WO1994019101A1 - Method of microemulsifying fluorinated oils - Google Patents

Method of microemulsifying fluorinated oils Download PDF

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Publication number
WO1994019101A1
WO1994019101A1 PCT/US1994/001633 US9401633W WO9419101A1 WO 1994019101 A1 WO1994019101 A1 WO 1994019101A1 US 9401633 W US9401633 W US 9401633W WO 9419101 A1 WO9419101 A1 WO 9419101A1
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surfactant
fluorinated
hydrogenated
microemulsion
water
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PCT/US1994/001633
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French (fr)
Inventor
Eric William Kaler
Kai-Volker Schubert
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Alliance Pharmaceutical Corp.
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Priority to US1801393A priority Critical
Priority to US08/018,013 priority
Application filed by Alliance Pharmaceutical Corp. filed Critical Alliance Pharmaceutical Corp.
Publication of WO1994019101A1 publication Critical patent/WO1994019101A1/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0019Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0026Blood substitute; Oxygen transporting formulations; Plasma extender
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01FMIXING, e.g. DISSOLVING, EMULSIFYING, DISPERSING
    • B01F17/00Use of substances as emulsifying, wetting, dispersing or foam-producing agents
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01FMIXING, e.g. DISSOLVING, EMULSIFYING, DISPERSING
    • B01F17/00Use of substances as emulsifying, wetting, dispersing or foam-producing agents
    • B01F17/0035Organic compounds containing halogen

Abstract

A method for controlling the formation of a microemulsion of fluorinated oils and water is disclosed. In particular, the addition of mixtures of fluorinated and hydrogenated surfactant to fluorinated oil and water is used to create a fluorinated oil microemulsion. The degree of hydrophilicity of the selected hydrogenated surfactant controls the temperature at which the microemulsion forms. The amphiphilic strength of the selected hydrogenated surfactant controls the concentration of fluorinated surfactant required for microemulsification of the fluorinated oil and water. As shown in figure 4, in forming a microemulsification containing water, perfluorodecalin, zonyl FSO-100(n-alkyl polyglycol ether with a perfluorinated alkyl chain) and C12E1 (hydrogenated surfactant produced by reacting C12, alkanol with 1 mol of ethylene oxide), the addition of increased concentrations of C12E1, lowers the temperature at which the microemulsion forms. The microemulsions are useful in treating body organs and delivering medicaments.

Description

METHOD OF MICROEMULSIFYING FLUORINATED OILS

Field of the Invention The present invention relates to fluorinated oil microe ulsions. More speeαfically, the present invention relates to the use of hydrogenated surfactants used in conjunction with a fluorinated surfactant to selectively control microemulsion formation of water and perfluorinated oils.

Background of the Invention Emulsions are systems consisting of two or more phases of incompletely miscible liquids. One example of two liquids which are immiscible in one another is water and a fluorocarbon oil. An emulsion of these two liquids contains two phases: a dispersed phase consisting of one of the liquids which is broken up into globules or particles; and a continuous or external phase consisting of the other liquid surrounding the globules of the dispersed phase.

When two immiscible liquids such as a fluorocarbon or fluorinated oil and water are added together, the liquids will normally separate from one another. In the case of fluorinated oil and water, the fluorinated oil will usually settle to the bottom of the mixture because it has a higher specific gravity than that of water. Further, the immiscible character of the liquids caused by the interfacial tension between the oil and the water resists the formation of an emulsion of the two liquids.

The creation of an emulsion commonly requires the application of energy to disperse one liquid into another as well as an emulsifying agent. In order to achieve an emulsion of a fluorinated oil and water, it is necessary to employ, for example, generous mechanical agitation or heat, to disperse the oil or water into droplets. In addition, an emulsifying agent can be added to the mixture. An emulsifying agent has the property of causing a reduction in the interfacial tension between the liquids, allowing formation of a greatly enlarged interfacial area, that is, increasing the number of droplets in a volume of the continuous phase. Emulsions comprising fluorinated or perfluorinated oils and an aqueous phase (which can contain other water based substances) are of particular interest. Fluorinated liquids or oils are "especially valuable for use in the treatment of several body organs. In particular, it has been found beneficial to deliver medicaments and the like to various portions of the body using the fluorocarbon as the delivery agent. To disperse the medicament uniformly In such situations, an emulsion is formed wherein the medicament, usually a water soluble substance is in the dispersed aqueous phase, and the oily fluorocarbon oil is the continuous phase.

