Simethicone, emulsion thereof, and preparation method therefor

Abstract

Simethicone and a preparation method therefor, and an emulsion comprising simethicone and a preparation method therefor. Simethicone with appropriate viscosity, strong defoaming capacity, no sedimentation, and good fluidity is obtained by using a specific ratio of dimethicone and silicon dioxide combined with the specific preparation method. In addition, the emulsion prepared by adopting an emulsifier and a thickener features good defoaming capacity, moderate viscosity, and good stability.

Description

A kind of simethicone and its emulsion and preparation method Technical Field

[0001] The present invention relates to the field of biomedicine technology, and in particular to simethicone and a preparation method thereof, as well as an emulsion containing simethicone and a preparation method thereof. Background Art

[0002] Dimethicone is α-(trimethylsilyl)-ω-methylpoly[oxy(dimethylsilylene)] (also known as dimethicone or polydimethylsiloxane). It has low 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 clinical practice, but dimethicone alone has weak defoaming ability.

[0003] Therefore, patent CN109512835A discloses a method for activating dimethicone, including mixing it with silicon dioxide and polyethylene glycol, to improve the defoaming ability, preferably 5s. However, experimental results show that the difficulty of passing through the colloid mill is most affected by the viscosity of dimethicone, and the appropriate viscosity is 550mm / s 2 Patent US3076768 discloses a method for preparing simethicone, which involves spraying 15% by weight of colloidal, precipitated silica onto dimethicone with a viscosity of 50 cps. The mixture is then heated to 275°C and held for 1 hour. Although dimethicone has high thermal stability, and high temperatures also have a beneficial effect on the dispersibility of silica, studies have found that high temperatures affect the stability of dimethicone. Therefore, a lower temperature is required during the preparation process. However, lower temperatures can result in uneven dispersion of the silica and easy stratification.

[0004] In this regard, the present applicant further studied and found that the performance of the composite of dimethicone and silicon dioxide is closely related to the molecular weight, and by controlling the molecular weight and distribution coefficient and combining with an optimized preparation process, a composite with better product performance can be obtained.

[0005] Furthermore, the compound of dimethicone and silicon dioxide (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 anhydrous ethanol, and almost insoluble in water and methanol. The structural formula is:

[0006] Simethicone belongs to the antifoaming class of drugs and is a stable nonionic surfactant. It mainly acts on the surface of bubbles present in the chyme and mucus in the digestive tract, reducing the bubble surface tension, promoting bubble bursting, and releasing gas. The released gas can be absorbed by the intestinal wall or discharged through intestinal peristalsis. The addition of silicon dioxide can promote the fusion and rupture of bubbles. Therefore, simethicone has excellent antifoaming and anti-flatulence effects. In addition, simethicone is a pharmacologically and physiologically inert substance. Its antifoaming effect is a purely physical effect and does not involve chemical reactions. Therefore, it can also be used by infants, pregnant women, and diabetics. After oral administration, simethicone does not react with any food or drugs, is not absorbed by the gastrointestinal tract, and is discharged in the form of prototype. Therefore, it has no systemic toxicity, that is, it does not have biological toxicity. To date, no adverse reactions related to taking simethicone have been observed. It can be widely used in infants, children, adults, pregnant women, surgical patients, elderly patients, etc.

[0007] Clinically, simethicone is primarily used to treat abdominal distension, flatulence, functional bloating, functional dyspepsia, irritable bowel syndrome, and other conditions caused by excessive gas production or accumulation, as well as to assist with abdominal imaging examinations. It can also be used to treat infant feeding intolerance and postoperative abdominal pain in infants. Currently, the existing pharmaceutical dosage forms containing simethicone include tablets, suspensions, capsules, and emulsions. Because emulsions are suitable for a wider range of people, this application conducts in-depth research on the formulation and production process of the emulsion.

[0008] Currently, there are relatively few simethicone emulsions on the market, research is limited, and their performance is suboptimal. For example, patent CN101229187A discloses a simethicone emulsion using polyethylene glycol stearate / palmitate and glycerides as emulsifiers and hydroxypropyl cellulose as a thickener, resulting in a particle size of 10-50 nanometers. While reduced particle size can improve suitability for infants, pregnant women, and diabetics, it is not the only criterion; the defoaming ability, viscosity, and stability of the emulsion are not mentioned. Summary of the Invention

[0009] In order to solve the problems of the prior art, the present application has conducted research on molecular weight and molecular weight distribution, and unexpectedly found that the compound with a specific molecular weight and molecular weight distribution range has better defoaming ability (within 5s), dimethicone and silicon dioxide will not settle and stratify, and has good storage stability, which better ensures the stable and controllable quality of the compound storage process. The emulsion prepared with the compound of this specific molecular weight distribution range has better product content uniformity, significantly improved defoaming ability, and the centrifugal stability of the emulsion product will not stratify, which better ensures the uniformity, stability, effectiveness and safety of the product for clinical use. The specific technical solution is as follows:

[0010] A first aspect of the present invention provides a pharmaceutical composition comprising a complex of dimethicone and silicon dioxide.

[0011] The weight average molecular weight of the composite is any value in the range of 20000-40000Mw or a range between any two values, preferably any value in the range of 22000-39000Mw or a range between any two values, more preferably any value in the range of 22000-36000Mw or a range between any two values, and still more preferably any value in the range of 24000-36000Mw or a range between any two values, for example, 20000Mw, 21000Mw, 22000Mw, 22500Mw, 22700Mw, 22800Mw, 22860Mw, 22900Mw, 23000Mw, 24000Mw, 25000Mw, 26000Mw, 27000Mw, 28500Mw, 28700Mw, 0Mw, 28760Mw, 28763Mw, 28800Mw, 28900Mw, 29000Mw, 30000Mw, 31000Mw, 32000Mw , 32400Mw, 32500Mw, 32530Mw, 32600Mw, 32700Mw, 32800Mw, 32900Mw, 33000Mw, 34 000Mw, 35000Mw, 36000Mw, 37000Mw, 38000Mw, 38200Mw, 38300Mw, 38400Mw, 38450 Mw, 38455Mw, 38500Mw, 38600Mw, 38700Mw, 38800Mw, 38900Mw, 39000Mw, 40000Mw, etc.

