Simethicone emulsion and preparation method thereof

Abstract

The invention provides the simethicone emulsion and the preparation method thereof, the emulsion adopts carbomer with a specific viscosity range, the obtained simethicone emulsion does not generate white flocculate in the stomach, the definition and accuracy of stomach examination are improved, and the obtained emulsion is appropriate in viscosity, strong in defoaming ability, free of sedimentation and easy to flow. The simethicone emulsion provided by the invention can better play a role in eliminating mucus and foam in gastroscopy and enteroscopy, improves the mucous membrane visibility and the focus detection rate, is suitable for different acidic environments, and improves the examination efficiency and the patient experience.

Description

Technical Field

[0001] This invention relates to the field of biomedical technology, specifically to an emulsion containing simethicone and its preparation method. Background Technology

[0002] Simethicone is a complex of dimethicone and silica, with the molecular formula (CH3)3Si[-O-Si(CH3)2]nCH3+SiO2. Existing simethicone emulsion products tend to flocculate after entering the stomach, severely affecting the visibility of the esophageal and gastric mucosa under endoscopy.

[0003] When simethicone emulsion is used as an antifoaming agent in gastroscopy, it can avoid the above-mentioned gastric flocculation to a certain extent. However, the antifoaming effect of simethicone emulsion is significantly lower than that of simethicone emulsion. Although it can avoid the flocculation problem of simethicone emulsion in the stomach, the antifoaming effect is not ideal, and the dosage may need to be increased, which increases the burden on patients and safety risks.

[0004] To address the above issues, existing studies recommend combining streptomycin and / or alkaline solutions. For example, the studies titled "The Effect of Streptomycin + Simethicone on the Efficacy of Painless Gastroscopy" (first published online in the Chinese Journal of Endoscopy, May 17, 2021) and "The Effect of Oral Administration of a Mixture of Streptomycin + Simethicone + Sodium Bicarbonate on the Quality of Gastroscopy" (first published online in the Chinese Journal of Endoscopy, March 30, 2020) disclose that administering a mixed solution of streptomycin, simethicone, and sodium bicarbonate to patients before gastroscopy, but requiring immediate preparation and oral administration within one hour of preparation, significantly improves the clarity of the endoscopic field of view. Oral administration after a storage time exceeding one hour significantly reduces the clarity of the endoscopic field of view and the detection rate of small lesions. Patent CN115400228A discloses "an anti-flocculation and defoaming agent for the digestive tract mucosa during gastroscopy and its preparation method, comprising 400mg of simethicone, 20000U-24000U of streptomycin, 1.6g-2.0g of a weakly alkaline substance such as sodium bicarbonate, and 1.0g-1.3g of xylitol. Nurses prepare the solution in batches according to the number of patients. After taking this defoaming agent 5-30 minutes before the gastroscopy, no flocculation or clumping occurred in the esophagus or stomach, and the pH value of the prepared defoaming agent remained unchanged for 3 hours." Patent CN 119280433A The document discloses "a gastroscopy-prepared anti-flocculation and defoaming agent for the digestive tract mucosa and its preparation method, which uses 80mg simethicone emulsion combined with 40ml of 2.5% sodium bicarbonate solution (containing 1000mg sodium bicarbonate) for pre-examination preparation, which can prevent flocculent precipitation and improve the cleaning effect of gastric mucosa." However, the above-mentioned method uses a large number of drug components, and needs to be prepared fresh for each use. The preparation process is complicated and requires high sterility conditions, high skill levels from medical personnel, and high cost, increasing the medical costs and safety risks for patients. Summary of the Invention

[0005] To address the problems of existing technologies, this invention researches and explores the product formulation of simethicone emulsions and unexpectedly discovers that carbomer of a specific viscosity can solve the flocculation problem of simethicone emulsions in the esophagus and stomach, significantly improving the clarity of gastric examination under gastroscopy and enhancing the product's gastric cleansing efficacy. Furthermore, the emulsion prepared using carbomer of this specific viscosity exhibits better product content uniformity, higher defoaming ability, and no stratification during centrifugation, ensuring the uniformity, stability, effectiveness, and safety of the product for clinical use. The specific technical solution is as follows: In a first aspect, the present invention provides an emulsion containing simethicone, comprising simethicone, an emulsifier, and carbomer, wherein the viscosity of the carbomer in the emulsion is any value or a range between any two values ​​from 40 to 80 Pa·s, preferably the viscosity of the carbomer is 40 to 60 Pa·s, for example 40 Pa·s, 41 Pa·s, 42 Pa·s, 43 Pa·s, 44 Pa·s, 45 Pa·s, 46 Pa·s, 47 Pa·s, 48 ​​Pa·s, 49 Pa·s, 50 Pa·s, 51 Pa·s, or 52 Pa·s. s, 53Pa.s, 54Pa.s, 55Pa.s, 56Pa.s, 57Pa.s, 58Pa.s, 59Pa.s, 60Pa.s, 61Pa.s, 62Pa.s, 63Pa.s, 64Pa.s, 65Pa.s, 66Pa.s , 67Pa.s, 68Pa.s, 69Pa.s, 70Pa.s, 71Pa.s, 72Pa.s, 73Pa.s, 74Pa.s, 75Pa.s, 76Pa.s, 77Pa.s, 78Pa.s, 79Pa.s, 80Pa.s.