In cases in which medicament is delivered to a portion of the body, it is of importance that the medicament be finely and uniformly distributed throughout the fluorocarbon. Often, the dispersed phase of an emulsion consists of very large droplets or globules, because of the interfacial tension. However, as stated above, emulsifying agents can be added which reduce these tensions and which allow the dispersed liquid to be broken into finer sized particles. Such particles normally would have a diameter of 100 nm or more. However, such large particle size is not always suitable for all therapies. In these cases, it has been an object to form "microemulsions" where the domains of oil and water have a characteristic size of less than about lOOnm. Microemulsions are distinguished from emulsions in a number of ways. Characteristically, microemulsions are formed spontaneously under the appropriate conditions and are thermodynamically stable single equilibrium phases. They are thus distinguished from thermodynamically unstable two-phase emulsions which requires homogenization or other energy consuming dispersion techniques. Microemulsions, once formed, persist indefinitely in that state, while the particle size of emulsions increases with time, until the two immiscible components are again separate phases. Microemulsions are advantageous because the small particle size does not appear to provoke the particle-size dependent side effects (flu-like symptoms, fever) found in the use of emulsions. It is also likely that the small microemulsion particle size significantly increases the half- life time of the microemulsion in the blood.

It is known in the prior art that a fluorocarbon microemulsion can be prepared from a mixture of an aqueous phase, such as water, a fluorocarbon and a fluorinated amphiphile (emulsifying agent) . It is known that in this three component, or ternary system, the temperature and the percentage of emulsifying agent added to the mixture are key variables in determining whether and when a microemulsion will form. For example, it is normally the case that emulsifying agents are less efficient in emulsifying liquids when the temperature is lower, meaning that more emulsifying agent is necessary to form a microemulsion at lower temperatures than at higher temperatures. This prior art method of forming a fluorinated oil microemulsion suffers because the method does not allow for controlled microemulsion formation with respect to temperature variation. This means that the microemulsion is stable only over a limited temperature range, which range may be incompatible in medical situation uses. Further, the fluorinated amphiphile is not very efficient in achieving emulsion formation, meaning that large quantities of the agent are necessary to create the microemulsion.

It has therefore been of particular interest that a method be found by which a microemulsion of water (or water based substance such as a medicament) and a fluorinated or perfluorinated oil may be formed, wherein the temperature at which the microemulsion forms can be controlled, and whereby the efficiency of the surfactant with respect to microemulsion formation can be controlled.

Summary of the Invention In order to overcome the above stated problems and limitations, the invention provides a method for forming a microemulsion of fluorinated oil and water. In one embodiment, the method comprises adding a mixture of hydrogenated and fluorinated surfactants to fluorinated oil and an aqueous phase. Specifically, it has been found that the n-alkyl polyglycol ethers (denoted as C^) with hydrophobic portions containing i carbons and the hydrophilic parts containing j ethoxy groups, either as pure components or in commercial blends, such as the C^ compounds C12E1, C6E5, C12E4, C12E23, or a phenylalkyl polyglycol ether such as Igepal CA210, are effective hydrogenated surfactants. When such hydrogenated surfactants are added, preferably in quantities of less than 25% by weight, to systems including fluorinated oils, an aqueous phase and fluorinated surfactants, microemulsions form.

Such hydrogenated surfactants have been found useful in microemulsifying mixtures in which the fluorinated oils are 1- bromo-perfluorooctane (PFOB) , perfluorodecalin (FD) , or perfluorinated perhydrogenated phenanthrene (FPh) , and when the fluorinated surfactant is a n-alkyl polyglycol ether with a perfluorinated alkyl chain, such as those commercially available as Zonyl FSO-100 (approximately fC7-sE8) or FSN-100 (approximately fC8E10) .

In another method, a hydrogenated surfactant is added to a ternary system of fluorinated oil, an aqueous phase and fluorinated surfactant in order to control the temperature at which the microemulsion is formed. In particular, the addition of a relatively weak hydrophilic (or hydrophobic) hydrogenated surfactant to such a ternary system acts to raise (or lower) the temperature at which the microemulsion will form for a given fluorinated surfactant concentration.

Likewise, a method is described in which a strong hydrophilic hydrogenated surfactant is added to a ternary system of fluorinated oil, water and fluorinated surfactant, whereby the temperature at which the microemulsion will form is raised for a given concentration of fluorinated surfactant.

