A simethicone emulsion and a method for preparing the same

Abstract

This invention belongs to the field of pharmaceutical preparations, and particularly relates to a dimethicone emulsion and its preparation method. The preparation method provided by this invention includes the following steps: a) grinding and mixing dimethicone and silica at 100-140°C to obtain an oil phase mixture; b) mixing sodium saccharin, ethylparaben, and water, and then mixing with sodium carboxymethyl cellulose to obtain an aqueous phase mixture; c) mixing the oil phase mixture, polysorbate 80, and sorbitan oleate, and then mixing with a portion of the aqueous phase mixture, followed by homogenization to obtain a primary emulsion; d) mixing the remaining aqueous phase mixture, an ethanol solution of butylated hydroxytoluene, and a fragrance, and then mixing with the primary emulsion, finally adding water to make up to a fixed volume and mixing to obtain the dimethicone emulsion. The preparation method provided by this invention has a short production cycle and high production efficiency, and the resulting dimethicone emulsion product has excellent defoaming ability and quality stability.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparations, and particularly relates to a dimethicone emulsion and its preparation method. Background Technology

[0002] Dimethylsiloxane is a polymer of dimethylsiloxane. It is a colorless, clear, oily liquid that is odorless or almost odorless. It is miscible in chloroform, ether, toluene, or xylene, but insoluble in water or ethanol.

[0003] Because dimethicone has a low surface tension, it can alter the surface tension of air bubbles, causing them to aggregate and burst, thus eliminating foam. Therefore, it is an important antifoaming agent in clinical practice. Clinically, it is often used to improve abdominal symptoms caused by gas in the gastrointestinal tract, to remove foamy mucus in the stomach during gastroscopy, and to expel intestinal gas during abdominal X-ray examination.

[0004] Dimethicone alone has weak defoaming ability and usually needs to be mixed with silica to enhance its defoaming ability. Dimethicone-silica defoaming compounds with a silica content between 4.0% and 7.0% are generally called dimethicone. Dimethicone-silica defoaming compounds with a silica content of less than 4.0% are generally called active dimethicone or dimethicone. Dimethicone-silica mixtures with a silica content of more than 7.0% have higher viscosity and poorer flowability and are often called silicone paste.

[0005] Dimethicone is insoluble in water and is physiologically inert, therefore it is not absorbed by the human body and is suitable for preparation into O / W type emulsions. In emulsions, dimethicone exists as fine oil droplets, exhibiting high dispersibility and strong defoaming ability.

[0006] Existing processes for preparing dimethicone emulsions generally suffer from low production efficiency and insufficient defoaming ability and quality stability, which require further improvement. Summary of the Invention

[0007] In view of this, the purpose of this invention is to provide a dimethicone emulsion and its preparation method. The preparation method provided by this invention has a short production cycle and high production efficiency, and the dimethicone emulsion product obtained has excellent defoaming ability and quality stability.

[0008] This invention provides a method for preparing a dimethicone emulsion, comprising the following steps:

[0009] a) Dimethicone oil and silica are ground and mixed at 100–140°C to obtain an oil phase mixture;

[0010] b) Mix sodium saccharin, ethylparaben, and water, and then mix with sodium carboxymethyl cellulose to obtain an aqueous mixture;

[0011] There is no specific order between steps a) and b).

[0012] c) The oil phase mixture, polysorbate 80 and sorbitan oleate are mixed evenly, and then mixed with a portion of the aqueous phase mixture. After homogenization, the primary emulsion is obtained.

[0013] d) Mix the remaining aqueous mixture, the ethanol solution of butylated hydroxytoluene, and the fragrance, then mix them with the primary emulsion, and finally add water to make up to a final volume and mix to obtain a dimethicone emulsion.

[0014] Preferably, in step a), the grinding time for grinding and mixing is 2 to 4 hours.

[0015] Preferably, in step b), the temperature of the water is 70–90°C.

[0016] Preferably, in step b), the amount of water used is 80-90 wt% of the total amount of water used to prepare the dimethicone emulsion.

[0017] Preferably, in step c), the amount of the aqueous phase mixture is 20-30 wt% of the total amount of the aqueous phase mixture.

