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  Method of making perfluorocarbon emulsions with non-fluorinated surfactantsUSPTO Application #: 20060193799Title: Method of making perfluorocarbon emulsions with non-fluorinated surfactants Abstract: The present invention provides a method of making a FC emulsion. The method comprises mixing an FC immiscible hydrophilic liquid and a solid emulsifying agent by agitation at a temperature elevated above the phase transition temperature of the emulsifying agent and below the boiling temperature of the FC immiscible hydrophilic liquid, and adding FC to the mixture of step (a) and agitating at the elevated temperature to disperse droplets of FC in the FC immiscible hydrophilic liquid to form the FC emulsion. The invention also provides another method of making an FC emulsion, which does not require a solid emulsifying agent. The method comprises mixing an FC immiscible hydrophilic liquid and an emulsifying agent to form a first mixture; mixing a stabilizing agent with the first mixture to form a second mixture; and mixing FC with the second mixture to form a third mixture to disperse droplets of FC in the FC immiscible hydrophilic liquid and to form the FC emulsion, wherein the stabilizing agent reduces ability of the droplets to move within a continuous phase of the FC emulsion. (end of abstract) Agent: Therox, Inc. - Irvine, CA, US Inventors: Jeffrey L. Creech, Li-Chien Hsu, Margaret A. Kivinski, Paul J. Zalesky USPTO Applicaton #: 20060193799 - Class: 424059000 (USPTO) Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Topical Sun Or Radiation Screening, Or Tanning Preparations The Patent Description & Claims data below is from USPTO Patent Application 20060193799. Brief Patent Description - Full Patent Description - Patent Application Claims
CROSS-REFERENCE TO THE RELATED APPLICATIONS [0001] This application is a divisional of U.S. patent application Ser. No. 10/253,572, filed Sep. 24, 2002, which is incorporated herein by reference. FIELD OF THE INVENTION [0002] The invention relates generally to stable emulsions capable of gas-supersaturation, and methods of their preparation and use. Specifically, the present invention relates to stable fluorocarbon emulsions prepared with non-fluorinated emulsifying and stabilizing agents and methods of their preparation utilizing conventional mixing equipment. BACKGROUND OF THE INVENTION [0003] Fluorocarbons (fluorine substituted hydrocarbons) and perfluorocarbons (fluorocarbons in which all of the hydrogen atoms have been replaced with fluorine) have numerous applications in the biomedical field because of their unique chemical and biological properties. These compounds are clear, colorless, odorless, nonflammable, biocompatible, and have low reactivity. In addition, they are capable of having dissolved in them large amounts of gases, including oxygen, carbon dioxide, and air, per unit volume (WO 96/40057). Accordingly, fluorocarbons (FCs) and perfluorocarbons (PFCs) have been successfully used as carriers in applications wherein oxygen must be supplied to organs and tissues. [0004] For example, it has been demonstrated that liquid ventilation with PFCs quickly and efficiently returns arterial oxygen and carbon dioxide blood gas pressures to normal physiological values in premature lambs suffering from respiratory distress syndrome (H.-J. Lehmler et al., Chemtech, 1999, v. 29, No. 10, 7-12). Aqueous emulsions of PFCs have been explored as artificial blood substitutes or as perfusion fluids for the preservation of internal organs to be transplanted (GB 1,549,038). Some FC blood substitutes, such as FLUOSOL.RTM. (Green Cross Corporation, Osaka, Japan) and OXYGENT.RTM. (Alliance Pharmaceutical Corp., San Diego, Calif.) have been clinically evaluated. A synthetic cerebrospinal fluid comprising an oxygenated FC emulsion has been used to deliver oxygen to ischemic neurologic tissue (U.S. Pat. No. 4,758,431). [0005] Compositions of FCs may also be used for the treatment of wounds, for example, burns, as described in U.S. Pat. No. 4,366,169. The patent teaches contacting a wound with a liquid fluorocarbon directly, or indirectly through a dressing, such as a sponge, gauze, foam, dispersion or gel. Recently, the application of FC emulsions in cosmetics and dermatology has been suggested. It is believed that by delivering oxygen into the skin, FC emulsions may improve skin metabolism, impede skin aging, and protect skin from injurious environmental effects (Oxynoid, O. E. et al., Art. Cells, Blood Subs., and Immob. Biotech., 1994, 22(4), 1331-1336). [0006] Fluorocarbons are extremely hydrophobic and are not miscible with most organic or aqueous systems. Therefore, typically, FCs and PFCs are used in the forms of aqueous emulsions, dispersions, and gels. The stability of the FC emulsions, dispersions, and gels is a key concern in their biomedical use (U.S. Pat. No. 6,113,919). [0007] The dispersed phase of fluorocarbon emulsions must have a stable particle size to be suitable for biomedical use. One of the shortcomings of existing emulsions is their low stability. The particle size of a commercially available fluorocarbon emulsion, such as FLUOSOL, for example, can be maintained only if it is transported and stored in a frozen state. The frozen emulsion is then defrosted and mixed with annex solutions before use. These storage requirements seriously limit the field of application of such fluorocarbon emulsions. Although more stable fluorocarbon emulsions are being developed, it is desirable to have fluorocarbon emulsions that are stable enough to store for long periods without refrigeration and in various packaging configurations for such applications, such as topical, spray, ointment, etc. [0008] Fluorocarbons are oily substances that are immiscible with water, and therefore, fluorocarbon-in-water emulsions are generally prepared by using emulsifying agents, such as lecithins and/or poloxamers, such as Pluronic-F-68, to disperse the fluorocarbon and stabilize the emulsion. However, most conventional emulsifying agents have a low affinity for fluorocarbons. [0009] Several strategies in preparing stable FC emulsions have been explored by researchers. One approach involves dispersing very small FC droplets, less than 0.3 .mu.m, preferably 20-200 nm in diameter, in a continuous phase. This approach is particularly advantageous in blood substitute applications because emulsions with larger droplet sizes can be dangerous in