CN116421559A - Stable simethicone emulsion and preparation method thereof - Google Patents
Stable simethicone emulsion and preparation method thereof Download PDFInfo
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- CN116421559A CN116421559A CN202310186280.9A CN202310186280A CN116421559A CN 116421559 A CN116421559 A CN 116421559A CN 202310186280 A CN202310186280 A CN 202310186280A CN 116421559 A CN116421559 A CN 116421559A
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- emulsion
- simethicone
- simethicone emulsion
- stable
- carbomer
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- 239000000839 emulsion Substances 0.000 title claims abstract description 148
- AMTWCFIAVKBGOD-UHFFFAOYSA-N dioxosilane;methoxy-dimethyl-trimethylsilyloxysilane Chemical compound O=[Si]=O.CO[Si](C)(C)O[Si](C)(C)C AMTWCFIAVKBGOD-UHFFFAOYSA-N 0.000 title claims abstract description 114
- 229940083037 simethicone Drugs 0.000 title claims abstract description 114
- 238000004945 emulsification Methods 0.000 title claims description 41
- 238000002360 preparation method Methods 0.000 title abstract description 27
- 229920002125 Sokalan® Polymers 0.000 claims abstract description 47
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims abstract description 46
- 229960001631 carbomer Drugs 0.000 claims abstract description 45
- 239000002245 particle Substances 0.000 claims abstract description 41
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 29
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 claims abstract description 26
- 229920002701 Polyoxyl 40 Stearate Polymers 0.000 claims abstract description 13
- 229940075507 glyceryl monostearate Drugs 0.000 claims abstract description 12
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 claims abstract description 12
- 238000002156 mixing Methods 0.000 claims abstract description 10
- 230000001804 emulsifying effect Effects 0.000 claims abstract description 7
- 238000010008 shearing Methods 0.000 claims abstract description 7
- 229940099429 polyoxyl 40 stearate Drugs 0.000 claims abstract description 6
- 238000000034 method Methods 0.000 claims description 34
- 238000003756 stirring Methods 0.000 claims description 29
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- 239000000203 mixture Substances 0.000 claims description 13
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 12
- 239000003995 emulsifying agent Substances 0.000 claims description 12
- 238000010438 heat treatment Methods 0.000 claims description 11
- 239000008213 purified water Substances 0.000 claims description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- 239000000796 flavoring agent Substances 0.000 claims description 9
- 239000000337 buffer salt Substances 0.000 claims description 8
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 claims description 8
- 235000010199 sorbic acid Nutrition 0.000 claims description 8
- 239000004334 sorbic acid Substances 0.000 claims description 8
- 229940075582 sorbic acid Drugs 0.000 claims description 8
- WBZFUFAFFUEMEI-UHFFFAOYSA-M Acesulfame k Chemical compound [K+].CC1=CC(=O)[N-]S(=O)(=O)O1 WBZFUFAFFUEMEI-UHFFFAOYSA-M 0.000 claims description 7
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 7
- 229960004998 acesulfame potassium Drugs 0.000 claims description 7
- 235000010358 acesulfame potassium Nutrition 0.000 claims description 7
- 239000000619 acesulfame-K Substances 0.000 claims description 7
- 239000007788 liquid Substances 0.000 claims description 7
- 239000000600 sorbitol Substances 0.000 claims description 7
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 6
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 6
- 239000011780 sodium chloride Substances 0.000 claims description 6
- 238000005303 weighing Methods 0.000 claims description 5
- 239000004973 liquid crystal related substance Substances 0.000 claims description 4
- CHHHXKFHOYLYRE-UHFFFAOYSA-M 2,4-Hexadienoic acid, potassium salt (1:1), (2E,4E)- Chemical compound [K+].CC=CC=CC([O-])=O CHHHXKFHOYLYRE-UHFFFAOYSA-M 0.000 claims description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 3
- 239000005711 Benzoic acid Substances 0.000 claims description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 3
- UDIPTWFVPPPURJ-UHFFFAOYSA-M Cyclamate Chemical compound [Na+].[O-]S(=O)(=O)NC1CCCCC1 UDIPTWFVPPPURJ-UHFFFAOYSA-M 0.000 claims description 3
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 claims description 3
- 235000018290 Musa x paradisiaca Nutrition 0.000 claims description 3
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 claims description 3
- 235000010233 benzoic acid Nutrition 0.000 claims description 3
- 229960004365 benzoic acid Drugs 0.000 claims description 3
- 239000000625 cyclamic acid and its Na and Ca salt Substances 0.000 claims description 3
- 229940050410 gluconate Drugs 0.000 claims description 3
- 235000010241 potassium sorbate Nutrition 0.000 claims description 3
- 239000004302 potassium sorbate Substances 0.000 claims description 3
- 229940069338 potassium sorbate Drugs 0.000 claims description 3
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 claims description 3
- 235000010234 sodium benzoate Nutrition 0.000 claims description 3
- 239000004299 sodium benzoate Substances 0.000 claims description 3
- 229960003885 sodium benzoate Drugs 0.000 claims description 3
- 229960001462 sodium cyclamate Drugs 0.000 claims description 3
- 240000005561 Musa balbisiana Species 0.000 claims 1
- WINXNKPZLFISPD-UHFFFAOYSA-M Saccharin sodium Chemical compound [Na+].C1=CC=C2C(=O)[N-]S(=O)(=O)C2=C1 WINXNKPZLFISPD-UHFFFAOYSA-M 0.000 claims 1
- 239000003242 anti bacterial agent Substances 0.000 claims 1
- 235000019634 flavors Nutrition 0.000 claims 1
- 239000012071 phase Substances 0.000 abstract description 20
- 238000009826 distribution Methods 0.000 abstract description 11
