while the reference preparation changes at 40°C and 60°C. The results show that the simethicone emulsion prepared by the method of the present invention is more convenient for storage and transportation.

[0083] Example 4

[0084] This example prepares simethicone emulsions with different concentrations of sweeteners and flavoring agents to examine the compliance of the simethicone emulsion. In this test example, the simethicone emulsion is prepared according to the method of Example 1, except that the content of sweeteners and flavoring agents in the finished product is different. The methicone emulsion of the reference preparation is a domestically marketed simethicone emulsion, which is an original imported product of Berlin-Chemie AG in Germany, with a trade name of Espumisan®. The compliance scoring criteria are shown in the following table:

[0085] Table 4 Compliance scoring criteria

[0086]

[0087] The results of the survey are shown in the following table:

[0088] Table 5 Compliance investigation results

[0089]

[0090] It can be seen from the test data that when the concentration of acesulfame potassium is 0.15 mg / ml and the concentration of banana essence is 0.02 mg / ml, the simethicone emulsion prepared by the method has the best taste and aroma, and the patient's compliance is the best when taking it.

[0091] Example 5

[0092] This example investigates the sorbic acid stability of the simethicone emulsion prepared by the method of Example 1 and the reference preparation. The simethicone emulsion of the reference preparation is a domestically marketed simethicone emulsion originally developed and imported by Berlin-Chemie AG of Germany, with the trade name Espumisan®.

[0093] The test method is: place two simethicone emulsion samples at 60±2℃, and test their defoaming ability and sorbic acid content in the emulsion at different time points. The results are shown in the following table:

[0094] Table 6 Results of the stability study of sorbic acid

[0095]

[0096] The method for detecting the defoaming ability is the same as in Example 2.

[0097] The detection method of sorbic acid is: determination according to the high performance liquid chromatography method (General Rules 0512 of Part IV of the Chinese Pharmacopoeia 2020 Edition).

[0098] It can be seen from the above test data that the simethicone emulsion prepared by the method of the present invention still has a high sorbic acid content after 30 days. Compared with the reference preparation, the sorbic acid in the present invention is more stable when an additional liquid is added after emulsification.

[0099] Finally, it should be noted that the above embodiments are only preferred embodiments of the present invention to illustrate the technical solution of the present invention, but not to limit it, and certainly not to limit the patent scope of the present invention. Any changes or modifications that are made to the main design concept and spirit of the present invention without any substantial meaning, and the technical problems they solve are still consistent with the present invention, should be included in the protection scope of the present invention; in addition, the direct or indirect application of the technical solution of the present invention in other related technical fields is also included in the patent protection scope of the present invention.

Claims

1. A method for preparing a simethicone emulsion, characterized in that: Each 1 ml of simethicone emulsion contains the following ingredients: 40 mg of simethicone, 3.0-3.4 mg of glyceryl behenate, 3.8-4.0 mg of lauroyl polyoxyethylene glyceride, 70.15 mg of sweetener, 2.0-2.4 mg of buffer, 0.6-0.8 mg of electrolyte, 0.4-0.6 mg of antibacterial agent, 3.0-3.2 mg of viscosity enhancer, 0.02 mg of flavoring agent, and the pH value of the simethicone emulsion is 4.8-5.2; The sweetener is non-crystalline sorbitol solution and acesulfame potassium; wherein the non-crystalline sorbitol solution contains 70 mg of non-crystalline sorbitol solution and 0.15 mg of acesulfame potassium, and the non-crystalline sorbitol content in the non-crystalline sorbitol solution is 0.2-0.4 mg / ml; the buffer is sodium citrate; the electrolyte is sodium chloride; the antibacterial agent is sorbic acid; the viscosity enhancer is microcrystalline cellulose-sodium carboxymethyl cellulose; and the flavoring agent is banana essence; The preparation method comprises the following steps: The oil phase is prepared by mixing simethicone and behenic acid glyceryl; water is added to lauroyl polyoxyethylene glyceride to prepare an aqueous phase; the remaining raw materials are mixed with water to prepare an additional liquid; the aqueous phase is added to the oil phase to prepare an emulsified solution, and the emulsified solution is added to the additional liquid, the pH value is adjusted to 4.8-5.2, water is added to the fixed volume, and the mixture is stirred evenly to obtain a simethicone emulsion; When preparing the additional liquid, add water to the container, heat to 75.0℃~85.0℃, add the prescribed amount of antibacterial agent, stir evenly, add sweetener, electrolyte and buffer, cool down, add viscosity enhancer under stirring, add water to make up the volume, continue stirring, and then let it stand for at least 12 hours, then add flavoring agent, stir, and the additional liquid is obtained.

2. The method for preparing a simethicone emulsion according to claim 1, wherein: Each 1 ml of simethicone emulsion contains the following ingredients: 40 mg of simethicone, 3.2 mg of glyceryl behenate, 3.9 mg of lauroyl polyoxyethylene glyceride, 70.15 mg of sweetener, 2.2 mg of buffer, 0.7 mg of electrolyte, 0.5 mg of antibacterial agent, 3.1 mg of viscosity enhancer, and 0.02 mg of flavoring agent.

3. The method for preparing a simethicone emulsion according to claim 1, characterized in that: When preparing the oil phase, place the prescribed amount of simethicone in a container, add the prescribed amount of behenic acid glyceryl, heat and stir until completely melted, stir, heat to 75.0°C~85.0°C, and keep warm to obtain the oil phase.

4. The method for preparing a simethicone emulsion according to claim 1, characterized in that: When preparing the water phase, water is placed in a container, and the prescribed amount of lauroyl polyoxyethylene glyceride is added, stirred, heated to 75.0°C to 85.0°C, and kept warm to obtain the water phase; In the aqueous phase, the mass ratio of lauroyl polyoxyethylene glyceride to water is 3.9:30-40.

5. A method for preparing a simethicone emulsion according to any one of claims 1 to 4, characterized in that: When preparing the emulsified solution, add the water phase into the oil phase, stir, open the pipe of the liquid preparation tank to shear, and then the emulsified solution is obtained.

6. The method for preparing a simethicone emulsion according to claim 1, characterized in that: Add the emulsified solution to the external liquid, stir, and then add sodium hydroxide solution or hydrochloric acid solution to adjust the pH value to 4.8~5.

2.

7. The method for preparing a simethicone emulsion according to claim 6, characterized in that: After adjusting the pH value, add purified water to make up the volume and continue stirring at a speed of 60-100 rpm for 15-60 minutes.

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