[0006] The emulsion contains, by mass-volume ratio, any value or range between any two values ​​of carbomer in the range of 0.4-0.9%, preferably 0.4-0.8%, more preferably 0.4-0.6%, such as 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, etc.

[0007] The emulsion contains 2%-10% simethicone by weight or volume, preferably 2%-8%, and more preferably 4%-6%, such as 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5%, 5.5%, 6.0%, 6.5%, 7.0%, 7.5%, 8.0%, etc.

[0008] The simethicone oil can be a composite of dimethicone oil and silica.

[0009] The emulsion contains, by weight and volume percentage, any value or range between any two values ​​of emulsifier from 0.6% to 2.0%, such as 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.05%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, etc.

[0010] Preferably, the emulsifier is a conventional emulsifier of the prior art, including nonionic emulsifiers, cationic emulsifiers, anionic emulsifiers, or amphoteric emulsifiers. For example, the emulsifier includes, but is not limited to, one or more of fatty acid glycerides, polyethylene glycol fatty acid esters, Tween, Span, poloxamer, stearyl palmitate, polyoxyethylene 15-hydroxystearate, polyoxyethylene hydrogenated castor oil, propylene glycol esters, or fatty acid amides.

[0011] More preferably, the fatty acid glycerides are selected from one or more of mono- and di-stearate glycerides, mono-stearate glycerides, or monooleate glycerides.

[0012] More preferably, the polyethylene glycol fatty acid ester is selected from one or more of the following: poly(40) stearate, polyethylene glycol 1500 stearate, polyethylene glycol 35 stearate, polyethylene glycol 40 stearate, polyethylene glycol 1500 palmitate, PEG-25 stearate, polyethylene glycol 10 monostearate, or polyethylene glycol-7-stearate.

[0013] More preferably, the Tween includes Tween 80.

[0014] More preferably, the poloxamer includes poloxamer 188.

[0015] More preferably, the propylene glycol ester is selected from one or more of propylene glycol monostearate, propylene glycol monooleate, or propylene glycol monolaurate.

[0016] In one specific embodiment of the present invention, the emulsifier is poly(40) stearate and glyceryl mono- and glyceryl di-stearate. The glyceryl mono- and glyceryl di-stearate is a mixture of mono-, di-, and tri-stearic acid and palmitic acid glycerides.

[0017] Preferably, the mass ratio of poly(40) stearate to glyceryl mono- and glyceryl distearate is any value in the range of (0.5-3):1 or any two values, preferably (0.6-1):1, for example (0.5, 0.55, 0.6, 0.61, 0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.68, 0.69, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1.0, 1.5, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 3):1.

[0018] In one specific embodiment of the present invention, the emulsion comprises, by weight-volume percentage: Simethicone: 2%-10%; Emulsifier: 0.6%-2.0%; Carbomer: 0.4%-0.9%.

[0019] The emulsion also includes one or more of the following: antibacterial agents, osmotic pressure regulators, pH regulators, flavoring agents, and solvents.

[0020] Preferably, the emulsion includes an antibacterial agent, and the emulsion preferably contains any value or a range between any two values ​​in the range of 0.06%-0.3% by mass-volume percentage, for example, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.11%, 0.12%, 0.13%, 0.14%, 0.15%, 0.2%, 0.25%, and 0.3% of the antibacterial agent.

[0021] The antibacterial agents include, but are not limited to, one or more of sorbic acid, potassium sorbate, benzoic acid, sodium benzoate, propionic acid, methyl nifedipine, ethyl nifedipine, propyl nifedipine, or butyl nifedipine.

[0022] In one specific embodiment of the present invention, the emulsion comprises, by weight-volume percentage: Simethicone: 2.0%-10.0%; Emulsifier: 0.6%-2%; Carbomer: 0.4%-0.9%; Antibacterial agent: 0.06%-0.3%.

[0023] Preferably, the emulsion contains any value or a range between any two values ​​from 0.2% to 0.6% by weight-volume percentage, such as 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, or 0.6% of an osmotic pressure regulator.

[0024] Preferably, the osmotic pressure regulator is an inorganic salt, such as one or more of potassium, sodium, calcium, magnesium, iron, or zinc salts. More preferably, sodium chloride, potassium chloride, etc.

[0025] In one specific embodiment of the present invention In one specific embodiment of the present invention, the emulsion comprises, by weight-volume percentage: Simethicone: 2.0%-10.0%; Emulsifier: 0.6%-2%; Carbomer: 0.4%-0.9%; Antibacterial agent: 0.06%-0.3%; Osmotic pressure regulator: 0.2%-0.6%.

[0026] Preferably, the pH value of the emulsion is any value between 3 and 6 or a range between any two values, such as 3, 3.5, 4, 4.5, 5, 5.5, 6, etc.

[0027] To ensure that the pH value of the emulsion is any value between 3 and 6 or a range between any two values, the emulsion also includes a pH adjuster.

[0028] The pH adjuster can be an inorganic acid, organic acid, inorganic base, organic base, or buffer solution, etc. Hydrochloric acid or sodium hydroxide is preferred as the pH adjuster.

