CN108567740A - Ring Ba Ming fat emulsion injections and preparation method thereof - Google Patents
Ring Ba Ming fat emulsion injections and preparation method thereof Download PDFInfo
- Publication number
- CN108567740A CN108567740A CN201710151069.8A CN201710151069A CN108567740A CN 108567740 A CN108567740 A CN 108567740A CN 201710151069 A CN201710151069 A CN 201710151069A CN 108567740 A CN108567740 A CN 108567740A
- Authority
- CN
- China
- Prior art keywords
- grams
- ming
- ring
- milligrams
- injection
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
-
- 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
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Molecular Biology (AREA)
- Biophysics (AREA)
- Dispersion Chemistry (AREA)
- Dermatology (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention provides a kind of ring Ba Ming fat emulsion injections, by following weight proportion at being grouped as：800 grams 990 grams of 2 grams 5 grams of 0.1 milligram 100 milligrams of ring Ba Ming, 100 grams 300 grams of injection soybean oil, 100 grams 300 grams of MCT Oil, 5 grams 20 grams of lecithin, 25 grams 75 grams of glycerine, 200 milligrams 500 milligrams of oleic acid or enuatrol, 0 gram 10 grams of stabilizer and water for injection.The present invention is prepared into homogeneous Breakup of Liquid Ring Ba Ming fat emulsion injections by using the form of drug-loaded emulsion agent, emulsion droplet uniform particle in long-term placement process, stability and safety are higher, there is good potential applicability in clinical practice, the method of the present invention is easy to operate, it is suitable for industrialized production, there is larger application value.
Description
Technical field
The present invention relates to pharmaceutical technology fields, and in particular to medicinal liquid injection more particularly to a kind of ring Ba Ming Fat Emulsions note
Penetrate liquid and preparation method thereof.
Ring Ba Ming (Cyclopamine) is steroid alkaloid, may act on Sonic hedgehog (Sonic hedgehog) access,
With potential antitumor activity.Ring Ba Ming is the crystalline powder of white or near-white；It is odorless, it is tasteless.The product have liposoluble
Property, it is readily soluble in ethyl alcohol, acetone or chloroform, it is slightly molten in tea oil or castor oil, it is insoluble in water.It, should in preparation preparation
Rapid delivery preparation is made in indissoluble or the drug for being slightly soluble in water, also to avoid harmful side effect caused by first pass effect, thus,
Common method is that intravenous formulations are made.Technical method is mainly：Soluble-salt is made, cosolvent is added, using mixing
Solvent uses solubilizer.
From blank Fat Emulsion Intralipid in 1961 since Sweden is formally approved for clinic, battalion used for intravenous injection
It supports type Fat Emulsion to be widely used, as the important component of parenteral nutrition, nutrition is provided for critical patient.And in recent years
Come, with the needs of disease treatment and further going deep into for research, the research of Fat Emulsion is no longer confined to answering for parenteral nutrition
It uses, drug is dissolved in and is redispersed in the drug-loaded emulsion that 100-1000nm is made in water phase in fat oil through lecithin emulsification,
The selectivity that administration route can be increased is widely used in intravenous injection, lung, eye and nasal-cavity administration etc..(woods is skilful
Flat, research and application [J] pharmacy of Zhou Jianping Lipid Emulsions as Drug Carriers are in progress, 2005,29 (8):359-364.) in drug containing fat
In fat emulsion injection, most of drug distribution avoids being in direct contact with water in oil phase or oil-water interfaces, for facile hydrolysis or to water
Sensitive drug plays the role of increasing stability.It avoids introducing the intravenous injection irritation that organic solvent generates simultaneously.So
And not all insoluble drug all can be made into fat emulsion injection, and when may also dilute drug be precipitated, note
It penetrates tract pain or causes the problems such as phlebitis, additives are to human body generation toxicity.Therefore, the Fat Emulsion of ring Ba Ming how is developed
Injection has important value.
Invention content
The present invention provides a kind of ring Ba Ming fat emulsion injections, by following weight proportion at being grouped as：
0.1 milligram -100 milligrams of ring Ba Ming, 100 grams -300 grams of injection soybean oil, MCT Oil 100
2 grams -5 grams of grams -300 grams, 5 grams -20 grams of lecithin, 25 grams -75 grams of glycerine, 200 milligrams -500 milligrams of oleic acid or enuatrol are stablized
800 grams -990 grams of 0 gram -10 grams of agent and water for injection.
Preferably, a kind of ring Ba Ming fat emulsion injections of the present invention, by following weight proportion at being grouped as：
0.1 milligram -100 milligrams of ring Ba Ming, 100 grams -300 grams of injection soybean oil, MCT Oil 100-
300 grams, 5-20 grams of lecithin, 25 grams-75 grams of glycerine, 200 milligrams-500 milligrams of oleic acid or 2 grams-5 grams of enuatrol, vitamin e1-
10 grams and 800 grams -990 grams of water for injection.Or
0.1 milligram -100 milligrams of ring Ba Ming, 100 grams -300 grams of injection soybean oil, MCT Oil 100
2 grams -5 grams of grams -300 grams, 5 grams -20 grams of lecithin, 25 grams -75 grams of glycerine, 200 milligrams -500 milligrams of oleic acid or enuatrol,
800 grams -990 grams of -10 milligrams of EDTA1 milligrams and water for injection.Or
0.1 milligram -100 milligrams of ring Ba Ming, 100 grams -300 grams of injection soybean oil, MCT Oil 100
2 grams -5 grams of grams -300 grams, 5 grams -20 grams of lecithin, 25 grams -75 grams of glycerine, 200 milligrams -500 milligrams of oleic acid or enuatrol, dimension life
800 grams -990 grams of plain E1 grams -10 grams, -10 milligrams of EDTA1 milligrams and water for injection.
Ring Ba Ming fat emulsion injections of the present invention are made of oil phase and water phase.
