Use of liquid fluorocarbons to facilitate pulmonary drug delivery

A multiple method step for delivering a medicament to the lungs, in connection with which, a biocompatible perfluorocarbon liquid is introduced into the lungs and the a microparticulate medicament is introduced into the lungs where it is dispersed into the pulmonary spaces which are filled or coated with the perfluorocarbon liquid.

FIELD OF THE INVENTION 
The present invention relates to a method for medicament delivery, and 
specifically relates to the use of biocompatible liquid fluorocarbons to 
facilitate delivery of medicaments in microparticulate form particularly 
for treatment of pulmonary and other physiological conditions. 
BACKGROUND OF THE INVENTION 
A wide variety of delivery systems are available for preventative or 
therapeutic administration of medicaments. Methods well known in the field 
include injection (subcutaneous, intravenous, intramuscular or 
intraperitoneal), delivery via a catheter, diffusion from a patch applied 
to the skin or a bolus implanted under the skin, intraocular delivery via 
liquid drops, ingestion of a pill, capsule or gelcap, and inhalation of an 
aerosol. Aerosol delivery systems generally rely on a mixture of the 
therapeutically active agent with one or more propellants and inactive 
ingredients to increase dispersion and stability of the active agent. 
Inhalation of the aerosol can be via either the nose or mouth and often is 
self-administered. Because of the small volume of each dosage, the 
propellant generally evaporates simultaneously or shortly after delivery 
of the active ingredient. 
Fluorocarbons are fluorine substituted hydrocarbon compounds that are 
biocompatible. Brominated fluorocarbons and other fluorocarbons are also 
known to be safe, biocompatible substances when appropriately used in 
medical applications. In addition to their use as aerosol propellants, 
they have been used in medical applications as imaging agents and as blood 
substitutes. U.S. Pat. No. 3,975,512 to Long uses fluorocarbons, including 
brominated perfluorocarbons, as a contrast enhancement medium in 
radiological imaging. 
Gases in general, including oxygen and carbon dioxide, are highly soluble 
in some fluorocarbons. This characteristic has permitted investigators to 
develop emulsified fluorocarbons as blood substitutes. For a general 
review of the use of fluorocarbons as blood substitutes see "Reassessment 
of Criteria for the Selection of Perfluorochemicals for Second-Generation 
Blood Substitutes: Analysis of Structure/Property Relationship" by Jean G. 
Riess, Artificial Organs 8:34-56, 1984. 
Oxygenatable fluorocarbons act as a solvent for oxygen. They dissolve 
oxygen at higher tensions and release it as the partial pressure 
decreases; carbon dioxide is similarly stored and released. When a 
fluorocarbon is used intravascularly, oxygenation of the fluorocarbon 
occurs naturally through the lungs. However, the fluorocarbon can be 
oxygenated prior to use in applications such as percutaneous transluminal 
coronary angioplasty, stroke therapy and organ preservation. 
Liquid breathing using oxygenated fluorocarbons has been demonstrated on 
several occasions. For example, an animal submerged in an oxygenated 
fluorocarbon liquid may exchange oxygen and carbon dioxide normally when 
the lungs fill with the fluorocarbon. Although the work of breathing is 
increased in total submersion experiments, the animal can derive adequate 
oxygen for survival by breathing the oxygenated fluorocarbon liquid. 
Full liquid breathing as a therapy presents significant problems. Liquid 
breathing in a hospital setting requires dedicated ventilation equipment 
capable of handling liquids. Moreover, oxygenation of the fluorocarbon 
being breathed must be accomplished separately. The capital costs 
associated with liquid breathing are considerable. Partial liquid 
ventilation techniques as disclosed in related U.S. application Ser. No. 
07/695,547 are a safe and convenient clinical application of liquid 
breathing using oxygenated fluorocarbons. 
A wide variety of pulmonary conditions exist in humans that are treatable 
with medicaments. Some conditions result from congenital defects, either 
as the result of premature birth and inadequate development of the lungs 
or from genetic abnormalities. One of these is Respiratory Distress 
Syndrome (RDS) that occurs in premature infants. Other distress conditions 
result from trauma to the lungs induced by exposure to particulate matter, 
infectious agents or injury. Adult Respiratory Distress Syndrome (ARDS) 
results from pulmonary trauma in adults. Infectious agents (bacterial, 
viral and fungal) can damage lungs by local infections and treatment of 
such diseases is well known. Immunocompromised patients such as people 
suffering from Acquired Immunodeficiency Syndrome (AIDS) or people 
undergoing drug treatment to suppress immunological rejection of 
transplanted organs also have increased susceptibility to lung infections. 
Lung cancer also affects thousands of people throughout the world and 
often results in their death. These diseases reflect only some of a wide 
variety of medical conditions associated with pulmonary distress. 
Lung Surfactant Conditions 
Lung surfactant functions to reduce surface tension within the alveoli thus 
permitting the alveoli to be held open under less pressure. (The 
Pathologic Basis of Disease, Robbins and Cotran eds., W. B. Saunders Co., 
New York, N.Y. 1979). Lung surfactant covers the lung surfaces, promotes 
alveolar expansion and mediates transfer of oxygen and carbon dioxide. 
Surfactant supplementation is beneficial in a number of medical therapies 
including, for example, for individuals with congenital lung surfactant 
deficiencies. 
Some medical procedures require that fluids be added to the lungs, for 
example, as a wash to remove endogenous or exogenous matter from patients 
with asthma, cystic fibrosis or bronchiectasis. Lavage with nonsurfactant 
liquids such as a physiological saline solution can remove natural lung 
surfactant, thus increasing lung trauma. Supplementation of lung 
surfactant may relieve this trauma. 
Currently, therapeutic surfactant supplements are used in infants when the 
amount of lung surfactant present is insufficient to permit proper 
respiratory function. Surfactant supplementation is most commonly used in 
Respiratory Distress Syndrome (RDS), a specific form of which is known as 
hyaline membrane disease, when surfactant deficiencies compromise 
pulmonary function. Hyaline membrane contains protein-rich, fibrin-rich 
edematous fluid mixed with cellular debris that impedes gaseous exchange 
in the lungs. Although RDS is primarily a disease of newborn infants, 
Adult Respiratory Distress Syndrome (ARDS), an adult form of the disease, 
has many similar characteristics and lends itself to similar therapies. 
RDS affects up to 40,000 infants each year in the United States accounting 
for up to 5,000 infant deaths annually. The primary etiology of RDS is 
attributed to insufficient amounts of pulmonary surfactant. Premature 
infants born before the 36th week of gestation are at greatest risk 
because of insufficient lung development. Neonates born at less than 28 
weeks of gestation have a 60-80% chance of developing RDS which may be a 
life-threatening condition. 
At birth, high inspiratory pressures are required to expand the lungs. When 
normal amounts of lung surfactant are present, the lungs retain up to 40% 
of the residual air volume after the first breath. With subsequent 
breaths, lower inspiratory pressures adequately aerate the lungs because 
the lungs now remain partially inflated. With low levels of surfactant, 
whether in infant or adult, the lungs are virtually devoid of air after 
each breath. The lungs collapse with each breath and the individual must 
continue to work as hard for each successive breath as she/he did for 
her/his first. Thus, exogenous therapy is required to facilitate breathing 
and minimize lung damage. 
A premature infant lacks sufficient surfactant necessary to breathe 
independently at birth. Because the lungs mature rapidly after birth, 
therapy is often only required for three or four days. After this critical 
period the lung has matured sufficiently to give the neonate an excellent 
chance of recovery. 
Adult Respiratory Distress Syndrome (ARDS) can occur as a complication of 
shock-inducing lung trauma, infection, burn or direct lung damage, immune 
hypersensitivity reactions, hemorrhage, or the inhalation of irritants 
that injure the lung epithelium and endothelium. Histologically, ARDS 
presents as diffuse damage to the alveolar wall accompanied by capillary 
damage. In addition, subsequent hyaline membrane formation creates a 
barrier to gaseous exchange which results in further loss of lung 
epithelium leading to decreased surfactant production and foci of 
collapsed alveoli (atelectasis). This initiates a vicious cycle of hypoxia 
and lung damage. Tumors, mucous plugs or aneurysms can also induce 
atelectasis. 
