WO1998016210A1

WO1998016210A1 - Fluorocarbon-containing agents for pulmonary lavage and drug delivery

Info

Publication number: WO1998016210A1
Application number: PCT/US1997/015091
Authority: WO
Inventors: Steven C. Quay
Original assignee: Sonus Pharmaceuticals, Inc.
Priority date: 1996-10-15
Filing date: 1997-08-27
Publication date: 1998-04-23
Also published as: AU4093097A

Abstract

Compositions including a low boiling point fluorocarbon which are useful for pulmonary (lung) lavage and drug delivery and methods for their use.

Description

FLUOROCARBON-CONTAINING AGENTS FOR PULMONARY LAVAGE AND DRUG DELIVERY

Field of The Invention The present invention is directed to compositions suitable for use in pulmonary lavage, for use in treatment of atelectasis, for drug delivery and methods of using the same.

Background of The Invention

Pulmonary lavage (sometimes called "lung lavage") is a process in which fluids are introduced through a catheter into the tracheo-bronchial system of a patient, usually for the purpose of removing secretions in patients who have infections, inflammatory conditions, tumors or in patients who produce secretions of abnormal viscosities, e.g. cystic fibrosis patients . Pulmonary lavage agents are also used diagnostically to obtain fluids to culture and identify infections for which the origin is not known.

In current hospital practice, pulmonary lavage is accomplished using small volumes of saline solution (e.g. 5 mLs) , typically 0.9% saline USP. The fluids are cleared from the patient with either suction or spontaneous coughing.

While the current technique is used millions of times a year in U.S. hospitals, there are drawbacks. For example, in some circumstances, patients need to be oxygenated before and after administration of the saline to ensure the patient does not suffer from lack of oxygen during the procedure. Saline lavage can also remove naturally occurring surfactant from the lungs which is critical to lung function. U.S. Patent 5,531,219 to Rosenberg, which is hereby incorporated by reference, describes the use of low vapor pressure, oxygenated fluorocarbons, such as perfluorooctylbromide, for delivering a medicament to the lungs. In this process, a multiple method step for delivering a medicament to the lungs is taught, including the steps of: introducing a volume of a fluorocarbon into the lungs and dispersing a microparticulate medicament in a breathable gas to form a gas/medicament dispersion. The dispersion is then introduced into the pulmonary air spaces such that the initial fluorocarbon and the gas-dispersed medicament are present simultaneously in the lungs of the patient . U.S. Patent 5,490,498 to Faithfull et . al . , which is also hereby incorporated by reference, describes the use of low vapor pressure, high boiling point oxygenated fluorocarbons, such as perfluorooctylbromide (boiling point=140-142°C) , for partial liquid breathing. Partial liquid breathing is a process in which the lungs are filled with a biocompatible liquid agent capable of carrying oxygen into the lungs and then mechanical ventilation is performed to move gases into and out of the lungs, with the administered fluorocarbon providing gas exchange with the blood. The advantage of using the specified luorocarbons is said to be that these chemicals are known to carry more oxygen per unit volume than saline, can act as a substitute for lung surfactant, and the low vapor pressure or high boiling point reduces the loss by evaporation.

The '498 patent also notes that the agents described therein would be improvements over the use of saline as a lavage agent. With this application, low vapor pressure liquids are used. Even with fluorocarbon agents such as are disclosed in the '219 and '498 patents, difficulties in the use of such agents for lavage or drug delivery remain. For example, the removal of any lavage agent can be complicated or risky for weak patients who cannot easily eliminate the agent by coughing, and for whom the application of suction to the lungs is counterproductive .

For these reasons, strategies which would identify agents which were not necessarily useful for partial liquid breathing but which could be useful for pulmonary lavage, drug delivery or treating atelectasis (incomplete expansion of the lung) , because they could more easily be removed from the lungs, would be desirable. The ability to incorporate therapeutic agents, such as surfactants, mucolytics, antibiotics, and anti-neoplastic drugs would also be desirable. A simpler administration procedure (rather than the complex procedure of the '219 patent) would be especially desirable. In the best case, modifications to (or substitutes for) any known agents would not compromise other beneficial properties such as overall biocompatibility and oxygen carrying ability. In all cases, being able to minimize the amount of agent used would be desirable.

