MXPA97009690A - Continuous microdispersions of fluorochemicals for the supply of agents farmaceuti - Google Patents

Abstract

A method for preparing a pharmaceutical microdispersion exhibiting improved bioavailability, which includes the following steps: providing a thermodynamically stable pharmaceutical composition comprising at least one pharmaceutical agent incorporated in a physiologically acceptable liquid carrier, the liquid carrier comprising one or more lipophilic solvents, such as fluorochemicals, and preferably at least one non-fluorinated co-solvent, and combining a stable pharmaceutical composition with an amount of at least one sufficient miscible diluent to initiate phase separation of the pharmaceutical agent from the pharmaceutical composition, wherein forms a microdispersion of the pharmaceutical composition. Also disclosed are microdispersed pharmaceutical compositions, and tools for forming said composition

Description

CONTINUOUS MICRODISPERSIONS OF FLUOROCHEMICALS FOR THE SUPPLY OF PHARMACEUTICAL AGENTS FIELD OF THE INVENTION The present invention relates, generally, with the formulations and methods for the administration of pharmaceutical agents to a physiological target. In preferred embodiments, the invention relates to dispersing improved fluorochemicals that can be used to improve the bioavailability and efficacy of lipophilic compounds having limited solubility in an aqueous physiological environment. These microdispersions can be formulated to facilitate administration, provide extended delivery profiles and increase drug stability, making them particularly suitable for the controlled and maintained delivery of lipophilic pharmaceutical agents. BACKGROUND OF THE INVENTION The effectiveness of many of the pharmaceutical agents is predicted in their ability to proceed to select the target and remain there in effective concentrations for a sufficient period of time to fulfill the desired diagnostic or therapeutic purpose. The difficulty of achieving this efficacy can be exaggerated by the location and environment of the target, as well as by the inherent physical characteristics of the compound administered. For example, the delivery of a medicament by means of days that are subject to repeated drainage or flow as part of the natural physiological functions of the body offer a significant impediment to the effective administration of pharmaceutical agents. In this regard, problems of supply and retention occur frequently when the compounds are administered through the respiratory or gastrointestinal tracts. Repeated administration of large doses is required to compensate for the amount of medication being washed or eliminated and to maintain an effective dose of regimens when these routes are used. Moreover, the molecular properties of the pharmaceutical compound can impair or impair absorption through the given delivery route, thereby resulting in a substantial reduction in efficacy. While efficient delivery of a pharmaceutical agent may be impaired, this is particularly true for lipophilic compounds that are not soluble in aqueous environments. For example, it is known that insoluble particles that undergo phagocytes or pinositosis, result in an accelerated turnover of the compound in the target. These reductions in delivery and retention time complicate the dosage regimens, representing a waste of pharmaceutical resources and generally reduce the overall efficiency of the medication administered. The difference of hydrophilic compounds, the supply of lipophilic drugs by conventional means has been and continues to be a problem. Unfortunately, a more promising number of diagnostic and therapeutic agents currently under development are bulky polycyclic molecules that tend to be relatively insoluble in water. The substantial physical size of these compounds, coupled with the intrinsic lipophilicity of their molecular structure, has severe limitations in their practical use for pharmaceutical applications. For example, oral administration of lipophilic agents using conventional tablets and capsules has the disadvantage that it has a variable average absorption of the drug administered and depends on factors such as the presence or absence of food, the pH of gastrointestinal noises and the average gastric emptying. Moreover, the insolubility of the large lipophilic particles tends to reduce the averages of delivery to a small amount of drug dissolved in the gastrointestinal fluid and which crosses the piterial barrier before being excreted. Finally, the degradation of unstable drugs by gastric noises and metabolizing enzymes of the drug can reduce the bioavailability of the drug to the point of presenting a therapeutic failure (Prescott, LF, in "Novel Drug Delivery and is Therapeutic Application" novel and its therapeutic application), John Wiley & amp; amp; amp;; Sons, New York, 1989, pp. 3-4). Other delivery routes are somewhat better when lipophilic compounds are administered using conventional delivery vehicles. Parenteral administration of these water insoluble documents requires that they be formulated in the form of oil in water emulsions or that they are solubilized in a water-miscible phase. This represents disadvantages associated with the formulation of a suitably stable dosage form that can be delivered by this route; These formulations often contain surfactant systems that, by themselves, can cause toxic side effects. For example, the current method is used for the intravenous administration of a highly lipophilic cancer treatment drug, Taxol® involves the use of polyoxyethylated castor oil as a vehicle that has been associated or that has been associated with hypersensitivity reactions. including dismea, brocospasm, urticaria and hypotension (Rowinskey, EK and Donehower, RC, New Eng. J. Med., 1995, 332, 1004). In addition, intravenous administration of drugs such as Taxol, which have high systemic toxicities, severely limit their therapeutic capacity (Balasubramanian, S.V. and Straubinger, R.M., Biochemistry, 1994, 33., 8941). Thus, despite the encouraging results with existing supply systems, the inherent low bioability of these lipophilic compounds in the target location due to their inefficient or toxic delivery systems substantially reduces their efficiency. Despite the difficulties associated with the supply of lipophilic medications, the potential advantages in the methods developed for these are great. Extensive work has been done to show that membrane permeability, bioavailability, and efficacy of drugs increase frequently by increasing lipophilicity (Banker GS and Rhodes, CT in "Modern Pharmaceutics", Marcel Dekker, Inc., New York , 1979, pp. 31-49; Hughes, PM and Mitra, AK, J. Ocul. Pharmac, 1993, 9, 299; Yokogawa, K., Nakashima, E, Ishizaki, J., Maeda, H., Nagano, T. and Ichimura, F., Pharm, Res. 1990, 7, 691; Hageluken, A., Grunbaum, L., Nurnberg, B., Harhammer, R., Schunack, W. and Seifert, R., Biochem. Pharmac., 1994, 47, 1789). The development of new systems for the delivery of these compounds can, therefore, significantly increase the therapeutic efficacy for the treatment of a variety of indications.

In this regard, a class of supply vehicles that have shown to be very promising when used for the administration of pharmaceutical agents are fluorochemicals. During recent years, it has been found that fluorochemicals have a wide range of application in the medical field as diagnostic and therapeutic agents. The use of fluorochemicals for the treatment of medical conditions is based, on a large scale, on the unique chemical and physical properties of these substances. In particular, the relatively low reactivity of fluorochemicals allows them to be combined with a wide variety of compounds without altering the properties of the incorporated agent. This relative inactivity, when coupled with other beneficial characteristics such as the ability to provide substantial amounts of oxygen, its radio opaque characteristic for certain forms of radiation and low surface energy, has made fluorochemicals invaluable for a number of applications. of diagnosis and therapy. For example, various fluorochemical emulsions have been used as oxygen carriers during medical procedures. Conventional oil-in-water emulsions, which can be infused directly into the system in the bloodstream, consist of a selected fluorochemical dispersed in the form of droplets in a continuous aqueous phase. Due to the high oxygen-carrying capacity of fluorochemicals, these emulsions are particularly useful as substitutes in the blood to provide oxygen to the vascular system. After the administration of the emulsions, the oxygen dissolved in the dispersed fluorochemical phase is released into the blood. Fluosol® (Green Cross Crop., Osaka, Japan), a commercially available oil-in-water emulsion contains fluorochemicals, and has been used as a gas carrier to oxygenate myocardium during percutaneous transluminal coronary angioplasty (R. Naito, K. Yokoyama, Technical Information Series No. 5 and 7, 1981). Fluorochemicals have also been used as a contrast enhancement medium in the radiological image by Long (U.S. Patent No. 3,975,512) and in nuclear magnetic resonance imaging (U.S. Patent No. 5,114,703). Other proposed medical uses include the treatment of cardiovascular and cerebrovascular diseases, coronary angioplasty, organ preservation and therapy for cancer; ultrasonic imaging and veterinary therapy (Riess LG, "Blood Compatible Materials and Devices": Perspective Towards the 21st Century, Technomisc Publishing, Co., Lancaster, PA, Ch. 14, 1991; Riess, JG, Vox. Sang., 61: 225, 1991). Conventional direct fluorochemical emulsions have been described in, for example, EP-A-0 255 443, FR-A-2 665 705, FR-A-2 677 360, FR-A 2 694 559, FR-A 2 679 150, PCT / WO90 / 15807, EP-A-311473 and US 3,975,512. In addition to the aforementioned oil-in-water emulsion systems, net fluorochemicals and their emulsions having a continuous fluorochemical phase have also been used in different medical applications. For example, net fluorochemicals have been evaluated for use in liquid ventilation applications. Currently one product, LiquiVent® (Alliance Pharmaceutical Corp., San Diego, CA), is under medical study for use in respiratory disease syndrome (RDS). These compositions can also be used in the treatment of premature infants with deficiency in lung development. Another product, Imagent Gl®, (Alliance Pharmaceutical Corp., San Diego, CA) a diagnostic agent tested by the FDA (Federal Drug Administration) composed of net fluorochemicals, is particularly useful for taking images in the gastrointestinal tract ( Gl). Fluorochemical fluids also have a potential utility in applications for ocular surgery, such as the replacement of intraocular lenses placed posteriorly and in the treatment of ocular ischemia (Lewis, H. and Sánchez, G., Ophthalmology, 1993 , 100, 1055; Blair, N.P., Baker, D.S., Rhode J.P., and Solomon, M., Arch Ophthalmol, 1989, 107. 417). While these applications are impressive, the ability to use fluorochemicals in the reliable supply of effective amounts of pharmaceutical agents, either in conjunction with fluorochemical-mediated therapy or in a separate dose regimen, would be of great benefit. The use of fluorochemical drug delivery vehicles would be particularly favorable for lipophilic medicaments which are insoluble in aqueous solutions and present special problems in aqueous physiological environments. For example, effective pulmonary administration of pharmaceutical compounds, both lipophilic and hydrophilic, would be especially advantageous. The pulmonary administration of drugs is a difficult problem because the introduction of the compounds directly into the lungs can not be effectively achieved by means of aqueous solutions or by fluorochemical emulsions in which the continuous phase is also aqueous. In addition, as seen in previous applications, fluorochemicals can be easily introduced into the lungs. This direct administration is critical in the treatment of pulmonary diseases such as poor vascular circulation of the diseased portions of the lungs that reduces the effectiveness of intravenous drug delivery. In addition to the treatment of pulmonary disorders, the pharmaceutical formulations of fluorochemicals administered to the lungs may also be useful in the treatment or diagnosis of diseases such as RDS, pulmonary circulation deteriorates cystifibrosis and lung cancer. In addition to the pulmonary route of administration, fluorochemicals can advantageously be used, that of the administration of compound by means of other routes, such as, for example, topical, oral, intraperitoneal or intraocular. Work in this area has shown that pulmonary delivery of biological agents through the alveolar surface can be facilitated when performed in conjunction with liquid ventilation (Wolfson, MR and Shaffer, TH, The FASEB J., 1990, 4, A1105 ), which is, using formulations that have a fluorochemical continuous phase rich in oxygen. This increase in efficacy observed in the compounds administered together with liquid ventilation in the damaged lungs can be due to different factors, including the high irrigation coefficients of some fluorochemicals in the pulmonary surface, an increase in the area of the alveolar surface due to the most effective pulmonary inflation and oxygen supply through fluorochemicals. Shaffer et al. Have also shown that pulmonary administration can improve the biological response of some drugs when compared to intravenous administration (Shaffer, TH, Wolfson, MR, Greenspan, JS and Rubenstein, SD, Art. Cells, Blood Sub. Immob. Biotech., 1994, 22, 315). Similarly, Kirkland (WO 92/18165) has shown that liquid mixtures of insoluble particulate fluorocarbons can be used as an effective imaging agent for radiographs or for magnetic resonance imaging. Kirkland produces these fluorocarbon blends with the addition of effervescent powder components formed using conventional manufacturing techniques and found that the gas provides a significant improvement of the obtained image. Thus, to move from these texts, the administration of pharmaceutical compounds, particularly therapeutics designed to be absorbed in the body, is not carried out without difficulties. A significant problem associated with the supply of drugs by conventional fluorochemicals is that the vast majority of drugs (lipophilic and hydrophilic) are insoluble in the fluorochemical phase. This may present a number of characteristics that involve the administration of the compounds including stability, particle size, reliability in the dose, dispersion consistency and bioability. For example, the current method of pulmonary administration involves the preparation of a crude dispersion of insoluble fluorochemical material and delivery by means of turbulent flow (Shaffer, TH, Wolfson, MR and Clark, L. C, Pediatric Pulmonology, 1992, 14 , 102). Thus, using these techniques for the supply of insoluble fluorochemical drugs (Shaffer et al., Art. Blood Subs. And Cells Immob. Biotech., 22: 1994; Pediatr. Pulmonol., 14: 102, 1992) results in a non-homogeneous, unreliable and non-reproducible drug supply due to the inefficient dispersion of the powder agent in the fluorochemical phase. Moreover, while suitable supply vehicles of comparable efficiency exist for hydrophilic compounds, the selection for lipophilic agents is much reduced. The suspension of the chlorofluorocarbon medicament volatile propellants of the current art are often heterogeneous systems that usually require dispersion before use. Thus, obtaining a relatively homogeneous distribution in the pharmaceutical compound is not always easily achieved in the "oily" fluorochemical. In addition, these formulations suffer from the disadvantages that they are prone to the addition of particles which, in the case of delivering aerosol, can result in clogging of the propellant system and inadequate delivery of the medicament. The growth of crystals in the suspension by means of the Ostwald maturation can also lead to heterogeneity in the particle size and can significantly reduce the useful life of the formulation. Another major problem with conventional dispersions, whether in emulsion or suspension, is the thickening of the particle. The thickening can occur by different mechanisms such as flocculation, fusion, molecular diffusion and coalescence. In a relatively short period of time these processes can enlarge or thicken the formulation to the point where it is no longer useful. Comparable problems can occur in fluorochemical suspensions designed for other routes of administration such as, for example, through the gastrointestinal tract or in the ocular environment. A further repression or limitation of conventional dispersions consists in the particle size distribution. For oral administration, the drug particles or smaller crystals, often in the order of 10 nm to 100 nm with large surface areas, are preferred because of their rapid diffusion to the delivery vehicle at the site of action.

