CA2203135A1 - Use of liquid fluorocarbons to facilitate pulmonary drug delivery - Google Patents

Abstract

A kit which includes a perfluorocarbon liquid and a microparticulate medicament dispersed in a gas is used in the treatment of a pulmonary condition in a mammal. The kit is used in a multiple step method for delivering the medicament to the lungs. In this method, a biocompatible perfluorocarbon liquid is introduced into the lungs and 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.

Description

CA 0220313~ 1997-04-18 USE OF IIQUID FIUQ~QCA~RONS TO FACILITATE PUIMONARY DRUG
DEIIVERY
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 Isubcutaneous, 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 flu u"a,bL - and other fluorocarbons are also known to be safe, biocompatible substances when a~r~ ialLI~ 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 ~ 6l"leC U.S. Patent No. 3,975,512 to Long uses fll uCdlL ~, including brominated p~ bons, as a contrast enhancement medium in radiological imagin~q.
Gases in general, including oxygen and carbon dioxide, are highly soluble in some rluo,ucd,Lons. This cl,a,acl~O,i~lil, has "~.lldlldd ;I~.o~liydlu~ to develop emulsified fluorocarbons as blood 3~b;~I;IUItS. For a general review of the use of fluorocarbons as blood ;,~bi,lilulos see "Peacse,~, tv,l of Criteria for the Selection of PL~IUUI~ hemicals for Suo~ ~ Co,.~.dliun Blood Substitutes: Analysis of StructL.~lR~ .Iy Relationship" by Jean G.
Riess, Artificial 0ro,ans 8:34-56, 1984.
OA~, '' rj .ucalbO ~ act as a solvent for oxygen. They dissolve oxygen at higher tensions and release it as the partial pressure dc.~OasO~ carbon dioxide is similarly stored and released. When a fluu.ucalb0r is used intravascularly, OA~, Iion of the flu.,.ucalb0ll occurs naturally through the lungs. However, the flu ucd,b~n can be oA~yOIldldd prior to use in applications such as percutaneous transluminal coronary a ~ p'~cty, stroke therapy and organ plt5olv Liquid breathing using oAyyOllal~oJ rl"..,..~d,L - has been dem. ~,àlod on several oc - For example, an animal sub",~.~ d in an oA~yO~Idled flu ocdlbQr liquid may exchange oxygen and carbon dioxide normally when the lungs fill with the ~luGrucalb~ Although the work of breathing is increased in total submersion eA~ RIllOllls~
the animal can derive adequate oxygen for survival by breathing the UA~ 2Ied rlu.JIucalbc.. liquid.
Full liquid breathing as a therapy presents significant problems. Liquid breathing in a hospital setting requires dedicated .~.lli6liùn equipment capable of handling liquids. Moreover, OA~!, ~ of the fluorocarbon being _ 1 _ -CA 0220313~ 1997-04-18 breathed must be accomplished separately. The capital costs a -; ~ with liquid breathing are considerable.
Partial liquid ventilation techniques as disclosed in related U.S. Application Serial No. 071695,5`47 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 5 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 IRDS) 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 10 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 c~ tinns a~s with pulmonary distress.
15 Lunq Surfactant Conditions Lung surfactant functions to reduce surface tension within the alveoli thus permitting the alveoli to be held open under less pressure (The Pal' rHQir Basis of Disease, Robbins and Cotran eds., W.B. Saunders Co., New York, NY 1979). Lung ~ullal,lalll covers the lung surfaces, promotes alveolar expansion and mediates transfer of oxygen and carbon dioxide. S... ~a~.lalll supplclilclltL is beneficial in a number of mediEal therapies including, for example, 20 for individuals with - j ' lung s~llDa~.lanl deR - - Somemedicalproceduresrequirethatfluidsbeadded to the lungs, for example, as a wash to remove erdQ~ ~ or e " - 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. Sul, ' - of lung ~ulDal,lalll may relieve this trauma.
Currently, therapeutic surfactant sup;' ~ ~nt~ are used in infants when the amount of lung sulra~, 25 present is insufficient to permit proper rl r' aldly function. Surfactant supplementation is most commonly used in Respiratory Distress Syndrome (RDS), a specific form of which is known as hyaline membrane disease, when ~u, Dal,la"l dcri ~;~s compromise r I ~m y 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 ~-, alory Distress Syndrome IARDS), an adult form of the disease, has many similar 30 charal,lcli~li.,a 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 alllibulcd to insufficient amounts of pulmonary surfactant. R~clllallJlc infants born before the 36th week of gestation are at greatest risk because of ;U~Urr;LjC~I lung development.
Neonates born at less than 28 weeks of gestation have a 60-80% chance of dl..', ~, RDS which may be a life-35 threatenjng ccnr~itinn CA 0220313~ 1997-04-18 WO 96/140S6 PCrlUS9~/14280 At birth, high " Jry 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 lun~qs are virtually devoid of air after each breath. The 5 lungs collapse with each breath and the individual must continue to work as hard for each successive breath as shelhe did for herlhis first. Thus, exogenous therapy is required to facilitate breathing and minimke lung dama~qe.
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 ;,ur~i";~..ll~ 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 hyp~ ..;,iti.i~y 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 (d~ ) This initiates a vicious cycle of hypoxia and lung damage. Tumors, mucous plugs or aneurysms can also induce d~ l,75i, 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.