The oil-phase component is：Ring Ba Ming, injection soybean oil, MCT Oil, lecithin, oleic acid or oil
Sour sodium, vitamin E.
The water-phase component is：Glycerine, EDTA, water for injection.
Ring Ba Ming fat emulsion injections of the present invention, the lecithin emulsifier are selected from egg yolk lecithin, soybean lecithin
Any one of fat, hydrogenated yolk lecithin, hydrogenated soy phosphatidyl choline or artificial synthesized lecithin.
Ring Ba Ming fat emulsion injections of the present invention, the stabilizer are selected from EDTA (ethanedioic acid tetraacethyl disodium) or dimension
Raw element E.
It is a further object of the present invention to provide the preparation method of ring Ba Ming fat emulsion injections, this method includes following step
Suddenly：
(1) feed proportioning system sterilization treatment：115 DEG C~121 DEG C high-temperature sterilization processing of boiling water of entire feed proportioning system, exclude to match
Air in material system, and replaced with nitrogen, 3~5 times repeatedly；
(2) preparation of spare water：10% water for injection of total dosage is put into colostrum tank, nitrogen charging gas drive oxygen (20min) is protected
25 DEG C -30 DEG C of temperature, it is spare；
(3) preparation of water phase：10% water for injection, the glycerine for taking total dosage, set in water phase tank, 115 DEG C~121 DEG C high temperature
Sterilize 15min, is cooled to 45 DEG C~50 DEG C, by filter, continues nitrogen charging gas drive oxygen, and sodium hydroxide solution is added and is uniformly mixed,
Heat preservation is spare to 45~50 DEG C；
(4) preparation of oil phase：Steam drying oil phase tank takes ring Ba Ming, injection soybean oil, MCT Oil
It is bubbled from bottom in oil phase tank, opening nitrogen, stirs evenly, be heated to 50 DEG C~70 DEG C, under the protection of nitrogen stream slowly
Lecithin is added, high-speed stirred to lecithin is uniformly dispersed；
(5) colostric fluid is prepared：By the oil phase of above-mentioned preparation and water phase in proportion (1:5-1:20) it is mixed, is mended by emulsification pump
It adds to the full amount of water for injection, controls temperature 50 C~70 DEG C, colostric fluid pH to 9.0~9.5 is adjusted with sodium hydroxide；
(6) high-pressure homogeneous：Make colostric fluid under nitrogen stream protection, between two tanks, by homogenizer, regulate pressure and
Temperature carries out homogeneous, and the pressure uses one-step valve pressure 150bar, and secondary valve pressure 500bar, 30 DEG C~45 DEG C of temperature will
Colostrum homogeneous (2-6 times) repeatedly, until liquid pH is 9.0~9.5, until average grain diameter is 200nm-300nm, milk particle is qualified；
(7) lower pressure homogenisation：First class pressure is unloaded, adjusting secondary pressure is 80bar, and 28 DEG C~32 are cooled to through heat exchanger
℃。
(8) nitrogen charging is filling：Colostric fluid is filtered, filling in cleaning ampoule bottle with conventional method under nitrogen stream protection
In, sealing, so that remaining oxygen is less than 3%；The filtering is through 5 μm of miillpore filter mistakes；
(9) rotation sterilizing：It rolls the bottled lotion after lid to set in high steam rotation sterilizing cabinet, 115 DEG C~121 DEG C hot pressing rotations
Turn sterilizing 30 minutes~45 minutes, ring Ba Ming fat emulsion injections are made.
The preparation of step (4) oil phase described in preparation method of the present invention, when being added stabilizer in formula, the stabilizer with
Other oil-phase components are added to together in oil phase tank.
The present invention is prepared into homogeneous Breakup of Liquid Ring Ba Ming fat emulsion injections by using the form of drug-loaded emulsion agent, long
Emulsion droplet uniform particle in phase placement process, stability and safety are higher.There are good potential applicability in clinical practice, the method for the present invention behaviour
Make simplicity, is suitable for industrialized production, there is larger application value.
Specific implementation mode
Ring Ba Ming self-controls, injection soybean oil (emerging (Tieling) pharmaceutcal corporation, Ltd), MCT Oil are (new
Emerging (Tieling) pharmaceutcal corporation, Ltd), lecithin (the Shanghai bio tech ltd Dong Shang), oleic acid (Shanghai east still biotechnology
Co., Ltd), enuatrol (the Shanghai bio tech ltd Dong Shang), vitamin E (the Shanghai bio tech ltd Dong Shang),
Glycerine (Hu'nan Erkang Pharmaceutical Co., Ltd.), EDTA (the Shanghai bio tech ltd Dong Shang), water for injection self-control, nothing
Water-ethanol (the Shanghai bio tech ltd Dong Shang).
1 ring Ba Ming fat emulsion injections of embodiment
Formula:5 milligrams of ring Ba Ming, 5 milliliters of absolute ethyl alcohols, 80 grams of injection soybean oil, MCT Oil
80g, 20 grams of egg yolk lecithin, 75 grams of glycerine, 500 milligrams of oleic acid add 100 grams of water for injection.