Unfortunately, it is generally not practical to produce particles having optimum characteristics using conventional methods such as air flow or grinding. Accordingly, many of the present formulations incorporate drug particles having average particle diameters in the order of a few microns or more. Many attempts have been made to solve these problems and provide vehicles for efficient fluorochemical supply. For example Evans and collaborators (Pharm. Res., 1991, 8, 629; U.S. Pat, 5,292,499; U.S. Pat. ,230,884) and Jinks et al. (U.S. Pat. 4,814,161) present the use of volatile propellants stabilized by lipids for pulmonary drug delivery. However, teaching for the use of liquid continuous fluorochemical media in aerosol formulations is not at all adequate, nor is their declaration of inclusion of large proportions of high boiling components in these formulations. Moreover, Evans et al. Limit their presentation to the solubility of the hydrophilic pharmaceutical component and does not mention the incorporation of hydrophobic compounds. In accordance with the above, it is an object of the present invention to provide microdispersions of fluorochemicals, with high bioability, incorporating diagnostic and therapeutic compounds that present an improved average life and stability. It is another object of the present invention to provide pharmaceutical compounds capable of effectively delivering lipophilic pharmaceutical agents. Another object of the present invention is to provide a method for the formulation of pharmaceutical microdispersions that exhibit improved bioavailability. SUMMARY OF THE INVENTION In general, the present invention fulfills the above objectives by providing novel fluorochemical microdispersions that can be used in the delivery of pharmaceutical agents at selected physiological sites. In the preferred embodiments, the pharmaceutical agents are lipophilic. More specifically, the present invention provides pharmaceutical microdispersions, with high bioavailability, having a continuous phase of liquid fluorochemical and a pharmaceutical agent containing a discontinuous phase. In contrast to formulations with the prior art, preferred exemplary embodiments of the present invention readily incorporate lipophilic, water-insoluble pharmaceuticals and diagnostic compounds for microdispersion administration. This advantageously provides an increase in the bioavailability of the lipophilic agent at the delivery site, leading to a more efficient delivery. Although the present invention is particularly useful for the delivery of water-insoluble compounds, it should be emphasized that different embodiments can be used for the advantageous delivery of pharmaceutical compounds that are soluble, at least to some extent in water. The pharmaceutical microdispersions shown herein may be either in the form of a suspension or in the form of an emulsion and may be made to facilitate the delivery of cash from pharmaceutical agents having different degrees of lipophilicity. The present invention is particularly useful for the incorporation of relatively lipophilic agents into microdispersions comprising either a sol or an emulsion. In other preferred embodiments the invention can be used to form isotropic microfine sols with fewer lipophilic pharmaceutical agents. Without taking into account the absolute lipophilicity of the pharmaceutical compound, the use of these formulations can increase the bioavailability and efficacy of the active agent. In addition, the pharmaceutical microdispersions of the present invention can be formulated to resist thickening and other degradative forces, therefore it provides improved stability and a longer life. It should be emphasized that unlike the suspensions of the prior art of pharmaceutical compounds in fluorochemicals, the novel microdispersions of the present invention are formed by an induced separation phase. More particularly, in one aspect of the invention the pharmaceutical agent or pharmaceutical agents selected, including lipophilic compounds, are first incorporated into a thermodynamically stable composition comprising at least one lipophilic material, such as a fluorochemical, and optionally at least one cosolvent. This composition can be a molecular solution. Preferred embodiments the cosolvent is a short chain alcohol or an alkyl sulfoxide. Then, the composition is combined with a diluent, preferably a fluorochemical, which is miscible with the thermodynamically stable composition. Significantly, the lipophilicity of the diluent is less than the lipophilicity of the composition. Accordingly, when a sufficient amount is combined, the diluent initiates a separation phase by forcing the pharmaceutical agent into a discontinuous phase and forming a pharmaceutical microdispersion having an improved bioavailability. The present invention is compatible with any pharmaceutical agent that can be solubilized in the thermodynamically stable composition, including hydrophilic and lipophilic agents. As indicated above, the pharmaceutical dispersions of the present invention can be formed either as an emulsion or as a suspension, depending on the individual requirements of the dose regime being attempted and the administration technique. The final form of the microdispersion can be selected by varying the concentration of the non-fluorinated cosolvent in the thermodynamically stable pharmaceutical composition, before combining it with the fluorochemical diluent. More specifically, if the final concentration of the cosolvent does not exceed its limit solubility in the combined formulation, it will remain in the continuous phase of the fluorochemical while the pharmaceutical agent undergoes a separation phase to form a discontinuous suspension. That is, the pharmaceutical agent including the lipophilic compounds will be dispersed in the form of a highly isotropic microfine suspension. Conversely, the concentration of the non-fluorinated cosolvent exceeds its solubility limit in the combined formulation, the excessive amount will force the continuous fluorochemical phase. In this case, the non-fluorinated cosolvent will associate with the lipophilic pharmaceutical agent to produce a discontinuous liquid phase resulting in an emulsion. Another aspect of the present invention relates to pharmaceutical formulations, with improved bioavailability, produced according to the method described below. In the preferred embodiment these formulations comprise a substantially homogeneous microdispersion of the pharmaceutically effective amount of at least one pharmaceutical agent in a liquid continuous phase, comprising one or more lipophilic, physiologically acceptable fluorochemicals, at least one cosolvent and at least one diluent . In the case of less lipophilic bioactive agents, water can be used as a cosolvent to form the thermodynamically stable composition before forming the dispersion. As explained above, the dispersion can be formed as a suspension or as inverse emulsions. In any of the formulations the discontinuous phase will preferably comprise microparticles having an average diameter in the order of 3 μm or less, and more preferably have average diameters significantly less than 1 μm. In particularly preferred embodiments the average diameters of the suspended particles will be less than 500 nm and even more preferably will be less than 200 nm or less than 100 nm.