- 239000008346 aqueous phase Substances 0.000 abstract description 5
- 230000000052 comparative effect Effects 0.000 description 37
- 239000002562 thickening agent Substances 0.000 description 31
- 230000008569 process Effects 0.000 description 27
- 235000013355 food flavoring agent Nutrition 0.000 description 8
- 239000003921 oil Substances 0.000 description 8
- 238000009472 formulation Methods 0.000 description 7
- 210000003022 colostrum Anatomy 0.000 description 6
- 235000021277 colostrum Nutrition 0.000 description 6
- 238000001514 detection method Methods 0.000 description 6
- 238000000265 homogenisation Methods 0.000 description 6
- 238000011835 investigation Methods 0.000 description 6
- 235000010356 sorbitol Nutrition 0.000 description 6
- 239000001509 sodium citrate Substances 0.000 description 5
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 5
- 229960002920 sorbitol Drugs 0.000 description 5
- 108010010803 Gelatin Proteins 0.000 description 4
- 239000000022 bacteriostatic agent Substances 0.000 description 4
- 239000006260 foam Substances 0.000 description 4
- 239000008273 gelatin Substances 0.000 description 4
- 229920000159 gelatin Polymers 0.000 description 4
- 235000019322 gelatine Nutrition 0.000 description 4
- 235000011852 gelatine desserts Nutrition 0.000 description 4
- 230000007774 longterm Effects 0.000 description 4
- 229960002668 sodium chloride Drugs 0.000 description 4
- 235000002639 sodium chloride Nutrition 0.000 description 4
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 3
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 3
- 239000001768 carboxy methyl cellulose Substances 0.000 description 3
- 238000005119 centrifugation Methods 0.000 description 3
- 230000032798 delamination Effects 0.000 description 3
- 210000001035 gastrointestinal tract Anatomy 0.000 description 3
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 3
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 3
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 3
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 3
- 229960001790 sodium citrate Drugs 0.000 description 3
- 235000011083 sodium citrates Nutrition 0.000 description 3
- FTLYMKDSHNWQKD-UHFFFAOYSA-N (2,4,5-trichlorophenyl)boronic acid Chemical compound OB(O)C1=CC(Cl)=C(Cl)C=C1Cl FTLYMKDSHNWQKD-UHFFFAOYSA-N 0.000 description 2
- 241000234295 Musa Species 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 230000002776 aggregation Effects 0.000 description 2
- 238000004220 aggregation Methods 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 229940085605 saccharin sodium Drugs 0.000 description 2
- 230000008719 thickening Effects 0.000 description 2
- RFVNOJDQRGSOEL-UHFFFAOYSA-N 2-hydroxyethyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCO RFVNOJDQRGSOEL-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 239000013504 Triton X-100 Substances 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 210000004913 chyme Anatomy 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 239000013256 coordination polymer Substances 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000009322 erkang Substances 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 206010016766 flatulence Diseases 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- YQEMORVAKMFKLG-UHFFFAOYSA-N glycerine monostearate Natural products CCCCCCCCCCCCCCCCCC(=O)OC(CO)CO YQEMORVAKMFKLG-UHFFFAOYSA-N 0.000 description 1
- SVUQHVRAGMNPLW-UHFFFAOYSA-N glycerol monostearate Natural products CCCCCCCCCCCCCCCCC(=O)OCC(O)CO SVUQHVRAGMNPLW-UHFFFAOYSA-N 0.000 description 1
- 229940087073 glycol palmitate Drugs 0.000 description 1
- 229940100242 glycol stearate Drugs 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000010907 mechanical stirring Methods 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 210000003097 mucus Anatomy 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 238000013386 optimize process Methods 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 239000006254 rheological additive Substances 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229920002545 silicone oil Polymers 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000001502 supplementing effect Effects 0.000 description 1
- 238000009827 uniform distribution Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/74—Synthetic polymeric materials
- A61K31/80—Polymers containing hetero atoms not provided for in groups A61K31/755 - A61K31/795
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Dispersion Chemistry (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Inorganic Chemistry (AREA)
- Nutrition Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Cosmetics (AREA)
Abstract
The invention discloses a stable simethicone emulsion and a preparation method thereof, wherein the stable simethicone emulsion comprises the following components in percentage by weight and volume: 4.00 percent of simethicone, 0.60 to 0.72 percent of polyoxyl 40 stearate, 0.36 to 0.42 percent of glyceryl monostearate, 0.50 to 0.70 percent of carbomer, a pH regulator and water. The invention also provides a stable simethicone emulsion and a preparation method thereof, and the simethicone emulsion is prepared by mixing a carbomer-containing aqueous phase with an oil phase containing simethicone, polyoxyl 40 stearate and glyceryl monostearate, and homogenizing for 30-60 min at a high shearing and emulsifying speed of 7200-13000 rpm. Using a particular prescription of the inventionThe preparation process of the simethicone emulsion has the pH value of 4.8-5.2, and the particle size distribution and viscosity are suitable (emulsion particle size D 10 1-3 μm, D 50 Is 3-6 mu m, D 90 The viscosity is between 90 and 150mpa.s and is 6 to 20 mu m, which meets the requirement of stability.