It is an object of the present invention to identify pulmonary lavage and drug delivery formulations and methods which have similar beneficial characteristics of some of the agents disclosed in the art and which further promote the performance and ease of use of an agent when administered to a patient.

Summary of The Invention

In order to attain these object, the present invention is directed to compositions and methods for pulmonary lavage in which a fluorocarbon having a relatively high vapor pressure or corresponding low boiling point is utilized. Specifically, agents having a boiling point between about 10°C and about 100°C are preferred and having a boiling point between about 20°C and about 65 °C are more preferred. These agents retain the biocompatibility and relatively high oxygen carrying characteristics of the known agents, but promote ease of use for lavage or drug delivery. The ease with which the objects of the present invention can leave the lung air space by spontaneous evaporation and without the need for mechanical ventilation or mechanical removal provides an advantage over prior methods .

The high pressure vapor pressure, low boiling point fluorine-containing chemical agents used in the invention can be supplied in an amount which is therapeutically effective for pulmonary (lung) lavage of a human subject, generally in volumes less than about 50 milliliters or most often less than 5-10 L. These volumes correspond to less than 1.0 mL/kg of the patient's body weight and preferably less than 0.1 mL/kg body weight. The agent will be in sterile form.

Among the high vapor pressure fluorocarbon chemicals used in the agent of the invention, those having good biocompatibility and high oxygen carrying capacity are preferred. As a result of their stability, perfluorocarbons are most preferred. Examples of these preferred chemicals include dodecafluoropentane , dodecafluoroneopentane , perfluorohexane , perfluorocyclopentane , perfluoroheptane, perfluorooctane, and mixtures thereof .

In a most preferred embodiment, either singly or in mixtures, perfluorohexane (tetradecafluorohexane, "TDFH") with a boiling point of 58°C or perfluoropentane (dodecafluoro-pentane or "DDFP") with a boiling point of about 28 °C is used, either neat or in emulsion form.

The present invention is also directed to a method for pulmonary (lung) lavage of a human subject by administering a therapeutically effective amount of a high vapor pressure fluorocarbon such as DDFP, or TDFH and permitting the agent, after lavage, to vaporize .

The present invention is also directed to fluorocarbon-containing pharmaceutical compositions useful for the treatment of cancer, adult respiratory distress syndrome, premature lungs in neonates, cystic fibrosis, pulmonary infections, pneumonia, Pneumocystis carini± infections, bacterial, fungal and viral infections.

Detailed Description of The Invention

This invention relates to fluorocarbon biocompatible chemicals suitable as pulmonary lavage agents, and methods of their use. The agents of the invention have a boiling point, under standard temperature and pressure conditions, of between about 10°C and about 100°C. While agents having lower vapor pressures (and higher boiling points) are described in the art as being useful, the agents of the present invention have the benefit of ease of removal from a patient's lungs, allowing small doses to be used and allowing use in extremely sick patients. For example, the agents of U.S. 5.490,498 patent require conventional ventilation equipment to be used because the volume of fluorocarbon in the lung is such that the liquid fluorocarbon cannot be exhaled by the patient. The low vapor pressures of the prior art agents also makes them less suitable for treating atelectasis, since they do not have the expansion capability that accompanies the liquid to gas phase shift. Finally, as drug delivery formulations, the chemicals of the present invention have the 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 .

The agents of the present invention require no mechanical ventilation equipment and make the administration procedure safer for patients, particularly those who are so weak that coughing is not possible or for whom the application of suction to the lungs is not advisable. The use of the high vapor pressure, low boiling point agents of the invention will be especially appropriate for neonates, with whom lung lavage is often necessary.

Fluorocarbons, such as DDFP or TDFH, are advantageous for use as pulmonary lavage 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 and due to their high density, which makes them tend to displace any material that is to be removed.