[0012] The molecular weight distribution coefficient of the composite is any value or a range between any two values ​​in the range of 1.0-4.0, preferably any value or a range between any two values ​​in the range of 1.0-3.0, or any value or a range between any two values ​​in the range of 1.0-2.0, or any value or a range between any two values ​​in the range of 1.2-1.8, for example, 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.

[0013] The weight average molecular weight and its distribution coefficient are measured by size exclusion chromatography.

[0014] The weight average molecular weight and its distribution coefficient are measured by a differential refractive index detector.

[0015] The weight average molecular weight and its distribution coefficient are calculated by GPC software.

[0016] The kinematic viscosity of the composite is 400-1800 mm 2 Any value in / s or a range between any two values, preferably 500-1500mm 2 Any value in / s or the range between any two values ​​or 600-1400mm 2 Any value in / s or a range between any two values, such as 400mm 2 / s、500mm 2 / s、600mm 2 / s、610mm 2 / s、613mm 2 / s、620mm 2 / s、630mm 2 / s、640mm 2 / s、650mm 2 / s、660mm 2 / s、670mm 2 / s、680mm 2 / s、690mm 2 / s、700mm 2 / s、800mm 2 / s、810mm 2 / s、820mm 2 / s、830mm 2 / s、840mm 2 / s、850mm 2 / s、860mm 2 / s、870mm 2 / s、880mm 2 / s、884mm 2 / s、890mm 2 / s、900mm 2 / s、1000mm 2 / s、1050mm 2 / s、1100mm 2 / s、1200mm 2 / s、1300mm 2 / s、1330mm 2 / s、1340mm 2 / s、1350mm 2 / s、1360mm 2 / s、1370mm 2 / s、1380mm 2 / s、1386mm 2 / s、1390mm 2 / s、1400mm 2 / s、1500mm 2 / s、1600mm 2 / s、1700mm 2 / s、1800mm 2 / s, etc.

[0017] The kinematic viscosity is any value between 20-30°C or a range between any two values, preferably the kinematic viscosity at 25°C.

[0018] In the composite, the kinematic viscosity of the dimethicone is 300-1000 mm 2 Any value in / s or a range between any two values, preferably 300-800mm 2 Any value in / s or the range between any two values ​​or 350-750mm 2 Any value in / s or a range between any two values, such as 300mm 2 / s、350mm 2 / s、400mm 2 / s、450mm 2 / s、500mm 2 / s、550mm 2 / s、600mm 2 / s、650mm 2 / s、700mm 2 / s、750mm 2 / s、800mm 2 / s、850mm 2 / s、900mm 2 / s、950mm 2 / s、1000mm 2 / s, etc.

[0019] In the composite, the particle size of the silica is any numerical value or a range value between any two values ​​of 1.0-8.0 μm, preferably any numerical value or a range value between any two values ​​of 4.0-8.0 μm or any numerical value or a range value between any two values ​​of 1.0-2.0 μm, for example, 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.

[0020] The silicon dioxide is hydrophilic. Preferably, the silicon dioxide is prepared by a gel method.

[0021] In the composite, the mass ratio of dimethicone to silicon dioxide is 100:(3.0-8.0), for example, 100:(3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, etc.).

[0022] The composite is prepared by mixing dimethicone and silicon dioxide, and heating the mixture to any value or range between 140-180°C (preferably any value or range between any two values ​​of 150-170°C), for example, 140°C, 145°C, 150°C, 155°C, 160°C, 165°C, 170°C, 175°C, 180°C, etc.

[0023] Preferably, after heating, the temperature needs to be kept warm for any value in the range of 3-6 hours or a range between any two values ​​(for example, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 5.5 hours, 6 hours, etc.).

[0024] Preferably, after the heat preservation, the temperature is lowered to any value in the range of 10-40° C. or any range between two values ​​(for example, 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 circulated under stirring. The cycle time is preferably any value in the range of 20-60 min or any range between two values, for example, 20, 25, 30, 35, 40, 45, 50, 55 or 60 min.

[0025] More preferably, the composite is obtained by mixing dimethicone and silicon dioxide, heating to 140-180° C., stirring for 3-6 hours, then cooling to 10-40° C., circulating under stirring for 20-60 minutes, and then filtering.

[0026] In a specific embodiment of the present invention, the composite is prepared by adding a prescribed amount of dimethicone at 10-40°C (preferably room temperature), starting stirring, and then slowly adding silicon dioxide. The speed of adding silicon dioxide is controlled so that the prescribed amount of silicon dioxide is added within no less than 1 hour. The temperature is then raised to 140-180°C, kept stirring for 3-6 hours, and then lowered to 10-40°C. The mixture is circulated for 20-60 minutes under stirring conditions and filtered to obtain the composite.

[0027] The pharmaceutical composition is used to treat a condition associated with excessive gas production or accumulation. Preferably, the condition is selected from abdominal pain, abdominal distension, flatulence, functional bloating, functional dyspepsia, or irritable bowel syndrome. Further preferably, the pharmaceutical composition is used to treat infant feeding intolerance or postoperative abdominal pain in infants.

[0028] The pharmaceutical composition is used for abdominal imaging examination or auxiliary examination.

[0029] The pharmaceutical composition is used to treat gastrointestinal diseases, preferably gastrointestinal diseases involving excessive gas production or accumulation.

[0030] The pharmaceutical composition may also include other drugs or compounds known in the prior art that can assist in treating diseases, such as prokinetic drugs, analgesics, local anesthetics, etc.

[0031] The pharmaceutical composition may further comprise pharmaceutically acceptable excipients, such as one or more of a carrier, excipient, diluent, lubricant, wetting agent, emulsifier, preservative, antioxidant, buffer, antibacterial agent, suspending agent, suspending aid, solubilizer, thickener, stabilizer, osmotic pressure regulator, pH regulator or flavoring agent.