The colloidal nature of the substantially homogeneous dispersion of the present invention provides improved bioavailability due to its rapid dissolution at the target site. Moreover, since the microdispersions of the present invention are produced by means of precipitation rather than mechanical comminution, the homogeneity of the formulation is significantly better than conventional compositions. That is, the dispersions of the present invention are highly isotropic. The microdispersions of the present invention may also comprise one or more additives that are present in the discontinuous pharmaceutical phase, in the continuous fluorochemical phase or in both phases, or at the interface therebetween. The additives may include, for example, mineral salts, buffers, oncotic and osmotic agents, flavors and acceptable agents, nutritional agents or any other ingredient capable of increasing the flavor characteristics of the microdispersions including their stability, therapeutic efficacy and tolerance. In particular, the microdispersions may incorporate fluorinated or non-fluorinated surfactants in order to provide additional stability to the formulation and retard the degradation that is generated due to thickening. Another aspect of the present invention relates to a method for delivering one or more pharmaceutical agents, including lipophilic compounds, for a physiological purpose. This method comprises the steps of providing the pharmaceutical formulation comprising a substantially homogeneous microdispersion of at least one pharmaceutical agent in a continuous liquid phase, wherein the liquid continuous phase comprises one or more lipophilic fluorochemicals, at least one non-fluorinated cosolvent and at least one a fluorochemical diluent; and introducing an effective pharmaceutical amount of a pharmaceutical formulation into a physiological site or target. It should be emphasized that, in the preferred embodiments, the formulations can be administered using different days including, but not limited to, the gastrointestinal tract, the respiratory tract, topical, intramuscular, intraperitoneal, nasal, pulmonary, vaginal, rectal administration, aural, oral or intraocular. As mentioned above, any lipophilic or hydrophilic pharmaceutical agent that can be incorporated into the thermodynamically stable composition can be effectively administered using the method noted above. Preferably, the pharmaceutical agents will have a log of octanol / water partition coefficient of at least 3, more preferably of less than 0.5 and even more preferably less than 2 while comprising less than 20% by weight of the formulation volume. Thus, one aspect of the present invention is a method for preparing the pharmaceutical microdispersion that exhibits improved bioavailability, this method comprises the steps of: providing a first composition of a first lipophilic liquid and a pharmaceutical agent in a single continuous phase, and adding to this first composition a sufficient amount of a second less lipophilic liquid than this first liquid, which is miscible in that first liquid, to cause a separation phase of the pharmaceutical agent to form a discontinuous microdispersed phase. Preferred lipophilic perfluorochemicals are halogenated fluorochemicals, 2-block or 3-block fluorocarbon-hydrocarbon compounds, halogenated ethers, polyethers, fluorocarbon hydrocarbon esters, fluorocarbon-hydrocarbon dioesters, fluorocarbon-hydrocarbon amines and fluorocarbon-hydrocarbon amides. By another definition, the preferred lipophilic fluorochemicals are CnF2n + 1X, XCnF2nX, where n = 3-8, X = Br, Cl or I; CnF2n + 1 - CmH2m + 1, CnF2n + 1 CH = CHCmH2m + 1, where n = 2-8 m = 2-6; CpH2p + 1.CnF2n-CmH2m + 1, where p = 2-6, m = 2-6 and n = 2-8; XCnF2nOCmF2mX, XCF2OCnF2nOCF2X, where n = 1-4, m = 1-4, X = Br, Cl or I; CnF2n-0-CmH2m + 1, where n = 2-8; m = 2-6; CpH2p + 1, where p = 2-6, m = 2-6 and n = 2-8: 1-bromo-F-octane (n-C8F17Br); 1-bromo-f-heptane (n-CvF15Br); 1-bromo-F-hexane (n-C6F13Br); perfluorooctyl chloride (n-C7F15Cl); 1, 6-dichloro-F-hexane (n-ClC6F12Cl); 1,4-dichloro-F-butane (n-C1C4FBC1); 1,4-dibromo-F-butane and 1,6-dibromo-F-hexane. In one embodiment of the method, the relatively lipophilic pharmaceutical agent is selected from a group consisting of respiratory drugs, antibiotics, anti-inflammatories, antineoplastic agents, anesthetics, ophthalmic agents, chemotherapeutic agents, cardeovascular agents, imaging agents and a combination of the same. Preferably the lipophilic pharmaceutical agents have a logarithm of octanol / water partition coefficient (Log Po / weight) greater than about -3. The fluorochemical diluent is preferably selected from a group consisting of bis (F-alkyl) ethanes, cyclic fluorocarbons, perfluorinated amines such as perfluorocarbons dominated, iodinated perfluorocarbons, chlorinated perfluorocarbons, perfluorooctyl chloride, hydruroperfluorooctyl, perfluoroalkylated esters, perfluoroalkylated polyesters, fluorocarbon-hydrocarbon compounds and a combination of them. The diluent is less lipophilic than the lipophilic fluorochemical. The cosolvent is advantageously selected from esters, alcohols, alkylsulphoxides, water, other non-fluorinated biocompatible solvents and a combination thereof. The method may also include the step of introducing a therapeutically beneficial amount of a physiologically acceptable gas into the pharmaceutical microdispersion. In addition, fluorinated or non-fluorinated surfactant can be used in the composition. In a preferred embodiment, the lipophilic pharmaceutical agent is about 20% weight on volume of the lipophilic fluorochemical concentration and less than about 50% weight on volume. The microdispersion can advantageously have an average particle diameter of less than about 3 μm, more preferably less than 1 μm. Particularly preferred embodiments comprise particles in the order of 500 nm as 200 nm, 100 nm or less and, in especially preferred embodiments in the order of 10 nm. The present invention also includes a fluorochemical microdispersion that exhibits an improved bioavailability prepared according to the above method. That also includes a pharmaceutical formulation, with high bioability, comprising a substantially homogeneous microdispersion of a pharmaceutical effective amount of at least one relatively lipophilic fluorochemical agent in a liquid continuous phase, the liquid continuous phase comprising 1 or more lipophilic fluorochemicals, physiologically acceptable, at least one cosolvent and at least one fluorochemical diluent. As mentioned above, the microdispersion can be a suspension or an emulsion. The different materials in the formulation will be described below in relation to the method. In one embodiment, the concentration of the relatively lipophilic pharmaceutical agent is less than about 20% weight on volume and the concentration of 1 or more lipophilic fluorochemicals is less than about 50 volume% on volume. Preferably, the microdispersion has a particular average diameter of less than about 3 or 1 μm. More preferably the particles will have an average diameter of less than 200 nm and may be in the range of nanometer; for example, 1, 2, 3, 4, 5, 7, 8 or 10 nm. In one embodiment, the therapeutically beneficial amount of the physiologically acceptable gas is incorporated into a liquid continuous phase. In another, the formulation includes a fluorinated or non-fluorinated surfactant. In addition, the invention includes a method for delivering 1 or more relatively lipophilic pharmaceutical agents to a physiological target, the method comprising the steps of: providing a pharmaceutical formulation with high bioavailability comprising a substantially homogeneous microdispersion of at least one relatively lipophilic pharmaceutical agent in a liquid continuous phase, the liquid continuous phase comprises 1 or more lipophilic fluorochemicals, at least one non-fluorinated cosolvent and at least one fluorochemical diluent; and introducing a pharmaceutically effective amount of a pharmaceutical formulation, with high bioavailability at the physiological site. The different components of the formulation are described below. The introduction of a pharmaceutical formulation in the physiologically selected site can be advantageously achieved, topically as subcutaneous, intramuscular, intraperitoneal, nasal, pulmonary, vaginal, rectal, aural, oral or ocular. In another embodiment of the present invention, there is provided a method for preparing pharmaceutical material, comprising the steps of: providing at least one composition of a first lipophilic liquid combined with a pharmaceutical agent in a single continuous phase, adding to the first composition a sufficient amount of a second less lipophilic liquid than the first liquid which is miscible in the first liquid to cause the separation phase of the pharmaceutical agent and form a discontinuous microdispersed phase. The discontinuous phase may be an emulsion or a suspension. Preferably, the first liquid and / or the second liquid is a fluorocarbon. Optionally, the composition includes a cosolvent to facilitate the combination of the pharmaceutical agent with a first liquid, although this is not required. The cosolvent is preferably a non-fluorocarbon. The continuous phase may comprise the fluorocarbon, and the pharmaceutical agent, or may comprise only the pharmaceutical agent. In one embodiment of the method, the first composition is stored for 6, 12 or 18 hours before being combined with the second liquid. In another embodiment, this is stored for 2, 3 or 5 days or 1, 2, 4, 10 or 20 weeks, or 6 months, 12 months, 18 months, 24 months and up to an indefinite amount of time before being used in the addition step. Finally, the present invention includes a set of instrument or equipment for making the pharmaceutical preparations, comprising: a first container having a first composition comprising a first lipophilic liquid fluorocarbon and a pharmaceutical agent in a single continuous phase; a second container containing a second liquid miscible with the first liquid, wherein the second liquid is less lipophilic than the first, so after the combination of the first composition and the second liquid, the separation phase of the pharmaceutical agent occurs to form a discontinuous microdispersed phase of the pharmaceutical agent. The first composition preferably also includes a non-fluorinated cosolvent in which the pharmaceutical agent is soluble. In another embodiment, the discontinuous phase resulting after the mixing comprises a pharmaceutical agent and a cosolvent. In another, this essentially consists of the pharmaceutical agent, or comprises a suspension of the pharmaceutical agent. Other objects, features and advantages of the present invention will become apparent to those skilled in the art upon consideration of the following detailed description of preferable exemplary embodiments thereof. DETAILED DESCRIPTION OF THE FORMS OF REALIZATION EXAMPLES In a broad aspect, the stable, high biohability pharmaceutical microdispersions of the present invention comprise a 2 phase systems with a continuous liquid fluorocarbon phase and a discontinuous lipophilic pharmaceutical phase. Preferably, the discontinuous phase is formed spontaneously as a result of the excess of the pharmacist's solubility in the continuous phase. Depending on whether the incorporated cosolvent is in discontinuous phase, the shape of the microdispersion can be inverse emulsion (the cosolvent is present in the discontinuous phase) or a suspension (the cosolvent is not present in the discontinuous phase). Unlike the fluorocarbon delivery vehicles of the prior art, the weakness of the present invention for incorporating relatively lipophilic pharmaceutical agents into homogeneous microdispersions allows their effective delivery to aqueous physiological sites. Other aspects of the present invention relate to the method for forming the microdispersions presented and the methods for their administration at the selected physiological sites. Those skilled in the art will further appreciate that because of the non-irritating and bacteriostatic properties and in fact, of the softness and lubrication of the fluorochemical microdispersions, the formulations of the present invention are extremely suitable for use in applications wherein the repeated or prolonged administration of medication. In order to appreciate the unique and unexpected characteristic of the present invention it should be emphasized that the formation of homogeneous, stable microdispersions is related to the relative lipophilicity of the components rather than absolute lipophilicity. That is, the lipophilicity of a component will influence the selection of the other components that are compatible with the invention. Accordingly, any pharmaceutical compound that is soluble and subsequently conducts the solution is compatible with the present invention. In preferred embodiments the lipophilic fluorochemical used in the liquid carrier must be sufficiently hydrophobic, when combined with at least one cosolvent, to incorporate the lipophilic pharmaceutical agent or agents, of interest in the thermodynamically stable composition. This thermodynamically stable composition must be, but does not require it to be a molecular solution. Accordingly, the selected lipophilic fluorochemical will be influenced by the lipophilicity of the pharmaceutical agents that are incorporated. Similarly, the selection of the fluorochemical diluent used to effect the desired separation phase will be influenced by the selection of the lipophilic carrier used when incorporating the pharmaceutical agent into the thermodynamically stable composition. Any fluorochemical diluent capable of producing the desired microdispersion from the thermodynamically stable composition can be selected. In other words, when the highly lipophilic fluorochemical is used to incorporate the pharmaceutical agent (also, preferably, highly lipophilic), a more lipophilic diluent (but less lipophilic than the fluorochemical in the thermodynamically stable solution can be used to initiate the Separation phase: Conversely, when the fluorochemical used in the thermodynamically stable composition is relatively less lipophilic (for a relatively non-lipophilic bioactive agent), the fluorochemical diluent required to produce the microdispersion will generally be less lipophilic. Fluorochemical and lipophilic fluorochemical that produces the desired microdispersion is considered to constitute part of the present invention, although the scope of the invention is defined by the formation of the desired dispersions, some indication of which components They will be combined in order to produce the preferred results can be obtained by comparing their lipophilicity as determined by methods well known in the art. The lipophilicity of a compound can be related to different parameters including the critical solution temperature in hexane (CSTH), the molar refraction (RJ and the logarithm of the octanol-water separation coefficient (log P0 / w) .While each of these methods are commonly used to predetermine the lipophilicity of different agents, certain methods are preferred for different classes of compounds For example, the lipophilicity of pharmaceutical compounds is typically measured and reported using the logarithm of the octanol / water partition coefficient (log P0 / w) Conversely, the lipophilicity of liquid fluorochemicals can generally be related to temperature of critical solution in n-hexane (CSTH), and molar refraction methods (RJ with CSTH standards which is the most common of the two) For the purpose of describing the present invention this convention will be followed. only explanatory, the exemplary lipophilicity values of the pharmaceutical agents will typically be provided as determined by the coefficient. octanol / water partition ratio while the exemplary lipophilicity values for liquid fluorochemicals will be provided as determined by the use of molar refractivity and CSTH. Those skilled in the art will appreciate that the critical solution temperature in n-hexane is defined as the temperature at which the equivolume mixture of n-hexane and the substances to be measured form 2 immiscible liquid phases from a simple liquid phase. . The molar refraction is calculated by the following equation: R »= Vm (n2 - l) / n2 + 2) where Vm and n are the molar volume and the refractive index respectively. In general, for a class of compound having the same carbon number at a lower value, greater lipophilicity of the compound is obtained. For the purpose of this application the values 1 are calculated using the computer model based on the contribution-addition group and the mechanical behavior based on the empirical observations. Accordingly, the values contained herein are harmed from the lipophilicity offered for merely explanatory purposes and in no way limit the scope of the invention. Finally, the octanol-water separation coefficient (P 0 / w) is the average of the amounts of a substance that is separated into equal volumes of octanol and water. That is, the lipophilic substance to be measured is transferred into the octanol / water mixture and the amount of substance in each phase is subsequently measured. As reported in the literature, the higher the value obtained, the greater the lipophilicity of the substance in question. In the preferred embodiments the present invention will be used in conjunction with pharmaceutical compounds having an octanol-water partition coefficient greater than about -3. Due to the low polarizability of highly fluorinated compounds, the solubility of non-fluorinated substances, including many lipophilic drugs, in fluorochemicals is very low. In order to incorporate pharmaceutically effective amounts of lipophilic agents into fluorochemicals, the fluorochemicals used must be relatively lipophilic in nature. The lipophilicity of fluorochemicals can be significantly increased by replacing the fluorine atom with more polarizable groups. Substituents that are particularly effective are polarizable halogens (ie, bromine, chlorine and iodine) and hydrocarbon chains. More particularly, lipophilic fluorochemicals or lipophilic fluorochemical combinations which are capable of promoting the dissolution and incorporation of the selected pharmaceutical agent or agents in thermodynamically stable compositions of the present invention are preferred. Exemplary lipophilic fluorochemicals that are particularly substituted for use in the invention contain 1 or more non-fluorinated halogen atoms (i.e., bromine, chlorine, iodine), or a group of hydrocarbon substituents (ie, C2H5). In a preferred embodiment, the fluorochemical contains up to 8 carbons. In a particularly preferred embodiment, the fluorochemical contains between 4 and 6 carbons. The molecular structures of the fluorochemicals used to form the thermodynamically stable composition can be linear, branched or contain cyclic structures. These may also be saturated or contain aromatic groups. As discussed above any lipophilic fluorochemical which is capable of incorporating the selected pharmaceutical agent into the thermodynamically stable composition is compatible with the techniques herein and falls within the scope of the invention. That is, the lipophilic fluorochemicals that can be used in the current invention is defined by the selected lipophilic pharmaceutical agent. Furthermore, it can be considered as an indicator of the lipophilic fluorochemicals that can be particularly beneficial, the values of molar refractivity and the critical solution temperature in n-hexane (CSTH). Preferably the relatively lipophilic fluorochemicals used to incorporate the selected pharmaceutical agent will have molar refractivity values of less than 45 cm 3 or CSTH values of less than 10 ° C. Particularly preferred embodiments, the relatively lipophilic fluorochemicals will not have molar refractivity values of less than about 40 cm 3 or CSTH values of less than about less than about 20 ° C. In an exemplary form of the invention, the lipophilic fluorochemical is 1,4-dibromo-F-butane at any molar reactivity value of about 36.68 cm 3. Table 1, immediately below, lists the molar refractivity values of this lipophilic fluorochemical and others that are compatible with the present invention.