The preparation of feed proportioning system：The 115 DEG C of high-temperature sterilization processing of boiling water of entire feed proportioning system, exclude in entire feed proportioning system
Air, and replaced with nitrogen, 3 times repeatedly；
The preparation of spare water：10 grams of waters for injection are put into colostrum tank, nitrogen charging gas drive oxygen (20min) keeps the temperature 25 DEG C -30
DEG C, it is spare；
The preparation of water phase：10 grams of waters for injection, glycerine are taken, are set in water phase tank, 115 DEG C of high-temperature sterilization 15min are cooled to 45
DEG C, it is uniformly mixed with spare water by filter (one hundred spy PVDF of section), continues nitrogen charging gas drive oxygen (20min), it is molten that sodium hydroxide is added
(5 milliliters) of liquid is uniformly mixed, and is kept the temperature to 45 DEG C, spare；
The preparation of oil phase：Steam drying oil phase tank takes ring Ba Ming, injection soybean oil, MCT Oil, 5
Milliliter absolute ethyl alcohol stirs evenly in oil phase tank, opening nitrogen from bottom bubbling, is heated to 55 DEG C, flings to ethyl alcohol, in nitrogen
Egg yolk lecithin is slowly added under the protection of stream, (10000 revs/min) stirring 15min of high speed to egg yolk lecithin are uniformly dispersed；
Colostric fluid is prepared：By oil phase and water phase according to 1:15 ratios are mixed by emulsification pump (about enlightening ECL1000), add note
It penetrates with water to 100 grams, controls 55 DEG C of temperature, colostrum pH to 9.2 is adjusted with sodium hydroxide；
It is high-pressure homogeneous：Colostric fluid is under nitrogen stream protection, between two tanks, by homogenizer, regulate certain pressure and
Temperature carries out homogeneous, and pressure uses one-step valve pressure 150bar, secondary valve pressure 500bar, by colostrum homogeneous (3 times) repeatedly,
It is 9.2 to liquid pH, 35 DEG C, average grain diameter 200nm-300nm of temperature, milk particle qualification；
Lower pressure homogenisation：First class pressure is unloaded, adjusting secondary pressure is 80bar, and 28 DEG C are cooled to through heat exchanger.
Nitrogen charging is filling：Homogeneous latex emulsion is filling in conventional method under nitrogen stream protection by the filtering of 5 μm of porous filtering-diaphragm filters
It in clean ampoule bottle (10 milliliters), seals, remaining oxygen in bottle is made to be less than 3%.
Rotation sterilizing：It rolls the bottled lotion after lid to set in high steam rotation sterilizing cabinet, 115 DEG C of 30 points of pressure rotation sterilizings
Clock.Ring Ba Ming fat emulsion injections 10 bottles (10 milliliters every bottle) are made.
2 ring Ba Ming fat emulsion injections of embodiment
Formula:5 milligrams of ring Ba Ming, 80 grams, MCT Oil 80g of injection soybean oil, egg yolk lecithin 20
Gram, 1 gram of enuatrol, 75 grams of glycerine adds 100 grams of water for injection.
The preparation of spare water：10 grams of waters for injection are put into colostrum tank, nitrogen charging gas drive oxygen (20min) keeps the temperature 25 DEG C -30
DEG C, it is spare；
The preparation of water phase：10 grams of waters for injection, glycerine are taken, are set in water phase tank, 115 DEG C of high-temperature sterilization 15min are cooled to 45
DEG C, it is uniformly mixed with spare water by filter (one hundred spy PVDF of section), continues nitrogen charging gas drive oxygen, 5 milliliters of sodium hydroxide solutions are added
It is uniformly mixed, keeps the temperature to 45 DEG C, it is spare；
The preparation of oil phase：Steam drying oil phase tank, weigh ring Ba Ming, injection soybean oil, MCT Oil,
Yolk phosphatidylglycerol, 5 milliliters of absolute ethyl alcohols, enuatrol stir evenly, add in oil phase tank, opening nitrogen from bottom bubbling
Heat flings to ethyl alcohol to 55 DEG C, and egg yolk lecithin is slowly added under the protection of nitrogen stream, and high-speed stirred to egg yolk lecithin is disperseed
Uniformly；
Remaining preparation process is the same as embodiment 1.
3 ring Ba Ming fat emulsion injections of embodiment
Formula:5 milligrams of ring Ba Ming, 80 grams, MCT Oil 80g of injection soybean oil, egg yolk lecithin 20
Gram, 75 grams of glycerine, 500 milligrams of oleic acid adds 100 grams of water for injection.
The preparation of spare water：10 grams of waters for injection are put into colostrum tank, nitrogen charging gas drive oxygen (20min) keeps the temperature 25 DEG C -30
DEG C, it is spare；
The preparation of water phase：10 grams of water for injection, glycerine are taken, is set in water phase tank, 115 DEG C of high-temperature sterilization 15min are cooled to 45
DEG C, it is uniformly mixed with spare water by filter, continues nitrogen charging gas drive oxygen, sodium hydroxide solution is added and is uniformly mixed, heat preservation to 45
DEG C, it is spare；
The preparation of oil phase：Steam drying oil phase tank, weigh ring Ba Ming, injection soybean oil, MCT Oil,
5 milliliters of absolute ethyl alcohols, oleic acid stir evenly in oil phase tank, opening nitrogen from bottom bubbling, are heated to 55 DEG C, fling to ethyl alcohol,
Egg yolk lecithin is slowly added under the protection of nitrogen stream, high-speed stirred to egg yolk lecithin is uniformly dispersed；
Remaining preparation process is the same as embodiment 1.
4 ring Ba Ming fat emulsion injections of embodiment
Formula:5 milligrams of ring Ba Ming, 20 grams, MCT Oil 20g of injection soybean oil, egg yolk lecithin 20
Gram, 5 grams of enuatrol, 5 grams of vitamin E, 75 grams of glycerine adds 100 grams of water for injection.
The preparation of spare water：10 grams of waters for injection are put into colostrum tank, nitrogen charging gas drive oxygen (20min) keeps the temperature 25 DEG C -30
DEG C, it is spare；
The preparation of water phase：10 grams of water for injection, glycerine are taken, is set in water phase tank, 115 DEG C of high-temperature sterilization 15min are cooled to 45
DEG C, it is uniformly mixed by filter (one hundred spy PVDF of section), continues nitrogen charging gas drive oxygen, sodium hydroxide solution is added and is uniformly mixed, heat preservation
It is spare to 45 DEG C；
The preparation of oil phase：Steam drying oil phase tank, weigh ring Ba Ming, injection soybean oil, MCT Oil,
5 milliliters of absolute ethyl alcohols, enuatrol, vitamin E stir evenly in oil phase tank, opening nitrogen from bottom bubbling, are heated to 55
DEG C, ethyl alcohol is flung to, egg yolk lecithin is slowly added under the protection of nitrogen stream, high-speed stirred to egg yolk lecithin is uniformly dispersed；
Remaining preparation process is the same as embodiment 1.