[0029] The emulsion also includes flavoring agents, which include one or more of sodium citrate, sodium saccharin (sodium o-benzoyl sulfimide), flavoring, sodium cyclohexanesulfonate, acesulfame potassium, sorbitol, sodium chloride, adenosine monophosphate, or acesulfame potassium. The flavoring can be one or more of banana, apple, orange, or grape flavoring.

[0030] The emulsion also includes a solvent, such as water or a buffer solution, for preparing a liquid formulation or dissolving the substances in the formulation.

[0031] The emulsion may also include a second active ingredient, which may include other known drugs or compounds that can be used as adjunctive treatments for diseases, such as prokinetic agents, analgesics, local anesthetics, etc.

[0032] The viscosity of the emulsion is any value or any two values ​​between 90-150 mPa·s, preferably any value or any two values ​​between 90-130 mPa·s, for example, 90 mPa·s, 91 mPa·s, 92 mPa·s, 93 mPa·s, 94 mPa·s, 95 mPa·s, 96 mPa·s, 97 mPa·s, 98 mPa·s, 99 mPa·s, 1... 00mPa.s, 101mPa.s, 102mPa.s, 103mPa.s, 104mPa.s, 105mPa.s, 106mPa.s, 107mPa.s, 108mPa.s, 109mP a.s, 110mPa.s, 115mPa.s, 120mPa.s, 125mPa.s, 130mPa.s, 135mPa.s, 140mPa.s, 145mPa.s or 150mPa.s, etc.

[0033] The polydimethylsiloxane content in the emulsion described in this invention is any value or a range between any two values ​​from 99% to 101%, such as 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, 100%, 100.1%, 100.2%, 100.3%, 100.4%, 100.5%, 100.6%, 100.7%, 100.8%, 100.9%, 101%, etc.

[0034] The emulsion is used to treat gastrointestinal disorders and / or disorders related to excessive gas production or accumulation. Preferably, the disorders are selected from abdominal pain, abdominal distension, flatulence, functional bloating, functional dyspepsia, or irritable bowel syndrome. Preferably, the emulsion is used to treat infant feeding intolerance or postoperative abdominal pain in infants.

[0035] The emulsion is used for abdominal imaging or auxiliary examinations.

[0036] Preferably, the emulsion is used as an adjunct diagnostic drug in colonoscopy and / or gastroscopy.

[0037] Preferably, when the emulsion is used as an auxiliary examination drug in gastroscopy, it does not produce obvious white flocculent material within 30 minutes of entering the stomach.

[0038] Preferably, when the emulsion is used as an adjunct diagnostic drug in gastroscopy, it does not produce obvious white flocculent material within 60 minutes of entering the stomach.

[0039] The emulsion is used to treat gastrointestinal diseases, preferably including gastrointestinal diseases with excessive gas production or accumulation.

[0040] The emulsion can be administered via any suitable route of administration, preferably gastrointestinal, such as orally.

[0041] The emulsion is for human or veterinary use.

[0042] In a second aspect, the present invention provides a method for preparing the above-mentioned emulsion, the method comprising mixing an aqueous phase and an oil phase at 60-90°C, homogenizing, adding carbomer, then adjusting the volume and filtering; wherein the oil phase comprises simethicone and an emulsifier.

[0043] Preferably, the preparation method includes: Carbomer was prepared into a dispersion of 1.7–4.25% (w / v); The aqueous phase is mixed with an oil phase containing simethicone and an emulsifier at 60-90°C and homogenized. Then, the prepared carbomer dispersion is added, the pH is adjusted, and the mixture is brought to volume and filtered. The aqueous phase may include osmotic pressure adjusters, antibacterial agents, and / or flavoring agents.

[0044] Preferably, the preparation method includes: A) Carbomer preparation: Prepare a dispersion of carbomer at a concentration of 1.7–4.25% (w / v); B) Aqueous phase preparation: Optionally add osmotic pressure regulator, antibacterial agent and / or flavoring agent to water, fill with nitrogen and keep warm at 40℃-90℃, stir until the solution is clear; C) Oil phase preparation: Under nitrogen protection, add simethicone oil, heat to 60-90℃ under shear conditions, add emulsifier, and shear disperse evenly; D) Preparation of primary emulsion: Control the mixing temperature of oil phase and water phase at 60-90℃. The oil phase prepared in C) and the water phase prepared in B) are mixed by shearing, and the mixture is sheared by self-circulation until a white emulsion is formed to form the primary emulsion. E) Homogenization: Adjust the homogenization pressure to 50-500 bar and control the temperature to 60-90℃. Homogenize the colostrum prepared in D) 2-8 times (e.g., 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times) to obtain emulsion I. F) pH adjustment and thickening stabilization: Add the prescribed amount of carbomer prepared in A) to the obtained E) emulsion I. After cooling, adjust the pH to 3.0-6.0, add water to make up to the prescribed amount, and mix well to obtain emulsion II. G) Filter the emulsion II obtained in F).

