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WO1999024016A1 - Emulsions pour administration par dispersion aerosol et administration de medicaments - Google Patents

Emulsions pour administration par dispersion aerosol et administration de medicaments Download PDF

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Publication number
WO1999024016A1
WO1999024016A1 PCT/US1998/023900 US9823900W WO9924016A1 WO 1999024016 A1 WO1999024016 A1 WO 1999024016A1 US 9823900 W US9823900 W US 9823900W WO 9924016 A1 WO9924016 A1 WO 9924016A1
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WIPO (PCT)
Prior art keywords
perfluoro
water
therapeutic agent
fluorocarbon
composition
Prior art date
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Ceased
Application number
PCT/US1998/023900
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English (en)
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WO1999024016A8 (fr
Inventor
Johnny Lai
Dean R. Kessler
Steven C. Quay
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Achieve Life Sciences Inc
Original Assignee
Sonus Pharmaceuticals Inc
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Publication date
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Priority to AU13148/99A priority Critical patent/AU1314899A/en
Publication of WO1999024016A1 publication Critical patent/WO1999024016A1/fr
Publication of WO1999024016A8 publication Critical patent/WO1999024016A8/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0026—Blood substitute; Oxygen transporting formulations; Plasma extender
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions

Definitions

  • the present invention is directed to compositions suitable for pulmonary drug delivery, more particularly, to compositions containing a fluorocarbon and a drug or a therapeutic agent which can be administered to the lungs of a patient.
  • Effective delivery of drugs and therapeutic agents to the lungs of a patient has long been sought as a simple and convenient means to administer a drug or therapeutic agent to a patient, as compared to other conventional methods such as, for example, oral ingestion, or intravenous or intramuscular injection.
  • pulmonary aerosols have been considered as such an easy and convenient means for drug delivery.
  • Dry powders containing drugs or therapeutic agents, or solutions or suspensions containing drugs or therapeutic agents have been considered as pulmonary aerosols. Dry drug powders with fine particle size are produced by mechanical or jet milling processes, then administered to patients using dry powder inhaling devices. Drug solutions or suspensions are administered to patients as aerosols with metered dose inhalers or with spray ultrasonic nebulizers.
  • One drawback of these methods is that less than 20% of the administered dose is typically delivered to the lungs. Most of the drug or therapeutic agent is either impacted onto the delivery device or lost in the mouth or the back of the throat due to the large size of the drug particles or aerosolized droplets.
  • Aqueous aerosols of drug solutions in particular suffer from large aerosol particle size. Variations in drug solubility also hamper the effectiveness of such aqueous aerosols .
  • This process includes the steps of: instilling a volume of a fluorocarbon into the lungs, dispersing a microparticulate medicament in a breathable gas to form a gas/medicament dispersion, and introducing the dispersion into the pulmonary air spaces such that the initial fluorocarbon and the gas-dispersed medicament are present simultaneously in the lungs of the patient.
  • the instillation of the fluorocarbon in this process likewise requires intubation of the patient.
  • pulmonary drug delivery agents which are easy to administer and easily removed from the lungs, are desirable.
  • pulmonary drug delivery agents that provide for aerosols with reduced particle size for more effective delivery of the drug or therapeutic agent to the lungs.
  • reduced surface tension of aerosolized particles would also improve the effectiveness of drug delivery as it would increase surface spreading of the particle upon deposition.
  • modifications to, or substitutes for, any known agents would not compromise other beneficial properties of the known agents, such as overall biocompatibility. In all cases, being able to maximize the amount of drug or therapeutic agent effectively administered to the patient while minimizing amount of the delivery agent used would be desirable.
  • the present invention meets the above and other needs and is directed to pulmonary drug delivery agents comprising drug- or therapeutic agent- containing solutions and relatively high vapor pressure, low boiling point fluorocarbons, and to methods of their use.
