CN100591721C - Poloxamer emulsion preparations - Google Patents
Poloxamer emulsion preparations Download PDFInfo
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- CN100591721C CN100591721C CN200480005486A CN200480005486A CN100591721C CN 100591721 C CN100591721 C CN 100591721C CN 200480005486 A CN200480005486 A CN 200480005486A CN 200480005486 A CN200480005486 A CN 200480005486A CN 100591721 C CN100591721 C CN 100591721C
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
- A61K8/04—Dispersions; Emulsions
- A61K8/06—Emulsions
- A61K8/068—Microemulsions
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
- A61K8/90—Block copolymers
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- 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
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
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- 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
- A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J3/00—Processes of treating or compounding macromolecular substances
- C08J3/02—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques
- C08J3/03—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques in aqueous media
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L71/00—Compositions of polyethers obtained by reactions forming an ether link in the main chain; Compositions of derivatives of such polymers
- C08L71/02—Polyalkylene oxides
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G2650/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G2650/28—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule characterised by the polymer type
- C08G2650/58—Ethylene oxide or propylene oxide copolymers, e.g. pluronics
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
An emulsion composition comprising: an aqueous component, a non-ionic block copolymer, and an oil wherein the copolymer comprises at least 10% by weight of the composition.
Description
Invention field
The present invention relates to can be used for microemulsion and the composition and the application of multiple medicine and personal care products.Especially, it provides and can be used for part and/or mucosal use water-insoluble or slightly soluble promoting agent to the surface of oesophagus, ear, vagina, rectum or eye or may be used on animal cuticle (human body skin) and/or the imbalance and the defective of treatment skin.It also provides a kind of microemulsion and composition that contains water-insoluble or slightly soluble promoting agent that be used to prepare.
Background technology
Many promoting agents in medicine and the cosmetic formulations contain oils, perhaps can not mix in water or insoluble.Because it is water-soluble that they lack, and is difficult to transport these promoting agents of significant quantity to obtain conceivable result of treatment.Therefore, people often wish to provide this class reagent (for example, being used for oral administration, topical application, intravenous injection, intramuscular injection, subcutaneous injection etc.) in aqueous composition.A kind of method that is used to prepare this based composition is to form emulsion.
Emulsion is a kind of by at least two kinds of heterogeneous systems of can not mixing liquid (as water and oil phase) forming, and a kind of liquid is with the drop form, be dispersed among the another kind of liquid with external phase and discontinuous phase.Discontinuous phase is known as disperse phase or interior phase in different time, and disperse to betide wherein be known as external phase or foreign minister mutually.When water was external phase, emulsion was known as oil-in-water (O/W), and when oil was external phase, emulsion was known as water-in-oil (W/O).The O/W emulsion is the emulsion of frequent use.But the W/O emulsion is welcome for many application, if instability problem can be overcome, then they will be used widely.
Huge emulsion is defined as the particle that is formed and had usually the 1-10 micron-scale by high shear mixing.Because oil and water constituent are separated into mutually distinctly along with the time, so this class emulsion is difficult to obtain, have the stability of minimum.And the drop size of this huge emulsion is along with the time increases.Developed several different methods already in order to stablize this class emulsion, for example, added additive as emulsifying agent and fine-particle solid and so on.
On the contrary, the microemulsion system by oil, water and suitable emulsifying agent are formed can spontaneously form (promptly stir with minimum and form), thereby be that thermokinetics is stable.This thermodynamic stability level is very welcome, but seldom can reach.Microemulsion system is in theory in the preservation period that does not have to have under the isolating normal condition endless, and huge emulsion then has limited preservation period.And it is constant that the drop size of this class microemulsion keeps, and usually less than 150nm (generally between 10-50nm), and this class microemulsion has low-down oil/water termination tension force.
Emulsion such as microemulsion, it is very important can allowing to provide in being suitable for the aqueous solution that human body uses the novel and effective promoting agent of water-insoluble or slightly soluble promoting agent to transport the system for exploitation.This class preparation of microemulsion is signifying that medicine transports the major technique obstacle of system, and this must select biocompatible, nontoxic, clinical acceptable raw material and form stable microemulsion liquid because of people.
In addition, because they are easy to be rinsed or degrade, they have very short retention time at the tissue place that they are applied on it, so, wishing the controlled of site and prolonging release that for guaranteeing promoting agent many known emulsion formulations suffer the hardship of unstable.This unstable is unwelcome especially, and this is because numerous biologic activity agent, for remaining valid property, must wish that the site stays the time of an elongated segment.
Consider above-mentioned factor, need be provided for transporting the emulsion formulations of promoting agent, they be many purposes and for example can be applied on part or the mucosal tissue.This class emulsion preferably should have high bioadhesion ability, can guarantee that contact continues the time of an elongated segment.And the promoting agent that they preferably should deliver very high quantity is to the coating site, is used for controlled and prolongs the tissue that is discharged into hope.
Though stable emulsion formulations had had record already,, these compositions need use high temperature melting all the components of oil phase usually, thus the particle that disperses a phase equably is among the particle of another phase.Microemulsion forms in the temperature greater than 75 ℃ usually, typically is about 90 ℃, and composition is slow cool to room temperature in a few hours or time a couple of days then, to produce emulsion.For in enormous quantities, this is a kind of costliness and time-consuming method.Also exist such risk, promptly emulsion will overheat, and for example causes some compositions to be degraded.Another kind can be used to prepare the method for stable emulsion, is by using tensio-active agent or emulsifying agent.Typically, tensio-active agent and the emulsifying agent that is used to prepare emulsion is selected from the group of being made up of hydrophilic surfactant and its mixture.In order to serve as tensio-active agent, a kind of compound must contain polarity or charged hydrophilic integral part and nonpolar lipophilic (hydrophobic) integral part; That is to say that a kind of surfactant compounds must be an amphoteric.A kind of through being commonly used to characterize the wetting ability of nonionic amphoteric substance and the empirical parameter that hydrophobic nature concerns, be hydrophil lipophil balance (" HLB " value).Have the tensio-active agent of low HLB value, be more lipophilic or hydrophobic, and in oil, have bigger solvability, and the tensio-active agent with higher HLB value is more hydrophilic, and in the aqueous solution, have bigger solvability.Hydrophilic surfactant is commonly considered as those and is had the HLB value greater than about 10 compound, and negatively charged ion, positively charged ion or zwitterionic compound, and the HLB yardstick is generally inapplicable to them.Should be understood that the HLB value of tensio-active agent only is a rough guide that is commonly used to guarantee to prepare industry, medicine and cosmetic emulsion.
One class successfully as the compound of producing tensio-active agent in huge emulsion and the microemulsion, had been the segmented copolymer poloxamer (poloxamer) of ethylene oxide and propylene oxide already.These a large amount of compounds have unusual character, and when they were freezing, they became liquid, but hardening when they heat, a kind of characteristic that is called thermal reversibility.This class thermal reversibility for be hopeful to handle the raw material that is fluid state but performance more suitably be gel or more the drug regimen situation of tacky state be useful.This compounds can be inhaled into and be used in the syringe that exact dosage desired is measured or easily apply or spray from divider from bottle when cooling.When poloxamer is heated to body temperature (for example, when being applied to skin or mucomembranous surface), the denseness that it is suitable that it thickens helps suitable oiling and adhesion.