Cvstic Diseases Cystic diseases are critical iung diseases that produce abnormally large air spaces in the lung pa,~,.ch~.na.
They generally are either congenic i",nl' lç,enic cystic disease or alveolar cysts.
B,. ' ".nic cysts are rare congenital malformations often ass~c- :~d with cystic disease of the liver, kidney and pancreas. The cystic cavities are either filled with mucinous se~ : s or air as a con~l5 ee of ballooning out under the Cu~ ' thrust of respiratory pressure. Infection of the cysts, especially those containing ~c."~ ns, may lead to U~Uyl~ La~ula~;a of the epithelium lining the cyst which may result in necrosis and a lung abscess.
Alveolar cysts are more common and may result from ~ ~ - ' abnormal development or from inflammatory disease with fibrosis, aging and d~i~,iu,àliun of the alveolar wall. The walls of alveolar cysts are thin and fragile while the surrounding lung tissue is cGIl~,ur~scd and a~ In fact, alveolar cysts that lose elasticity are blown up like a balloon with each inspiration.
Cyst cavities are often filled with mucinous 5~.1U -~- that serve as prime sites for development of infection which may promote abscess formation resulting in lung collapse or ;..l~ iOàl pulmonary emphysema. Because CA 0220313~ 1997-04-18 excessive secretions accumulate in the lungs, they may require lavage treatments to clear them of excess mucinous So~ 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 ac-;oc: ~l d with 5 cysts.
Luna Cancer Lung cancer accounts for a significant portion (5-8%) of deaths in the United States and throughout the industrialized world. Cancers originating in the lungs are generally one of four types: squamous cell carcinoma (about 3040% of all lung tumors), adenocarcinoma (about 3W0%), large cell anaplastic carcinoma (less than 10%), and 10 small cell anaplastic carcinoma ~approximately 20%). Of these, adenocarcinomas and small cell cancers are most dangerous because they tend to m~lr~ to other sites in the body.
Most lung cancers occur in or on bronchial walls near the branch point into the trachea althou~qh 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 15 by administering chemotherapeutic agents directly into the lungs by ;~ tjQn 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 di(~ t~, pallh,ularl~ for delivery to selected pulmonary tissue. Thus the present invention will have ~,; 'e~ul~dd U~dlu~J uli~ application.
SUMMARY OF THE INVENTION
According to one aspect of the invention, there is provided a method for pulmonary drug delivery. The method includes ;.,lludu~ luv into the pulmonary air passages of a mammalian host a volume of pe"ll ..cdlbo liquid substantially equivalent to or less than the pulmonary r,,"~,i ' residual capacity of the host. The method further includes introducing a po. 'l ~d or other m;LIupdllil~ulal~ medicament dispersed in a gas into the pulmonary air 30 passages of the host, such that said p~l~luul~Jcalbc,~ liquid and said medicament are sin,.':~ :e 51y present in pulmonary air passages of the host. In one embodiment, a first volume of the perfluorocarbon liquid is introduced prior to inl,~luLOun of the medicament. In another embodiment, a second volume of perfluG,u..a,L liquid is ;"lrud~ d into the pulmonary air passages of the host subsequent to administration of the medicament. In yet another embodiment, the medicament is il,ll.:ll e~d prior to illl,. h of the p .rk. .u~,a,bcn liquid. Another 35 embodiment includes lavage with a F-~ rh~u~uca~bL . Iiquid performed prior to i~ udu~liull of the medicament. In one embodiment, the method includes an additional step after the steps of ~ v p~lr;uu~uca~bLl liquid and CA 0220313~ 1997-04-18 introducing the powdered or microparticulate medicament, that is the removal of the perfluorocarbon liquid from the pulmonary air pZ--~9f- 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 per~luu,uca,L~ 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 perflL~..ucalbor 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.
Prd~, hl~, the medicament is an antibacterial. In a preferred embodiment, the medicament is an a"liLu"ce. 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 deoxyrib l^qco The medicament in another embodiment enhances activity of the immune system of the host. In a preferred 20 embodiment, the medicament is an immunosuppressor. In another preferred embodiment, the medicament is a ~l C ~f ~ ~t DETAILED DESCBII~llON 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 b,ll-d : of a perfluorocarbon liquid into the lungs and 25 illl~odubliua of a medicament in microparticulate form. In one embodiment, the first step is i"l, d(: of a p~.rluuruca~b~"~ liquid into the lungs followed by a second step of introducing a m;c,~,,uz.lil,ulate medicament. In another embodiment, the first step is illlludùLIiun of a m;",opd,lil,uldle medicament which is further distributed into the lungs by a second step of blllodul.b~y a perflu .Ocdlbùn !iquid into the lungs. Another embodiment of the method involvesfirst,inl,ud.,,,b.yar~.llùol.-~bonliquidintothelungs,theni"l,~duc;"yamicropa,li~ ldlemedicamentinto 30 the host's lungs, and subs~ introducing a second volume of p~,iluo,.~~ bon liquid into the lungs. In all of these embodiments, p~,~i UCdlL~ liquid can be removed from the lungs by ~.a,uc.dliùll or by such mechanical means as are typically used in standard lavage ~.,ucedu,~,,, 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, L,~ and alveoli.