[0032] The dosage forms of the pharmaceutical composition include, but are not limited to, tablets, granules, syrups, suspensions, capsules or emulsions, etc. Various dosage forms can be prepared according to conventional production methods in the pharmaceutical field.

[0033] The pharmaceutical composition can be administered by any suitable route, preferably by gastrointestinal administration, such as oral administration.

[0034] The pharmaceutical composition may contain a complex having a weight ratio of any value between 0.01-99.5% or a range between any two values ​​(specifically, 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.).

[0035] The pharmaceutical composition is a human or veterinary medicine.

[0036] In a second aspect of the present invention, a method for preparing the above-mentioned pharmaceutical composition is provided, comprising mixing dimethicone and silicon dioxide, and heating the mixture to any value between 140-180°C or a range between any two values, for example, 140°C, 145°C, 150°C, 155°C, 160°C, 165°C, 170°C, 175°C, 180°C, etc.

[0037] Preferably, after heating, the temperature is kept warm for any value in the range of 3-6 hours or a range between any two values ​​(for example, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 5.5 hours, 6 hours, etc.).

[0038] Preferably, after the heat preservation, the temperature is further reduced to any value in the range of 10-40°C or a range between any two values, and then circulated under stirring conditions, preferably filtered after the circulation.

[0039] Preferably, the cycle time is any value between 20 and 60 minutes or a range between any two values, such as 20, 25, 30, 35, 40, 45, 50, 55 or 60 minutes.

[0040] Further preferably, the preparation method comprises: adding a prescribed amount of dimethicone, stirring and adding silicon dioxide, then heating to 140-180°C, keeping warm and stirring, then lowering the temperature to 10-40°C, circulating under stirring conditions and filtering.

[0041] Preferably, the speed of adding silicon dioxide is controlled to complete the addition of the prescribed amount in no less than 1 hour.

[0042] In one embodiment of the present invention, the preparation method comprises adding a prescribed amount of dimethicone at 10-40°C, starting stirring, and then slowly adding silicon dioxide, controlling the speed of adding silicon dioxide to complete the addition of the prescribed amount of silicon dioxide within no less than 1 hour, heating to 140-180°C, keeping warm and stirring for 3-6 hours, then cooling to 10-40°C, circulating under stirring conditions for 20-60 minutes, and then filtering to obtain.

[0043] The third aspect of the present invention provides an emulsion, which comprises the above-mentioned complex or the above-mentioned pharmaceutical composition or the pharmaceutical composition obtained by the above-mentioned preparation method, and an emulsifier.

[0044] The emulsion contains a complex of any value between 2% and 10% or a range between any two values, preferably any value between 2% and 8% or a range between any two values, preferably any value between 4% and 6% or a range between any two values, such as 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 9% or 10% or the like, in terms of mass volume percentage.

[0045] The compound is a compound of dimethicone and silicon dioxide.

[0046] The emulsion contains an emulsifier in an amount of 0.6% to 2% or in a range between any two values ​​according to mass volume percentage, for example, 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% or the like.

[0047] The mass ratio of the complex to the emulsifier is any value in (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, for example, (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.

[0048] In a specific embodiment of the present invention, the emulsion comprises, in parts by mass:

[0049] Any value between 20 and 100 parts of the above-mentioned complex or pharmaceutical composition, or a range between any two values, such as 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 100 parts; and,

[0050] Any value between 6 and 20 parts of the emulsifier or a range between any two values, 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.

[0051] Preferably, the emulsifier is a conventional emulsifier in the prior art, including nonionic emulsifiers, cationic emulsifiers, anionic emulsifiers or zwitterionic emulsifiers, etc. 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.

[0052] More preferably, the fatty acid glyceride is selected from one or more of mono- and distearic acid glyceryl, monostearic acid glyceryl or monooleic acid glyceryl.

[0053] Further 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.

[0054] Further preferably, the Tween comprises Tween 80.

[0055] More preferably, the poloxamer comprises poloxamer 188.

[0056] More preferably, the propylene glycol ester is selected from one or more of propylene glycol monostearate, propylene glycol monooleate or propylene glycol monolaurate.

[0057] In a specific embodiment of the present invention, the emulsifier is polyoxyl (40) stearate and glyceryl mono- and distearate. The glyceryl mono-, di-, tri-stearic acid and palmitic acid mixed glyceride.

[0058] Preferably, the mass ratio of polyoxyl (40) stearate to glyceryl mono- and distearate is any value in (0.5-3):1 or a range between any two values, preferably (0.6-2.5):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.

[0059] The emulsion also includes a thickener.

[0060] In the emulsion, according to the mass volume ratio, the thickener is contained in an amount of any value between 0.4-0.8% or a range value between any two values, preferably 0.4-0.6% of the thickener, for example, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8% and the like.

[0061] Preferably, in the emulsion, the final concentration of the thickener is any value in the range of 4-8 mg / mL or a range between any two values, preferably 4-6 mg / mL, for example, 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.

[0062] 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.

[0063] 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.

[0064] In a specific embodiment of the present invention, the emulsion comprises, in parts by mass:

[0065] Any value between 20 and 100 parts of the above-mentioned complex or pharmaceutical composition, or a range between any two values, 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.;

[0066] Any value or range between any two values ​​of 6-20 parts of 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.; and,

[0067] The thickener can be any value between 4 and 8 parts 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.

[0068] Preferably, the thickening agent 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.

[0069] In a specific embodiment of the present invention, the thickener is carbomer and / or hydroxypropyl methylcellulose.

[0070] The mass ratio of carbomer to hydroxypropyl methylcellulose is any value in (1.8-2.4):1 or a 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.

[0071] The emulsion further comprises one or more of a bacteriostat, an osmotic pressure regulator, a pH regulator, a flavoring agent, a solvent or a buffer.