The ideal gelation temperature can be realized control by the concentration of regulating this segmented copolymer, and lower copolymer concentration provides higher gelation temperature.For prepare a kind of composition that this class changes that has during useful temperature on commercial or physiology, the concentration of this multipolymer needs 18-20wt% at least.But, have found that, the multipolymer of introducing high density can make composition become very gluing or " agglutinationization ", even and the solution that contains the 18-20wt% poloxamer is " liquid phase ", usually also has high viscosity, so these solution needed unable to get up effect in low viscosity, the free-pouring situation before changing.For this reason, typical copolymer emulsion contains usually and is less than 10% multipolymer.
Promoting agent
Promoting agent is chemical substance or compound, and when being administered into organism (human body or animal are generally human body), they can cause the pharmacological action of hope.Promoting agent in many medicines and the cosmetic formulations contains oils or can not mix in water or insoluble.An example of this class promoting agent is tea tree oil (TTO).
TTO belongs to tree Melaleuca alternafolia from Australian white spirit layer by distillation stem separates with the oil that leaf obtains and obtains.TTO has pharmaceutical properties, comprises antibiotic, antiviral, anti-inflammatory and antifungal property.In addition, TTO can provide soothing sensation when with people's skin contact.But the character of TTO only is suitable for the multiple system that transports of condition that needs by preparation and is developed and applied.When the TTO product that is water-based face cream form was exposed in the air, TTO becomes branch that oxidation takes place and some chemical ingredientss can change their characteristic, thereby influences the validity and the security of medicine.Many existence that are used in the water emulsifying agent of solubilising TTO also can suppress or hinder the activity of TTO.As gel suspension, TTO tends to separate from the gel basic components, particularly when suspension contains concentration and is higher than 2%TTO, a kind of by temperature variation (for example surpassing 30 ℃ temperature) and/or apply the process that the physics shearing force is enhanced as mediating gel suspension.
In order to transport the TTO of significant quantity, people wish to use in such a way oils, i.e. their both's maintenances continue the time of an elongated segment with skin contact and transport the TTO of possible maximum concentration.Because they are that thermokinetics is stable, therefore, microemulsion preparation is very welcome.
The present invention will form the safe and effective medicine micro emulsion and transport system as its purpose, and this system that transports does not need preparation just to can be made into to be used for high temperature preparation.Other purpose of the present invention and aspect will clearly be illustrated by following description of the present invention.
Summary of the invention
According to the present invention, a kind of composition that is used to transport the water-insoluble promoting agent is provided, perhaps more particularly a kind of microemulsion comprises: a kind of aqueous component and a kind of non-ionic block copolymer and at least aly be promoting agent or have the water-insoluble promoting agent and be dissolved in wherein oil.
In the present invention, term " emulsion " comprises huge emulsion and microemulsion.
The present composition will have bioadhesion or mucoadhesive matter with wishing.Preferably, said composition will be liquid or gel form.Most preferably, micro emulsion composition will exist with gel, perhaps will be a kind of like this liquid, and it has the ability of agglutinationization when contacting with skin or mucosal tissue.
According to second kind of embodiment, the invention provides a kind of micro emulsion or composition that is used to transport the water-insoluble promoting agent, comprise a kind of aqueous component and a kind of non-ionic block copolymer, a kind of hydrophilic, nonionic short chain fatty acid emulsifying agent and at least aly be promoting agent or have the water-insoluble promoting agent and be dissolved in wherein oil.
According to the third embodiment, the invention provides a kind of method that is used to prepare this microemulsion composition, may further comprise the steps:
(a), make this multipolymer be dissolved in this aqueous solution substantially at suitable temp mixed copolymer and a kind of aqueous solution; And
(b) under cold temperature, mix and a kind ofly be promoting agent or have the water-insoluble promoting agent and be dissolved in wherein oil and the moisture copolymer solution that makes in step (a), form microemulsion.
According to the 4th kind of invention mode, the invention provides a kind of method that is used to prepare this microemulsion composition, may further comprise the steps:
(a), make this multipolymer be dissolved in this aqueous solution substantially at suitable temp mixed copolymer and a kind of aqueous solution;
(b) at low temperatures, mix a kind of hydrophilic, nonionic short chain fatty acid emulsifying agent and a kind ofly be promoting agent or have the water-insoluble promoting agent and be dissolved in wherein oil, form a kind of oil mixt; With
(c) at low temperatures, be blended in the solution that solution that step (a) makes and step (b) make, form microemulsion.
Also provide the microemulsion composition that forms by aforesaid method in this.
The present composition will have extensively various application.When the part was applied to the animal skin layer, said composition can contain the reagent that is used for promoting physical attraction or shelters the body image of imbalance or disease, the treatment of replacement or additional body imbalance.Same reagent may have cosmetic effect or drug effect, and this depends on used quantity and administering mode.
In another aspect of this invention, the present composition can be incorporated among other composition, to give final composition thickening character.This class thickening character comprises the overall viscosity of raising and the welcome viscosity response to temperature.Said composition can be used as thickening material in the invalid pH scope of other thickening material.
In addition, the present composition can be incorporated among other composition, to give the said composition ramollescence.In this regard, after being applied to skin or other mucous membrane, said composition also can be served as the film forming biologically active agent.This film forming biologically active agent can be used as the blocking layer, prevents the loss of moisture content from skin when the challenge of treatment biology.
Those skilled in the art can describe subsequently by research, and other aspects and advantages of the present invention are obtained clearly understanding.
Detailed description of the Invention
Introduction
It will be appreciated by those skilled in the art that the present invention described herein except specifically described situation, admits of other changes and improvements.Should be appreciated that and the present invention includes all these changes and improvements.The present invention also be included in the institute mentioning in the specification sheets or hint in steps, feature, composition and compound, individually or jointly, arbitrarily and all combination or any two or more step or the feature of these steps or feature.
The present invention is not limited to described from here embodiment institute restricted portion, and these embodiments only are to be used for illustrative purpose.The product of function equivalence, composition and method belong among the scope of the invention described herein significantly.
The specification sheets of all publications cited herein (comprising patent, patent publications, journal articles, laboratory manual, books or other document) therefore is merged in according to reference.The reference that all constitute prior art or the present invention relates to those skilled in the art's a common practise part repeats no more.
In whole specification sheets, unless context needs in addition, word " comprises " or its variant will be interpreted as expression and comprise described integer or integer group but do not get rid of other integer or integer group arbitrarily.
Used herein for other definition of selecting word for use, can in detailed description of the present invention, find and be applied in full among.Unless otherwise prescribed, all other scientific and technical terminologies used herein all have the common equivalent of understanding with one skilled in the art of the present invention.
