CN100457086C - Aseptic medicine composition - Google Patents
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- CN100457086C CN100457086C CNB031038573A CN03103857A CN100457086C CN 100457086 C CN100457086 C CN 100457086C CN B031038573 A CNB031038573 A CN B031038573A CN 03103857 A CN03103857 A CN 03103857A CN 100457086 C CN100457086 C CN 100457086C
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Abstract
The present invention relates to bacteria-free medicine composition, and is especially medicine composition containing treating or medicine preparation.
Description
The present patent application is that application number is CN95197780.6, the applying date to be the dividing an application of the China national stage that enters PCT application in March 17 nineteen ninety-five.
Technical field
The present invention relates to aseptic medicinal composition, particularly contain the pharmaceutical composition of treatment or pharmaceutical preparation and edetate.
Background technology
Propofol is a kind of injectable anesthetis, and it has hypnotic character, can be used to induce and keep general anesthesia, also can be used for calmness in as care unit.Propofol is highly successful anesthetis, and sells on market with the trade mark of " Diprivan ".It can be used for the mankind and also can " Rapinovet " use for the veterinary for trade mark.
Injectable anesthetis, for example propofol can directly administration in blood.This causes anesthetis to work rapidly, and its influence depends on that almost completely anesthetis passes through the speed of blood-brain barrier.Therefore anesthetis must have enough lipoid dissolubility can go to reduce the relevant function of brain by this barrier.But the common water solublity of the height dissolved molecule of lipoid is bad, therefore is difficult to make intravenous prescription.In some cases, may obtain a kind of narcotic water soluble salt that discharges the soluble free alkali of lipoid in vivo.This does not accomplish under many circumstances, though done a lot of research work, is impracticable to propofol yet.Therefore be necessary to carry out very basic research work, the prescription of exploitation propofol is so that obtain warm-blooded animal is comprised the medicament composition of human administration.
Applicant has been found the anesthesia character of propofol and has been submitted the number of patent application 13739/74 of Britain to, and has been approved for British patent 1472793.Corresponding patent also the U.S. and much other territory obtained approval (United States Patent (USP) 4056635,4452817 and 4798846).
A kind of aseptic propofol and a kind of aseptic medicinal diluent or medicament composition of carrier of containing of these patent special requirement.This medicament composition is suitable for directly or is used for the warm-blooded animal drug administration by injection behind a kind of liquid diluting dilution agent.
On the one hand, British patent 1472793 has been described in aseptic admixture, and is by the compositions that propofol and water and a kind of surfactant or other solubilizer form, preferably moisture.On the other hand, it is a kind of aqueous that said composition is described, and in aseptic admixture, is formed by propofol and water and a kind of additional water miscible nonaqueous solvent.Aspect further one, it is a kind of emulsion oil-in-water that said composition is described.In this emulsion, propofol or separately or be dissolved in a kind of and the immiscible solvent of water changes into emulsion with a kind of surfactant and water and milk.
Further aspect another, said composition is described be a kind of propofol with solid diluent for example, lactose, saccharin sodium or a kind of solid mixture that encircles glucosan, this compositions is suitable for diluting with a kind of aseptic aqueous diluent.
This patent has been described the compositions that much can contain the injection of propofol, for example includes various surfactants, various solubilizers, other solvent, other component (being selected from stabilizing agent, preservative agent and antioxidant), buffer agent and opening property of solution improver.
Applicant is suitable for being developed to the preparation of market sale for the prescription of determining that type and has carried out far-ranging research most.After number of research projects, (Cremophor is a kind of water formulation of trade mark of derivant of polyoxyethylene castor oil to have selected a kind of propofol and surfactant Cremophor EL.What Cremophor EL was used as existing intravenous injection anesthetis alphaxalonel/Alphadolone (' Althesin ') adds the dissolubility carrier, and the modified model of Cremphor is used as intravenous injection anesthetis propanidid (' Epontol ') and adds the dissolubility carrier.