[0045] More preferably, the preparation method includes: A) Preparation of carbomer: Add purified water to the preparation vessel, add carbomer while stirring, and prepare a dispersion of 1.7-4.25% (W / V); B) Aqueous phase preparation: Add 30-80% of the total volume of purified water to the preparation tank, and optionally add osmotic pressure regulator, antibacterial agent and / or flavoring agent. Fill with nitrogen and keep warm at 40℃-90℃, and stir until the solution is clear. C) Oil phase preparation: Under nitrogen protection, add simethicone oil, heat to 60-90℃ under shear conditions, add emulsifier, and shear disperse evenly; D) Preparation of primary emulsion: Control the mixing temperature of oil phase and water phase at 60-90℃, mix the oil phase prepared in C) and the water phase prepared in B) by shearing to form primary emulsion; E) Homogenization: Adjust the homogenization pressure to 50-500 bar and control the temperature to 50-90℃. Homogenize the colostrum prepared in D) 2-8 times to obtain emulsion I. F) pH adjustment and thickening stabilization: Under stirring, add the prescribed amount of carbomer prepared in A) to emulsion I obtained in E). After cooling, add a pH adjuster to adjust the pH to 3.0-6.0. Add purified water to make up to the prescribed amount and mix well to obtain emulsion II. G) Filtration and filling: F) The obtained emulsion II is filtered and then filled.

[0046] A third aspect of the invention provides a method for treating a disease, the method comprising applying the emulsion described above to a subject in need.

[0047] The application can be performed via any suitable route of administration, preferably gastrointestinal, such as oral administration.

[0048] The diseases mentioned include, but are not limited to, diseases related to excessive gas production or accumulation. Preferably, the diseases are selected from abdominal pain, abdominal distension, flatulence, functional bloating, functional dyspepsia, or irritable bowel syndrome.

[0049] The conditions mentioned include, but are not limited to, infant feeding intolerance or postoperative abdominal pain in infants.

[0050] The diseases mentioned include, but are not limited to, gastrointestinal diseases, preferably including gastrointestinal diseases with excessive gas production or accumulation.

[0051] In a fourth aspect, the present invention provides a method for an abdominal imaging examination or an auxiliary examination, the method comprising applying the emulsion described above to a subject in need.

[0052] Preferably, a method for colonoscopy and / or gastroscopy is provided, the method comprising applying the emulsion described above to a subject in need.

[0053] The beneficial effects of this invention are: 1) When the emulsion of the present invention is used as an auxiliary examination drug in gastroscopy, no obvious white flocculent material appears during the gastroscopy. Compared with existing simethicone emulsion products, the field of view of gastroscopy is clearer and the examination results are more accurate. 2) The emulsion of this invention has good long-term stability: the stability can reach 24 months, the viscosity of the formulation is maintained at 90-150 mPa.s, the content of main components, preservatives, etc. does not decrease significantly, the product does not separate, and the safety is good. 3) The emulsion of the present invention has strong defoaming ability and can play a good defoaming role.

[0054] The mass-volume percentage mentioned in this invention specifically refers to g / ml. For example, a mass-volume percentage of 1% means 1g / 100ml.

[0055] The W / V mentioned in this invention specifically refers to g / ml, for example, 1% (W / V) means 1g / 100ml.

[0056] The term "pharmaceutically acceptable" as used in this invention refers to the biological activity and characteristics of the active substances in the applied product that neither significantly stimulate the organism nor inhibit it.

[0057] The term "treatment" as used in this invention refers to slowing down, interrupting, preventing, controlling, stopping, alleviating, reducing, or reversing a sign, symptom, disorder, condition, or progression or severity of a disease after it has begun to develop, but does not necessarily involve the complete elimination of all disease-related signs, symptoms, conditions, or disorders.

[0058] The term "effective amount" as used in this invention refers to the amount or dose of the medicament of this invention that provides the desired treatment or prevention after being administered to an individual or organ in one or more doses.

[0059] The "subject" described in this invention can be a human or a non-human mammal, or a cell, tissue, or organ of a human or non-human mammal. The non-human mammal can be a wild animal, a zoo animal, an economically important animal, a pet, a laboratory animal, etc. Preferably, the non-human mammal includes, but is not limited to, pigs, cattle, sheep, horses, donkeys, foxes, raccoon dogs, minks, camels, dogs, cats, rabbits, mice (e.g., rats, mice, guinea pigs, hamsters, gerbils, chinchillas, squirrels), or monkeys, etc. Attached Figure Description

[0060] The embodiments of the present invention will now be described in detail with reference to the accompanying drawings, wherein: Figure 1 The results of the in vitro gastric fluid simulation test of emulsion 2 in Experiment Example 1 at 0, 30 and 60 min show the phenomena.

[0061] Figure 2 The results of the in vitro gastric fluid simulation test of emulsion 3 in Experiment Example 1 at 0, 30 and 60 min show the phenomena.

[0062] Figure 3 The results of the in vitro gastric fluid simulation test of the comparative emulsion 1 in Experiment Example 1 are shown at 0, 30 and 60 min.

[0063] Figure 4 The results of the in vitro gastric fluid simulation test of Emulsion 2 in Experiment Example 1 are shown at 0, 30 and 60 min.

[0064] Figure 5 The results of the in vitro gastric fluid simulation test of commercially available simethicone emulsion in Experiment Example 1 were shown at 0, 30, and 60 minutes.

[0065] Figure 6 The results of the in vitro gastric fluid simulation test of commercially available dimethicone emulsion in Test Example 1 were shown at 0, 30, and 60 minutes.

[0066] Figure 7 shows the endoscopic field of view of the pig in Experiment 2 using Emulsion 3. The observed areas are: a: antrum; b: body; c: fundus.