One of the therapeutic purposes of pulmonary lavage with objects of this invention is to treat collapse or incomplete expansion of alveoli, or a segment of the lung (a condition known as atelectasis) . The high vapor pressure of the objects of this invention will accomplish that treatment most effectively, by entering the collapsed alveoli as a dense liquid and then expanding as the phase shift to a gas is accomplished. Expansion of the alveolar spaces is thereby facilitated.

Generally, for lavage, the high vapor pressure chemicals of the invention will be used as neat liquids. Lavage using these agents can be accomplished with very small volumes of liquid. For example, 5-10 ml of liquid DDFP can be used with an adult patient or less than 0.2 mL/kg.

The most preferred form of the agent of the invention for lavage is a neat (pure) formulation of DDFP. DDFP, having a boiling point of about 29°C, is a liquid at room temperature, but becomes a gas after it enters and is warmed by the body. Since the difference between room temperature and the body is relatively small, and the boiling point of DDFP is between the two, the agent will enter as a liquid and remain a liquid for a time sufficient to act as a lavage agent. DDFP is relatively insoluble in water and therefore is not readily absorbed in the body nor does it easily dissolve lung surfactant, which prevents removal of this important lung constituent .

Thus, once in the lungs, it persists as a liquid until it slowly warms through its boiling point to body temperature (about 37°C) and then is exhaled by the patient . Thus, once administered as a pulmonary lavage agent, neat DDFP can be easily extracted from the lungs either by mechanical coughing by the patient, i.e. expectoration from the patient, by vacuum suction, in which both the agent and any debris in the lungs and/or by simply allowing the DDFP to vaporize .

While DDFP or TDFH are the preferred embodiment of 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 fewer than nine carbon atoms will have the necessary vapor pressure characteristics. The following list contains some of the fluorine-containing compounds which are objects of the present invention:

Chemical M.W. B.P. C . Group

Propane, 2- (trifluoromethyl) -

1,1,1,3,3,3-hexafluoro 211 12.03

2-Butene, 3 -methyl 68 14.0 1

Methane, disilano 76.25 14.7 11

Ethyl nitrite 75.07 16.0 11

Ethyl amine 45.08 16.6 10

Tungsten hexafluoride 298 17.5 11

2,3-Dimethyl-2-norbornano 140.23 19.0 11

Ethylene, 1, l-dichloro-2, 2-difluoro 133 19.0 3

Methane, bromo fluoro 112.93 19.0 3

1-Butene, 3 -methyl 70.13 20.0 1

Borine, trimethyl 55.91 20.0 11

Fluorinert, FC-87 (3M Trade Mark) Unknown 20.0 3

Cyclopropane, 1,1-dimethyl 70.13 20.6 1

Acetaldehyde 44.05 20.8 7

Acetyl flouride 62.04 20.8 9

Borine, dimethyl, methoxy 71.19 21.0 11

Ethylene, 1, 2-dichloro-l, 2-difluoro 132.92 21.1 3

Ethylene, dichloro difluoro 132.92 21.1 3

Methane, difluoro- iodo 177.92 21.6 3

Diacetylene 50.08 22.0 1

Propylene, 2-chloro 76.53 22.6 3

Carvone- {d} 150.22 23.0 11

Methane, trichloro luoro 137.37 23.7 3

1, 3-Dioxolane-2-one, 4-methyl 102.09 24.2 1

Methane, dibromo difluoro 209.82 24.5 3

2-Pentanone, 4-amino-4-methyl 115.18 25.0 10

Methane, chloro difluoro nitro 131.47 25.0 3

Propane, heptafluoro- 1-nitro 215.03 25.0 3

Cyclopentene, 3 -chloro 102.56 25.0 3

1,4-Pentadiene 68.12 26.0 1

1,5-Heptadiyne 92.14 26.0 1

3-Butene-2-one, 4-phenyl {trans} 146.19 26.0 2

Propane, 1, 1, 2,2, 3-Pentafluoro 134.06 26.0 3

2-Butyne 54.09 27.0 1

Ethane, 2, 2-dichloro-l, 1, 1-trifluoro 152.9 27.0 3

Cyclopentene, Octafluoro 211.05 27.0 3 l-Nonene-3-yne 122.21 27.0 1

2-Methyl butane 72.15 27.8 1

Butane, 2-methyl 72.15 27.8 1

Ethane, 1,2-dichlorotrifluoro 152.9 28.0 3

Ether, difluoromethyl 2,2,2-trifluoroethyl 150.05 28.0 3

Cyclopropane, 1,2-dimethyl {trans, 1} 70.13 28.0 1

Vinyl ether 70 28.0 6

Cyclopropane, 1,2-dimethyl {trans, dl} 70.13 29.0 1

Toluene, 2,4-diamino 122.17 29.0 2

1-Pentene, perfluoro 250.04 29.0 3

1-Butyne, 3 -methyl 68.12 29.5 1

1-Pentene 70.13 30.0 1

1-Pentene, 3 , 3 ,4 , 4 , 5, 5, 5-heptafluoro 196 30.0 3

Ethylene, idotrifluoro 207.9 30.0 3

Styrene, 3-fluoro 122.14 30.0 11

1-Pentene, 3-bromo 149.03 30.5 3

Pentane, perfluoro 288.04 30.5 3

Ethane, 1, 2-difluoro 66.05 30.7 3

Butane, 3-methyl, 1, 1, 1-trifluoro 126.12 31.0 3

1-Butene, 2-methyl 70.13 31.2 1

Formic acid, methyl ester 60.05 31.5 9

Methane sulfonyl chloride, trifluoro 168.52 31.6 3

Ethane, 1, 1-dichloro-l-fluoro 116.95 32.0 3

Pentane, 1- fluoro 90.14 32.0 3

Acetylene-diido 277.83 32.0 3

Propane, 2-amino 59.11 32.4 10

Butane, 1-fluoro 76.11 32.5 3

Methyl isopropyl ether 74.12 32.5 6

Propylene, 1-chloro 76.53 32.8 3

Butyraldehyde , 2 -bromo 151 33.0 3

2-Butene, 2-chloro-l, 1, 1, 4, 4 , 4-hexafluoro 198.5 33.0 3

1,3 -Butadiene, 1, 2, 3-trichloro 157.43 33.0 3

Butene, 2-chloro-l, 1, 1, 4, 4, 4-hexafluoro 199 33.0 3 bis- (Dimethyl phosphino) amine 137.1 33.5 10

1, 3 -Butadiene, 2 -methyl 68.12 34.0 1

1-Butene-3-yne, 2-methyl 66.1 34.0 1 Isoprene 68..12 34.0 1

Methane, chloro dinitro 140.48 34.0 3

Propane, 1,2-epoxy 58.08 34.3 6

Cyclopropane , ethyl 70.13 34.5 1 Ethyl ether 74.12 34.5 6

Dimethyl disulfide, hexafluoro 202.13 34.6 11

Ethylene, 1, 2-dichloro-l-fluoro 115 35.0 3

Propane, 1, 2-dichlorohexafluoro 220.93 35.0 3

Ethyl vinyl ether 72.11 35.0 6 Propane, 2-chloro 78.54 35.7 3

Methane, bromo-chloro- fluoro 147.37 36.0 3

Piperidine, 2,3, 6-trimethyl 127.23 36.0 11

1 , 2 , 3 -Nonadecane tricarboxylic acid, 2- 500.72 36.0 9 hydroxy, trimethylester Dimethyl ethyl amine 73.14 36.0 10 n-Pentane 72.15 36.1 1

2-Pentene {trans} 70.13 36.3 1

Cyclobutane , methyl 70.13 36.3 1

Ethyl methyl amine 59.11 36.7 10 2-Pentene {cis} 70.13 36.9 1

Cyclopropane, 1,2-dimethyl {cis} 70.13 37.0 1 Ethylene, 1,1-dichloro 96.94 37.0 3 Propylene, 1-chloro- {trans} 76.53 37.4 3 Ethylene, 1, l-dichloro-2-fluoro 114.93 37.5 3 Methane, dichloro 84.93 40.0 3

Methane, iodo- 141.94 42.4 3 Ethane, 1,1-dichloro 98 57.3 3 perfluorohexane 58 perfluoroheptane 80-82 perfluorooctane 99-100

M.W. is molecular weight.