Applicant has been carried out the research of detailed series on one's body animal, and finally preparation to the administration of people more than 1000.But, after about five or six years, reported seldom counting among the patients anaphylaxis to have occurred.Anaphylaxis is a kind of abnormality reaction.Do not know in all examples whether be the anaphylaxis that Cremophor EL causes entirely, but the patent applicant has made the conclusion that must seek and develop another kind of propofol prescription.
Carried out the work of a large amount of selection prescriptions, the final selected exploitation emulsion oil-in-water that is over.Succeeded in developing in 1986 and put goods on the market with trade mark ' Diprivan '.Since then, this prescription has entered a lot of markets, the world, and the anesthesia doctor thinks that propofol is that very big advantage, the medicine that quality is fabulous and extremely successful are arranged.In a word, propofol is a kind of anesthetis of of short duration effect, is applicable to inducing and keeping of general anaesthesia, and the local anesthesia technology is augmented in calmness, make the patient's calmness that purifies the blood with fresh air of accepting monitoring, the mind calmness in care unit Chinese and foreign department and diagnostic procedure.Propofol can big dose injection of one or many vein or transfusion continuously.It can leave from blood flow soon or metabolism falls.Like this, can easily control the degree of depth of anesthesia, patient restores very soon behind the disconnected medicine, compares with using other anesthetis, and patient's brains is clearer.After using propofol, when anaesthetizing as sucking than other general anesthesia technology, the nausea and vomiting side reaction of appearance wants much less.In order to make the anesthesia doctor that the leeway of the suitable medicine of wideer selection be arranged in medical material, the applicant has considered to widen range of propofol formulations.For example, the applicant has developed a kind of oil in water emulsion formulation of propofol, wherein the concentration of propofol is the twice of selling medicament on the market, consider and further develop this class preparation, keep the quality of ' Diprivan ' as described above, and the acceptable chemistry of expert and the physical stability and the easy-to-use preparation of anesthesia doctor or care unit (ICU) are provided.
The severe case particularly in the calmness that care unit etc. is located is used, in the ratio that strengthens ' Diprivan '.In order to make this class severe case calmness, use ' Diprivan ' with transfusion usually.This will use ' doser ', and it comprises the storage narrow-necked earthen jar (representational is a vial or syringe) of a propofol, by suitable pipeline, receives an adapter, link then on the syringe needle that inserts venous patient.
The injection of such ' doser ' is subjected to infection by microorganisms, has been in one of infectious reason of care unit patient disease by identification.Thereby as in the U.S., the general requirements of federal food drug and cosmetic act and FAD (FDA) is that this ' doser ' should often be changed when using ' Diprivan ', requires this ' doser ' will change in per at least 6 or 12 hours according to the medicine of being given.
The environment of care unit is extremely busy commonplace, and has the pressure of controlling cost in other department of public medical unit.At least changed ' doser ' nurse to the high-tech level of care unit in per 6 or 12 hours, the expert of monitoring or anesthesia doctor are very time taking.When a lot of severe cases of care unit infused simultaneously, situation was just so especially.
So the patent applicant has expected studying a kind of new prescription of propofol, so that make the replacing of ' doser ' needn't frequent like that (once) as per 24 hours.To the nurse, the expert of monitoring or anesthesia doctor are just more convenient like this; Alleviated medical personnel's pressure, few operation ' doser ' also may reduce the expense of care unit.
We have carried out number of research projects, and find to add a small amount of selected reagent in ' Diprivan ', can make the medicament of being given than obviously reducing the number of times that needs to change ' doser ' now; In other words, administration time and twice the more intermediary time of changing device has all significantly improved.Because increased the amount that administration time has also increased administration, user is more convenient, reduces the waste of ' Diprivan ' and also controlled expense.
In addition, just in case wrong the disposal caused unexpected outside the contamination, it is minimum that medicament can make the chance of microbial growth drop to.
The prescription that our British patent 1472793 discloses propofol can randomly contain the interpolation component that is selected from stabilizing agent, antiseptic and antioxidant of one or more, as propyl p-hydroxybenzoate, butylated hydroxy-methylbenzene derivant, ascorbic acid and sodium metabisulfite; Metal ion chelation agent is as sodium ethylene diamine tetracetate; And foam reducing composition, as polyorganosiloxane ramification, as dimethicone or silicon methyl-silicone oil.
