REVERSE GELS COMPRISING A CONTINUOUS FLUORINATED PHASE

Abstract: Fluorinated reverse gel compositions incorporating nonfluorinated surfactants are disclosed. The compositions, comprising a continuous fluorinated phase and a disperse aqueous phase, are formed by combining a nonfluorinated surfactant with at least one highly fluorinated organic compound and at least one partially fluorinated and partially hydrogenated organic compound. This fluorinated dispersion is then combined with an aqueous solution to provide a reverse gel that may be used for wound treatment, lubrication, or the delivery of active principles.

Description: REVERSE GELS COMPRISING A CONTINUOUS FLUORINATED PHASE Field of the Invention The present invention is directed to reverse fluorocarbon gels for the transport of pharmaceutical compounds and other active principles. Background of the Invention Highly fluorinated or perfluorinated compounds are known for being chemically and biologically inert as well as their ability to dissolve respiratory gases (Riess J.G. in Fluorine in Medicine, R.E. Banks, K.C. Lowe (eds), Rapra Technol. Ltd., Shawbury, U.K. 1994). Due to this gas-carrying ability, f luorocarbons have proved to be useful in the biomedical field in a pure form or as components of emulsions. In the form of direct emulsions (oil-in-water), fiuorocarbons can be used as temporary blood substitutes in perioperative hemodilution, treatment of cardiac or cerebral ischemia, as adjuvant in the treatment of cancer, or as oxygenating fluid for the preservation of organs. (Riess J.G. in "Fiuorocarbon-based in vivo oxygen Transport and Delivery Systems), Vox Sanguinis, 61, 225 (1991). In pure or "neat" form, fiuorocarbons are presently being tested clinically for the treatment of the respiratory distress syndrome (Liquivent®, Alliance Pharm. Corp. San Diego, USA, T.H. Shaffer and col. in ISBS, Biomat., Art. Cells Immob. Biotech., 24, 1994, and in Pediatric Pulmoπology, 14, 102 (1992)). Fluorocarbon emulsions for the transport of oxygen and of active principles in cosmetics and dermatology have been described in WO 94/00098. At low concentrations (about 0.1 to 50% v/v) some of these emulsions may be incorporated in relatively low viscosity gels. The use of fiuorocarbons in the form of emulsions or of direct gels i.e. in which the continuous phase is water, has also been described. These formulations of fluorocarbon gels require the use of a gelifying agent and a stabilizing agent. Thus, US Pat. No. 5,073,378 describes direct gels for use in the treatment of burns. The disclosed gels, wherein the continuous phase is water, comprise solutions of collagen containing a growth factor and a small quantity of fluorocarbon. US Pat. No. 4,569,784 describes a stable fluorocarbon gel comprising, at most, 50% by volume of fluorocarbon. A considerable quantity of surfactant must be incorporated in the formulations in order to stabilize the resulting gei. The disclosed gels are prepared by a complex procedure involving a step in which an emulsion is concentrated by centrifugation. The document FR-A-2 630 347 describes direct gels of fiuorocarbons comprising a very high proportion of water (60 to 98% in volume). As a consequence the quantity of fluorocarbon is low. Other direct gels comprising an aqueous continuous phase and highly concentrated in fluorocarbon are known. Examples include the gels described in the Patent application FR-A-2 710 840. These gels are formed of polyaphrons of fluorocarbon surrounded by the aqueous continuous phase and, accordingly, could not permit the controlled release of hydrosoluble active principles. Direct gels were also disclosed in Applicants' co-pending U.S. patent application 08/483,946. This application discloses the use of lipophiHc/fluorophilic compounds to form stable dispersions which may advantageously be used for drug delivery. Reverse gels, those with an aqueous discontinuous phase, formed from phospholipids and from a hydrogenated oil, such as the isopropyl palmitate, have been described by Scartazzini et al (J. Phys. Chem. 1988, 92, 829). These reverse gels (or organogels) were studied by Willimann et al (J. Pharm. Sci., 1992, 81, 871) as matrixes for the transdermal transport of medicaments (scopolamine, broxaterol), of a inated acids and of peptides, and can also be used as medium for enzymatic reactions. However, these reverse gels do not contain any fiuorocarbons. Reverse gels containing fluorocarbon as the continuous phase and water as the discontinuous or internal phase have been described in the literature (Ravey JC et al, Prog, colloid polym. Sci., Vol. 82, p. 218-28, 1990) but these gels are limited to a maximum fluorocarbon concentration of 50% v/v. Moreover, the disclosed gels contain a fluorinated surfactant of the polyoxyethylene type. Conversely, there does not appear to be any mention of the use of fluorocarbon reverse gels comprising phospholipids or other nonfluorinated surfactants. The very low solubility of such surfactants in fiuorocarbons would tend to lead those skilled in the art to believe that they could not be used to form stabilized gel systems comprising a fluorocarbon continuous phase. Accordingly, there remains a need for reverse gels comprising high concentrations of at least one fluorinated compound and a biocompatible surfactant wherein the gels are capable of dissolving and transporting large amounts of