  • the invention is further directed to providing pulmonary aerosols of these formulations having reduced aerosol particle size for improved delivery, reduced surface tension of the aerosolized droplets for better surface spreading properties once deposited, and facilitated exhalation of the delivery agent to minimize the amount of the delivery agent used.
  • Therapeutic agents, drugs or other medicaments or pharmaceutical compositions that can be used in the present invention include, for example, those agents, drugs, medicaments or compositions that are useful for the treatment of cancer, cystic fibrosis, pulmonary infections, neonatal premature lungs, adult respiratory distress syndrome (ARDS) , pneumonia, Pneumocystis carinii infections, bacterial, fungal and viral infections, diabetes, anemia, hypopituitarism, osteoporosis and cardiovascular diseases and others .
  • Fluorocarbons effective for use in the present invention have relatively high vapor pressures or corresponding low boiling points. Specifically, those fluorocarbons having a boiling point between about -30° to about 150°C are preferred.
  • perfluorocarbons are most preferred as a result of their stability.
  • preferred perfluorocarbons include dodecafluoropentane, dodecafluoroneopentane , perfluorocyclopentane, perfluoro-2 -methyl pentane, perfluorohexane, perfluoroheptane, perfluorooctane, perfluorodecalin and isomers and mixtures thereof.
  • perfluoro-2- methyl pentane, perfluorohexane, perfluorooctane or perfluorodecalin are used, either singly or in mixtures .
  • the delivery agents of one embodiment of the invention are stable water-in-oil emulsions or microemulsions of an aqueous dispersed phase containing a water-soluble therapeutic agent and a fluorocarbon continuous phase formed of high vapor pressure, low boiling point fluorocarbons effective for use in the invention.
  • These emulsions are stable and capable of being aerosolized and produce fine aerosol particles for effective delivery of the therapeutic agent to the pulmonary system of a patient by inhalation.
  • the emulsions or microemulsions can also include one or more fluorosurfactants for further stabilizing the emulsions or microemulsions.
  • the emulsions or microemulsions include a fluorosurfactant and an additional fluorine-containing cosurfactant .
  • Preferred cosurfactants include partially or fully fluorinated primary n-alcohols and fluorinated acids. The addition of these cosurfactants can significantly increase the volume of water that can be effectively emulsified, thereby allowing for incorporation of larger quantities of water-soluble therapeutic agents for pulmonary delivery.
  • the invention further provides for methods of delivering a drug or therapeutic agent to the pulmonary system of a patient using formulations of the invention.
  • One such method involves the steps of preparing a stable water-in-oil emulsion or microemulsion in which a water-soluble therapeutic agent is dissolved in an aqueous continuous phase the emulsion or microemulsion, the oil phase of the emulsion or microemulsion comprising a high vapor pressure, low boiling point fluorocarbon effective for use in the invention.
  • the emulsion or microemulsion is then delivered to the pulmonary system of a patient.
  • the delivery step may be accomplished by aerosolizing the emulsion or microemulsion.
  • the emulsion or microemulsion can be directly instilled into the patient's lungs.
  • FIG. 1 is a diagram showing a system for measuring aerosol particle size.
  • Fluorocarbon bio-compatible chemicals most suitable for use as pulmonary drug delivery agents according to the present invention are relatively high vapor pressure, low boiling point fluorocarbons having a boiling point, under standard temperature and pressure conditions, of between about -30°C to about 150°C. These fluorocarbons have high enough vapor pressures, and are used in small enough amounts, to effectively deliver drugs or therapeutic agents to the lung and then to leave the air spaces of the lungs via evaporation. These chemicals have the further advantage that very soon after they are delivered to the lungs, they have completely evaporated, leaving no residue fluorocarbon to produce toxicity or unwanted pharmaceutical effects and leaving a highly concentrated, highly effective dosage of the active medicament.
  • fluorocarbons are further advantageous for use as pulmonary drug delivery agents due to their low surface tension, and low viscosity (relative to aqueous solutions) , which enables the agent to penetrate deeply into the lungs for maximum efficiency.