5 ring Ba Ming fat emulsion injections of embodiment
Formula:5 milligrams of ring Ba Ming, 20 grams, MCT Oil 20g of injection soybean oil, egg yolk lecithin 20
Gram, 500 milligrams of oleic acid, 75 grams of glycerine, adds 100 grams of water for injection by EDTA5 milligrams.
The preparation of spare water：10 grams of waters for injection are put into colostrum tank, nitrogen charging gas drive oxygen (20min) keeps the temperature 25 DEG C -30
DEG C, it is spare；
The preparation of water phase：10 grams of water for injection, glycerine, EDTA is taken to set in water phase tank, 115 DEG C of high-temperature sterilization 15min, drop
Temperature is uniformly mixed to 45 DEG C, by filter (one hundred spy PVDF of section) with spare water, continues nitrogen charging gas drive oxygen, and sodium hydroxide solution is added
It is uniformly mixed, keeps the temperature to 45 DEG C, it is spare；
The preparation of oil phase：Steam drying oil phase tank, weigh ring Ba Ming, injection soybean oil, MCT Oil,
5 milliliters of absolute ethyl alcohols stir evenly in oil phase tank, opening nitrogen from bottom bubbling, are heated to 55 DEG C, fling to ethyl alcohol, in nitrogen
Egg yolk lecithin is slowly added under the protection of air-flow, high-speed stirred to egg yolk lecithin is uniformly dispersed；
Remaining preparation process is the same as embodiment 1.
6 ring Ba Ming fat emulsion injections of embodiment
Formula:5 milligrams of ring Ba Ming, 20 grams, MCT Oil 20g of injection soybean oil, egg yolk lecithin 10
Gram, 75 grams of glycerine, 5 milligrams of EDTA adds 100 grams of water for injection.
The preparation of spare water：10 grams of waters for injection are put into colostrum tank, nitrogen charging gas drive oxygen (20min) keeps the temperature 25 DEG C -30
DEG C, it is spare；
The preparation of water phase：10 grams of water for injection, glycerine, EDTA is taken to set in water phase tank, 115 DEG C of high-temperature sterilization 15min, drop
Temperature is uniformly mixed to 45 DEG C, by filter with spare water, continues nitrogen charging gas drive oxygen, and sodium hydroxide solution is added and is uniformly mixed, protects
Temperature is spare to 45 DEG C；
The preparation of oil phase：Steam drying oil phase tank, weigh ring Ba Ming, injection soybean oil, MCT Oil,
5 milliliters of absolute ethyl alcohols stir evenly in oil phase tank, opening nitrogen from bottom bubbling, are heated to 55 DEG C, fling to ethyl alcohol, in nitrogen
Egg yolk lecithin is slowly added under the protection of air-flow, high-speed stirred to egg yolk lecithin is uniformly dispersed；
Remaining preparation process is the same as embodiment 1.
7 ring Ba Ming fat emulsion injections of embodiment
Formula:5 milligrams of ring Ba Ming, 20 grams of injection soybean oil, 20 grams of MCT Oil, egg yolk lecithin 20
Gram, 500 milligrams of oleic acid, 75 grams of glycerine, 5 grams of vitamin E EDTA5 milligrams, adds 100 grams of water for injection.
The preparation of spare water：10 grams of waters for injection are put into colostrum tank, nitrogen charging gas drive oxygen (20min) keeps the temperature 25 DEG C -30
DEG C, it is spare；
The preparation of water phase：10 grams of water for injection, glycerine, EDTA is taken to set in water phase tank, 115 DEG C of high-temperature sterilization 15min, drop
Temperature is uniformly mixed to 45 DEG C, by filter (one hundred spy PVDF of section) with spare water, continues nitrogen charging gas drive oxygen, and sodium hydroxide solution is added
It is uniformly mixed, keeps the temperature to 45 DEG C, it is spare；
The preparation of oil phase：Steam drying oil phase tank, weigh ring Ba Ming, injection soybean oil, MCT Oil,
5 milliliters of absolute ethyl alcohols, oleic acid, vitamin E stir evenly in oil phase tank, opening nitrogen from bottom bubbling, are heated to 55 DEG C,
Ethyl alcohol is flung to, egg yolk lecithin is slowly added under the protection of nitrogen stream, high-speed stirred to egg yolk lecithin is uniformly dispersed；
Remaining preparation process is the same as embodiment 1.
8 ring Ba Ming fat emulsion injections of embodiment
Formula：5 milligrams of ring Ba Ming, 20 grams, MCT Oil 20g of injection soybean oil, egg yolk lecithin 20
Gram, 5 grams of enuatrol, 75 grams of glycerine, 5 grams of vitamin E, 5 milligrams of EDTA adds 100 grams of water for injection.
The preparation of spare water：10 grams of waters for injection are put into colostrum tank, nitrogen charging gas drive oxygen (20min) keeps the temperature 25 DEG C -30
DEG C, it is spare；
The preparation of water phase：10 grams of water for injection, glycerine, EDTA is taken to set in water phase tank, 115 DEG C of high-temperature sterilization 15min, drop
Temperature is uniformly mixed to 45 DEG C, by filter (one hundred spy PVDF of section) with spare water, continues nitrogen charging gas drive oxygen, and sodium hydroxide solution is added
It is uniformly mixed, keeps the temperature to 45 DEG C, it is spare；
The preparation of oil phase：Steam drying oil phase tank, weigh ring Ba Ming, injection soybean oil, MCT Oil,
5 milliliters of absolute ethyl alcohols, enuatrol, vitamin E stir evenly in oil phase tank, opening nitrogen from bottom bubbling, are heated to 55
DEG C, ethyl alcohol is flung to, egg yolk lecithin is slowly added under the protection of nitrogen stream, high-speed stirred to egg yolk lecithin is uniformly dispersed；
Remaining preparation process is the same as embodiment 1.