CA 0220313~ 1997-04-18 WO 96/14056 PCT/US9~;/14280 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 nebulked suspension or any other form 5 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 aerosolked 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 10 medicament dispersed in a gas into the pulmonary air pass~g~
By 'nperfluorocarbon 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 15 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 andlor that its vapor pressure at 37C is less than 760 torr.
Replts~..ldli.~p~lllùu.,,,,ha..licalsincludebis(F-alkyl)ethanessuchas C4F8CH-CH,,CFg(sometimesdesignated "F44En), i-C3FgCH~CHC6Fl3 (nF-i36En), and C6Fl3CH-CHC6F~3 (nF-66En);cyclic ~Lo~ucd,bc~ls, such as C10F18 (nF-decalinn, ''pe,~luu,~ "~alin" or "FDC"), F-adamantane(nFAn), F-m~lh,' '~ntane(nFMA"), F-1,3-dimethyladamantane (nFDMAn), F-di-or F-trimethylbicyclol3,3,11nonane ("nonanen); pel iluJ,i,,dled amines, such as F-tripropylamine(nFTPAn) and F-tri-butylamine ("FTBA"), F-4-",~lh,10cldi,1d" ,uinolizine ("FMOQn), F-n methyl-decahydroisoquinoline (nFMlQn), F-n-m~ ldec h,d~oquinoline (nFHQ"), F-n cyclohexylpurrolidine (nFCHPn) and F-2-b~lyllelldll~dlu~L~dll (nFC-75nor "RM101"). Brominatedp ,~luo~lcalL1rsinclude1-brornt h~,,L~d~cd~luu,uoctane(C8F,7Br,sometimesdc~;u,,,dl~d perfluorooctylbromideornPFOBn), 1-bromopenta-decafluoroheptane(C7Fl5Br), and 1-bron,ul,i 'cca~luorohexane(C6Fl3Br, sometimes known as perfluorohexylbromide or "PFHB"). Other brominated lluo~ucd~L -- are disclosed in US Patent No. 3,975,512 to Long.
Also cc~tr~p'~tpd are p~,~luu,uc~l,L,ons having no,l~lù.,,i,,e substituents, such as p~,~; roG~.Iyl chloride, p~,~lur,r,~ ~yl hydride, and similar compounds having different numbers of carbon atoms.
Additional perfluorocarbons c~ mr'~tPd in accu,da"~.e with this invention include p~ u.ualkylated ethers or polyethers, such as (CF3)2CFO(CF2CF2)20CF(CF3)2, (CF3)2CFO lCF2CF2)30CF(CF3), (CF3)CFO(CF2CF2)F, (CF3)2CFO(CF2CFJ2F, (C6Fl3)20. Further, fluo~ ,dl bc r hydrocarboncompounds, such as, for example, compounds having the general formula CnF2n~1-Cn.F2n.~1, CnF2n~l0Cn.F2n.~1, or CnF2nt1CF~CHCnF2n~1, where n and n' are the same or different and are from about 1 to about 10 (so long as the c ,: ' is a liquid at room; , dl~ ). Such compounds, for example, include C8F17C2Hs and C6F13 CH~CHC6H13. It will be 3" .~Cial~d that esters, thioethers, and other variously modified mixed C'uv.uc.llL h1dl~LalL compounds are also encompassed within the broad CA 0220313~ 1997-04-18 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 -3as exchan~qe including FC-75, FC-77, RM-101, Hostinert 130, APF-145, APF-140, APF-125, perfluorodecalin, perfluorooctylbromide, 5 perfluorobutyl-tetrahydrofuran, perfluoropropyl-tetrahydropyran, dimethyl-adamantane, trimethyl-bicyclo-nonane, and mixtures thereof. Preferred perfluorocarbons are characterized by havini~: (a) an average molecular wei~qht range from about 350 to 570; ~b) viscosity less than about 5 centipoise at 25C; Ic) boiling point greater than about 55C; (d) vapor pressure in the range from about 5 to about 75 torr, and more preferably from about 5 to about 50 torr, at 25C; (e) density in the range of about 1.6 to about 2 gmlcm~; and (f) surface tensions (with air) of about 12 to 10 about 20 dynelcm.
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. All~.ual;..,l~, it may be delivered as liquid under pressure, as is done during liquid breathing. Moreover, an aerosol of liquid perfluorocarbon may be 15 inhaled either through the nose or the mouth. Partial liquid ventilation techniques using u,.~" ~ted fluorocarbons are disclosed in related U.S. Application Serial No. 071695,547.
The volume of pllil~ul~,calbO 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 20 of expiration. For different apr' liu,,s, 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. F'l~e,di,ly, the volume of pe~L.~.~.ca,bon liquid is at least 10% of the host's pulmonary FRC. In another embodiment, the volume of perflu ~.calbùn 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. All~lllali.~ly, 25 the volume of perfluo,uca,ba.l Iiquid 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 perflu Lca,L ~ may be within certain ranges instead of discrete .,11se- 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 30 using standard methods known in the art.
Partial filling of the lung with pel~luulucalbcm (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 alveoiar lining; and (c) provides a low surface tension medium for exchange of the p .vd~ ~d or other microparticulate drug delivered by inhalation or by forcing a gaseous s~ . into the lungs.
35 In one embodiment, the gaseous suspension is introduced by means of a c ~..lk.aal gas ~...lilali.... Il, dlor ap~,a~ dll~. By not exceeding the patient's FRC, the barotrauma a ~ e- ted with liquid breathing is avoided and added CA 0220313~ 1997-04-18 mechanical stress caused by inhalation or forced introduction of the powdered drug is preciuded. 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 usinvq a conventional ventilator may also be employed. This is particularly desirable when perfluorocarbon is maintained in the lungs for facilitated 5 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 andlor 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.
10 However, high vapor pressures render them less suitable for use in facilitated drug delivery in which the drug must remain in the lunys 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, PFoCI 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 pa~ 19 - The preferred technique for this particular purpose is to simply permit the .v. Iluv~ - rbon to evaporate from the pulmonary air F-~ sn3 ~ Positive pressure gas ventilation using a conventional .v..li6lvr may be used to facilitate V.UI-~.di- during or after treatment resulting in substantially complete e~a~Jc.dlivn from the lungs in a time period (determined by the vapor pressure of the perfluorocarbon) on the order 20 of hours for ~:t, dli~ns in which F~ lluufvcv,Ll~ fills a significant fraction of the patient's FRC.
The Lu,vca,Lvn of choice should have 1, ' vI,a,aclv,i~liL~ 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 andlor serves as a lung vu, Idvla,ll. Fluorocarbons are biocompatible and most are amenable to sterilization techniques. ~or example, they can be heat-sterilized under pressure (by using an 25 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 . Opal i- '~t~ - , for inhalation or for forced introduction into the lungs. Preferably, p-~ dv.ud medicament is i,,lludù~,~d. Powder may be obtained by standard drying and crushing methods or by freeze drying and dispersal of the, ~ Pnt in a gas. Inhalation or forced (positive pressure) introduction, either nasal 30 or oral, of the medicaments can be achieved by any of a variety of methods known in the art. These include mechanical s-~pe~-: n by agitation of the medicament in a closed chamber followed by inhalation, or forced ;~lrudvvl of the ~ ,.a -:- n 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 , : which is placed into an air stream such as by injection of the powdered drug into a positive pressure ~.v.llilaliOU tube or into an 35 endotracheal tube at the moment of i, I or when air is forced into the lungs. Metered dosages may be mechanically injected into such devices. Fc.. ' ~d medicament may be dispersed in air by using the Venturi effect, CA 0220313~ 1997-04-18 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 Qas and inhalation of the aerosolized bolus is also known in the art as described in PCT published application W0 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 oxy~en 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 surfactantsupplements 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 oxygenlcarbon dioxide exchange to continue.
Because perflu ~ocalL has at least some of the functional properties of a lung surfactant it can be used in lavage. When combined with i"~ of any of a variety of p . '~,ud or other microparticulate medicinal substances, lavage can be additionally advantageous.
The method disclosed herein is particularly well suited for ll~all..~,..l of cystic diseases because the 20 perflu uca,b~ liquid fills cysts and holds them open in a relatively static position thus relieving the mechanical stress on the cystic tissue. Inl,ud~.~liu,. of p P ~d antibiotics into the lungs either by ha': or forced i"l-"dul~i- 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 IG~ rbon are relatively dense compared to body fluids, the p~,i;..J",ca,bon 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 S6LI~ 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 sec,~ build up within the cysts, perflu uGa,L can be administered in a volume approaching 100% of the pulmonary functional residual capacity. The pO. 'u.~d antibiotic is then administered by inhalation or forced introduction of a gaseous s- ~per of microparticles. After su~h,ienl time to allow drug uptake by the lung tissue, any remaining p~ - bon may be removed using lavage or other techniques well known in the field of pulmonary treatment. Because the perfluorocarbon is relatively dense compared _g_ .