[0018] Preferably, in step c), the pressure of the homogenization process is 200–700 bar.

[0019] Preferably, in step c), the homogenization temperature is 10–40°C.

[0020] Preferably, in step c), the homogenization process is performed 4 to 8 times.

[0021] Preferably, in step d), each 100L of the dimethicone emulsion contains 2kg of dimethicone, 0.04-0.08kg of silica, 0.3-0.6kg of polysorbate 80, 0.3-0.6kg of sorbitan oleate, 0.8-1.6kg of sodium carboxymethyl cellulose, 0.08-0.12kg of ethylparaben, 0.0005-0.0015kg of butylated hydroxytoluene, 1-2kg of ethanol, 0.04-0.06kg of sodium saccharin, and 0.01-0.03kg of flavoring.

[0022] This invention provides a dimethicone emulsion, prepared according to the preparation method described in the above technical solution.

[0023] Compared with the prior art, the present invention provides a dimethicone emulsion and its preparation method. The preparation method provided by the present invention includes the following steps: a) grinding and mixing dimethicone and silica at 100-140°C to obtain an oil phase mixture; b) mixing sodium saccharin, ethylparaben, and water, and then mixing with sodium carboxymethyl cellulose to obtain an aqueous phase mixture; there is no specific order between steps a) and b); c) mixing the oil phase mixture, polysorbate 80, and sorbitan oleate, and then mixing with a portion of the aqueous phase mixture, followed by homogenization to obtain a primary emulsion; d) mixing the remaining aqueous phase mixture, an ethanol solution of butylated hydroxytoluene, and a fragrance, and then mixing with the primary emulsion, and finally adding water to make up to a fixed volume and mixing to obtain the dimethicone emulsion. This invention employs a high-temperature grinding process to prepare an oil phase from dimethicone and silica. A water phase is prepared by mixing sodium saccharin, ethylparaben, sodium carboxymethyl cellulose, and a certain amount of water. A primary emulsion is then prepared by combining the oil phase, emulsifier, and a portion of the water phase. Other excipients and the primary emulsion are then added sequentially to the remaining water phase, brought to a final volume, and mixed thoroughly to obtain the dimethicone emulsion. The method of this invention for preparing dimethicone emulsion offers advantages such as short production time, high production efficiency, strong operability, good reproducibility, and the final product exhibits excellent defoaming ability and quality stability, making it suitable for large-scale commercial production. Attached Figure Description

[0024] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on the provided drawings without creative effort.

[0025] Figure 1 The particle size distribution diagram of the sample in Example 1 provided by the present invention;

[0026] Figure 2 The particle size distribution diagram of the sample in Example 2 provided by the present invention;

[0027] Figure 3 The particle size distribution diagram of the sample in Example 3 provided by the present invention;

[0028] Figure 4 Particle size distribution diagram of the reference formulation sample provided by this invention;

[0029] Figure 5 The content detection chromatogram of sample 0 in Example 2 of this invention;

[0030] Figure 6 The content detection chromatogram of the sample in Example 2 of this invention under accelerated 3-month investigation;

[0031] Figure 7 The content detection chromatogram of the sample in Example 2 of this invention was obtained after accelerated testing over 6 months. Detailed Implementation

[0032] The technical solutions in the embodiments of the present invention will be clearly and completely described below. 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 skilled in the art without creative effort are within the scope of protection of the present invention.

[0033] This invention provides a method for preparing a dimethicone emulsion, comprising the following steps:

[0034] a) Grind and mix dimethyl silicone oil and silica to obtain an oil phase mixture;

[0035] b) Mix sodium saccharin, ethylparaben, and water, and then mix with sodium carboxymethyl cellulose to obtain an aqueous mixture;

[0036] There is no specific order between steps a) and b).

[0037] c) The oil phase mixture, polysorbate 80 and sorbitan oleate are mixed evenly, and then mixed with a portion of the aqueous phase mixture. After homogenization, the primary emulsion is obtained.

[0038] d) Mix the remaining aqueous mixture, the ethanol solution of butylated hydroxytoluene, and the fragrance, then mix them with the primary emulsion, and finally add water to make up to a final volume and mix to obtain a dimethicone emulsion.