  • the low surface tension of the agent further provides for improved spreading properties of the agent upon deposition on lung surfaces that in turn provide for more effective drug delivery to the lungs.
  • the fluorocarbons can also provide for improved solubility of the drug or therapeutic agents.
  • the fluorocarbons of the present invention produce fine aerosol particles of ⁇ 5 ⁇ m, making them highly effective for pulmonary drug delivery.
  • Particle size and particle size ranges are important factors for an effective pulmonary drug delivery agent.
  • the preferred particle size of a delivery agent is between 1-6 ⁇ m. Aerosolized particles of such a size are able to penetrate and deposit deep into the lungs or alveoli. Larger particles impact and deposit in the upper respiratory tract whereas particles that are too small can be easily exhaled prior to deposition.
  • fluorocarbons having higher boiling points than those effective for other applications, such as pulmonary lavage are effective for drug delivery. This is because the amounts of fluorocarbons used for drug delivery are smaller than the amounts used for lung lavage, yet these fluorocarbons still have vapor pressures high enough to ensure adequate evaporation and excretion of the fluorocarbons from the lung air space after deposition of the drug. Of the selected fluorocarbons, those having higher relative boiling points can enhance deeper pulmonary deposition of the medicament, as such fluorocarbons will not evaporate as quickly during aerosolization and pulmonary delivery as compared to lower boiling point fluorocarbons .
  • perfluorocarbons such as dodecafluoropentane, perfluorohexane (perfluoro-2- methyl pentane) , perfluorooctane and perfluorodecalin are the preferred fluorocarbons for use in the invention
  • other high vapor pressure fluorocarbons which are liquids at room temperature, but which vaporize to a significant extent at body temperature will be useful.
  • the following list, showing boiling points and vapor pressures indicates that, for the preferred fluorocarbon compounds, only those having between one to ten carbon atoms will have the necessary vapor pressure characteristics.
  • the following list contains some of the fluorine- containing compounds that are within the scope of the present invention:
  • M.W. is molecular weight.
  • B.P. is boiling point.
  • Group is chemical group.
  • Fluorine-containing emulsions are also contemplated in the present invention, such as a liquid-in-liquid emulsion of the type described in U.S. Patent Application No. 08/148,284 and related U.S. Patents Nos. 5,558,853 and 5,558,855 which are co-assigned to Sonus Pharmaceuticals Inc., and are hereby incorporated by reference. Such emulsions are stable and sterilizable. Fluorocarbons with boiling points from -30°C to 150°C are most effective for forming emulsions for aerosolization and drug delivery according to the present invention.
  • emulsions also yield aerosols with reduced particle size for improved pulmonary delivery, reduced surface tension of the aerosolized droplets for better surface spreading properties once deposited in the lungs, and facilitated exhalation of the drug carrier due to the high vapor pressure of the fluorocarbon. These emulsions also provide stability over time, and ease of manufacture, as well as ease of use.
  • a water soluble medicament can be emulsified in a fluorocarbon continuous phase with the use of a surfactant to form a water-in-oil emulsion or a water-in-oil microemulsion.
  • a water-in-oil emulsion of an aqueous dispersed phase and fluorocarbon continuous phase will yield a liquid composition that is milky-white in color
  • a water-in-oil microemulsion of an aqueous dispersed phase and a fluorocarbon continuous phase will yield a liquid composition that is bluish in color and translucent .
  • the result is a stable water-in-oil emulsion or microemulsion that can be aerosolized for inhalation or alternatively instilled directly into the tracheobronchial tree for pulmonary delivery of the medicament .
  • the fluorocarbon phase is then exhaled leaving the medicament (as dissolved in the water phase) behind for absorption and/or therapeutic effect.
  • the fluorocarbon phase provides greater density to the aerosolized droplets, which assists in penetrating deeper into the pulmonary tree, and also provides for lower surface tension to give enhanced spreading to the droplets upon deposition.
