Simethicone and emulsion and preparation method thereof

Abstract

The invention provides simethicone and a preparation method thereof, and an emulsion containing simethicone and a preparation method thereof. The simethicone which is appropriate in viscosity, high in defoaming capacity, free of sedimentation and easy to flow is obtained by adopting the simethicone and the silicon dioxide in a specific proportion and matching with a specific preparation method. In addition, the emulsion prepared by selecting the emulsifier and the thickener is better in defoaming capacity, moderate in viscosity and good in stability.

Description

Technical Field

[0001] The present invention relates to the field of biomedical technologies, and particularly to a simethicone and a preparation method thereof, as well as an emulsion containing simethicone and a preparation method thereof. Background Art

[0002] Dimethicone is α-(trimethylsilylmethyl)-ω-methylpoly[oxy(dimethylsilylene)] (also known as dimethicone or polydimethylsiloxane). It has a small surface tension and can change the surface tension of bubbles, causing them to burst, thereby eliminating foam. It is a commonly used medical defoaming agent in clinics. However, the defoaming ability of pure dimethicone is weak.

[0003] Therefore, Patent CN109512835A discloses an activation method for dimethicone, which includes mixing it with silica and polyethylene glycol, improving the defoaming ability, preferably to 5 s. However, the experimental results show that the ease of colloidal grinding is most affected by the viscosity of dimethicone, and a suitable viscosity is 550 mm / s. 2 . Patent US3076768 discloses a preparation method for simethicone, which is to spray colloidal and precipitated silica with a weight ratio of 15% onto dimethicone with a viscosity of 50 cps, heat the mixture to 275°C and keep it warm for 1 h. Although dimethicone has high thermal stability and high temperature also has a beneficial effect on the dispersibility of silica, it is found that high temperature affects the stability of dimethicone. Therefore, a lower temperature needs to be selected during the preparation process, but a lower temperature will cause uneven dispersion of silica and easy stratification, etc.

[0004] In this regard, the present application further studies and finds that the performance of the complex of dimethicone and silica is closely related to the molecular weight. By controlling the molecular weight and distribution coefficient and cooperating with an optimized preparation process, a complex with better product performance can be obtained.

[0005] Furthermore, the complex of dimethicone and silica (also known as simethicone) has the molecular formula (CH3)3Si[-O-Si(CH3)2]nCH3 + SiO2. This product is a milky white viscous oily liquid, slightly soluble in ethyl acetate, dichloromethane, methyl ethyl ketone and toluene, very slightly soluble or almost insoluble in absolute ethanol, and almost insoluble in water and methanol. The structural formula is:

[0006]

[0007] Simethicone belongs to the category of defoaming drugs and is a stable non-ionic surfactant. It mainly acts on the surface of the bubbles present in the chyme and mucus in the digestive tract, reducing the surface tension of the bubbles, promoting the rupture of the bubbles, and releasing the gas. The released gas can be absorbed by the intestinal wall or excreted through intestinal peristalsis. The addition of silicon dioxide can promote the fusion and rupture of the bubbles. Therefore, simethicone has good defoaming and anti-swelling effects. In addition, simethicone is a pharmacologically and physiologically inert substance, and its defoaming effect is a pure physical effect without involving chemical reactions. Therefore, it can also be used by infants, pregnant and lying-in women, and diabetics. After oral administration, simethicone does not react with any food or drug, is not absorbed by the gastrointestinal tract, and is excreted in its original form. Therefore, it has no systemic toxicity, that is, it does not have biological toxicity. So far, no adverse reactions related to the administration of simethicone have been observed, and it can be widely used in infants, children, adults, pregnant women, surgical patients, elderly patients, etc.

[0008] Clinically, simethicone is mainly used to treat abdominal distension, flatulence, functional abdominal distension, functional dyspepsia, irritable bowel syndrome caused by excessive gas production or accumulation, and to assist in abdominal imaging examinations, etc. It can also be used to treat infant feeding intolerance and postoperative abdominal pain in infants. Currently, the drug dosage forms containing simethicone in the prior art include tablets, suspensions, capsules, emulsions, etc. Since emulsions are suitable for a wider range of people, this application conducts in-depth research on the formulation and production process of emulsions.

[0009] Currently, there are few marketed simethicone emulsion products, the research is not in-depth, and the performance is not ideal. For example, Patent CN101229187A discloses a simethicone emulsion using polyethylene glycol stearate / palmitate and glyceride as emulsifiers and hydroxypropyl cellulose as a thickener, and the obtained particle size is 10 - 50 nanometers. Although the reduction of particle size can better adapt to infants, pregnant and lying-in women, and diabetics, this is not the only indicator, and the defoaming ability, viscosity, and stability of the emulsion are not mentioned. Summary of the Invention

[0010] To solve the problems of the prior art, this application conducts research on the molecular weight and molecular weight distribution, and unexpectedly discovers a complex with a specific molecular weight and molecular weight distribution range, which has better defoaming ability (within 5 seconds), dimethicone and silicon dioxide will not settle and stratify, and has good storage stability, better ensuring the quality stability and controllability of the complex during storage. The emulsion prepared with the complex in this specific molecular weight distribution range has better product content uniformity, significantly improved defoaming ability, and the emulsion product will not stratify during centrifugation stability, better ensuring the uniformity, stability, effectiveness, and safety of the product during clinical use. The specific technical solutions are as follows:

[0011] In the first aspect of the present invention, a pharmaceutical composition is provided, and the pharmaceutical composition comprises a complex of dimethicone and silica.

[0012] The weight-average molecular weight of the complex is any value in the range of 20,000 - 40,000 Mw or a range value between any two values, preferably any value in the range of 22,000 - 39,000 Mw or a range value between any two values, more preferably any value in the range of 22,000 - 36,000 Mw or a range value between any two values, still more preferably any value in the range of 24,000 - 36,000 Mw or a range value between any two values, such as 20,000 Mw, 21,000 Mw, 22,000 Mw, 22,500 Mw, 22,700 Mw, 22,800 Mw, 22,860 Mw, 22,900 Mw, 23,000 Mw, 24,000 Mw, 25,000 Mw, 26,000 Mw, 27,000 Mw, 28,500 Mw, 28,700 Mw, 28,760 Mw, 28,763 Mw, 28,800 Mw, 28,900 Mw, 29,000 Mw, 30,000 Mw, 31,000 Mw, 32,000 Mw, 32,400 Mw, 32,500 Mw, 32,530 Mw, 32,600 Mw, 32,700 Mw, 32,800 Mw, 32,900 Mw, 33,000 Mw, 34,000 Mw, 35,000 Mw, 36,000 Mw, 37,000 Mw, 38,000 Mw, 38,200 Mw, 38,300 Mw, 38,400 Mw, 38,450 Mw, 38,455 Mw, 38,500 Mw, 38,600 Mw, 38,700 Mw, 38,800 Mw, 38,900 Mw, 39,000 Mw, 40,000 Mw, etc.

[0013] The molecular weight distribution coefficient of the complex is any value in the range of 1.0 - 4.0 or a range value between any two values, preferably any value in the range of 1.0 - 3.0 or a range value between any two values or any value in the range of 1.0 - 2.0 or a range value between any two values or any value in the range of 1.2 - 1.8 or a range value between any two values, such as 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, etc.

[0014] The weight-average molecular weight and its distribution coefficient are measured by size exclusion chromatography.

[0015] The weight-average molecular weight and its distribution coefficient are measured by a differential refractive index detector.