9 ring Ba Ming fat emulsion injection stability tests of embodiment
Embodiment 1-8 is prepared into ring Ba Ming fat emulsion injections and sets illumination (4500 ± 500lx), 40 DEG C, 60 DEG C of each placements
10 days, observe its physical appearance (character).
| Influence factor is tested | Ring Ba Ming fat emulsion injections |
| 0 day | White uniformity emulsion liquid, no drug precipitation are precipitated |
| Illumination × 10 day | Without significant change |
| 40 DEG C × 10 days | Without significant change |
| 60 DEG C × 10 days | Without significant change |
It takes ring Ba Ming fat emulsion injections to be placed in 40 DEG C ± 2 DEG C, carry out accelerated test under conditions of RH75% ± 5%, and
25 DEG C ± 2 DEG C, carry out long term test, observation period physical appearance under conditions of RH60% ± 10%.
| Accelerated test | Ring Ba Ming fat emulsion injections |
| 0 month | White uniformity emulsion liquid, no drug precipitation are precipitated |
| January | Without significant change |
| 2 months | Without significant change |
| March | Without significant change |
| June | Without significant change |
| Accelerate measurement result in March | Ring Ba Ming fat emulsion injections |
| PH value | 6.89 |
| Average grain diameter | 257.5nm |
| Long term test | Ring Ba Ming fat emulsion injections |
| 0 month | White uniformity emulsion liquid, no drug precipitation are precipitated |
| March | Without significant change |
| June | Without significant change |
| September | Without significant change |
| December | Without significant change |
| 18 months | Without significant change |
| 24 months | Without significant change |
Embodiment 9
Fat emulsion injection of the present invention has good stability and clinical safety, this hair is prepared according to embodiment 1-8
Bright fat emulsion injection (C8~24), sterilising conditions select 117 DEG C of hot pressing rotation sterilizing 35min, product 1-8 of the present invention are made.
Place it in room temperature environment, when rigid place, place 3,6,12,24 months and take sample survey, observe its character and
Measure pH value, milk particle, bacterium, MCT Oil content, fat content, lysophosphatide and ring Ba Ming contents, experiment
As a result as follows：
After room temperature is stored 24 months, product characteristics do not change fat emulsion injection of the present invention.
Milk particle is smaller, more uniform.It is not greater than the milk particle of 500nm, the milk particle of 200~300nm accounts for 99.1% or more.Micro- life
Object is qualified.Injection soybean oil, MCT Oil content do not change substantially with storage preliminary phase ratio.Haemolysis phosphorus
Fat content, ring Ba Ming do not change with storage preliminary phase than substantially.
1-8 product Hypersensitive tests results of the embodiment of the present invention are feminine gender.Product 1-8 hemolytic test results of the present invention are the moon
Property.Intravenous drip product 1-8 of the present invention is acted on without apparent vascular stimulation.
The ring Ba Ming fat emulsion injections of the present invention selectively deliver active medicine, avoid gastrointestinal irritation and activating agent in stomach
Inactivation in enteron aisle.In the case where no gastrointestinal tract inactivates, less activating agent can generate therapeutic effect.In addition, of the invention
Ring Ba Ming fat emulsion injection rapid delivery of pharmaceuticals activating agents it to be conveyed into blood stream of patients rapidly, improve biological utilisation
Degree, rapid action.
Embodiment 10
1-8 product 5mg of the embodiment of the present invention are taken, are dissolved with 50ml ethyl alcohol, carry out the content of ring Ba Ming as follows
Detection
Chromatographic condition ACQUITY BEH C18 chromatographic columns (50mm × 2.1mm ID, 1.7 μm) (Waters, US)；
Mobile phase A：2mmol ammonium hydrogencarbonate aqueous solutions, Mobile phase B：Acetonitrile,
Gradient elution：
0~10min, 5%~95%B；
10~15min, 95%B；
15~20min, 95%~5%B；
Flow velocity：0.3mL·min-1；Column temperature：40℃；Sampling volume：5μL.
The detection method, good separating effect are efficient.
| Assay | The percentage of labelled amount |
| Embodiment 1 | 97% |
| Embodiment 2 | 99% |
| Embodiment 3 | 99% |
| Embodiment 4 | 101% |
| Embodiment 5 | 98% |
| Embodiment 6 | 102% |
| Embodiment 7 | 99% |
| Embodiment 8 | 101% |
The research and design of 11 ring Ba Ming fat emulsion injections of the present invention of embodiment:
(1) changes of contents of the detection temperature to ring Ba Ming
Ring Ba Ming bulk pharmaceutical chemicals are respectively put into 30 DEG C -90 DEG C of insulating box, were sampled respectively at the 0th, 5,10 day, precision amount
It takes ring Ba Ming bulk pharmaceutical chemicals appropriate, adds solution of the methanol dilution to every 1mL containing about ring Ba Ming 0.1mg.HPLC measures containing for ring Ba Ming
Amount variation.
For ring Ba Ming under 30 DEG C of -90 DEG C of temperature conditions, no decomposition generates impurity.
| Changes of contents | 0 day | 5 days | 10 days |
| 30℃ | It is unchanged | It is unchanged | It is unchanged |
| 60℃ | It is unchanged | It is unchanged | It is unchanged |
| 90℃ | It is unchanged | It is unchanged | It is unchanged |
(2) optimization (N=3, X ± s) with oily type and dosage of ring Ba Ming fat emulsion injections.
Ring Ba Ming 0.4mg, injection soybean oil 10-100g,
Ring Ba Ming 0.4mg, injection MCT Oil 10-100g.
