CN112791120B - A pharmaceutical oral emulsion, and its preparation method and application - Google Patents
A pharmaceutical oral emulsion, and its preparation method and application Download PDFInfo
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- CN112791120B CN112791120B CN201911022519.9A CN201911022519A CN112791120B CN 112791120 B CN112791120 B CN 112791120B CN 201911022519 A CN201911022519 A CN 201911022519A CN 112791120 B CN112791120 B CN 112791120B
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- oral emulsion
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- pharmaceutical
- pharmaceutical oral
- emulsifier
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- 239000000839 emulsion Substances 0.000 title claims abstract description 107
- 238000002360 preparation method Methods 0.000 title claims description 21
- 239000003995 emulsifying agent Substances 0.000 claims abstract description 63
- XMGQYMWWDOXHJM-UHFFFAOYSA-N limonene Chemical compound CC(=C)C1CCC(C)=CC1 XMGQYMWWDOXHJM-UHFFFAOYSA-N 0.000 claims abstract description 40
- GRWFGVWFFZKLTI-UHFFFAOYSA-N α-pinene Chemical compound CC1=CCC2C(C)(C)C1C2 GRWFGVWFFZKLTI-UHFFFAOYSA-N 0.000 claims abstract description 40
- 239000003814 drug Substances 0.000 claims abstract description 38
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims abstract description 29
- 229920000053 polysorbate 80 Polymers 0.000 claims abstract description 29
- NWGKJDSIEKMTRX-AAZCQSIUSA-N Sorbitan monooleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O NWGKJDSIEKMTRX-AAZCQSIUSA-N 0.000 claims abstract description 23
- WEEGYLXZBRQIMU-UHFFFAOYSA-N 1,8-cineole Natural products C1CC2CCC1(C)OC2(C)C WEEGYLXZBRQIMU-UHFFFAOYSA-N 0.000 claims abstract description 20
- GRWFGVWFFZKLTI-IUCAKERBSA-N 1S,5S-(-)-alpha-Pinene Natural products CC1=CC[C@@H]2C(C)(C)[C@H]1C2 GRWFGVWFFZKLTI-IUCAKERBSA-N 0.000 claims abstract description 20
- MVNCAPSFBDBCGF-UHFFFAOYSA-N alpha-pinene Natural products CC1=CCC23C1CC2C3(C)C MVNCAPSFBDBCGF-UHFFFAOYSA-N 0.000 claims abstract description 20
- 229960005233 cineole Drugs 0.000 claims abstract description 20
- 229940087305 limonene Drugs 0.000 claims abstract description 20
- 235000001510 limonene Nutrition 0.000 claims abstract description 20
- WEEGYLXZBRQIMU-WAAGHKOSSA-N Eucalyptol Chemical compound C1C[C@H]2CC[C@]1(C)OC2(C)C WEEGYLXZBRQIMU-WAAGHKOSSA-N 0.000 claims abstract description 19
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 15
- 239000007957 coemulsifier Substances 0.000 claims abstract description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 47
- 239000003921 oil Substances 0.000 claims description 45
- 235000019198 oils Nutrition 0.000 claims description 45
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 37
- 239000004519 grease Substances 0.000 claims description 15
- 235000012424 soybean oil Nutrition 0.000 claims description 12
- 239000003549 soybean oil Substances 0.000 claims description 12
- 206010011224 Cough Diseases 0.000 claims description 11
- 206010062717 Increased upper airway secretion Diseases 0.000 claims description 11
- 208000026435 phlegm Diseases 0.000 claims description 11
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 5
- 239000002131 composite material Substances 0.000 claims description 4
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 claims description 3
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 claims description 3
- 229940093471 ethyl oleate Drugs 0.000 claims description 3
- 206010061218 Inflammation Diseases 0.000 claims description 2
- 239000002202 Polyethylene glycol Substances 0.000 claims description 2
- 230000003467 diminishing effect Effects 0.000 claims description 2
- 230000004054 inflammatory process Effects 0.000 claims description 2
- 229940057917 medium chain triglycerides Drugs 0.000 claims description 2
- 229920001223 polyethylene glycol Polymers 0.000 claims description 2
- 150000002632 lipids Chemical class 0.000 claims 3
- 238000000034 method Methods 0.000 abstract description 8
- 229920001213 Polysorbate 20 Polymers 0.000 abstract description 6
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 abstract description 6
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 abstract description 6
- 239000004359 castor oil Substances 0.000 abstract description 5
- 235000019438 castor oil Nutrition 0.000 abstract description 5
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 abstract description 5
- 230000007794 irritation Effects 0.000 abstract description 5
- 239000002245 particle Substances 0.000 abstract description 5
- 238000010521 absorption reaction Methods 0.000 abstract description 4
- 239000007788 liquid Substances 0.000 abstract description 4
- -1 polyoxyethylene Polymers 0.000 abstract description 4
- CTKXFMQHOOWWEB-UHFFFAOYSA-N Ethylene oxide/propylene oxide copolymer Chemical compound CCCOC(C)COCCO CTKXFMQHOOWWEB-UHFFFAOYSA-N 0.000 abstract description 3