The preferred implementation explanation
The invention provides a kind of microemulsion composition, comprise the multipolymer of 10wt% at least, this multipolymer preferably has thermal reversibility matter.With regard to known to the applicant, the multipolymer level of this quantity has exceeded the level that exists in other oil-copolymer based microemulsion.But used multipolymer is the heat inverse time in microemulsion, and oil-copolymer compositions can prepare at low temperatures.But the applicant finds that emulsifying agent before adding multipolymer and oily combination can allow to prepare at low temperatures microemulsion astoundingly.
According to the present invention, a kind of composition that is used to transport the water-insoluble promoting agent is provided, perhaps more particularly a kind of microemulsion comprises: a kind of aqueous component and a kind of non-ionic block copolymer and at least aly be promoting agent or have the water-insoluble promoting agent and be dissolved in wherein oil.
Microemulsion described herein will comprise the segmented copolymer that accounts for this emulsion weight 10-50% quantity, more preferably the weight amount of segmented copolymer is between about 10.1-40%, when the segmented copolymer weight amount accounts for the important following scope in office of this emulsion will be very welcome: 10.5-35%, 11-30%, 12-25%, 13-20% or 14-18%.Therefore, as an example of the present invention, segmented copolymer can account for 15% of this emulsion weight.
Except segmented copolymer was present in this microemulsion with aforementioned weight range, people expected that also it still is hot reversible multipolymer.
In preferred implementation of the present invention, microemulsion or composition will have bioadhesion or mucoadhesive matter.This class character will be consistent with microemulsion that makes with liquid or preferred gel form or composition.When preparing by this way, microemulsion or composition will can be used for part and/or mucosal use water-insoluble or the slightly soluble promoting agent surface to oesophagus, ear, vagina, rectum or eye, or may be used on the imbalance and the defective of animal cuticle (human body skin) and/or treatment skin.Desirably, microemulsion or composition will exist or will prepare in such a way with gel, promptly have jellied ability when contacting with skin or mucosal tissue.
When first kind of described microemulsion of embodiment of preparation the present invention, ideally, oily and hot reversible multipolymer will be to mix at low temperatures.When mixing is when carrying out at low temperatures with the weight range that draws place regulation, composition just can form a kind of stable microemulsion that can be coated on skin or the mucosal tissue.
In second kind of embodiment, a kind of microemulsion or composition that is used to transport the water-insoluble promoting agent of the present invention comprises a kind of aqueous component and a kind of non-ionic block copolymer, a kind of hydrophilic, nonionic short chain fatty acid emulsifying agent and at least aly is promoting agent or has the water-insoluble promoting agent and be dissolved in wherein oil.
When second kind of described microemulsion of embodiment of preparation the present invention, ideally, oil and emulsifying agent will mix, and then be applied on the hot reversible multipolymer.When mixing is when carrying out at low temperatures with the weight range that draws place regulation, composition can form a kind of stable microemulsion that can be applied on skin or the mucosal tissue apace.
The multipolymer that is used for the present invention is the segmented copolymer (poloxamer) of ethylene oxide and propylene oxide preferably, preferably those multipolymers of being represented by following general formula:
HO(C
2H
4O)
a(C
3H
6O)
b(C
2H
4O)
aH
Wherein, b is between 15-67, and a is between 2-130, and the unitary overall proportion of a accounts for the 20-90% of poloxamer weight.It is about 1 that the molecular weight ranges of poloxamer is preferably, 000-20, and 000, and it preferably has thermal reversibility matter.For instance, only segmented copolymer can be poloxamer 407, as with Pluronic
The poloxamer that the name of F127 (BASF AG) or SynperonicPE/F127 (Uniqema) is sold.
According to the present invention, preferred solvent is the fatty acid component with polyethoxylated side chain.For example, suitable emulsifying agent may be Laureth-4, Laureth-9, Laureth-23, PPG-26-Buteth-26/PEG-40 hydrogenated castor oil or PEG-40 hydrogenated castor oil.When this class emulsifying agent is used for when of the present invention, the weight amount of this emulsifying agent accounts for the about 0.5-50% of weight of microemulsion usually.
Physics-chem characteristic of the present invention makes this microemulsion be suitable as the carrier that transports of water-insoluble or slightly soluble promoting agent.It is particularly suitable for by skin or transporting by mucous membrane.In this regard, oil phase can comprise the oils that food, makeup and medicine industry are commonly used, for example, and oils, long-chain alcohol, the glyceryl ester of lipid acid or the fatty ester of unit alcohol in natural or synthetic source.These ester classes and alcohols can be to be liquid under straight or branched, saturated or unsaturated and the room temperature.This oil phase also can contain can be dissolved in this oil phase or can with this oil phase blended promoting agent.
Oils of the present invention can have the inherent pharmaceutical properties and form the promoting agent of microemulsion and/or contain dissolved promoting agent (they can be dissolved in maybe and can be mixed in this oil).Promoting agent can include, but is not limited to antiseptic-germicide (as microbiotic, anti-mycotic agent and antivirotic), antiphlogiston, antihistaminic, thymoleptic, narcotic, antitumour drug, enzyme, cardiovascular drug, polynucleotide, genetic material, virus vector, immune-active agent, photographic developer, immunosuppressor, peptide, protein etc. and their composition.Select the pharmacy effective dose of promoting agent for use, can determine by using technology known in the art.
Preferably, the weight amount of used oil in the microemulsion will account for about 0.1-80% of this emulsion weight, more preferably accounts for the 1-30% of this emulsion weight, and the 3-15% that accounts for this emulsion weight is very welcome.In an example of the present invention, this oil will account for about 6% of this emulsion gross weight.
Very preferably in the form, this oil is tea tree oil (TTO) in the present invention.For promoting agent is the situation of TTO, and microemulsion will have fungicidal activity.This based composition for example can be used to treatment: transport treatment as sexually transmitted disease (STD) (for example HIV) and so on disease by vagina; By topical formulations treatment pustulosis and herpes labialis, by coating in the nose eliminate MRSAs with as otitis media, external otitis, Cuo blister, periodontitis, gingivitis, paronychia, onychomycosis and the secondary infection that links to each other with operation, dermatitis, burn etc.
According to the third embodiment, the invention provides a kind of method that is used to prepare this microemulsion composition, may further comprise the steps:
(a), make this multipolymer be dissolved in this aqueous solution substantially at suitable temp mixed copolymer and a kind of aqueous solution; With
(b) under cold temperature, mix and a kind ofly be promoting agent or have the water-insoluble promoting agent and be dissolved in wherein oil and the moisture copolymer solution that makes in step (a), form microemulsion.
According to the step (a) of this method, multipolymer mixes with a kind of aqueous solution at suitable temp, makes this multipolymer be dissolved in this aqueous solution substantially.The dissolving of multipolymer and aqueous solution will almost take place in moment at about 6 ℃.A kind of replacement scheme is, multipolymer can at room temperature contain water dissolution with this and mix, and condition is to make it to spend the night under semicontinuous or continuously stirring.
" cold temperature " used herein expression is lower than about 15 ℃ temperature, is preferably about 4-12 ℃, most preferably is lower than about 100C.