It is inconvenient adding known antiseptic to emulsion oil-in-water in as ' Diprivan '.Speak of above, Diprivan ' is inducing of a kind of general anesthesia and keeps and abirritative anesthetis.Dosage may be very big, during especially for calmness.Therefore, a large amount of antiseptic may be applied to the patient who accepts processing.Thereby, must very carefully select additive in order to satisfy the regulations restrict of medication management mechanism; Especially antiseptic is used for disposable dose, final sterilization and parenteral injection be with becoming and/or various guide, as the U.S., do not advise in Britain and the European Pharmacopoeia or the exercise question of careful statement.
In addition, additive is joined also have a special difficult problem in the emulsion oil-in-water of injection.It is believed that for effectively, the anti-microbial properties of any antiseptic must be at the aqueous phase competence exertion.The lipophile antiseptic that is mixed with representative dosage is can be not effective, although there is certain participation at the two-phase interface place, is insufficient in the amount of aqueous phase additive.Increase the total amount of this class antiseptic, the antiseptic of unacceptable high dose can be arranged in oil reservoir again, toxigenicity problem that extremely I haven't seen you for ages.
On the other hand, add hydrophilic antiseptic, also can have problems as ionic substance.In emulsion oil-in-water, add ionic material and can make the emulsion instability.The ion load becomes big (owing to the reason of ionic species concentration), and the stable charging (Zeta potential) on the thin oil droplet can change.This change in electrical charge has increased possibility of collision between the thin oil droplet, thereby has increased the physical instability of emulsion.
Summary of the invention
We have studied a kind of the adding in the oil-in-water emulsion in a series of antimicrobials.This reagent must not have big harmful effect to the physics and the chemical stability of emulsion.In addition, this reagent should possess the antimicrobial acivity of looking for.
Find that some potential reagent make the emulsion instability.Other potential reagent then can not provide the antimicrobial acivity of looking for.In addition, the reagent that we seek in the past can provide this class activity level, but in order to make physical instability drop to minimum, and it is minimum that complete problem is dropped to, and makes the concentration of this class reagent low as much as possible again.
After a series of working hard, comprise and consider known antiseptic phenyl mercuric acetate, phenyl Mercury pernitrate., benzylalcohol, chlorobutanol, chloro cresol and phenol, study known antiseptic sodium metabisulfite, sodium sulfite, methyl hydroxy benzoic acid sodium, propyl hydroxy sodium benzoate, we can not find a kind of antiseptic that can satisfy our requirement.We have studied may have us and want whether other reagent of the effect sought is available.We are surprised to find that and think that once reagent-the edetate that is not a kind of broad spectrum antimicrobial is unique reagent that can satisfy our requirement.The front is spoken of, and it is a kind of possible metal ion chelation agent that the sodium salt of ethylenediaminetetraacetic acid is spoken of in British patent 1472793.Two examples that contain Chremophor of this patent have comprised sodium ethylene diamine tetracetate.
Therefore the invention provides a kind of medicament composition that is used for parenteral, said composition comprises a kind of oil-in-water emulsion, wherein propofol is dissolved in a kind of immiscible with water solvent, this solution with water emulsifying is also stable with a kind of surfactant, and said composition also contains enough prevention microorganisms edetate that (when accidental external pollution takes place) significantly do not grow in 24 hours at least.
For a kind of emulsion oil-in-water, we refer to a kind of system of tangible biphase equilibrium, but as integral body, dynamic stabilization, thermodynamic instability.This is a kind of situation opposite with micellar preparation fully, is thermodynamically stable as Cremophor EL preparation.