intravenous use (GB 1,549,038; U.S. Pat. No. 4,865, 836). However, since the gas dissolved in a larger droplet may be released over a more extended period of time, stable emulsions comprising larger FC droplets are desirable to achieve a maximum therapeutic effect in topical applications. [0010] A surfactant (or emulsifying agent) may be used to stabilize the dispersed droplets through the electrostatic and steric repulsion of the surfactant molecules that surround each dispersed PFC or FC droplet. For example, U.S. Pat. Nos. 4,569,784 and 4,879,062 describe a stable gel of FC comprising up to 10% (wt/wt) emulsifier. The FC gel is prepared by a multi-step procedure comprising preparing an FC emulsion, concentrating the FC emulsion by a high-speed centrifugation, and removing excess fluid by a separation process. In this method, the type and the quantity of the surfactant used is not crucial, as long as it provides effective emulsification. However, this method involves a complex multi-step procedure and requires high pressure homogenization or sonically-induced cavitations to effectively disperse fluorocarbons in water. [0011] Another approach to improving the stability of fluorocarbon emulsions is to develop more effective surfactants, for example, those which are fluorophilic. Fluorinated surfactants have been shown to improve the stability of FC emulsions (U.S. Pat. No. 6,113,919) However, this class of surfactants has also been shown to have a negative environmental impact that led to the withdrawal of some previously commercially available fluorinated surfactants. [0012] U.S. Pat. Nos. 5,573,757 and 6,113,919 focus on the further improvement of the available surfactant systems. A stable FC emulsion is prepared by utilizing a combination of a surfactant and a fluorophilic/lipophylic compound, which act together in association to stabilize the emulsion by surrounding the dispersed droplets and preventing their coalescence. However, the environmental concerns associated with such fluorinated compounds have greatly limited their use and availability in recent years. [0013] Another strategy is to prepare microemulsions, i.e., preparations of compounds which organize themselves spontaneously into dispersed systems (U.S. Pat. No. 3,778,381; FR A 2 515 198). Microemulsions, while stable thermodynamically, require a substantial amount of surfactants in their formulations, which may lead to bioincompatibiltiy for medical applications. In an example of a microemulsion described by Cecutti et al., Eur. J. Med. Chem., 24, 485-492 (1989), the dispersed phase is itself totally constituted of mixed hydrocarbon/fluorocarbon molecules. Thermodynamically stable microemulsions, when broken, can be restored by a mild agitation. U.S. Pat. No. 4,722,904 teaches a PFC microemulsion comprising a system of two surfactants, the primary surfactant being non-ionic and water-soluble, and the secondary surfactant being hydrotropic and present in an amount sufficient to disorder any water-primary surfactant gels. However, it is not clear whether such microemulsions are suitable for biomedical and cosmetic applications. So far, PFC microemulsions have been used only as reference liquid for the calibration and/or quality control of blood gas analyzers (U.S. Pat. Nos. 4,151,108 and 4,722,904) and their safety for intravenous use has been questioned (U.S. Pat. No. 6,113,919). [0014] U.S. Pat. No. 5,637,318 describes a dermatological agent containing an emulsion of asymmetrical lamellar aggregates comprising FC surrounded by at least three layers of phospholipid molecules. The dermatological agent is prepared using an ultrasonic disintegrator and the stability of the emulsion is achieved by limiting the size of the lamellar aggregates to 50-1000 nm, with a mean diameter of 244 nm. [0015] Therefore, a number of conventional FC emulsions, dispersions, and gels are prepared by multi-step complex methods that utilize a high-pressure apparatus or ultrasound to form an emulsion and require further concentration by centrifugation. Other FC emulsions are stabilized with fluorinated surfactants that cause certain environmental concerns or by forming microemulsions that have not been used in biomedical applications to date. Still another group of FC emulsions limit the size of the FC droplets and do not provide an optimal therapeutic effect in topical applications. SUMMARY OF THE INVENTION [0016] In view of the above-noted shortcomings of the conventional FC emulsions and methods of their preparation, it is an object of the present invention to provide stable FC emulsions using non-fluorinated emulsifying agents. It is also an object of the present invention to provide simple and low energy methods for preparing stable FC emulsions and gels by utilizing conventional mixing equipment. It is a further object of the present invention to provide methods that allow the preparation of stable FC emulsions with a broad range of FC droplet sizes. [0017] These and other objects are achieved in the present invention by using a stabilizing agent that reduces the ability of the FC droplets to move within the continuous phase. Conventionally, the FC emulsions are stabilized either by decreasing the size of the dispersed FC droplets and/or by selecting a surfactant that surrounds the fluorocarbon droplets reducing interfacial surface tension and causing electrostatic and steric repulsion between the droplets, inhibiting their coalescence. The present invention, on the other hand, stabilizes the FC emulsion by further decreasing the ability of the dispersed FC droplets to move within the continuous phase. This result is achieved by several means including using a stabilizing agent to alter the physical properties of the continuous phase, an emulsifying agent, and a method of making the emulsion that result in a highly stabilized fluorocarbon emulsion. [0018] Accordingly, one aspect of the present invention is directed to a fluorocarbon (FC) emulsion, comprising: [0019] a continuous FC immiscible hydrophilic liquid phase; and [0020] a dispersed phase comprising FC suspended as droplets within the continuous phase; Continue reading... Full patent description for Method of making perfluorocarbon emulsions with non-fluorinated surfactants Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Method of making perfluorocarbon emulsions with non-fluorinated surfactants patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. 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