WO 96/14056 PCr/US95/14280 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 5 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 'e '~ 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 10 the patient into a position that favors accumulation of an administered perfluorocarbon near cancerous lung tissue, the introduced powdered anticancer drugs are s 'e ~ Iocalized 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 15 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 perflu ucalL in conjunction with a medicament, the medicament can be directed to particular portions of the lung because of the relative density of perflu ..cl,lbn. compared to body tissue. By orienting the patient apl" ~r ia~ the c~ Iu,. ~bon can s~ accumulate in certain alveoli holding them open and thus making them relatively more ~c~c ' ' to the introduced medicament 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, perflu ucdlL liquids can be used to remove endogenous or foreign material from the interior of the lungs. Perflu~"~.ca,L 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 perfll ,.ca,L-~chave lung ~l Paclalll properties, removal of the natural lung 3~ al.lalll is minimized. The density of perfluorocarbon liquids is generally twice that of water and body tissue which permits the pe~ ,c~lbûn 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 pelilùu,uca,L . ~anced drug delivery as a complete treatment of, for example, a patient with cystic fibrosis whose lungs accumulate excess mucinous SeGI~i- S.
The general principles of the present invention may be more fully appreciated by reference to the following non-limiting examples.

CA 0220313~ 1997-04-18 WO 96/14056 PCr/US95114280 EXAMPLE 1: Deliverv of Surfactant Suonlements 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 5 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 (a~ ) leading to localized hypoxia. The patient is treated by usin~q 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.
15 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, PFoCI and PFoH is administered.
Surfactant supplements c ~ g of proteins (SP-A, SP-B and SP-C) derived from extracts prepared from human or animal lung lavaye are administered by inhalation of a powdered form of the supplement. Another 20 m;",upa,li~ulate therapeutic agent that serves as a lung ~ulPa~ld~l includes synthetic mixtures of phospholipids, including a mixture of diphr ~, hl ti~ylcholine and phosphoglycerol in a ratio of 7:3. The F D~ d ~Ld surfactant is administered by ' ' where the m;.,,ù~.a,li~.ulate is periodically injected as a fine suspension into the positive pressure ~la~.lild - line or via the endotracheal tube at the moment of inspiration. The surfactant is either the p,ui --e ~. type or the phospholipid type or an admixture of both depending on the extent of lung damage as 25 determined by the treating physician. Following inhalation of the ~" PaLIalll supplement s.,~ n, a second volume of perfluo,u,,a, on liquid is administered to ensure complete ~ of the surfactant to all lung tissue surfaces.
The second volume of perfluu,uca,Lon will also ensure that the alveoli will remain open due to the presence of F~ uca~bcr Iiquid in the alveoli between surfactant supplement lltan Depending on the extent of tissue damage the perfluoroca,L ~r ~ rd delivery of surfactant supplement 30 is periodically repeated. As healing p,uy,~ses and the patient's natural ~ulPal,lalll is replaced by supplemental ~u,PaLla,,l, it may be possible to allow the perfluo,u~albo to completely E., pr al~ between dosages of the s . r1l~nAnt~' sulPa~,lallL. As healing pluylt;,s6s and alveoli remain open even without intra-alveolar p.,.~ll,ur..ca,bc .
~-~hsEq~. - l dosages of supplemental surfactant may be inhaled following admi";~lldi r of smaller volumes of p~.R~,ol.-~ bon liquid (0.01% to 10% of the normal FRC of the patient) andlor use of ,c~.~h.u,L-~bons with a relatively high vapor pressure, including F44E, FDC, FTPA, FMOQ, FMlQ, FHQ FCHP, FC 75, RM-101, C7F,5Br and C6Fl~Br.