We refer to edetate (EDTA) and derivant thereof to noun " edetate ", just are called disodium EDTA as two sodio-derivatives.The salt that common the present invention is suitable for is the salt that affinity is lower than calcium among the EDTA.The used special derivant of the present invention comprises the tetrasodium salt and the calcium disodium chelate salt of sodium versenate salt, ethylenediaminetetraacetic acid.The character of edetate is not strict, as long as it can be under the situation of the extraneous contamination of chance, the remarkable growth that can stop microorganism at least 24 hours is (as after low external contamination, as 10-10
3Bacterium colony generates unit, and under temperature range 20-25 ℃, preferably increase is no more than 10 times).Can find out that calcium disodium salt of EDTA has some advantages than other additive by following experimental section, but disodium EDTA is an exception.Certainly, disodium EDTA most preferably.
The molar concentration (with respect to EDTA free acid) of edetate in compositions of the present invention is generally 3 * 10
-6To 9 * 10
-4Preferably, the amount of edetate is 3 * 10
15To 7.5 * 10
-4, as 5 * 10
-5To 5 * 10
-4In the scope, more preferably 1.5 * 10
-4To 3.0 * 10
-4In the scope, be most preferably about 1.5 * 10
-4
Compositions of the present invention typically contains the propofol by 0.1 to 5% (weight).Preferably compositions contains the propofol by 1 to 2% (weight), especially, and about 1% or about 2%.
Another aspect of the present invention, propofol are used a kind of surfactant and water and milkization individually.Propofol preferably was dissolved in earlier before emulsifying in a kind of and the not miscible mutually solvent of water.
Accounting for composition weight with the suitable amount of the mutually not miscible solvent of water and be up to 30%, more suitably is 5-25%, 10-20% preferably, about especially 10%.
Solvent a lot of and that water is not miscible mutually can be used for compositions of the present invention.Typically, the solvent not miscible mutually with water is a vegetable oil, as soybean oil, safflower oil, Oleum Gossypii semen, Semen Maydis oil, Oleum helianthi, Oleum Arachidis hypogaeae semen.Oleum Ricini or olive oil.Preferred vegetable oil is a soybean oil.Selectively, with the immiscible solvent of water be a kind of ester of medium or long-chain fatty acid, as single-, two-, or triphenol glyceride; Or the spy of a kind of chemical modification or production material is as ethyl oleate, isopropyl myristate, isopropyl palmitate, glyceride or poly-oxyl hydrogenated castor oil.Selectable in addition and the immiscible solvent of water can be the oil of Hai Sheng such as cod liver oil or from other oil of fish.The solvent that is suitable for also comprises distillate, as the soybean oil of Cortex cocois radicis distillate or modification.Compositions of the present invention in addition can contain two or more above-mentioned and the immiscible solvents of water.
Propofol, individually or be dissolved in one with the immiscible solvent of water in, with a kind of surfactant emulsifying.The surfactant that is suitable for comprises: synthetic non-ionic surface active agent, ether and ester and polypropylene-polyethylene block copolymer as ethoxylation, with the phospholipid (as prepared) of phospholipid such as naturally occurring phospholipid such as ovum and fabaceous lecithin or modifying artificial processing by physics fractional distillation and/or chromatographic isolation, or its mixture.Preferred surfactants is lecithin and soybean phospholipid.
Compositions of the present invention is suitable for and is deployed into the neutral pH of physiology, and typical scope is 6.0-8.5, if necessary can regulate with alkali such as oxychloride sodium.
Compositions of the present invention can make compositions and blood that isoosmotic pressure be arranged as glycerol with the improver that mixes suitable osmotic pressure.
Compositions of the present invention is typically the preparation of sterilized water, can be according to technology of preparing commonly used as sterilizing or finally sterilizing with autoclave.
Compositions of the present invention can be used as anesthetis, comprises being used for inducing and keeping of calm and general anesthesia.Therefore the invention provides on the other hand warm-blooded animal, comprise that the people anaesthetizes the method for (comprising inducing and keeping of calm and general anesthesia), comprises a kind of aseptic water preparation compositions that contains the oil-in-water type emulsion, parenteral.Propofol in emulsion individually or with the immiscible solvent of water in and water carry out emulsifying, and make it stable with a kind of surfactant.Said composition also contains a kind of edetate of effective dose.