oxygen and/or active principles. In such compositions the oxygen would primarily be carried in the fluorocarbon continuous phase while the active principle or pharmaceutical compound would preferably be carried in the aqueous dispersed phase although it may be distributed among the two phases. There also remains a need to have a well defined gel transport system capable of carrying both hydrophilic and lipophilic active principles and pharmaceutical compounds. Summary of the Invention These and other objects are achieved by the gel compositions and methods of the present invention which provide reverse fluorochemical gels capable of carrying physiologically significant amounts of oxygen and hydrophilic or lipophilic active principles. Surprisingly- it was found that such reverse gels could be formed by combining relatively high concentrations of fluorocarbon with nonfluorinated surfactants such as phospholipids. Through the use of HC/FC compounds the nonfluorinated surfactants act to form generally homogeneous dispersions. This novel use of such surfactants unexpectedly provides for the formation of stable gel systems having effective transport and delivery capabilities for physiological gases and active principles such as pharmaceutical compounds. In a broad aspect the fluorinated reverse gels disclosed herein comprise an aqueous phase dispersed in a continuous fluorinated phase. Preferably, the continuous fluorinated phase comprises a mixture of a highly fluorinated organic compound and at least one partially fluorinated and partially hydrogenated (HC/FC) organic compound. An effective dispersing amount of at least one nonfluorinated surfactant maintains the stability of the gel. Selected embodiments of the invention may further comprise additives, including active principles, incorporated within the fluorinated reverse gel. Additives may be distributed in the disperse aqueous phase, the continuous fluorinated phase or dispersed throughout the entire gel. Accordingly, one aspect of the present invention comprises fluorinated reverse gels comprising: a continuous phase comprising at least one highly fluorinated organic compound and at least one partially fluorinated and partially hydrogenated (HC/FC) organic compound; a dispersed aqueous phase; and an effective dispersing amount of at least one nonfluorinated surfactant wherein said dispersed aqueous phase comprises less than about 50% v/v of said reverse gel. In the gels of the present invention the concentration of the continuous fluorinated phase may comprise from about 50% v/v to about 99.9% v/v depending on the characteristics desired. Preferably the concentration of the continuous phase will comprise more than about 60% v/v and even more preferably greater than 70% v/v. For many applications continuous phase concentrations of greater than about 75% v/v or about 80% v/v will be desired. For other applications, particularly those that are topical in nature, gels having continuous phase concentrations greater than about 85% v/v or about 90% v/v will be preferred. Within the continuous phase the concentration of the highly fluorinated organic compound may vary from about 0.01% v/v to about 99.9% v/v depending on the properties desired. It will be therefore be appreciated that the viscosity of the instantly disclosed fluorinated reverse gels may be selected to enhance the uptake of any incorporated active principles or prolong retention at the site of application. Gel components and concentrations may be altered to provide a composition having the desired viscosity. For example, the final concentration of the disperse aqueous phase may be increased to yield a relatively less viscous gel. Similarly, altering the procedure used to form the gel, i.e. varying the power or duration of sonication, can produce dispersions of different consistencies. However, in each case the gels of the present invention exhibit a remarkable stability due to the advantageous properties of the nonfluorinated surfactants. Thus, other embodiments of the present invention include methods for forming a fluorinated reverse gel comprising the steps of: combining at least one partially fluorinated and partially hydrogenated (HC/FC) organic compound with an effective dispersing amount of at least one nonfluorinated surfactant and at least one highly fluorinated organic compound to provide a dispersion preparation; and admixing said dispersion preparation with an aqueous solution to provide a fluorinated reverse gel comprising a disperse aqueous phase of less than about 50% v/v. Those skilled in the art will appreciate that different techniques may be employed within the broad scope of the present invention to actually form the desired reverse gel. For example, the admixing or dispersing step may be accomplished through sonication, mechanical convection or other conventional means. Similarly, the order in which the components are combined is not critical and may be adjusted for ease of production or cost considerations. In this respect a particularly preferred embodiment of the present invention is directed to methods for the preparation of a fluorinated reverse gels comprising the steps of: combining a nonfluorinated surfactant with at least one partially fluorinated and partially hydrogenated (HC/FC) organic compound to obtain a homogeneous mixture; dispersing said homogeneous mixture in at least one highly fluorinated