[0067] Figure 8 The image shows the gastroscopy field of view of the patient in Experiment 3 of Emulsion 3 (the gastric mucosa surface is clean, without foam or flocculent deposits).

[0068] Figure 9 The images show the endoscopic field of view of patients who underwent experiments with commercially available simethicone emulsion in Case 3 (grayish-white flocculent precipitates were visible on the gastric mucosa).

[0069] Figure 10 shows the gastroscopy field images of patients in Experiment 3 who underwent the combined use of commercially available simethicone emulsion and streptomycin (the gastric mucosa surface was relatively clean, with no obvious foam or flocculent precipitate). Detailed Implementation

[0070] 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.

[0071] Unless otherwise specified, the experimental methods used in the examples are conventional methods.

[0072] Unless otherwise specified, all materials and reagents used in the examples are commercially available.

[0073] The materials or reagents used in the examples are from the following sources: Simethicone oil, homemade, batch number 25110303 Stearic acid polyoxyethylene (40) ester, purchased from Nanjing Well Pharmaceutical Group Co., Ltd. Glyceryl monostearate and glyceryl distearate, purchased from Carver, France Sorbic acid, purchased from Hunan Ercon Pharmaceutical Co., Ltd. Carbomer was purchased from Guizhou Xinzihong Pharmaceutical Excipients Co., Ltd., Guangzhou Kangqiao Hanpu Pharmaceutical Co., Ltd., and Lubrizol Advanced Materials, Inc. Sorbitol, purchased from Roquette China (Food) Co., Ltd. Artificial gastric fluid, purchased from Shanghai Yuanye Biotechnology Co., Ltd., pH 1.2 ± 0.2. Dimethicone emulsion, purchased from Sichuan Jianneng Pharmaceutical Co., Ltd. Simethicone emulsion, purchased from Berlin-Chemie AG Streptomycin, purchased from Beijing Taide Pharmaceutical Co., Ltd. Sodium bicarbonate granules, purchased from Guangzhou Kanghe Pharmaceutical Co., Ltd. Emulsion quality characteristic determination 1) Determination of polydimethylsiloxane content: Determine by infrared spectrophotometry (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0402). Accurately weigh approximately 2g of the sample, add 5mL of methanol, mix well, accurately add 25mL of n-hexane, mix well, shake for 10 minutes, allow to stand, separate the n-hexane layer, add 3g of anhydrous sodium sulfate, mix well, centrifuge for 5 minutes, and use the supernatant as the test solution. Accurately weigh an equal amount of polydimethylsiloxane reference standard, add 2mL of water, mix well, and repeat the procedure. Use the supernatant as the reference solution. Take 2mL of water, repeat the procedure, and use the supernatant as the blank solution.

[0074] Measurement method: The measurement wavelength is 1111 cm. -1 -1428cm -1 The absorption cell was 0.5 mm. The absorbance of the test sample and the reference solution was measured separately, and the reading was 1260 ± 4 cm⁻¹. -1 The absorbance can be calculated using the following formula.

[0075] A T : Absorbance of the test solution; A R : Absorbance of the reference solution; W T : Sample weight, mg; W R Reference standard sample weight, mg; ρ: Relative density of the emulsion, g / mL; C R The content of polydimethylsiloxane in the reference standard, % C标 Theoretical content of polydimethylsiloxane in the emulsion, mg / mL.

[0076] 2) Defoaming ability test of emulsion: Defoaming solution: Weigh a sample equivalent to 300 mg of simethicone, dilute it with water to 30.0 g, mix well, and use it as the defoaming solution.

[0077] Foaming bath solution: Take an appropriate amount of octyl phenyl polyol 9, dissolve and dilute it with warm water to prepare a solution containing approximately 10mg per ml, keep it warm in hot water for later use as a foaming solution. Measurement method: Measure 100 ml of foaming solution and 0.5 ml of defoaming solution into a 250 ml stoppered round bottle. Fix the round bottle on a vibrator and vibrate it at a frequency of 250-300 times per minute, an angle of 10°, a radius of 10 cm, and a duration of 10 seconds. Record the time from the end of the vibration to the appearance of clear spots on the surface of the first part of the non-foaming liquid.

[0078] 3) Emulsion viscosity determination: Viscosity was determined according to the viscosity determination method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0633, Method III). An appropriate amount of this product was added to a 41mm coaxial cylindrical double-slit measuring cup. The temperature was controlled in a circulating water bath at 20±1℃. The viscosity was measured using a 41mm coaxial cylindrical double-slit measuring rotor. The shear rate was 171 s⁻¹. -1 The dynamic viscosity should be 90-150 mPa·s.

[0079] 4) Carbomer viscosity determination: Take 2.5g of carbomer that has been dried under reduced pressure at 80℃ for 1 hour, add 500ml of water while stirring, and continue stirring at 800 rpm until evenly dispersed. Reduce the stirring speed to 600 rpm and continue stirring for 20 minutes. Then reduce the stirring speed to 300 rpm. Adjust the pH value to 7.3-7.8 with 18% sodium hydroxide solution. Let it stand in a 25℃ water bath for 1 hour. Centrifuge at 3000 rpm for 4 minutes (the centrifugation time can be appropriately increased to remove air bubbles). Select rotor No. 5 at a speed of 20 rpm and determine the dynamic viscosity (see the third method of rotor-type rotational viscometer in General Chapter 0633 of Part IV of the 2020 edition of the Chinese Pharmacopoeia for details).