Description
Technical Field
The invention belongs to the technical field of simethicone pharmaceutical preparations, and particularly relates to a stable simethicone emulsion and a preparation method thereof.
Background
Simethicone (Simethicone) is a mixture of Simethicone (90.5-99.0%) and silicon dioxide (4.0-7.0%), is a stable nonionic surfactant, can change the surface tension of bubbles existing in chyme and mucus in the digestive tract, decompose and release gas, and can be clinically applied to treating discomfort caused by excessive aggregation of gas in the gastrointestinal tract and assist in abdominal imaging examination.
Simethicone emulsion currently marketed in China is mainly a product originally developed by Berlin-Chemie AG in Germany and has the trade name of
The imported registration standard JX20140233 prescribes simethicone emulsion as stable emulsion with viscosity of 90-150 mpa.s and no delamination after centrifugation, but the particle size of the emulsion is not limited.
The original developer patent CN101229187A discloses a simethicone emulsion which takes polyethylene glycol stearate/palmitate and glyceride as an emulsifier and hydroxypropyl cellulose as a thickener, and discloses a preparation method: firstly preparing 30% simethicone colostrum, then mixing with water phase containing hydroxypropyl cellulose, stirring to be uniform, and obtaining the simethicone emulsion with emulsion particle size of 10-50 nm. However, the patent does not disclose specific emulsification processes and parameters, and the resulting emulsions are subject to emulsion breaking and other instability phenomena between different batches, even within the same batch.
Document 1 (Luo Xiaohong. Preparation and content analysis of simethicone emulsion of new formulation and pharmacodynamic investigation on animal model [ D ]. University of southwest 2016) "3.2.1.3 choice of thickener", a simethicone emulsion with carbomer as thickener is disclosed for improving the stability of an as-ground emulsion with hydroxypropyl cellulose as thickener; "3.2.2 preparation process" discloses the best preparation method of emulsion: adding simethicone into water phase containing emulsifier, stirring at 600rpm for 60min to form colostrum, mixing with the rest water phase containing carbomer, and stirring to obtain stable simethicone emulsion. However, the emulsion particle size is not studied in this document, and since the emulsion obtained by the emulsification process has a stirring rate of 600rpm which is too low, there is a risk that the emulsion particle size is too large, so that the discharge of fine bubbles in the gastrointestinal tract is inconvenient and the relief of flatulence is limited.
Therefore, the preparation of simethicone emulsion with small emulsion particle size and satisfactory stability is still an unsolved technical problem in the art, and on the basis of improving the stability of the simethicone emulsion by using carbomer as a thickener, the applicant tries to further optimize the preparation process to solve the technical problem.
The applicant has further found that, as to the prior art means for solving the problem of excessively large emulsion particle size, a high shear or high pressure homogenizing emulsification process is mainly used.
For example, document 2 (high-speed shearing emulsification method, wang Shujun, liu Gongyan, etc.. A silicone oil emulsion [ J ]. Fine chemical, 2014,31 (7): 6.) discloses a simethicone emulsion in which gelatin is used as a thickener, and the emulsion is sheared at a high speed of 11000rpm for 10 minutes on the basis of mechanical stirring at 800rpm, whereby the average particle diameter of the emulsion can be reduced from 10.7 μm to 1.2. Mu.m.