organic compound to provide a dispersion preparation; and adding said dispersion preparation to an aqueous solution to provide a fluorinated reverse gel comprising a dispersed aqueous phase of less than about 50% v\v. It will be appreciated that the gels of the present invention may be used in combination with various additives, including active principles, or by themselves. Preferably, the reverse gels of the present invention are used in connection with the biomedical field, in particular for transdermal transport of active principles such as therapeutic or diagnostic agents. In other cases the gels may be used, with or without additives, as protective creams, for lubrication, in cosmetics, or to create a deposit effect, for example subcutaneous or in a cavity of the body. Particularly preferred routes of administration include ocular, oral, topical, vaginal and rectal as well as parenteral. Accordingly, in another aspect the present invention provides a method for delivering an active principle to a patient comprising: providing fluorinated reverse gel comprising a disperse aqueous phase; a continuous fluorocarbon phase comprising at least one partially fluorinated and partially hydrogenated (HC/FC) organic compound and at least one highly fluorinated organic compound; an effective dispersing amount of at least one nonfluorinated surfactant; at least one active principle; and administering said fluorinated reverse gel to a patient. Other objects, features and advantages of the present invention will be apparent to those skilled in the art from a consideration of the following detailed description of preferred exemplary embodiments thereof. Detailed Description of the Invention While the present invention may be embodied in many different forms, disclosed herein are specific illustrative embodiments thereof that exemplify the principles of the invention. It should be emphasized that the present invention is not limited to the specific embodiments illustrated. The disclosed invention comprises- reverse gels of the water-in-fluorocarboπ type. These gels tend to comprise aqueous microdo ains dispersed in a relatively large proportion of fluorocarbon and, in preferred embodiments, may be used for the transport and delivery of therapeutic or diagnostic agents. The continuous phase composed of fluorocarbon is characterized by its ability to dissolve physiological gases such as nitric oxide or oxygen, its generally soothing effect on tissue and its relative impermeability towards non-fluorinated substances. These properties give the reverse gels of the present invention the important ability to diminish the rate of release of encapsulated hydrophilic drugs. Accordingly, the reverse gels of the present invention are particularly advantageous for the delivery of medicaments by the transdermal route. They may also be used to protect the epidermis and enhance the treatment of wounds and burns. In this respect they may be used to reduce the risk of the developing bedsores. In addition, the disclosed gels are also suitable for subcutaneous use and as a drug depot in the natural cavities of the body where they provide for deposit and of progressive release of an active principle. As previously indicated the water-in-fiuorocarbon reverse gels are relatively stable over time and can be sterilized thermally. In a broad aspect the present invention provides fluorinated reverse gels comprising: a continuous phase comprising at least one highly fluorinated organic compound and at least one partially fluorinated and partially hydrogenated (HC/FC) organic compound; a dispersed aqueous phase; and an effective dispersing amount of at least one nonfluorinated surfactant wherein said dispersed aqueous phase comprises less than about 50% v/v of said reverse gel. As used herein the term gel indicates a preparation having a viscosity greater than the respective viscosities of the individual fluorocarbon and water phases. The term reverse gel designates a viscoelastic and homogeneous dispersion of a minor aqueous phase in a fluorinated continuous phase. The reverse character of these gels i.e. the presence of a continuous fluorinated phase is demonstrated by the fact that it is easy to dilute them in a fluorocarbon and not in an aqueous solution. According to the invention, the gel can also comprise one or more additives chosen from among cosurfactants, active principles, mineral salts, amino acids, buffering agents, oncotic agents, osmotic agents, organic solvents, physiological gases, dispersing agents, polymers, absorption enhancers (agents susceptible of augmenting percutaneous absorption), i munoactive principles, nutritive agents, stabilizers, and other compounds capable of improving the characteristics, stability, efficacy and tolerance of the reverse gels. As used herein, the term "active principles" is held to mean any bioactive agent, including therapeutic or diagnostic agent, that may be used to treat a condition or disease. Those skilled in the art will appreciate that these additives may be dispersed throughout the aqueous phase, the fluorinated continuous phase, in each of the two phases or in the surfactant film. Thus, the aqueous phase can contain one or several hydrosoluble additives and, in particular, active principles. Conversely, the fluorinated continuous phase may be used to transport, in a dissolved or dispersed form, a relatively hydrophobic