[0080] 5) Emulsion stability test: Take this product, shake well, take 10 mL and place it in a centrifuge tube, centrifuge at 2000 rpm for 6 minutes, there should be no layering.

[0081] Example 1: Preparation of the emulsion Simethicone emulsion 1-emulsion 5 were prepared, and their formulations are shown in Table 1.

[0082] Table 1

[0083] The preparation process is as follows: 1) Preparation of carbomer: Add purified water to the preparation vessel, and slowly add the thickener while stirring to prepare a dispersion with a mass-volume ratio of 3.12% (W / V).

[0084] 2) Aqueous phase preparation: Add 50-60% of the total volume of purified water to the preparation tank, add osmotic pressure regulator, antibacterial agent and flavoring agent, fill with nitrogen and keep warm at 60℃-70℃, and stir until the solution is clear.

[0085] 3) Oil phase preparation: Under nitrogen protection, add simethicone oil complex, heat to 50-60℃ under shear conditions, add emulsifier, and shear disperse evenly.

[0086] 4) Preparation of colostrum: Control the mixing temperature of the oil phase and water phase at 60-70℃, and mix the oil phase and water phase through a shearing machine to form a colostrum. Shear the colostrum through a self-circulating system until a white emulsion is obtained.

[0087] 5) Homogenization: Adjust the pressure of the homogenizer to 100 bar and control the temperature of the liquid to 55-65℃. Homogenize the colostrum 4 times to obtain emulsion I.

[0088] 6) pH adjustment and thickening stabilization: While stirring, add the thickener prepared in step 1) to emulsion I. After cooling, simultaneously add sodium hydroxide solution to adjust the pH of the solution to 4.5-5.5, and add purified water to bring the volume to the prescribed amount. Mix thoroughly to obtain emulsion II.

[0089] 7) Filtration and filling of the drug solution: Emulsion II is filtered and then filled.

[0090] Comparative Example 1: Preparation of Comparative Emulsion Simethicone oil comparative emulsions 1-3 were prepared, and their formulations are shown in Table 2.

[0091] Table 2

[0092] The preparation process is as follows: 1) Preparation of carbomer: Add purified water to the preparation vessel, and slowly add the thickener while stirring to prepare a dispersion with a mass-volume ratio of 3.12% (W / V).

[0093] 2) Aqueous phase preparation: Add 50-60% of the total volume of purified water to the preparation tank, add osmotic pressure regulator, antibacterial agent and flavoring agent, fill with nitrogen and keep warm at 60℃-70℃, and stir until the solution is clear.

[0094] 3) Oil phase preparation: Under nitrogen protection, add simethicone oil complex, heat to 50-60℃ under shear conditions, add emulsifier, and shear disperse evenly.

[0095] 4) Preparation of colostrum: Control the mixing temperature of the oil phase and water phase at 60-70℃, and mix the oil phase and water phase through a shearing machine to form a colostrum. Shear the colostrum through a self-circulating system until a white emulsion is obtained.

[0096] 5) Homogenization: Adjust the pressure of the homogenizer to 100 bar and control the temperature of the liquid to 55-65℃. Homogenize the colostrum 4 times to obtain emulsion I.

[0097] 6) pH adjustment and thickening stabilization: While stirring, add the thickener prepared in step 1) to emulsion I. After cooling, simultaneously add sodium hydroxide solution to adjust the pH of the solution to 4.5-5.5, and add purified water to bring the volume to the prescribed amount. Mix thoroughly to obtain emulsion II.

[0098] 7) Filtration and filling of the drug solution: Emulsion II is filtered and then filled.

[0099] Experimental Example 1: In vitro gastric fluid simulation test (a) Experimental method: Add artificial gastric fluid to a beaker and stir magnetically at 50 r / min. The temperature of the artificial gastric fluid in the beaker is controlled at 37℃. Add the sample to the artificial gastric fluid (artificial gastric fluid: emulsion = 5:1) solution and observe the properties of the liquid in the beaker and the sedimentation time at 0 min, 30 min and 60 min respectively.

[0100] (II) Experimental Results: In vitro simulated gastric juice tests were conducted on emulsions 1-5 prepared in the examples, comparative emulsions 1-3, commercially available simethicone emulsions, and commercially available dimethicone emulsions. In the simulated gastric juice, the solutions of each sample exhibited different states. The specific results are shown in Table 3 below: Table 3

[0101] (III) Experimental Conclusions: The results of the in vitro gastric fluid simulation test for emulsions 2 and 3 are as follows: Figure 1-2 Figures 3-4 show the in vitro gastric fluid simulation test results for control emulsion 1 and control emulsion 2; Figures 5-6 show the in vitro gastric fluid simulation test results for commercially available simethicone emulsion and commercially available dimethicone emulsion.