[0016] The weight-average molecular weight and its distribution coefficient are obtained by calculation with GPC software.

[0017] The kinematic viscosity of the complex is any value within the range of 400 - 1800 mm 2 / s or a range value between any two values, preferably 500 - 1500 mm 2 / s or a range value between any two values or 600 - 1400 mm 2 / s or a range value between any two values, such as 400 mm 2 / s, 500 mm 2 / s, 600 mm 2 / s, 610 mm 2 / s, 613 mm 2 / s, 620 mm 2 / s, 630 mm 2 / s, 640 mm 2 / s, 650 mm 2 / s, 660 mm 2 / s, 670 mm 2 / s, 680 mm 2 / s, 690 mm 2 / s, 700 mm 2 / s, 800 mm 2 / s, 810 mm 2 / s, 820 mm 2 / s, 830 mm 2 / s, 840 mm 2 / s, 850 mm 2 / s, 860 mm 2 / s, 870 mm 2 / s, 880 mm 2 / s, 884 mm 2 / s, 890 mm 2 / s, 900 mm 2 / s, 1000 mm 2 / s, 1050 mm 2 / s, 1100 mm 2 / s, 1200 mm 2 / s, 1300 mm 2 / s, 1330 mm 2 / s, 1340 mm 2 / s, 1350 mm 2 / s, 1360 mm 2 / s, 1370 mm 2 / s, 1380 mm 2 / s, 1386 mm 2 / s, 1390 mm 2 / s, 1400 mm 2 / s, 1500 mm 2 / s, 1600 mm 2 / s, 1700 mm 2 / s, 1800 mm 2 / s etc.

[0018] The kinematic viscosity is any value within 20 - 30 °C or a range value between any two values, preferably the kinematic viscosity at 25 °C.

[0019] In the composite, the kinematic viscosity of the dimethicone is any value within 300 - 1000 mm 2 / s or a range value between any two values, preferably any value within 300 - 800 mm 2 / s or a range value between any two values or any value within 350 - 750 mm 2 / s or a range value between any two values, such as 300 mm 2 / s, 350 mm 2 / s, 400 mm 2 / s, 450 mm 2 / s, 500 mm 2 / s, 550 mm 2 / s, 600 mm 2 / s, 650 mm 2 / s, 700 mm 2 / s, 750 mm 2 / s, 800 mm 2 / s, 850 mm 2 / s, 900 mm 2 / s, 950 mm 2 / s, 1000 mm 2 / s etc.

[0020] In the composite, the particle size of the silica is any value within 1.0 - 8.0 μm or a range value between any two values, preferably any value within 4.0 - 8.0 μm or a range value between any two values or any value within 1.0 - 2.0 μm, such as 1.0 μm, 1.5 μm, 2.0 μm, 2.5 μm, 3.0 μm, 3.5 μm, 4.0 μm, 4.5 μm, 5.0 μm, 5.5 μm, 6.0 μm, 6.5 μm, 7.0 μm, 7.5 μm, 8.0 μm etc.

[0021] The silica is hydrophilic. Preferably, the silica is obtained by gel method.

[0022] In the composite, the mass ratio of dimethicone to silicon dioxide is 100:(3.0 - 8.0), such as 100:(3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, etc.).

[0023] The described composite is obtained by mixing dimethicone and silicon dioxide and then heating to any value or the range value between any two values within 140 - 180°C (preferably any value or the range value between any two values within 150 - 170°C), such as heating to 140°C, 145°C, 150°C, 155°C, 160°C, 165°C, 170°C, 175°C, 180°C, etc.

[0024] Preferably, after heating, it is necessary to keep warm for any value or the range value between any two values within 3 - 6 h (such as 3 h, 3.5 h, 4 h, 4.5 h, 5 h, 5.5 h, 6 h, etc.).

[0025] Preferably, after the heat preservation, it further includes cooling to any value or the range value between any two values within 10 - 40°C (such as 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40°C), and then a step of circulating under stirring conditions. The preferred circulating time is any value or the range value between any two values within 20 - 60 min, such as 20, 25, 30, 35, 40, 45, 50, 55, or 60 min, etc.

[0026] More preferably, the described composite is obtained by mixing dimethicone and silicon dioxide, heating to 140 - 180°C, keeping warm and stirring for 3 - 6 h, then cooling to 10 - 40°C, and filtering after circulating for 20 - 60 min under stirring conditions.

[0027] In a specific embodiment of the present invention, the composite is added with the prescribed amount of dimethicone at 10 - 40°C (preferably at room temperature), stirring is started, and then silicon dioxide is slowly added. The adding speed of silicon dioxide is controlled to add the prescribed amount of silicon dioxide within no less than 1 h, and then heated to 140 - 180°C, kept warm and stirred for 3 - 6 h, then cooled to 10 - 40°C, and the composite is obtained by filtering after circulating for 20 - 60 min under stirring conditions.

[0028] The described pharmaceutical composition treats diseases associated with excessive gas production or accumulation. Preferably, the diseases are selected from abdominal pain, abdominal distension, flatulence, functional abdominal distension, functional dyspepsia, or irritable bowel syndrome. More preferably, the pharmaceutical composition treats infantile feeding intolerance or postoperative abdominal pain in infants.

[0029] The described pharmaceutical composition is used for abdominal imaging examinations or auxiliary examinations.

[0030] The described pharmaceutical composition treats gastrointestinal diseases, preferably gastrointestinal diseases including excessive gas production or accumulation.

[0031] The described pharmaceutical composition may further include other known drugs or compounds in the prior art that can assist in treating diseases. For example, gastrokinetic drugs, analgesics, local anesthetics, etc.

[0032] The described pharmaceutical composition also includes pharmaceutically acceptable excipients, such as one or more of a carrier, excipient, diluent, lubricant, wetting agent, emulsifier, preservative, antioxidant, buffer, bacteriostatic agent, suspending agent, co-suspending agent, solubilizer, thickening agent, stabilizer, osmotic pressure regulator, pH regulator, or flavoring agent, etc.

[0033] The dosage forms of the described pharmaceutical composition include, but are not limited to, tablets, granules, syrups, suspensions, capsules, or emulsions, etc. Among them, various dosage forms can be prepared according to the conventional production methods in the pharmaceutical field.

[0034] The described pharmaceutical composition can be administered by any suitable route of administration, preferably gastrointestinal administration, such as oral administration.

[0035] The described pharmaceutical composition may contain a complex in a weight ratio of any value or a range value between any two values from 0.01 - 99.5% (specifically, such as 0.01%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, 99.5%, etc.).

[0036] The described pharmaceutical composition is for human or veterinary use.

[0037] In the second aspect of the present invention, a preparation method of the above-mentioned pharmaceutical composition is provided, including mixing dimethicone and silicon dioxide, and then heating to any value or a range value between any two values from 140 - 180°C, such as heating to 140°C, 145°C, 150°C, 155°C, 160°C, 165°C, 170°C, 175°C, 180°C, etc.

[0038] Preferably, after heating, keep the temperature for any value or the range value between any two values within 3 - 6 h (such as 3 h, 3.5 h, 4 h, 4.5 h, 5 h, 5.5 h, 6 h, etc.).

[0039] Preferably, after heat preservation, it further includes the step of cooling to any value or the range value between any two values within 10 - 40 °C, and then circulating under stirring conditions. Preferably, filter after circulation.