Table 1 Molar refractivity values for relatively lipophilic fluorochemicals More particularly, the lipophilic fluorochemicals contemplated for use in the formation of thermodynamically stable compositions of the present invention include halogenated fluorochemicals (ie, CnF2n + 1 X, XCnF2nX, where n = 3.8, X = Br, Cl or I) , fluorocarbon-hydrocarbon compounds of 2 blocks or three blocks (ie, CnF2n + 1-CmH2m + 1, CnF2n + 1 CH = CHCmH2ra + 1, where n = 2.8, m = 2.6 or CpH2p + 1-CnF2n-CmH2m +1, where p = 1.6, m = 1. 6 and n = 2.6), halogenated esters or polyesters (ie, XCnF2nOCmF2mX, XCF2OCnF2nOCF2X, where n, m = 1.4, X = Br, Cl or I) and fluorocarbon-hydrocarbon esters of 2 blocks or 3 blocks (ie CnF2n + 1-0-CmH2m + 1, where n = 2.8, m = 2.6 or CpH2p + 1-0-CnF2n-0-CmH2m + 1, where p = 2.6, m = 2.6 and n = 2.8). The halogenated hydrocarbon and fluorocarbon fluorocarbon compounds containing other linking groups, such as for example esters, thioesters, amines and amides are also suitable for use in the formation of the thermodynamically stable compositions of the present invention. Mixtures of fluorochemicals are also contemplated. Other suitable fluorochemicals may include brominated perfluorocarbons, such as, for example, n-C "-F9Br, 1-bromo-F-heptane (n-C7F15Br), and 1-bromo-F-hexane (n-C6F13Br). Also contemplated are fluorochemicals having non-fluorinated substituents, such as for example perfluorooctyl chloride (n-C7F15Cl), 1,6-dichloro-F-hexane (n-ClC6F12Cl), and 1,4-dichloro-F-butane (n- ClC4F8Cl). Particularly preferred is 1,4-dibromo-F-butane and 1,6-dibromo-F-hexane.

In the preferred embodiments, the relatively lipophilic fluorochemical will comprise less than 50% volume by volume of the presented pharmaceutical microdispersions. Moreover, preferred lipophilic fluorochemicals have sufficiently low vapor pressures to avoid significant loss of a liquid caused by evaporation during storage or delivery. More specifically, lipophilic fluorochemicals are preferred which have boiling points, at ambient pressure, greater than about 37 ° C. As detailed above, any physiologically acceptable fluorochemical diluent can be used for a particular microdispersion not so long as it is capable of initiating the required separation phase. Generally, this means that the lipophilicity of the fluorochemical diluent will be less than the lipophilicity of the fluorochemical comprising the thermodynamically stable composition. The ability to use different fluorochemicals as diluents is a particular advantage since it can be selected based on biocompatibility, to perform certain characteristics of the microdispersion such as the average particle size or the viscosity of the continuous phase or can be selected based on the characteristics no techniques such as costs or availability. Biocompatibility (preferred PFC) includes F-decalin, F-perhydropenantron, F-octane, F-tripropylamines, F-tributylamine, PFOB, F44E. While the range of the measured lipophilicity for the fluorochemicals diluents is generally less than the range of measured lipophilicity of fluorochemicals comprising the thermodynamically stable composition, there may be an overlap. For example, when a highly lipophilic fluorochemical is used to form the stable composition, the fluorochemical having some lipophilicity (but not as much as that of the highly lipophilic fluorochemical) can be used as a diluent to initiate the separation phase and produce the desired microdispersion. In another formulation it may be possible to use a fluorochemical having some lipophilicity to comprise the thermodynamically stable composition and use an extremely non-lipophilic fluorochemical to produce the microdispersion. Both microdispersions are within the scope of the present invention even when the same fluorochemical is used as a diluent in one or the other case to form the thermodynamically stable composition in any case. Nevertheless, as well as the discussion about the lipophilic fluorochemicals above, the values of molar refractivity and critical solution temperatures in n-hexane (CSTH) if it can be used to indicate which fluorochemical is more suitable to be compatible with the invention. This is particularly true when the measured values are compared to the measured values of the lipophilic fluorochemical. Preferably, the fluorochemical used to initiate the separation phase will have molar refractivity values greater than about 38 cm 3 or CSTH values greater than about -40 ° C. In particularly preferred embodiments, diluent fluorochemicals will have molar reactivity pains greater than about 45 cm3 or CSTH values greater than about 20 ° C. Table 2, immediately below, lists the molar refractivity values of fluorochemicals that are useful as diluents in the present invention.

TABLE 2 MOLAR REFRACTIVITY VALUES FOR RELATIVELY NON-LIPOFILIC FLUOROCHEMICALS Fluorochemicals useful as diluents in the present invention include bis (F-alkyl) such as for example C4F9CH = CHC4F9 (sometimes designated "F-44E"), i-C3F9CH = CHC6F13 ("F-Í36E"), and C6F13CH = CHC6F13 ("F66E"); cyclic fluorochemicals, such as for example C10F18 ("F-decalin", "perfluorodecalin" or "FDC"), F-adamantine, ("FA"), F-methyladamantane ("FMA"), F-1,3-dimethyladamantane ( "FDMA"), F-di-or F-trimethylbicyclo [3, 3, 1] nonane ("nonane"); perfluorinated amines, such as for example F-tripropylamine ("FTPA") and F-tributylamine ("FTBA"), F-4-methyloctahydroquinolizana ("FMOQ"), FN-methyl-decahydroisoquinoline ("FMIQ"), FN-methyldehydroquinoline ( "FHQ"), FN-cyclohexylpurrolidine ("FCHP") and F-2-butyltetrahydrofuran ("FC75" or "FC77"). Other fluorochemicals that can be used as diluents include brominated fluorochemicals, such as 1-bromo-heptadecafluoro-octane (C8F17Br, sometimes referred to as perfluorooctyl bromide or "PFOB"), 1-bromopenta-decafluoroheptane (C7F15Br), and 1-bromotridecafluorohexane (C6F13Br, sometimes known as perfluorohexylbromide or "PFHB"). Other brominated fluorochemicals are presented in U.S. Patent No. 3,975,512 to Log. Also contemplated are fluorochemicals having non-fluorinated substituents, such as for example perfluorooctyl chloride, perfluorooctyl hydride and similar compounds having different numbers of carbon atoms. Fluorochemicals further contemplated according to the invention include perfluoroalkylated ethers or polyethers, such as (CF3) 2CFO (CF2CF2) 2OCF (CF3) 2, (CF3) 2CFO- (CF2CF2) 3OCF (CFRM1013) 2, (CF3) 2CFO (CF2CF2) XF, wherein X 1 . 6 (CF3) 2CFO (CF2CF2) 2F, (C6F13) 20. The fluorochemical hydrocarbon compounds, such as for example compounds having the general formula CnF2n + 1-CnF2n + 1, CnF2n. + 10CnF2n, + 1, or CnF2n + 1CH = CHCnF2n. + 1, where n and n 'are the same or different and are from about 1 to about 10 (as far as the compound is a liquid of room temperature). These compounds, for example, include C8F17C2H5 and C6F13CH = CHC6H13. It will be appreciated that thioester esters or other modified mixed hydrocarbon fluorochemical compounds and fluorocarbons are also included in the broad definition of fluorochemicals suitable for use in the present invention. In preferred embodiments the diluent comprises approximately 50 volume / volume of the microdispersions presented. Mixtures of fluorochemicals are also contemplated. Additionally, fluorochemicals that are not mentioned here, but that have the properties written in the presentation, can also serve for the formation of microdispersions. As mentioned above, some fluorochemicals have relatively high vapor pressure and correspond to low boiling points which makes them less suitable for use as diluents in the present invention. In particular, these volatile compounds are less useful for pulmonary administration and partial liquid respiration of the medicament. This includes 1-bromotridecafluorohexane (C6F13Br) and F-2-butyltetrahydrofuran ("FC-75" or "RM101"). More specifically, lipophilic fluorochemicals which have a boiling point at ambient pressure above 37 ° C are very advantageous. As pulmonary drug supply is an important aspect of the present invention the fluorochemicals selected as diluents (and to a certain extent the lipophilic fluorochemicals) will have the functional characteristics that allow their temporary use as a lung surfactant, for oxygen supply, in the removal of material inside the lung or to inflate collapsed portions of the lung. Fluorochemicals are compatible and most are useful for sterilization techniques. For example, they can be sterilized by heat (such as an autoclave) or sterilize by radiation.