- 229920003171 Poly (ethylene oxide) Polymers 0.000 abstract description 3
- 210000001035 gastrointestinal tract Anatomy 0.000 abstract description 3
- 229920001993 poloxamer 188 Polymers 0.000 abstract description 3
- 229940044519 poloxamer 188 Drugs 0.000 abstract description 3
- 238000002156 mixing Methods 0.000 description 28
- 238000003756 stirring Methods 0.000 description 28
- 230000001804 emulsifying effect Effects 0.000 description 19
- 229960004063 propylene glycol Drugs 0.000 description 16
- 238000010008 shearing Methods 0.000 description 14
- 230000000694 effects Effects 0.000 description 11
- 239000002994 raw material Substances 0.000 description 10
- 238000005303 weighing Methods 0.000 description 10
- 230000003110 anti-inflammatory effect Effects 0.000 description 9
- 238000005119 centrifugation Methods 0.000 description 9
- 239000008213 purified water Substances 0.000 description 8
- 150000001875 compounds Chemical class 0.000 description 7
- 239000000796 flavoring agent Substances 0.000 description 6
- 235000013355 food flavoring agent Nutrition 0.000 description 6
- 239000000203 mixture Substances 0.000 description 5
- 235000013772 propylene glycol Nutrition 0.000 description 5
- 210000003022 colostrum Anatomy 0.000 description 4
- 235000021277 colostrum Nutrition 0.000 description 4
- 239000003755 preservative agent Substances 0.000 description 4
- 239000003381 stabilizer Substances 0.000 description 4
- 238000009210 therapy by ultrasound Methods 0.000 description 4
- 239000000341 volatile oil Substances 0.000 description 4
- 235000005976 Citrus sinensis Nutrition 0.000 description 3
- 240000002319 Citrus sinensis Species 0.000 description 3
- 239000007764 o/w emulsion Substances 0.000 description 3
- 230000002335 preservative effect Effects 0.000 description 3
- 210000002784 stomach Anatomy 0.000 description 3
- 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 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 2
- 206010070840 Gastrointestinal tract irritation Diseases 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- 230000006838 adverse reaction Effects 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000004945 emulsification Methods 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 235000003599 food sweetener Nutrition 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 229920003063 hydroxymethyl cellulose Polymers 0.000 description 2
- 229940031574 hydroxymethyl cellulose Drugs 0.000 description 2
- 210000004400 mucous membrane Anatomy 0.000 description 2
- 230000035699 permeability Effects 0.000 description 2
- 239000004302 potassium sorbate Substances 0.000 description 2
- 235000010241 potassium sorbate Nutrition 0.000 description 2
- 229940069338 potassium sorbate Drugs 0.000 description 2
- YPFDHNVEDLHUCE-UHFFFAOYSA-N propane-1,3-diol Chemical compound OCCCO YPFDHNVEDLHUCE-UHFFFAOYSA-N 0.000 description 2
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 2
- 235000010234 sodium benzoate Nutrition 0.000 description 2
- 239000004299 sodium benzoate Substances 0.000 description 2
- 235000019202 steviosides Nutrition 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000003765 sweetening agent Substances 0.000 description 2
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 1
- 125000002006 1,8-cineol group Chemical group 0.000 description 1
- 108010011485 Aspartame Proteins 0.000 description 1
- 235000005979 Citrus limon Nutrition 0.000 description 1
- 244000131522 Citrus pyriformis Species 0.000 description 1
- 208000019505 Deglutition disease Diseases 0.000 description 1
- 239000004383 Steviol glycoside Substances 0.000 description 1
- UEDUENGHJMELGK-HYDKPPNVSA-N Stevioside Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@]12C(=C)C[C@@]3(C1)CC[C@@H]1[C@@](C)(CCC[C@]1([C@@H]3CC2)C)C(=O)O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O UEDUENGHJMELGK-HYDKPPNVSA-N 0.000 description 1
- 239000000605 aspartame Substances 0.000 description 1
- 235000010357 aspartame Nutrition 0.000 description 1
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 1
- 229960003438 aspartame Drugs 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 229960001617 ethyl hydroxybenzoate Drugs 0.000 description 1
- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 description 1
- 229960005150 glycerol Drugs 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 239000001525 mentha piperita l. herb oil Substances 0.000 description 1
- GYCKQBWUSACYIF-UHFFFAOYSA-N o-hydroxybenzoic acid ethyl ester Natural products CCOC(=O)C1=CC=CC=C1O GYCKQBWUSACYIF-UHFFFAOYSA-N 0.000 description 1
- 235000019477 peppermint oil Nutrition 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 1
- 235000019633 pungent taste Nutrition 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229960003885 sodium benzoate Drugs 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 229930182488 steviol glycoside Natural products 0.000 description 1