  • a water-in-oil microemulsion according to the present invention is obtained by vortexing water (5-20% v/v) with a low boiling point fluorocarbon (95-80% v/v) , preferably perfluoro-2- methyl pentane, perfluorohexane, perfluorooctane or perfluorodecalin, in the presence of a low concentration of a fluorosurfactant (0.1-1.5 w/w) together with an additional fluorine-containing cosurfactant .
  • a cosurfactant (s) causes a relatively large volume of water (10-20% v/v) to be efficiently emulsified, producing a bluish, translucent liquid.
  • water-in-oil microemulsions are the preferred formulations of the invention for aerosolization and drug delivery, due to their homogeneity and thermodynamic stability prior to use. Also, as these water-in-oil microemulsions can incorporate relatively large volumes of water, as compared to other emulsions, these water-in-oil microemulsions have the added advantage being able carry and deliver greater quantities of drug or therapeutic agent solubilized in the aqueous phase .
  • the fluorosurfactants preferred for use in emulsions of the present invention can be both straight chain and branched chain fluorocarbons.
  • These fluorosurfactants can be, for example, PEG Telomer B, DEA-PAS, FSO 100, FSN 100, FC-171, FC- 170C, FC-100, FC-129, FC-120, TBS, FSA, or UR, and are preferably PEG Telomer B, FC-171 or FC-170C due to their non-ionic character and low water solubility.
  • Preferred fluorosurfactants for use as cosurfactants include partially or fully fluorinated primary n-alcohols such as 1H, lH-perfluoro-1-octanol or 1H, lH-perfluoro-1-heptanol, and fluorinated acids such as perfluoro-n-octanoic acid or perfluoro-n- decanoic acid.
  • fluoro-n-octanoic acid or perfluoro-n- decanoic acid Most preferably, water-in-oil microemulsions are formed by combining the fluorosurfactant PEG Telomer B with the cosurfactants 1H, lH-perfluoro-1-octanol or 1H, lH-perfluoro-1- heptanol .
  • Example 1 The general principles of the present invention will be more fully appreciated by reference to the following non-limiting examples.
  • Example 1 The general principles of the present invention will be more fully appreciated by reference to the following non-limiting examples.
  • a water soluble medicament can be emulsified in a fluorocarbon continuous phase with the use of an appropriate surfactant (s) and dispersed within a water-in-oil emulsion or water-in-oil microemulsion.
  • the resulting mixture can be aerosolized for inhalation or instilled directly into the tracheobronchial tree for pulmonary delivery of the medicament .
  • Water containing a dissolved, therapeutic agent i.e., insulin
  • a dissolved, therapeutic agent i.e., insulin
  • the surfactant used is a fluorosurfactant, PEG Telomer B at a concentration of 0.13% (w/w).
  • the dispersion is then aerosolized and administered via inhalation to the subject for pulmonary delivery of the therapeutic agent.
  • FC-170C and FC-171 are also useful as fluorosurfactants in the invention.
  • Water-in-oil emulsions are formed as above with water content less than 0.5% (w/w) and FC-170C or FC-171 fluorosurfactant content less than 0.25% (w/w).
  • a bluish, translucent water-in-oil microemulsion can be produced that contains 20% water (v/v) with the use of an additional surfactant.
  • the aqueous phase containing medicament is emulsified in perfluoro-2 -methyl pentane, perfluorohexane, perfluorooctane, perfluorodecalin or other low boiling fluorocarbon with the use of 2% PEG Telomer B and 1.1% 1H, lH-perfluoro-1-octanol or other biocompatible fluorosurfactant .
  • the resultant microemulsion is then aerosolized for pulmonary drug delivery.
  • microemulsion milky, white solution
  • microemulsion blue, translucent liquid
  • PFH Perfluorohexane (includes the use of perfluoro-2-methyl pentane)
  • PFMP perfluoro-2-methyl pentane (includes the use of perfluorohexane)
  • PFOctanol 1H, lH-Perfluoro-1-octanol
  • PFMP perfluoro-2-methyl pentane (includes the use of perfluorohexane)
  • PFOctanol 1H, lH-Perfluoro-1-octanol
  • the emulsions of Example 1 can also contain other pharmaceuticals or medicaments to treat various conditions.