In addition, sterilization by ultrafiltration is also contemplated. In a normal physiological system, surfactants work to reduce the surface tension of the alveolar tissue. The surfactant in the lung is in the continuous water fluid in the alveolus. Typically, the surface tension in the absence of pulmonary surfactant is ca. 70 d / cm decreasing to about 0 d / cm in the presence of a pulmonary surfactant. Fluorochemicals that have low surface tension values (typically in the range of 20 dines / cm) and that have the benefit of dissolving extremely large amounts of gases such as oxygen and carbon oxide. Perfluorochemicals are suitable for use, and brominated fluorochemicals are particularly preferred. Moreover, the low surface tension deteriorated by the continuous phase to the fluorochemical of the present invention can increase the bioability of the incorporated pharmaceutical agent and therefore increase its effectiveness. Although the reduction in surface tension is an important parameter in judging fluorochemicals and perfluorochemicals as a pulmonary delivery vehicle, or for use in partial liquid respiration, a novel and not so obvious feature of some fluorochemicals is their apparent ability to disperse in the entire respiratory membrane. As well as the ability of fluorochemicals to reduce surface tension, the ability of some fluorochemicals to disperse evenly and effectively on the pulmonary surface can increase bioability and improve the utilization of the incorporated pharmaceutical agent. The total surface area of the respiratory membrane is extremely wide (ca 160 m2 per adult). Thus, the effective fluorochemical for partial liquid respiration and the drug supply must be able to cover the lung surface with a relatively small volume. The ability of some substances to cover the measured surface area can be described by their dispersion coefficient. The oil-in-water dispersion coefficients for fluorochemicals can be expressed with the following equation: S (or in w) = yw / a- (yw / o + yo / a) where S (or in w), represents the dispersion coefficient; y = interfacial tension; w / a = water / air; w / o = water / oil; ó / a = oil / air. If the fluorochemical presents a positive dispersion coefficient, then it will spontaneously disperse on the surface of the respiratory membrane. Fluorochemicals have a dispersion coefficient of at least 1, such as for example perfluorooctyl bromide, they are particularly preferred as diluents for microdispersion in the use for the administration of pulmonary medicaments. Of course it should be emphasized that fluorochemicals with lower coefficients can be used to formulate microdispersions according to the present invention and can be used for the effective administration of medicaments including pulmonary administration. In addition to improving the bioavailability of the incorporated pharmaceutical agent, adequate coverage of the lung surface is beneficial in restoring the transfer of oxygen and carbon dioxide and in lubricating the surface of the lungs to minimize additional lung trauma. In this sense, fluorochemicals useful as diluents are generally capable of promoting gas exchange. It is also true for the previous lipophilic fluorochemicals. Accordingly, in the preferred embodiments, the microdispersions of the present invention will be enriched by the introduction of a physiologically acceptable gas. In addition to the fluorochemicals used in the present invention, the microdispersions preferably contain at least one non-fluorinated cosolvent to facilitate the incorporation of the lipophilic pharmaceutical agent into the pharmaceutically stable composition. Preferably this cosolvent is completely miscible in the selected lipophilic fluorochemical and comprises up to 75 volume / volume of the thermodynamically stable composition. Those skilled in the art will appreciate that the miscibility of the cosolvent to a certain, will be in dependent concentrations. In most preferred embodiments, the concentration of the non-fluorinated cosolvent comprises up to 50% volume / volume of the thermodynamically stable composition. In the embodiments employed of the invention, a cosolvent selected from a group consisting of ethers, alcohols, alkylsulphoxides, water and a combination thereof is preferably included. Co-solvents that are particularly suitable for use with the present invention are short chain alcohols (carbon with chain length <; 4 carbon) or an alkylsulfoxide such as, for example, dimethylsulfoxide. In a particularly preferred embodiment, the cosolvent is ethanol. Water can be used in the preferred embodiment by incorporating the appropriate lipophilic fluorochemicals and / or the pharmaceutical compounds. As discussed above, the concentration of the non-fluorinated cosolvent is an important factor in determining whether the microdispersion is generated as a suspension (a solid discontinuous phase) or as an emulsion (a liquid dispersed in another liquid discontinuous phase) generally, the Suspension will be formed when the concentration of cosolvents in the pharmaceutical microdispersion does not exceed the solubility in the same. In this case the cosolvent remains in the continuous fluorochemical phase as the lipophilic pharmaceutical compound is forced out through the combination with the diluent. Conversely, when the concentration of cosolvent exceeds its solubility in the pharmaceutical microdispersion after the addition of the diluent, the insoluble volume will be forced into the discontinuous phase with the pharmaceutical agent thereby forming an emulsion. The inherent ability to easily alter the shape of the microdispersion depending on the route of administration that is attempted is the main advantage of the invention, and allows to attenuate the drug delivery profiles and regimens. As mentioned above, the microdispersions of the present invention may also comprise 1 or more additives which are present in the discontinuous pharmaceutical phase, in the fluorochemical continuous phase in both phases or at the interphase interface. Among other additives, 1 or more fluorinated and non-fluorinated surfactants may be present in the thermodynamically stable composition. Surfactants are ampicillin molecules that contain both a "hydrophilic of the head group" and a "lipophilic of the tail". Typically, the surfactant forms a monomolecular layer in liquid-liquid and liquid-solid interfaces reducing the interfacial tension. This reduction in interfacial tension significantly decreases the thickening of the microdispersion and can significantly increase its lifetime. Among the surfactants contemplated for use in the present invention are fluorinated and non-fluorinated phospholipids including phosphatidylethanolamines, phosphatidic acids, and phosphatidylcholines. Emulsifying agents suitable for the use of the present invention include, but are not limited to, fluorinated or non-fluorinated glyceroglycolipids, egg yolk lecithins, salts of fatty acids, ethers linked with lipids and diacyl phosphates. The pharmaceutical microdispersions of the present invention are capable of delivering any desired pharmaceutical agent that can be incorporated into the thermodynamically stable composition and forced into the discontinuous phase through the addition of a fluorochemical diluent. As used herein, the term "pharmaceutical agent" defines any therapeutic or diagnostic compound or composition that can be administered to an animal. Preferred pharmaceutical agents include hydrophilic nonionic drugs with solubility in ethanol or lipophilic medicaments. More preferably, the incorporated pharmaceutical agents are lipophilic agents. Preferably, the pharmaceutical microdispersions of the present invention incorporate less than about 10% w / v of a diagnostic or therapeutic agent. The precise amount of pharmaceutical agents incorporated in the microdispersions of the present invention depends on the agent selected, the dose required, and the form of the drug actually incorporated into the microdispersion. Those skilled in the art will appreciate that these determinations can be made using well-known techniques in combination with the techniques of the present invention. Preferred pharmaceutical agents respiratory agents, antibiotics, antivirals, mydriatics, antiglaucoma, anti-inflammatories, antihistamines, antineoplastic agents, anesthetics, ophthalmic agents, cardeovascular agents, active principles, nucleic acids, genetic material, immunoactive agents, imaging agents, inmonosupressive agents, gastrointestinal agents and combinations of same. The forms of embodiments employed in the present invention comprise anti-inflammatory agents such as glucocorticosteroids (ie cortisone, prenisone, prenisolone, dexamethasone, betamethasone, beclomethasone diproprionate, triamcinolone, acetonide, flunisolide), xanthine (eg theophylline, caffeine), chemotherapeutic agents. (for example cyclophosphamide, lomustine, methotrexan, cisplatin, and taxane derivatives), antibiotics (for example aminoglycosides, penicillins, cephalosporins, buffaloes, quinolones, tetracyclines, chloramphenicol), bronchodilators such as for example B2-antagonist (for example adrenaline, isoprenaline, salmeterol, albuterol, salbutamol, terbutaline, formoterol) and surfactants. Still other exemplary forms of the invention include α / β adrenergic blockers (eg Normodina®, Trandato®), angiotensin-converting enzyme inhibitors (ie Vasotec®), antiarrhythmics, β-blockers, calcium channel blockers, agents inotropic agents, vasodilators, vasopressors, anesthetics (for example morphine) and ophthalmic agents (ie, polymyxin B, Neomycin, Gramicidin). More preferred agents include glucocorticosteroid, taxane derivatives (ie, Taxol®, Taxotere®) and drug packet forms typically administered as stable derivatives (ie, Gentimycin, Ciprofloxacin). In accordance with the present invention, those skilled in the art will appreciate that different forms of these compounds can be used to modify the therapeutic index of pharmaceutically active agents. Similar to the fluorochemicals mentioned above, the selection of pharmaceutical agents and, in particular, the lipophilic compounds are limited only to the ability to incorporate into the desired microdispersions as presented in the invention. Still, some indicators of the compatibility of an individual pharmaceutical agent can be derived from the measured value of their lipophilicity. Unlike the fluorochemical components of the present invention, the convention is measured and the lipophilicity of the pharmaceutical compound is reported using the logarithm of the octanol / water partition coefficient (Log P0 / w). In this system the increase in lipophilicity corresponds to the value of the logarithm P0 / w. Preferably the pharmaceutical agents incorporated in the present invention will have a logarithm P0 / w greater than about -3. More preferably the pharmaceutical agents will have a Po / w logarithm greater than about 0.5 and even more preferably greater than about 2. Those skilled in the art will appreciate values above 0.5 indicating that the compound has limited solubility in an aqueous environment. The octanol / water partition coefficient of the different lipophilic pharmaceutical agents of the example compatible with the techniques of the present invention are reproduced in Table 3 below.

Table 3 Octanol / water partition coefficient (Pn?) Of different drugs.

Tang-Liu, D.D.S., Richman, J.B.and Liu, S.S., J. Ocul.

Pharmac., 1992, 8, 267. Hughes, P.M. and Mitra, A.K., J. Ocul. Pharmac., 1993, 9, 299. 3 Hageluken, A., Grunbaum, L., Nurnberg, B., Harhammer, R., Schunack, W. and Seifert, R., Biochem. Pharmac., 1994, 47, 1789. 4 Moriguchi, I., Hirono, S., Liu, Q., Nakagome, I. and Matsuchita, Y., Chem, Pharm. Bull., 1992, 40, 127. 5 Yokogawa, K., Nakachima, E., Ishizaki, J., Maeda, H., Nagano, T. and Ichimura, F., Pharm. Res. 1990, 7, 691. a in octanol / pH 7.4 isotonic phosphate buffer at 37 ° C.