B.P. is boiling point.

C. Group is chemical group.

CHEMICAL GROUP DESIGNATION 1 Aliphatic hydrocarbons and/or derivatives

2 Aromatic hydrocarbons and/or derivatives

3 Organic halides and/or derivatives

6 Ethers and/or derivatives

7 Aldehydes and/or derivatives 9 Carboxylic acids and/or derivatives

10 Amines and/of derivatives

11 Miscellaneous

Other fluorine-containing compounds which are objects of the present invention are disclosed in 5,393,524; 5,409,688; 5,558,094 and 5,558,854 which are co-assigned to Sonus Pharmaceuticals Inc., and are hereby incorporated by reference.

One potential disadvantage of using lower molecular weight fluorocarbon compounds for lung lavage is that such compounds may be less effective as surfactant substitutes, when compared with the low vapor pressure agents described in the art. However, this can be advantageously addressed by using a fluorocarbon containing formulation which includes an appropriate lung surfactant or lung surfactant substitute . One such formulation would be a liquid- in- liquid emulsion of the type described in U.S. Patent Application No. 08/148,284 and related patents U.S. 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, sterilizable, fluorocarbon containing emulsions described for use in ultrasound contrast. Surfactants used to stabilize the emulsions can be selected to include lung surfactant substitutes.

An advantage to incorporating the high vapor pressure agent of the invention in such an emulsion is that the emulsion has both an aqueous component for carrying water soluble therapeutic agents, and a hydrophobic fluorocarbon, such as DDFP, for carrying additional therapeutic agents which are not water soluble. The combination of a hydrophobic fluorocarbon and an aqueous phase, stabilized by a surfactant which is selected to be a lung surfactant substitute is a preferred form of the invention. One such formulation is a dispersion of DDFP in water stabilized by PEG Telomer B surfactant. Thus, formulations according to the present invention include high vapor pressure fluorocarbon liquids as the dispersed phase of a liquid in liquid aqueous emulsion, the emulsion stabilized with fluorine containing surfactants (such as the many described in U.S. Application No. 08/148,284 and related patent U.S. 5,558,853) selected for their lung surfactant substitute properties.

For drug delivery the medicament to be administered to the lungs can be incorporated with the fluorocarbon by numerous ways known to those skilled in the art. For example, fluorocarbon-insoluble drugs or agents can be suspended as a solid-in-liquid or liquid-in-liquid dispersion in the fluorocarbon. Water-soluble medicaments can be dissolved or suspended in water and a water-in-oil , microemulsion, or oil-in-water emulsion can be prepared (where the fluorocarbon is the oil phase or is dissolved in the oil phase) . The general principles of the present invention may be more fully appreciated by reference to the following non-limiting examples.

Example 1.

Use of Neat Liquid High Vapor Pressure Fluorocarbon

The procedure is useful for aspirating secretions from the tracheobronchial tree in patients who are unable to expectorate them on their own; to maintain a patient airway; to prevent or treat lung infection or cancer; to treat atelectasis, and to obtain a sterile sputum specimen for diagnostic studies. The equipment needed can vary but, as an example, a Ballard closed suction system or an open suction system, sterile suction catheters, resuscitation bag and mask, and unit dose vials of sterile dodecafluoropentane or perfluorohexane (3-5 cc) is used. The procedure is as follows:

1. Ascertain that patient requires suctioning by auscultating breath sounds. 2. Explain procedure to patient.

3. Position patient as 45 degree angle.

4. Wash hands .

5. Obtain necessary equipment .

6. Turn on wall suction and set pressure at 135-145 mm Hg .

7. Pre-oxygenate patient.

8. Attach suction catheter to connecting tubing, leaving suction catheter in sterile package . 9. Open water-soluble lubricant package.