CA 0220313~ 1997-04-18 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-5 specific antibody).
EXAMPLE 2: Deliverv of an An~ir~nror Druq 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-HCI (e.g., AdriamycinTM), a cytotoxic agent active against a variety of solid tumors. Doxorubicin is an antibiotic that vvLti.vl~ kills malignant cells and causes tumor 10 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 pel~lcvlucalvlr will pool 3vlvvli~ 1~ around the area. The patient is allowed to breath pure oxygen for appluAi~la~ ten to fifteen minutes before perfluorocarbon liquid is introduced into the pulmonary air passages under pressure âS in liquid breathing. A volume of pe,~ bon liquid substantially equivalent to 0.1%
15 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 callc~lvvs tissue. Unilateral or local delivery (lobar, segmental) may be preferred depending on the location of the tumor.
A perfluD,vcdlbvn liquid with a relatively low vapor pressure is used because it must remain in the lungs 20 for a longer period (hours) for effective administration of the h ~ Preferred perfluorocarbons include PFOB, F-nonmame, FDMA, F-adamatane, F66E, Fi36E, PFoCI and PFoH, administered alone or in combination.
Freeze-dried pcn,.dl ~d 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 mglm2 because overdosing increases the risk of cardio,,,~vpalh~ and resultant heart failure.
25 Because doxorubicin also causes severe local tissue necrosis, care must be taken to limit exposure of healthy tissue to the drug. hd~dldliuu of sv. Davl-al,~ 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 anliva~vel drug's c~luluAiv;ly. By administering surfactant supplements to the entire lung surface after administration of doxorubicin, surfactant lost due to chemical assault of the normal tissue 30 may be replaced in the lung.
The patient remains oriented in the position to promote p Lv,,- L enhanced delivery to the tumor until all of the po,~lvvrv- ~bon is dissipated by evaporation. Then the patient is allowed to rest normally.
Other an~ o~ lh antimetabolites, alone or in combination, are also contemplated for use as chemull,v,a~Evlibs with this method. They include 5-fluor-2,4 (1H,3H) pyrimidinedione ("5-FU"), vinblastine sulfate 35 (especially for ca,v;"vllla that are resistant to other chemotherapeutic agents), and mvlhvlld~dl~v (pa,Ovvldlly for s, cell and small cell lung cancers).

CA 0220313~ 1997-04-18 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 srtes 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.
10 EXAMPLE 3: DeliverY of Antibiotic for Treatment of Infection Associated with Bronchitis A child hospitalked with severe bronchitis resulting from the flu is treated with amoxiciilin trihydrate (namoxicillinn), 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 ~.,li6l r from which he breathes pure oxygen for about ten to fifteen minutes. Then, 15 perfluorocarbon is introduced into the lungs under pressure as in liquid breathing. A volume of pe, DL~ bon 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 i"l, udu.,l,d. Perfluorocarbons with a relatively high vapor pressure, including F44E, FDC, FTPA, FMOQ, FMIQ, FHQ FCHP, FC-75, RM-101, C7F1sBr and C6Ft3Br, are preferred because they will be more readily evaporated by normal or ventilator-assisted breathing after treatment is completed. After the perfluo,ucd,L~
20 has been administered, a dosage of p.,~ d amoxiciliin of approximately 1 to 10 mglkg is introduced into the child's lungs under pressure supplied by the positive pressure ventilator. Evaporation of the ~ D~,u,ucu,bcn occurs during ~..li6 -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 mglkglday in divided dosages every 8 hours).
The same treatment is repeated in a second dosage approximately 8 hours later and Ol~ltd~l~, at 8 hour intervals until infection appears to be culllll " d by the drug. After one or a few tl~a~ using pellh ucd,b-:
enhanced antibiotic delivery, the child can be maintained on standard oral dosages of amoxicillin.
In addition to antibiotics, decongL,I~- Is (e.g., ephedrine HCI) in microparticulate form may be included in the introduced antibiotic dosage to limit mucus se",ttiu.,s. Additionally, if there is evidence of i"~,: injury to 30 the lung tissue, ~ dCICI ,, nonts (see Example 1) may be included during inhalation of the antibiotic.

Immunccu,,,plo,,,;~ed patients such as those affected by AIDS or those taking imm~..csu~,u,~s .;.~i drugs to avoid transplant rejection are unusually susceptible to i"~ci ~ inc!uding pulmonary ill~l,liuns. The perflu uca,bo,u enhanced drug delivery method may be used to treat such patients.

CA 0220313~ 1997-04-18 EXAMPLE 4: Treatment of ' Ir- uDromised Patient for Luna 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 perflu ocalLv 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 perfluoroca,Lv z ~ ' anced delivery of amoxicillin, he is switched to oral dosages of 500 mg every 8 hours for appruAi.,,dlul~ 8 to 10 days.

Alveolar Illacl~ 5 are ~ L~ i., cells that migrate into the lungs in response to irritation where they engulf and remove foreign objects such as bacteria or foreign particles. Perfluu..,~a,bLr enhanced treatment with 15 agents that increase activity of alveolar Illa",Lr' 1a~s speeds removal of foreign irritants in the lungs.
EXAMPLE 5: Deliverv of Immunolonicallv Active Factors to Enhance Pulmonarv ~ n Activitv Ccll rr~iqted immunity depends on cells called ",a-"-, ' vs S that attack foreign objects and pathogens by engulfing them and removing them from the body through p ut~ '~li., digestion and physical removal to the Iymphatic system. Macrophages migrate into the lungs when foreign irritants are present. "lL ~, h23Ps are activated by 20 Iymphokines which are proteins produced by certain classes of T cells. This process can be painfully slow because it involves a cascade of events: ma.".r' ll engulf the foreign invader and partially digest it; r"~b,~r' ~ges present antigens derived from the invader on their cell surface; these antigens are then recognized by antigen-specific T-cells which in turn produce l~ l; h~L: -, to solicit migration of other, hag~ , cells to the site.
By delivering identified ma.,.-r~, sctivating Iymphokines to the lungs shortly after exposure to bacterial 25 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 Iymphokine that enhances ",aL", ' j activity.
A worker in a chemical p,~ss g plant who has been exposed to a large amount of pallh,ulal~ irritant as a result of an industrial accident presents with severe respiratory distress. The patient's lungs are first treated by lavage with ~ ' .- Lon liquid (using a volume equal to 100% of the patient's pulmonary FRC) using lavage 30 i ' , well known in the field to remove the majority of easily dislodged particulates. The perflu ocalbu liquid is mechanically removed by using standard lavage techniques. Then the patient is treated with powdered IL-2 using the F ~I,.v.ucd,LGn-enhanceddelivery method.
The patient is placed on a conventional ventilator and allowed to breath pure oxygen for appl u~-illldlel~ ten to fifteen minutes before perfluorocarbon liquid is introduced into the pulmonary air passages by injecting the liquid 35 into and through an - ~LII. h~ ' tube between breaths. The volume of perfluorocarbon liquid bllr~.d~,~ed is SUbSlalllidlly E~ to 100% of the normal pulmonary FRC of the patient as calculated by methods well known CA 0220313~ 1997-04-18 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, PFoCI 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 damaye 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. Allv,,,dti.vl~, a single inhalation of IL-2 may be followed with multiple inhalations of Sul~al,lalll supplement to maintain the alveolar surface during, ' ~v ~lev;v 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 Inflammatorv Reaction bY Deliverv of ImmunosuPPressive Dru~
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 c...v.~;, .Ivy facility and is treated with m;vlupallibulate E' 1idr (6afluoro-11,~, 16a, 17, 21-~ ,dhyd,u,~y~,~vu,la 1, 4diene-3, 20 dione cyclic-16, 17-acetyl with acetone) by using the p~ vu..--rbon enhanced delivery method.
Because acute inflammation results in severely restricted ability to breath, the patient is placed on a positive pressure ~ ;lalul from which he breathes pure oxygen for about ten to fifteen minutes. Then, a dosage of 0.25 0.5 mg of flunisolide, a c Ovcvlv.. ' with marked antiinflammatory and antiallerûic activity pel~h.u,uvd,Lr is il~lluduved into the lungs under pressure supplied by the ventilator as described in Example 5. Then ,cv.~Pv,ur.-~bon liquid is introduced into the lungs under pressure as in liquid breathing or via an; ' lldclledl tube between breaths of air supplied by continued positive pressure ~ i6liull. A volume of p~ bon 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 inl~.d ^ed depending on the degree of alveolar c~r ~,i Perfluorocarbons with a relatively high vapor pressure, including F44E, FDC, FTPA, FMOQ, FMIQ, FHQ FCHP, FC 75, RM-101, C7FlsBr and C6F13Br, are preferred because they will be more readily v.v~c.dlvd by normal or ventilator-assisted breathing after ll~allllv..l is completed. The flunisolide dosage administered is 0.25 0.5 mg and may be repeated arr uxilllal~ 10 12 hours later 35 if necevsd,y. Because the drug is readily dispersed to the alveoli by introduction of the perfluorocarhv-vn liquid, the ' ' dosage required is less than required by patients using standard self-administered aerosol inhaler systems.