In advanced cases of respiratory distress, whether in neonates or adults, 
the lungs are solid and airless. The alveoli are small and crumpled, while 
the proximal alveolar ducts and bronchi are overdistended. Hyaline 
membranes line the alveolar ducts and scattered proximal alveoli. 
The critical threat to life in respiratory distress is inadequate pulmonary 
exchange of oxygen and carbon dioxide resulting in metabolic acidosis. In 
infants, acidosis together with the increased effort required to bring air 
into the lungs, is a lethal combination for about 20-30% of affected 
babies. 
Cystic Diseases 
Cystic diseases are critical lung diseases that produce abnormally large 
air spaces in the lung parenchyma. They generally are either congenic 
bronchogenic cystic disease or alveolar cysts. 
Bronchiogenic cysts are rare congenital malformations often associated with 
cystic disease of the liver, kidney and pancreas. The cystic cavities are 
either filled with mucinous secretions or air as a consequence of 
ballooning out under the continued thrust of respiratory pressure. 
Infection of the cysts, especially those containing secretions, may lead 
to progressive metaplasia of the epithelium lining the cyst which may 
result in necrosis and a lung abscess. 
Alveolar cysts are more common and may result from congenital abnormal 
development or from inflammatory disease with fibrosis, aging and 
deterioration of the alveolar wall. The walls of alveolar cysts are thin 
and fragile while the surrounding lung tissue is compressed and 
atelectatic. In fact, alveolar cysts that lose elasticity are blown up 
like a balloon with each inspiration. 
Cyst cavities are often filled with mucinous secretions that serve as prime 
sites for development of infection which may promote abscess formation 
resulting in lung collapse or interstitial pulmonary emphysema. Because 
excessive secretions accumulate in the lungs, they may require lavage 
treatments to clear them of excess mucinous secretions to facilitate 
easier breathing and prevent infections. Cystic diseases are progressive 
in nature leading to deterioration of elastic and reticulin fibers that 
predisposes the tissue to rupture. Thus, it is important to treat cystic 
disease both by relieving inhalation stress on the cystic tissue and by 
treating the frequent infections associated with cysts. 
Lung Cancer 
Lung cancer accounts for a significant portion (5-8%) of deaths in the U.S. 
and throughout the industrialized world. Cancers originating in the lungs 
are generally one of four types: squamous cell carcinoma (about 30-40% of 
all lung tumors), adenocarcinoma (about 30-40%), large cell anaplastic 
carcinoma (less than 10%), and small cell anaplastic carcinoma 
(approximately 20%). Of these, adenocarcinomas and small cell cancers are 
most dangerous because they tend to metastasize to other sites in the 
body. 
Most lung cancers occur in or on bronchial walls near the branch point into 
the trachea although adenocarcinomas often occur in the middle to outer 
third of the lung. Because all of these areas are exposed to carcinogens 
in the air, they are susceptible to neoplastic development. Exposure to 
air also makes them treatable by administering chemotherapeutic agents 
directly into the lungs by inhalation. However, inhalation therapy has 
limited application because it exposes both the tumor and healthy tissue 
to highly toxic chemotherapeutic reagents. Furthermore, as tumors grow 
within the lung, portions of lung tissue may become relatively shielded by 
the tumor and thus inaccessible to inhalation therapy. 
Because of the wide variety of pulmonary diseases and disorders that occur 
in humans, there is a need for effective ways to deliver medicaments to 
the lungs. Because the lungs serve as a primary site for exchange of 
compounds with the blood, pulmonary delivery can also be used to deliver 
drugs into the blood stream. The present invention has the advantage over 
current methods of drug delivery because it is a relatively rapid delivery 
system of medicaments, particularly for delivery to selected pulmonary 
tissue. Thus the present invention will have widespread therapeutic 
application. 
SUMMARY OF THE INVENTION 
According to one aspect of the invention, there is provided a method for 
pulmonary drug delivery. The method includes introducing into the 
pulmonary air passages of a mammalian host a volume of perfluorocarbon 
liquid substantially equivalent to or less than the pulmonary functional 
residual capacity of the host. The method further includes introducing a 
powdered or other microparticulate medicament dispersed in a gas into the 
pulmonary air passages of the host, such that said perfluorocarbon liquid 
and said medicament are simultaneously present in pulmonary air passages 
of the host. In one embodiment, a first volume of the perfluorocarbon 
liquid is introduced prior to introduction of the medicament. In another 
embodiment, a second volume of perfluorocarbon liquid is introduced into 
the pulmonary air passages of the host subsequent to administration of the 
medicament. In yet another embodiment, the medicament is introduced prior 
to introduction of the perfluorocarbon liquid. Another embodiment includes 
lavage with a perfluorocarbon liquid performed prior to introduction of 
the medicament. In one embodiment, the method includes an additional step 
after the steps of introducing perfluorocarbon liquid and introducing the 
powdered or microparticulate medicament, that is the removal of the 
perfluorocarbon liquid from the pulmonary air passages. Preferably, the 
perfluorocarbon liquid is removed from the pulmonary air passages by 
evaporation. In another preferred embodiment, the perfluorocarbon liquid 
is removed from the pulmonary air passages by mechanical means such as 
aspiration or physical manipulation. 
In a preferred embodiment, the volume of introduced perfluorocarbon liquid 
is equivalent to 0.01% to 100% of the pulmonary functional residual 
capacity of the host. In another embodiment, the volume of perfluorocarbon 
liquid is at least about 1%, 2% or 5% of the pulmonary functional residual 
capacity of the host. Alternatively, the volume of perfluorocarbon liquid 
is at least 10% of the pulmonary functional residual capacity of the host. 
In another preferred embodiment, the volume of perfluorocarbon liquid is 
at least 20% of the pulmonary functional residual capacity of the host. In 
one embodiment, the volume of perfluorocarbon liquid is not more than 
about 60% or 75% of the pulmonary functional residual capacity of the 
host. In another preferred embodiment, the volume of perfluorocarbon 
liquid is not more than about 40% or 50% of the pulmonary functional 
residual capacity of the host. In yet another embodiment, the volume of 
perfluorocarbon liquid is not more than about 15%, 20%, 25% or 30% of the 
pulmonary functional residual capacity of the host. 
In one embodiment, the medicament is an antibiotic. In another embodiment, 
the medicament is an antiviral. Preferably, the medicament is an 
antibacterial. In a preferred embodiment, the medicament is an anticancer 
agent. In one embodiment, the medicament is a surfactant supplement. In 
another embodiment, the medicament is at least one enzyme. Preferably, the 
enzyme is a proteinase. In another embodiment, the enzyme is a 
deoxyribonuclease. The medicament in another embodiment enhances activity 
of the immune system of the host. In a preferred embodiment, the 
medicament is an immunosuppressor. In another preferred embodiment, the 
medicament is a decongestant. 
DETAILED DESCRIPTION OF THE INVENTION 
The method of the present invention provides for delivery of a medicament 
to the pulmonary air passages of a mammalian host by a multiple step 
process involving introduction of a perfluorocarbon liquid into the lungs 
and introduction of a medicament in microparticulate form. In one 
embodiment, the first step is introduction of a perfluorocarbon liquid 
into the lungs followed by a second step of introducing a microparticulate 
medicament. In another embodiment, the first step is introduction of a 
microparticulate medicament which is further distributed into the lungs by 
a second step of introducing a perfluorocarbon liquid into the lungs. 
Another embodiment of the method involves first, introducing a 
perfluorocarbon liquid into the lungs, then introducing a microparticulate 
medicament into the host's lungs, and subsequently introducing a second 
volume of perfluorocarbon liquid into the lungs. In all of these 
embodiments, perfluorocarbon liquid can be removed from the lungs by 
evaporation or by such mechanical means as are typically used in standard 
lavage procedures, including aspiration or physical manipulation of the 
patient such as lowering the patient's head to permit the liquid to drain 
out under the influence of gravity. 
By "pulmonary air passages" is meant parts of the lungs normally occupied 
by air including the pulmonary channels, spaces within the trachea, left 
and right bronchi, bronchioles and alveoli. 