[0072] Preferably, the emulsion includes an antibacterial agent, and the emulsion preferably contains an antibacterial agent in an amount of 0.06% to 0.15% or a range between any two values ​​(for example, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.11%, 0.12%, 0.13%, 0.14%, 0.15%) according to the mass volume percentage.

[0073] Preferably, the emulsion includes an antibacterial agent, and the final concentration of the antibacterial agent in the emulsion is preferably any value between 0.6 and 1.5 mg / mL or a range value between any two values, for example, 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.

[0074] In the emulsion, the mass ratio of the complex to the antibacterial agent is any value in (30-70):1 or a range between any two values, for example, (30, 31, 32, 33, 34, 35, 40, 45, 50, 55, 60, 65, 66, 67, 68, 69, 70):1.

[0075] 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.

[0076] In one embodiment of the present invention, the emulsion comprises, by mass volume percentage:

[0077] Complex or pharmaceutical composition: 2%-10%;

[0078] Emulsifier: 0.6%-2%;

[0079] Thickener: 0.4%-0.8%;

[0080] Antibacterial agent: 0.06%-0.15%.

[0081] In a specific embodiment of the present invention, the emulsion comprises, in parts by mass:

[0082] Any value between 20 and 100 parts of the above-mentioned complex or pharmaceutical composition, or a range between any two values, 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.;

[0083] Any value between 6 and 20 parts of the emulsifier or a range between any two values, 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.;

[0084] Any value between 4 and 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,

[0085] 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.

[0086] The emulsion further includes an osmotic pressure regulator, and the final concentration of the osmotic pressure regulator in the emulsion is preferably any value between 2 and 6 mg / mL or a range 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.

[0087] The emulsion contains an osmotic pressure regulator in an amount of 0.2% to 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.

[0088] 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.

[0089] 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, more preferably sodium chloride, potassium chloride or the like.

[0090] In a specific embodiment of the present invention, the emulsion comprises, in parts by mass:

[0091] Any value between 20 and 100 parts of the above-mentioned complex or pharmaceutical composition, or a range between any two values, 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.;

[0092] Any value between 6 and 20 parts of the emulsifier or a range between any two values, 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.;

[0093] Any value between 4 and 8 parts of the 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.;

[0094] Any value between 0.6 and 1.5 parts of the antibacterial agent or a range between any two values, such as 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, etc.; and,

[0095] Any value between 2 and 6 parts of the osmotic pressure regulator or a range between any two values, 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.

[0096] 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.

[0097] The pH regulator can be an inorganic acid, an organic acid, an alkali, a buffer solution, etc. Preferably, it is hydrochloric acid or sodium hydroxide.

[0098] The flavoring agent includes one or more of sodium citrate, sodium saccharin (sodium o-benzoylsulfonimide), flavor, sodium cyclamate, acesulfame potassium, sorbitol, sodium chloride, adenosine monophosphate, or acesulfame potassium. The flavor can be one or more of banana flavor, apple flavor, orange flavor, or grape flavor.

[0099] The emulsion also includes water, solvent or buffer, etc., which are used to prepare liquid preparations or dissolve various substances in the prescription or provide an environment for the reaction.

[0100] The viscosity of the emulsion is any value in the range of 90-150 mPa.s or a range between any two values, preferably any value in the range of 90-120 mPa.s or a range between any two values, preferably any value in the range of 95-110 mPa.s or a range between any two values, such as 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, 111 mPa.s, 112 mPa.s, 113 mPa.s, 114 mPa.s, 115 mPa.s, 116 mPa.s, 117 mPa.s, 118 mPa.s, 119 mPa.s, 120 mPa.s, 121 mPa.s, 122 mPa.s, 123 mPa.s, 124 mPa.s, 125 mPa.s, 126 mPa.s, 127 mPa.s, 128 mPa.s, 129 mPa.s, 130 mPa.s, 131 mPa.s, 132 mPa.s, 133 mPa.s, 134 mPa.s mPa.s, 100mPa.s, 101mPa.s, 102mPa.s, 103mPa.s, 104mPa.s, 105mPa.s, 106mPa.s, 107mPa.s, 108mPa.s, 10 9mPa.s, 110mPa.s, 115mPa.s, 120mPa.s, 125mPa.s, 130mPa.s, 135mPa.s, 140mPa.s, 145mPa.s or 150mPa.s, etc.

[0101] The polydimethylsiloxane content is any value between 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.

[0102] The emulsion is used to treat a condition associated with excessive gas production or accumulation. Preferably, the condition is 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.

[0103] The emulsion is used for abdominal imaging examination or auxiliary examination.

[0104] The emulsion is used to treat gastrointestinal disorders, preferably gastrointestinal disorders involving excessive gas production or accumulation.

[0105] The emulsion may also include other drugs or compounds known in the prior art that can assist in treating diseases, such as prokinetic drugs, analgesics, local anesthetics, etc.

[0106] The emulsion can be prepared according to conventional production methods in the pharmaceutical field.

[0107] The emulsion can be administered by any suitable route, preferably by the gastrointestinal tract, such as orally.

[0108] The emulsion is for human or veterinary use.

[0109] In a fourth aspect of the present invention, a method for preparing the above-mentioned emulsion is provided, which comprises mixing an aqueous phase and an oil phase at 60-90°C, homogenizing, then fixing the volume, and filtering; the oil phase comprises the above-mentioned pharmaceutical composition or complex, and an emulsifier.

[0110] Preferably, the preparation method comprises:

[0111] The thickener is prepared into a dispersion with a viscosity of 4000-11000cp;

[0112] The aqueous phase containing an osmotic pressure regulator, an antibacterial agent and / or a flavoring agent is mixed with the oil phase containing the above-mentioned pharmaceutical composition and an emulsifier at 60-90° C. and homogenized. Then, the prepared thickener is added and the pH is adjusted. The volume is constant and the mixture is filtered.

[0113] Preferably, the preparation method comprises:

[0114] A) Thickener preparation: The thickener is prepared into a dispersion with a viscosity of 4000-11000cp;

[0115] B) Aqueous Phase Preparation: Add osmotic pressure regulator, antibacterial agent and / or flavoring agent to water, aerate with nitrogen, and stir until the solution is clear.