[0040] Preferably, the circulation time is preferably any value or the range value between any two values within 20 - 60 min, such as 20, 25, 30, 35, 40, 45, 50, 55 or 60 min, etc.

[0041] More preferably, the preparation method includes: adding the prescribed amount of dimethicone, stirring and adding silica, then heating to 140 - 180 °C, keeping the temperature and stirring, then cooling the temperature to 10 - 40 °C, and filtering after circulation under stirring conditions.

[0042] Preferably, the rate of adding silica is controlled to be no less than adding the prescribed amount within 1 h.

[0043] In an embodiment of the present invention, the preparation method includes adding the prescribed amount of dimethicone at 10 - 40 °C, starting stirring, and then slowly adding silica. The rate of adding silica is controlled to be no less than adding the prescribed amount of silica within 1 h, heating to 140 - 180 °C, keeping the temperature and stirring for 3 - 6 h, then cooling to 10 - 40 °C, and filtering after circulating for 20 - 60 min under stirring conditions.

[0044] In the third aspect of the present invention, an emulsion is provided. The emulsion contains the above-mentioned complex or the above-mentioned pharmaceutical composition or the pharmaceutical composition obtained by the above-mentioned preparation method, and an emulsifier.

[0045] The emulsion contains the complex in any value or the range value between any two values within 2% - 10% by mass - volume percentage, preferably any value or the range value between any two values within 2% - 8%, more preferably any value or the range value between any two values within 4% - 6%, such as 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 9% or 10% of the complex, etc.

[0046] The complex is a complex of dimethicone and silica.

[0047] The emulsion contains an emulsifier in a mass-volume percentage of any value from 0.6% to 2% or a range value between any two values, such as an emulsifier of 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.05%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2%, etc.

[0048] The mass ratio of the complex to the emulsifier is any value from (3 - 10):1 or a range between any two values, preferably (4 - 10):1 or (3 - 5):1 or (3.3 - 5):1 or (4 - 6):1, such as (3, 3.2, 3.3, 3.33, 3.4, 3.5, 3.8, 3.9, 4, 4.5, 5, 5.5, 6, 6.25, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10):1.

[0049] In a specific embodiment of the present invention, the emulsion comprises, by mass parts:

[0050] Any value from 20 - 100 parts or a range between any two values of the above complex or pharmaceutical composition, such as 20 parts, 25 parts, 30 parts, 35 parts, 40 parts, 45 parts, 50 parts, 55 parts, 60 parts, 65 parts, 70 parts, 75 parts, 80 parts, 85 parts, 90 parts, 95 parts or 100 parts, etc.; and,

[0051] Any value from 6 - 20 parts or a range between any two values of the emulsifier, such as 6 parts, 7 parts, 8 parts, 9 parts, 10 parts, 11 parts, 12 parts, 13 parts, 14 parts, 15 parts, 16 parts, 17 parts, 18 parts, 19 parts, 20 parts, etc.

[0052] Preferably, the emulsifier is a conventional emulsifier in the prior art, including non - ionic emulsifiers, cationic emulsifiers, anionic emulsifiers or zwitterionic emulsifiers, etc. For example, the emulsifier includes but is not limited to one or more of glycerol fatty acid esters, polyethylene glycol fatty acid esters, Tween, Span, poloxamer, stearyl palmitate, polyoxyethylene 15 - hydroxy stearate, polyoxyethylene hydrogenated castor oil, propylene glycol esters or fatty acid amides.

[0053] More preferably, the glycerol fatty acid ester is selected from one or more of glyceryl monostearate, glyceryl distearate or glyceryl monooleate.

[0054] More preferably, the polyethylene glycol fatty acid ester is selected from one or more of polyoxyl (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.

[0055] More preferably, the Tween includes Tween 80.

[0056] More preferably, the poloxamer includes poloxamer 188.

[0057] More preferably, the propylene glycol ester is selected from one or more of propylene glycol monostearate, propylene glycol monooleate, or propylene glycol monolaurate.

[0058] In a specific embodiment of the present invention, the emulsifier is polyoxyl (40) stearate and glyceryl mono- and distearate. The glyceryl mono- and distearate is a mixed glyceride of mono-, di-, and tristearic acids and palmitic acid.

[0059] Preferably, the mass ratio of polyoxyl (40) stearate to glyceryl mono- and distearate is any value or the range between any two values in (0.5 - 3):1, preferably (0.6 - 2.5):1, such as (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.

[0060] The emulsion further includes a thickening agent.

[0061] In the emulsion, according to the mass - volume ratio, it contains a thickening agent in the range of any value or the range between any two values in 0.4 - 0.8%, preferably 0.4 - 0.6% of the thickening agent, such as 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8% and other thickening agents.

[0062] Preferably, in the emulsion, the final concentration of the thickening agent is any value or the range between any two values in 4 - 8 mg / mL, preferably 4 - 6 mg / mL, such as 4 mg / mL, 4.5 mg / mL, 5 mg / mL, 5.5 mg / mL, 6 mg / mL, 6.5 mg / mL, 7 mg / mL, 7.5 mg / mL, or 8 mg / mL, etc.

[0063] Preferably, the mass ratio of the complex to the thickener is any value in (4-15):1 or a range between any two values, preferably (5-14):1, for example, (4, 4.1, 4.2, 4.5, 5, 5.5, 5.6, 5.7, 6, 6.5, 6.6, 6.7, 6.8, 6.9, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11, 11.5, 12, 13, 13.2, 13.3, 13.4, 13.5, 14, 15):1.

[0064] Preferably, in the emulsion, the mass ratio of the emulsifier to the thickener is any value in (1-5):1 or a range between any two values, preferably (1.3-3.5):1, for example (1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.75, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 4, 4.5, 5):1.

[0065] In a specific embodiment of the present invention, the emulsion comprises, by weight:

[0066] Any value or range between any two values ​​of 20-100 parts of the above-mentioned complex or pharmaceutical composition, for example, 20 parts, 25 parts, 30 parts, 35 parts, 40 parts, 45 parts, 50 parts, 55 parts, 60 parts, 65 parts, 70 parts, 75 parts, 80 parts, 85 parts, 90 parts, 95 parts, 100 parts, etc.;

[0067] Any value or range between any two values ​​of 6-20 parts of emulsifier, for example 6 parts, 7 parts, 8 parts, 9 parts, 10 parts, 11 parts, 12 parts, 13 parts, 14 parts, 15 parts, 16 parts, 17 parts, 18 parts, 19 parts, 20 parts, etc.; and,

[0068] The thickener can be any value between 4 and 8 parts or a range between any two values, for example, 4 parts, 4.5 parts, 5 parts, 5.5 parts, 6 parts, 6.5 parts, 7 parts, 7.5 parts, 8 parts, etc.

[0069] Preferably, the thickener comprises one or more of carbomer, xanthan gum, methylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, guar gum, carrageenan, gum arabic, pectin, alginate, agarose, polyvinyl alcohol or povidone. Wherein, the carbomer can be one or more of carbomer homopolymer, carbomer copolymer or carbomer interpolymer. The model of the carbomer can be one or more of 934P, 974P or 971P.

[0070] In a specific embodiment of the present invention, the thickener is carbomer and / or hydroxypropyl methylcellulose.

[0071] The mass ratio of the carbomer to the hydroxypropyl methylcellulose is any value within the range of (1.8 - 2.4):1 or the range between any two values, such as 1.8:1, 1.9:1, 2:1, 2.1:1, 2.2:1, 2.3:1, or 2.4:1.