However, comparative example 1 of CN110721151A discloses a simethicone emulsion using carbomer as a thickener, which was homogenized 1 to 4 times by shearing at 6000rpm for 30min and a high pressure homogenizer at 0 to 300bar to obtain a small particle size emulsion (D) 10 0.5 μm, D 50 1.3 μm, D 90 22 μm) there is a problem of stability of delamination after centrifugation.
Therefore, in the preparation process of simethicone emulsion taking carbomer as a thickener, the existing high-shear or high-pressure homogenizing and emulsifying process is simply replaced and directly applied, and the particle size and stability of the emulsion cannot meet the requirements.
The inventors have found through analysis that simethicone emulsion using carbomer as thickener disclosed in the prior art such as patent document 1 and patent CN110721151a adopts a preparation method of preparing simethicone colostrum by an emulsification process and adding the residual water phase containing carbomer. The prior art has a few reports on the preparation method of simethicone emulsion by adding carbomer as a thickener before an emulsification process.
The reason for this may be that the prior art teaching of paragraph 35, et al, of patent CN102283809a, does not act as a thickening stabilizer because rheology modifiers such as carbomers degrade under the influence of high pressure homogenization, and is preferably added after high pressure homogenization.
In summary, in the preparation of simethicone emulsion using carbomer as a thickener, whether the preparation of the simethicone emulsion with small particle size and good stability can be achieved by changing the adding sequence of the thickener and optimizing the emulsification process and parameters has uncertainty. That is, this is a solution difficult problem that has not been solved by the person skilled in the art.
Disclosure of Invention
The invention aims to solve the technical problems that: on the basis of taking carbomer as a thickening agent, the thickening agent is added before an emulsification process, and optimized high-shear emulsification process parameters are adopted, so that emulsion particle size D is prepared 10 1-3 μm, D 50 Is 3-6 mu m, D 90 6-20 mu m, and stable simethicone emulsion.
In order to solve the technical problems, the invention is realized by the following technical scheme:
the stable simethicone emulsion comprises the following components in percentage by weight and volume: 4.00 percent of simethicone, 0.60 to 0.72 percent of polyoxyl 40 stearate, 0.36 to 0.42 percent of glyceryl monostearate, 0.50 to 0.70 percent of carbomer, a pH regulator and water; wherein, the liquid crystal display device comprises a liquid crystal display device,
the pH regulator is one or more selected from sodium hydroxide, potassium hydroxide and triethanolamine; the pH of simethicone emulsion is 4.8-5.2, and the particle diameter D of the emulsion 10 1-3 μm, D 50 Is 3-6 mu m, D 90 Is 6-20 mu m.
Preferably, the carbomer model is selected from one or more of 934P, 974P, 971P, more preferably carbomer 971P.
Preferably, the simethicone emulsion has a viscosity of from 90 to 150mpa.s, more preferably from 100 to 150mpa.s.
Preferably, the simethicone emulsion further comprises a buffer salt selected from one or more of citrate, acetate, gluconate, and more preferably sodium citrate.
Preferably, the simethicone emulsion further comprises a bacteriostatic agent selected from one or more of sorbic acid, potassium sorbate, benzoic acid, sodium benzoate, more preferably sorbic acid.
Preferably, the simethicone emulsion further comprises a flavoring agent, wherein the flavoring agent is one or more selected from sorbitol, sodium chloride, acesulfame potassium, saccharin sodium, sodium cyclamate and banana essence.
Preferably, a stable simethicone emulsion comprises the following components in percentage by weight and volume:
a method for preparing a stable simethicone emulsion, comprising the steps of:
(1) And weighing simethicone with a prescription amount, heating to 70-80 ℃, adding the emulsifier polyoxyl 40 stearate and glyceryl monostearate with the prescription amount, and stirring until the mixture is melted to obtain an oil phase.
(2) Weighing the purified water with the prescription amount, adding carbomer and pH regulator with the prescription amount under heating and stirring, and stirring to obtain uniform and clear viscous liquid to obtain water phase.
(3) Emulsification: slowly adding the water phase in the step (2) into the oil phase in the step (1), stirring and uniformly mixing, and emulsifying and homogenizing for 30-60 min at a high shearing speed of 7200-13000 rpm to obtain the simethicone emulsion.
Preferably, the heating temperature in step (2) is 70-80℃and the stirring speed is 800-1000 rpm.
Preferably, in the step (2), the purified water with the prescription amount is weighed, carbomer with the prescription amount and a pH regulator are added under the heating and stirring state, one or more of buffer salt, a bacteriostatic agent and a flavoring agent are added, and the mixture is stirred until the mixture is uniform and clear viscous liquid, so that the water phase is prepared.