  • Premature lungs A water-in-oil fluorocarbon emulsion or microemulsion containing surfactants containing phospholipids, neutral lipids, fatty acids, and surfactant-associated proteins, licithin, fluorine-containing surfactants and other amphophilic materials to mimic the surface-tension lowering properties of natural lung surfactant.
  • Cystic Fibrosis A water-in-oil fluorocarbon emulsion or microemulsion containing recombinant human deoxyribonuclease I stabilized in the aqueous phase with pharmaceutical excipients such as buffers, osmotic agents, viscogens, antioxidants, and the like.
  • AIDS-associated Pulmonary Infections For the treatment of the protozoan Pneu ocystis carinii , a sterile, non-pyrogenic formulation of pentamidine isothionate suspended or emulsified in a low boiling liquid, including dodecafluoropentane, dodecafluoro- neopentane, perfluorohexane, perfluorocyclopentane, perfluoroheptane, and perfluorooctane.
  • Pneumonia Any antibiotic or combination of antibiotics known in the art to be useful for pulmonary infections (bacterial, viral, fungal), dissolved, suspended, or emulsified in or with a chemical selected from the group consisting of dodecafluoropentane , dodecafluoroneopentane , perfluorohexane, perfluorocyclopentane, perfluoroheptane, and perfluorooctane or other low boiling fluorocarbons.
  • Cancer Any anti-neoplastic or combination of anti-neoplasties known in the art to be useful for pulmonary cancer, dissolved, suspended, or emulsified in or with a chemical selected from the group consisting of dodecafluoropentane, dodecafluoroneopentane , perfluorohexane , perfluorocyclopentane, perfluoroheptane, and perfluorooctane .
  • Hormone Delivery Delivery of hormones such as erythropoietin to treat anemia, insulin to treat diabetes, growth hormone to treat hypopituitarism, calcitonin to treat osteoporosis, and others can be dissolved, suspended, or emulsified in a water-in-oil fluorocarbon emulsion or microemulsion for therapeutic delivery.
  • the continuous phase consists of low boiling fluorocarbons such as dodecafluoropentane, perfluoro-2-methyl pentane, perfluorooctane, perfluorodecalin and the dispersed phase consists of the hormone contained in an aqueous solution.
  • Infections Delivery of antimicrobial agents such as tobramycin and anti-infective agents such as recombinant human granulocyte colony-stimulating factor which is used to prevent infection in cancer patients undergoing certain types of chemotherapy and bone marrow transplants. Following emulsification of the therapeutic agent in aforementioned fluorocarbon emulsions, emulsion is administered via aerosolization and inhalation.
  • antimicrobial agents such as tobramycin
  • anti-infective agents such as recombinant human granulocyte colony-stimulating factor which is used to prevent infection in cancer patients undergoing certain types of chemotherapy and bone marrow transplants.
  • Anti-coagulants Delivery of anticoagulants or clot reducing agents such as streptokinase or urokinase or others known in the art to be useful for cardiovascular care may be dissolved, suspended or emulsified in or with fluorocarbon containing emulsions or microemulsions such as perfluorohexane, perfluorooctane and perfluorodecalin for administration via inhalation.
  • fluorocarbon containing emulsions or microemulsions such as perfluorohexane, perfluorooctane and perfluorodecalin for administration via inhalation.
  • water-in-oil emulsions were analyzed to determine particles sizes and particle size ranges upon aerosolization using a Pulsed Doppler Particle Analyzer.
  • the emulsions of Table 4 were passed through a Di Vilbiss nebulizer, with the probe volume set at 1 cm from the top of the nebulizer mouthpiece.
  • Particle mean diameters ranged from 4.65 to 7.76 ⁇ m, as depicted in Table 1 below. Estimated particle ranges are from 1-14 ⁇ m. As shown in Table 4, the particle size of the resultant aerosol can be reduced, depending on the ratios of emulsion constituents.