Implement general anesthesia, comprise and induce (consumption as the adult is 2.0-2.5mg/kg) and keep (4-12mg/kg/hr according to appointment), and for the dosage level of the propofol that produces sedation effect (as 0.3-4.5mg/kg/hr), these all can find from the important literature of propofol.In addition, according to the normal technical ability in this area, anesthesia doctor and/or doctor can change dosage, make particular patient reach satisfied effect.
The advantage of speaking of above that contains edetate in propofol composition also is suitable for the injection fats emulsion.This emulsion is one day or longer to patient's time of administration of needs generally.Injection fats emulsion (also being called injection nutrient emulsion) usually with transfusion to the extra calorie of needs and the nutrition that is fit to, be unwilling or can not be oral or the patient infusion of other way again.The injection fats emulsion is kept positive nitrogen balance and the energy (as fat) in suitable source, vitamin and trace element is provided.This class emulsion generally is used to the occasion of guarding, but also is used for other hospital and home devices.The example of this injection fats emulsion has Intralipid (Pharmacia sale), Lipofundin (Braun) and Travamulsion (Baxter).Intralipid, Lipofundin and Travamulsion are trade marks.
Therefore, in yet another aspect, the invention provides a kind of injection fats emulsion, it contains the edetate of sufficient amount, can stop the remarkable growth of microorganism at least in 24 hours.Particularly the invention provides a kind of aseptic water preparation compositions that contains the oil-in-water type emulsion, is used for parenteral.A kind of and the immiscible water used in solvent emulsifying of water in emulsion, and stablized with a kind of surfactant, said composition also contains sufficient amount can stop the microorganism phenomenal growth at least within 24 hours edetate.
In addition, advised United States Patent (USP) 4168308 is for example seen in the administration in emulsion oil-in-water of various medicines.Thereby, the invention provides a kind of aseptic water preparation compositions that is used for parenteral in other one side.Said composition comprises the emulsion oil-in-water that contains a kind of treatment or pharmaceutical preparation.Preparation in emulsion or individually or be dissolved in water emulsifying in a kind of and the immiscible solvent of water, and stable with a kind of surfactant, said composition also contains sufficient amount can stop the microorganism phenomenal growth at least within 24 hours edetate.
Suitable treatment or pharmaceutical preparation be can be in emulsion oil-in-water those preparations of parenteral.Representational preparation is lipophilic cpd such as antifungal, anesthetis, antibacterial, anticarcinogen, and antiemetic acts on the preparation such as the Ben first Er Dan System of central nervous system, steroid, barbiturate and vitamin preparation.Particularly the present invention relates to a kind of usually in one day or longer time to the sort of emulsion oil-in-water of patient's administration of needs.
Description of drawings
Fig. 1 is a preparation technology's of the present invention schematic flow sheet.
Specific embodiments
The explanation of typical and preferred propofol composition of the present invention and preparation thereof is used to contain in the injection fats emulsion and emulsion oil-in-water of treatment or pharmaceutical preparation through after suitably revising.
Preparation:
All procedure of processings are all carried out under nitrogen protection, and weight is meant the weight of final volume.
A kind of method for making of the aseptic aqueous emulsion oil-in-water that is used for parenteral is as follows:
1. use glycerol (2.25%, weight), disodiumedetate hydrate (0.0055%, weight), sodium hydroxide (general 60mgL
-1) and water make the water that is used to inject.Stir this mixture and be heated to about 65 ℃.
2. water removes by filter particulate matter with filter and it is moved in the blender.
3. carry out simultaneously with above, by Oleum Glycines (10.0%, weight), propofol (1.0%, weight) and lecithin (1.2%, weight) prepare a kind of oil phase in a container.Mixture all dissolves until all components about 75 ℃ of following stirrings of temperature.
4. mixture is removed particulate matter and is added to aqueous phase through a static mixer through a filter.
5. the material in the mixer, temperature is maintained at about 65 ℃.Mixture is through a high-pressure homogenizer and cooler (heat-exchange system) circulation, until reaching needed oil droplet size (about 250 millimicrons of average oil droplet size).