Compared with the prior art, the simethicone emulsion and the preparation method thereof provided by the invention have the beneficial effects that:
1) The simethicone emulsion provided by the invention adopts 0.50-0.70% of carbomer as a thickener, and the carbomer is added before an emulsification process, and adopts optimized high-shear emulsification process parameters to prepare emulsion particle size D 10 1-3 μm, D 50 Is 3-6 mu m, D 90 Stable emulsion with 6-20 mu m and viscosity of 90-150 mpa.s; the emulsion can maintain high temperature stability at 60deg.C and long-term stability.
2) According to the preparation method of simethicone emulsion, provided by the invention, the thickening agent carbomer is added into the water phase before an emulsification process, so that uneven and unstable colostrum described in comparative example 4 is avoided, and the uniformity and stability of the particle size distribution of the finally prepared simethicone emulsion are improved.
3) The preparation method of simethicone emulsion provided by the invention adopts a high-shear emulsification homogenizing process with the rotating speed of 7200-13000 rpm and the homogenizing speed of 30-60 min, and the emulsion with small emulsion particle size and uniform distribution is prepared; meanwhile, the carbomer structure is prevented from being damaged to provide proper viscosity of 100-150 mpa.s, which is greatly beneficial to improving the stability of emulsion, and even the stability at high temperature of 60 ℃ and long-term stability.
Detailed Description
The technical scheme of the invention is further described below by referring to examples. The scope of the invention includes but is not limited to these embodiments, and all changes and equivalents that do not depart from the spirit of the invention are intended to be included therein.
The concentration or the using amount percentage of the components in the embodiment of the invention is weight volume percentage, and 1 percent is 1g/100ml.
The pH regulator in the embodiment of the invention is used for regulating the pH of the carbomer solution so as to change the viscosity of the carbomer solution, and can be selected from alkaline substances such as sodium hydroxide, potassium hydroxide, triethanolamine and the like.
The buffer salt used in the examples and comparative examples of the present invention is used for maintaining the pH of the solution, and may be selected from common buffer salts such as citrate, acetate, gluconate and the like.
The bacteriostat used for inhibiting the growth of microorganisms in the embodiment and the comparative example can be selected from common bacteriostats such as sorbic acid, potassium sorbate, benzoic acid, sodium benzoate and the like.
The flavoring agent in the embodiment and the comparative example is used for improving the taste of the solution and can be selected from common flavoring agents such as sorbitol, sodium chloride, acesulfame potassium, saccharin sodium, sodium cyclamate, banana essence and the like.
The carbomers described in the examples and comparative examples of the present invention are used as thickening agents in a model number selected from 934P, 974P, 971P and the like which are commonly used for oral formulations.
The model and manufacturer information of the main instruments and reagents used in the examples and comparative examples of the present invention are as follows:
instrument:
laboratory electric mixer (model: AM300L-P; manufacturer: shanghai Ind instruments & meters Co., ltd.)
Laboratory vacuum emulsion stirring reactor (model: AIR-1L; manufacturer: shanghai European river mechanical equipment Co., ltd.)
High shear emulsifying machine (model: CS-21-1057; manufacturer: shanghai Yiken equipment Co., ltd.)
Reagent:
simethicone: commercially available from Hunan Jiudian Hongyang pharmaceutical Co., ltd
Polyoxyl (40) stearate: purchased from Nanjing Will pharmaceutical Co., ltd
Glycerol monostearate: available from Hunan Erkang pharmaceutical Co., ltd
Carbomer: purchased from Shanghai Co., ltd
Example 1
The simethicone emulsion provided by the invention has the following formula:
TABLE 1 formulation of Simethicone emulsion from EXAMPLE 1
| Action | Component (A) | Concentration (%) |
| Active ingredient | Simethicone | 4.00 |
| Emulsifying agent | Polyoxyl (40) stearate | 0.66 |
| Emulsifying agent | Glyceryl monostearate | 0.40 |
| Thickening agent | Carbomer 971P | 0.64 |
| PH regulator | Sodium hydroxide | 0.07 |
| Buffer salt | Sodium citrate | 0.44 |
| Bacteriostatic agent | Sorbic acid | 0.11 |
| Flavoring agent | Sorbitol solution | 21.17 |
| Flavoring agent | Sodium chloride | 0.07 |
| Flavoring agent | Acesulfame potassium | 0.02 |
| Solvent(s) | Purified water | 78.22 |
The simethicone emulsion provided by the invention has the following preparation process:
(1) An oil phase: the simethicone with the prescription amount is weighed, heated to 70-80 ℃, added with the emulsifier polyoxyl (40) stearate and glyceryl monostearate with the prescription amount, and stirred until the mixture is melted.
(2) Aqueous phase: taking a proper amount of purified water, adding sodium hydroxide with a prescription amount, and preparing sodium hydroxide solution; heating 60% of purified water with a prescription amount to 70-80 ℃, slowly adding carbomer with the prescription amount under the stirring speed of 800-1000 rpm, stirring until the carbomer is completely dispersed, adding sodium hydroxide solution, sorbic acid, acesulfame potassium, sodium chloride, sodium citrate and sorbitol solution with the prescription amount, supplementing the purified water, and stirring until the carbomer is uniform and clear viscous liquid.