or fiuorophilic active principle. The surfactant film between the phases can also contribute to the transport of active principles. Solvents and other organic derivatives such as, for example, ethanol, N-methylpyrrolidone, dimethylsulfoxide or ethyldecylsulfoxide, or laurocapranne, can be added to facilitate the penetration of the active principles into the dermis. In preferred embodiments these absorption enhancers are miscible with the aqueous phase and are dispersed in conjunction with it when the gels are formed. Such absorption enhancers can markedly increase the uptake of therapeutic or diagnostic compounds thereby lowering the effective dose. The highly fluorinated organic compounds comprising a portion of the fluorinated continuous phase in the disclosed preparations are typically chosen for their low toxicity, gas dissolving capacity, surface tension and spreading coefficient. Particularly preferred fluorochemicals will be capable of delivering therapeutically significant amouπts of gases including nitric oxide or oxygen. Such compounds may make up to 99.9% v/v of the fluorinated continuous phase. In general, the highly fluorinated or perfluorinated organic compounds may be linear, branched or cyclic, saturated or unsaturated fluorinated compounds. Conventional structural derivatives of these fluorochemicals are also contemplated as being within the scope of the present invention as well. In addition, these totally or partially fluorinated compounds may contain one or more hetero-atoms such as 0, S or N and/or atoms of bromine or chlorine. As used herein the term "highly fluorinated" indicates that at least 30% of the hydrogen atoms in the hydrocarbon oil or derivative thereof have been replaced with fluorine atoms. Preferably, these fluorochemicals comprise from 2 to 16 carbon atoms and include, but are not limited to, linear, cyclic or polycyclic perfluoroalkanes, bis(perfluoroalkyl)alkenes, perfluoroethers, perfiuoroamines, perfluoroalkyl bromides, perfluoroalkyl chlorides and mixtures thereof. in particularly preferred embodiments the fluorocarbon is preferably perfluorooctyl bromide, perfluorooctylethane, the perfluoropolyethers fabricated by Ausi ont (Centra Recerche e Sviluppo, BOLLATE, Italy) and APF-brand fiuorocarbons fabricated by Air Products and Chemicals, Inc. (Allentown, PA). Other preferred fluorochemicals include perf luoroctane C,F 18 , perf luorodecane C^F^, perfluorodecyl bromide C 10 F 21 Br (PFDB), bis (perfluorobutyl) ethene (F-44E) or perfluorodecalin (FDC). In addition to the aforementioned compounds, exemplary fluorochemicals which are contemplated for use in the present invention generally include halogenated fluorochemicals (i.e. C n F 2n+ ,X, XC n F 2n X, where n - 2-10, X - Br, Cl or I) and, in particular, 1-bromo-F- butane π-C 4 F 9 Br, 1-bromo-F-hexane(n-C 6 F 13 Br), 1-bromo-F-heptane(n-C 7 F l5 Br), 1,4-dibromo-F-butane aπd 1,6-dibromo-F- hexane. Other useful brominated fluorochemicals are disclosed in US Patent No. 3,975,512 to Long and are incorporated herein by reference. Specific fluorochemicals having chloride substituents, such as perfluorooctyl chloride (n-C 8 F, 7 CI), 1,8-dichloro-F-octane (n-CIC 8 F 16 CI), 1,6-dichloro-F-hexane (n-CIC 6 F, 2 CI), and 1, 4-dichloro-F-butane (n- CIC 4 F 8 CI) are also preferred. Still other useful fluorinated compounds comprise, for example, perfluorodiisopropyldecalin, perfluoron- butyldecalin, perfluorodixylylmethane, perfluorodixyiylethane, perf luoroperhydrophenanthreπe and their mixtures. in addition to the highly fluorinated organic compounds the fluorinated phase of the reverse gels of the present invention comprises at least one partially fluorinated and partially hydrogenated (HC/FC) organic compound. While not wishing to limit the present invention in any way or be bound to any one theory, it is believed that these HC/FC compounds interact with the nonfluorinated surfactants facilitating an isotropic dispersion and providing for the novel characteristics of the disclosed gels. In preferred embodiments the partially fluoriπated/partially hydrogenated (FC/HC) compounds used correspond to one of the following formulae: CnF2n + 1 CmH2m + 1 , CnF2n + 1 CH - CHCmH2m + 1 and CnF2n + 10CmH2 + 1 , where 2< n < 12 and 1 <m < 16. In particularly preferred embodiments the FC/HC compound will comprise C 6 F, 3 C 10 H 21 (Fomblin Z from Ausimont). Preferably the reverse emulsion contains between 0.01% and 10% w/v of a nonfluorinated surfactant or mixture of surfactants. Because of their excellent biocharacteristics, phospholipids are generally the most preferred class of hydrogenated surfactants. More particularly, phospholipids that tend to adopt the reverse hexagonal phase at low temperatures and concentrations are favored. Accordingly, phosphatidylethanolamines and phosphatidic acids and the like are preferred. In particularly preferred embodiments, the phospholipid has some molecular solubility in the continuous oily phase. Selected embodiments of the invention comprise, phosphatidic acids or phosphatidylethanolamines containing at least one mono-unsaturated fatty acyl moiety. Most preferably, the phosphatidic acid or phosphatidylethanolamine is 1,2-dioleoylphosphatidic or 1,2-dioleoylphosphatidylethanolamine respectively. Other nonfluorinated surfactants suitable for use in the emulsions of the present invention include, but are