- 235000019411 steviol glycoside Nutrition 0.000 description 1
- 150000008144 steviol glycosides Chemical class 0.000 description 1
- 229940013618 stevioside Drugs 0.000 description 1
- OHHNJQXIOPOJSC-UHFFFAOYSA-N stevioside Natural products CC1(CCCC2(C)C3(C)CCC4(CC3(CCC12C)CC4=C)OC5OC(CO)C(O)C(O)C5OC6OC(CO)C(O)C(O)C6O)C(=O)OC7OC(CO)C(O)C(O)C7O OHHNJQXIOPOJSC-UHFFFAOYSA-N 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/61—Myrtaceae (Myrtle family), e.g. teatree or eucalyptus
-
- 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
- A61K31/01—Hydrocarbons
- A61K31/015—Hydrocarbons carbocyclic
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
-
- 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
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- 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
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- 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
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/10—Expectorants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/14—Antitussive agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Natural Medicines & Medicinal Plants (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Pulmonology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Alternative & Traditional Medicine (AREA)
- Biotechnology (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Nutrition Science (AREA)
- Dispersion Chemistry (AREA)
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- Medicinal Preparation (AREA)
Abstract
The invention provides a pharmaceutical oral emulsion, which comprises a pharmaceutical composition composed of eucalyptol, limonene and alpha-pinene, and an emulsifying agent and a coemulsifier, wherein the emulsifying agent is selected from two or more of Tween 80, tween 20, span 80, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil and poloxamer 188. The invention also provides a method for preparing the medicine oral emulsion and application of the medicine oral emulsion. The oral emulsion of the medicine can reduce the irritation of gastrointestinal tracts and improve the compliance of patients, and meanwhile, the emulsion liquid drops have smaller particle size, can promote the absorption of the medicine and have good centrifugal stability.
Description
Technical Field
The invention relates to the field of pharmaceutical preparations, in particular to a pharmaceutical oral emulsion, a preparation method and application thereof. More particularly, the invention relates to a pharmaceutical oral emulsion containing eucalyptol, limonene and alpha-pinene, and a preparation method and application thereof.
Background
The pharmaceutical composition of eucalyptol, limonene and alpha-pinene is a cough relieving, anti-inflammatory and phlegm eliminating medicine with definite curative effect. The existing oral preparation containing eucalyptol, limonene and alpha-pinene is only enteric soft capsules, the problem of dysphagia is found in the market sales of children, and meanwhile, if the capsules are ruptured and released in the stomach, the pungent odor can be reflected out of the stomach, and the oral preparation also has certain pungency to the stomach. Meanwhile, the existing dosage form of the pharmaceutical composition has the problem of poor compliance of patients in taking.
Thus, there is a need to develop an oral formulation that reduces gastrointestinal irritation and improves patient compliance.
Disclosure of Invention
It is therefore an object of the present invention to provide a pharmaceutical oral emulsion which reduces gastrointestinal irritation and improves patient compliance. The medicine oral emulsion has good centrifugal stability, the particle size of liquid drops can reach the nanometer level, and the medicine absorption can be promoted.
Another object of the present invention is to provide a method for preparing the pharmaceutical oral emulsion of the present invention.
It is a further object of the present invention to provide the use of the pharmaceutical oral emulsion of the present invention.
In the present invention, the term "Emulsion" refers to a two-phase liquid that is immiscible with each other, wherein one phase is dispersed in the other phase in the form of droplets to form a non-uniformly dispersed liquid formulation.
The aim of the invention is achieved by the following technical scheme.
In one aspect, the invention provides a pharmaceutical oral emulsion comprising a pharmaceutical composition consisting of eucalyptol, limonene and alpha-pinene, and an emulsifier and a co-emulsifier, wherein the emulsifier is selected from two or more of tween 80, tween 20, span 80, polyoxyethylated castor oil, polyoxyethylated hydrogenated castor oil and poloxamer 188.