According to the 4th kind of embodiment, the invention provides a kind of method that is used to prepare this microemulsion composition, may further comprise the steps:
(a), make this multipolymer be dissolved in this aqueous solution substantially at suitable temp mixed copolymer and a kind of aqueous solution;
(b) at low temperatures, mix a kind of hydrophilic, nonionic short chain fatty acid emulsifying agent and a kind ofly be promoting agent or have the water-insoluble promoting agent and be dissolved in wherein oil, form a kind of oil mixt; With
(c) at low temperatures, be blended in the solution that solution that step (a) makes and step (b) make, form microemulsion.
" low temperature " used herein expression is lower than about 60 ℃ temperature, is preferably about 15-40 ℃, more preferably about 20-30 ℃, most preferably is about room temperature.The ability of preparation microemulsion of the present invention is very significant under these temperature, because it can provide the feature that is different from numerous other preparation microemulsion methods (it need prepare microemulsions at about 90 ℃).
Have been found that the microemulsion composition that the present invention makes has wonderful feature, promptly add oil/emulsifier mixture to moisture poloxamer solution when room temperature, the temperature when taking place to solidify by change can change the thermal reversibility matter of poloxamer.This most obvious when acting on high poloxamer/oil ratio value.
Microemulsion composition of the present invention provides the limpid colourless gel that is particularly suitable for medicine and human body nursing application.For example, form considerably less remnants when dehydration, this is very important in some applications, for example in eye coating medicine.The other advantage of microemulsion composition of the present invention is that they still keep limpid and transparent before causing environmental change and afterwards.These characteristics of reversible gelling microemulsion composition make it can be suitable for pharmaceutical composition well.
The application advantage of this performance of microemulsion composition is that this prescription can carry out administration with fluxion when room temperature.When contacting with bodily tissue, it becomes gluing, thereby changes its flowing property, what is more important, and its cleaning from the coating site greatly reduces.
It will be appreciated by those skilled in the art that microemulsion composition of the present invention can be used for extensively various medicine and the human body nursing is used.For pharmaceutical compositions, the significant quantity pharmaceutically active agents that can give welcome effect of drugs is incorporated among the reversible gelling composition of the present invention.
When being prepared according to the inventive method, microemulsion composition can also comprise that one or more medicines can accept additive, vehicle carrier and thinner.This class additive, vehicle carrier and thinner include, but is not limited to water, salt solution, ethanol, glucose, glycerine, lactose, sucrose Sorbitol Powder, N.F,USP MANNITOL, starch, Sudan Gum-arabic, calcium phosphate, alginate, tragacanth, gelatinum, Calucium Silicate powder, Microcrystalline Cellulose, polyvinylpyrrolidone, Mierocrystalline cellulose, aqueous syrup, methylcellulose gum, hydroxy-benzoic acid methyl ester and hydroxy-benzoic acid propyl diester, mica, Ying Zhi Suan Magnesium and mineral oil or their composition.These prescriptions also can comprise lubricated reagent, pH buffer reagent, wetting agent, emulsification suspending agent, sanitas, sweeting agent or seasonings, defoamer, polymkeric substance, oxidation inhibitor, sequestrant, viscous regulator, nourishing agent, flavouring agent, tinting material, odorant agent, opalizer, suspending agent, binding agent, filler, softening agent, lubricant and their mixture in addition.Can be included in the specific selection of the composition among the composition described herein, generally depend on the type of preparation.
In addition, acid or alkali also can be incorporated among the microemulsion, to promote processing, to improve stability or for other reason.The example that medicine can be accepted alkali comprises amino acid, amino acid ester, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium bicarbonate, aluminium hydroxide, lime carbonate, Qing Yangization Magnesium, Gui Suan Lv Magnesium, synthetic pure aluminium silicate, synthetic hydroconite (hydrocalcite), aluminum magnesium hydroxide, diisopropylethylamine, thanomin, quadrol, trolamine, triethylamine, tri-isopropanolamine, Trimethylamine 99, three (methylol) aminomethane (TRIS) etc.Alkali (they are the salt that medicine can be accepted acid) also is suitable, as acetate, vinylformic acid, hexanodioic acid, alginic acid, alkyl sulfonic acid, amino acid, xitix, phenylformic acid, boric acid, butyric acid, carbonic acid, citric acid, lipid acid, formic acid, fumaric acid, glyconic acid, hydroquinone sulfonic acid, saccharosonic acid, lactic acid, toxilic acid, oxalic acid, to bromo-benzene sulfonic acid, propionic acid, tosic acid, Whitfield's ointment, stearic acid, succsinic acid, tannic acid, tartrate, thiol guanidine-acetic acid, toluenesulphonic acids, uric acid etc.The salt of many protonic acids such as sodium phosphate, sodium hydrogen phosphate and SODIUM PHOSPHATE, MONOBASIC also can be used.When this alkali was a kind of salt, positively charged ion can be the suitable and acceptable positively charged ion of medicine arbitrarily, as ammonium ion, basic metal, alkaline-earth metal etc.Preferred cationic comprises sodium, potassium, lithium, magnesium, calcium and ammonium.
Suitable acid is medicine acceptable organic acid or mineral acid.The example of suitable inorganic acid comprises hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, sulfuric acid, nitric acid, boric acid, phosphoric acid etc.Suitable organic acid example comprises acetate, vinylformic acid, hexanodioic acid, alginic acid, alkyl sulfonic acid, amino acid, xitix, phenylformic acid, boric acid, butyric acid, carbonic acid, citric acid, lipid acid, formic acid, fumaric acid, glyconic acid, hydroquinone sulfonic acid, saccharosonic acid, lactic acid, toxilic acid, methylsulfonic acid, oxalic acid, to bromo-benzene sulfonic acid, propionic acid, tosic acid, Whitfield's ointment, stearic acid, succsinic acid, tannic acid, tartrate, thiol guanidine-acetic acid, toluenesulphonic acids, uric acid etc.
When the enzyme reduction was carried out in the hydrophilic active agent, the present composition also can contain a kind of enzyme inhibitors.For example, enzyme inhibitors is disclosed in Bernskop-Schnurch (1998), among " Theuse of inhibitory agents to overcome enzymatic barrier toperorally administered therapeutic peptides andproteins, " Controlled Release 52:1-16.