  • the emulsion containing 90% perfluorodecalin (v/v), 10% water (v/v), and 1.5% PEG Telomer B (w/v) has a particle mean diameter of 5.64 ⁇ m
  • the emulsion containing 80% perflorodecalin (v/v), 20% water (v/v), and 0.1% PEG Telomer B (w/v) has a mean particle diameter of 4.65 ⁇ m. These values are both smaller than the particle mean diameters of either aerosolized water or perfluorodecalin, which are 7.27 ⁇ m and 6.91 ⁇ m respectively, and allow for deeper penetration of the particles into the lung.
  • PFD Perfluorodecalin
  • PFH Perfluorohexane(s)
  • PTB PEG Telomer B
  • Aerosolization of Water- in-Oil Microemulsions The microemulsions according to the invention can be aerosolized to produce aerosol particles suitable for drug delivery under conditions approximating those found in the lungs.
  • aerosolized water-in-oil microemulsions were analyzed to determine particle size distributions under conditions simulating delivery to the lungs.
  • Four different formulations were analyzed including a control formulation, a 0.9% saline solution, a 95% PFD formulation, and an 80% PFD formulation.
  • the 95% PFD formulation comprised 95% perfluorodecalin (v/v) , 5% water (v/v), 2% PEG Telomer B (w/v) and 1.1% perfluoro-1-octonal (w/v) .
  • the 80% PFD formulation comprised 80% perfluorodecalin (v/v) , 20% water (v/v), 2.0% PEG Telomer B (w/v), and 1.1% perfluoro- 1-octonal (w/v) .
  • the control formulation was an aqueous solution containing 2.0% PEG Telomer B (w/v) and 1.1% perfluoro-1-octonal (w/v).
  • FIG. 1 shows the schematic of the experimental setup including the nebulizer, an oral larynx cast, a sample chamber (2.3 L volume, "Lucite” brand material) , Aerodynamic Particle Sizer (APS) and its dilutor (TSI, Inc., St. Paul, MN) .
  • a humidifier to condition air in the chamber was included producing a relative humidity of 91%.
  • the flow rate to the APS was 5 L/min. Aerosols generated from the nebulizers were delivered through the cast, into the chamber and then to the APS for size measurement.
  • the APS is a real-time instrument based on time-of-flight principles. Basically, the aerosol is accelerated through a nozzle. Larger particles obtain slower velocities because of inertia. The particle velocity was measured by passing two laser beams near the nozzle exit. The time of a particle passing through the beams was recorded and converted to particle size. The instrument indicates the particle size distribution in terms of number, surface area, and mass.
  • Tables 5 and 6 list mean particle sizes of the aerosolized formulations in terms of mass median aerodynamic diameters (MMAD) , and respective geometric standard deviations ( ⁇ d ) .
  • the mean particle size was determined by using the Hospitec and Retec nebulizers to aerosolize the emulsions through an oral larynx cast, in the presence of and in high humidity (91%) .
  • the presence of the oral larynx cast, the sample chamber, and high humidity most closely approximates the conditions for pulmonary delivery of an aerosolized emulsion.
  • the 2.3L volume of the sample chamber approximates the inspiratory reserve volume (IRV) of the lungs, which is the added volume of a patient's lungs upon maximum inspiration. This volume thus approximates the volume of air added to the lungs upon deep inhalation. Passing the aerosolized particles through this volume thus simulates the dilution effect for the particles upon administration of the aerosolized formulation to a patient .
  • IMV inspiratory reserve volume
  • the MMADs of the tested particles ranged from 2.6 to 8.1 ⁇ m.
  • the aerosol particles produced from the 80% PFD formulation using both nebulizers had considerably smaller MMADs than particles formed from the saline solution (0.9% NaCl) .
  • These results indicate that aerosols of the emulsions, due to the smaller size of the particles, would provide deeper penetration into the pulmonary system for improved drug delivery.