[0072] The emulsion further includes one or more of an antibacterial agent, an osmotic pressure regulator, a pH regulator, a flavoring agent, a solvent, or a buffer.

[0073] Preferably, the emulsion includes an antibacterial agent, and the emulsion preferably contains any value within the range of 0.06% - 0.15% by mass / volume or the range value between any two values (such as 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.11%, 0.12%, 0.13%, 0.14%, 0.15%) of the antibacterial agent.

[0074] Preferably, the emulsion includes an antibacterial agent, and the final concentration of the antibacterial agent in the emulsion is preferably any value within the range of 0.6 - 1.5 mg / mL or the range value between any two values, such as 0.6 mg / mL, 0.7 mg / mL, 0.8 mg / mL, 0.9 mg / mL, 1.0 mg / mL, 1.1 mg / mL, 1.2 mg / mL, 1.3 mg / mL, 1.4 mg / mL, 1.5 mg / mL, etc.

[0075] In the emulsion, the mass ratio of the complex to the antibacterial agent is any value within the range of (30 - 70):1 or the range between any two values, such as (30, 31, 32, 33, 34, 35, 40, 45, 50, 55, 60, 65, 66, 67, 68, 69, 70):1.

[0076] The antibacterial agent includes, but is not limited to, one or more of sorbic acid, potassium sorbate, benzoic acid, sodium benzoate, propionic acid, methyl paraben, ethyl paraben, propyl paraben, or butyl paraben.

[0077] In a specific embodiment of the present invention, the emulsion contains, by mass / volume:

[0078] Complex or pharmaceutical composition: 2% - 10%;

[0079] Emulsifier: 0.6% - 2%;

[0080] Thickener: 0.4% - 0.8%;

[0081] Antibacterial agent: 0.06%-0.15%.

[0082] In a specific embodiment of the present invention, the emulsion comprises, in parts by mass:

[0083] Any value or range between any two values ​​of 20-100 parts of the above-mentioned complex or pharmaceutical composition, such as 20 parts, 25 parts, 30 parts, 35 parts, 40 parts, 45 parts, 50 parts, 55 parts, 60 parts, 65 parts, 70 parts, 75 parts, 80 parts, 85 parts, 90 parts, 95 parts or 100 parts, etc.;

[0084] Any value or range between any two values ​​of 6-20 parts of emulsifier, for example, 6 parts, 7 parts, 8 parts, 9 parts, 10 parts, 11 parts, 12 parts, 13 parts, 14 parts, 15 parts, 16 parts, 17 parts, 18 parts, 19 parts, 20 parts, etc.;

[0085] Any value from 4 to 8 parts of thickener or a range between any two values, such as 4 parts, 4.5 parts, 5 parts, 5.5 parts, 6 parts, 6.5 parts, 7 parts, 7.5 parts, 8 parts, etc.; and,

[0086] Any value between 0.6 and 1.5 parts of the antibacterial agent or a range between any two values, for example, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, etc.

[0087] The emulsion also includes an osmotic pressure regulator, and the final concentration of the osmotic pressure regulator in the emulsion is preferably any value between 2-6 mg / mL or a range value between any two values, for example, 2 mg / mL, 2.5 mg / mL, 3 mg / mL, 3.5 mg / mL, 4 mg / mL, 4.5 mg / mL, 5 mg / mL, 5.5 mg / mL, 6 mg / mL, etc.

[0088] The emulsion contains an osmotic pressure regulator in an amount of any value between 0.2% and 0.6% or a range between any two values ​​(e.g., 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%) according to mass volume percentage.

[0089] In the emulsion, the mass ratio of the complex to the osmotic pressure regulator is any value in (8-15):1 or a range value between any two values, preferably any value in (10-14):1 or a range value between any two values, for example (8, 9, 10, 11, 12, 13, 14, 15):1.

[0090] 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. More preferably, it is sodium chloride, potassium chloride, etc.

[0091] In a specific embodiment of the present invention, the emulsion comprises, by mass parts:

[0092] Any value or the range value between any two values in 20 - 100 parts of the above complex or pharmaceutical composition, such as 20 parts, 25 parts, 30 parts, 35 parts, 40 parts, 45 parts, 50 parts, 55 parts, 60 parts, 65 parts, 70 parts, 75 parts, 80 parts, 85 parts, 90 parts, 95 parts or 100 parts, etc.;

[0093] Any value or the range value between any two values in 6 - 20 parts of the emulsifier, such as 6 parts, 7 parts, 8 parts, 9 parts, 10 parts, 11 parts, 12 parts, 13 parts, 14 parts, 15 parts, 16 parts, 17 parts, 18 parts, 19 parts, 20 parts, etc.;

[0094] Any value or the range between any two values in 4 - 8 parts of the thickener, such as 4 parts, 4.5 parts, 5 parts, 5.5 parts, 6 parts, 6.5 parts, 7 parts, 7.5 parts, 8 parts, etc.;

[0095] Any value or the range value between any two values in 0.6 - 1.5 parts of the bacteriostatic agent, such as 0.6 parts, 0.7 parts, 0.8 parts, 0.9 parts, 1.0 parts, 1.1 parts, 1.2 parts, 1.3 parts, 1.4 parts, 1.5 parts, etc.; and,

[0096] Any value or the range value between any two values in 2 - 6 parts of the osmotic pressure regulator, such as 2 parts, 2.5 parts, 3 parts, 3.5 parts, 4 parts, 4.5 parts, 5 parts, 5.5 parts, 6 parts, etc.

[0097] The pH value of the emulsion is any value or the range value between any two values in 3 - 6, such as 3, 3.5, 4, 4.5, 5, 5.5, 6, etc.

[0098] The pH regulator can be inorganic acid, organic acid, base, buffer solution, etc. Preferably, it is hydrochloric acid or sodium hydroxide.

[0099] The flavoring agent includes one or more of sodium citrate, sodium saccharin (sodium o - benzoyl sulfimide), essence, sodium cyclamate, acesulfame potassium, sorbitol, sodium chloride, adenosine monophosphate or potassium acetyl sulfamate. The essence can be one or more of banana - flavored essence, apple - flavored essence, orange - flavored essence or grape - flavored essence.

[0100] The emulsion also includes water, a solvent, a buffer solution, etc., which are used to prepare liquid preparations, dissolve various substances in the prescription, or provide an environment for the reaction.

[0101] The viscosity of the emulsion is any value in the range of 90 - 150 mPa·s or a range value between any two values, preferably any value in the range of 90 - 120 mPa·s or a range value between any two values, more preferably any value in the range of 95 - 110 mPa·s or a range value between any two values. 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, 100 mPa·s, 101 mPa·s, 102 mPa·s, 103 mPa·s, 104 mPa·s, 105 mPa·s, 106 mPa·s, 107 mPa·s, 108 mPa·s, 109 mPa·s, 110 mPa·s, 115 mPa·s, 120 mPa·s, 125 mPa·s, 130 mPa·s, 135 mPa·s, 140 mPa·s, 145 mPa·s, or 150 mPa·s, etc.

[0102] The content of polydimethylsiloxane is any value in the range of 99 - 101% or a range value between any two values. For example, 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.

[0103] The emulsion is used to treat diseases related to excessive gas production or aggregation. Preferably, the diseases are selected from abdominal pain, abdominal distension, flatulence, functional abdominal distension, functional dyspepsia, or irritable bowel syndrome. More preferably, the emulsion is used to treat infantile feeding intolerance or postoperative abdominal pain in infants.