[0039] In the preparation method provided by the present invention, in step a), the dimethicone oil and silicon dioxide are preferably stirred and mixed before grinding.

[0040] In the preparation method provided by this invention, in step a), the grinding temperature for grinding and mixing is 100-140℃, but can be, but is not limited to, 100℃, 110℃, 120℃, 130℃ or 140℃. In this invention, the grinding temperature is preferably different depending on the production batch. Taking the production of 200L batch of dimethicone emulsion as an example, the grinding temperature is preferably 120℃±5℃.

[0041] In the preparation method provided by this invention, in step a), the grinding and mixing time is preferably 2 to 4 hours, but can be, but is not limited to, 2 hours, 2.5 hours, 3 hours, 3.5 hours, or 4 hours. In this invention, the grinding time is preferably different depending on the production batch. Taking the production of 200L batch of dimethicone emulsion as an example, the grinding time is preferably 3 hours.

[0042] In the preparation method provided by the present invention, in step a), after the grinding and mixing is completed, the resulting oil phase mixture is cooled to room temperature.

[0043] In the preparation method provided by this invention, in step b), the water is preferably purified water; the temperature of the water is preferably 70-90°C, but can be, but is not limited to, 70°C, 75°C, 80°C, 85°C, or 90°C. In this invention, to achieve a better mixing effect, the temperature of the water is more preferably 80°C ± 5°C.

[0044] In the preparation method provided by the present invention, in step b), the amount of water used is preferably 80-90 wt% of the total amount of water used to prepare the dimethicone emulsion, but may be, but is not limited to, 80 wt%, 85 wt%, or 90 wt%.

[0045] In the preparation method provided by the present invention, in step a), after mixing with the sodium carboxymethyl cellulose, the resulting aqueous mixture is cooled to room temperature.

[0046] In the preparation method provided by this invention, in step c), the amount of the aqueous phase mixture is preferably 20-30 wt% of the total amount of the aqueous phase mixture, and can be, but is not limited to, 21 wt%, 22 wt%, 23 wt%, 24 wt%, 25 wt%, 26 wt%, 27 wt%, 28 wt%, 29 wt%, or 30 wt%. In this invention, to achieve a better mixing effect, the amount of the aqueous phase mixture is more preferably 25 wt% of the total amount of the aqueous phase mixture.

[0047] In the preparation method provided by this invention, in step c), the pressure of the homogenization treatment is preferably 200-700 bar, but can be, but is not limited to, 200 bar, 300 bar, 400 bar, 500 bar, 600 bar, or 700 bar. In this invention, to achieve better homogenization effect, the pressure of the homogenization treatment is more preferably 350 bar ± 50 bar.

[0048] In the preparation method provided by this invention, in step c), the homogenization temperature is preferably 10–40°C, but can be, but is not limited to, 10°C, 20°C, 30°C, or 40°C. In this invention, to achieve better homogenization, the homogenization temperature is more preferably 25°C ± 5°C.

[0049] In the preparation method provided by the present invention, in step c), the homogenization process is preferably performed 4 to 8 times, but can be, but is not limited to, 4, 5, 6, 7, or 8 times.

[0050] In the preparation method provided by the present invention, in step d), the ethanol solution of butylated hydroxytoluene is preferably prepared by mixing butylated hydroxytoluene and ethanol.

[0051] In the preparation method provided by the present invention, in step d), the flavoring is preferably fresh milk flavoring.

[0052] In the preparation method provided by this invention, in step d), each 100L of the dimethicone emulsion preferably contains 2kg of dimethicone, 0.04-0.08kg of silica, 0.3-0.6kg of polysorbate 80, 0.3-0.6kg of sorbitan oleate, 0.8-1.6kg of sodium carboxymethyl cellulose, 0.08-0.12kg of ethylparaben, 0.0005-0.0015kg of butylated hydroxytoluene, and 1-2kg of other components. The ingredients include 0.04-0.06 kg of ethanol, 0.01-0.03 kg of sodium saccharin, and more preferably 2 kg of dimethicone, 0.06 kg of silica, 0.45 kg of polysorbate 80, 0.45 kg of sorbitan oleate, 1.2 kg of sodium carboxymethyl cellulose, 0.1 kg of ethylparaben, 0.001 kg of butylated hydroxytoluene, 1.5 kg of ethanol, 0.05 kg of sodium saccharin, and 0.02 kg of flavoring.