By "mammalian host" is meant humans and other mammals for veterinary or 
research purposes, including lambs, pigs, rabbits, cats and dogs. 
By "microparticulate medicament" is meant a medicament in powdered form, in 
microcrystalline suspension, in a clathrate with other compounds, in an 
aerosol, in a gaseous phase, in a nebulized suspension or any other form 
of small particles that can be suspended in a gas that is well known in 
the art, with the proviso in one preferred embodiment that it does not 
include a drug dispersed in an aerosolized perfluorocarbon that is a 
liquid at body temperature. 
By "introduction of a microparticulate medicament" is meant either active 
inhalation by the host of a medicament in gaseous suspension or passive 
introduction into the host's lungs by forcing microparticulate medicament 
dispersed in a gas into the pulmonary air passages. 
By "perfluorocarbon liquid" is meant any fluorinated carbon compound with 
appropriate physical properties of biocompatibility. These properties are 
generally met by perfluorocarbons having low viscosity, low surface 
tension, low vapor pressure, and high solubility for oxygen and carbon 
dioxide making them able to readily promote gas exchange while in the 
lungs. The perfluorocarbon liquid may be made up of atoms of carbon and 
fluorine, or may be a fluorochemical having atoms other than just carbon 
and fluorine, e.g., bromine or other nonfluorine substituents. 
It is preferred, however, that the perfluorocarbon have at least 3 or 4 
carbon atoms and/or that its vapor pressure at 37.degree. C. is less than 
760 torr. 
Representative perfluorochemicals include bis(F-alkyl) ethanes such as 
C.sub.4 F.sub.9 CH.dbd.CH.sub.4 CF.sub.9 (sometimes designated "F-44E"), 
i-C.sub.3 F.sub.9 CH.dbd.CHC.sub.6 F.sub.13 ("F-i36E"), and C.sub.6 
F.sub.13 CH.dbd.CHC.sub.6 F.sub.13 ("F-66E"); cyclic fluorocarbons, such 
as C10F18 ("F-decalin", "perfluorodecalin" or "FDC"), F-adamantane ("FA") 
, F-methyladamantane ("FMA"), F-1,3-dimethyladamantane ("FDMA"), F-di- or 
F-trimethylbicyclo[3,3,1]nonane ("nonane"); perfluorinated amines, such as 
F-tripropylamine ("FTPA") and F-tri-butylamine ("FTBA"), 
F-4-methyloctahydroquinolizine ("FMOQ"), F-n-methyl-decahydroisoquinoline 
("FMIQ"), F-n-methyldecahydroquinoline ("FHQ"), F-n-cyclohexylpurrolidine 
("FCHP") and F-2-butyltetrahydrofuran ("FC-75" or "RM101"). 
Brominated perfluorocarbons include 1-bromo-heptadecafluoro-octane (C.sub.8 
F.sub.17 Br, sometimes designated perfluorooctylbromide or "PFOB"), 
1-bromopentadecafluoroheptane (C.sub.7 F.sub.15 Br) , and 
1-bromotridecafluorohexane (C.sub.6 F.sub.13 Br, sometimes known as 
perfluorohexylbromide or "PFHB"). Other brominated fluorocarbons are 
disclosed in U.S. Pat. No. 3,975,512 to Long. 
Also contemplated are perfluorocarbons having nonfluorine substituents, 
such as perfluorooctyl chloride, perfluorooctyl hydride, and similar 
compounds having different numbers of carbon atoms. 
Additional perfluorocarbons contemplated in accordance with this invention 
include perfluoroalkylated ethers or polyethers, such as (CF.sub.3).sub.2 
CFO(CF.sub.2 CF.sub.2).sub.2 OCF(CF.sub.3).sub.2, (CF.sub.3).sub.2 
CFO(CF.sub.2 CF.sub.2).sub.3 OCF(CF.sub.3), (CF.sub.3)CFO(CF.sub.2 
CF.sub.2)F, (CF.sub.3).sub.2 CFO(CF.sub.2 CF.sub.2).sub.2 F, (C.sub.6 
F.sub.13).sub.2 O. Further, fluorocarbon-hydrocarbon compounds, such as, 
for example, compounds having the general formula C.sub.n F.sub.2n+1 
C.sub.n' F.sub.2n'+1, C.sub.n F.sub.2n+1 OC.sub.n' F.sub.2n'+1, or C.sub.n 
F.sub.2n+1 CF.dbd.CHC.sub.n' F.sub.2n'+1, where n and n' are the same or 
different and are from about 1 to about 10 (so long as the compound is a 
liquid at room temperature). Such compounds, for example, include C.sub.8 
F.sub.17 C.sub.2 H.sub.5 and C.sub.6 F.sub.13 CH.dbd.CHC.sub.6 H.sub.13. 
It will be appreciated that esters, thioethers, and other variously 
modified mixed fluorocarbon-hydrocarbon compounds are also encompassed 
within the broad definition of "fluorocarbon" liquids suitable for use in 
the present invention. Mixtures of fluorocarbons are also contemplated and 
are considered to fall within the meaning of "fluorocarbon liquids" as 
used herein. Additional "fluorocarbons" contemplated are those having 
properties that would lend themselves to pulmonary gas exchange including 
FC-75, FC-77, RM-101, Hostinert 130, APF-145, APF-140, APF-125, 
perfluorodecalin, perfluorooctylbromide, perfluorobutyl-tetrahydrofuran, 
perfluoropropyl-tetrahydropyran, dimethyladamantane, 
trimethyl-bicyclo-nonane, and mixtures thereof. Preferred perfluorocarbons 
are characterized by having: (a) an average molecular weight range from 
about 350 to 570; (b) viscosity less than about 5 centipoise at 25.degree. 
C.; (c) boiling point greater than about 55.degree. C.; (d) vapor pressure 
in the range from about 5 to about 75 torr, and more preferably from about 
5 to about 50 torr, at 25.degree. C.; (e) density in the range of about 
1.6 to about 2 gm/cm.sup.3 ; and (f) surface tensions (with air) of about 
12 to about 20 dyne/cm. 
The perfluorocarbon liquid is typically introduced into the pulmonary air 
passages after a period of at least ten to fifteen minutes of breathing 
pure oxygen. The perfluorocarbon may be conventionally introduced by 
simply injecting the liquid into and through an endotracheal tube between 
breaths. Alternatively, it may be delivered as liquid under pressure, as 
is done during liquid breathing. Moreover, an aerosol of liquid 
perfluorocarbon may be inhaled either through the nose or the mouth. 
Partial liquid ventilation techniques using oxygenated fluorocarbons are 
disclosed in related U.S. application Ser. No. 07/695,547. 
The volume of perfluorocarbon liquid introduced into the pulmonary air 
passages should preferably be substantially equivalent to 0.01% to 100% of 
the normal pulmonary functional residual capacity (FRC) of the host. By 
"pulmonary functional residual capacity" is meant the volume of space in 
the pulmonary air passages at the end of expiration. For different 
applications, different amounts of perfluorocarbon are preferred. In one 
embodiment, the volume of perfluorocarbon liquid is at least 1%, 2%, 3% or 
5% of the pulmonary FRC of the host. Preferably, the volume of 
perfluorocarbon liquid is at least 10% of the host's pulmonary FRC. In 
another embodiment, the volume of perfluorocarbon liquid is at least 20% 
of the pulmonary FRC of the host. In other preferred embodiments, the 
volume of perfluorocarbon liquid is not more than 30%, 50% or 75% of the 
host's pulmonary FRC. Alternatively, the volume of perfluorocarbon liquid 
is not more than 20% of the pulmonary FRC of the host. The normal 
pulmonary FRC of the host is calculated by methods well known in the art. 
It will be appreciated by those skilled in the art that preferred volumes 
of filling the lungs with perfluorocarbons may be within certain ranges 
instead of discrete percentages. Thus, preferred embodiments of the 
invention include administration of perfluorocarbon of 0.01-1%, 0.01-10%, 
1-10%, 1-20%, 5-50%, 10-70%, 50-75%, 50-100% and 75-100% of the host's 
pulmonary FRC, calculated using standard methods known in the art. 