[0104] The emulsion is used for abdominal imaging examinations or auxiliary examinations.

[0105] The emulsion is used to treat gastrointestinal diseases, preferably gastrointestinal diseases including excessive gas production or aggregation.

[0106] The emulsion may further include other known drugs or compounds in the prior art that can assist in treating diseases. For example, gastrointestinal motility agents, analgesics, local anesthetics, etc.

[0107] The emulsion can be prepared according to the conventional production methods in the pharmaceutical field.

[0108] The emulsion can be administered by any suitable route, preferably gastrointestinal administration, such as oral administration.

[0109] The emulsion is for human or veterinary use.

[0110] In the fourth aspect of the present invention, a method for preparing the above emulsion is provided. The preparation method includes mixing the aqueous phase and the oil phase at 60-90 °C, homogenizing, then making up the volume and filtering; the oil phase contains the above drug composition or complex, and an emulsifier.

[0111] Preferably, the preparation method includes:

[0112] Preparing the thickener into a dispersion with a viscosity of 4000-11000 cp;

[0113] Mixing the aqueous phase containing an osmotic pressure regulator, a bacteriostatic agent and / or a flavoring agent with the oil phase containing the above drug composition and an emulsifier at 60-90 °C, homogenizing, then adding the prepared thickener and adjusting the pH, making up the volume and filtering.

[0114] Preferably, the preparation method includes:

[0115] A) Preparation of thickener: Preparing the thickener into a dispersion with a viscosity of 4000-11000 cp;

[0116] B) Preparation of aqueous phase: Adding an osmotic pressure regulator, a bacteriostatic agent and / or a flavoring agent to water, filling with nitrogen and keeping warm at 40 °C - 90 °C, and stirring until the solution is clear;

[0117] C) Preparation of oil phase: Under nitrogen protection, adding the above drug composition or the drug composition obtained by the above preparation method, heating to 60-90 °C under a shearing state, adding an emulsifier, and shearing and dispersing evenly;

[0118] D) Preparation of primary emulsion: Controlling the mixing temperature of the oil phase and the aqueous phase at 60-90 °C, mixing the oil phase prepared in C) and the aqueous phase prepared in B) by shearing, and self-circulating and shearing until a white emulsion is formed to obtain the primary emulsion;

[0119] E) Homogenization: Adjusting the homogenization pressure to 50-500 bar, controlling the temperature at 60-90 °C, and homogenizing the primary emulsion prepared in D) 2-8 times (such as 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times) to obtain emulsion I;

[0120] F) pH value adjustment and thickening and stabilization: Adding the thickener prepared in A) in the prescribed amount to the emulsion I obtained in E), after cooling, adjusting the pH value to 3.0-6.0, adding water to make up the volume to the prescribed amount, and mixing evenly to obtain emulsion II;

[0121] G) Filtering the emulsion II obtained in F).

[0122] Further preferably, the preparation method includes:

[0123] A) Preparation of thickener: Add purified water into a preparation tank, add the thickener under stirring, and prepare a dispersion with a viscosity of 4000 - 11000 cp;

[0124] B) Preparation of aqueous phase: Add 30 - 80% of the total volume of purified water into a preparation tank, add osmotic pressure regulators, bacteriostatic agents and / or flavoring agents, heat and keep warm at 40°C - 90°C under nitrogen filling, and stir until the solution is clear;

[0125] C) Preparation of oil phase: Under nitrogen protection, add the above-mentioned complex, pharmaceutical composition or the pharmaceutical composition obtained by the above preparation method, heat up to 60 - 90°C under shearing, add an emulsifier, and shear and disperse evenly;

[0126] D) Preparation of primary emulsion: Control the mixing temperature of the oil phase and the aqueous phase at 60 - 90°C, mix the oil phase prepared in C) and the aqueous phase prepared in B) through shearing to form a primary emulsion;

[0127] E) Homogenization: Adjust the homogenization pressure to 50 - 500 bar, control the temperature at 60 - 90°C, and homogenize the primary emulsion prepared in D) 2 - 8 times to obtain emulsion I;

[0128] F) pH adjustment and thickening and stabilization: Add the thickener prepared in A) in the prescription amount to the emulsion I obtained in E) under stirring. After cooling, add a pH regulator to adjust the pH value to 3.0 - 6.0 at the same time, add purified water to make up to the prescription amount, and mix evenly to obtain emulsion II;

[0129] G) Filtration and filling: The emulsion II obtained in F) is filtered and then filled.

[0130] In the fifth aspect of the present invention, a method for treating a disease is provided, and the method includes administering the above-mentioned complex, a pharmaceutical composition containing the complex or the above-mentioned emulsion to a subject in need.

[0131] The administration can be any suitable administration route, preferably gastrointestinal administration, such as oral administration.

[0132] The diseases include but are not limited to diseases related to excessive gas production or aggregation. Preferably, the diseases are selected from abdominal pain, abdominal distension, flatulence, functional abdominal distension, functional dyspepsia or irritable bowel syndrome.

[0133] The diseases include but are not limited to infant feeding intolerance or postoperative abdominal pain in infants.

[0134] The diseases include but are not limited to gastrointestinal diseases, preferably gastrointestinal diseases including excessive gas production or aggregation.

[0135] In the sixth aspect of the present invention, a method for abdominal imaging examination or auxiliary examination is provided, and the method includes applying the above-mentioned complex, pharmaceutical composition containing the complex or the above-mentioned emulsion to a subject in need.

[0136] Advantages of the present invention:

[0137] 1) The content of the main component is relatively high. In the preparation process, the emulsion can be separated from the equipment well without loss of the active ingredient.

[0138] 2) The long-term stability of the preparation is good: the stability can reach 6 months after opening, the viscosity of the preparation remains at 90 - 150 mPa·s, the content of the main component and the content of sorbic acid do not decrease significantly, the product does not delaminate, and the safety is good.

[0139] 3) The molecular weight distribution affects the viscosity, fluidity and stability, and affects the defoaming ability of the preparation.

[0140] "Pharmaceutically acceptable" as used in the present invention means that it neither significantly stimulates the organism nor inhibits the biological activity and characteristics of the active substance of the administered product.

[0141] "Treatment" as used in the present invention means to slow down, interrupt, prevent, control, stop, alleviate, or reverse the progression or severity of a sign, symptom, disorder, disease, or illness after the disease has begun to develop, but does not necessarily involve the complete elimination of all disease-related signs, symptoms, illnesses, or disorders.

[0142] "Effective amount" as used in the present invention refers to the amount or dose of the drug of the present invention that provides the desired treatment or prevention after being administered to an individual or organ in a single or multiple doses.

[0143] "Subject" as used in the present invention can be a human or non-human mammal, or can be cells, tissues or organs of a human or non-human mammal. The non-human mammal can be a wild animal, zoo animal, economic animal, pet, experimental animal, etc. Preferably, the non-human mammal includes but is not limited to pigs, cows, sheep, horses, donkeys, foxes, raccoons, minks, camels, dogs, cats, rabbits, rats (such as rats, mice, guinea pigs, hamsters, gerbils, chinchillas, squirrels) or monkeys, etc. Detailed implementation manners

[0144] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only part of the embodiments of the present invention, rather than all. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts belong to the scope of protection of the present invention.

[0145] Unless otherwise specified, the experimental methods used in the examples are all conventional methods.

[0146] Unless otherwise specified, the materials, reagents, etc. used in the examples are all commercially available.