Ring Ba Ming 0.4mg, injection soybean oil 5-50g, injection MCT Oil 5-50g,
Drug-loaded emulsion agent is prepared, precondition is main ingredient there should be a certain amount of solubility in oil for injection.Otherwise
Stable drug-loaded emulsion agent can not be prepared.The ring Ba Ming fat emulsion injections of the present invention are intended being a kind of load of long term storage
Medicine fat emulsion should at least be stablized in 2 years.Therefore it has to ensure that selected oil for injection has ring Ba Ming enough dissolvings
Degree and stability, it is also necessary to improve the drugloading rate of oil for injection.
(3) process modification of the oil phase of ring Ba Ming fat emulsion injections
In this research, directly ring Ba Ming and phosphatide are added in oil phase, still have insoluble matter, explanation after 60 DEG C of heating 1h
Drug is not dissolved completely in oil phase.First ring Ba Ming and egg yolk lecithin are dissolved in appropriate absolute ethyl alcohol, 40-50 DEG C of heating
Then 0.5h flings to ethyl alcohol and oil phase is added under nitrogen stream.
Experimental result shows, drug and egg yolk lecithin dissolved after absolute ethyl alcohol heating it is rapid and complete, still,
It being added after coemulsifier, dissolving is rapider and complete, can avoid degradation caused by phosphatide and drug long-time heating,
Clear load medicine oil phase can be obtained, is stored under 4-6 DEG C of refrigerated condition 72 hours and keeps clarification.
(4) optimization (N=3, X ± s) of the lecithin dosage of ring Ba Ming fat emulsion injections.
Ring Ba Ming 2mg, injection soybean oil 40g, absolute ethyl alcohol 2g, oleic acid 0.2g, glycerine 5g, egg yolk lecithin 1-40g,
Water for injection adds to 500mL.
When the content of egg yolk lecithin increases to a certain extent, Fat Emulsion grain size no longer reduces, and forms saturation state, egg
Yellow lecithin is preferably 20g/1000ml.
(5) optimization (N=3, X ± s) of the oleic acid dosage of ring Ba Ming fat emulsion injections.
Ring Ba Ming 2mg, injection soybean oil 40g, absolute ethyl alcohol 2g, oleic acid 0.05-0.8g, glycerine 5g, egg yolk lecithin
10g, water for injection add to 500mL.
When the content of oleic acid increases to a certain extent, Fat Emulsion grain size no longer reduces, and forms full
| Oleic acid (g) | Appearance | Oil droplet | Grain size (nm) | pH |
| 0.05 | Milky | On a small quantity | 401.2 | 9.27 |
| 0.1 | White | On a small quantity | 405.1 | 9.41 |
| 0.2 | White | Nothing | 253.4 | 9.17 |
| 0.4 | White | Nothing | 258.5 | 9.26 |
| 0.8 | White | Nothing | 261.3 | 9.14 |
And state, oleic acid are preferably 0.4g/1000ml.
(6) formulation optimization of ring Ba Ming fat emulsion injections.
By experiment of single factor, is evaluated with indexs such as appearance, grain sizes, study and inquired into stabilizer and antioxidant pair
The influence of ring Ba Ming fat emulsion injections.
Ring Ba Ming 2mg, injection soybean oil 40g, absolute ethyl alcohol 2g, oleic acid 0.05g, glycerine 5g, egg yolk lecithin 8g,
EDTA (0-4mg), VE (0-4g), water for injection adds to 500mL.40 DEG C of quality evaluations for placing 10 days.
| Serial number | EDTA(mg) | VE(g) | Appearance | Oil droplet | Grain size (nm) | pH |
| A | Milky | On a small quantity | 301.5 | 9.47 | ||
| B | 1 | Milky | On a small quantity | 298.6 | 9.45 | |
| C | 2 | White | Nothing | 291.3 | 9.41 | |
| D | 4 | White | Nothing | 296.7 | 9.37 | |
| E | 1 | Milky | On a small quantity | 294.9 | 9.52 | |
| F | 2 | Milky | On a small quantity | 290.1 | 9.43 | |
| G | 4 | Milky | On a small quantity | 288.6 | 9.39 | |
| H | 1 | 1 | Milky | Nothing | 257.4 | 9.21 |
| I | 2 | 2 | White | Nothing | 261.3 | 9.30 |
| J | 4 | 4 | White | Nothing | 266.8 | 9.18 |
(7) colostric fluid homogenization pressure is preferred
Liquid raw material forms:Ring Ba Ming 2mg, injection soybean oil 40g, absolute ethyl alcohol 2g, oleic acid 0.05g, glycerine 5g, egg
Yellow phosphorus phosphatidyl glycerol 20g, egg yolk lecithin 8g, EDTA 2mg, VE 2g, water for injection add to 500mL.
It is high-pressure homogeneous：Make colostric fluid under nitrogen stream protection, between two tanks, by homogenizer, regulates certain pressure
And temperature, homogeneous is carried out, pressure uses one-step valve pressure (100,150,200) bar, secondary valve pressure (500,550,600)
Bar, by colostrum homogeneous (3 times) repeatedly, until liquid pH is 9.0~9.5, and 30 DEG C~45 DEG C of temperature, milk particle qualification；Take colostric fluid
500mL9 grams of progress pressure is preferred, and evaluation index includes：The percentage of 100nm or more particles is accounted for 200-300nm or more particles.
| The pressure (bar) of one-step valve | The pressure (bar) of secondary valve | Percentage |
| 100 | 500 | 30.1 |
| 100 | 550 | 34.5 |
| 100 | 600 | 40.8 |
| 150 | 500 | 50.2 |
| 150 | 550 | 37.1 |
| 150 | 600 | 32.4 |
| 200 | 500 | 30.1 |
| 200 | 550 | 32.7 |
| 200 | 600 | 31.6 |
Homogenize temperature, number it is preferred
Liquid forms:Ring Ba Ming 2mg, injection soybean oil 40g, absolute ethyl alcohol 2g, oleic acid 0.05g, glycerine 5g, yolk ovum
Phosphatide 8g, EDTA2mg, VE2g, water for injection add to 500mL.