A method is also described for controlling the concentration of fluorinated surfactant which is necessary to form a microemulsion of fluorinated oil and water. In this method, a weak amphiphile is added to the ternary system in order to raise the concentration of fluorinated surfactant which is necessary to emulsify the liquids at a given temperature. A strong amphiphile is added to the ternar system in order to lower the concentration of the fluorinate surfactant necessary to emulsify the liquids.

A hydrogenated surfactant, used in cohj-unction with fluorinated surfactant and added to a system of fluorinate oil and water, affects the temperature and concentration o the fluorinated surfactant at which a microemulsion forms Therefore, the choice of a hydrogenated surfactant wit appropriate properties can favorably affect the conditions o microemulsion formation.

These and other aspects of the invention will becom apparent from a study of the following description in whic reference is directed to the following drawings.

Description of the Drawings Figure 1 is a three dimensional Gibbs diagram wit indices of oil, water, and amphiphile plotted agains temperature, illustrating a phase diagram plotted on a plan in which the oil/water ratio is 50% by volume.

Figure 2 is a planar illustration of the phase diagram o Figure 1.

Figure 3 is a graph illustrating the phase diagram fo various ternary mixtures of fluorinated oils, water an fluorinated surfactant, plotted against temperature and weigh in percent of surfactant when the water to oil ratio by volum is 50%.

Figure 4 is a graph illustrating the phase diagram for mixture of water, FD, FSO-100 at various concentrations o added C^E-L plotted against temperature and weight surfactant/weight of water plus oil, when the water/FD rati by volume is 50%.

Figure 5 is a graph which illustrates the linea relationship between the concentration by weight of adde hydrogenated surfactant C12Eα to the temperature of microemulsion formation T in a ternary mixture of water, F and FSO-100.

Figure 6 is a graph which illustrates the phase diagra for a mixture of water, FPh and FSO-100 at various concentrations of added C^E.,^ plotted against temperature and weight surfactant/weight of water plus oil, when the water/FPh ratio by volume is 50%.

Figure 7 is a graph which illustrates the phase diagram for a mixture of water, PFOB and FSO-100 at various concentrations of added C12E23 plotted against temperature and weight surfactant/weight of water plus oil when the water/PFOB ratio by volume is 50%.

Figure 8 is a graph which illustrates the phase diagram for a mixture of water, PFOB and FSO-100 at various concentrations of added C6E5 plotted against temperature and weight surfactant/weight of water plus oil when the water/PFOB ratio by volume is 50%.

Figure 9 is a graph illustrating the effect of the addition of hydrogenated surfactants having varying hydrophilic and amphiphilic characteristics upon a ternary system of water, fluorinated oil and fluorinated surfactant.

Figure 10 is a graph illustrating a vertical section through the phase prism of the pseudote nary system H20-PFOB- FSO-100-C12EX at γ = 10wt% and δ = 10wt%.

Figure 11 is a schematic diagram of the effect of added hydrogenated surfactants (C(CiEj) on the phase behavior of the system: water, perfluorinated oil and fluorinated surfactant

(FC8E8) . The "fish" of the system: water, perfluorinated oil, and fluorinated surfactant is drawn in the center. The effect of added hydrogenated surfactant on the size and location of the three phase body is shown as the dotted "fishes."