Partial filling of the lung with perfluorocarbon: (a) maintains FRC and 
prevents surface tension-induced alveolar closure during expiration; (b) 
reduces surface tension along much of the alveolar surface where 
perfluorocarbon lies against the alveolar lining; and (c) provides a low 
surface tension medium for exchange of the powdered or other 
microparticulate drug delivered by inhalation or by forcing a gaseous 
suspension into the lungs. In one embodiment, the gaseous suspension is 
introduced by means of a conventional gas ventilation respirator 
apparatus. By not exceeding the patient's FRC, the barotrauma associated 
with liquid breathing is avoided and added mechanical stress caused by 
inhalation or forced introduction of the powdered drug is precluded. 
Delivery of perfluorocarbon to a single lobe (unilateral) or local portion 
(lobar, segmental) is also contemplated. In conjunction with 
perfluorocarbon and medicament treatment, continuous positive pressure 
breathing using a conventional ventilator may also be employed. This is 
particularly desirable when perfluorocarbon is maintained in the lungs for 
facilitated drug delivery over relatively long periods (up to about 3 
hours). This may be achieved by using a volume of perfluorocarbon of about 
100% of the patient's FRC and/or by using a relatively low vapor pressure 
perfluorocarbon, because both impede rapid evaporation of the 
perfluorocarbon. 
Some fluorocarbons having relatively high vapor pressure may be useful for 
drug therapy in which a single dose of drug is rapidly administered such 
as for those drugs that are quickly absorbed through the lung tissue. 
However, high vapor pressures render them less suitable for use in 
facilitated drug delivery in which the drug must remain in the lungs for a 
longer period of time (hours). Fluorocarbon liquids contemplated for such 
long-term drug delivery include PFOB, F-nonmame, FDMA, F-adamatane, F66E, 
Fi36E, PFoCl and PFoH. Lower vapor pressures are additionally important 
from an economic standpoint because significant percentages of 
fluorocarbon having high vapor pressure would be lost due to evaporation 
during longer-term therapies. 
Following the perfluorocarbon-facilitated medicament delivery, the 
perfluorocarbon liquid may be removed from the pulmonary air passages. The 
preferred technique for this particular purpose is to simply permit the 
perfluorocarbon to evaporate from the pulmonary air passages. Positive 
pressure gas ventilation using a conventional ventilator may be used to 
facilitate evaporation during or after treatment resulting in 
substantially complete evaporation from the lungs in a time period 
(determined by the vapor pressure of the perfluorocarbon) on the order of 
hours for situations in which perfluorocarbon fills a significant fraction 
of the patient's FRC. 
The fluorocarbon of choice should have functional characteristics that 
would permit its use temporarily for facilitated medicament delivery 
because it additionally permits inflation of collapsed portions of the 
lung, gaseous (oxygen and carbon dioxide) exchange and/or serves as a lung 
surfactant. Fluorocarbons are biocompatible and most are amenable to 
sterilization techniques. For example, they can be heat-sterilized under 
pressure (by using an autoclave) or sterilized by radiation. In addition, 
sterilization by ultrafiltration is also contemplated. 
A variety of medicaments may be used as therapeutics using the present 
invention's method. All must be in a form that is a microparticulate 
suspension for inhalation or for forced introduction into the lungs. 
Preferably, powdered medicament is introduced. Powder may be obtained by 
standard drying and crushing methods or by freeze-drying and dispersal of 
the medicament in a gas. Inhalation or forced (positive pressure) 
introduction, either nasal or oral, of the medicaments can be achieved by 
any of a variety of methods known in the art. These include mechanical 
suspension by agitation of the medicament in a closed chamber followed by 
inhalation, or forced introduction of the suspension from an opening in 
the chamber. Microparticles can be inhaled from standard aerosol delivery 
systems which are well known in the art. The host may receive a 
particulate suspension which is placed into an air stream such as by 
injection of the powdered drug into a positive pressure ventilation tube 
or into an endotracheal tube at the moment of inspiration or when air is 
forced into the lungs. Metered dosages may be mechanically injected into 
such devices. Powdered medicament may be dispersed in air by using the 
Venturi effect, where air is moved at right angles across a Venturi tube 
causing the powdered drug to be drawn through the tube and dispersed into 
the air that is inhaled or mechanically introduced into the lungs. 
Pulsatile delivery of medicament in a volume of gas and inhalation of the 
aerosolized bolus is also known in the art as described in PCT published 
application WO 9407514, and the delivery techniques described therein can 
be used in the present invention. 
Perfluorocarbons can serve as temporary lung surfactants because they are 
biologically compatible, decrease the surface tension sufficiently within 
the alveoli, cover the lung surface easily and promote oxygen and carbon 
dioxide exchange. When used in conjunction with introduction of a powdered 
or other microparticulate medicament, perfluorocarbon can facilitate 
delivery of the medicament to the lungs where it is absorbed by lung 
tissue or where it acts on substances covering the lung tissue such as 
hyaline membrane or fungal infections. Perfluorocarbon enhanced drug 
delivery can also be used to deliver drugs systemically by administering 
the drug to the lungs where translocation across pulmonary membranes takes 
place, allowing the drug to rapidly enter the blood system. 
Therapeutic surfactant supplements delivered via perfluorocarbon, a 
biocompatible oxygenatable liquid, would benefit individuals who, for any 
of a variety of reasons, lack normal levels of lung surfactant. Using the 
present invention, powdered supplemental surfactant can be delivered 
directly to the affected area of the lungs while allowing normal 
oxygen/carbon dioxide exchange to continue. 
Because perfluorocarbon has at least some of the functional properties of a 
lung surfactant it can be used in lavage. When combined with introduction 
of any of a variety of powdered or other microparticulate medicinal 
substances, lavage can be additionally advantageous. 
The method disclosed herein is particularly well suited for treatment of 
cystic diseases because the perfluorocarbon liquid fills cysts and holds 
them open in a relatively static position thus relieving the mechanical 
stress on the cystic tissue. Introduction of powdered antibiotics into the 
lungs either by inhalation or forced introduction of the drug then is used 
to directly treat any infection in the cysts. 
The method not only relieves stress during inhalation but also concentrates 
the drug directly at the site of the infection. Because perfluorocarbon 
are relatively dense compared to body fluids, the perfluorocarbon will 
tend to sink and fill the cyst cavity, thus holding it open for delivery 
of the antibiotic upon inhalation. Direct administration of the drug to 
the cysts also obviates the need for systemic administration of 
antibiotics which lead to loss of intestinal flora. This is especially 
important for individuals with chronic cystic disease who are constantly 
in danger of developing lung infections due to the presence of mucinous 
secretions in the cysts and thus are exposed to repeated antibiotic 
treatment. 
Perfluorocarbon may be used in sufficient volume to combine facilitated 
drug delivery with lung lavage for treatment of cystic disease. If 
mucinous secretions build up within the cysts, perfluorocarbon can be 
administered in a volume approaching 100% of the pulmonary functional 
residual capacity. The powdered antibiotic is then administered by 
inhalation or forced introduction of a gaseous suspension of 
microparticles. After sufficient time to allow drug uptake by the lung 
tissue, any remaining perfluorocarbon may be removed using lavage or other 
techniques well known in the field of pulmonary treatment. Because the 
perfluorocarbon is relatively dense compared to mucinous secretions, the 
perfluorocarbon will tend to displace the secretions in the cysts and 
subsequent removal of the perfluorocarbon will facilitate simultaneous 
removal of accumulated mucinous secretions. 
Introduction of anticancer agents directly into the lungs by inhalation or 
positive pressure introduction of a gaseous suspension of microparticles 
may be used to treat lung tumors. This type of therapy exposes both 
healthy and tumorous tissue to the anticancer drug, most of which are 
cytotoxic. Healthy lung tissue can be shielded from the toxic anticancer 
agent by first treating the patient with surfactant supplements using the 
perfluorocarbon enhanced delivery method. Then, the anticancer agent may 
be selectively administered to the tumor area by using the perfluorocarbon 
enhanced delivery method. Because perfluorocarbons are more dense than 
water and body tissue they tend to sink or pool into certain portions of 
the lungs depending on the orientation of the patient. By orienting the 
patient into a position that favors accumulation of an administered 
perfluorocarbon near cancerous lung tissue, the introduced powdered 
anticancer drugs are selectively localized in the tumor-affected area. 