[0053] The preparation method provided by this invention involves using high-temperature grinding to prepare an oil phase from dimethicone and silica, and preparing an aqueous phase from sodium saccharin, ethylparaben, sodium carboxymethyl cellulose, and a certain amount of water. The oil phase, emulsifier, and a portion of the aqueous phase are then combined to form a primary emulsion. Other excipients and the primary emulsion are then added sequentially to the remaining aqueous phase, brought to a final volume, and mixed thoroughly to obtain the dimethicone emulsion. The method of this invention provides a short production time, high production efficiency, strong operability, good reproducibility, and the final product exhibits excellent defoaming ability and quality stability, making it suitable for large-scale commercial production.

[0054] This invention also provides a dimethicone emulsion, prepared according to the preparation method described above. The dimethicone emulsion provided by this invention has excellent defoaming ability and quality stability.

[0055] For clarity, the following examples will be used to provide a detailed description.

[0056] Example 1

[0057] (1) Prescription

[0058] Dimethicone 2kg silicon dioxide 0.06kg Polysorbate 80 0.45kg Sorbitan oleate 0.45kg Butylated hydroxytoluene 0.001kg ethanol 1.5kg Sodium carboxymethyl cellulose 1.2kg Ethylparaben 0.1kg Sodium saccharin 0.05kg Fresh milk flavoring 0.02kg Add purified water to 100L

[0059] (2) Preparation method

[0060] ① Mix dimethicone and silica evenly, grind at 100°C for 2 hours, cool to room temperature to obtain an oil phase mixture;

[0061] ② Take 90 wt% of the total water volume of the prescription, add sodium saccharin and ethylparaben, stir until dissolved, then add sodium carboxymethyl cellulose, stir until fully swollen, cool to room temperature, and obtain an aqueous mixture;

[0062] ③ Add polysorbate 80 and sorbitan oleate to the oil phase mixture, stir and mix until the color is uniform, then slowly add 30wt% of the aqueous phase mixture, stir thoroughly until a white emulsion is formed, and no oil droplets are observed to precipitate, thus obtaining an oil-water premix.

[0063] ④ Add the oil-water premix to a high-pressure nano-homogenizer, adjust the homogenization pressure to 200 bar, control the homogenization temperature at about 25°C, and homogenize the oil-water premix 4 times to obtain the colostrum.

[0064] ⑤ Add butylated hydroxytoluene to ethanol and stir until dissolved to obtain a butylated hydroxytoluene ethanol solution;

[0065] ⑥ Add fresh milk flavoring and butylated hydroxytoluene ethanol solution to the remaining aqueous phase mixture in sequence, stir and mix evenly, then add the initial emulsion, stir and mix, add water to make up the volume, and continue to stir evenly to obtain dimethicone emulsion.

[0066] Example 2

[0067] (1) Prescription

[0068] Dimethicone 4kg silicon dioxide 0.12kg Polysorbate 80 0.9kg Sorbitan oleate 0.9kg Butylated hydroxytoluene 0.002kg ethanol 3kg Sodium carboxymethyl cellulose 2.4kg Ethylparaben 0.2kg Sodium saccharin 0.1kg Fresh milk flavoring 0.04kg Add purified water to 200L

[0069] (2) Preparation method

[0070] ① Mix dimethicone and silica evenly, grind at 120°C for 3 hours, cool to room temperature to obtain an oil phase mixture;

[0071] ② Take 90wt% of the total water volume of the prescription in purified water at 80℃, add sodium saccharin and ethylparaben, stir until dissolved, then add sodium carboxymethyl cellulose, stir until fully swollen, cool to room temperature, and obtain an aqueous mixture;

[0072] ③ Add polysorbate 80 and sorbitan oleate to the oil phase mixture, stir and mix until the color is uniform, then slowly add 25 wt% of the aqueous phase mixture, stir thoroughly until a white emulsion is formed, and no oil droplets are observed to precipitate, thus obtaining an oil-water premix.