Detailed Description of the Preferred Embodiment

The discovery that the addition of a hydrogenated surfactant to a fluorinated oil/water/fluorinated surfactant system is useful in microemulsion formation was unexpected in light of microemulsion formation testing of ternary systems of fluorinated oil, water, and fluorinated surfactants, and fluorinated oil, water, and hydrogenated surfactants. In order to understand the phase behavior of a ternary system of fluorinated oil, water and a surfactant, it is helpful to examine the interaction of the elements of this system on a three dimensional Gibbs triangle. Figure illustrates a system of water (A) , oil (B) and a surfactant o amphiphile (C) as plotted vertically against temperature (T) . As illustrated, when a plane is drawn in which represents constant oil to water ratio Φ, where Φ is 50% by volum (represented by plane CDEF) , the phase diagram of th fluorocarbon oil and water components is represented by a shape. For convenience, this plane (CDEF) is illustrated i two dimensions in Figure 2. As illustrated in Figure 2, area 1 represents the desire homogeneous microemulsion phase. Area 2 represents an area i which a water in oil microemulsion phase is in equilibriu with a excess water phase, or an oil in water microemulsio phase in equilibrium with an excess oil phase. Area 3 represents a situation where both oil rich and water ric phases are in equilibrium with a microemulsion phase. Lastly, area L represents a situation where a lamellar liquid crystal is in equilibrium with either a water rich or oil rich excess phase. Point X» the point at which the phase diagram crosses itself and forms the tail which surrounds area 1, marks the point of entry into the microemulsion phase on the phase diagram. Point X thus represents a measure of the efficiency of the amphiphile used in the oil/water mixture. As illustrated in Figure 2, X is represented in part by χr the minimum amount of amphiphile required to completely microemulsify equal amounts of water and oil . As illustrated in Figure 2, X can be defined in any mixture by knowing the values of 31 and T. Figure 3 illustrates the results of tests in which a fluorinated oil, water and a fluorinated non-ionic surfactants of the type F- (CF2) i-CH2-CH2-0- (CH2-CH2-0) j-H (a non-ionic n- alkyl polyglycol ether with a perfluorinated alkyl chain, wherein the hydrophobic portion contains i carbons and the hydrophilic part contains j ethoxy groups, hereinafter noted as FCiEj) , were mixed (either as pure components or in commercial blends) . Figure 3 illustrates a phase diagram for each of three fluorinated oils tested: 1-Bromo- perfluorooctane (PFOB) , perfluorodecalin (FD) and perfluorinated perhydrogenated phenanthrene (FPh) , when the water to oil volume ratio Φ is 50%. In particular, Figure 3 illustrates the presence of a homogeneous microemulsion phase (denoted as area 1) , when the phase diagram is plotted against temperature T in degrees C on the y-axis, and against γ (the concentration by weight of the fluorinated surfactant) on the x-axis, when the fluorinated surfactant FSO-100 (brand name Zonyl FSO-100, and being approximately FC7 SE8) is used. It is noted that the phase boundaries are not horizontal as in Figure 2 because of impurities in the liquids used. It is clear from this Figure that FPh is the most hydrophobic, meaning that it is the most resistant to microemulsion formation with water, of the three fluorinated oils. This is clear because area 1 for the FPh test, which represents the homogeneous microemulsion phase of the diagram, is found at a high temperature and fluorinated surfactant concentration. In fact, X, the point which demarks the entry into the microemulsion phase occurs at T = 77.5 °C and x = 13.3%. In contrast, the fluorinated oil FD has an X at T = 70.5 °C and x = 8.3%. Lastly, PFOB has an X at T = 59.2 °C and = 4.7%.

This testing confirmed that already known: that a fluorinated surfactant will microemulsify a fluorinated oil and water, if the temperature and concentration of the surfactant are correct.

A ternary mixture of water, a fluorinated oil, and a hydrogenated surfactant or amphiphile was also tested in order to determine whether the addition of a hydrogenated surfactant is useful in forming a microemulsion of fluorinated oil and water. It was determined that hydrogenated surfactants are not useful in microemulsion formation of fluorinated oils and water. It is believed that the repulsive interaction between the fluorinated oil and the amphiphile causes this result. It is believed, therefore, that for an amphiphile to be effective, a necessarv condition is that the hydrophobic part of the molecule be soluble in the oil of interest.

Lastly, testing was done in which a hydrogenated surfactant or amphiphile was added to a ternary system of fluorinated oil, water, and fluorinated surfactant. The results were quite unexpected.

First, the ternary system of water/FD/FSO-100 which was described above was tested with the addition of various concentrations by weight (δ) of n-alkyl polyglycol ethers. Specifically, in this test, C12E1 (used here as the commercial blend Neodol 23-1) , a hydrophobic non-ionic hydrogenated surfactant was used. Figure 4 illustrates the phase diagrams for this test, plotted against temperature T in degrees C on the y-axis, and against concentration by weight γ of the fluorinated surfactant FSO-100 on the x-axis. This graph compares the phase diagrams for the situations in which no hydrogenated surfactant was added to the system, or in other words, where the system is purely a ternary system of water/FD/FSO-100 such as that tested above, versus situations in which hydrogenated surfactant was added to the system. As illustrated in Figure 4, as the concentration by weight δ of the hydrogenated surfactant C12E1 added to the system increases, X, or the microemulsion formation point occurs at a lower temperatures. At the same time, however, the efficiency of the surfactant remains nearly constant, meaning that more fluorinated surfactant is not necessary for microemulsion formation, even when the temperature is lower. This is illustrated by the fact that X occurs at a nearly constant value of γ. It is also clear that the addition of the hydrogenated surfactant has the effect of lowering the temperature at which the microemulsion forms, as is illustrated by the point X for δ=0% and δ=3%. In fact, as illustrated in Figure 5, the addition of

Figure imgf000011_0001
to this ternary system causes an almost linear drop in the temperature T at which X occurs. Figure 6 illustrates that the addition of the same hydrogenated surfactant, C12E1, to a ternary system of water/FPh/FSO-100 where the oil/water ratio Φ by volume is 50%, has the same effect as upon the water/FD/FSO-100 system. Clearly, the addition of the hydrogenated surfactant has the effect of lowering the temperature T at which the microemulsion forms, as well as allowing sut-h formation at this lower temperature without requiring the addition of fluorinated surfactant. Thus, the addition of the hydrogenated surfactant to the fluorinated surfactant caused the efficiency of the fluorinated surfactant to increase.