The medicine oral emulsion provided by the invention is characterized in that the emulsifier is a tween 80 and span 80 composite emulsifier.
The pharmaceutical oral emulsion provided by the invention, wherein the content of the emulsifier is 3.0-6.0%, preferably 4.0-5.5% based on the weight of the pharmaceutical oral emulsion.
The pharmaceutical oral emulsion provided by the invention further comprises a co-emulsifier, wherein the co-emulsifier is selected from one or more of ethanol, propylene glycol, glycerol and polyethylene glycol, preferably one or more of propylene glycol, glycerol and polyethylene glycol 400, more preferably propylene glycol, and most preferably 1, 2-propylene glycol.
The pharmaceutical oral emulsion provided by the invention, wherein the content of the auxiliary emulsifier is 1.0-3.0%, preferably 1.2-1.8% based on the weight of the pharmaceutical oral emulsion.
The invention provides a pharmaceutical oral emulsion, wherein the pharmaceutical composition further comprises grease and water; preferably, the oil is selected from one or more of soybean oil, medium chain triglycerides and ethyl oleate, most preferably soybean oil.
The pharmaceutical oral emulsion provided by the invention, wherein the content of the pharmaceutical composition is 5.0-20%, preferably 5.0-13.0% based on the weight of the pharmaceutical oral emulsion.
The medicine oral emulsion provided by the invention, wherein the content of the grease is 1.0-8.0% and the content of the water is 72.0-85.0% based on the weight of the medicine oral emulsion; preferably, the content of the grease is 3.0-5.0%, and the content of the water is 75.0-82.0%.
The pharmaceutical oral emulsion provided by the invention, wherein the pharmaceutical composition consists of 40.0-65.0% of eucalyptol, 20.0-45.0% of limonene and 5.0-25.0% of alpha-pinene based on the weight of the pharmaceutical composition.
According to the pharmaceutical oral emulsion provided by the invention, preferably, the emulsifier is two or more of tween 80, span 80, polyoxyethylene castor oil and poloxamer 188. Most preferably, the emulsifier is a mixture of span 80 and tween 80. In a preferred embodiment, the weight ratio of span 80 to tween 80 is from 1:4 to 99.
In a preferred embodiment of the invention, the pharmaceutical oral emulsion is an oil-in-water emulsion.
In a preferred embodiment of the present invention, the pharmaceutical oral emulsion may further comprise flavouring agents, preservatives and/or stabilizers; preferably, the flavoring agent comprises 0.5-3.0%, the preservative comprises 0.1-1.2% and/or the stabilizer comprises 0.05-0.15% by weight of the pharmaceutical oral emulsion.
In certain embodiments of the invention, the flavoring agent is a sweetener and/or a flavoring agent; the preservative is selected from one or more of sodium benzoate, potassium sorbate, ethyl hydroxybenzoate and sorbic acid; and/or the stabilizer is selected from hydroxymethyl cellulose and/or xanthan gum.
In certain embodiments of the invention, the sweetener is selected from one or more of steviol glycosides, sucrose, sodium saccharin, and aspartame; and/or the flavoring agent is selected from one or more of sweet orange essential oil, lemon essence, sweet orange essence and peppermint oil.
In another aspect, the invention provides a method for preparing the pharmaceutical oral emulsion of the invention, comprising the following steps:
(1) Weighing the raw materials, adding the eucalyptol, the limonene and the alpha-pinene into the grease, and uniformly mixing to obtain the medicine-containing grease;
(2) Adding emulsifying agent and auxiliary emulsifying agent into the above medicated oil, and completely mixing to form oil phase;
(3) Directly taking water as water phase or adding optional flavoring agent, preservative and/or stabilizer into water to completely mix them to form water phase;
(4) Pouring the oil phase into the water phase, and uniformly mixing to obtain the medicine oral emulsion.
In certain embodiments of the present invention, the mixing conditions described in steps (1) to (3) of the preparation method comprise: stirring in a constant-temperature water bath at 10-40 ℃, preferably 30 ℃ at a rotating speed of 30-60 r/min, preferably 45-55 r/min for 0.5-2 hours, preferably 1 hour. Preferably, in the step (4), the mixing is performed by an ultrasonic method, a grinding method, a high-speed shearing method and/or a homogenizing method.
In certain embodiments of the present invention, in step (4) of the preparation method, the pharmaceutical oral emulsion may be prepared by: shearing for 8-12 min, such as 10 min, at 8000-12000 r/min, such as 10000r/min under high speed shearing machine, homogenizing for 2-5 min, such as 3 min, under 10-30 bar, such as 20bar, to obtain the final product.