CA 0220313~ 1997-04-18 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,t~, 160, 17,21-tetrahydroxypregna-1,4-diene-3,20-dione),triamcinolone acetonide l9-fluoro-11~, 16a, 17,21-tetrahydruA~ a 1~4 diene-3,20-dionecyclic 16,17-acetal),beclomethasonedipropionate(9-chloro-11~,17,21-trihydroxy-16~"~th~1p.e~qna-1,4-diene-3,20-dione 17,21-dipropionate), betamethasone sodium phosphate (9-fluoro-11,~, 17,21-trihydroxy-16,~
methylpre~qna-1,4-diene-3,20-dione 21-sodium phosphate), hydrocortisone (pre~na~ene-3,20-dione, 21 (acetyloxy)-11, 17-dihydroxy n^~t~tP) dexamethasone sodium phosphate (9-fluoro-11~, 17-dihydroxy-160-methyl-21-(phosphono-oxy)pregna-1,4-diene-3,20dione 17,21-disodium salt), and triamcinolone acetonide (9-fluoro-11,B, 16a, 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 ~sso.~ d 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 Enzvmes to Dissolve Hvaline Membranes Hyaline membranes contain protein-rich, fibrin rich ed~"-atL fluid admixed with cellular debris. As such they are degraded by enzymes that dissolve proteins and celiular debris including nucleic acids. RL,~l,,o,oca,bon enhanced delivery of ,u,ului,,ases and deoxyribc.,.,Ll,dase 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 (a~ h cl~
is put on a positive pressure ventilator using standard practices. After being allowed to breath pure oxygen for ap~ u)-illldlel~ ten to fifteen minutes, pe"' r""d,bcnliquid is i"l~.dl ~ed into the pulmonary air passages by injecting the liquid into and through an ~ d~ ' tube between breaths of air supplied by c~ l ~d positive pressure ,,c.,lild6un. P~ .u,uc~,L liquid equivalent to arplu,dll,dl~'y 100% of the normal pulmonary FRC of the patient (calculated by well known methods) is i"ll"du"æ,d into the pulmonary air psssn6ss The perflul.u.,d,bon liquid b,l,.d d 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-ada"ldld,læ" F66E, Fi36E, PFoCI and PFoH is - ' ~d.
A combination of a ~.,u ,n/ ~iLH~ul~h~, and de~.~y,;' o ~ P both in powder form, are h~llud~ued by ' ' - of the microparticles. Fjb.;"GI~ is derived from bovine plasma and primarily digests fibrinous P~"da~
deoxyribl, Inase is derived from bovine pancreas and attacks deoxyribonucleic acid (DNA) to produce large Fol~ Jt;-les. Dosage of the enzyme o~ ' Oo,l is 5 25 units (Loomis) of liL,i..cly~;" and 3,000-15,000 units (C~"i~lu.ls~.,) of deGx~ r!~ AC~, dt:llæl~ J on the extent of hyaline ",~"~b,~ ~or",di )r in the patient's lungs.
35 The powdered enzymes are administered by inhalation where the powder is periodically injected as a fine S~l?p~ ; m into the positive pressure v~ i r line or via the endoll ' - ' tube.

CA 0220313~ 1997-04-18 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 sene 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 J 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 United States.
EXAMPLE 8: Treatment of Tuberculosis bv Localized Deliverv of Anti-inflammatorv AnliLa/.t~!Hdl The perflu uLa,Lorenhanced 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 babl~,iu~ld~;, of tubercule bacillus. Powdered streptomycin sulfate, effective against most forms of drug-resistant tuberculosis, may also be included in the inhaled lher~."~..li".
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 g, L~itd: - ~' low point so that perfluorocarbon pools sel~ around the area. The patient is allowed to breath pure oxygen for o~, UAilllal~l~ ten to fifteen minutes before perfluGrucd,L~r liquid is introduced into the pulmonary air passages under pressure as in liquid breathing. A
volume of perflu~,uca,Lcr 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 perfluu.b~,a,L 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 alllibacl~lidl agents. Preferred p~, ~I,,Gruca,bc include PFOB, F non~n, FDMA, F-adamatane, F66E, Fi36E, PFoCI and PFoH, administered alone or in combination.
A ,c~ d lh~ ,u~lh, comprising one or more afiliba~ ,ial~ (e.g., sodium mephenamine combined with SII~ LhI sulfate) is inhaled by the patient. The patient is not moved for a period up to three hours to allow the a"libacl~ ls to be absorbed by the affected tissue. During that time, normal breathing will result in e~a~Juldli of the p~ .uruca,~a.l 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 pel~luo,oca,bon en~ ed drug delivery method may be used to deliver drugs for other therapeutic purposes.