(3) Emulsification: slowly adding the water phase in the step (2) into the oil phase in the step (1), stirring and uniformly mixing, and emulsifying and homogenizing for 30-60 min at a high shearing speed of 7200-13000 rpm to obtain the simethicone emulsion.
Examples 2 to 7
The preparation of simethicone emulsion was carried out according to the thickener amount, emulsifier amount and high shear homogenizing speed in examples 2-7 shown in Table 2, corresponding to the corresponding preparation conditions in alternative example 1.
TABLE 2 preparation conditions for examples 2-7 Simethicone emulsion
Example 8 Simethicone emulsion product quality detection
Product quality detection is carried out on simethicone emulsion prepared in examples 1-7, wherein detection items comprise viscosity, particle size distribution, emulsion stability and defoaming capability, and the detection process is as follows:
viscosity: taking the product, determining according to law (China pharmacopoeia 2020 edition, fourth division rule 0633 third method), adopting Anton Paar (MCR 92) rheometer, rotor (CP 25-2), shearing rate being 169s -1 The dynamic viscosity at 20℃was measured.
Particle size distribution: taking the product, determining according to a law (the third method of the fourth edition of Chinese pharmacopoeia 2020 edition, general rule 0982), adopting a SYMPATC laser particle sizer, dispersing medium water, and determining the particle size under the dispersion condition of 1500rpm- (60-120 s) -0%.
Emulsion stability: taking the product, shaking uniformly, taking 10ml of the product, placing the product into a centrifuge tube, centrifuging the product for 6 to 15 minutes at a rotating speed of 2000 to 4000rpm, and observing whether layering exists.
Defoaming ability: taking two parts of 1.0% trie X-100 (Triton X-100) solution without foam, respectively injecting 50ml into two clean 250ml measuring cylinders with plugs, taking 0.4ml (2.0 ml each time by washing the measuring cylinder twice) of the product, placing one measuring cylinder into the other measuring cylinder, sealing the two measuring cylinders, intensively shaking for 5 times, standing for 1 minute, measuring the foam height, dividing the foam height in the emulsion adding measuring cylinder by the foam height (100%) in the emulsion non-adding measuring cylinder, and calculating the defoaming capability.
Examples 1-7 simethicone emulsion product quality test results:
TABLE 3 quality detection results for Simethicone emulsion products of examples 1-7
Table 3 the test results show that:
(1) carbomer usage primarily affects emulsion viscosity; the amounts of the emulsifier polyoxyl (40) stearate and the glyceryl monostearate mainly influence the particle size of the emulsion; the three components have a correlation effect, and only when the carbomer dosage is within the range of 0.50-0.70%, the dosage of the emulsifier polyoxyl (40) stearate and the glyceryl monostearate is respectively within the range of 0.60-0.72% and 0.36-0.42%, the viscosity and the particle size distribution of the prepared simethicone emulsion are only within the target range, so that the stability requirement of the emulsion is met.
(2) The simethicone emulsion is prepared by adopting a high-shear emulsification homogenizing process, controlling the emulsification rotating speed to 7200-13000 rpm and the emulsification time to 30-60 min, and the viscosity and the particle size distribution of the simethicone emulsion are only in a target range, so that the emulsion stability requirement is met.
Further, experimental studies have shown that when the emulsifier polyoxyl (40) stearate is used in an amount greater than 0.72%, or glyceryl monostearate is used in an amount less than 0.36%, the emulsion particle size of the resultant simethicone emulsion is greater than the target range, with a risk of long-term stability. The pH regulator and buffer salt type, the bacteriostatic agent type and the dosage, and the corrigent type and the dosage within the pH range of 4.8-5.2 do not influence the particle size, the viscosity and the stability of simethicone emulsion, and conventional replacement selection can be made.
Comparative examples 1-3 investigation of thickener types and amounts
The effect of different types of thickeners (sodium carboxymethylcellulose, gelatin) and carbomer usage (0.25%) on simethicone emulsion product quality was examined.
Simethicone emulsion formulation:
comparative example 1 differs from example 1 in that: the thickener was 0.57% sodium carboxymethylcellulose.
Comparative example 2 differs from example 1 in that: the thickener was 0.57% gelatin.
Comparative example 3 differs from example 1 in that: the thickener was 0.25% carbomer.
The preparation process of simethicone emulsion comprises the following steps: simethicone emulsion was prepared by substituting the corresponding components in example 1 with the kinds and amounts of the thickeners in comparative examples 1 to 3.