[0116] C) Oil phase preparation: under nitrogen protection, add the above-mentioned pharmaceutical composition or the pharmaceutical composition obtained by the above-mentioned preparation method, raise the temperature to 60-90°C under shearing state, add emulsifier, and shear and disperse uniformly;

[0117] D) Colostrum Preparation: Control the mixing temperature of the oil phase and the water phase at 60-90°C, and mix the prepared oil phase (C) and the prepared water phase (B) by shearing, with self-circulating shearing until a white emulsion is formed to form colostrum;

[0118] E) Homogenization: adjusting the homogenization pressure to 50-500 bar and controlling the temperature to 60-90° C., homogenizing 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;

[0119] F) pH adjustment and thickening and stabilization: add the prescribed amount of thickener prepared in A) to the emulsion I obtained in E), cool it down, adjust the pH to 3.0-6.0, add water to make up to the prescribed amount, and mix well to obtain emulsion II;

[0120] G) The emulsion II obtained in F) is filtered.

[0121] Further preferably, the preparation method comprises:

[0122] A) Preparation of thickener: Add purified water to the preparation tank and add thickener while stirring to prepare a dispersion with a viscosity of 4000-11000cp;

[0123] B) Aqueous Phase Preparation: Add 30-80% of the total volume of purified water to the preparation tank, add an osmotic pressure regulator, antibacterial agent and / or flavoring agent, aerate with nitrogen, and stir until the solution is clear;

[0124] C) Oil phase preparation: Under nitrogen protection, add the above-mentioned complex, pharmaceutical composition or pharmaceutical composition obtained by the above-mentioned preparation method, raise the temperature to 60-90°C under shearing state, add emulsifier, and shear and disperse uniformly;

[0125] D) Colostrum preparation: Control the mixing temperature of the oil phase and the water phase at 60-90°C, and mix the oil phase prepared in C) and the water phase prepared in B) by shearing to form colostrum;

[0126] E) Homogenization: adjusting the homogenization pressure to 50-500 bar and controlling the temperature to 60-90° C., homogenizing the colostrum prepared in D) 2-8 times to obtain Emulsion I;

[0127] F) pH adjustment and thickening and stabilization: The thickener prepared in the prescribed amount in A) is added to the emulsion I obtained in E) under stirring. After cooling, a pH adjuster is added to adjust the pH to 3.0-6.0. Purified water is added to make up to the prescribed amount, and the mixture is mixed uniformly to obtain emulsion II.

[0128] G) Filtration and filling: F) The obtained emulsion II is filtered and then filled.

[0129] In a fifth aspect, the present invention provides a method for treating a disease, which comprises administering the above-mentioned complex, a pharmaceutical composition comprising the complex, or the above-mentioned emulsion to a subject in need thereof.

[0130] The administration may be by any suitable route, preferably by gastrointestinal administration, such as oral administration.

[0131] The disease includes but is not limited to diseases associated with excessive gas production or accumulation. Preferably, the disease is selected from abdominal pain, abdominal distension, flatulence, functional bloating, functional dyspepsia or irritable bowel syndrome.

[0132] The diseases include, but are not limited to, infant feeding intolerance or infant postoperative abdominal pain.

[0133] The diseases include, but are not limited to, gastrointestinal diseases, preferably gastrointestinal diseases involving excessive gas production or accumulation.

[0134] In a sixth aspect, the present invention provides a method for abdominal imaging examination or auxiliary examination, which comprises applying the above-mentioned complex, a pharmaceutical composition comprising the complex, or the above-mentioned emulsion to a subject in need.

[0135] Beneficial effects of the present invention:

[0136] 1) The main ingredient content is high, and the emulsion can be well separated from the equipment during the formulation process without losing the active ingredient;

[0137] 2) The preparation has good long-term stability: stability after opening can reach 6 months, the viscosity of the preparation is maintained at 90-150mPa.s, the content of the main ingredient and sorbic acid does not decrease significantly, the product does not delaminate, and the safety is good;

[0138] 3) Molecular weight distribution affects viscosity, fluidity and stability, and affects the defoaming ability of the preparation.

[0139] The term "pharmaceutically acceptable" as used herein means that the pharmaceutical composition neither significantly stimulates the organism nor inhibits the biological activity and properties of the active substance of the administered product.

[0140] As used herein, "treating" means slowing, interrupting, preventing, controlling, stopping, alleviating, or reversing the progression or severity of a sign, symptom, disorder, condition, or disease after the disease has begun to develop, but does not necessarily involve the complete elimination of all disease-associated signs, symptoms, conditions, or disorders.

[0141] The "effective amount" of the present invention refers to the amount or dosage of the drug of the present invention that provides the desired treatment or prevention after administration to an individual or organ in a single or multiple doses.

[0142] The "subject" described in the present invention can be a human or 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, zoo animal, commercial animal, pet, 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), monkeys, etc. DETAILED DESCRIPTION

[0143] The following is a clear and complete description of the technical solutions in the embodiments of the present invention. Obviously, the embodiments described are only some embodiments of the present invention, not all. All other embodiments obtained by ordinary technicians in this field based on the embodiments of the present invention without making any creative efforts are within the scope of protection of the present invention.

[0144] Unless otherwise specified, the experimental methods used in the examples are conventional methods.

[0145] Unless otherwise specified, the materials and reagents used in the examples can be obtained from commercial sources.

[0146] The materials or reagents used in the examples are from the following sources:

[0147] Dimethicone was purchased from Jiangxi Alpha High-Tech Pharmaceutical Co., Ltd., product number 20181101;

[0148] Silica, purchased from Grace, product number 1000341778;

[0149] Stearic acid polyoxyethylene (40) ester, purchased from Nanjing Well Pharmaceutical Group Co., Ltd., product number B01513;

[0150] Glyceryl mono- and distearate, purchased from Jaffar, France, product number 172388;

[0151] Sorbic acid was purchased from Hunan Erkang Pharmaceutical Co., Ltd. with the product number 103720180801;

[0152] Carbomer, purchased from Lubrizol, product number 0102222730;

[0153] Hydroxypropyl methylcellulose, purchased from Dow Chemical, product number 1071799127;

[0154] Sorbitol was purchased from Roquette China (Food) Co., Ltd. with the product number 1926H.