CA 0220313~ 1997-04-18 EXAMPLE 9: Treatment of Pulmonarv Emboli bv Inhalation of Powdered Urokinase After Perfluorocarbon Infusion Occlusion of a pulmonary artery by blot clot leads to arterial obstruction. Obstruction may iead 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.
5Urokinase injected intravenously is often used to promote Iysis 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 10gastrointestinal 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 15y~u~ ' low point. Then the patient is allowed to breath pure oxygen for applo~i",d~ ten to fifteen minutes.
PerflL~.~,ca,L r liquid is introduced into the pulmonary air passages under pressure as in liquid breathing. The volume of pelllùù,ucd,bc liquid ;~ ..du~.ad 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 perflu ocd,L~ will tend to pool in the area near the 20 embolism. Unilateral or local delivery (lobar, segmental) may be preferred depending on the location in which the pe, liUu~l~Cd~Lù~ should settle. The perfluorocarbon liquid introduced is one that has a relatively high vapor pressure because the urokinase will be i"L,ud~..,ed rapidly. If pulmonary infarction has already occurred and alveoli are c-"7, ed, a low vapor pressure p~ Lu.~,ca,i,on may be used to simultaneously open the alveoli.
After the p~,lluu,ocd,Lon has settled into the area of the embolism, a single dose of powdered urokinase 25 is inhaled and the patient is allowed to breath normally so that remaining Fe ihlu~ul,alb~ is c.a,uùldlud. The patient is monitored for hemolysis in the lung and ~u. lacla"l 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 ~...bc' m, the concc,,~,dUun is higher near the site where activity is needed. Hence, problems asso~,;aled with internal bleeding resulting from systemic delivery are overcome.
Chronic c~nditions such as accumulation of mucinous sec,~licas 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 S~LI~I;U;IS by lavage prior to drug delivery. r CA 0220313~ 1997-04-18 EXAMPLE 10: Treatment of Cvstic Fibrosis bv Removal of Excess Mucinous Se~ from Lunns and Administration of Powdered Enzvmes A adolescent with cystic fibrosis periodically experiences difficulty breathin~q because cavities in her lun~qs are filled with mucinous secretions. This condition frequently bads to infection of the cysts, especially by 5 Streptococcus bacteria. Accumulation of secretions also makes her lun~q epithelium lining susceptible to progressive metaplasia which may result in necrosis and a lun~q abscess. Therefore it is advantageous to periodically clear her lun~qs of excess mucinous secretions to facilitate easier breathin~q 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 reticuiin fibers that predisposes the tissue to rupture, it is important also to both relieve 10 inhalation stress on the cystic tissue.
The adolescent who is currently experiencin~q breathing difficulty due to accumulation of mucinous secretions in her lungs is first treated with perfluorocarbon liquid as a lavaye to remove some of the excess secretions. She is placed on a conventional .,..li6; and allowed to breath pure oxygen for app.uAilllalul~ ten to fifteen minutes.
Then UA~.v ~tPd perfluu,ucarbu.. liquid is introduced into her pulmonary air passages under pressure as for liquid 15 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 r .~I.,v.ocdH 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 a~ l . F66E, Fi36E, PFoCI and PFoH is administered. After sufficient time for the perflu~ru~a,b~ liquid to infuse her lun~qs (up to an 20 hour) and displace accumulated seclLF s, the perfluorocarbon and displaced SeLI~I;UI1S are removed mechanically using c .~..lio,)al lavage procedures.
After lavage is completed, the adql~ ~c~nt is administered a second volume of pe~ 2 ucd~L 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, u~ . and d~vA~ib~ rlDase enzymes as in Example 7 is 25 introduced using positive pressure supplied by a ventilator. The enzymes will clear any residual mucinous s~.... ~
that remain after lavage. The patient is allowed to rest while her breathing is assisted by a positive pressure 6ldt:r until all remaining ~ ~ ucalbe has e~ pc dlud(up to aboutthree hours).

_19_

Claims (62)

WE CLAIM:

1. A method for pulmonary drug delivery, comprising the steps of:
introducing into 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;
dispersing a microparticulate medicament in a breathable gas to form a gaseous suspension; and introducing said gaseous suspension into the pulmonary air passages of the host, such that said perfluorocarbon liquid and said microparticulate medicament are simultaneously present in the pulmonary air passages of the host.

2. The method of Claim 1, wherein said volume of said perfluorocarbon liquid is introduced prior to introduction of said gaseous suspension.

3. The method of Claim 2, further comprising the step of introducing a second volume of perfluorocarbon liquid into the pulmonary air passages of said host subsequent to administration of said gaseous suspension.

4. The method of Claim 1, wherein said gaseous suspension is introduced prior to introduction of said perfluorocarbon liquid.

5. The method of Claim 4, wherein lavage with a perfluorocarbon liquid is performed prior to introduction of said gaseous suspension.

6. The method of Claim 1, further comprising, after the steps of introducing perfluorocarbon liquid and introducing said gaseous suspension, a step of removing the perfluorocarbon liquid from the pulmonary air passages.

7. The method of Claim 6, wherein the perfluorocarbon liquid is removed from the pulmonary air passages by evaporation.

8. The method of Claim 6, wherein the perfluorocarbon liquid is removed from the pulmonary air passages by mechanical means.