The method of combining liquid perfluorocarbon treatment with inhalation or 
forced introduction of a gaseous suspension of therapeutic compounds has a 
number of advantages over other forms of drug delivery. The 
perfluorocarbon-enhanced delivery can be used for medicaments that would 
otherwise be ineffective or destroyed by delivery systemically. For 
example, proteins usually cannot be administered orally because they are 
destroyed in the alimentary tract. Some proteins may invoke severe 
allergic reactions and shock in the mammalian host if administered 
systemically such as intramuscularly or intravenously. 
Furthermore, by using perfluorocarbon in conjunction with a medicament, the 
medicament can be directed to particular portions of the lung because of 
the relative density of perfluorocarbon compared to body tissue. By 
orienting the patient appropriately, the perfluorocarbon can selectively 
accumulate in certain alveoli holding them open and thus making them 
relatively more accessible to the introduced medicament suspension. 
In each instance, the amount of drug used should be an effective amount for 
local or systemic treatment of the targeted condition. Effective amounts 
of pharmaceuticals can be readily determined either empirically or by 
consulting standard reference materials. 
In addition to enhanced drug delivery, perfluorocarbon liquids can be used 
to remove endogenous or foreign material from the interior of the lungs. 
Perfluorocarbon liquid can be substituted for conventional physiological 
saline solutions used in lavage. Because perfluorocarbons are 
oxygenatable, they provide oxygen to the person during the treatment 
allowing for longer and less dangerous lavage procedure. In addition, 
because some perfluorocarbons have lung surfactant properties, removal of 
the natural lung surfactant is minimized. The density of perfluorocarbon 
liquids is generally twice that of water and body tissue which permits the 
perfluorocarbon to sink below and displace the material to be removed. 
Then when the perfluorocarbon is removed by mechanical means well known in 
the practice of lavage, the displaced material will float and be 
simultaneously removed. These properties are particularly important when 
lavage is combined with perfluorocarbon-enhanced drug delivery as a 
complete treatment of, for example, a patient with cystic fibrosis whose 
lungs accumulate excess mucinous secretions.

The general principles of the present invention may be more fully 
appreciated by reference to the following non-limiting examples. 
EXAMPLE 1 
Delivery of Surfactant Supplements 
Powdered surfactant supplements are beneficial for treating individuals 
with lung surfactant deficiencies including premature infants with RDS 
(born before 36 weeks gestation) and adults with ARDS resulting from lung 
trauma. 
An adult who has ARDS because of burn injury and smoke inhalation resulting 
from being inside a burning building has severe damage to the lung 
epithelium and endothelium accompanied by capillary damage. Because of 
epithelium damage the patient also has decreased surfactant production and 
foci of collapsed alveoli (atelectasis) leading to localized hypoxia. The 
patient is treated by using the perfluorocarbon-enhanced delivery method 
in which the medicament inhaled or introduced by forcing a gaseous 
microparticulate suspension is a surfactant supplement in powdered form. 
The patient is placed on a conventional ventilator and allowed to breath 
pure oxygen for approximately ten to fifteen minutes. Then perfluorocarbon 
liquid is introduced into the pulmonary air passages by injecting the 
liquid into and through an endotracheal tube between breaths of air 
supplied by continued positive pressure ventilation. The volume of 
perfluorocarbon liquid introduced into the pulmonary air passages is 
substantially equivalent to 100% of the normal pulmonary functional 
residual capacity (FRC) of the patient, calculated by methods well known 
in the art. The perfluorocarbon liquid introduced is one that has a 
relatively low vapor pressure because the surfactant supplement must 
remain in the lungs for a longer period of time (hours). Thus, either one 
or a combination of PFOB, F-nonmame, FDMA, F-adamatane, F66E, Fi36E, PFoCl 
and PFoH is administered. 
Surfactant supplements consisting of proteins (SP-A, SP-B and SP-C) derived 
from extracts prepared from human or animal lung lavage are administered 
by inhalation of a powdered form of the supplement. Another 
microparticulate therapeutic agent that serves as a lung surfactant 
includes synthetic mixtures of phospholipids, including a mixture of 
diphosphatidylcholine and phosphoglycerol in a ratio of 7:3. The powdered 
surfactant is administered by inhalation where the microparticulate is 
periodically injected as a fine suspension into the positive pressure 
ventilation line or via the endotracheal tube at the moment of 
inspiration. The surfactant is either the proteinaceous type or the 
phospholipid type or an admixture of both depending on the extent of lung 
damage as determined by the treating physician. Following inhalation of 
the surfactant supplement suspension, a second volume of perfluorocarbon 
liquid is administered to ensure complete dispersion of the surfactant to 
all lung tissue surfaces. The second volume of perfluorocarbon will also 
ensure that the alveoli will remain open due to the presence of 
perfluorocarbon liquid in the alveoli between surfactant supplement 
treatments. 
Depending on the extent of tissue damage the perfluorocarbon-enhanced 
delivery of surfactant supplement is periodically repeated. As healing 
progresses and the patient's natural surfactant is replaced by 
supplemental surfactant, it may be possible to allow the perfluorocarbon 
to completely evaporate between dosages of the supplemental surfactant. As 
healing progresses and alveoli remain open even without intra-alveolar 
perfluorocarbon, subsequent dosages of supplemental surfactant may be 
inhaled following administration of smaller volumes of perfluorocarbon 
liquid (0.01% to 10% of the normal FRC of the patient) and/or use of 
perfluorocarbons with a relatively high vapor pressure, including F44E, 
FDC, FTPA, FMOQ, FMIQ, FHQ FCHP, FC-75, RM-101, C.sub.7 F.sub.15 Br and 
C.sub.6 F.sub.13 Br. 
In addition to delivery of therapeutics for treating damaged lung tissue, 
the method can also be used to administer anticancer drugs to a patient 
suffering from lung cancer. Any of a variety of anticancer drugs that can 
be formulated into a microparticulate form may be delivered including a 
chemotherapeutic drugs (eg., adriamycin), a radionuclide (alone or linked 
to a cancer-specific antibody), and a toxin such a ricin (alone or linked 
to a cancer-specific antibody). 
EXAMPLE 2 
Delivery of an Anticancer Drug 
A patient suffering from adenocarcinoma in the middle to outer third of the 
lung that has not metastasized to other sites in the body is treated with 
powdered doxorubicin-HCl (e.g., Adriamycin.TM.), a cytotoxic agent active 
against a variety of solid tumors. Doxorubicin is an antibiotic that 
selectively kills malignant cells and causes tumor regression by binding 
to nucleic acids. 
The patient is first oriented into a position where the tumor-affected area 
is located at a gravitational low point so that liquid perfluorocarbon 
will pool selectively around the area. The patient is allowed to breath 
pure oxygen for approximately ten to fifteen minutes before 
perfluorocarbon liquid is introduced into the pulmonary air passages under 
pressure as in liquid breathing. A volume of perfluorocarbon liquid 
substantially equivalent to 0.1% to 50% of the normal pulmonary FRC of the 
patient (calculated by methods well known in the art) is introduced. The 
amount will depend on the size and location of the tumor so that the 
introduced perfluorocarbon will tend to pool around the cancerous tissue. 
Unilateral or local delivery (lobar, segmental) may be preferred depending 
on the location of the tumor. 
A perfluorocarbon liquid with a relatively low vapor pressure is used 
because it must remain in the lungs for a longer period (hours) for 
effective administration of the chemotherapeutic. Preferred 
perfluorocarbons include PFOB, F-nonmame, FDMA, F-adamatane, F66E, Fi36E, 
PFoCl and PFoH, administered alone or in combination. 