[0102] The experimental results above show that the appearance of white flocculent matter in simethicone emulsions under the strongly acidic environment of gastric juice is significantly improved with the increase of carbomer viscosity. Specifically, compared with emulsions 1-3, the viscosity of carbomer used in simethicone emulsions was <40 mPa·s. White flocculent matter appeared as soon as the simethicone emulsion entered the simulated gastric juice, and the solution showed obvious stratification. The amount of white flocculent matter continued to increase with time. Conversely, in emulsions 1-5, the viscosity of carbomer used in simethicone emulsions was ≥40 mPa·s. No white flocculent matter appeared within 60 minutes after the simethicone emulsion entered the simulated gastric juice. The solution was a uniform white suspension, which was basically consistent with the state of commercially available dimethicone emulsions in simulated gastric juice. Commercially available simethicone emulsions showed a lot of white flocculent matter as soon as they entered the simulated gastric juice, and the solution showed obvious stratification. The amount of white flocculent matter continued to increase with time.

[0103] Experimental Example 2: In vivo gastroscopy in animals (I) Experimental Methods: 1. Experimental animal: Pig, weighing about 30kg.

[0104] 2. Preoperative preparation: All animals should be fasted for 24 hours before administration but allowed to drink water. Water should be withheld for 12 hours before administration.

[0105] 3. Test groups: Emulsion 1-Emulsion 5, 6 animals in each group.

[0106] 4. Administration regimen: For animals under light anesthesia, after locating the esophagus with a laryngoscope, insert a gavage tube and administer 10 ml of emulsion 1-emulsion 5.

[0107] 5. Gastroscopy (effectiveness indicator): 30 minutes after administration, all animals were general anesthetized, and a gastrointestinal endoscope was inserted to observe the gastric fundus, body, and antrum. Video and photographs were taken of the endoscopic findings.

[0108] 6. Intraoperative observation (safety indicators): Monitor and record indicators such as heart rate, respiratory rate, and blood oxygen saturation before, during, and after anesthesia. During the observation period from drug administration to the end of the experiment, closely observe the animals for systemic adverse reactions such as vomiting, diarrhea, allergies, and lethargy, and record the time of occurrence, severity, and duration.

[0109] (II) Experimental Results: The results of endoscopic examination of simethicone emulsions 1-5 in pigs showed that, under endoscopic visualization, no foam, mucus, or flocculent material was observed in the antrum, body, and fundus of the stomach. The field of view was clear, and details of the gastric tissue could be clearly observed. Figure 7 The images shown are images of the gastroscopic field of view of one of the test animals before and after administration of emulsion 3.

[0110] Experimental Case 3: Intra-patient gastroscopy trial (a) Experimental Groups: Experimental group: 15ml of simethicone emulsion, 6 patients (3 males and 3 females); Control group 1: 15ml of commercially available simethicone emulsion, 6 patients (2 males and 4 females); Control group 2: 15ml of commercially available simethicone emulsion + 20000U of streptomycin + 30ml of 2.5% sodium bicarbonate solution, 6 patients (3 males and 3 females).

[0111] (II) Method of use: Patients should fast and abstain from water for at least 6-8 hours before the gastroscopy. 10-30 minutes before the gastroscopy, instruct the patient to take the test drug orally. After administration, the patient should bend over, wiggle their body, and then lie down and be instructed to turn over 360 degrees.

[0112] The patient was given intravenous anesthesia, and oxygen was administered via nasal cannula and electrocardiogram monitoring was performed during the procedure. The gastroscopy was completed, and the nursing staff recorded the gastroscopy procedure and the observed indicators.

[0113] (III) Observation indicators: The primary endpoint indicator is the clarity of the endoscopic field of view: whether there is foam, mucus, or flocculent deposits in the antrum, body, and fundus of the stomach according to the gastroscopy; the secondary indicator is the production of flocculent deposits in the gastric cavity, i.e. whether grayish-white flocculent matter is visible under the endoscope.

[0114] (IV) Experimental Results: Observation of the formation of flocculent precipitates in the gastric cavity after oral administration of simethicone emulsion: In the experimental group, very few grayish-white flocculent substances were observed in the same gastric observation area. The observation field was clear and there was no foam or mucus. Figure 8 As shown. In control group 1, most patients showed obvious grayish-white flocculent material distributed in the gastric observation area, affecting gastroscopy observation, such as... Figure 9 The image shown is a gastroscopy field of view of one of the experimental patients. In control group 2, fewer grayish-white flocculent substances were observed, the field of view was clearer, and there was less foam and virtually no mucus. Figure 10 The image shown is a gastroscopy field of view of one of the experimental patients.

[0115] (V) Experimental Conclusions: Compared with existing simethicone emulsion products, the simethicone emulsion of this invention, when used before gastroscopy, can effectively cleanse the digestive tract without producing white flocculent matter, providing a clear field of vision, which is beneficial for observing subtle mucosal lesions. Furthermore, this method does not require the addition or preparation of other drugs compared to existing technologies, resulting in lower cost, simpler usage, and higher cost-effectiveness. Compared with the existing combination of simethicone emulsion and streptomycin, the simethicone emulsion of this invention is slightly superior in terms of white flocculent matter, clarity of vision, and defoaming ability. Moreover, the simethicone emulsion of this invention is more convenient to use, requires less expertise from medical personnel, has lower usage costs, and is safer.

[0116] Experimental Example 4: Detection of Key Indicators for Simethicone Emulsions The key quality indicators of simethicone emulsions 1-5 prepared in Example 1, such as polydimethylsiloxane content, defoaming ability, viscosity, and emulsion stability, all meet the standard requirements and are not significantly different from the corresponding indicators of commercially available simethicone emulsions. This indicates that the quality of emulsions 1-5 is comparable to that of commercially available simethicone emulsion products. The results are shown in Table 4.