Because the microdispersions of the present invention are only suitable for use in a variety of physiological applications such as ocular, oral, pulmonary, rectal, subcutaneous, intramuscular, intraperitoneal, nasal, vaginal or aural administration of drugs or diagnostic compounds , a variety of pharmaceutical agents can be incorporated herein. In accordance with the above, the list above of pharmaceutical agents is exemplary only and is not intended to be a limitation. Another unique advantage provided by the microdispersions of the present invention is the ability to be used in the form of free bases of the incorporated pharmaceutical agent rather than in less effective salt forms. That is, the efficacy of the lipophilic forms of the drug has been shown in many cases to be more potent than the less lipophilic forms of the drug such as salts. The non-reactive nature of the fluorochemical microdispersions allow the incorporation of particularly effective base forms of the selected pharmaceutical agent. Those skilled in the art will appreciate that the use of these more potent drugs improves the bioability of the incorporated pharmaceutical agent and reduces the doses that must be administered. It will also be appreciated by those skilled in the art that the appropriate amount of drug and the time of dosage can be determined by the formulations according to the information that already exists and without the need for experimentation. It is important to note that fluorochemical microdispersions can be administered by different routes, depending on the indication of the treatment. For example, intranasal or intrapulmonary administration (ie, endotracheal tube or pulmonary catheter), aerosolization or nebulization that are contemplated for the treatment of respiratory or systemic diseases. An example may include the treatment of lung cancer or other systemic cancers with taxane derivatives by pulmonary administration of this medicament. Due to the low aqueous solubility of paclitaxel (ie Taxol) it is formulated in a mixture of polyoxyethylated castor oil and ethanol (Bristol Myers Squibb) which is intended for intravenous administration. In addition to the manifestations of hypersensitivity associated with the delivery vehicle itself (bronchospasm and hypotension), other systemic toxicities associated with paclitaxel, such as cardiac toxicity and neorotoxicity, limit the useful potential of this drug (Arabic, SG, Christian, MC, Fisherman, JS, Cazenave, LA, Sarosy, G., Suffness, M., Adams, J., Canetta, R., Cole, KE, and Friedman, MA, J. Nati, Canc.Inst. Monogr, 1993, No 15, 11). The administration of paclitaxel by the intrapulmonary route in the form of a fluorochemical suspension can significantly improve the safety profile of the drug by eliminating the use of biologically active delivery vehicles and by reducing the concentration of the drug in the circulation required for efficacy of the medication. Intraperitoneal, subcutaneous and ocular administration are also contemplated. The fluorochemical microdispersions of the invention can also be used to deliver diagnostic and therapeutic agents in the gastrointestinal tract by means of oral administration. A contemplated example would be the supply of antibiotics by the gastro-intestinal tract line for the treatment of infections with Heliobacter pylori. Heliobacter pylori has been implicated as the cause of gastric ulcers and stomach cancer. The activities of antibiotics in the treatment of H. pylori infections could be administered in the form of a suspension or soles of fluorochemicals with a submicron size. As discussed above, the microdispersions of the present invention can be prepared by incorporating a lipophilic pharmaceutical agent in a thermodynamically stable composition comprising at least one lipophilic fluorochemical and at least one non-fluorinated cosolvent. Depending on the presence of optional additives such as for example surfactants, the thermodynamically stable composition may or may not be a molecular solution. In any case, once the thermodynamically stable composition is formed it can be combined with the fluorochemical diluent. Generally the diluent is of a volume greater than that of the thermodynamically stable composition. As the combination equilibrates, the separation phase begins by reducing the lipophilicity of the entire system, which causes the lipophilic pharmaceutical agent and possibly a portion of the cosolvent to bind in its discontinuous phase to form the microdispersion. The discontinuous phase may be in the form of an inverse emulsion or a suspension, in any case, the substantially homogeneous microdispersions of the present invention may comprise extremely small particles having an average diameter in the order of 10 nanometers. As used herein, the terms "particulate" or "particulate" will refer to the discontinuous phase of the microdispersions whether in their solid or liquid phase. In the present invention, these small particles (preferably having an average diameter smaller than 500 nm) evenly distributed increase the bioability of the pharmaceutical agents incorporated in the selected physiological target due to their relatively large surface area and their dissolution time correspondingly Quick. Conversely, by altering the components of the microdispersion, the reaction conditions or the time during which the reaction is allowed to process, the incorporated particles can grow to a size of a few microns. Those skilled in the art will appreciate that the ability to control the incorporated particle size can be used to attenuate and extend the drug delivery profiles and optimize the dosage regimens. Preferably, the average particle diameter will be less than about 3 μm and preferably less than about 1 μm. In many preferred embodiments, the average particle diameter will be only a few manometers, ie 2, 3, 4, 5, 7 or 10 nanometers. As discussed above, the inverse emulsions of the present invention comprise a discontinuous pharmaceutical / cosolvent phase and a perfluorochemical continuous phase. As with the suspension, the inverse emulsions of the present invention may incorporate fluorinated or non-fluorinated surfactants to promote stability. The amount of surfactant employed is generally less than about 10% (w / v) of the total volume. The emulsion can be formed following the combination of the diluent and the thermodynamically stable composition using methods well known in the art. For example, the inverse emulsions of the invention are typically prepared by emulsifying the formulation by means of conventional homogenization such as microfluorization, sonication or homogenization under pressure. Both in the inverse emulsions and in the suspension in the present invention can be sterilized for example by radiation or by filtration. Advantageously, the pharmaceutical formations, with high bioability, of the present invention can be administered by a physician in a sterile pre-package form. More particularly, the formulations can be supplied as stable preformed microdispersions of easy administration or as separate mixtures of mixing components. Typically, when supplied as components, the fluorochemical diluent will be packaged separately from the pharmaceutical composition in a dynamically stable manner. The microdispersion can then be formed at any time before its use by simply combining the contents of each container. In the preferred embodiment the present invention can be provided as a kit comprising: a first container having a first composition comprising a first lipophilic liquid chlorocarbon and a pharmaceutical agent in a simple continuous phase; and a second container having a second liquid miscible with the first liquid, wherein the second liquid is less lipophilic than the first liquid, such that after the combination of the first composition and the second liquid the separation phase of the agent Pharmaceutical occurs to form the discontinuous microdispersed phase of the pharmaceutical agent. The following examples of the various exemplary formulations of the present invention illustrate, without limiting the exemplary methods for their formation and the resulting characteristics. For purposes of clarity in the following examples, the thermodynamically stable composition of the invention will be defined as "composition 1". In order to illustrate the advantages of the present invention and to show its wide applicability, various lipophilic pharmaceutical agents were used to form pharmaceutical suspensions such as described above. Each microdispersion produced was tested for a particle size distribution.

EXAMPLE 1 PREPARATION OF A PREDNISONE SUSPENSION IN A FLUOROCHEMISTRY 3 mL of the following continuous fluorochemical suspension was prepared: Composition 1: 0.38% weight / volume of prednisone (Sigma Chemical Co.) was dissolved in a solution composed of 1, 4- dibromo- F-butane (50% volume / volume, Exfluor, Austin, TX) and ethyl alcohol grade NF (50% volume / volume Spectrum Chemical Co.) Fluorochemical diluent: Perfluorooctylbromide (Atochem, France).

An aliquot of composition 1 (60 μl) was injected into a 12 x 100 ml test tube with a syringe into a sample of perfluorooctyl bromide (PFOB; 3 ml). The tube was capped and the contents mixed gently by inverting the tube. A drug with submicron, opalescent particle size was obtained in the fluorocarbon suspension. The particle size distribution of the dispersion was measured using a photon correlation spectroscopy (PCS) in a Nicomp 270 photon correlation spectrophotometer.

(Pacific Scientific). The dispersion of the drug from the resultant had an average particle diameter of 60 + 42 nm. EXAMPLE 2 PREPARATION OF A PACLITAXEL SUSPENSION IN FLUOROCHEMISTRY 3 ml of a continuous suspension of fluorochemicals was prepared as follows: Composition 1: 0.40% w / v paclitaxel (Sigma Chemical Co.) was dissolved in a solution composed of 1, 4- dibromo-F-butane (50% volume / volume, Exfluor, Austin, TX) and ethyl alcohol of NF grade (50% volume / volume; Spectrum Chemical Co.). The fluorochemical diluent: perfluorooctylbromide (Atochem, France).

An aliquot of composition 1 (60 μl) was injected with a syringe into a sample of perfluorooctyl bromide (PFOB; 3 ml) contained in a test tube of 12 x 100 mm. The tube was capped and the contents mixed gently by inverting the tube. A medicament with submicron particle size, opalescent, was obtained in the fluorocarbon suspension. The particle size distribution of the dispersion was measured using a photon correlation spectroscopy (PCS) in a Nicomp 270 photon correlation spectrophotometer.

(Pacific Scientific). The resulting drug dispersion had an average particle diameter of 50 + 32 nm. EXAMPLE 3 PREPARATION OF A SUSPENSION OF PREDNISOLONE IN A FLUOROCHEMICAL 3 ml of the continuous fluorochemical suspension was prepared as follows: Composition 1: 0.38% weight / volume of prednisolone (Sigma Chemical Co.) was dissolved in a solution composed of 1,4-dibromo-F-butane (80% volume / volume; Exfluor, Austin, TX) and NF grade ethyl alcohol (20% volume / volume; Spectrum Chemical Co.).

The fluorochemical diluent: Perfluorooctylbromide (Atochem, France). An aliquot of composition 1 (60 μl) was injected with a syringe into a sample of perfluorooctylbromide (PFOB; 3 ml) contained in a 12 x 100 mm test tube, the tube was capped and the contents mixed gently by inverting the tube. A drug with submicron opalescent particle size was obtained in the fluorocarbon suspension. The particle size distribution of the dispersion was measured using photon ratio spectroscopy (PCS) in a Nicomp 270 photon correlation spectrophotometer (Pacific Scientific). The resulting drug dispersion has an average particle diameter of 57 + 32 nm.

EXAMPLE 4 PREPARATION OF A SUSPENSION OF DIAZEPAN IN FLUOROCHEMICAL 3 mL of the following fluorochemical continuous suspension was prepared: Composition 1: 0.38% weight / volume of prednisolone (Sigma Chemical Co.) was dissolved in a solution composed of 1, -dibromo-F - butane (90% volume / volume; Exfluor, Austin, TX) and NF grade ethyl alcohol (10% volume / volume; Spectrum Chemical Co.). The fluorochemical diluent: perfluorooctilbromide (Atochem, France) An aliquot of composition 1 (180 μl) was injected with a syringe into a sample of perfluorooctylbromide (PFOB; 3 ml) contained in a test tube of 12 x 100 mm the tube was capped and the content was mixed gently by inverting the tube. A drug with submicron opalescent particle size was obtained, in the fluorocarbon suspension. The particle size distribution of the dispersion was measured using photon ratio spectroscopy (PCS) in a Nicomp 270 photon correlation spectrophotometer (Pacific Scientific). The resulting drug dispersion has an average particle diameter of 65 + 28 nm. The above examples demonstrate the reproducibility and applicability of the present invention in a variety of lipophilic pharmaceutical agents. It is important to note that in each of the examples described above an isotropic or substantially homogeneous microdispersion is formed without mixing excessively or without the need for complicated processing. Moreover, the uniformity of the particle size distribution and the homogeneity of the suspension are superior to the suspensions formed using conventional methods of adding dry powders to the continuous phase. In addition, the particle size is extremely small allowing rapid dissolution in the aqueous environment at the selected site. Additional studies were carried out to determine the importance of the concentration of the cosolvent in the particle size. EXAMPLE 5 EFFECT OF CONCENTRATION OF COETHYL ON PARTICLE SIZE A series of suspensions of prednisone in PFOB was prepared to evaluate the effect of ethyl alcohol concentration on the particle size distribution. The sample preparation and the particle size analysis were described in Example 1 with the only difference being the relative concentrations of 1,4-dibromo-F-butane and ethanol in composition 1. The results of the composition of the solution and the particle size is shown in table 4 below. TABLE 4 EFFECT OF THE CONCENTRATION OF COETILE IN THE DIAMETER OF PARTICLES OF THE MEDICINAL PRODUCT The particle size distribution of prednisone in the final dispersion were not significantly different from the coetyl concentration of composition 1 of up to 50% volume / volume. A significant increase in the average particle size was observed for the suspension prepared with 70% volume / volume of the solution containing the drug with ethyl alcohol. Although not desired is limited to any theory of operation, it is believed that the observed results can be explained as follows. It is not that a core is formed in the supersaturated solution, it begins to grow by accretion and decreases the concentration of the dissolved solute. Therefore, there is a competition for the material between the nucleation process and the crystal growth and the faster nucleation results in smaller particles. The concentrations of prednisone in the solutions contain small amounts of ethanol that are much closer to the maximum solubility in the lipophilic fluorochemical such as when the composition 1 was mixed with the fluorochemical diluent, the solution contained in the drug does not diffuse as for achieve supersaturation. As a result of this, the nucleation averages are faster and the particle size smaller when compared to the solution containing high concentrations of ethanol. By making the concentration of the lipophilic pharmaceutical agent in the thermodynamically stable composition closest to its solubility limit. It is possible to further reduce the average particle size and increase bioability. In any case, the above example demonstrates the ability to control the size of the particles produced to optimize the effectiveness of the incorporated medicament. The following study was carried out to illustrate the compatibility of different co-solvents with the techniques of the present invention. EXAMPLE 6 USE OF DIMETHYL SULFOXIDE AS A COSOLVENT IN THE PREPARATION OF PREDNISONE SUSPENSION IN FLUOROCHEMICAL 3 mL of the following fluorochemical suspension was prepared: Composition 1: 0.38% weight / volume of prednisone (Sigma Chemical Co.) was dissolved in a solution composed of 1,4-dibromo-F-butane (75% volume / volume; Exfluor, Austin, TX) and ethyl alcohol NF grade (20% volume / volume; Spectrum Chemical Co) and dimethyl sulfoxide (5% volume / volume; Aldrich Chemical Co.). The fluorochemical diluent: Perfluorooctyl bromide (Atochem, France). An aliquot of composition 1 (60 μl) was injected with a syringe into a sample of perfluorooctylbromide (PFOB; 3 ml) contained in a 12 x 100 mm test tube, the tube was capped and the contents mixed gently by inverting the tube.