[0155] Example 1: Preparation of Simethicone Complex

[0156] 1. Experimental Group 1

[0157] 1) Add the prescribed amount of dimethyl silicone oil at room temperature and start stirring. Slowly add the silicon dioxide into the batching tank (control the addition speed to add the prescribed amount in no less than 1 hour).

[0158] 2) Reaction: Heat the solution to 150°C and stir for 4 hours.

[0159] 3) Subpackaging and filtration: Lower the temperature of the liquid to 40°C and circulate the liquid under stirring for 40 minutes. Subpackaging is then completed. The specific formula is shown in Table 1.

[0160] 2. Experimental Group 2

[0161] 1) Add the prescribed amount of dimethyl silicone oil at room temperature and start stirring. Slowly add the silicon dioxide into the batching tank (control the addition speed to add the prescribed amount in no less than 1 hour).

[0162] 2) Reaction: Heat the solution to 140°C and stir for 5 hours.

[0163] 3) Subpackaging and filtration: Lower the temperature of the liquid to 20°C and circulate the liquid under stirring for 20 minutes. Subpackaging is then completed. The specific formula is shown in Table 1.

[0164] 3. Experimental Group 3

[0165] 1) Add the prescribed amount of dimethyl silicone oil at room temperature and start stirring. Slowly add the silicon dioxide into the batching tank (control the addition speed to add the prescribed amount in no less than 1 hour).

[0166] 2) Reaction: Heat the solution to 170°C and stir for 6 hours.

[0167] 3) Subpackaging and filtration: Lower the temperature of the liquid to 25°C and circulate the liquid under stirring for 60 minutes. Subpackaging is then completed. The specific formula is shown in Table 1.

[0168] 4. Experimental Group 4

[0169] 1) Add the prescribed amount of dimethyl silicone oil at room temperature and start stirring. Slowly add the silicon dioxide into the batching tank (control the addition speed to add the prescribed amount in no less than 1 hour).

[0170] 2) Reaction: Heat the solution to 180°C and stir for 3 hours.

[0171] 3) Subpackaging and filtration: Lower the temperature of the liquid to 10°C and circulate the liquid under stirring for 30 minutes. Subpackaging is then completed. The specific formula is shown in Table 1.

[0172] 5. Experimental Group 5

[0173] 1) Add the prescribed amount of dimethyl silicone oil at room temperature and start stirring. Slowly add the silicon dioxide into the batching tank (control the addition speed to add the prescribed amount in no less than 1 hour).

[0174] 2) Reaction: Heat the solution to 160°C and stir for 3.5 hours.

[0175] 3) Subpackaging and filtration: Lower the temperature of the liquid to 10°C and circulate the liquid under stirring for 30 minutes. Subpackaging is then completed. The specific formula is shown in Table 1.

[0176] 6. Experimental Group 6

[0177] 1) Add the prescribed amount of dimethyl silicone oil at room temperature and start stirring. Slowly add the silicon dioxide into the batching tank (control the addition speed to add the prescribed amount in no less than 1 hour).

[0178] 2) Reaction: Heat the solution to 150°C and stir for 4.5 hours.

[0179] 3) Subpackaging and filtration: Lower the temperature of the liquid to 20°C and circulate the liquid under stirring for 45 minutes for filtration. Subpackaging is then completed. The specific formula is shown in Table 1.

[0180] 7. Experimental Group 7

[0181] 1) Add the prescribed amount of dimethyl silicone oil at room temperature and start stirring. Slowly add the silicon dioxide into the batching tank (control the addition speed to add the prescribed amount in no less than 1 hour).

[0182] 2) Reaction: Heat the solution to 180°C and stir for 5.5 hours.

[0183] 3) Subpackaging and filtration: Lower the temperature of the liquid to 25°C and circulate the liquid under stirring for 25 minutes. Subpackaging is then completed. The specific formula is shown in Table 1.

[0184] Table 1

[0185] 8. Comparison Group 1

[0186] 1) Add the prescribed amount of dimethyl silicone oil at room temperature and start stirring. Slowly add the silicon dioxide into the batching tank (control the addition speed to complete the addition in no less than 1 hour).

[0187] 2) Reaction: Heat the solution to 150°C and stir for 4 hours.

[0188] 3) Sub-packaging and filtration: The temperature of the liquid medicine is lowered to 25°C, and the liquid medicine is circulated and filtered for 40 minutes under stirring conditions, and then sub-packaging is obtained. The specific prescription is shown in Table 2.

[0189] 9. Comparison Group 2

[0190] 1) Add the prescribed amount of dimethyl silicone oil at room temperature and start stirring. Slowly add silicon dioxide into the batching tank (control the addition speed to be no less than 1 until the addition is complete).

[0191] 2) Reaction: Heat the solution to 170°C and stir for 5 hours.

[0192] 3) Sub-packaging and filtration: The temperature of the liquid medicine is lowered to 20°C, and the liquid medicine is circulated and filtered for 20 minutes under stirring conditions, and then sub-packaging is obtained. The specific prescription is shown in Table 2.

[0193] 10. Comparison Group 3

[0194] 1) Add the prescribed amount of dimethyl silicone oil at room temperature and start stirring. Slowly add silicon dioxide into the mixing tank (control the addition speed to be no less than 1 until the addition is complete).

[0195] 2) Reaction: Heat the solution to 140°C and stir for 6 hours.

[0196] 3) Sub-packaging and filtration: The temperature of the liquid medicine is lowered to 20°C, and the liquid medicine is filtered through a circulation process for 60 minutes under stirring conditions, and then the liquid medicine is sub-packed. The specific prescription is shown in Table 2.