In other embodiments of the present invention, in step (4) of the preparation method, the pharmaceutical oral emulsion may also be prepared by: ultrasonic treatment is carried out in an ultrasonic instrument with the frequency of 40-60 Hz, such as 50Hz, for 0.5-2 hours, such as 1 hour, to obtain colostrum, and then circulation is carried out in a homogenizer for 3-6 minutes, such as 5 minutes, under the pressure of 40-60 bar, such as 50bar, to obtain the oral emulsion.
In yet another aspect, the invention provides the use of the pharmaceutical oral emulsion of the invention in the preparation of a medicament for relieving cough, diminishing inflammation and/or eliminating phlegm.
The types of the emulsifying agent and the auxiliary emulsifying agent have great influence on the emulsifying effect and the centrifugal stability of the prepared medicine oral emulsion. The inventors have unexpectedly found that for the pharmaceutical composition comprising eucalyptol, limonene and alpha-pinene according to the invention, when using the specific emulsifiers and/or co-emulsifiers according to the invention, an oral emulsion is obtained which has a better emulsifying effect, smaller emulsion droplet size and better centrifugal stability. And other emulsifying agents and auxiliary emulsifying agents are adopted, so that a better emulsifying effect is difficult to achieve, the particle size of emulsion drops is larger, and layering is more after centrifugation. In particular, in a preferred embodiment of the present invention, the best results are achieved by using tween 80 and span 80 complex emulsifier as emulsifier in combination with propylene glycol as co-emulsifier. The oral emulsion of the medicine has good cough relieving, anti-inflammatory and/or phlegm eliminating effects.
The medicine oral emulsion of the invention has the following characteristics:
1. the medicine oral emulsion is an oil-in-water emulsion, has small droplet size, is beneficial to accelerating medicine absorption and covering up the irritation of volatile oil substances, reduces adverse reactions of gastrointestinal tracts, and can improve the medicine taking compliance of patients;
2. the medicine oral emulsion has good centrifugal stability and meets the pharmacopoeia requirements;
3. the oily medicine is prepared into the oral emulsion, so that the accurate dosage can be ensured, and the use is convenient;
4. the oral emulsion of the medicine can improve the permeability to skin and mucous membrane and reduce the irritation.
Detailed Description
The invention is further illustrated below in connection with examples which are merely illustrative and are not meant to limit the scope of the invention in any way.
The reagents and starting materials used in the following examples are all commercially available.
Example 1
Prescription:
the preparation method comprises the following steps:
(1) Using soybean oil as grease, mixing the grease with eucalyptol, limonene and alpha-pinene to prepare medicine-containing grease;
(2) The emulsifier is prepared from tween 80, span 80 and tween 20 according to the following weight percentage:
emulsifier 1 contains 18.7% span 80+81.3% tween 80;
emulsifier 2 contains span 80 of 9.3% and tween 80 of 90.7%;
emulsifier 3 contains span 80 of 0.9% and tween 80 of 99.1%;
emulsifier 4 is tween 80;
emulsifier 5 contains 41.2% Tween 80+58.8% Tween 20;
emulsifier 6 is tween 20;
the emulsifying agent and the auxiliary emulsifying agent 1, 2-propylene glycol are added into the medicine-containing grease prepared in the step (1) respectively, so that the medicine-containing grease is completely mixed to form an oil phase, the oil phase is poured into water, the mixture is uniform, the emulsifying effect after standing for a short time and 24 hours is observed without centrifugal operation, and the result is shown in the table 1.
TABLE 1 emulsification Effect of emulsifiers of different groups
As can be seen from the results in table 1, the use of tween 80 or tween 20 alone as an emulsifier did not give a good emulsifying effect. The inventors have unexpectedly found that the emulsion for oral administration obtained using the tween 80 and span 80 complex emulsifier has the best emulsifying effect and the best stability.
Example 2
Prescription:
the preparation method comprises the following steps of preparing the medicine oral emulsion by using different oils, emulsifying agents and auxiliary emulsifying agents:
(1) Weighing the raw materials, adding the eucalyptol, the limonene and the alpha-pinene into the grease, and uniformly mixing to obtain the medicine-containing grease;
(2) Adding emulsifying agent and auxiliary emulsifying agent into the above medicated oil, and completely mixing to form oil phase;
(3) Pouring the oil phase into purified water, and mixing to obtain the final product. Wherein soybean oil is used as oil, different emulsifying agents and auxiliary emulsifying agents are used for preparing the oral emulsion of the medicine, and the emulsifying effect is observed, and the result is shown in Table 2.