notlimitedto,phosphatidylcholines,N-monomethyl-phosphatidylethanolaminesJ4,N-dimethyl-phosphatidy L ethanolamines, phosphatidyl ethylene glycols, phosphatidylmethanols, phosphatidylethanols, phosphatidylpropanols, phosphatidylbutanols, phosphatidylthioethanols, diphytaπoyl phosphatides, cardiolipins, cholesterol, gfyceroglycolipids, egg yolk phospholipids, salts of fatty acids, phosphatidylserines, phosphatidylglycerols, aminoethylphosphonolipid, dipalmitoyl phosphatidylcholesterol, ether-linked lipids and dicetylphosphate. Conventional detergents with low hydrophilic-lipophilic balance (ca. 2-10) may also be used as surfactants. Preferred detergents of this type include SPANS® (sorbitan tetraoleate, sorbitan tetrastearate, sorbitan tristearate, sorbitan tripalmitate, sorbitan trioleate, and sorbitan distearate). Guerbet alcohol ethoxylates, dialkyl noni surfactants and dialkylzwitterioπic surfactants including betaines and sulfobetaines are also contemplated for use as emulsifying agents. in particularly preferred embodiments the nonfluorinated surfactants used in the invention are phospholipids. Natural, synthetic or modified phospholipids are used, for example natural or modified egg-yolk lecithin. In addition to the principle nonfluorinated surfactant, one or more secondary surfactants, or co-surfactants, can be added if necessary. The reverse gels of the invention may be obtained by the dispersion, under continuous stirring, of the nonfluorinated surfactant in the FC/HC compound to obtain a homogeneous mixture. This mixture may then dispersed in the highly fluorinated organic compound, either by mechanical stirring or by sonication to provide a dispersion preparation. The addition of water to this dispersion with mixing leads to the formation of the reverse gel. The gels obtained are more or less transparent according to the formulation. Accordingly, as previously alluded to the gels may be prepared through the steps of: combining a nonfluorinated surfactant with at least one partially fluorinated and partially hydrogenated (HC/FC) organic compound to obtain a homogeneous mixture; dispersing said homogeneous mixture in at least one highly fluorinated organic compound to provide a dispersion preparation; and adding said dispersion preparation to an aqueous solution to provide a fluorinated reverse gel comprising a dispersed aqueous phase of less than about 50% v\v. The steps may be accompanied by conventional techniques such as sonication, mechanical mixing or stirring to ensure homogeneous dispersion of the components and an isotropic gel matrix. Based on the formulation used the gels may be transparent or opalescent. When the composition is to be used in biomedical applications, the reverse gel can further be subjected to a sterilization treatment, which can be effected for example by heating in an autoclave. As alluded to previously, when the gel comprises additives, including active principles, these can be added to the aqueous phase, to the oily phase or to both phases. This may be effected during preparation of the gel by combining lipophilic additives with the FC/HC compound and the hydrophilic additives to the aqueous solution that will form the aqueous phase. Conversely, the desired active principle may be incorporated following formation of the reverse gel. Regardless of when they are added the reverse gels of the present invention are capable of delivering additives to a patient, including active principles such as therapeutic or diagnostic agents. Those skilled in the art will appreciate that the desired compounds may be incorporated in either the disperse phase, the continuous phase or at the interface between the phases. The ultimate disposition of the additive will primarily depend on its molecular properties and the technique used to form the reverse gel incorporating the compound. For example, lipophilic agents may be combined with the fluorinated continuous phase at any time including prior to, during or subsequent to the formation of the gel. Conversely, any water soluble agent may be combined with the discontinuous phase used to form the selected reverse gel. As used herein, the term active principle is defined to mean any bioactive agent, pharmaceutical compound or composition, including diagnostic and therapeutic agents, which may be administered to an animal to treat a disease, disorder or condition. Preferred active principles include hydrophilic drugs with solubility in water and lipophilic drugs. Preferably, the formulations of the present invention incorporate less than about 50% w/v of an active principle. Diagnostic agents will typically be incorporated at higher concentrations than therapeutic agents. The precise amount of active principle incorporated in the reverse gels of the present invention is dependent upon the agent of choice, the required dose, and the form of the drug actually used for incorporation. Those skilled in the art will appreciate that such determinations may be made by using well-known pharmacological techniques in combination with the teachings herein. Preferred active principles comprise hydrophilic and lipophilic respiratory agents, antibiotics, antivirals, mydriatics, antiglaucomas, anti-inflammatories, aπtihistaminics, antineoplastics, anesthetics, ophthalmic agents, enzymes, cardiovascular agents, nucleic acids, genetic material, viral vectors, immunoactive agents, imaging agents, immunosuppressive