9. The method of Claim 1, wherein the volume of perfluorocarbon liquid is equivalent to 0.01% to 100% of the pulmonary functional residual capacity of the host.

10. The method of Claim 1, wherein the volume of perfluorocarbon liquid is at least 1% of the pulmonary functional residual capacity of the host.

11. The method of Claim 1, wherein the volume of perfluorocarbon liquid is at least 2% of the pulmonary functional residual capacity of the host.

12. The method of Claim 1, wherein the volume of perfluorocarbon liquid is at least 5% of the pulmonary functional residual capacity of the host.

13. The method of Claim 1, wherein the volume of perfluorocarbon liquid is at least 10% of the pulmonary functional residual capacity of the host.

14. The method of Claim 1, wherein the volume of perfluorocarbon liquid is at least 20% of the pulmonary functional residual capacity of the host.

15. The method of Claim 1, wherein the volume of perfluorocarbon liquid is not more than 75% of the pulmonary functional residual capacity of the host.

16. The method of Claim 1, wherein the volume of perfluorocarbon liquid is not more than 50% of the pulmonary functional residual capacity of the host.

17. The method of Claim 1, wherein the volume of perfluorocarbon liquid is not more than 30% of the pulmonary functional residual capacity of the host.

18. The method of Claim 1, wherein the volume of perfluorocarbon liquid is not more than 20% of the pulmonary functional residual capacity of the host.

19. The method of Claim 1, wherein the medicament is an antibiotic.

20. The method of Claim 1, wherein the medicament is an antiviral.

21. The method of Claim 1, wherein the medicament is an antibacterial.

22. The method of Claim 1, wherein the medicament is an anticancer agent.

23. The method of Claim 1, wherein the medicament is a surfactant supplement.

24. The method of Claim 1, wherein the medicament is at least one enzyme.

25. The method of Claim 24, wherein said enzyme is a proteinase.

26. The method of Claim 24, wherein said enzyme is a deoxyribonuclease.

27. The method of Claim 1, wherein the medicament enhances activity of the immune system of the host.

28. The method of Claim 1, wherein the medicament is an immunosuppressor.

29. The method of Claim 1, wherein the medicament is a decongestant.

30. A kit comprising a perfluorocarbon liquid and a microparticulate medicament wherein said microparticulate medicament is dispersed in a breathable gas to form a gaseous suspension prior to said perfluorocarbon liquid and said gaseous suspension being separately introduced into the pulmonary air passages of a mammal for treatment of a pulmonary condition.

31. The kit of Claim 30, wherein the volume of perfluorocarbon liquid is equivalent to 0.01% to 100% of the pulmonary functional residual capacity of the mammal.

32. The kit of Claim 30, wherein the volume of perfluorocarbon liquid is at least 1% of the pulmonary functional residual capacity of the mammal.

33. The kit of Claim 30, wherein the volume of perfluorocarbon liquid is at least 2% of the pulmonary functional residual capacity of the mammal.

34. The kit of Claim 30, wherein the volume of perfluorocarbon liquid is at least 5% of the pulmonary functional residual capacity of the mammal.

35. The kit of Claim 30, wherein the volume of perfluorocarbon liquid is at least 10% of the pulmonary functional residual capacity of the mammal.

36. Canceled.

37. Canceled.

38. Canceled.

39. Canceled.

40. Canceled.

41. The kit of Claim 30, wherein the medicament is an antibiotic.

42. The kit of Claim 30, wherein the medicament is an antiviral agent.

43. The kit of Claim 30, wherein the medicament is an antibacterial agent.

44. The kit of Claim 30, wherein the medicament is an anticancer agent.

45. The kit of Claim 30, wherein the medicament is a surfactant supplement.

46. The kit of Claim 30, wherein the medicament is at least one enzyme.

47. The kit of Claim 46, wherein said enzyme is a proteinase.

48. The kit of Claim 46, wherein said enzyme is a deoxyribonuclease.

49. The kit of Claim 30, wherein the medicament enhances activity of the immune system of the mammal.

50. The kit of Claim 30, wherein the medicament is an immunosuppressor.

51. The kit of Claim 30, wherein the medicament is a decongestant.

52. The kit of Claim 30, wherein the pulmonary condition is a lung surfactant condition.

53. The kit of Claim 30, wherein the pulmonary condition is a cystic disease.

54. The kit of Claim 30, wherein the pulmonary condition is a lung cancer.

55. The kit of Claim 30, wherein the pulmonary condition is an infection.

56. Use of a microparticulate medicament in the manufacture of a pharmaceutical preparation for treatment of a pulmonary condition in a mammal wherein said microparticulate medicament is dispersed in a breathable gas to form a gaseous suspension that is introduced into the pulmonary air passages of said mammal followed by the pulmonary introduction of a volume of said fluorocarbon liquid substantially equivalent to or less than the pulmonary functional residual capacity of the mammal such that said fluorocarbon liquid and said microparticulate medicament are simultaneously present in the pulmonary air passages of the mammal.

57. The medicament of Claim 56, wherein a second volume of a fluorocarbon liquid is introduced prior to introduction of said gaseous suspension.

58. The medicament of Claim 56, wherein lavage with a fluorocarbon liquid is performed prior to introduction of said gaseous suspension.

59. The medicament of Claim 56, further comprising removal of the fluorocarbon liquid from the pulmonary air passages.

60. Use of a microparticulate medicament in the manufacture of a pharmaceutical preparation for treatment of a pulmonary condition in a mammal wherein said microparticulate medicament is dispersed in a breathable gas to form a gaseous suspension, said gaseous suspension being introduced into the pulmonary air passages of said mammal following the pulmonary introduction of a volume of said fluorocarbon liquid substantially equivalent to or less than the pulmonary functional residual capacity of the mammal such that said fluorocarbon liquid and said microparticulate medicament are simultaneously present in the pulmonary air passages of the mammal.

61. The medicament of Claim 60, wherein a second volume of a fluorocarbon liquid is introduced after introduction of said gaseous suspension.

62. The medicament of Claim 60, further comprising removal of the fluorocarbon liquid from the pulmonary air passages.