[0147] The sources of the materials or reagents used in the examples are as follows:

[0148] Dimethicone, purchased from Jiangxi Alpha High-Tech Pharmaceutical Co., Ltd., product number 20181101;

[0149] Silica, purchased from Grace, product number 1000341778;

[0150] Polyoxyl 40 stearate, purchased from Nanjing Weir Pharmaceutical Co., Ltd., product number B01513;

[0151] Glycerol monostearate and distearate, purchased from Gattefosse France, product number 172388;

[0152] Sorbic acid, purchased from Hunan Erkang Pharmaceutical Co., Ltd., product number 103720180801;

[0153] Carbomer, purchased from Lubrizol, product number 0102222730;

[0154] Hydroxypropyl methylcellulose, purchased from Dow Chemical, product number 1071799127;

[0155] Sorbitol, purchased from Roquette China (Food) Co., Ltd., product number 1926H.

[0156] Example 1: Preparation of Simethicone Complex

[0157] 1. Test Group 1

[0158] 1) Feeding: Add the prescribed amount of dimethicone at room temperature and start stirring. Slowly add silica into the batching tank (the feeding speed is controlled to finish adding the prescribed amount in no less than 1 hour).

[0159] 2) Reaction: Heat the liquid medicine to 150 °C and keep stirring for 4 hours.

[0160] 3) Sub-packaging and filtration: When the temperature of the liquid medicine drops to 40 °C, filter the liquid medicine through circulation for 40 minutes under stirring conditions. Then it is obtained by sub-packaging. The specific prescription is shown in Table 1.

[0161] 2. Test Group 2

[0162] 1) Feeding: Add the prescribed amount of dimethicone at room temperature and start stirring. Slowly add silica into the batching tank (the feeding speed is controlled to finish adding the prescribed amount in no less than 1 hour).

[0163] 2) Reaction: Heat the liquid medicine to 140 °C and keep it warm with stirring for 5 h.

[0164] 3) Sub-packaging and filtration: Let the temperature of the liquid medicine drop to 20 °C and filter the liquid medicine through circulation for 20 min under stirring conditions. Then sub-packaging can be obtained. The specific prescription is shown in Table 1.

[0165] 3. Test Group 3

[0166] 1) Charging: Add the prescribed amount of dimethicone at room temperature and start stirring. Slowly add silicon dioxide into the batching tank (the charging speed is controlled to complete the prescribed amount in no less than 1 h).

[0167] 2) Reaction: Heat the liquid medicine to 170 °C and keep it warm with stirring for 6 h.

[0168] 3) Sub-packaging and filtration: Let the temperature of the liquid medicine drop to 25 °C and filter the liquid medicine through circulation for 60 min under stirring conditions. Then sub-packaging can be obtained. The specific prescription is shown in Table 1.

[0169] 4. Test Group 4

[0170] 1) Charging: Add the prescribed amount of dimethicone at room temperature and start stirring. Slowly add silicon dioxide into the batching tank (the charging speed is controlled to complete the prescribed amount in no less than 1 h).

[0171] 2) Reaction: Heat the liquid medicine to 180 °C and keep it warm with stirring for 3 h.

[0172] 3) Sub-packaging and filtration: Let the temperature of the liquid medicine drop to 10 °C and filter the liquid medicine through circulation for 30 min under stirring conditions. Then sub-packaging can be obtained. The specific prescription is shown in Table 1.

[0173] 5. Test Group 5

[0174] 1) Charging: Add the prescribed amount of dimethicone at room temperature and start stirring. Slowly add silicon dioxide into the batching tank (the charging speed is controlled to complete the prescribed amount in no less than 1 h).

[0175] 2) Reaction: Heat the liquid medicine to 160 °C and keep it warm with stirring for 3.5 h.

[0176] 3) Sub-packaging and filtration: Let the temperature of the liquid medicine drop to 10 °C and filter the liquid medicine through circulation for 30 min under stirring conditions. Then sub-packaging can be obtained. The specific prescription is shown in Table 1.

[0177] 6. Test Group 6

[0178] 1) Charging: Add the prescribed amount of dimethicone at room temperature and start stirring. Slowly add silicon dioxide into the batching tank (the charging speed is controlled to complete the prescribed amount in no less than 1 h).

[0179] 2) Reaction: Heat the liquid medicine to 150 °C and keep it warm with stirring for 4.5 h.

[0180] 3) Sub - packaging filtration: The temperature of the liquid medicine is reduced to 20 °C, and the liquid medicine is filtered through circulation for 45 minutes under stirring conditions. Then it is sub - packaged to obtain the product, and the specific prescription is shown in Table 1.

[0181] 7. Test Group 7

[0182] 1) Feeding: Add the prescribed amount of dimethicone at room temperature and start stirring. Slowly add silicon dioxide into the batching tank (the feeding speed is controlled to finish adding the prescribed amount in no less than 1 hour).

[0183] 2) Reaction: Heat the liquid medicine to 180 °C and keep stirring for 5.5 hours.

[0184] 3) Sub - packaging filtration: The temperature of the liquid medicine is reduced to 25 °C, and the liquid medicine is filtered through circulation for 25 minutes under stirring conditions. Then it is sub - packaged to obtain the product, and the specific prescription is shown in Table 1.

[0185] Table 1

[0186]

[0187]

[0188] 8. Control Group 1

[0189] 1) Feeding: Add the prescribed amount of dimethicone at room temperature and start stirring. Slowly add silicon dioxide into the batching tank (the feeding speed is controlled to finish adding in no less than 1 hour).

[0190] 2) Reaction: Heat the liquid medicine to 150 °C and keep stirring for 4 hours.

[0191] 3) Sub - packaging filtration: The temperature of the liquid medicine is reduced to 25 °C, and the liquid medicine is filtered through circulation for 40 minutes under stirring conditions, then it is sub - packaged to obtain the product, and the specific prescription is shown in Table 2.

[0192] 9. Control Group 2

[0193] 1) Feeding: Add the prescribed amount of dimethicone at room temperature and start stirring. Slowly add silicon dioxide into the batching tank (the feeding speed is controlled to finish adding in no less than 1 hour).

[0194] 2) Reaction: Heat the liquid medicine to 170 °C and keep stirring for 5 hours.

[0195] 3) Sub - packaging filtration: The temperature of the liquid medicine is reduced to 20 °C, and the liquid medicine is filtered through circulation for 20 minutes under stirring conditions, then it is sub - packaged to obtain the product, and the specific prescription is shown in Table 2.

[0196] 10. Control Group 3

[0197] 1) Feeding: Add the prescribed amount of dimethicone at room temperature and start stirring. Slowly add silicon dioxide into the batching tank (the feeding speed is controlled to finish adding in no less than 1 hour).

[0198] 2) Reaction: Heat the liquid medicine to 140 °C and keep it warm with stirring for 6 h.

[0199] 3) Sub-packaging filtration: Let the temperature of the liquid medicine drop to 20 °C, and filter the liquid medicine through circulation for 60 min under stirring conditions, then sub-package to obtain the product. The specific prescription is shown in Table 2.