TABLE 2 emulsification Effect of pharmaceutical oral emulsions with different emulsifiers, co-emulsifiers
From the above, the types of emulsifying agent and co-emulsifying agent have great influence on the emulsifying effect and centrifugal stability of the prepared pharmaceutical oral emulsion. The inventors have unexpectedly found that the emulsion for oral administration obtained when using tween 80 and span 80 as a complex emulsifier and using 1, 2-propanediol as a co-emulsifier is the best emulsifying effect and has the best centrifugal stability.
According to the prescription proportion, the compound emulsifier of Tween 80 and span 80 (weight ratio of 1:0.1) is used as an emulsifier, 12-propylene glycol is used as a co-emulsifier, and the emulsifying effect of the oral emulsion of the medicine prepared by using different types of grease is as follows:
table 3: emulsifying effect of oral emulsion of medicine prepared from different oils
Therefore, when the tween 80 and span 80 composite emulsifier is used as an emulsifier and the 1, 2-propylene glycol is used as a co-emulsifier, different oils are used, so that good emulsifying effect and centrifugal stability can be realized.
Example 3
Prescription:
the preparation process comprises the following steps:
(1) Weighing the raw materials according to the prescription proportion, adding eucalyptol, limonene and alpha-pinene into soybean oil, uniformly mixing, and stirring in a constant-temperature water bath at 30 ℃ at a rotating speed of 50rpm for 1 hour to obtain medicated oil;
(2) Adding Tween 80 and span 80 (weight ratio of 1:0.07) compound emulsifier and 1, 2-propylene glycol into the above medicated oil, stirring in constant temperature water bath at 30deg.C and rotation speed of 50rpm for 2 hr, and completely mixing to form oil phase;
(3) Dripping the mixed oil phase into purified water under stirring, shearing at 10000r/min under a high-speed shearing machine for 10 min, homogenizing after shearing, and homogenizing under 20bar pressure for 3 min to obtain oral emulsion.
The oral emulsion has good emulsifying effect, good centrifugal stability and no layering after centrifugation. The oral emulsion has good cough relieving, anti-inflammatory and/or phlegm eliminating effects.
Example 4
Prescription:
the preparation process comprises the following steps:
(1) Weighing the raw materials according to the proportion, adding eucalyptol, limonene and alpha-pinene into ethyl oleate, uniformly mixing, and stirring in a constant-temperature water bath at 25 ℃ at a rotating speed of 40rpm for 2 hours to obtain the medicine-containing grease;
(2) Adding Tween 80 and span 80 (weight ratio of 1:0.05) compound emulsifier and 1, 2-propylene glycol into the above medicated oil, stirring in constant temperature water bath at 25deg.C at 40rpm for 1 hr, and completely mixing to form oil phase;
(3) Adding sucrose and sodium benzoate into purified water, stirring in a constant temperature water bath at 25deg.C and 40rpm for 0.5 hr, and completely mixing to form water phase;
(4) The oil phase is dripped into the water phase under stirring, then sheared for 10 minutes under a high-speed shearing machine at a rotating speed of 10000r/min, homogenized after shearing is finished, and homogenized for 3 minutes under a pressure of 20bar, thus obtaining the oral emulsion.
The oral emulsion has good emulsifying effect, good centrifugal stability and no layering after centrifugation. The oral emulsion has good cough relieving, anti-inflammatory and/or phlegm eliminating effects.
Example 5
Prescription:
the preparation process comprises the following steps:
(1) Weighing the raw materials according to the proportion, adding eucalyptol, limonene and alpha-pinene into soybean oil, uniformly mixing, and stirring in a constant-temperature water bath at 15 ℃ at a rotating speed of 50rpm for 2 hours to obtain medicated oil;
(2) Adding Tween 80 and span 80 (weight ratio of 1:0.02) compound emulsifier and 1, 2-propylene glycol into the above medicated oil, stirring in a constant temperature water bath at 15deg.C and 50rpm for 1 hr, and completely mixing to form oil phase;
(3) Adding sweet orange essential oil, potassium sorbate and hydroxymethyl cellulose into purified water, stirring in constant temperature water bath at 15deg.C and rotation speed of 50rpm for 0.5 hr, and completely mixing to form water phase;
(4) The oil phase is dripped into the water phase under stirring, then sheared for 10 minutes under a high-speed shearing machine at a rotating speed of 10000r/min, homogenized after shearing is finished, and homogenized for 3 minutes under a pressure of 20bar, thus obtaining the oral emulsion.
The oral emulsion has good emulsifying effect, good centrifugal stability and no layering after centrifugation. The oral emulsion has good cough relieving, anti-inflammatory and/or phlegm eliminating effects.