Freeze-dried powdered doxorubicin is then inhaled at a dosage determined by 
the physician depending on the size of the tumor to be treated. Generally 
10 mg or less per dosage is inhaled and cumulative doses should never 
exceed 550 mg/m.sup.2 because overdosing increases the risk of 
cardiomyopathy and resultant heart failure. Because doxorubicin also 
causes severe local tissue necrosis, care must be taken to limit exposure 
of healthy tissue to the drug. Inhalation of surfactant supplements (see 
Example 1) may be combined with chemotherapy treatment. By administering 
surfactant supplements to the entire lung surface before administration of 
doxorubicin, the healthy tissue may be protected from the anticancer 
drug's cytotoxicity. By administering surfactant supplements to the entire 
lung surface after administration of doxorubicin, surfactant lost due to 
chemical assault of the normal tissue may be replaced in the lung. 
The patient remains oriented in the position to promote perfluorocarbon 
enhanced delivery to the tumor until all of the perfluorocarbon is 
dissipated by evaporation. Then the patient is allowed to rest normally. 
Other antineoplastic antimetabolites, alone or in combination, are also 
contemplated for use as chemotherapeutics with this method. They include 
5-fluor-2,4 (1H,3H)-pyrimidinedione ("5-FU"), vinblastine sulfate 
(especially for carcinoma that are resistant to other chemotherapeutic 
agents), and methotrexate (particularly for squamous cell and small cell 
lung cancers). 
Because all antineoplastic antimetabolites are highly toxic, administration 
should be carefully supervised by a qualified physician with experience in 
cancer chemotherapy. Administration of chemotherapeutics using this method 
should be done, at least initially, while the patient is hospitalized to 
monitor the patient for evidence of toxicity, especially for hemorrhage 
from the treated site. 
A patient with bronchitis associated with flu, cold, or chronic conditions 
including emphysema has an excess of mucus secretion in the bronchial 
tree. The accumulated mucous secretions serve as primary sites for growth 
of bacteria or fungus in infected lungs. Infections that occur in 
conjunction with respiratory distress may also be treated using the method 
to enhance delivery of antibiotics. 
EXAMPLE 3 
Delivery of Antibiotic for Treatment of Infection Associated with 
Bronchitis 
A child hospitalized with severe bronchitis resulting from the flu is 
treated with amoxicillin trihydrate ("amoxicillin"), a semisynthetic 
antibiotic with broad spectrum bacteriocidal activity against 
gram-positive and gram-negative organisms including streptococci, 
pneumococci, and nonpenicillinase-producing staphylococci. The child is 
placed on a positive pressure ventilator from which he breathes pure 
oxygen for about ten to fifteen minutes. Then, perfluorocarbon is 
introduced into the lungs under pressure as in liquid breathing. A volume 
of perfluorocarbon liquid substantially equivalent to 0.1% to 50% of the 
child's normal pulmonary functional residual capacity (calculated by 
methods well known in the art) is introduced. Perfluorocarbons with a 
relatively high vapor pressure, including F44E, FDC, FTPA, FMOQ, FMIQ, FHQ 
FCHP, FC-75, RM-101, C.sub.7 F.sub.15 Br and C.sub.6 F.sub.13 Br, are 
preferred because they will be more readily evaporated by normal or 
ventilator-assisted breathing after treatment is completed. After the 
perfluorocarbon has been administered, a dosage of powdered amoxicillin of 
approximately 1 to 10 mg/kg is introduced into the child's lungs under 
pressure supplied by the positive pressure ventilator. Evaporation of the 
perfluorocarbon occurs during ventilator-assisted breathing following 
antibiotic treatment. Because the antibiotic is delivered to the site of 
the infection, the amount of antibiotic used is decreased compared to 
standard oral dosages (40 mg/kg/day in divided dosages every 8 hours). 
The same treatment is repeated in a second dosage approximately 8 hours 
later and thereafter at 8 hour intervals until infection appears to be 
controlled by the drug. After one or a few treatments using 
perfluorocarbon enhanced antibiotic delivery, the child can be maintained 
on standard oral dosages of amoxicillin. 
In addition to antibiotics, decongestants (e.g., ephedrine HCl) in 
microparticulate form may be included in the introduced antibiotic dosage 
to limit mucus secretions. Additionally, if there is evidence of 
infectious injury to the lung tissue, surfactant supplements (see Example 
1) may be included during inhalation of the antibiotic. 
Immunocompromised patients such as those affected by AIDS or those taking 
immunosuppressive drugs to avoid transplant rejection are unusually 
susceptible to infections including pulmonary infections. The 
perfluorocarbon-enhanced drug delivery method may be used to treat such 
patients. 
EXAMPLE 4 
Treatment of Immunocompromised Patient for Lung Infection 
An adult with AIDS presents at an emergency facility with a high grade 
fever and bronchial congestion indicating that he has a pulmonary 
infection. He is treated with amoxicillin using perfluorocarbon-enhanced 
delivery as in Example 3 except that the perfluorocarbon liquid is 
introduced before and after introduction of an adult dosage of powdered 
amoxicillin of approximately 10 to 100 mg every 8 hours. Because of his 
immunocompromised state and greater potential for alveolar collapse 
resulting from his weakened condition, introduction of the perfluorocarbon 
liquid before introduction of the antibiotic will ensure that alveoli are 
open. Introduction of perfluorocarbon liquid after introduction of the 
antibiotic will ensure complete dispersal of the antibiotic to all lung 
tissue. A volume of perfluorocarbon liquid substantially equivalent to 50% 
of his normal pulmonary functional residual capacity (calculated by 
methods well known in the art) is introduced at both times. Following a 
day or two of perfluorocarbon-enhanced delivery of amoxicillin, he is 
switched to oral dosages of 500 mg every 8 hours for approximately 8 to 10 
days. 
Alveolar macrophages are phagocytic cells that migrate into the lungs in 
response to irritation where they engulf and remove foreign objects such 
as bacteria or foreign particles. Perfluorocarbon-enhanced treatment with 
agents that increase activity of alveolar macrophages speeds removal of 
foreign irritants in the lungs. 
EXAMPLE 5 
Delivery of Immunologically Active Factors to Enhance Pulmonary Macrophage 
Activity 
Cell-mediated immunity depends on cells called macrophages that attack 
foreign objects and pathogens by engulfing them and removing them from the 
body through proteolytic digestion and physical removal to the lymphatic 
system. Macrophages migrate into the lungs when foreign irritants are 
present. Macrophages are activated by lymphokines which are proteins 
produced by certain classes of T cells. This process can be painfully slow 
because it involves a cascade of events: macrophages engulf the foreign 
invader and partially digest it; macrophages present antigens derived from 
the invader on their cell surface; these antigens are then recognized by 
antigen-specific T-cells which in turn produce lymphokines to solicit 
migration of other phagocytic cells to the site. 
By delivering identified macrophage-activating lymphokines to the lungs 
shortly after exposure to bacterial or particulate irritants, the process 
of macrophage-mediated removal is increased and removal of the irritant 
occurs more rapidly. Interleukin-2 (IL-2) is a multifunctional lymphokine 
that enhances macrophage activity. 
A worker in a chemical processing plant who has been exposed to a large 
amount of particulate irritant as a result of an industrial accident 
presents with severe respiratory distress. The patient's lungs are first 
treated by lavage with perfluorocarbon liquid (using a volume equal to 
100% of the patient's pulmonary FRC) using lavage techniques well known in 
the field to remove the majority of easily dislodged particulates. The 
perfluorocarbon liquid is mechanically removed by using standard lavage 
techniques. Then the patient is treated with powdered IL-2 using the 
perfluorocarbon-enhanced delivery method. 
The patient is placed on a conventional ventilator and allowed to breath 
pure oxygen for approximately ten to fifteen minutes before 
perfluorocarbon liquid is introduced into the pulmonary air passages by 
injecting the liquid into and through an endotracheal tube between 
breaths. The volume of perfluorocarbon liquid introduced is substantially 
equivalent to 100% of the normal pulmonary FRC of the patient as 
calculated by methods well known in the art. The perfluorocarbon liquid 
introduced is one that has a relatively low vapor pressure because the 
surfactant supplement may remain in the lungs for a period of hours. Thus, 
either one or a combination of PFOB, F-nonmame, FDMA, F-adamatane, F66E, 
Fi36E, PFoCl and PFoH is administered. 