A drug with submicron opalescent particle size was obtained in the fluorocarbon suspension. The particle size distribution of the dispersion was measured using a photon ratio spectroscopy (PCS) in a Nicomp 270 photon correlation spectrophotometer.

(Pacific Scientific). The resulting drug dispersion has an average particle diameter of 41 + 38 nm. This experiment demonstrates that, according to the techniques of the present, different cosolvents or combinations thereof can be used to produce microdispersions with high bioavailability of submicron particles. Similarly, the described experiment demonstrates the ability to use different perfluorochemical diluents.

EXAMPLE 7 PREPARATION OF PREDNISON MICRODISPERSIONS IN DIFFERENT FLUOROCHEMICAL DILUENTS An aliquot of composition 1 (60 μl) was prepared in the example and injected with a syringe in different fluorochemical diluents (3 ml) contained in 12 x 100 mm test tubes. The tubes were covered and the contents mixed gently by inverting the tubes. A drug of submicron, opalescent particle size was obtained in fluorocarbon suspensions. The particle size distributions of the dispersions were measured using photon correlation and spectroscopy (PCS) in a Nicomp 270 photon correlation spectrophotometer (Pacific Scientific). All tested fluorochemical supply vehicles produced continuous fluorochemical suspensions with submicron particle size. The results are summarized in the Table below.

TABLE 5 PARTICLE SIZE OF PREDNISONE SUSPENSION IN DIFFERENT FLUOROCHEMICAL DILUENTS As can be seen in the above Table, the effective suspensions of the present invention can be formed using different fluorochemical diluents. These different diluents can be selected based on techniques and non-technical criteria such as the ability to transport gas, viscosity and cost. This allows the formulations to be easily made to adapt to different situations. In addition to the suspensions discussed in the previous examples, microdispersions can be formed as an emulsion as demonstrated in the following examples.

EXAMPLE 8a PREPARATION OF EMULSIONS CONTAINING PREDNISONE WITHOUT SURFACTANT 3 ml of the continuous emulsion was prepared with fluorochemical, with submicron particle size as follows: Composition 1: 0.49% weight / volume of prednisone (Sigma Chemical Co.) was dissolved in a solution composed of 1,4-dibromo-F-butane (70% volume / volume; Exfluor: Austin, TX) and ethyl alcohol of NF grade (30% volume / volume; Spectrum Chemical Co.) An aliquot of composition 1 (60 μl) was injected with a syringe, in different fluorochemical diluents (3 ml), contained in 12 x 100 mm test tubes. The tubes were capped and immersed in a sonicator bath (Branson Model 3200) for 5 seconds to obtain a milky dispersion in a continuous fluorochemical medium. The dispersion of the particle size of the dispersions was measured using photon correlation spectroscopy (PCS) in a Nicomp 270 photon correlation spectrophotometer (Pacific Scientific). The results are summarized in Table 6 below.

TABLE 6 AVERAGE PARTICLE DIAMETER FOR EMULSIONS CONTINUOUS FLUOROCHEMICAL PHARMACISTS This information shows that liquid particles in the order of nanometers can easily be formed using the techniques demonstrated herein. Those skilled in the art appreciated that these emulsions significantly increase the bioability of the incorporated pharmaceutical agent. It is important to note that while emulsions are formed without a surfactant, similar results could be obtained with the inclusion of numerous fluorinated or non-fluorinated surfactants. EXAMPLE 8b USE OF DIMETHYL SULPHIDE IN THE PREPARATION OF EMULSIONS CONTAINING SURFACTANT-FREE MEDICINES 3 ml of the continuous fluorochemical emulsion was prepared, with the following submicron particle size: Composition 1: 2.4% weight / volume of prednisone was dissolved (Sigma Chemical Co.) in a solution composed of dimethylsulfoxide (50% volume / volume; Aldrich Chemical Co.) and ethyl alcohol of NF grade (50% volume / volume; Spectrum Chemical Co.). An aliquot of composition 1 (30 μl) was injected with a syringe into different fluorochemical delivery vehicles (3 ml) arranged in 12 x 100 mm test tubes. The tubes were capped and subjected to a sonicator bath (Branson Model 3200) for 5 seconds. A milky emulsion was obtained in a continuous fluorochemical medium. The particle size distribution of the dispersions was measured using a photon correlation spectroscopy (PCS) of a Nicomp 270 photon correlation spectrophotometer (Pacific Scientific). The results are summarized in the Table below.

TABLE 7 AVERAGE PARTICLE DIAMETER FOR CONTINUOUS FLUOROCHEMICAL EMULSIONS As with the suspensions, the data of Examples 8a and 8b show that different combinations of components can be used to effectively form the emulsions of the present invention. Due to the low interfacial tension between the fluorochemical and the medicament containing the cosolvent phase, the formation of stable liquid-liquid dispersions (ie, inverse emulsions) is possible without the use of surfactants.

EXAMPLE 9 PREPARATION OF A SUSPENSION OF CIPROFLOXACIN, WITH SUBMICRON PARTICLE SIZE, IN FLUOROCHEMISTS 3 ml of the fluorochemical suspension, with submicron particle size, was prepared as follows: Composition 1: 0.35 weight / volume of cirpofloxaxine-HCl was dissolved ( Miles, Inc.) in the presence of 100 mg Na2Co3 (NF grade, Spectrum Chemical) in a solution composed of 1,4-dibromo-F-butane (50% and NF grade ethyl alcohol (50% volume / volume; Exfluor, Austin, TX) and ethyl alcohol of NF grade (50% volume / volume, Spectrum Chemical Co.). Fluorochemical diluents: Perfluorooctyl bromide (Atochem, France). An aliquot of composition 1 (90μl) was injected with a syringe into a sample of perfluorooctyl bromide (PFOB; 3 ml) contained in a test tube of 12 x 100 mm. The tube was plugged and mixed gently by inverting the tube. A drug of the size of submicron, opalescent particles was obtained to the fluorocarbon suspension. The particle size distribution of the dispersions was measured using photon correlation spectroscopy (PCS) in a Nicomp 270 photon correlation spectrophotometer. The resulting drug dispersion had an average particle diameter of 55 + 47 nm. This example further shows the ability of the present invention to form pharmaceutical microdispersions, with high bioability, incorporating a wide variety of pharmaceutical examples.

EXAMPLE 10 IN VITRO EFFICACY OF AN ANTIBIOTIC SUSPENSION (CIPROFLOXACIN) WITH SUBMICRON PARTICLE SIZE The suspension of ciprofloxacin prepared in Example 9 was titrated with respect to its antibacterial activity using standard techniques. To avoid bacterial infection in the lung, for each test sample, a suspension culture of E. coli was maintained on a clock crystal with a monolayer of bronchial / epithelial cells of a normal human. The experimental procedure is as follows: a) Prepare the monolayer of epithelial cells of the lung and a normal human. b) Add 60 μl of the E. coli culture in the clock crystal with lung epithelial cells in a 96-well dish. c) Cultivate for 1 hour at 37 ° C, then add 100 μl of the ciprofloxacin / PFOB suspension or control solution to each watch crystal where a total culture medium of 1 ml is present. It was incubated at 37 ° C overnight. d) Aspirate the culture mixture and dilute it with an LB medium (1: 2). e) Take 20 μl of the diluted mixture and place it in an LB dish for an initial titration of E. coli. The dishes with E. coli were incubated at 37 ° C overnight. f) Different dilutions were made according to the initial titer of each mixture in order to determine the exact titration on each watch crystal. Duplicate sets of tests were developed for each treatment. g) The titre of E. coli was calculated by multiplying the number of colonies developed in each dish by a dilution factor for each evaluated clock crystal. h) The level of toxicity of the cell was evaluated by means of cell shape, bioability and density under the microscope. The results are summarized in Table 8 below: TABLE 8 ANTIBACTERIAL EFFICACY AND RELATIVE TOXICITY OF THE EPITHELIAL CELL OF THE HUMAN LUNG FOR A SUSPENSION OF CIPROFLOXACIN IN PERFLUOROOCTIL BROMIDE * Higher values indicate higher relative toxicity. Those skilled in the art will appreciate that the above data indicate that: 1) All suspensions of ciprofloxacin in PFOB demonstrated equivalent antibacterial capacity with their corresponding positive controls, ie antibiotics dissolved in a saline or buffer. 2) A dose response of antibacterial ability was observed. 3) Negative controls, treatments by saline solution and the vehicle alone or without any treatment for suspension cultures of E. coli, showed no inhibition of bacterial growth. 4) The controls with the treatments for PFOB, 1,4-dibromo-F-butane and 1,4-dibromo-F-butane showed no improvement for bacterial growth or to slightly decrease bacterial growth. 5) The formulations tested did not exert any significant toxicity in the epithelial cells. Accordingly, the above data show that the microdispersion preparation is substantially homogeneous according to the invention, do not adversely affect the efficacy of the incorporated pharmaceutical agent. In addition, the example clearly demonstrates the safety and effectiveness of the microdispersions themselves. Those skilled in the art will make these results strongly indicate that these pharmaceutical microdispersions will exert the same antibacterial action in vivo. Those skilled in the art will further appreciate that the present invention can be realized in other specific forms without departing from the spirit or the central attributes thereof. And that the above description of the present invention describes the exemplary embodiments thereof, and it is understood that other variations may be contemplated as part of the scope of the present invention. Accordingly, the present invention is not limited by the particular embodiments that have been described in detail therein. In addition, reference should be made to the appended claims as indicative of the scope and content of the present invention.