Next, the ternary system of water/FD/FSO-100 was tested with the addition of the hydrogenated surfactant C12E23, which is hydrophilic. Figure 7 illustrates phase diagrams for various concentrations by weight δ of C12E23 when plotted against temperature T and concentration γ by weight of fluorinated surfactant. As can be seen in Figure 7, the addition of the hydrophilic hydrogenated surfactant caused the temperature at which the microemulsion was formed to increase. This fact is illustrated by the movement of X to X' with the addition of the hydrophilic hydrogenated surfactant.

The ternary system of water/PFOB/FSO-100 was tested with the addition of a weak amphiphile, C6E5. As illustrated in Figure 8, the addition of a 10% concentration by weight δ of C6EB caused the location of the microemulsion phase (designated as area 1) to form at a lower temperature T. This is clear because the point of homogeneous microemulsion formation moved from X to X' ■ Further, the concentration x of fluorinated surfactant which was necessary to form the microemulsion also increased from X to X' • In other words, variation in the amphiphilic strength of the hydrogenated surfactant caused the microemulsion formation point to move as well. In this case, where the amphiphilic strength of the hydrogenated surfactant was weak, the efficiency of the fluorinated surfactant was lessened.

Testing was also conducted on a ternary system of water, PFOB and FSN-100 by adding the hydrogenated surfactant Igepal CA210 (a phenylalkyl polyglycol ether) . In this system, only a small amount of water was present. It was determined that when 25% by weight of Igepal CA210 was added, microemulsions were found when the water content increased to over 30% by volume.

The hydrophobic nonionic surfactant C^E-,^ clearly influences the phase behavior of the ternary systems: water- perfluorinated oil-fluorinated surfactant such that microemulsion formation moves to lower temperatures. The hydrophilicity of the added fourth component (the hydrogenated surfactant) is an important lever with which to move the phase behavior with respect to temperature. In addition, variation of the amphiphilic strength of the hydrogenated surfactant is expected to change the concentration δ, and experiments confirm this. When a less efficient amphiphile, C6E5, is added to the fluorinated mixtures with δ = 10wt%, microemulsion formation occurs at higher surfactant concentrations and the three phase body is located at a slightly higher temperature.

From the above testing and observation, there is believed to be an empirical rule that in a ternary system of fluorinated or perfluorinated oil, water and a fluorinated surfactant, that the temperature T at which X will occur for a given mixture will remain constant if, for each change of i in the hydrogenated surfactant formula Ej, j is changed by 2. Therefore, the addition of hC12H6 or hC10E5 to a ternary system of fluorinated oil/water/fluorinated surfactant will cause the temperature T at which X occurs to remain nearly constant. It is noted, however, that in fluorinated mixtures, a fluorocarbon chain of about 8 carbons has a hydrogenated analog of about 12 carbon atoms. Further, the hydrophilic E.j groups are influenced by the electron withdrawing group R£. Because of these two factors, it is believed that FC^ corresponds to hC(15i)E(j.3) . For example, FC8E8 and hC12E5, when added to a the ternary system of water and PFOB, should result in a similar X-

Further, the efficiency of the fluorinated amphiphile will almost certainly increase by adding a longer chain hydrogenated surfactant, such as C14E;) or C16E3. In such cases, X will move to a lower value of γ. Similarly, the efficiency of the fluorinated amphiphile will decrease by adding a weaker hydrogenated amphiphile. for example, X will be at a higher value of γ when hC10E5 is added to the same ternary, system as hC12E6.