[0197] Table 2

[0198] 7. Determination of quality characteristics of simethicone complex

[0199] 1) Molecular weight distribution: Determine by size exclusion chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0514). Take an appropriate amount of this product, dissolve it in tetrahydrofuran, and dilute it to a solution containing approximately 10 mg per 1 mL as the test solution. Separately, take five polystyrene reference substances of known molecular weight, dissolve them in the mobile phase, and dilute them to a solution containing 4 mg per 1 mL as the reference solution. Use highly cross-linked polystyrene-divinylbenzene polymer resin as the filler; tetrahydrofuran as the mobile phase; and determine the concentration using a differential refractive index detector. Calculate the weight-average molecular weight and molecular weight distribution coefficient Dα of the test substance using GPC software.

[0200] 2) Viscosity: Take this product and inspect it according to the law (Method 0633, Part 4, General Rules, 2020 Edition of the Chinese Pharmacopoeia) to determine the kinematic viscosity of this product at 25°C.

[0201] 3) Defoaming Ability: Dissolve 5.0g of docusate sodium in 1L of water in a water bath to prepare a foaming solution. Place in warm water and keep warm until ready for use. Add 0.250g of this product to butanone, shake to dissolve, and quantitatively transfer to a 50mL volumetric flask to prepare a defoaming solution. Place 100mL of the foaming solution and 1mL of the defoaming solution in a 250mL stoppered round bottle. Secure the bottle to an oscillator and oscillate at a frequency of 250-300 times per minute, an oscillation angle of 10°, an oscillation radius of 10cm, and a oscillation time of 10 seconds. Record the time from the end of oscillation to the appearance of the first portion of foam-free liquid surface.

[0202] 4) Sedimentation: The prepared composite was placed in n-hexane and observed for 24 hours to see whether silica sedimentation occurred.

[0203] 8. Results of composite mass determination

[0204] The molecular weight of the experimental groups 1-4 complexes is in the range of 22000-38000. The complexes have moderate viscosity, good fluidity, good defoaming ability, are not prone to sedimentation, and have good stability. When the molecular weight of the control group is low, the complexes will produce a small amount of sedimentation and the defoaming ability will be weakened. When the molecular weight is high, the complexes have poor fluidity, are prone to sedimentation, and have weak defoaming ability. The specific results are shown in Table 3.

[0205] Fluidity determination: Take 10ml of this product and put it into a 20ml stoppered test tube. Rotate it 180° and record the time and angle of the liquid when all the liquid flows to the opposite side. The shorter the time, the better the fluidity. Normally, it should flow completely to the opposite side within 15s.

[0206] Table 3

[0207] Example 2: Complex stability test

[0208] The simethicone complexes obtained from the test groups 1-4 and the comparative groups 1-3 in Example 1 were stored in a stability box at 40°C ± 2°C. The molecular weight and distribution coefficient, viscosity, defoaming ability, and properties (whether sedimentation and stratification) of the products were measured in 3 and 6 months, respectively. The results are shown in Table 4.

[0209] Table 4

[0210] Accelerated testing results showed that the simethicone complexes prepared in test groups 1-7 were very stable, with no significant differences in molecular weight, distribution coefficient, viscosity, or defoaming ability compared to day 0, and virtually no sedimentation. Comparative groups 1-3 showed prolonged defoaming times, decreased defoaming ability, and significant sedimentation and stratification. In contrast, the viscosity of comparative groups 1 and 3 increased significantly, and the product's fluidity deteriorated. By the sixth month of accelerated testing, they had become almost semisolid, with acceptable fluidity, making them unsuitable for use in emulsion preparation.

[0211] During the preparation of the composite, slowly adding silica into the batching tank (the addition speed is controlled to be no less than 1 hour) can help to form a dispersion effect of the composite and improve the stability of the composite.

[0212] Example 3: Preparation of Emulsions Emulsions were prepared using the simethicone complexes obtained from test groups 1, 3, 4, 6 and comparison groups 1-3 in Example 1.

[0213] 1. Prescriptions are shown in Table 5-6.

[0214] Table 5

[0215] Table 6

[0216] 2. Preparation process

[0217] 1) Preparation of thickener: Add purified water into the preparation tank and slowly add thickener while stirring to prepare a dispersion with a viscosity of 4000-11000cp.

[0218] 2) Preparation of aqueous phase: Add 30-80% of the total volume of purified water into the preparation tank, add osmotic pressure regulator, antibacterial agent, and flavoring agent, fill with nitrogen and keep at 40℃-90℃, and stir until the solution is clear.

[0219] 3) Oil phase preparation: under nitrogen protection, add simethicone complex, heat to 60-90°C under shear state, add emulsifier, and shear and disperse evenly.

[0220] 4) Colostrum Preparation: Control the mixing temperature of the oil phase and the water phase at 60-90°C and mix them through a shearing machine to form colostrum. The colostrum is sheared in a self-circulating manner until it becomes a white emulsion.

[0221] 5) Homogenization: Adjust the homogenizer pressure to 50-500 bar, control the liquid temperature to 60-90°C, and homogenize the colostrum 2-8 times through the homogenizer to obtain Emulsion I.

[0222] 6) pH Adjustment and Thickening and Stabilization: Add the thickener prepared in step 1) to Emulsion I while stirring. After cooling, add sodium hydroxide solution to adjust the pH of the solution to 3.0-6.0. Add purified water to the prescribed volume. Mix thoroughly to obtain Emulsion II.

[0223] 7) Filtration and filling of drug solution: Emulsion II is filled after filtration.

[0224] 3. Determination of emulsion quality characteristics

[0225] 1) Determination of polydimethylsiloxane content: Determine according to infrared spectrophotometry (Chinese Pharmacopoeia 2020 Edition Part IV General Chapter 0402). Take about 2g of this product, accurately weigh it, add 5mL of methanol, mix well, accurately add 25mL of n-hexane, mix well, shake for 10 minutes and let it stand, separate the n-hexane layer, add 3g of anhydrous sodium sulfate, mix well and centrifuge for 5 minutes, and take the supernatant as the test solution. Take an equal amount of polydimethylsiloxane reference substance, accurately weigh it, add 2mL of water, mix well, operate in the same way, and take the supernatant as the reference solution. Take 2mL of water, operate in the same way, and take the supernatant as the blank solution.