[0073] ④ Add the oil-water premix to a high-pressure nano-homogenizer, adjust the homogenization pressure to 350 bar, control the homogenization temperature at about 25°C, and homogenize the oil-water premix 6 times to obtain the colostrum.

[0074] ⑤ Add butylated hydroxytoluene to ethanol and stir until dissolved to obtain a butylated hydroxytoluene ethanol solution;

[0075] ⑥ Add fresh milk flavoring and butylated hydroxytoluene ethanol solution to the remaining aqueous phase mixture in sequence, stir and mix evenly, then add the initial emulsion, stir and mix, add water to make up the volume, and continue to stir evenly to obtain dimethicone emulsion.

[0076] Example 3

[0077] (1) Prescription

[0078] Dimethicone 10kg silicon dioxide 0.3kg Polysorbate 80 2.25kg Sorbitan oleate 2.25kg Butylated hydroxytoluene 0.005kg ethanol 7.5kg Sodium carboxymethyl cellulose 6kg Ethylparaben 0.5kg Sodium saccharin 0.25kg Fresh milk flavoring 0.1kg Add purified water to 500L

[0079] (2) Preparation method

[0080] ① Mix dimethicone and silica evenly, grind at 135°C for 4 hours, cool to room temperature to obtain an oil phase mixture;

[0081] ② Take 90wt% of the total water volume of the prescription in purified water at 75℃, add sodium saccharin and ethylparaben, stir until dissolved, then add sodium carboxymethyl cellulose, stir until fully swollen, cool to room temperature, and obtain an aqueous mixture;

[0082] ③ Add polysorbate 80 and sorbitan oleate to the oil phase mixture, stir and mix until the color is uniform, then slowly add 20 wt% of the aqueous phase mixture, stir thoroughly until a white emulsion is formed, and no oil droplets are observed to precipitate, thus obtaining an oil-water premix.

[0083] ④ Add the oil-water premix to a high-pressure nano homogenizer, adjust the homogenization pressure to 400 bar, control the homogenization temperature at about 30°C, and homogenize the oil-water premix 8 times to obtain the colostrum.

[0084] ⑤ Add butylated hydroxytoluene to ethanol and stir until dissolved to obtain a butylated hydroxytoluene ethanol solution;

[0085] ⑥ Add fresh milk flavoring and butylated hydroxytoluene ethanol solution to the remaining aqueous phase mixture in sequence, stir and mix evenly, then add the initial emulsion, stir and mix, add water to make up the volume, and continue to stir evenly to obtain dimethicone emulsion.

[0086] Example 4

[0087] The main quality indicators of the samples from Examples 1, 2, and 3 were tested, including appearance, pH value, emulsion stability, defoaming ability, content, particle size distribution, and zeta potential, and compared with the original reference formulation produced by Kissei Pharmaceuticals Co., Ltd. (Kirio Pharmaceuticals Co., Ltd., Japan). The testing methods for each quality indicator and the comparison results of the self-made samples and the reference formulation are as follows:

[0088] (1) pH value detection method

[0089] The pH value of the emulsion was determined according to the General Chapter 0631 pH value determination method in Part IV of the 2020 edition of the Chinese Pharmacopoeia.

[0090] (2) Methods for testing emulsion stability

[0091] According to the General Rules, Part IV of the 2020 edition of the Chinese Pharmacopoeia, the emulsion should not separate into layers when centrifuged at 4000 rpm (approximately 1800 × g) for 15 minutes using a centrifuge with a radius of 10 cm.

[0092] (3) Defoaming ability testing method

[0093] Take two 50 mL portions of a non-foaming 1 wt% Triton X-100 (octyl phenyl polyol-9) aqueous solution and carefully pour them into two clean 250 mL stoppered graduated cylinders. Measure 2.0 mL of the emulsion into one of the graduated cylinders, seal both cylinders, and shake vigorously 5 times. After 1 minute, measure the foam height. Using the foam amount of the non-emulsion sample as 100%, calculate the defoaming ability based on the amount of foam reduced in the test sample. It should not be less than 80%.