IL-2 is administered by introduction of a microparticulate form that is 
injected as a fine suspension into the positive pressure ventilation line 
or via the endotracheal tube during a positive pressure ventilation. Other 
microparticulate therapeutic agents that serve as lung surfactant 
supplements (see Example 1) may also be included if the treating physician 
suspects damage to the surfactant or underlying tissue caused by 
inhalation of the chemical particles or the subsequent lavage. Multiple 
inhalations of IL-2 and surfactant supplements may be made while the 
perfluorocarbon remains in the lung. Alternatively, a single inhalation of 
IL-2 may be followed with multiple inhalations of surfactant supplement to 
maintain the alveolar surface during phagocytosis of the foreign 
particles. 
Following treatment, the perfluorocarbon dissipates by evaporation during 
normal breathing. 
Acute inflammation of the lungs that occurs following exposure to noxious 
or allergic-reaction producing particles may be treated with 
perfluorocarbon-enhanced delivery of immunosuppressive drugs. 
EXAMPLE 6 
Treatment of Acute Inflammatory Reaction by Delivery of Immunosuppressive 
Drug 
When macrophages and polymorphonuclear cells rapidly invade pulmonary 
tissue in response to exposure to noxious or virulent particle, the lungs 
become inflamed leading to much discomfort and breathing difficulty. 
Immunosuppressive drugs including anti-inflammatory steroids are often 
used to decrease inflammation. Dispersal of the anti-inflammatory steroids 
into the lungs is critical to relieve the symptoms. 
A person exposed to a massive dose of pollen suffers a severe allergic 
reaction and extreme difficulty breathing. The person presents at an 
emergency facility and is treated with microparticulate flunisolide 
(6.alpha.-fluoro-11.beta., 16.alpha., 17, 21-tetrahydroxypregna-1, 
4-diene-3, 20 dione cyclic-16, 17-acetyl with acetone) by using the 
perfluorocarbon enhanced delivery method. 
Because acute inflammation results in severely restricted ability to 
breath, the patient is placed on a positive pressure ventilator from which 
he breathes pure oxygen for about ten to fifteen minutes. Then, a dosage 
of 0.25-0.5 mg of flunisolide, a corticosteroid with marked 
anti-inflammatory and anti-allergic activity perfluorocarbon is introduced 
into the lungs under pressure supplied by the ventilator as described in 
Example 5. Then perfluorocarbon liquid is introduced into the lungs under 
pressure as in liquid breathing or via an endotracheal tube between 
breaths of air supplied by continued positive pressure ventilation. A 
volume of perfluorocarbon liquid substantially equivalent to 0.1% to 100% 
of the patient's normal pulmonary functional residual capacity (calculated 
by methods well known in the art) is introduced, depending on the degree 
of alveolar constriction. Perfluorocarbons with a relatively high vapor 
pressure, including F44E, FDC, FTPA, FMOQ, FMIQ, FHQ FCHP, FC-75, RM-101, 
C.sub.7 F.sub.15 Br and C.sub.6 F.sub.13 Br, are preferred because they 
will be more readily evaporated by normal or ventilator-assisted breathing 
after treatment is completed. The flunisolide dosage administered is 
0.25-0.5 mg and may be repeated approximately 10-12 hours later if 
necessary. Because the drug is readily dispersed to the alveoli by 
introduction of the perfluorocarbon liquid, the flunisolide dosage 
required is less than required by patients using standard 
self-administered aerosol inhaler systems. After therapy is completed, the 
patient is maintained on perfluorocarbon for up to 3 hours to keep alveoli 
open if inflammation does not subside quickly. When inflammation subsides, 
the perfluorocarbon is allowed to dissipate by evaporation during 
breathing. 
Use of the method with other anti-inflammatory agents including 
triamcinolone (9-fluoro-11.beta., 16.alpha., 
17,21-tetrahydroxypregna-1,4-diene-3,20-dione), triamcinolone acetonide 
(9-fluoro-11.beta., 16.alpha., 
17,21-tetrahydroxypregna-1,4-diene-3,20-dione cyclic 16, 17-acetal), 
beclomethasone dipropionate (9-chloro-11.beta., 
17,21-trihydroxy-16.beta.-methylpregna-1,4-diene-3,20-dione 
17,21-dipropionate), betamethasone sodium phosphate (9-fluoro-11.beta., 
17,21-trihydroxy-16.beta.-methylpregna-1,4-diene-3,20-dione 21-sodium 
phosphate), hydrocortisone (pregna-4-ene-3,20-dione, 21 (acetyloxy)-11, 
17-dihydroxy-acetate), dexamethasone sodium phosphate (9-fluoro-11.beta., 
17-dihydroxy-16.alpha.-methyl-21-(phosphono-oxy)pregna-1,4-diene-3,20-dion 
e 17,21-disodium salt), and triamcinolone acetonide (9-fluoro-11.beta., 
16.alpha., 17,21-tetrahydroxypregna-1,4-diene-3,20-dione-cyclic 
16,17-acetal), is also contemplated. 
Because hyaline membranes substantially interfere with gaseous exchange in 
the lungs associated with ARDS and hyaline membrane disease in infants, 
dissolving hyaline membranes increases the patient's ability to utilize 
oxygen and excrete carbon dioxide. 
EXAMPLE 7 
Delivery of Enzymes to Dissolve Hyaline Membranes 
Hyaline membranes contain protein-rich, fibrin-rich edematous fluid admixed 
with cellular debris. As such they are degraded by enzymes that dissolve 
proteins and cellular debris including nucleic acids. 
Perfluorocarbon-enhanced delivery of proteinases and deoxyribonuclease 
dissolves hyaline membranes making them more easily removed by normal 
cellular (i.e., macrophage) action. 
An adult with ARDS accompanied by hyaline membrane formation and foci of 
collapsed alveoli (atelectasis) is put on a positive pressure ventilator 
using standard practices. After being allowed to breath pure oxygen for 
approximately ten to fifteen minutes, perfluorocarbon liquid is introduced 
into the pulmonary air passages by injecting the liquid into and through 
an endotracheal tube between breaths of air supplied by continued positive 
pressure ventilation. Perfluorocarbon liquid equivalent to approximately 
100% of the normal pulmonary FRC of the patient (calculated by well known 
methods) is introduced into the pulmonary air passages. The 
perfluorocarbon liquid introduced is one that has a relatively low vapor 
pressure because the surfactant supplement must remain in the lungs for a 
longer period of time (hours). Thus, either one or a combination of PFOB, 
F-nonmame, FDMA, F-adamatane, F66E, Fi36E, PFoCl and PFoH is administered. 
A combination of a proteinase, fibrinolysin, and deoxyribonuclease, both in 
powder form, are introduced by inhalation of the microparticles. 
Fibrinolysin is derived from bovine plasma and primarily digests fibrinous 
exudates; deoxyribonuclease is derived from bovine pancreas and attacks 
deoxyribonucleic acid (DNA) to produce large polynucleotides. Dosage of 
the enzyme combination is 5-25 units (Loomis) of fibrinolysin and 
3,000-15,000 units (Christensen) of deoxyribonuclease, depending on the 
extent of hyaline membrane formation in the patient's lungs. The powdered 
enzymes are administered by inhalation where the powder is periodically 
injected as a fine suspension into the positive pressure ventilation line 
or via the endotracheal tube. 
If the patient also suffers from loss of surfactant due to hyaline-membrane 
induced hypoxia, surfactant supplement (see Example 1) may be included in 
the enzyme inhalation mixture. The synthetic phospholipid type of 
surfactant supplement is preferred because the proteinaceous type would 
serve as a competitive inhibitor of the proteinase in the enzyme mixture. 
Alternatively, either the protein or phospholipid type of surfactant 
supplement may be used subsequent to inhalation of the enzyme combination. 
Proteinaceous surfactant supplement could be used to "stop" the activity 
of the enzyme mixture by competitively inhibiting the fibrinolysin. 
Depending on the extent of tissue damage from hypoxia the perfluorocarbon 
liquid is periodically replaced to open collapsed alveoli during healing 
because evaporation will decrease the volume of retained perfluorocarbon. 