Comparative examples 1-3 simethicone emulsion product quality test results:
TABLE 4 quality test results of comparative examples 1-3 Simethicone emulsion products
From table 4 in combination with table 3, it can be seen that:
when the thickener is sodium carboxymethyl cellulose (comparative example 1), gelatin (comparative example 2) or carbomer (comparative example 3) with an amount of less than 0.50%, the simethicone emulsion obtained is too thin to detect viscosity, and the emulsion is uneven and unstable such as delamination. According to common knowledge, the emulsion has excessive viscosity, which is liable to cause poor fluidity and dispersibility.
Therefore, simethicone emulsions meeting both particle size and stability requirements can be prepared only when carbomer is used in an amount ranging from 0.50 to 0.70%.
Comparative example 4 order of thickener addition investigation
The influence of the addition of the thickener carbomer on the product quality of simethicone emulsion after the emulsification process was examined.
Formulation of simethicone emulsion: as in example 1.
The preparation process of simethicone emulsion comprises the following steps:
(1) An oil phase: the simethicone with the prescription amount is weighed, heated to 70-80 ℃, added with the emulsifier polyoxyl (40) stearate and glyceryl monostearate with the prescription amount, stirred and dissolved.
(2) Aqueous phase 1: taking a proper amount of purified water, heating to 70-80 ℃, adding the sorbic acid, acesulfame potassium, sodium chloride, sodium citrate and sorbitol with the prescribed amount under stirring, and stirring until the sorbic acid, acesulfame potassium, sodium citrate and sorbitol are dissolved.
(3) Aqueous phase 2: taking a proper amount of purified water, heating to 70-80 ℃, adding carbomer, stirring until no aggregation exists, adding sodium hydroxide solution, and stirring and uniformly mixing.
(4) Emulsification: adding the water phase 1 in the step (2) into the oil phase in the step (1), stirring and uniformly mixing, and carrying out high-shear emulsification and homogenization at a rotating speed of 9000-10000 rpm for 10-30 min to obtain the colostrum.
(5) Adding the water phase 2 obtained in the step (3) into the colostrum obtained in the step (4), stirring and mixing uniformly, and homogenizing for 10-30 min.
Comparative example 4 simethicone emulsion product quality test results:
TABLE 5 comparative example 4 Simethicone emulsion product quality detection results
From table 5 in combination with table 3, it can be seen that:
when the thickening agent carbomer is added after the emulsification process, the simethicone emulsion obtained after high-shear emulsification and homogenization has higher viscosity and is not layered after centrifugation, but the emulsion particle size distribution is very uneven. The reason for this is: the primary emulsion particle size distribution formed is uneven and unstable, and the added carbomer-containing aqueous phase only plays a role in thickening and stabilizing, and is limited in that the primary emulsion cannot withstand excessively severe emulsification process conditions, so that the particle size distribution cannot be further improved.
Therefore, the carbomer can be thickened, stabilized and the particle size distribution improved only when the thickener carbomer is added before the emulsification process and the emulsification process parameters are optimized.
Comparative examples 5-7 emulsification Process and parameter investigation
The influence of different emulsification processes (high-pressure homogenization) and high-shear emulsification homogenization speeds (6000 rpm and 14000 rpm) on the quality of simethicone emulsion products was examined.
Formulation of simethicone emulsion: as in example 1.
The preparation process of simethicone emulsion comprises the following steps:
comparative example 5 differs from example 1 in that: the high shear emulsification homogenizing speed in the step (3) is 6000rpm.
Comparative example 6 differs from example 1 in that: the high shear emulsification homogenizing speed in the step (3) is 14000rpm.
Comparative example 7 differs from example 1 in that: step (3) emulsification: slowly adding the water phase in the step (2) into the oil phase in the step (1), stirring and mixing uniformly, and homogenizing for 1 time at a high pressure of 230bar to obtain simethicone emulsion.
Comparative examples 5-7 simethicone emulsion product quality test results:
TABLE 6 quality test results of comparative examples 5-7 Simethicone emulsion products
Note that: in comparative example 5 "/", which means that the properties were not acceptable, the emulsion stability was not examined any more.
From table 6 in combination with table 3, it can be seen that:
(1) when the high-pressure homogenizing emulsification process (comparative example 7) or the high-shear emulsifying homogenizing rotation speed (comparative example 6) higher than 13000rpm is adopted, the viscosity of the obtained simethicone emulsion is reduced to different degrees, and the instability phenomena such as layering and the like occur although the particle size meets the requirement.
(2) When a high shear emulsification homogenizing speed (comparative example 5) of less than 7200rpm is used, the viscosity of the obtained simethicone emulsion exceeds the standard, the emulsion particle size is too large and the distribution is uneven, and the simethicone emulsion is a viscous liquid with white particles, which indicates that the target product is not formed. The emulsion stability of comparative example 5 was no longer examined because of its unacceptable behavior.