Usually, inhibitor can be divided into following a few class: be not based on amino acid whose inhibitor (as P-amino-benzene carbonamidine, FK-448, camostat mesylate and Sodium glycocholate); The amino acid of amino acid and modification (as aminoboronic acid derivative and n-acetylcysteine); The peptide of peptide and modification (he decides as bacitracin, phosphonic acids two peptide derivatives, Pepstatin, antipain, leupeptin, Chymotrypsin, elastatin, bestatin, hosphoramindon, tetracycline, cell fission chalone potato carboxypeptidase inhibitor and Ah); Bunching propylhomoserin proteinase inhibitor (killing (worm) ovum agent people and human pancreas's insulin inhibitor) as Trypsin inhibitor,Trasylol, Bowman-Birk inhibitor, soybean insulin inhibitor, egg white insulin inhibitor, chicken; Recombiner (as EDTA, EGTA, 1,10-phenanthrolene and hydroxyquinoline); With mucous membrane adhesive polymer and polymer inhibitor conjugate (as polyacrylic acid ester derivative, chitosan, Mierocrystalline cellulose, chitosan-EDTA, chitosan-EDTA-antipain, polyacrylic acid-bacitracin, carboxymethyl cellulose-Pepstatin and polyacrylic acid-Bowman-Birk inhibitor).The selection of enzyme inhibitors and level are decided according to toxicity, specificity and the inhibition potential of proteolytic enzyme.
Being discussed below of application-specific and preparation is described.
Esophagus, oral cavity and cheek are used: one is used to use the signal of this microemulsion will be used to provide a kind of suitable carriers, is used for transporting effect of drugs in the oesophagus internal layer.In this regard, the mucoadhesive matter of microemulsion of the present invention makes said composition be suitable for control and promotes effect of drugs to this oesophagus internal layer.The shearing sensibility of microemulsion composition liquid undergoing treatment therein is to be sprayed in the application in oral cavity also to be fully used under shear conditions, adhesion takes place and becomes sticky in solution in the oral cavity, for antiseptic-germicide such as chloro hexadine (chlorohexadine) or air freshener provide depository.
Medicament for the eyes is used: numerous medicament for the eyes is to be coated on the eyes, is coated to the cornea zone typically.The most frequently used form of medication is a drop.The bioavailability of medicine is very low usually, and this is because liquid preparation owing to shed tears and blink and be removed from eyes fast, causes frequent administration of needs and uneven medicine to transport.
Microemulsion composition described herein provides a kind of novel carriers, is used to obtain the more mcroorganism utilization ratio of the insoluble or partly soluble medicament for the eyes promoting agent of topical.The preparation that contains this class promoting agent can the drop form apply, and they become sticky or gelling when with eye contact.Because gelling can be finished when low concentration polymer, so, when drop instils, fuzzy can being minimized.
When being used by this way, microemulsion composition preferably is used for transporting biologically active substance, as narcotic, iridodilator and cycloplegic, antiseptic-germicide (antibacterium, antimycotic, antiviral), anti-inflammatory agent, be used for the treatment of glaucomatous reagent, eyes Decongestant, diagnostic reagent and Wound-healing agent.
Protecting nose uses: microemulsion of the present invention also can be used for transporting medicine in nasal cavity.Protect the nose medicine and transport the alternatives that is considered to a kind of administered parenterally route (they have proved to have low oral bioavailability rate).In order to improve the bioavailability of nasal administration, people had made efforts already to improve the residence time of preparation in nasal cavity.The nose of medicine transports to provide and is better than the advantage that other transports method, comprises that system fast absorbs, lower dosage, begins result of treatment of wishing and the pharmacokinetics of improving more quickly.In addition, it provides a kind of alternative route that is used for administration peptide medicine, and they have low bioavailability via oral route usually and normally are administered parenterallys.
The microemulsion combination is used to transport as Decongestant, antihistaminic agent, osteoporosis agent, hormone, antitumour drug, parkinsonism medicine etc. with available potentially.This composition also can be used for vaccine to be used, as the vaccine of those anti-current row common cold virus.
Vagina/rectum is used: emulsion compositions of the present invention shows that also can be used for transporting biologically active agent (as TTO) arrives vagina or rectal cavity.These transport the alternatives that route has been considered to biologically active agent administration parenteral route (they verified have low oral bioavailability rate).In order to improve the utilization ratio of vagina or rectal administration biologically active agent, people have made efforts to improve the residence time of preparation in these cavitys.These routes provide and have been better than the advantage that other transports method, comprise that system fast absorbs, lower dosage, begin result of treatment of wishing and the pharmacokinetics of improving more quickly.
The animal doctor uses: microemulsion of the present invention is useful for the treatment human body diseases not only, and can be used for providing treatment for animal care.As for veterinary product, microemulsion combination shows and can be used for preparing local skin product such as antiseptic-germicide, anti-mycotic agent, pruritus and antiseborrheia, reodorant and sanitas/wound healing preparation.Ear will comprise the ear sanitising agent with product, contain or not contain as the antimycotic promoting agent.Eye will comprise eyes moisture retention liquid or antibiotic preparation with product.
The human body nursing is used: microemulsion composition of the present invention also is particularly suitable for cosmetic applications.For example, form very small amount of remnants when dehydration, this is very important in some applications, as in the makeup of partially coated.An other advantage of the present composition is, on critical temperature or pH and under the time still keep limpid and transparent.These characteristics of microemulsion make it fine and are suitable among the make-up composition.
In order to prepare make-up composition, the cosmetic significant quantity promoting agent that can give welcome makeup effect is incorporated among the microemulsion composition of the present invention.Preferably, selected reagent can make and himself be dispersed among the microemulsion composition.Can expect that reversible gelling composition of the present invention can prepare, and is to drop within the scope of the invention under conditions for sterilization.
Representative makeup and human body nursing that micro emulsion composition can be used for are wherein used, and include, but is not limited to baby products, bathing preparation, eye make-up preparation, balm, achromaticity hair preparation, colour cosmetic, hair-dyeing preparation, Toiletry preparation, the preparation of having a manicure, dental health product, the preparation of having a shave, skin care formulation and solarization black preparation such as tanned face cream, gel and skin-care liquid, indoor skin tanning preparation.
Make-up composition can be arbitrary form.Suitable form includes, but is not limited to skin-care liquid, face cream, powder stick (sticks), rolls preparation, mousse, aerosol spray, the pad coating formula preparation (pad-applied formulations) of putting formula container dress on the skin and becomes film preparation.
The preparation of the above-mentioned make-up composition of mentioning and other preparation can realize by means of any cosmetic preparation handbook and industry periodical (they can obtain at cosmetic industry).These bibliographys can provide the preparation of standard, and they can be improved among preparation by adding or substituting microemulsion composition of the present invention.Suitable handbook comprises Cosmetics and Toiletries Magazine, Vol.111 (March, 1996); Formulary:Ideas for Personal Care; Croda, Inc, Parsippany, N.J. (1993); With Cosmeticon:Cosmetic Formulary, BASF, so they can all introduce, and are made for reference.
Preparation of drug combination can realize by means of arbitrarily pharmaceutical preparation handbook and industry periodical (they can obtain in the medicine industry).These bibliographys can provide the preparation of standard, and they can be improved among preparation by adding or substituting microemulsion composition of the present invention.Suitable handbook comprises Pharmaceutics and ToiletriesMagazine, Vol.111 (March, 1996); Formulary:Ideas forPersonal Care; Croda, Inc, Pars ippany, N.J. (1993); With Pharmaceuticon:Pharmaceutics Formulary, BASF, so they can all introduce, and are made for reference.