6. cool off the emulsion oil-in-water that obtains, and it is transferred in the filling containers.
7. filter this emulsion and, use autoclave up then in its container of under nitrogen protection, packing into.
Emulsion after final the filtration can join in the container of various volumes as ampoule bottle (20ml), in phial (50ml and 100ml) and the syringe pre-installed.
A kind of emulsion oil-in-water that contains 2% (by weight) propofol can use the same method and make with the component of following quantity:
The emulsion oil-in-water that contains 1% (by weight) propofol in addition can use the same method and make with the component of following quantity:
Biological activity
With male Mus (18-22g) parenteral of preparation to 10 every group, dosage is 5-40mg/kg.Observe calmness and anesthesia with dosage.
Microbial activity (relatively)
Emulsion oil-in-water propofol (1%) (trade mark of the Diprivan:Zeneca company) preparation of having bought on market adds dense additive aqueous solution, can make the preparation that contains various additives.The pH of these preparations is about 7.5.
The gravy culture fluid preservative effectiveness test of the American Pharmacopeia of four kinds of standards adds to microorganism in these advance copy prescriptions, and about 200 bacterium colonies of every ml generate unit.The prescription of test is cultivated down at 30 ℃, checks count plate after 24 and 48 hours.
The result
Prescription with sodium pyrosulfite (0.1%)
Prescription decolouring occurs and shows chemically unstable.
Prescription with sodium sulfite (0.1%)
Prescription with hydroxybenzoate (0.2 methyl ester/0.02 propyl ester)
Prescription with sodium ethylene diamine tetracetate calcium (0.1%)
Prescription with edta disodium dihydrate (0.1%)
(pH is about 5.5)
Microbial activity (further comparative result)
The flushing suspension preservative effectiveness test of the American Pharmacopeia of four kinds of standards adds to microorganism in these test recipes, and every milliliter of about 100 bacterium colonies generate unit.The prescription of test is cultivated 24 and 48 hours duplicate test count plates down at 25 ℃; Write down twice result.
' Diprivan ' (1% propofol)
Prescription with disodiumedetate water two compounds (0.0055%)
Above-mentioned prescription was once further estimated with other related microorganism.
Obtained containing the microbiological data of the corresponding prescription of 2% propofol in the same way.
The injection fats emulsion
(containing Oleum Glycines (10%), lecithin (1.2%), glycerol (2.25%), sodium hydroxide (in right amount) and water for injection)
Injection fats emulsion (as above) with edta disodium dihydrate (0.0055%)
ND: on 1ml inclines plate, do not measure microorganism
With relevant microorganism above prescription is further estimated.
More than the definite microorganism of test has staphylococcus aureus ATCC 6538, escherichia coli ATCC 8739, Pseudomonas aeruginosa ATCC 9027 and white candida mycoderma ATCC 10231.
A preferred embodiment of the present invention provides a kind of a kind of aseptic medicinal composition that contains the oil-in-water type emulsion.In emulsion, propofol is dissolved in a kind of and the immiscible solvent of water and water emulsifying, and a kind of surfactant of reuse is stable.Said composition also contains each staphylococcus aureus ATCC 6538 of a kind of enough preventions, escherichia coli ATCC 8739, the edetate of Pseudomonas aeruginosa ATCC 9027 and white candida mycoderma ATCC 10231 some of not 11-fold increase in 24 hours.Determination test is that every kind of microorganism flushing suspension is joined in the said composition, and its amount generates unit for about 50 bacterium colonies of every ml, and temperature is 20-25 ℃, and this sample is cultivated down at 20-25 ℃, and after 24 hours, the check count plate.
Claims (1)
1. aseptic medicinal composition that is used for parenteral, it is the emulsion oil-in-water that contains propofol, wherein be dissolved in the propofol water emulsifying in a kind of and the immiscible solvent of water, and it is stable with a kind of surfactant, said composition also contains the edetate of some, and wherein the scope of the molar concentration of edetate is 3 * 10
-5～9 * 10
-4, and comprise a kind of antifungal, anesthetis, antibacterial, anticarcinogen, antiemetic, central nervous system agent, steroid or vitamin preparation in the described compositions.