[0200] Table 2

[0201]

[0202]

[0203] 7. Determination of the quality characteristics of the simethicone complex

[0204] 1) Molecular weight distribution: Determine according to the molecular exclusion chromatography method (General Chapter 0514, Volume IV of Chinese Pharmacopoeia 2020 Edition). Take an appropriate amount of this product, dissolve and dilute it with tetrahydrofuran to prepare a solution containing about 10 mg per 1 mL as the test solution. Separately take 5 polystyrene reference substances with known molecular weights, dissolve and dilute them with the mobile phase to prepare solutions containing 4 mg per 1 mL as the reference solutions. Use a highly cross-linked polystyrene-divinylbenzene polymer resin as the filler; use tetrahydrofuran as the mobile phase; determine with a differential refractive index detector. Calculate the weight-average molecular weight and the molecular weight distribution coefficient Dα of the test product by GPC software.

[0205] 2) Viscosity: Take this product and check it according to law (the first method in General Chapter 0633, Volume IV of Chinese Pharmacopoeia 2020 Edition), and determine the kinematic viscosity of this product at 25 °C.

[0206] 3) Defoaming ability: Take 5.0 g of sodium docusate, add 1 L of water, heat it in a water bath to dissolve, and use it as the foaming solution. Keep it warm in warm water for standby; take 0.250 g of this product, add methyl ethyl ketone, shake to dissolve and quantitatively transfer it to a 50 mL volumetric flask as the defoaming solution. Take 100 mL of the foaming solution and 1 mL of the defoaming solution into a 250 mL stoppered round bottle, fix the round bottle on an oscillator and oscillate, the oscillation frequency is 250 - 300 times per minute, the oscillation angle is 10°, the oscillation radius is 10 cm, and the oscillation time is 10 seconds. Record the time from the end of oscillation to the moment when the surface of the first part of the non-foamy liquid appears.

[0207] 4) Sedimentation property: Place the prepared complex in n-hexane and observe whether silicon dioxide sedimentation occurs within 24 h.

[0208] 8. Results of the complex quality determination

[0209] The molecular weight of the complexes in Test Group 1-4 ranges from 22,000 to 38,000. The complexes have a moderate viscosity, good fluidity, excellent defoaming ability, are not prone to sedimentation, and have good stability. When the molecular weight of the control group is relatively low, a small amount of sedimentation occurs in the complexes and the defoaming ability weakens; when the molecular weight is relatively high, the fluidity of the complexes is poor, sedimentation is likely to occur, and the defoaming ability weakens. The specific results are shown in Table 3.

[0210] Determination of fluidity: Take 10 ml to 20 ml of this product in a stoppered test tube, rotate it 180°C and record the time for all the liquid to flow to the opposite side and the liquid angle. The shorter the time, the better the fluidity. Usually, it should completely flow to the opposite side within 15 s.

[0211] Table 3

[0212]

[0213] Example 2: Stability test of the complex

[0214] Place the simethicone complexes obtained from Test Group 1-4 and Control Group 1-3 in Example 1 in a stability chamber at 40°C ± 2°C for storage. Measure the molecular weight and distribution coefficient, viscosity, defoaming ability, and properties (whether sedimentation and layering occur) of the products at 3 and 6 months respectively. The results are shown in Table 4.

[0215] Table 4

[0216]

[0217]

[0218]

[0219] The results of the accelerated test show that the simethicone complexes prepared in Test Group 1-7 have very good stability. There are no significant differences in the molecular weight, distribution coefficient, viscosity, and defoaming ability compared with day 0, and almost no sedimentation occurs. The defoaming time of Control Group 1-3 is prolonged, the defoaming ability decreases, and obvious sedimentation and layering can be observed; the viscosity of Control Group 1 and 3 increases significantly instead, the fluidity of the product becomes poor, and by the 6th month of acceleration, it almost becomes a semi-solid and is not suitable for use in the preparation of emulsions.

[0220] During the preparation of the complex, slowly add silica into the batching tank (the feeding speed is controlled to be completed in no less than 1 h), which can help the dispersion effect of the finally formed complex and improve the stability of the complex.

[0221] Example 3: Preparation of emulsion Use the simethicone complexes obtained from Test Group 1, 3, 4, 6 and Control Group 1-3 in Example 1 to prepare emulsions.

[0222] 1. The prescription is shown in Tables 5-6.

[0223] Table 5

[0224]

[0225] Table 6

[0226]

[0227]

[0228] 2. Preparation Process

[0229] 1) Preparation of thickening agent: Purified water is added to the preparation tank, and the thickening agent is slowly added under stirring to prepare a dispersion with a viscosity of 4000 - 11000 cp.

[0230] 2) Preparation of aqueous phase: Purified water accounting for 30 - 80% of the total volume is added to the preparation tank, and osmotic pressure regulator, bacteriostatic agent, and flavoring agent are added. It is filled with nitrogen and kept warm at 40℃ - 90℃, and stirred until the solution is clear.

[0231] 3) Preparation of oil phase: Under nitrogen protection, dimethicone complex is added, and the temperature is raised to 60 - 90℃ under shearing, and the emulsifier is added and sheared and dispersed evenly.

[0232] 4) Preparation of primary emulsion: The mixing temperature of the oil phase and the aqueous phase is controlled at 60 - 90℃, and the oil phase and the aqueous phase are mixed through a shearing machine to form a primary emulsion. The primary emulsion is self-circulated and sheared into a white emulsion.

[0233] 5) Homogenization: The pressure of the homogenizer is adjusted to 50 - 500 bar, the temperature of the liquid medicine is controlled at 60 - 90℃, and the primary emulsion is homogenized through the homogenizer 2 - 8 times to obtain Emulsion Ⅰ.

[0234] 6) pH value adjustment and thickening and stabilization: Under stirring, the thickening agent prepared in 1) of the prescription amount is added to Emulsion Ⅰ. After cooling, at the same time, sodium hydroxide solution is added to adjust the pH value of the liquid medicine to 3.0 - 6.0, and purified water is added to make up the volume to the prescription amount. Mix evenly to obtain Emulsion Ⅱ.

[0235] 7) Filtration and filling of liquid medicine: Emulsion Ⅱ is filtered and then filled.

[0236] 3. Determination of Quality Characteristics of Emulsion

[0237] 1) Determination of polydimethylsiloxane content: It is determined according to the infrared spectrophotometry (General Chapter 0402, Volume IV of Chinese Pharmacopoeia 2020 Edition). Take about 2 g of this product, accurately weigh it, add 5 mL of methanol, mix well, accurately add 25 mL of n-hexane, mix well, shake for 10 minutes and then let it stand. Separate the n-hexane layer, add 3 g of anhydrous sodium sulfate, mix well and centrifuge for 5 minutes. Take the supernatant as the test solution. Take an equal amount of polydimethylsiloxane reference substance, accurately weigh it, add 2 mL of water, mix well, and operate in the same way. Take the supernatant as the reference solution. Take 2 mL of water, operate in the same way, and take the supernatant as the blank solution.

[0238] Method of determination: The determination wavelength is 1111 cm -1 -1428 cm -1 , the absorption cell is 0.5 mm. Measure the absorbances of the test solution and the reference solution respectively, and read the absorbance at 1260 ± 4 cm -1 . Calculate according to the following formula to obtain the result.

[0239]

[0240]

[0241] A T : Absorbance of the test solution; A R : Absorbance of the reference solution;

[0242] W T : Sampling weight of the test sample, mg; W R : Sampling weight of the reference substance, mg;

[0243] ρ: Relative density of the emulsion, g / mL;

[0244] C R : Content of polydimethylsiloxane in the reference substance, %;

[0245] C 标 : Theoretical content of polydimethylsiloxane in the emulsion, mg / mL.