agents, peptides, proteins, physiological gases, gastrointestinal agents and combinations thereof. Further exemplary embodiments of the present invention comprise anti-inflammatory agents such as the glucocorticosteroids (Le. cortisone, prednisone, prednisolone, dexamethasone, betamethasone, Beclomethasone diproprionate, Triamcinolone acetonide, Flunisolide), xaπthines (Le. theophylline, caffeine), chemotherapeutics (Le. cyclophosphamide, lomustine, methotrexate, cisplatin, carboxy platin, taxane derivatives), antibiotics (i.e. aminoglycosides, penicillins, cephalosporins, macolides, quiπoiones, tetracyclines, chloramphenicol), broπchodilatorssuch as the B j -agonists (Le. adrenaline, isoprenaline, salmeterol, salbutamol, terbutaline, f ormoterol) and surfactants. Still other exemplary embodiments include alβ adrenergic blockers (Le. Normodyne, Trandate), angiotensin converting enzyme inhibitors (Le. Vasotec), antiarrhythmics, beta blockers, calcium channel blockers, inotropic agents, vasodilators, vasopressors, anesthetics (Le. morphine) and ophthalmic agents (Le. Polymyxin B, Neomycin, Gramicidin). In accordance with the present invention, those skilled in the art will appreciate that various forms of these compounds may be used to obtain the desired therapeutic index. Because the reverse emulsions of the present invention are uniquely suited for use in a wide variety of physiological applications such as ocular, topical, oral, pulmonary, rectal, synovial, subcutaneous, intraperitoneal, nasal, vaginal, or aural administration of medicaments or diagnostic compounds, almost any compound may be effectively delivered. Accordingly, the foregoing list of active principles is exemplary only and not intended to be limiting. It will also be appreciated by those skilled in the art that the proper amount compound administered and the timing of the dosages may be determined for the formulations in accordance with already-existing information and without undue experimentation. Delivery of active principles by the transdermal route, as an alternative to the more traditional ways of administration, i.e. orally or by percutaneous injection, is particularly preferred. Other preferred delivery routes comprise the formation of a deposit of active substances, for example under the epidermis, the dermis or in one of the cavities of the body. Particularly preferred active principles generally belong to one of the foilowing families: antiinflammatories, antibiotics, antifungals, antibacterials and antineopiasics. Other characteristics and advantages of the invention will be seen upon review of the following non-limiting examples which illustrate preferred embodiments thereof. Example 1 Reverse water-in-fluorocarbon gel containing perfluorooctyl bromide (perflubron), a FC/HC compound (C6F13C10H21, F6H10), water and a phospholipid. The phospholipid (of egg-yolk, Lipoid) (100 mg) is dispersed in the mixed fluorinated/hydrocarbon derivative C 6 F 13 C, 0 H 21 (4 ml) by sonication (5 min, 30°C). The perfluorooctyl bromide (6 ml) is added slowly. A fluid opalescent dispersion is obtained. The purified water (0.18 ml) is added dropwise to this dispersion. A yellow, transparent, continuous-phase fluorocarbon is obtained in a few seconds after the addition of water. This gel can be sterilized thermally (121 °C, 15 min, 15 N m-2) without apparent degradation. No apparent degradation (crystallization or phase-separation) occurs after 6 months at room temperature. Examples 2 to 9 The same operational procedure as in Example 1 is followed to prepare the gels of the attached table. Different phospholipids, different fiuorocarbons and/or quantities of fluorocarbon are used in addition to water. In all cases stable gels are obtained. Table I Ex Fluorocarbon Water Phospholipid Gel Characteristics (mL) (mL) (mg) 2 PF0Ba/F6H10b Hydrogenated Transparent 0.18 Lipoid E 100-3 6/4 100 mg 3 PFPEc:F6H10 Lipoid, yellow opalescent 0.18 Egg yolk 6/4 100 mg 4 APF-240d/F6H10 Lipoid, yellow opalescent 0.18 Egg yolk 6/4 100 mg 5 PFPE/F6H10 Lipoid, yellow opalescent 0.18 Egg yolk 6/4 100 mg 6 PFOB/F6H10 Lipoid, yellow opalescent 0.05 Egg yolk 6/4 100 mg 7 PF0B/F6H10 Lipoid, yellow opalescent 0.025 Egg yolk 6/4 100 mg 8 PF0B/F6H10 Lipoid, yellow opalescent 0.54 Egg yolk 6/4 100 mg 9 PF0B/F6H10 Lipoid, yellow opalescent 0.9 Egg yolk 6/4 500 mg a) PFOB : perfluorooctyl bromide b) F6H10 : C 6 F 13 C 10 H 21 (Fomblin Z from Ausimont) c) PFPE : perfluoropolyether, d) APF 240: (perfluorodiisopropyldecalin commercialized by Air Products and Chemicals Inc.)] The foregoing examples serve to demonstrate the stability and versatility of the present invention. In particular, sterilization of the reverse gel did not adversely affect the consistency or stability of the preparation. Those skilled in the art will further appreciate that the present invention may be embodied in other specific forms without departing from the spirit or central attributes thereof. In that the foregoing description of the present invention discloses only exemplary embodiments thereof, it is to be understood that other variations are contemplated as being within the scope of the present invention. Accordingly, the present invention is not limited to the particular embodiments which have been described in detail herein. Rather, reference should be made to the appended claims as indicative of the scope and content of the invention.