Priority Applications (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB031038573A CN100457086C (en) | 1995-03-17 | 1995-03-17 | Aseptic medicine composition |
| CNB2006101018633A CN100450473C (en) | 1995-03-17 | 1995-03-17 | Aseptic medicinal composition |
| CNB2006101018629A CN100512877C (en) | 1995-03-17 | 1995-03-17 | Germ-free medicinal compositions |
| HK07113544.7A HK1105807A1 (en) | 1995-03-17 | 2006-07-20 | Sterile pharmaceutical composition |
| HK06108122.8A HK1087642A1 (en) | 1995-03-17 | 2006-07-20 | Sterile pharmaceutical composition |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB031038573A CN100457086C (en) | 1995-03-17 | 1995-03-17 | Aseptic medicine composition |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN95197780A Division CN1106192C (en) | 1995-03-17 | 1995-03-17 | Oil in water emulsions containing 2, 6 -diisopropyl phenic and ehtylenedinamine-tetra acetic salt |
Related Child Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2006101018629A Division CN100512877C (en) | 1995-03-17 | 1995-03-17 | Germ-free medicinal compositions |
| CNB2006101018633A Division CN100450473C (en) | 1995-03-17 | 1995-03-17 | Aseptic medicinal composition |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1748672A CN1748672A (en) | 2006-03-22 |
| CN100457086C true CN100457086C (en) | 2009-02-04 |
Family
ID=36604451
Family Applications (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2006101018633A Expired - Lifetime CN100450473C (en) | 1995-03-17 | 1995-03-17 | Aseptic medicinal composition |
| CNB031038573A Ceased CN100457086C (en) | 1995-03-17 | 1995-03-17 | Aseptic medicine composition |
| CNB2006101018629A Expired - Lifetime CN100512877C (en) | 1995-03-17 | 1995-03-17 | Germ-free medicinal compositions |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2006101018633A Expired - Lifetime CN100450473C (en) | 1995-03-17 | 1995-03-17 | Aseptic medicinal composition |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2006101018629A Expired - Lifetime CN100512877C (en) | 1995-03-17 | 1995-03-17 | Germ-free medicinal compositions |
Country Status (2)
| Country | Link |
|---|---|
| CN (3) | CN100450473C (en) |
| HK (1) | HK1087642A1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114983939A (en) * | 2022-06-27 | 2022-09-02 | 辰欣药业股份有限公司 | Propofol emulsion injection and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4452817A (en) * | 1974-03-28 | 1984-06-05 | Imperial Chemical Industries Plc | Anaesthetic compositions containing 2,6-diisopropylphenol |
| US4970209A (en) * | 1985-10-25 | 1990-11-13 | International Nutritional Research Institute Ab | Fat emulsions |
-
1995
- 1995-03-17 CN CNB2006101018633A patent/CN100450473C/en not_active Expired - Lifetime
- 1995-03-17 CN CNB031038573A patent/CN100457086C/en not_active Ceased
- 1995-03-17 CN CNB2006101018629A patent/CN100512877C/en not_active Expired - Lifetime
-
2006
- 2006-07-20 HK HK06108122.8A patent/HK1087642A1/en not_active IP Right Cessation
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4452817A (en) * | 1974-03-28 | 1984-06-05 | Imperial Chemical Industries Plc | Anaesthetic compositions containing 2,6-diisopropylphenol |
| US4970209A (en) * | 1985-10-25 | 1990-11-13 | International Nutritional Research Institute Ab | Fat emulsions |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101002732A (en) | 2007-07-25 |
| CN100450473C (en) | 2009-01-14 |
| CN100512877C (en) | 2009-07-15 |
| HK1087642A1 (en) | 2006-10-20 |
| CN1748672A (en) | 2006-03-22 |
| CN1977825A (en) | 2007-06-13 |
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