Example 6
Prescription:
the preparation process comprises the following steps:
(1) Weighing the raw materials according to the proportion, adding eucalyptol, limonene and alpha-pinene into medium chain triglyceride, uniformly mixing, and stirring in a constant temperature water bath at 15 ℃ at a rotating speed of 50rpm for 2 hours to obtain medicated oil;
(2) Adding Tween 80 and span 80 (weight ratio of 1:0.05) compound emulsifier and 1, 3-propylene glycol into the above medicated oil, stirring in a constant temperature water bath at 15deg.C and 50rpm for 1 hr, and completely mixing to form oil phase;
(3) Adding stevioside into purified water, stirring in a constant temperature water bath at 15 ℃ at 50rpm for 0.5 hour, and completely mixing to form a water phase;
(4) The oil phase is dripped into the water phase under stirring, then sheared for 10 minutes under a high-speed shearing machine at a rotating speed of 10000r/min, homogenized after shearing is finished, and homogenized for 3 minutes under a pressure of 20bar, thus obtaining the oral emulsion.
The oral emulsion has good emulsifying effect, good centrifugal stability and no layering after centrifugation. The oral emulsion has good cough relieving, anti-inflammatory and/or phlegm eliminating effects.
Example 7
Prescription:
the preparation process comprises the following steps:
(1) Weighing the raw materials according to the proportion, adding eucalyptol, limonene and alpha-pinene into soybean oil, uniformly mixing, and stirring in a constant-temperature water bath at 15 ℃ at a rotating speed of 50rpm for 2 hours to obtain medicated oil;
(2) Adding Tween 80 and span 80 compound emulsifier (weight ratio of 1:0.03) and 1, 2-propylene glycol into the above medicated oil, stirring in a constant temperature water bath at 15deg.C and 50rpm for 1 hr, and completely mixing to form oil phase;
(3) The oil phase is dripped into the water phase under stirring, then sheared for 10 minutes under a high-speed shearing machine at a rotating speed of 10000r/min, homogenized after shearing is finished, and homogenized for 3 minutes under a pressure of 20bar, thus obtaining the oral emulsion.
The oral emulsion has good emulsifying effect, good centrifugal stability and no layering after centrifugation. The oral emulsion has good cough relieving, anti-inflammatory and/or phlegm eliminating effects.
Example 8
Prescription:
the preparation process comprises the following steps:
(1) Weighing the raw materials according to the proportion, adding eucalyptol, limonene and alpha-pinene into soybean oil, uniformly mixing, and stirring in a constant-temperature water bath at 30 ℃ at a rotating speed of 50rpm for 1 hour to obtain medicated oil;
(2) Adding Tween 80 and span 80 (weight ratio of 1:0.01) compound emulsifier and 1, 2-propylene glycol into the above medicated oil, stirring in constant temperature water bath at 30deg.C and rotation speed of 50rpm for 2 hr, and completely mixing to form oil phase;
(3) Dripping the oil phase into purified water under stirring, performing ultrasonic treatment in an ultrasonic instrument with frequency of 50Hz for 1 hr to obtain colostrum, and circulating in a homogenizer under pressure of 50bar for 5 min to obtain oral emulsion.
The oral emulsion has good emulsifying effect, good centrifugal stability and no layering after centrifugation. The oral emulsion has good cough relieving, anti-inflammatory and/or phlegm eliminating effects.
Example 9
Prescription:
the preparation process comprises the following steps:
(1) Weighing the raw materials according to the proportion, adding eucalyptol, limonene and alpha-pinene into soybean oil, uniformly mixing, and stirring in a constant-temperature water bath at 40 ℃ at a rotating speed of 60rpm for 1 hour to obtain medicated oil;
(2) Adding Tween 80 and span 80 (weight ratio of 1:0.05) compound emulsifier and 1, 2-propylene glycol into the above medicated oil, stirring in constant temperature water bath at 30deg.C and rotation speed of 50rpm for 2 hr, and completely mixing to form oil phase;
(3) Dripping the oil phase into purified water under stirring, performing ultrasonic treatment in an ultrasonic instrument with frequency of 40Hz for 2 hours to obtain colostrum, and circulating in a homogenizer for 5 minutes under pressure of 50bar to obtain the oral emulsion.
The oral emulsion has good emulsifying effect, good centrifugal stability and no layering after centrifugation. The oral emulsion has good cough relieving, anti-inflammatory and/or phlegm eliminating effects.