Claims: WHAT IS CLAIMED IS: 1. A fluorinated reverse gel comprising : a continuous phase comprising at least one highly fluorinated organic compound and at least one partially fluorinated and partially hydrogenated (HC/FC) organic compound; a dispersed aqueous phase; and an effective dispersing amount of at least one nonfluorinated surfactant wherein said dispersed aqueous phase comprises less than about 50% v/v of said reverse gel. 2. The reverse gel of Claim 1, wherein said at least one nonfluorinated surfactant is selected from the group consisting of alcohols, salts of fatty acids, phosphatidylcholines, N-monomethyl-phosphatidylethanolamines, phosphatidic acids, phosphatidylethanolamines, N,N-dimethyl-phosphatidyl-ethanolamines,phosphatidylethylene glycols, phosphatidylmethanols, phosphatidylethanols, phosphatidylpropanols, phosphatidylbutanols, phosphatidylthioethanols, diphytaπoyl phosphatides, egg yolk phospholipids, cardiolipins, glycerglycolipids, phosphatidylserines, phosphatidylglycerols and aminoethylphosphonolipids. 3. The reverse gel of claim 1 wherein said nonfluorinated surfactant is a phospholipid. 4. The reverse gel of claim 3 wherein said phospholipid is natural or modified egg yolk lecithin. 5. The reverse gel of claim 1 wherein the fluorinated continuous phase comprises at least 60% v/v. 6. The reverse gel of claim 1 wherein the fluorinated continuous phase comprises at least 70% v/v. 7. The reverse gel of claim 1 further comprising an additive. 8. The reverse gel of claim 7 wherein said additive is selected from the group consisting of active principles, mineral salts, amino acids, buffering agents, oncotic agents, osmotic agents, nutritive agents, dispersing agents, absorption enhancers, physiological gases, i munoactive principles, organic solvents, polymers, and combinations thereof. 9. The reverse gel of claim 8 wherein the additive is an active principle and said active principle is a therapeutic or diagnostic agent selected from the group consisting of respiratory agents, antibiotics, antivirals, mydriatics, antiglaucomas, anti-inflammatories, antihistaminics, antineoplastics, anesthetics, ophthalmic agents, enzymes, cardiovascular agents, nucleic acids, genetic material, viral vectors, immunoactive agents, imaging agents, immunosuppressive agents, peptides, proteins and gastrointestinal agents. 10. The reverse gel of claim 1 wherein said at least one highly fluorinated organic compound is selected from the group consisting of perfluoroalkanes, fluorinated cyclic compounds, halogenated fluorochemicals, fluorinated alkenes, fluorinated ethers, fluorinated polyethers, fluorinated amines, fluorinated hydrides and derivatives thereof. 11. The reverse gel of claim 1 wherein said partially fluorinated and partially hydrogenated (HC/FC) organic compound comprises a formula selected from the group consisting of CnF2n+1CmH2m+1, CnF2n+1CH2CH-CHCmH2m+1, CnF2n+1CH-CHCmH2m+ 1, CnF2n+10CmH2m+1 and combinations thereof wherein 2< n < 12 and 1 <m< 16. 12. The reverse gel of claim 1 further comprising a therapeutically effective amount of at least one physiological gas. 13. The reverse gel according to claim 1 wherein the aqueous phase comprises micelles, vesicles or other colloidal aggregates. 14. A method for forming a fluorinated reverse gel comprising the steps of: combining at least one partially fluorinated and partially hydrogenated (HC/FC) organic compound with aπ effective dispersing amount of at least one nonfluorinated surfactant and at least one highly fluorinated organic compound to provide a dispersion preparation; and admixing said dispersion preparation with an aqueous solution to provide a fluorinated reverse gel comprising a disperse aqueous phase of less than about 50% v/v. 15. The method of Claim 14, wherein said at least one nonfluorinated surfactant is selected from the group consisting of alcohols, salts of fatty acids, phosphatidylcholines, N-monomethyl-phosphatidylethanolamines, phosphatidic acids, phosphatidylethanolamines, N,N-dimethyl-phosphatidyl-ethanolamines,phosphatidylethylene glycols, phosphatidylmethanols, phosphatidylethanols, phosphatidylpropanols, phosphatidylbutanols, phosphatidylthioethanols, diphytanoyl phosphatides, egg yolk phospholipids, cardiolipins, glycergiycolipids, phosphatidylserines, phosphatidylglycerols and aminoethylphosphonolipids. 16. The method of claim 14 wherein said nonfluorinated surfactant is a phospholipid. 17. The method of claim 14 further comprising the step of incorporating at least one additive in said fluorinated reverse gel. 18. The method of claim 17 wherein said additive is selected from the group consisting of active principles, mineral salts, amino acids, buffering agents, oncotic agents, osmotic agents, nutritive agents, dispersing agents, absorption enhancers, immunoactive principles, organic solvents, polymers, and combinations thereof. 