But the representative drugs of the moisture response composition administration of the application of the invention or treatment are transported system and are comprised (but never being limited to) mucosal treatment such as esophagus, ear, rectum, cheek, oral cavity, vagina and urinary tract application: topical therapeutic, as wound care, skin care and teat dips; And intravenously/subcutaneous treatment, as (as the joint), spinal cord and subcutaneous treatment in intramuscular, the bone, tissue augment, antiseized and parenteral drug transports.
Term used herein " animal " is to be used for representing Mammals such as primate, comprises people, sheep, horse, ox, pig, dog, cat, mouse; It also comprises bird, Reptilia and fish.
It will be appreciated by those skilled in the art that two or more pharmaceutical agents can be certain effects and combine.Essential activeconstituents quantity can be determined by simple experiment.
Present invention is described by following example now, and these examples only provide for the purpose of illustration, is not limitation of the present invention.
Best mode carries out an invention
Example 1-prepares vaginal jellies B
The A part
Add 15.6g Lutrol
F127 is to 84.4g deionized water (it remains on 6 ℃ temperature).Combine with slow mixing, the air of taking away with reduction is at Lutrol
After the F127 dissolving, be placed on vacuum and continue several minutes to remove the air that all are carried secretly.
The B part
Add the 0.20g fumaric acid among 5.0g alcohol, by stirring up to its dissolving.Cool off this solution to 10 ℃.
The C part
In conjunction with 3.0g tea tree oil (Tea Tree oil), 5.0g propylene glycol and 2.0g undecylenic acid, and mix with the dissolving all the components.Cool off this solution to 10 ℃.
Preparing gel
Lutrol with the 84.8gA part
F127 solution is put in the container, and remains on 10 ℃.The fumaric acid solution and the thorough mixing that add the 5.2gB part lentamente keep solution at 10 ℃.Under the mild stirring effect, add the tea tree oil solution of 10.0g C part lentamente, keep solution at 10 ℃ simultaneously.If desired, by being placed, gel removes all inflations in a vacuum.Make gel be warmed to room temperature.
Example 2-prepares poloxamer gel 8C
The A part
Heating 76.3g deionized water slowly adds 16.7g poloxamer 407, and stirs lasting about 2 hours gently to 60-65 ℃, perhaps all dissolves and the solution retrogradation up to all poloxamers.Make the solution cool to room temperature and make it to spend the night.Adopt potassium hydroxide, regulator solution pH is to 4.2-5.0.
The B part
In conjunction with 3.0gPPG-26-Buteth-26/PEG-40 hydrogenated castor oil, 3.0g tea tree oil and 1.0g D-alpha-tocopherol acetic ester, mix lightly.
Preparing gel
The tea tree oil solution that adds the 7.0gB part is among the room temperature poloxamer solution of 93.0gA part.Mix by stirring gently, up to the solution retrogradation.
Example 3-prepares poloxamer gel 8E
The A part
Heating 73.4g deionized water slowly adds 16.0g poloxamer 407, and stirs lasting about 2 hours gently to 60-65 ℃, perhaps all dissolves and the solution retrogradation up to all poloxamers.Make the solution cool to room temperature and make it to spend the night.Adopt potassium hydroxide, regulator solution pH is to 4.2-5.0.
The B part
In conjunction with 2.0gLaureth-4,1.0gLaureth-23,6.0g tea tree oil and 1.0g D-a-tocopherol acetate, 0.1g 1.0M (1U/g) Vitamin A (retinylpalmitate) and 0.5g panthenol.Heated solution mixes with the dissolving all the components gently to 40-45 ℃.
Preparing gel
The tea tree oil solution that adds the 10.6gB part is in the room temperature poloxamer solution of 89.4gA part.Under stirring gently, mix, up to the solution retrogradation.
The antimicrobial test of example 4-gel preparation
Use huge dilution and little dilution process, these products are tested by using 96-hole droplet price fixing.The highest gel strength of test is 50% product.
Test organism is Ao Lisi staphylococcus (Staphylococcus aureus) NCTC 6571, intestinal bacteria Escherichia (Escherichia coli) NCTC10418, Pseudomonas aeruginosa (Pseudomonas aeruginosa) NCTC 10662 and candiyeast (yeast Candida albicans) ATCC 10231.
Inoculum prepares in dual intensity Mueller Hinton substratum, causes single intensity
The ultimate density of substratum and organism is at about 5x10
5The ultimate density of cfu/mL.Test was cultivated 24 hours at 37 ℃.After the time, by from the dish well, removing 5 μ L dish is carried out time cultivation, and spot is inoculated on the Mueller Hinton agar.All inferior cultivations all are to cultivate 24 hours, and colony is counted.
Minimum inhibition concentration (MIC) is defined as the minimum product concentration that causes keeping or reducing inoculum.Minimum cidal concentration (MCC) is defined as the minimum product concentration that causes inoculum 99.9% death.
Claims (62)
1. emulsion compositions comprises: a kind of aqueous component, the reversible non-ionic block copolymer of a kind of heat and a kind of oil, and the oil that described grease separation is used from food, makeup or medicine industry, wherein, described copolymer comprised said composition weight at least 10%.
2. the emulsion compositions of claim 1, it also comprises hydrophilic nonionic short chain fatty acid emulsifying agent.
3. method that is used to prepare emulsion compositions may further comprise the steps:
(a), make this multipolymer be dissolved in this aqueous solution substantially at the reversible multipolymer of suitable temp mixture heat and a kind of aqueous solution; With
(b) under cold temperature, mix and a kind ofly be promoting agent or have the water-insoluble promoting agent and be dissolved in wherein oil and the moisture copolymer solution that makes in step (a), to form emulsion.
4. the described method of claim 3, wherein, described oil is to mix with the moisture copolymer solution that step (a) makes being lower than about 15 ℃ temperature.
5. the described method of claim 3, wherein, described oil is to mix with the moisture copolymer solution that step (a) makes about 4-12 ℃ temperature.
6. the described method of claim 3, wherein, described oil is to mix with the moisture copolymer solution that step (a) makes being lower than about 10 ℃ temperature.
7. method that is used to prepare emulsion compositions may further comprise the steps:
(a), make this multipolymer be dissolved in this aqueous solution substantially at the reversible multipolymer of suitable temp mixture heat and a kind of aqueous solution;
(b) at low temperatures, mix a kind of hydrophilic, nonionic short chain fatty acid emulsifying agent and a kind ofly be promoting agent or have the water-insoluble promoting agent and be dissolved in wherein oil, form a kind of oil mixt; With
(c) at low temperatures, be blended in the solution that solution that step (a) makes and step (b) make, to form emulsion.
8. the described method of claim 7, wherein, the solution that makes in step (a) is to mix with the solution that step (b) makes being lower than about 60 ℃ temperature.
9. the described method of claim 7 wherein, is that temperature between about 15-40 ℃ is mixed with the solution that step (b) makes at the solution that step (a) makes.
10. the described method of claim 7 wherein, is that temperature between about 20-30 ℃ is mixed with the solution that step (b) makes at the solution that step (a) makes.