  • the smaller size of these particles also indicates that these particles might evaporate more rapidly than aerosol particles produced from other formulations after deposition.
  • Table 5 Hospitec nebulizer, with oral larynx cast and high humidity.
  • a therapeutic drug or protein can be incorporated into the formulations of the invention without affecting the stability of the formed emulsion.
  • Cromolyn sodium a drug used in the treatment of asthma, was prepared in an aqueous solution at a concentration of 40 mg/ml .
  • Stable water-in-oil microemulsions were prepared, as discussed above, wherein the microemulsion contained 20% (v/v) of the cromolyn sodium solution as the dispersed phase and 80% (v/v) of either perfluoro-2- methyl pentane or perfluorodecalin as the continuous phase, with 8% (w/v) PEG Telomer B, and 2.0-2.2% (w/v) of 1H, lH-perfluoro-1-octonal or 1H,1H- perfluoroheptanol, as shown in Table 7 below.
  • a stable water-in-oil microemulsion was prepared with a 20% (v/v) solution of bovine serum albumin at a concentration of 100 mg/ml as the dispersed phase and an 80% (v/v) solution of perfluorodecalin as the continuous phase, with 8% PEG Telomer B and 2.5% 1H, lH-perfluoro-1-octonal (Table 7) .
  • PFMP perfluoro-2-methyl pentane (includes the use of perfluorohexane)
  • PFOctanol 1H, lH-Perfluoro-1-octanol

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Abstract

L'invention concerne des compositions contenant des solutions renfermant un médicament ou un agent thérapeutique et des fluorocarbones pour administrer le médicament ou l'agent thérapeutique dans les poumons. Des fluorocarbones convenables ont des pressions de vapeur relativement élevées ou des points d'ébullition correspondants faibles, de préférence, compris entre -30 °C et environ 150 °C, et comprennent du dodécafluoropentane, dodécafluoronéopentane, perfluorocyclopentane, perfluoro-2-méthyl pentane, perfluorohexane, perfluoroheptane, perfluoro-octane, perfluorodécaline et des isomères, ainsi que leurs mélanges. Les émulsions dispersées par aérosol de ces fluorocarbones produisent de fines particules aérosol de ≤ 5 νm et peuvent aussi assurer une solubilité améliorée du médicament ou de l'agent thérapeutique. Les fluorocarbones présentent aussi des pressions de vapeur suffisamment élevées et sont utilisés en quantités suffisamment petites pour administrer de manière efficace le médicament ou l'agent thérapeutique dans les poumons et pour quitter les cavités aériennes des poumons par évaporation.
PCT/US1998/023900 1997-11-10 1998-11-09 Emulsions pour administration par dispersion aerosol et administration de medicaments Ceased WO1999024016A1 (fr)

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AU13148/99A AU1314899A (en) 1997-11-10 1998-11-09 Emulsions for aerosolization and drug delivery

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120076777A1 (en) * 2010-07-01 2012-03-29 Mtm Research Llc Anti-fibroblastic fluorochemical emulsion therapies
EP2587917A4 (fr) * 2010-07-01 2015-05-06 Mtm Res Llc Thérapies au moyen d'émulsions fluorochimiques antifibroblastiques
EP3302432A4 (fr) * 2015-05-27 2018-12-12 Nuvox Pharma LLC Traitement des complications aiguës de la drépanocytose
US12239719B2 (en) 2016-05-16 2025-03-04 Mt Research, Llc Fluorochemical targeted therapies
US12239707B2 (en) 2018-05-07 2025-03-04 Mt Research, Llc Photodynamic compositions and methods of use

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EP2587917A4 (fr) * 2010-07-01 2015-05-06 Mtm Res Llc Thérapies au moyen d'émulsions fluorochimiques antifibroblastiques
US9351943B2 (en) * 2010-07-01 2016-05-31 Matthew T. McLeay Anti-fibroblastic fluorochemical emulsion therapies
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