19. The method of claim 14 wherein said at least one highly fluorinated organic compound is selected from the group consisting of perfluoroalkanes, fluorinated cyclic compounds, halogenated fluorochemicals, fluorinated alkenes, fluorinated ethers, fluorinated polyethers, fluorinated amines, fluorinated hydrides and derivatives thereof. 20. The method of claim 14 wherein said partially fluorinated and partially hydrogenated (HC/FC) organic compound comprises a formula selected from the group consisting of CnF2π+1CmH2m+1, CnF2n+1CH2CH-CHCmH2m+1, CnF2n+1CH-CHCmH2m+1, CnF2n+10CmH2m+1 and combinations thereof wherein 2<n < 12 and 1 <m < 16. 21. A fluorinated reverse gel formed according to the method of claim 14. 22. A method for the preparation of a fluorinated reverse gel comprising the steps of: combining a nonfluorinated surfactant with at least one partially fluorinated and partially hydrogenated (HC/FC) organic compound to obtain a homogeneous mixture; dispersing said homogeneous mixture in at least one highly fluorinated organic compound to provide a dispersion preparation; and adding said dispersion preparation to aπ aqueous solution to provide a fluorinated reverse gel comprising a dispersed aqueous phase of less than about 50% v\v. 23. The method of claim 22 further comprising the step of subjecting said fluorinated reverse gel to a thermal sterilization treatment. 24. The method of Claim 22 wherein said at least one nonfluorinated surfactant is selected from the group consisting of alcohols, salts of fatty acids, phosphatidylcholines, N-monomethyl phosphatidylethanolamines, phosphatidic acids, phosphatidylethanolamines, N,N-dimethyl phosphatidyl-ethanolamiπes,phosphatidylethyleneglycols, phosphatidylmethanols, phosphatidylethanols, phosphatidylpropanols, phosphatidylbutanols, phosphatidylthioethanols, diphytanoyl phosphatides, egg yolk phospholipids, cardiolipins, glycerglycoDpids, phosphatidylserines, phosphatidylglycerols and amiπoethylphosphonolipids. 25. The method of claim 22 further comprising the step of incorporating at least one active principle in said fluorinated reverse gel. 26. A method for delivering an additive to a patient comprising: providing fluorinated reverse gel comprising a disperse aqueous phase; a continuous fluorocarbon phase comprising at least one partially fluorinated and partially hydrogenated (HC/FC) organic compound and at least one highly fluorinated organic compound; an effective dispersing amount of at least one nonfluorinated surfactant; at least one additive; and administering said fluorinated reverse gel to a patient. 27. The method of claim 26 wherein said at least one nonfluorinated surfactant is selected from the group consisting of alcohols, salts of fatty acids, phosphatidylcholines, N-monomethyl-phosphatidylethaπolamines, phosphatidic acids, phosphatidylethanolamines, N,N-dimethyl-phosphatidyl-ethanolamines,phosphatidylethyleneglycols, phosphatidylmethanols, phosphatidylethanols, phosphatidylpropanols, phosphatidylbutanols, phosphatidylthioethanols, diphytanoyl phosphatides, egg yolk phospholipids, cardiolipins, glycerglycolipids, phosphatidylserines, phosphatidylglycerols and aminoethylphosphonolipids. 28. The method of claim 26 wherein said additive is selected from the group consisting of active principles, mineral salts, amino acids, buffering agents, oncotic agents, osmotic agents, nutritive agents, physiological gases, dispersing agents, absorption enhancers, immunoactive principles, organic solvents, polymers, and combinations thereof. 29. The method of claim 28 wherein the additive is an active principle and said active principle is a therapeutic or diagnostic agent selected from the group consisting of respiratory agents, antibiotics, antivirals, mydriatics, antiglaucomas, anti-inflammatories, antihistaminics, antineoplastics, anesthetics, ophthalmic agents, enzymes, cardiovascular agents, nucleic acids, genetic material, viral vectors, immunoactive agents, imaging agents, immunosuppressive agents, peptides, proteins and gastrointestinal agents. 30. The method of claim 26 wherein said fluorinated reverse gel is administered to a patient using a route of administration selected from the group consisting of topical, subcutaneous, pulmonary, intramuscular, intraperitoneal, nasal, vaginal, rectal, aural, oral and ocular routes.

Inventors: KRAFFT MARIE-PIERRE, RIESS JEAN G, KRAFFT, MARIE-PIERRE, RIESS, JEAN, G.
Applicants: ALLIANCE PHARMA, KRAFFT MARIE PIERRE, RIESS JEAN G, ALLIANCE PHARMACEUTICAL CORP., KRAFFT, MARIE-PIERRE, RIESS, JEAN, G.
Application year: 1996
Main classification: A61K7
IPC codes: A61K8, A61K9, A61Q19