(8) colostric fluid is high-pressure homogeneous：Make colostric fluid under nitrogen stream protection, between two tanks, by homogenizer, regulates
Certain pressure and temperature carry out homogeneous, and pressure uses one-step valve pressure 150bar, secondary valve pressure 500bar, repeatedly by colostrum
Homogeneous (2,3,4 times), until liquid pH is 9.0~9.5, (25 DEG C, 30 DEG C, 35 DEG C, 40 DEG C, 45 DEG C, milk particle is qualified for temperature；It takes just
500mL9 grams of progress pressure of lotion is preferred, and evaluation index includes：The hundred of 100nm or more particles are accounted for 200-300nm or more particles
Score.
| Homogenization cycles | Temperature (DEG C) | Percentage |
| 2 | 25 | 20.8 |
| 2 | 30 | 23.0 |
| 2 | 35 | 27.1 |
| 2 | 40 | 27.5 |
| 2 | 45 | 28.8 |
| 3 | 25 | 36.2 |
| 3 | 30 | 37.1 |
| 3 | 35 | 39.6 |
| 3 | 40 | 35.2 |
| 4 | 25 | 36.8 |
| 4 | 30 | 35.2 |
| 4 | 35 | 37.1 |
| 4 | 40 | 35.3 |
Claims (9)
1. ring Ba Ming fat emulsion injections, which is characterized in that the ring Ba Ming fat emulsion injections by following weight proportion at
It is grouped as：
0.1 milligram -100 milligrams of ring Ba Ming, 100 grams -300 grams of injection soybean oil, 100 gram -300 of MCT Oil
Gram, 5 grams -20 grams of lecithin, 25 grams -75 grams of glycerine, 200 milligrams -500 milligrams of oleic acid or 2 grams -5 grams of enuatrol, 0 gram of stabilizer -
10 grams and 800 grams -990 grams of water for injection.
2. ring Ba Ming fat emulsion injections, which is characterized in that the ring Ba Ming fat emulsion injections by following weight proportion at
It is grouped as：
0.1 milligram -100 milligrams of ring Ba Ming, 100 grams -300 grams of injection soybean oil, MCT Oil 100-300
Gram, 5-20 grams of lecithin, 25 grams-75 grams of glycerine, 200 milligrams-500 milligrams of oleic acid or 2 grams-5 grams of enuatrol, vitamin e1-10
Gram and 800 grams -990 grams of water for injection.
3. ring Ba Ming fat emulsion injections, which is characterized in that the ring Ba Ming fat emulsion injections by following weight proportion at
It is grouped as：
0.1 milligram -100 milligrams of ring Ba Ming, 100 grams -300 grams of injection soybean oil, 100 gram -300 of MCT Oil
Gram, 5 grams -20 grams of lecithin, 25 grams -75 grams of glycerine, 200 milligrams -500 milligrams of oleic acid or 2 grams -5 grams of enuatrol, EDTA1 milligrams -
10 milligrams and 800 grams -990 grams of water for injection.
4. ring Ba Ming fat emulsion injections, which is characterized in that the ring Ba Ming fat emulsion injections by following weight proportion at
It is grouped as：
0.1 milligram -100 milligrams of ring Ba Ming, 100 grams -300 grams of injection soybean oil, 100 gram -300 of MCT Oil
Gram, 5 grams -20 grams of lecithin, 25 grams -75 grams of glycerine, 200 milligrams -500 milligrams of oleic acid or 2 grams -5 grams of enuatrol, vitamin e1
800 grams -990 grams of grams -10 grams, -10 milligrams of EDTA1 milligrams and water for injection.
5. the ring Ba Ming fat emulsion injections according to any one of claim 1-4, which is characterized in that the oil-phase component
For：Ring Ba Ming, injection soybean oil, MCT Oil, lecithin, oleic acid or enuatrol or vitamin E；The water
It coordinates and is divided into：Glycerine, EDTA or water for injection.
6. the ring Ba Ming fat emulsion injections according to any one of claim 1-4, which is characterized in that the lecithin breast
Agent is in egg yolk lecithin, soybean lecithin, hydrogenated yolk lecithin, hydrogenated soy phosphatidyl choline or artificial synthesized lecithin
It is any.
7. the ring Ba Ming fat emulsion injections according to any one of claim 1-4, which is characterized in that the stabilizer choosing
From EDTA or vitamin E.
8. the preparation method of the ring Ba Ming fat emulsion injections as described in any one of claim 1-4, which is characterized in that the party
Method includes the following steps：
(1) feed proportioning system sterilization treatment：115 DEG C~121 DEG C high-temperature sterilization processing of boiling water of entire feed proportioning system, exclude dispensing system
Air in system, and replaced with nitrogen, 3~5 times repeatedly；
(2) preparation of spare water：10% water for injection of total dosage, nitrogen charging gas drive oxygen 20min, heat preservation 25 are put into colostrum tank
It is DEG C -30 DEG C, spare；
(3) preparation of water phase：10% water for injection, the glycerine for taking total dosage, set in water phase tank, 115 DEG C~121 DEG C high-temperature sterilizations
15min is cooled to 45 DEG C~50 DEG C, by filter, continues nitrogen charging gas drive oxygen, and sodium hydroxide solution is added and is uniformly mixed, heat preservation
It is spare to 45~50 DEG C；
(4) preparation of oil phase：Steam drying oil phase tank takes ring Ba Ming, injection soybean oil, MCT Oil in oil
In phase tank, opens nitrogen and be bubbled from bottom, stir evenly, be heated to 50 DEG C~70 DEG C, be slowly added under the protection of nitrogen stream
Lecithin, high-speed stirred to lecithin are uniformly dispersed；
(5) colostric fluid is prepared：By the oil phase of above-mentioned preparation and water phase in proportion 1:5-1:20 are mixed by emulsification pump, add injection
With water to full dose, temperature 50 C~70 DEG C are controlled, colostric fluid pH to 9.0~9.5 is adjusted with sodium hydroxide；
(6) high-pressure homogeneous：Make colostric fluid under nitrogen stream protection, between two tanks, by homogenizer, regulates pressure and temperature
Degree carries out homogeneous, and the pressure uses one-step valve pressure 150bar, and secondary valve pressure 500bar, 30 DEG C~45 DEG C of temperature will be first
Newborn homogeneous 2-6 times repeatedly, until liquid pH is 9.0~9.5, until average grain diameter is 200nm-300nm, milk particle is qualified；
(7) lower pressure homogenisation：First class pressure is unloaded, adjusting secondary pressure is 80bar, and 28 DEG C~32 DEG C are cooled to through heat exchanger.