In summary, the addition of hydrogenated surfactants to systems containing water, fluorinated or perfluorinated oils and a fluorinated surfactant leads to microemulsion formation. Preferably, the amount of hydrogenated surfactant added is less than 25% by weight of the mixture. Most preferably, the weight ratio of hydrogenated to fluorinated surfactant is no greater than 25%. As illustrated in Figure 9, changing the hydrophilicity of the hydrogenated surfactant moves the phase body on the temperature scale while the concentration γ of the surfactant remains constant. In such a situation, choice of the hydrogenated surfactant with respect to its hydrophilicity allows specific selection of the temperature at which the microemulsion will forms. Such a situation is illustrated by the phase graphs listed as T, T' and T' ' in Figure 9. In this Figure, T represents a situation where no hydrogenated surfactant has been added. T' represents the phase diagram where a hydrophilic hydrogenated surfactant has been added, and T' ' represents the phase diagram where a less hydrophilic (or a "hydrophobic" substance) hydrogenated surfactant has been added.

Varying the amphiphilic strength of the hydrogenated surfactant moves the phase body on the surfactant concentration γ scale while the temperature at which the microemulsion forms remains constant. In this case, changing the amphiphilic strength of the hydrogenated surfactant allows selection of the concentration of efficiency of the fluorinated surfactant need for microemulsion formation.

Such a situation is illustrated by the phase graphs listed as γ, γ' and γ' ' in Figure 9. In this Figure, γ represents the phase diagram when no hydrogenated surfactant has been added, γ' represents the phase diagram where a strong amphiphilic hydrogenated surfactant has been added, and γ" represents the phase diagram where a weak amphiphilic hydrogenated surfactant has been added. It is clear from Figure 9 that proper choice of hydrogenated surfactant allows the control and identification of the temperature and fluorinated surfactant concentration at which a microemulsion of a fluorinated oil and water will occur.

Although this invention has been described in terms of certain preferred embodiments, other embodiments that are apparent to those of ordinary skill in the art are also within the scope of this invention. Accordingly, the scope of the invention is intended to be defined only by reference to the following claims.

Claims

WE CLAIM :
1. A method for forming a fluorinated oil microemulsion, comprising the steps of: combining a fluorinated oil, an aqueous phase, at, fluorinated surfactant and a hydrogenated surfactant in such a manner that a microemulsion forms.
2. A method as claimed in Claim 1, wherein the microemulsion is formed by combining a mixture of the fluorinated and hydrogenated surfactants with a mixture of the fluorinated oil and the aqueous phase.
3. A method as claimed in Claim 1, wherein the microemulsion is formed by adding the hydrogenated surfactant to a mixture of the fluorinated oil, the aqueous phase, and the fluorinated surfactant.
4. A method as claimed in any one of Claims 1, 2, or 3, wherein the microemulsion comprises no more than 25% (w/w) of the hydrogenated surfactant.
5. A method as claimed in any one of Claims 1-4 where the weight ration of hydrogenated surfactant to fluorinated surfactant comprises no more than 25%.
6. A method as claimed in any one of Claims 1-5, wherein the hydrogenated surfactant is selected from a group consisting of an n-alkyl polyglycol ether and a phenylalkyl polyglycol ether.
7. A method as claimed in any one of Claims 1-5 wherein the hydrogenated surfactant is selected from the group consisting of C12E1# C6E5, C12E4, C12E23.
8. A method as claimed in any one of Claims 1-6 wherein the fluorinated surfactant comprises an n-alkyl polyglycol ether having a perfluorinated alkyl chain.
9. A method as claimed in Claim 8, wherein the fluorinated surfactant comprises a n-alkyl polyglycol ether with a perfluorinated alkyl chain.
10. A method as claimed in Claim 8, wherein the fluorinated surfactant is selected from the group consisting of FSO-100 and FSN-100.
11. A method as claimed in Claim 8, wherein the fluorinated oil is selected from the group consisting of 1- bromo-perfluorooctane, perfluorodecalin, or perfluorinated perhydrogenated phenanthrene.
12. A metf-hod as claimed in any one of Claims 1-5, wherein the hydrogenated surfactant is hydrophilic.
13. A method as claimed in any one of Claims 1-5, wherein the hydrogenated surfactant is hydrophobic.
14. A method as claimed in any one of Claims 1-5, wherein the hydrogenated surfactant is amphiphilic.
15. A microemulsion, comprising an aqueous phase, a fluorinated oil, a fluorinated surfactant and a hydrogenated surfactant.
16. A microemulsion as claimed in Claim 15, wherein the hydrogenated surfactant is selected from a group consisting of a n-alkyl polyglycol ether and a phenylalkyl polyglycol ether.
17. A microemulsion as claimed in Claim 15, wherein the hydrogenated surfactant is selected from the group consisting of C12Elf C6E5, C12E4, C12E23, and Igepal CA210.
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