[0226] Measurement method: The measurement wavelength is 1111cm -1 -1428cm -1 The absorption cell is 0.5 mm, and the absorbance of the test and reference solutions is measured respectively, and the reading is 1260 ± 4 cm -1 The absorbance is calculated according to the following formula.

[0227] A T : absorbance of the test solution; A R : absorbance of reference solution;

[0228] W T: Sample weight of the test sample, mg; W R : Reference substance weight, mg;

[0229] ρ: relative density of emulsion, g / mL;

[0230] C R : Polydimethylsiloxane content in the reference substance, %;

[0231] C 标 : Theoretical content of polydimethylsiloxane in emulsion, mg / mL.

[0232] 2) Defoaming Ability: Take two portions of 50 mL of a non-foaming 1.0% Triton X-100 solution and carefully inject them into two clean 250 mL stoppered measuring cylinders. Measure 0.4 mL of this product (rinse the measuring cylinder twice with water, 2.0 mL each time) and place it into one of the measuring cylinders. Seal both measuring cylinders tightly and shake them vigorously 5 times. Let them stand for 1 minute. Measure the foam height. Divide the height of the reduced foam in the emulsified measuring cylinder by the height of the foam in the unemulsified measuring cylinder (100%) to calculate the defoaming ability, which should be no less than 80%.

[0233] 3) Viscosity: Determine according to the viscosity determination method (Chinese Pharmacopoeia 2020 Edition Part IV General Rules 0633 Third Method), take an appropriate amount of this product and add it to a 41mm coaxial cylinder double slit measuring cup, control the temperature in a circulating water bath at 20±1℃, use a 41mm coaxial cylinder double slit measuring rotor to measure, and the shear rate is 171s -1 The dynamic viscosity should be 90-150mPa·s.

[0234] 4) Emulsion stability: 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 stratification.

[0235] 4. Test results

[0236] The key quality indicators of the simethicone emulsions (emulsions 1-4) prepared by the simethicone complexes prepared by test groups 1, 3, 4, and 6 in Example 1 and the emulsifiers, thickeners, osmotic pressure regulators, etc. in appropriate proportions, such as polydimethylsiloxane content, defoaming ability, viscosity, and emulsion stability, all met the standard requirements; the key quality indicators of the simethicone complexes prepared by comparative groups 1-3 in Example 1 and the emulsifiers, thickeners, etc. in other proportions, such as polydimethylsiloxane content, defoaming ability, viscosity, and emulsion stability, of the simethicone emulsions (comparative emulsions 1-3), all met the standard requirements. The results are shown in Table 7.

[0237] Table 7

[0238] The preferred embodiments of the present invention are described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within 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 scope of protection of the present invention.

[0239] It should also be noted that the various specific technical features described in the above specific embodiments can be combined in any appropriate manner without contradiction. In order to avoid unnecessary repetition, the present invention will not further describe various possible combinations.

Claims

1. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises a complex of dimethicone and silicon dioxide, wherein the weight average molecular weight of the complex is 20000-40000Mw, preferably 22000-36000Mw, preferably 24000-36000Mw.

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

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

8.

4. The pharmaceutical composition according to claim 1, characterized in that In the composite, the mass ratio of dimethicone to silicon dioxide 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 to 4, and an emulsifier.

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

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

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

1.

9. The emulsion according to claim 5, characterized in that The emulsifier is selected from one or more of fatty acid glyceride, polyethylene glycol fatty acid ester, Tween, Span, poloxamer, stearyl palmitate, polyoxyethylene 15 hydroxystearate, polyoxyethylene hydrogenated castor oil, propylene glycol ester or fatty acid amide; Preferably, the fatty acid glyceride is selected from one or more of mono- and distearic acid glyceryl, mono-stearic acid glyceryl or mono-oleic acid glyceryl; 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; Preferably, the Tween comprises Tween 80; Preferably, the poloxamer comprises poloxamer 188; Preferably, the propylene glycol ester is 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 to 9, characterized in that The emulsion also includes a thickener; Preferably, the emulsion contains 0.4%-0.8% thickener in terms of mass volume percentage; Preferably, the thickener comprises one or more of carbomer, xanthan gum, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, guar gum, carrageenan, gum arabic, pectin, alginate, agarose, polyvinyl alcohol or povidone; More preferably, the thickener is carbomer and / or hydroxypropyl methylcellulose.

11. The emulsion according to claim 5, characterized in that The emulsion also includes one or more of an antibacterial agent, an osmotic pressure regulator, a pH regulator or a flavoring agent.

12. The emulsion according to claim 11, characterized in that The emulsion contains 0.06%-0.15% of an antibacterial agent in terms of mass volume percentage; Preferably, the antibacterial 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, characterized in that The emulsion contains 0.2%-0.6% of an osmotic pressure regulator in terms of 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, characterized in that The pH value of the emulsion is 3-6.

15. The emulsion according to claim 5, characterized in that The emulsion comprises, by mass volume percentage: Complex: 2%-10%; Emulsifier: 0.6%-2%; Thickener: 0.4%-0.8%; Antibacterial agent: 0.06%-0.15%; Osmotic pressure regulator: 0.2%-0.6%.

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

17. Use of the pharmaceutical composition according to any one of claims 1 to 4 or the emulsion according to any one of claims 5 to 16, characterized in that: The applications described include: A) use in the preparation of a medicament for treating a disease associated with excessive gas production or accumulation, preferably, the disease is selected from abdominal pain, abdominal distension, flatulence, functional bloating, functional dyspepsia or irritable bowel syndrome; or B) Use in the preparation of drugs for abdominal imaging examination or auxiliary examination.

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