[0117] Table 4

[0118] Test Example 5: Emulsion Storage Stability Test The stability of Emulsions 1-5 from Examples 1 and 5, as well as commercially available simethicone emulsions, was observed under accelerated conditions of 40℃±2℃ and 75%±5%RH. Key parameters were measured at 0, 1, 2, 3, and 6 months. The experimental results showed that the simethicone emulsions 1-5 prepared in Example 1 of this invention had good stability. Under accelerated conditions of high temperature and high humidity for 6 months, the key indicators such as emulsion properties, pH value, defoaming ability, viscosity, and main component content showed little change, indicating stable emulsion quality that met product stability requirements.

[0119] The specific stability test results of emulsions 1-3 and commercially available simethicone emulsions are shown in Tables 5-8.

[0120] Table 5

[0121] Table 6

[0122] Table 7

[0123] Table 8

[0124] The preferred embodiments of the present invention have been described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the scope of the technical concept of the present invention, various simple modifications can be made to the technical solution of the present invention, and these simple modifications all fall within the protection scope of the present invention.

[0125] It should also be noted that the various specific technical features described in the above specific embodiments can be combined in any suitable manner without contradiction. In order to avoid unnecessary repetition, the present invention will not describe the various possible combinations separately.

Claims

1. An emulsion, characterized in that, The emulsion comprises simethicone, an emulsifier, and carbomer, wherein the viscosity of the carbomer is 40-80 Pa·s; preferably 40-60 Pa·s.

2. The emulsion according to claim 1, characterized in that, The emulsion contains 0.4-0.9% carbomer by weight-volume percentage (g / ml); preferably, it contains 0.4-0.6% carbomer.

3. The emulsion according to claim 1, characterized in that, The viscosity of the emulsion is 90-150 mPa·s; preferably, the viscosity of the emulsion is 90-130 mPa·s.

4. The emulsion according to claim 1, characterized in that, The emulsion contains 2%-10% simethicone by weight / volume percentage; Preferably, the emulsion contains 2%-8% simethicone by weight / volume percentage; Preferably, the emulsion contains 4%-6% simethicone oil by weight-volume percentage.

5. The emulsion according to claim 1, characterized in that, The emulsion contains 0.6%-2.0% emulsifier by weight-volume percentage.

6. The emulsion according to claim 1, characterized in that, The emulsifier is selected from one or more of the following: fatty acid glycerides, polyethylene glycol fatty acid esters, Tween, Span, poloxamer, stearate palmitate, polyoxyethylene 15-hydroxy stearate, polyoxyethylene hydrogenated castor oil, propylene glycol esters, or fatty acid amides. Preferably, the fatty acid glycerides are selected from one or more of mono- and di-stearate glycerides, mono-stearate glycerides, or monooleate glycerides. Preferably, the polyethylene glycol fatty acid ester is selected from one or more of the following: poly(40) stearate, polyethylene glycol 1500 stearate, polyethylene glycol 35 stearate, polyethylene glycol 40 stearate, polyethylene glycol 1500 palmitate, PEG-25 stearate, polyethylene glycol 10 monostearate, or polyethylene glycol-7-stearate. Preferably, the Tween includes Tween 80; Preferably, the poloxamer includes poloxamer 188; Preferably, the propylene glycol ester is selected from one or more of propylene glycol monostearate, propylene glycol monooleate, or propylene glycol monolaurate.

7. The emulsion according to claim 1, characterized in that, The emulsion also includes one or more of the following: antibacterial agents, osmotic pressure regulators, pH regulators, or flavoring agents.

8. The emulsion according to claim 7, characterized in that, The emulsion contains 0.06%-0.3% antibacterial agent by weight-volume percentage; Preferably, the antibacterial agent includes one or more of sorbic acid, potassium sorbate, benzoic acid, sodium benzoate, propionic acid, methyl nifedipine, ethyl nifedipine, propyl nifedipine, or butyl nifedipine.

9. The emulsion according to claim 7, characterized in that, The emulsion contains 0.2%-0.6% osmotic pressure regulator by weight-volume percentage; Preferably, the osmotic pressure regulator is an inorganic salt, such as one or more of potassium salts, sodium salts, calcium salts, magnesium salts, iron salts, or zinc salts.

10. The emulsion according to claim 1, characterized in that, The pH value of the emulsion is 3.0-6.0; preferably, the pH value of the emulsion is 4.0-6.0; preferably, the pH value of the emulsion is 4.5-5.

5.

11. The emulsion according to claim 7, characterized in that, The emulsion comprises, by weight and volume percentage: Simethicone: 2.0%-10.0%; Emulsifier: 0.6%-2.0%; Carbomer: 0.4%-0.9%; Antibacterial agent: 0.06%-0.3%; Osmotic pressure regulator: 0.2%-0.6%.

12. The application of any one of the emulsions according to claims 1-11, characterized in that, The applications include: A) Use in the preparation of medicaments for treating diseases related to gastrointestinal disorders and / or excessive gas production or accumulation, preferably, the diseases being selected from abdominal pain, abdominal distension, flatulence, functional bloating, functional dyspepsia, or irritable bowel syndrome; or, B) Application in the preparation of drugs for abdominal imaging examinations or auxiliary examinations.

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