10. Glove both hands using sterile technique. 11. Remove catheter from packaging and lubricate using sterile technique.

12. Insert catheter (without vacuum applied) through patient's nose and advance it until obstruction is met then retract it slightly

(entrance to trachea will usually be met by coughing) .

13. Instill 3-5 mL of sterile DDFP down the trachea via the irrigation port to help loosen and liquefy secretions and to promote expansion of the alveoli.

14. Place the thumb over control port of catheter and apply suction (no longer than 10 seconds) , while rotating catheter between thumb and forefinger withdrawing slowly at the same time. Intermittent suction is safest .

15. Re-oxygenate and deep breathe patient.

16. Allow patient at least one minute rest before resuctioning .

17. When suctioning is complete, sterilely dispose of all non-reusable equipment.

The material suctioned can be submitted for diagnostic tests, such as immunoassays, microbiological cultures, and cytopathology by standard methods.

Alternatively, the DDFP can be left in place and allowed to evaporate without suction. The DDFP will be largely gone in a matter of minutes . The other high vapor pressure fluorocarbons dodecafluoroneopentane , perfluorohexane , perfluorocyclopentane, perfluoroheptane, and perfluorooctane may also be used.

Delivery of pulmonary surfactants can be afforded by dissolving or suspending such biocompatible amphiphilic materials in the fluorocarbon and not performing the suction step.

Example 2

Use of High Vapor Pressure Fluorocarbon Emulsions

A 10 mL quantity of EchoGen brand emulsion is administered in the same procedure described in Example 1. EchoGen is an emulsion containing dodecafluoropentane (DDFP) , PEG Telomer B and sucrose .

Example 3

Additional uses of High Vapor Pressure Liquids

The fluids of Example 1 and 2 can also contain other pharmaceuticals or medicaments to treat various pulmonary conditions. The following conditions can be treated with the following formulations:

Premature lungs : DDFP or TDFH suspension of natural or synthetic lung surfactants containing phospholipids, neutral lipids, fatty acids, and surfactant-associated proteins, lecithin, fluorine- containing surfactants and other amphiphilic materials to mimic the surface-tension lowering properties of natural lung surfactant .

Cystic Fibrosis: A water-in-oil fluorocarbon emulsion 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 Pneumocystis carinii , a sterile, non-pyrogenic formulation of pentamidine isethionate 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 .

Adult Respiratory Distress Syndrome: DDFP or TDFH as neat liquids or containing a suspension of natural or synthetic lung surfactants containing phospholipids, neutral lipids, fatty acids, and surfactant-associated proteins, and other amphiphilic materials to mimic the surface-tension lowering properties of natural lung surfactant.

Although the invention has been described in some respects with reference to specified preferred embodiments thereof, many variations and modifications will be apparent to those skilled in the art. It is, therefore, the intention that the following claims not be given a restrictive interpretation but should be viewed to encompass such variations and modifications that may be routinely derived from the inventive subject matter disclosed.

Claims

What is claimed is:

1. A composition for performing pulmonary lavage comprising dodecafluoropentane, perfluorohexane, or mixtures thereof.

2. The composition of claim 1 comprising dodecafluoropentane .

3. The composition of claim 1 comprising perfluorohexane .

4. A composition comprising a liquid including a fluorocarbon, having a boiling point of 5°C to

100°C, in an amount therapeutically effective for lung lavage of a human subject.

5. A composition according to claim 4 wherein said fluorocarbon is selected from the group consisting of dodecafluoropentane, dodecafluoroneopentane, perfluorohexane, perfluorocyclopentane, perfluoroheptane, and perfluorooctane .

6. A composition according to claim 4 wherein said fluorocarbon is perfluoropentane, perfluoro- hexane, or mixtures thereof.

7. A composition according to claim 4 wherein said amount is less than 5 milliliters.

8. A composition according to claim 4 wherein said fluorocarbon has a boiling point between 15°C and 60°C.

9. A composition according to claim 4 wherein said liquid is a neat liquid of said fluorocarbon.

10. A composition according to claim 4 wherein said liquid comprises a dispersion of said fluorocarbon in water.

11. A composition according to claim 10 wherein said dispersion is stabilized with a surfactant which can act as a lung surfactant substitute.