As healing progresses, the perfluorocarbon is allowed to completely 
evaporate through normal breathing, with or without mechanical 
ventilation. 
Perfluorocarbon-enhanced drug delivery may be used to treat tuberculosis, a 
disease which is increasing in frequency in the U.S. 
EXAMPLE 8 
Treatment of Tuberculosis by Localized Delivery of Anti-Inflammatory 
Antibacterial 
The perfluorocarbon-enhanced method is used for delivery of the sodium salt 
of mephenamine in microparticulate form. The drug serves as a local 
anti-inflammatory with bacteriostatic and bacteriocidal activities, 
including bacteriostasis of tubercule bacillus. Powdered streptomycin 
sulfate, effective against most forms of drug-resistant tuberculosis, may 
also be included in the inhaled therapeutic. 
The patient diagnosed with tuberculosis is first oriented into a position 
where the affected area (determined by X rays or other non-invasive 
diagnostic means) is located at a gravitational low point so that 
perfluorocarbon pools selectively around the area. The patient is allowed 
to breath pure oxygen for approximately ten to fifteen minutes before 
perfluorocarbon liquid is introduced into the pulmonary air passages under 
pressure as in liquid breathing. A volume of perfluorocarbon liquid 
substantially equivalent to 0.1% to 100% of the patient's normal FRC 
(calculated by methods well known in the art) is introduced. The amount 
will depend on the location and area affected by the infection so that the 
introduced perfluorocarbon will tend to pool around the infected tissue. 
Unilateral or local delivery (lobar, segmental) may be preferred depending 
on the extent of the infection. 
A perfluorocarbon liquid with a relatively low vapor pressure is used 
because it must remain in the lungs for a longer period (hours) for 
effective administration of the antibacterial agents. Preferred 
perfluorocarbons include PFOB, F-nonmame, FDMA, F-adamatane, F66E, Fi36E, 
PFoCl and PFoH, administered alone or in combination. 
A powdered therapeutic comprising one or more antibacterials (e.g., sodium 
mephenamine combined with streptomycin sulfate) is inhaled by the patient. 
The patient is not moved for a period up to three hours to allow the 
antibacterials to be absorbed by the affected tissue. During that time, 
normal breathing will result in evaporation of the perfluorocarbon liquid. 
Treatment may be repeated weekly for a period of months with systemic 
antibiotics administered between treatments to help clear the infection. 
In addition to diseases that directly affect the lungs, the 
perfluorocarbon-enhanced drug delivery method may be used to deliver drugs 
for other therapeutic purposes. 
EXAMPLE 9 
Treatment of Pulmonary Emboli by Inhalation of Powdered Urokinase After 
Perfluorocarbon Infusion 
Occlusion of a pulmonary artery by blot clot leads to arterial obstruction. 
Obstruction may lead to infarction of the underlying lung parenchyma. 
Sudden death may occur in the case of a saddle embolus where the 
obstruction is at the major branches of the pulmonary arteries and blood 
flow through the lungs ceases. 
Urokinase injected intravenously is often used to promote lysis of 
pulmonary embolism. Urokinase, an enzyme produced by the kidney, acts on 
the endogenous fibrinolytic system. It converts plasminogen to the enzyme 
plasmin which degrades fibrin clots as well as plasminogen and other 
plasma proteins. However, intravenously injected urokinase has a half-life 
of about 20 minutes or less because it is rapidly degraded by the liver. 
Furthermore, systemic injection of urokinase is contraindicated in cases 
in which there has been recent surgery or gastrointestinal bleeding. 
A patient with a pulmonary embolism may be treated using the 
perfluorocarbon-enhanced drug delivery method where the urokinase is 
inhaled as a powder (the low molecular weight form which may also contain 
inert carriers such as mannitol, albumin and sodium chloride). 
Depending on the location of the embolism, the patient is oriented so that 
the embolism is located at a gravitational low point. Then the patient is 
allowed to breath pure oxygen for approximately ten to fifteen minutes. 
Perfluorocarbon liquid is introduced into the pulmonary air passages under 
pressure as in liquid breathing. The volume of perfluorocarbon liquid 
introduced into the pulmonary air passages is substantially equivalent to 
0.1% to 100% of the normal pulmonary FRC of the patient calculated by 
methods well known in the art. The amount will depend on the size and 
location of the embolism so that the introduced perfluorocarbon will tend 
to pool in the area near the embolism. Unilateral or local delivery 
(lobar, segmental) may be preferred depending on the location in which the 
perfluorocarbon should settle. The perfluorocarbon liquid introduced is 
one that has a relatively high vapor pressure because the urokinase will 
be introduced rapidly. If pulmonary infarction has already occurred and 
alveoli are collapsed, a low vapor pressure perfluorocarbon may be used to 
simultaneously open the alveoli. 
After the perfluorocarbon has settled into the area of the embolism, a 
single dose of powdered urokinase is inhaled and the patient is allowed to 
breath normally so that remaining perfluorocarbon is evaporated. The 
patient is monitored for hemolysis in the lung and surfactant supplements 
(see Example 1) may be included in the urokinase dosage to protect 
pulmonary tissue during administration. Because enhanced delivery of the 
urokinase occurs at a region near the embolism, the concentration is 
higher near the site where activity is needed. Hence, problems associated 
with internal bleeding resulting from systemic delivery are overcome. 
Chronic conditions such as accumulation of mucinous secretions in the lungs 
of people afflicted with cystic fibrosis may also be treated by using the 
method, where the perfluorocarbon liquid serves the additional function of 
removing excess secretions by lavage prior to drug delivery. 
EXAMPLE 10 
Treatment of Cystic Fibrosis by Removal of Excess Mucinous Secretions from 
Lungs and Administration of Powdered Enzymes 
A adolescent with cystic fibrosis periodically experiences difficulty 
breathing because cavities in her lungs are filled with mucinous 
secretions. This condition frequently leads to infection of the cysts, 
especially by Streptococcus bacteria. Accumulation of secretions also 
makes her lung epithelium lining susceptible to progressive metaplasia 
which may result in necrosis and a lung abscess. Therefore it is 
advantageous to periodically clear her lungs of excess mucinous secretions 
to facilitate easier breathing and prevent infections, and to administer 
dosages enzymes as in Example 7 to clear residual accumulated secretions. 
Because cystic fibrosis leads to deterioration of the lungs' elastic and 
reticulin fibers that predisposes the tissue to rupture, it is important 
also to both relieve inhalation stress on the cystic tissue. 
The adolescent who is currently experiencing breathing difficulty due to 
accumulation of mucinous secretions in her lungs is first treated with 
perfluorocarbon liquid as a lavage to remove some of the excess 
secretions. She is placed on a conventional ventilator and allowed to 
breath pure oxygen for approximately ten to fifteen minutes. Then 
oxygenated perfluorocarbon liquid is introduced into her pulmonary air 
passages under pressure as for liquid breathing. The volume of 
perfluorocarbon liquid introduced into the pulmonary air passages is 
substantially equivalent to 100% of her normal pulmonary FRC, calculated 
by methods well known in the art. The perfluorocarbon liquid introduced is 
one that has a relatively low vapor pressure because it will be removed 
mechanically and evaporation should be minimized. Thus, either one or a 
combination of PFOB, F-nonmame, FDMA, F-adamatane, F66E, Fi36E, PFoCl and 
PFoH is administered. After sufficient time for the perfluorocarbon liquid 
to infuse her lungs (up to an hour) and displace accumulated secretions, 
the perfluorocarbon and displaced secretions are removed mechanically 
using conventional lavage procedures. 
After lavage is completed, the adolescent is administered a second volume 
of perfluorocarbon liquid under pressure as for liquid breathing. The 
volume and type of perfluorocarbon liquid are substantially as used in the 
lavage procedure. Then a dosage of powdered proteolytic and 
deoxyribonuclease enzymes as in Example 7 is introduced using positive 
pressure supplied by a ventilator. The enzymes will clear any residual 
mucinous secretions that remain after lavage. The patient is allowed to 
rest while her breathing is assisted by a positive pressure ventilator 
until all remaining perfluorocarbon has evaporated (up to about three 
hours).