[0246] 2) Defoaming ability: Take two portions of 50 mL each of a 1.0% Triton X-100 solution without foam, and carefully inject them into two clean 250 mL stoppered graduated cylinders respectively. Measure 0.4 mL of this product (rinse the measuring device twice with 2.0 mL of water each time) and place it in one of the graduated cylinders. Close the stoppers of the two graduated cylinders tightly, shake them strongly 5 times, let them stand for 1 min, measure the foam height, and calculate the defoaming ability by dividing the height of the reduced foam in the graduated cylinder with the emulsion added by the height of the foam in the graduated cylinder without the emulsion added (100%). The defoaming ability should not be less than 80%.

[0247] 3) Viscosity: Determined according to the Viscosity Determination Method (General Chapter 0633, Method 3, Volume IV, Chinese Pharmacopoeia 2020 Edition). Take an appropriate amount of this product and add it to a 41 mm coaxial cylinder double-slit measuring cup. Control the temperature in a circulating water bath at 20 ± 1 °C. Use a 41 mm coaxial cylinder double-slit measuring rotor to measure. The shear rate is 171 s -1 The kinematic viscosity should be 90 - 150 mPa·s.

[0248] 4) Emulsion stability: Take this product, shake well, take 10 mL and place it in a centrifuge tube. Centrifuge at a speed of 2000 revolutions per minute for 6 minutes. There should be no layering phenomenon.

[0249] 4. Test results

[0250] The key quality indicators of the simethicone emulsion (Emulsion 1 - 4) prepared from the simethicone complex prepared in Test Groups 1, 3, 4, and 6 in Example 1 and appropriate proportions of emulsifiers, thickeners, osmotic pressure regulators, etc., such as the content of polydimethylsiloxane, defoaming ability, viscosity, and emulsion stability, all meet the standard requirements; the key quality indicators of the simethicone emulsion (Control Emulsion 1 - 3) prepared from the simethicone complex prepared in Control Groups 1 - 3 in Example 1 and other proportions of emulsifiers, thickeners, etc., such as the content of polydimethylsiloxane, defoaming ability, viscosity, and emulsion stability, do not meet the standard requirements. The results are shown in Table 7.

[0251] Table 7

[0252] Group Content of polydimethylsiloxane (%) Defoaming ability Emulsion stability Viscosity (mPa.s) Emulsion 1 99.5％ 98％ No delamination 110 Emulsion 2 99.8％ 97％ No delamination 99 Emulsion 3 100.2％ 99％ No delamination 120 Emulsion 4 100.5％ 98％ No delamination 136 Control emulsion 1 82.5％ 76％ Delamination 172 Control emulsion 2 95.6％ 80％ Delamination 85 Control emulsion 3 88.7％ 82％ Delamination 160

[0253] 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 solutions of the present invention, and these simple modifications all fall within the protection scope of the present invention.

[0254] In addition, it should be noted that, in the case of no contradiction, the various specific technical features described in the above specific embodiments can be combined in any suitable manner. To avoid unnecessary repetition, the present invention will not separately describe various possible combination methods.

Claims

1. A pharmaceutical composition, characterized in that, the pharmaceutical composition comprises a complex of dimethicone and silica, and the weight average molecular weight of the complex is 20,000 - 40,000 Mw, preferably 22,000 - 36,000 Mw, more preferably 24,000 - 36,000 Mw.

2. The pharmaceutical composition according to claim 1, characterized in that, The kinematic viscosity of the said composite is 400 - 1800 mm 2 / s, preferably 500 - 1500 mm 2 / s, preferably 600 - 1400 mm 2 / s.

3. The pharmaceutical composition according to claim 1, characterized in that, the molecular weight distribution coefficient of the complex is 1.0 - 4.0, preferably 1.0 - 3.0, more preferably 1.0 - 2.0, most preferably 1.2 - 1.

8.

4. The pharmaceutical composition according to claim 1, characterized in that, in the complex, the mass ratio of dimethicone to silica is 100:(3.0 - 8.0).

5. An emulsion, characterized in that, the emulsion comprises the pharmaceutical composition according to any one of claims 1 - 4, and an emulsifier.

6. The emulsion according to claim 5, characterized in that, the emulsion contains 2% - 10% of the complex by mass - volume percentage; preferably, the emulsion contains 2% - 8% of the complex by mass - volume percentage; more preferably, the emulsion contains 4% - 6% of the complex by mass - volume percentage.

7. The emulsion according to claim 5, characterized in that, the emulsion contains 0.6% - 2.0% of the emulsifier by mass - volume percentage.

8. The emulsion according to claim 5, characterized in that, wherein, the mass ratio of the complex to the emulsifier is (3 - 10):1, preferably (3 - 5):

1.

9. The emulsion according to claim 5, characterized in that, the emulsifier is selected from one or more of fatty acid glycerides, polyethylene glycol fatty acid esters, Tween, Span, poloxamer, stearyl 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 glycerol monostearate, glycerol monostearate and glycerol monooleate; preferably, the polyethylene glycol fatty acid esters are selected from one or more of polyoxyl 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 esters are selected from one or more of propylene glycol monostearate, propylene glycol monooleate or propylene glycol monolaurate.

10. The emulsion according to any one of claims 5 - 9, characterized in that, the emulsion further comprises a thickener; preferably, the emulsion contains 0.4% - 0.8% of the thickener by mass - volume percentage; Preferably, the thickening agent includes one or more of carbomer, xanthan gum, methylcellulose, hydroxyethylcellulose, hypromellose, hydroxypropylcellulose, sodium carboxymethylcellulose, guar gum, carrageenan, arabic gum, pectin, alginate, agarose, polyvinyl alcohol or povidone; More preferably, the thickening agent is carbomer and / or hypromellose.

11. The emulsion according to claim 5, wherein, the emulsion further includes one or more of a bacteriostatic agent, an osmotic pressure regulator, a pH regulator or a flavoring agent.

12. The emulsion according to claim 11, wherein, the emulsion contains 0.06%-0.15% of the bacteriostatic agent by mass / volume percentage; Preferably, the bacteriostatic agent includes one or more of sorbic acid, potassium sorbate, benzoic acid, sodium benzoate, propionic acid, methyl paraben, ethyl paraben, propyl paraben or butyl paraben.

13. The emulsion according to claim 11, wherein, the emulsion contains 0.2%-0.6% of the osmotic pressure regulator by mass / volume percentage; Preferably, the osmotic pressure regulator is an inorganic salt, such as one or more of potassium salt, sodium salt, calcium salt, magnesium salt, iron salt or zinc salt.

14. The emulsion according to claim 5, wherein, the pH value of the emulsion is 3-6.

15. The emulsion according to claim 5, wherein, the emulsion contains by mass / volume percentage: Complex: 2%-10%; Emulsifier: 0.6%-2%; Thickening agent: 0.4%-0.8%; Bacteriostatic agent: 0.06%-0.15%; Osmotic pressure regulator: 0.2%-0.6%.

16. The emulsion according to any one of claims 5-15, wherein, the viscosity of the emulsion is 90-150 mPa·s.

17. An application of the pharmaceutical composition according to any one of claims 1-4 or the emulsion according to any one of claims 5-16, wherein, the application includes: A) An application in the preparation of a drug for treating a disease related to excessive gas production or aggregation, preferably, the disease is selected from abdominal pain, abdominal distension, flatulence, functional abdominal distension, functional dyspepsia or irritable bowel syndrome; or, B) An application in the preparation of a drug for abdominal imaging examination or auxiliary examination.

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