12. A composition according to claim 11 wherein said surfactant is selected from a member of the group consisting of lecithin, phospholipids, or fluorine- containing surfactants.

13. A composition according to claim 4 further comprising a therapeutic agent selected from the group consisting of antibiotic, anti- infective, anti- inflammatory, or antineoplastic pharmaceuticals.

14. A method of lung lavage in a human subject comprising the step of administering a liquid including a fluorocarbon with a boiling point of 10 °C to 100°C to said human subject, in an amount which is therapeutically effective for pulmonary lavage.

15. A method according to claim 14 wherein said fluorocarbon is selected from the group consisting of decafluorobutane, dodecafluoropentane, dodeca- fluoroneopentane, perfluorohexane, sulfur hexa- fluoride and perfluorocyclopentane, perfluoroheptane, and perfluorooctane, or mixtures thereof.

16. A method according to claim 14 wherein said fluorocarbon is perfluoropentane, perfluorohexane or mixtures thereof .

17. A method according to claim 14 wherein said amount is less than 10 milliliters.

18. A method according to claim 14 wherein said fluorocarbon has a boiling point between 15°C and 60°C.

19. A method according to claim 14 wherein said liquid is a neat liquid of said fluorocarbon.

20. A method according to claim 14 wherein said liquid comprises a dispersion of said fluorocarbon in water.

21. A method according to claim 20 wherein said dispersion is stabilized with a surfactant which can act as a lung surfactant substitute.

22. A method according to claim 20 wherein said surfactant is selected from a member of the group consisting of lecithin, phospholipids, or fluorine- containing surfactants .

23. A method of lung lavage comprising the step of administering a therapeutically effective amount of a perfluoropentane-containing liquid to the broncho- tracheal area of a human subject.

24. A method of lung lavage comprising the step of administering a therapeutically effective amount of a perfluorohexane-containing liquid to the broncho- tracheal area of a human subject.

25. A composition comprising a liquid including perfluorohexane, dodecafluoropentane and mixtures thereof in an amount therapeutically effective for treatment of premature lungs.

26. The composition of claim 25 further comprising one or more surfactants selected from the group consisting of phospholipids, neutral lipids, fatty acids, lecithin, or fluorine-containing surfactants and surfactant-associated proteins.

27. A composition comprising a liquid including perfluorohexane, dodecafluoropentane and mixtures thereof in an amount therapeutically effective for treatment of adult respiratory distress syndrome.

28. The composition of claim 27 further comprising one or more surfactants selected from the group consisting of phospholipids, neutral lipids, fatty acids, lecithin, or fluorine-containing surfactants and surfactant-associated proteins.

29. A composition comprising a fluorocarbon having a boiling point of 5°C to 100°C and a pharmaceutical agent wherein said agent is suspended or dissolved in said fluorocarbon and said agent is supplied in a pharmaceutically effective amount.

30. The composition of claim 29 wherein said fluorocarbon is selected from the group consisting of dodecafluoropentane , dodecafluoro-neopentane , perfluorohexane , perfluorocyclopentane , perfluoroheptane, and perfluorooctane .

31. The composition of claim 29 further comprising one or more surfactants selected from the group consisting of phospholipids, neutral lipids, fatty acids, lecithin, or fluorine-containing surfactants and surfactant-associated proteins.

32. The composition of claim 29 wherein said agent is deoxyribonuclease I and said deoxyribonuclease I is supplied in an amount effective to treat cystic fibrosis.

33. The composition of claim 29 wherein said agent is pentamidine isethionate said pentamidine isethionate is supplied in an amount effective to treat a Pneumocystis carinii infection.

34. The composition of claim 29 wherein said agent is an antibiotic and said antibiotic is supplied in an amount effective to treat a pulmonary infection.

35. The composition of claim 34 wherein said infection is selected from the group consisting of viral, bacterial or fungal infections.

36. The composition of claim 29 wherein said agent has anitineoplastic activity and said agent is supplied in an effective amount to treat cancer,,