11. the described method of claim 7, wherein, the solution that makes in step (a) is to mix with the solution that step (b) makes in room temperature.
12. claim 3 or 7 described methods, wherein, described multipolymer is at about 6 ℃ temperature dissolved.
13. claim 3 or 7 described methods, wherein, described multipolymer is a dissolved at room temperature under semicontinuous or continuously stirring.
14. the emulsion compositions that forms by the described method of claim 3.
15. the emulsion compositions that forms by the described method of claim 7.
16. claim 1,2,14 or 15 arbitrary described compositions, wherein, described emulsion is a microemulsion.
17. claim 1,2,14 or 15 arbitrary described compositions, wherein, the about 10-50% of the described composition weight of described copolymer comprised.
18. claim 1,2,14 or 15 arbitrary described compositions, wherein, the about 10.1-40% of the described composition weight of described copolymer comprised.
19. claim 1,2,14 or 15 arbitrary described compositions, wherein, described multipolymer comprises within the described segmented copolymer weight amount in office one following scope: 10.5-35%, the 11-30%, 12-25%, 13-20% or the 14-18% that account for described composition weight.
20. claim 1,2,14 or 15 arbitrary described compositions, wherein, the described composition weight 15% of described copolymer comprised.
21. claim 1,2,14 or 15 arbitrary described compositions, wherein, described multipolymer comprises hot reversible multipolymer.
22. the described composition of claim 20, wherein, described multipolymer comprises the segmented copolymer of ethylene oxide and propylene oxide, that is, and and poloxamer.
23. the described composition of claim 22, wherein, described multipolymer is represented by following general formula:
HO(C
2H
4O)
a(C
3H
6O)
b(C
2H
4O)
aH
Wherein, b is between 15-67, and a is between 2-130, and the unitary overall proportion of a accounts for the 20-90% of described multipolymer weight.
24. the described composition of claim 23, wherein, the molecular weight ranges of described multipolymer is about 1,000-20,000.
25. the described composition of claim 22, wherein, described multipolymer is a poloxamer 407.
26. claim 2 or 15 described compositions, wherein, described emulsifying agent is a kind of fatty acid component with polyethoxylated side chain.
27. claim 2 or 15 described compositions, wherein, described emulsifying agent is to be selected from following listed material: Laureth-4, Laureth-9, Laureth-23, PPG-26-Buteth-26/PEG-40 hydrogenated castor oil and PEG-40 hydrogenated castor oil.
28. claim 2 or 15 described compositions, wherein, described emulsifying agent accounts for the about 0.5-50% of weight of microemulsion.
29. claim 1,2,14 or 15 arbitrary described compositions, wherein, described oil is a kind of promoting agent or has the water-insoluble promoting agent and be dissolved in wherein.
30. claim 1,2,14 or 15 arbitrary described compositions, wherein, described oil is to be selected from following listed material: the fatty ester of the glyceryl ester of long-chain alcohol, lipid acid or unit alcohol.
31. the described composition of claim 30, described ester and alcohol at room temperature are liquid.
32. claim 1,2,14 or 15 arbitrary described compositions, wherein, described oil contain can be dissolved in oil phase or can with oil phase blended promoting agent.
33. claim 1,2,14 or 15 arbitrary described compositions, wherein, described oil constitutes the promoting agent of described emulsion.
34. the described composition of claim 33, wherein, described oil contain can be dissolved in oil phase or can with oil phase blended promoting agent.
35. the arbitrary described composition of claim 32-34, wherein, described promoting agent is to be selected from the group that comprises following substances: antiseptic-germicide, antiphlogiston, antihistaminic, thymoleptic, narcotic, antitumour drug, enzyme, cardiovascular drug, polynucleotide, genetic material, virus vector, immune-active agent, photographic developer, immunosuppressor, peptide and protein and their composition.
36. the described composition of claim 35, wherein said antiseptic-germicide is selected from microbiotic, anti-mycotic agent and antivirotic.
37. the arbitrary described composition of claim 32-34, wherein, described promoting agent exists with medicine effective quantity.
38. claim 1,2,14 or 15 arbitrary described compositions, wherein, described oil accounts for the about 0.1-80% of described emulsion weight.
39. claim 1,2,14 or 15 arbitrary described compositions, wherein, described oil accounts for the about 1-30% of described emulsion weight.
40. claim 1,2,14 or 15 arbitrary described compositions, wherein, described oil accounts for the about 3-15% of described emulsion weight.
41. claim 1,2,14 or 15 arbitrary described compositions, wherein, described oil accounts for described emulsion weight about 6%.
42. claim 1,2,14 or 15 arbitrary described compositions, wherein, described oily be tea tree oil.
43. the described composition of claim 42, it has fungicidal activity.
44. claim 1,2,14 or 15 arbitrary described compositions, wherein, described emulsion has bioadhesion or mucoadhesive matter.
45. claim 1,2,14 or 15 arbitrary described compositions, wherein, described emulsion is liquid or gel form.
46. the described composition of claim 45, wherein, described emulsion compositions is a gel.
47. claim 1,2,14 or 15 arbitrary described compositions, wherein, described emulsion compositions is a kind of liquid that can agglutinationization when contacting with skin or mucosal tissue.
48. claim 1,2,14 or 15 arbitrary described compositions also contain one or more pharmacology acceptable additive, vehicle, carrier or thinner.
49. claim 1,2,14 or 15 arbitrary described compositions, wherein, described composition also contains acceptable acid of one or more pharmacology or alkali.
50. claim 1,2,14 or 15 arbitrary described compositions, wherein, described composition also contains the salt of acceptable acid of one or more pharmacology or alkali.
51. claim 1,2,14 or 15 arbitrary described compositions, wherein, described composition also contains one or more pharmacology can accept enzyme inhibitors.
52. claim 1,2,14 or 15 arbitrary described compositions are used to be applied topically to the lip-deep purposes of animal cuticle.
53. claim 1,2,14 or 15 arbitrary described compositions are used for the purposes of mucosal use on esophagus, ear, vagina, rectum or the ocular surface of animal.
54. the described purposes of claim 52, wherein, described composition also comprises the reagent that can promote physical attraction or shelter the body image of imbalance or disease.
55. the described purposes of claim 54, wherein, described composition can also be treated SOM.
56. claim 1,2,14 or 15 arbitrary described compositions are used for giving the purposes of other composition thickening character.
57. the described purposes of claim 56, wherein, described composition can be given the overall viscosity of raising.
58. the described purposes of claim 56, wherein, described composition can be given the viscosity response to temperature.
59. claim 1,2,14 or 15 arbitrary described compositions are used for giving the purposes of the softening character of other composition.
60. claim 1,2,14 or 15 arbitrary described compositions on skin or other mucous membrane as the purposes of film forming biologically active agent.
61. the described purposes of claim 60, wherein, described film forming biologically active agent also serves as the blocking layer, to prevent the loss of water part from skin.