Therefore, simethicone emulsion meeting the requirements of particle size and stability can be prepared only on the premise that the thickening agent carbomer is added before the emulsification process, wherein the optimized emulsification process is a high-shear homogenizing process, the optimized process parameters are the emulsification rotating speed of 7200-13000 rpm and the emulsification time of 30-60 min.
EXAMPLE 9 stability investigation
After placing the samples (example 1, example 2 and comparative example 4) at a high temperature of 60 ℃ for 30 days for lofting, the simethicone emulsion product quality was measured.
Stability study results for example 1, example 2 and comparative example 4:
TABLE 7 stability investigation results for example 1, example 2 and comparative example 4
Note that: in comparative example 4 "/", which means that the properties were not acceptable, the emulsion stability was not examined any more.
As can be seen from table 7:
(1) when the particle size of simethicone emulsion is not satisfactory for 0 day (comparative example 4), after the temperature is 60 ℃ and Wen Fangyang days, the viscosity of the simethicone emulsion exceeds the standard, the particle size of the emulsion is further increased, the emulsion is a viscous liquid with obvious floating oil, the emulsion has obvious difference with the properties of a target product, and the emulsion has long-term stability risk.
The emulsion stability of comparative example 4 was no longer examined because of its unacceptable behavior.
(2) Only when the viscosity, particle size and stability of simethicone emulsion were all satisfactory for 0 day (example 1 and example 2), the viscosity, particle size and stability of simethicone emulsion remained satisfactory after Wen Fangyang days at 60 ℃.
In summary, the simethicone emulsion formulation and process (examples 1-7) of the present invention can be used to prepare a particle size D 10 1-3 μm, D 50 Is 3-6 mu m, D 90 The simethicone emulsion has the viscosity of 90-150 mpa.s and 6-20 mu m, and the stability meets the requirements.
Claims (10)
1. The stable simethicone emulsion is characterized by comprising the following components in percentage by weight and volume: 4.00 percent of simethicone, 0.60 to 0.72 percent of polyoxyl 40 stearate, 0.36 to 0.42 percent of glyceryl monostearate, 0.50 to 0.70 percent of carbomer, a pH regulator and water; wherein, the liquid crystal display device comprises a liquid crystal display device,
the pH regulator is one or more selected from sodium hydroxide, potassium hydroxide and triethanolamine;
the pH value of the simethicone emulsion is 4.8-5.2, and the emulsion particle diameter D 10 1-3 μm, D 50 Is 3-6 mu m, D 90 Is 6-20 mu m.
2. The stable simethicone emulsion of claim 1, wherein said carbomer type is selected from one or more of 934P, 974P, 971P; more preferably carbomer 971P.
3. A stable simethicone emulsion as claimed in claim 1, having a viscosity of from 90 to 150mpa.s, more preferably from 100 to 150mpa.s.
4. The stable simethicone emulsion of claim 1, further comprising a buffer salt selected from one or more of citrate, acetate, gluconate.
5. The stable simethicone emulsion of claim 1, further comprising a bacteriostat selected from one or more of sorbic acid, potassium sorbate, benzoic acid, sodium benzoate.
6. The stable simethicone emulsion of claim 1, further comprising a flavoring selected from one or more of sorbitol, sodium chloride, acesulfame potassium, sodium saccharin, sodium cyclamate, banana flavor.
7. A stable simethicone emulsion as claimed in any one of claims 1 to 6, characterized by the following composition in weight volume percent:
8. a method of preparing a stable simethicone emulsion as claimed in any one of claims 1 to 7, including the steps of:
(1) Weighing simethicone with a prescription amount, heating to 70-80 ℃, adding the emulsifier polyoxyl 40 stearate and glyceryl monostearate with the prescription amount, and stirring to melt to obtain an oil phase;
(2) Weighing the purified water with the prescription amount, adding carbomer and pH regulator with the prescription amount under heating and stirring, and stirring to obtain uniform and clear viscous liquid to obtain water phase;
(3) Emulsification: slowly adding the water phase in the step (2) into the oil phase in the step (1), stirring and uniformly mixing, and emulsifying and homogenizing for 30-60 min at a high shearing speed of 7200-13000 rpm to obtain the simethicone emulsion.
9. The method for preparing a stable simethicone emulsion as claimed in claim 8, wherein the heating temperature in the step (2) is 70-80 ℃ and the stirring speed is 800-1000 rpm.
10. The method of preparing a stable simethicone emulsion of claim 8, wherein step (2) further comprises: weighing the purified water with the prescription amount, adding carbomer and pH regulator with the prescription amount under heating and stirring, adding one or more of buffer salt, antibacterial agent and correctant, and stirring to obtain uniform and clear viscous liquid to obtain water phase.
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