Comparative example 1
Prescription:
the preparation process comprises the following steps:
(1) Weighing the raw materials according to the proportion, adding eucalyptol, limonene and alpha-pinene into soybean oil, uniformly mixing, and stirring in a constant-temperature water bath at 40 ℃ at a rotating speed of 60rpm for 1 hour to obtain medicated oil;
(2) Adding Tween 80 and 1, 2-propylene glycol into the above medicated oil, stirring in constant temperature water bath at 30deg.C and rotation speed of 50rpm for 2 hr, and completely mixing to form oil phase;
(3) Dripping the oil phase into purified water under stirring, performing ultrasonic treatment in an ultrasonic instrument with frequency of 40Hz for 2 hours to obtain colostrum, and circulating in a homogenizer for 5 minutes under pressure of 50bar to obtain the oral emulsion.
The oral emulsion is obviously layered after centrifugation.
The formulation and process were the same as in example 1 except that the type of emulsifier used was different from that used in example 9. As can be seen from the experimental results, the emulsion of comparative example 1, which was emulsified using tween 80 as a single emulsifier, had a significantly increased particle size and the emulsion had poor centrifugal stability, as compared with example 9. Therefore, the invention preferably adopts the Tween 80 and span 80 composite emulsifier as the emulsifier, unexpectedly and remarkably improves the centrifugal stability of the emulsion and remarkably reduces the particle size of emulsion liquid drops.
As can be seen from the above examples, the pharmaceutical oral emulsion of the present invention has the following characteristics:
1. the medicine oral emulsion is an oil-in-water emulsion, has small droplet size, is beneficial to accelerating medicine absorption and covering up the irritation of volatile oil substances, reduces adverse reactions of gastrointestinal tracts, and can improve the medicine taking compliance of patients;
2. the medicine oral emulsion has good centrifugal stability and meets the pharmacopoeia requirements;
3. the oily medicine is prepared into the oral emulsion, so that the accurate dosage can be ensured, and the use is convenient;
4. the oral emulsion of the medicine can improve the permeability to skin and mucous membrane and reduce the irritation.
Claims (13)
1. A pharmaceutical oral emulsion is characterized by comprising a pharmaceutical composition consisting of eucalyptol, limonene and alpha-pinene, and an emulsifying agent and a co-emulsifying agent, wherein the emulsifying agent is a tween 80 and span 80 composite emulsifying agent, the co-emulsifying agent comprises propylene glycol,
wherein, based on the weight of the pharmaceutical composition, the pharmaceutical composition consists of 40.0-65.0% of eucalyptol, 20.0-45.0% of limonene and 5.0-25.0% of alpha-pinene;
the content of the emulsifier is 3.0-6.0%.
2. The pharmaceutical oral emulsion according to claim 1, wherein the content of the emulsifier is 4.0-5.5% based on the weight of the pharmaceutical oral emulsion.
3. The pharmaceutical oral emulsion of claim 1, wherein the co-emulsifier further comprises one or more of ethanol, glycerol, and polyethylene glycol.
4. The pharmaceutical oral emulsion of claim 1, wherein the co-emulsifier is present in an amount of 1.0 to 3.0% based on the weight of the pharmaceutical oral emulsion.
5. The pharmaceutical oral emulsion of claim 4, wherein the co-emulsifier is present in an amount of 1.2-1.8% based on the weight of the pharmaceutical oral emulsion.
6. The pharmaceutical oral emulsion of claim 1, wherein the pharmaceutical composition further comprises a lipid and water.
7. The pharmaceutical oral emulsion of claim 6, wherein the lipid is selected from one or more of soybean oil, medium chain triglycerides and ethyl oleate.
8. The pharmaceutical oral emulsion of claim 6, wherein the lipid is soybean oil.
9. The pharmaceutical oral emulsion of claim 1, wherein the pharmaceutical composition is present in an amount of 5.0-20.0% based on the weight of the pharmaceutical oral emulsion.
10. The pharmaceutical oral emulsion of claim 9, wherein the pharmaceutical composition is present in an amount of 5.0-13.0% based on the weight of the pharmaceutical oral emulsion.
11. The pharmaceutical oral emulsion of claim 6, wherein the oil content is 1.0-8.0% and the water content is 72.0-85.0% based on the weight of the pharmaceutical oral emulsion.
12. The pharmaceutical oral emulsion of claim 11, wherein the content of grease is 3.0-5.0% and the content of water is 75.0-82.0% based on the weight of the pharmaceutical oral emulsion.
13. Use of a pharmaceutical oral emulsion according to any one of claims 1 to 12 for the preparation of a medicament for relieving cough, diminishing inflammation and/or eliminating phlegm.
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| CN101015524A (en) * | 2007-02-15 | 2007-08-15 | 沈阳药科大学 | Coenzyme Q10 oral emulsion and preparing process thereof |
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