[0094] (4) Content detection method

[0095] The emulsion content was determined according to the General Chapter 4 <0402 Infrared Spectrophotometry> of the 2020 edition of the Chinese Pharmacopoeia.

[0096] (5) Particle size detection method

[0097] The particle size of the emulsion was determined using a laser particle size analyzer.

[0098] (6) Zeta potential detection method

[0099] The zeta potential of the emulsion was determined using a zeta potential analyzer.

[0100] (7) Test Results

[0101]

[0102] Comparative test results show that the dimethicone emulsion prepared using the method of this invention has similar quality indicators to the original reference formulation produced by Kissei Pharmaceuticals Co., Ltd. (Kirio Pharmaceutical Co., Ltd.). Particle size distribution charts for each sample are shown below. Figures 1-4 .

[0103] Example 5

[0104] According to the "Guidelines for Stability Testing of Raw Materials and Preparations" in General Chapter 4 of the 2020 edition of the Chinese Pharmacopoeia, the samples from Example 2 were placed at a temperature of 40℃±2℃ and a relative humidity of 75%±5% for 6 months. Samples were taken at 3 and 6 months to assess the quality of the samples, and compared with samples from 0 months prior to the test. The main quality indicators examined included appearance, pH value, emulsion stability, defoaming ability, content, microbial limits, particle size distribution, and zeta potential. The accelerated testing results are as follows:

[0105]

[0106] The above results indicate that the dimethicone emulsion prepared using the method of this invention exhibits relatively stable quality. After 6 months of accelerated storage (40℃, 75% RH), the quality indicators of the sample from Example 2, including appearance, pH value, emulsion stability, defoaming ability, content, microbial limit, particle size distribution, and zeta potential, showed no significant changes compared to day 0. Content detection chromatograms of the samples after 0 months, 3 months of accelerated storage, and 6 months of accelerated storage are shown in the figures. Figures 5-7 .

[0107] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A method for preparing a dimethicone emulsion, characterized by, Includes the following steps: a) Dimethicone oil and silica are ground and mixed at 100–140°C to obtain an oil phase mixture; b) Mix sodium saccharin, ethylparaben, and water, and then mix with sodium carboxymethyl cellulose to obtain an aqueous mixture; There is no specific order between steps a) and b). c) The oil phase mixture, polysorbate 80 and sorbitan oleate are mixed evenly, and then mixed with a portion of the aqueous phase mixture. After homogenization, the primary emulsion is obtained. d) Mix the remaining aqueous mixture, the ethanol solution of butylated hydroxytoluene, and the fragrance, then mix them with the primary emulsion, and finally add water to make up to a final volume and mix to obtain a dimethicone emulsion.

2. The production method according to claim 1, characterized by, In step a), the grinding time for grinding and mixing is 2 to 4 hours.

3. The preparation method according to claim 1, characterized in that, In step b), the temperature of the water is 70–90°C.

4. The method of claim 1, wherein, In step b), the amount of water used is 80-90 wt% of the total amount of water used to prepare the dimethicone emulsion.

5. The preparation method according to claim 1, characterized in that, In step c), the amount of the aqueous phase mixture is 20-30 wt% of the total amount of the aqueous phase mixture.

6. The method of claim 1, wherein, In step c), the pressure of the homogenization process is 200–700 bar.

7. The preparation method according to claim 1, characterized in that, In step c), the homogenization process is carried out at a temperature of 10–40°C.

8. The method of claim 1, wherein, In step c), the homogenization process is performed 4 to 8 times.

9. The method of claim 1, wherein, In step d), each 100L of the dimethicone emulsion contains 2kg of dimethicone, 0.04-0.08kg of silica, 0.3-0.6kg of polysorbate 80, 0.3-0.6kg of sorbitan oleate, 0.8-1.6kg of sodium carboxymethyl cellulose, 0.08-0.12kg of ethylparaben, 0.0005-0.0015kg of butylated hydroxytoluene, 1-2kg of ethanol, 0.04-0.06kg of sodium saccharin, and 0.01-0.03kg of flavoring.

10. A simethicone emulsion characterized in that, Prepared according to the preparation method according to any one of claims 1 to 9.

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