62. being used for treating being selected from, the described composition of claim 43 comprises the following disease group purposes of middle disease in groups: sexually transmitted disease (STD), HIV, pustulosis, herpes labialis, otitis media, external otitis, Cuo blister, periodontitis, gingivitis, paronychia, onychomycosis and the secondary infection that links to each other with operation, dermatitis and burn.
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| AU2003900887A AU2003900887A0 (en) | 2003-02-27 | 2003-02-27 | Poloxamer emulsion preparations |
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| CN100591721C true CN100591721C (en) | 2010-02-24 |
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| AU2009239429B2 (en) * | 2008-04-21 | 2013-08-29 | Otonomy, Inc. | Auris formulations for treating otic diseases and conditions |
| WO2010076730A1 (en) * | 2009-01-02 | 2010-07-08 | Donald, Jenny | Method for the treatment of an hiv infection |
| EA023396B1 (en) * | 2010-04-01 | 2016-05-31 | Фарманест Аб | Thermogelling anaesthetic compositions |
| PT2689774T (en) * | 2011-03-21 | 2019-04-05 | Broda Tech Co Ltd | Reversely thermo-reversible hydrogel compositions |
| ITMI20131927A1 (en) * | 2013-11-20 | 2015-05-21 | Cosmo Technologies Ltd | EMULSIONS OR MICROEMULSIONS FOR USE IN ENDOSCOPIC MUCOSAL RESECTIONING AND / OR ENDOSCOPIC SUBMUCOSAL DISSECTION. EMULSIONS OR MICROEMULSIONS FOR USE IN ENDOSCOPIC MUCOSAL RESECTION AND / OR ENDOSCOPIC SUBMUCOSAL DISSECTION |
| MY178060A (en) * | 2014-03-25 | 2020-09-30 | Genentech Inc | Methods of preparing a poloxamer for use in cell culture medium |
| US10351750B2 (en) | 2017-02-03 | 2019-07-16 | Saudi Arabian Oil Company | Drilling fluid compositions with enhanced rheology and methods of using same |
| KR101852718B1 (en) * | 2017-04-04 | 2018-05-18 | 주식회사 제네웰 | Kit for pain reduction of incision site after surgical operation |
| KR102544922B1 (en) * | 2017-12-21 | 2023-06-16 | 시그마-알드리치 컴퍼니., 엘엘씨 | Poloxamer compositions and methods of making and using the same |
| IT201900018752A1 (en) * | 2019-10-14 | 2021-04-14 | Alessandro Tosetti | COMPOSITION BASED ON ESSENTIAL OILS FOR DENTAL USE FOR THE TREATMENT OF PERIODONTITIS AND PERIMPLANT MUCOSITE |
| RU2762506C1 (en) * | 2021-01-20 | 2021-12-21 | Общество С Ограниченной Ответственностью «Диамед-Фарма» | Agent for applying oral and nasal cavities and method for its use as part of complex therapy of infectious and inflammatory diseases of nasal and oral cavities |
| CN114455621B (en) * | 2022-01-11 | 2023-10-27 | 兰州交通大学 | Preparation method of needle-shaped calcium carbonate |
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| AU4312489A (en) * | 1988-09-23 | 1990-04-18 | Cetus Corporation | Lipid microemulsions for culture media |
| JPH0791555B2 (en) * | 1989-12-22 | 1995-10-04 | 株式会社資生堂 | Cleaning composition |
| CA2185803C (en) * | 1994-03-18 | 2006-07-11 | Edward M. Rudnic | Emulsified drug delivery systems |
| ES2094688B1 (en) * | 1994-08-08 | 1997-08-01 | Cusi Lab | MANOEMULSION OF THE TYPE OF OIL IN WATER, USEFUL AS AN OPHTHALMIC VEHICLE AND PROCEDURE FOR ITS PREPARATION. |
| SE9601421D0 (en) * | 1996-04-12 | 1996-04-12 | Astra Ab | New composition |
| DE19723308A1 (en) * | 1997-06-04 | 1998-12-10 | Wolfgang A Prof Dr Wohlrab | Microemulsions useful for topical administration of e.g. local anaesthetics |
| FR2788007B1 (en) * | 1999-01-05 | 2001-02-09 | Oreal | NANOEMULSION BASED ON BLOCK COPOLYMERS OF ETHYLENE OXIDE AND PROPYLENE OXIDE, AND ITS USES IN THE COSMETIC, DERMATOLOGICAL AND / OR OPHTHALMOLOGICAL FIELDS |
| WO2000051550A1 (en) * | 1999-03-01 | 2000-09-08 | Basf Corporation | Cold processed water-in-oil emulsions |
| EP1202719B1 (en) * | 1999-06-21 | 2006-05-31 | Kuhnil Pharmaceutical Co., Ltd. | Anesthetic composition for intravenous injection comprising propofol |
| SE0000774D0 (en) * | 2000-03-08 | 2000-03-08 | Astrazeneca Ab | New formulation |
| US6623765B1 (en) * | 2000-08-01 | 2003-09-23 | University Of Florida, Research Foundation, Incorporated | Microemulsion and micelle systems for solubilizing drugs |
-
2003
- 2003-02-27 AU AU2003900887A patent/AU2003900887A0/en not_active Abandoned
-
2004
- 2004-02-20 AU AU2004215921A patent/AU2004215921A1/en not_active Abandoned
- 2004-02-20 EA EA200501368A patent/EA017434B1/en not_active IP Right Cessation
- 2004-02-20 JP JP2006501371A patent/JP2006519272A/en active Pending
- 2004-02-20 WO PCT/AU2004/000218 patent/WO2004076561A1/en active Search and Examination
- 2004-02-20 CA CA2516863A patent/CA2516863C/en not_active Expired - Fee Related
- 2004-02-20 EP EP04712958A patent/EP1597318A4/en not_active Withdrawn
- 2004-02-20 BR BRPI0408056-4A patent/BRPI0408056A/en not_active IP Right Cessation
- 2004-02-20 CN CN200480005486A patent/CN100591721C/en not_active Expired - Fee Related
-
2005
- 2005-09-22 NO NO20054395A patent/NO20054395L/en not_active Application Discontinuation
-
2009
- 2009-06-09 AU AU2009202265A patent/AU2009202265B2/en not_active Ceased
Also Published As
| Publication number | Publication date |
|---|---|
| AU2004215921A1 (en) | 2004-09-10 |
| WO2004076561A1 (en) | 2004-09-10 |
| BRPI0408056A (en) | 2006-02-14 |
| EP1597318A4 (en) | 2006-06-14 |
| AU2003900887A0 (en) | 2003-03-13 |
| EA017434B1 (en) | 2012-12-28 |
| NO20054395L (en) | 2005-09-22 |
| AU2009202265B2 (en) | 2012-02-16 |
| CN1753949A (en) | 2006-03-29 |
| CA2516863C (en) | 2011-12-06 |
| CA2516863A1 (en) | 2004-09-10 |
| EP1597318A1 (en) | 2005-11-23 |
| EA200501368A1 (en) | 2006-02-24 |
| AU2009202265A1 (en) | 2009-07-02 |
| JP2006519272A (en) | 2006-08-24 |
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