Claims (54)

1. CLAIMS 1. A method for preparing a pharmaceutical microdispersion having improved bioavailability, this method comprises the steps of: - Providing a thermodynamically stable pharmaceutical composition comprising at least one pharmaceutical agent incorporated in the physiologically acceptable liquid carrier, this liquid carrier comprises 1 or more lipophilic fluorochemicals and at least one non-fluorinated covalent; and combining the stable pharmaceutical composition with an amount of at least one sufficient fluorochemical diluent to initiate the separation phase of at least one pharmaceutical agent from the thermodynamically stable pharmaceutical composition wherein the pharmaceutical microdispersion is formed.
2. 2. The method according to claim 1, wherein the pharmaceutical microdispersion is a suspension.
3. 3. The method according to claim 1, wherein the pharmaceutical microdispersion is an emulsion.
4. 4. The method according to claim 1, wherein 1 or more lipophilic perfluorochemicals are selected from a group consisting of halogenated fluorochemicals, fluorocarbon-diblock or triblock hydrocarbon compounds, halogenated esters, polyesters, fluorocarbon-hydrocarbon, esters , fluorocarbon-hydrocarbon thioesters, fluorocarbon-hydrocarbon amines and fluorocarbon-hydrocarbon amides.
5. 5 . The method according to claim 1, wherein one or more fluorochemicals are selected from the group consisting of: CnF2n + 1X, XCnF2nX, wherein n = 3-8, X = Br, Cl or I; CnF2n + 1 - CmH2m + 1, CnF2n + 1 CH = CHCmH2m + 1, where n = 2-8 m = 2-6; CpH2p + 1_CnF2n-CmH2m + 1, where p = 2-6, m = 2-6 and n = 2-8; XCnF2nOCmF2roX, XCF2OCnF2nOCF2X, where n = 1-4, m = 1-4, X = Br, Cl or I; CnF2n-0-CraH2m + 1, where n = 2-8; m = 2-6; CpH2p + 1, where p = 2-6, m = 2-6 and n = 2-8: 1-bromo-F-octane (n-C8F17Br); 1-bromo-f-heptane (n-C7F15Br); 1-bromo-F-hexane (n-C6F13Br); perfluorooctyl chloride (n-C7F15Cl); 1, 6-dichloro-F-hexane (n-ClC6F12Cl); 1,4-dichloro-F-butane (n-ClC4F8Cl); 1,4-dibromo-F-butane and 1,6-dibromo-F-hexane.
6. The method according to claim 1, wherein, at least one pharmaceutical agent is selected from a group consisting of respiratory drugs, antibiotics, anti-inflammatories, antiomyoplastics, anesthetics, ophthalmic agents, chemotherapeutic agents, cardeovascular agents, agents for image and combinations thereof.
7. The method according to claim 1, wherein at least one pharmaceutical agent has a logarithm of octanol / water partition coefficient (Log Po / w) greater than about -3.
8. The method according to claim 1, wherein at least one fluorochemical diluent is selected from a group consisting of bis (F-alkyl) esters, cyclic fluorocarbons, perfluorinated amines, gruminated perfluorocarbons, perfluorooctyl chloride, perfluorooctyl hydride, perfluoroalkylated ethers perfluoroalkylated polyethers, hydrocarbon-hydrocarbon compounds and combinations thereof.
9. The method according to claim 1 wherein at least one non-fluorinated cosolvent is selected from a group consisting of ethers, alcohols, alkylsulphoxides, water and combinations thereof.
10. The method according to claim 1, further comprising the step of introducing a therapeutically beneficial amount of a physiologically acceptable gas into the pharmaceutical microdispersion.
11. 11. The method according to claim 1, further comprising the step of adding fluorinated or non-fluorinated surfactants.
12. The method according to claim 1, wherein the concentration of at least one pharmaceutical agent is less than about 10% w / v and the lipophilic fluorochemical concentration is less than about 50% v / v.
13. The method according to claim 1, wherein the microdispersion has an average particle diameter of less than about 3 μl.
14. 14. The method according to claim 13, wherein the microdispersion has an average particle diameter of approximately 1 μl.
15. 15. A pharmaceutical pressure having an improved bioavailability prepared according to the method of claim 1.
16. 16. A pharmaceutical microdispersion having improved bioavailability prepared according to the method of claim 2.
17. 17. A pharmaceutical microdispersion having improved bioavailability , prepared according to the method of claim 3.
18. 18. A pharmaceutical microdispersion having an improved bioavailability, prepared according to the method of claim 14.
19. 19. A pharmaceutical formulation, with high bioability comprising: A substantially homogeneous microdispersion of a pharmaceutically effective amount of at least one pharmaceutical agent in a continuous liquid phase, this liquid continuous phase comprises 1 or more physiologically acceptable lipophilic fluorochemicals, at least one cosolvent and at least one fluorochemical diluent.
20. 20. A pharmaceutical formulation, with high bioability according to claim 19, wherein the substantially homogeneous microdispersion is a suspension.
21. 21. A pharmaceutical formulation, with high bioability according to claim 19, wherein the substantially homogeneous microdispersion is an emulsion.
22. 22. A pharmaceutical formulation, with high bioability, according to claim 19, wherein 1 or more lipophilic, physiologically acceptable fluorochemicals are selected from a group consisting of halogenated fluorochemicals, fluorocarbon-hydrocarbon ester compounds, fluorocarbon-hydrocarbon thioesters, Fluorocarbon-hydrocarbon amines and fluorocarbon-hydrocarbon amides.
23. 23. A pharmaceutical formulation, with high bioability according to claim 19, wherein at least one pharmaceutical agent is selected from a group consisting of respiratory drugs, antibiotics, anti-inflammatories, antineoplastic, anesthetics, ophthalmic agents, cardeovascular agents, agents for image and combinations thereof.
24. 24. A pharmaceutical formulation, with high bioability according to claim 19, wherein at least one pharmaceutical agent has a octanol / water partition log coefficient (Log P0 / w) greater than about -3.
25. 25. A pharmaceutical formulation, with high bioability according to claim 19, wherein at least one fluorochemical diluent is selected from a group consisting of bis (F-alkyl) ethenes, cyclic fluorocarbons, perfluorinated amines, brominated perfluorocarbons, perfluorooctyl chloride, perfluorooctyl hydride, perfluoroalkylated esters of perfluoroalkylated polyesters, fluorocarbon-hydrocarbon compounds and combinations thereof.
26. 26. A pharmaceutical formulation, with high bioability according to claim 19, wherein at least one non-fluorinated cosolvent is selected from a group consisting of ethers, alcohols, alkylsulphoxides, water and in combinations thereof.
27. A pharmaceutical formulation, with high bioability according to claim 19 wherein the concentration of at least one pharmaceutical agent is less about 10% weight / volume and the concentration of 1 or more lipophilic fluorochemicals is less about 50% volume / volume .
28. 28. A pharmaceutical formulation, with high bioability, according to claim 19 wherein the microdispersion has an average particle diameter of less than 1 μl.
29. 29. A pharmaceutical formulation, with high bioability according to claim 19, wherein the therapeutically beneficial amount of a physiologically acceptable gas is incorporated in the liquid continuous phase.
30. 30. A pharmaceutical formulation, with high bioability, according to claim 19, further comprising a fluorinated or non-fluorinated surfactant.
31. 31. The method for delivering 1 or more lipophilic pharmaceutical agents to a physiological target, this method comprises the steps of: providing a pharmaceutical formulation with high bioavailability comprising a substantially homogeneous microdispersion of at least one pharmaceutical agent in a continuous liquid phase, the continuous liquid phase comprising 1 or more lipophilic fluorochemicals, at least one non-fluorinated cosolvent and at least one fluorochemical diluent; and introducing a pharmaceutically effective amount of a pharmaceutical formulation with high bioability into the physiological target.
32. 32. The method according to claim 31 wherein the pharmaceutical formulation is a suspension.
33. 33. The method according to claim 31, wherein the pharmaceutical formulation is an emulsion.
34. 34. The method according to claim 31, wherein 1 or more lipophilic perfluorochemicals are selected from a group consisting of halogenated fluorochemicals, fluorocarbon-hydrocarbon compounds of 2 or 3 blocks, halogenated ethers, polyethers, fluorocarbon-hydrocarbon ethers, Fluorocarbon-hydrocarbon amines and fluorocarbon-hydrocarbon amides.
35. 35. The method according to claim 31, wherein at least one lipophilic pharmaceutical agent is selected from a group consisting of respiratory medicaments, antibiotics, anti-inflammatories, antineoplastic agents, anesthetics, ophthalmic agents, cardeovascular agents, imaging agents and combination of them.
36. 36. The method according to claim 31, wherein at least one lipophilic pharmaceutical agent has a logarithm of octanol / water partition coefficient (Log P0 / w) greater than about -3.
37. 37. The method according to claim 31, wherein at least one fluorochemical diluent is selected from a group consisting of bis (F-alkyl) ethanes, cyclic fluorocarbons, perfluorinated amines, brominated perfluorocarbons, perfluorooctyl chloride, perfluorooctyl hydride, ethers perfluoroalkylated, perfluoroalkylated polyethers, fluorocarbon-hydrocarbon compounds and combinations thereof.
38. 38. The method according to claim 31, wherein at least one non-fluorinated cosolvent is selected from a group consisting of ethers, alcohols, alkylsulphoxides, water and combinations thereof.
39. 39. The method according to claim 31, wherein the concentration of at least one lipophilic pharmaceutical agent is less about 10% weight / volume and the concentration of 1 or more lipophilic fluorochemicals is less about 50% volume / volume.
40. 40. The method according to claim 31, wherein the pharmaceutical formulation with high bioability has an average particle size of less than 1 μl.
41. 41. The method according to claim 31, further comprising the step of introducing a therapeutically beneficial amount of a physiologically acceptable gas into a pharmaceutical formulation with high bioavailability.
42. 42. The method according to claim 31, wherein the introduction of the pharmaceutical formulation into the physiological target is achieved topically, subcutaneously, intramuscularly, intraperitoneally, nasally, pulmonally, vaginally, rectally, aurally, orally or ocularly.
43. 43. The method for preparing the pharmaceutical material, comprising the steps of: providing a first composition of a first lipophilic liquid and a pharmaceutical agent in a single continuous phase, and adding to the first composition a sufficient amount of a second, less lipophilic liquid that the first liquid which is miscible in this first liquid, to cause the separation phase of the pharmaceutical agent and form a continuous microdispersed phase.
44. 44. The method according to claim 44, wherein the separation step results in an inverse emulsion.
45. 45. The method according to claim 43, wherein the separation phase results in a suspension.
46. 46. The method according to claim 43, wherein the first composition further includes a cosolvent in which the pharmaceutical agent is soluble.
47. 47. The method according to claim 46, wherein the cosolvent is a non-fluorocarbon.
48. 48. The method according to claim 47 wherein the discontinuous phase comprises a cosolvent and a pharmaceutical agent.
49. 49. The method according to claim 43, further comprising the step of storing the first composition for at least one week before the addition step.
50. 50. The method according to claim 43, wherein the first liquid is a fluorocarbon.
51. 51. A kit for making the pharmaceutical preparation, comprising: a first container having a first composition comprising a first lipophilic liquid fluorocarbon and a pharmaceutical agent in a single continuous phase; and a second container having a second liquid miscible with the first liquid, wherein the second liquid is less lipophilic than the first, such that after the combination of the first composition and the second liquid, the separation phase of the second liquid occurs. pharmaceutical agent to form a discontinuous microdispersed phase of the pharmaceutical agent.
52. 52. The kit according to claim 51, wherein the first composition further includes a non-fluorocarbon cosolvent in which the pharmaceutical agent is soluble.
53. 53. The kit according to claim 52, wherein the discontinuous phase comprises at least one pharmaceutical agent and a cosolvent.
54. 54. The kit according to claim 52 wherein the discontinuous phase comprises a suspension of the pharmaceutical agent.