(8) nitrogen charging is filling：Colostric fluid is filtered, under nitrogen stream protection it is filling in cleaned in ampoule bottle with conventional method,
Sealing makes remaining oxygen in bottle be less than 3%；The filtering is through 5 μm of miillpore filter mistakes；
(9) rotation sterilizing：It rolls the bottled lotion after lid to set in high steam rotation sterilizing cabinet, 115 DEG C~121 DEG C hot pressing rotations are gone out
Ring Ba Ming fat emulsion injections are made in bacterium 30 minutes~45 minutes.
9. the preparation method of the ring Ba Ming fat emulsion injections described in any one of claim 1-4, which is characterized in that the step
Suddenly the preparation of (4) oil phase, when stabilizer is added in formula, the stabilizer is added to oil phase tank together with other oil-phase components
It is interior.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710151069.8A CN108567740A (en) | 2017-03-14 | 2017-03-14 | Ring Ba Ming fat emulsion injections and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710151069.8A CN108567740A (en) | 2017-03-14 | 2017-03-14 | Ring Ba Ming fat emulsion injections and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN108567740A true CN108567740A (en) | 2018-09-25 |
Family
ID=63577216
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710151069.8A Pending CN108567740A (en) | 2017-03-14 | 2017-03-14 | Ring Ba Ming fat emulsion injections and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108567740A (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105147609A (en) * | 2015-10-28 | 2015-12-16 | 辅必成（上海）医药科技有限公司 | Diethylstilbestrol fat emulsion injection |
| CN105193722A (en) * | 2015-10-28 | 2015-12-30 | 辅必成（上海）医药科技有限公司 | Dimercaprol fat emulsion injection |
| WO2016196928A1 (en) * | 2015-06-04 | 2016-12-08 | PellePharm, Inc. | Topical formulations for delivery of hedgehog inhibitor compounds and use thereof |
-
2017
- 2017-03-14 CN CN201710151069.8A patent/CN108567740A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016196928A1 (en) * | 2015-06-04 | 2016-12-08 | PellePharm, Inc. | Topical formulations for delivery of hedgehog inhibitor compounds and use thereof |
| CN105147609A (en) * | 2015-10-28 | 2015-12-16 | 辅必成（上海）医药科技有限公司 | Diethylstilbestrol fat emulsion injection |
| CN105193722A (en) * | 2015-10-28 | 2015-12-30 | 辅必成（上海）医药科技有限公司 | Dimercaprol fat emulsion injection |
Non-Patent Citations (1)
| Title |
|---|
| 冯晓雪等: "环巴明抑制SHH信号通路缓解大鼠神经病理性疼痛", 《基础医学与临床》 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101384247B (en) | Compositions and methods for making and using nanoemulsions | |
| CN104427976B (en) | Hydrophobic depot formulations of active ingredient and preparation method thereof | |
| CN106456541A (en) | Compositions of nanoemulsion delivery systems | |
| CN101288642A (en) | Taxanes medicine preparation for intravenous injection and preparation method thereof | |
| WO2016177346A1 (en) | Cabazitaxel fat emulsion injection, and preparation method and use thereof | |
| CN100375621C (en) | Vinorelbine liposome micro ball injection and its prepn | |
| CN114796111A (en) | A concentrated solution containing insoluble drug and emulsion prepared from the same | |
| Deng et al. | Quality by design approach for the preparation of fat-soluble vitamins lipid injectable emulsion | |
| CN104352566A (en) | Oil-in-water compound chlortetracycline nanoemulsion | |
| CN105769765A (en) | Hydroxyprogesterone caproate fat emulsion injection | |
| CN105748409A (en) | Protopanoxadiol submicroemulsion preparation as well as preparation method and application thereof | |
| CN105147609A (en) | Diethylstilbestrol fat emulsion injection | |
| CN109010269A (en) | A kind of fat emulsion injection of aprepitant | |
| CN106074383B (en) | Progestational hormone medicine lipid microsphere injection and preparation method thereof | |
| CN102475681A (en) | Separation-type water suspension medicament for treating dermatopathy | |
| CN105534904B (en) | Docetaxel for Injection composition and preparation method thereof | |
| CN108567740A (en) | Ring Ba Ming fat emulsion injections and preparation method thereof | |
| CN106137963B (en) | Antiarrhythmic drug fat emulsion injection and preparation method thereof | |
| CN100386078C (en) | Nimodipine emulsion injection liquid and method for preparing the same | |
| CN105534903B (en) | Injection paclitaxel composition and preparation method thereof | |
| CN105832744B (en) | A kind of Alprostadil freeze-dried emulsion composition of injection | |
| CN104274391B (en) | Rifaximin-containing pharmaceutical preparation | |
| Mühlebach | Basics in clinical nutrition: Drugs and nutritional admixtures | |
| CN104644548B (en) | Lecithin is as taxol and its combination of derivative injection medicine and application | |
| CN105193722B (en) | Dimercaprol fat emulsion injection |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20180925 |