AU2006200277B2

AU2006200277B2 - Perforated microparticles and methods of use

Info

Publication number: AU2006200277B2
Application number: AU2006200277A
Authority: AU
Inventors: Luis A Dellamary; Alexey Kabalnov; Ernest G Schutt; Thomas E Tarara; Jeffrey G Weers
Original assignee: Nektar Therapeutics
Current assignee: Novartis AG
Priority date: 1997-09-29
Filing date: 2006-01-23
Publication date: 2008-04-10
Anticipated expiration: 2018-09-29
Also published as: AU2006200277A1

Description

AUSTRALIA

Patents Act 1990 COMPLETE SPECIFICATION STANDARD PATENT Applicant: NEKTAR THERAPEUTICS Invention Title: PERFORATED MICROPARTICLES AND METHODS OF USE The following statement is a full description of this invention, including the best method of performing it known to us: Va o PERFORATED MICROPARTICLES AND METHODS OF USE 0 SField of the Invention One or more embodiments of the present invention relate to the formulation, methods of production, and methods of delivery, of perforated microstructures comprising an active Sagent.

0 SBackground of the Invention STargeted drug deivery means are particularly desirable where toxicity or bioavailablity of the phannaceutical compound is an issue. Specific drug delivery methods and compositions that effectively deposit the compound at the site of action potentially serve to minimize toxic side effects, lower dosing requirements and decrease therapeutic costs. In this regard, the development of such systems for pulmonary drug delivery has long been a goal of the pharmaceutical industry.

The three most common systems presently used to deliver drugs locally to the pulmonary air passages are dry powder inhalers (PIs), metered dose inhalers (MDls) and nebulizers. MDIs, the most popular method of inhalation administration, may be used to delver medcaments in a solublized form or as a dspersion. Typically MDls comprise a Freon or other relatively high vapor pressure propellant that forces aerosolized medication into the respiratory tract upon activation of the device. Unlike MDIs, DPIs generally rely entirely on the patient's inspiratory efforts to introduce a medcament in a dry powder form to the lungs. Finally, nebulizers form a medicament aerosol to be inhaled by imparting energy to a liquid solution. More recently, direct pulmonary delivery of drugs during liquid ventilation or pulmonary lavage using a fluorochemical medium has also been explored. While each of these methods and associated systems may prove effective in selected situations, inherent drawbacks, including formulation limitations, can lnit their use.

The MDI is dependent on the propulsive force of the propellant system used in its manufacture.

Traditionally, the propellant system has consisted of a mixture of chlorofluorocarbons (CFCs) which are selected to provide the desired vapor pressure and suspension stability. Currently, CFCs such as Freon 11, Freon 12, and Freon 114 are the most widely used propellants in aerosol formulations for inhalation administration. While such systems may be used to deliver solublized drug, the selected bioactiva agent is typically incorporated in the form of a fine particulate to provide a dispersion. To minimize or prevent the problem of aggregation in such systems, surfactants are often used to coat the surfaces of the bioactive agent and assist in wetting the particles with the aerosol propellant. The use of surfactants in this way to maintain substentially uniform dispersions is said to stabilize" the suspensions.

0 o Unfortunately, traditional chlorofluorocarbon propellants are now believed to deplete stratospheric ozone and, as a consequence, are being phased out. This, in turn, has led to the development of aerosol c formulations for pulmonary drug delivery employing so-called environmentally friendly propellants. Classes of propellants which are believed to have minimal ozone-depletion potential in comparison with CFCs are perfluorinated compounds (PFCs and hydrofluoroalkanes (HFAs). While selected compounds in these classes may function effectively as biocompatible propellants, many of the surfactants that were effective in stabilizing drug suspensions in CFCs are no longer effective in these new propellant systems. As the solubility of the surfactant in the HFA decreases, diffusion of the surfactant to the interface between the drug particle o and HFA becomes exceedingly slow, leading to poor wetting of the medicament particles and a loss of suspension stability. This decreased solubility for surfactants in HFA propellants is likely to result in 0 decreased efficacy with regard to any incorporated bioactive agent.

More generally, drug suspensions in liquid fluorochemicals, including HFAs, comprise heterogeneous systems which usually require redispersion prior to use. Yet, because of factors such as patient compliance obtaining a relatively homogeneous distribution of the pharmaceutical compound is not always easy or successful. In addition, prior art formulations comprising micronized particulates may be prone to aggregation of the particles which can result in inadequate delivery of the drug. Crystal growth of the suspensions via Ostwald ripening may also lead to particle size heterogeneity and can significantly reduce the shelf-life of the formulation. Another problem with conventional dispersions comprising micronized dispersants is particle coarsening. Coarsening may occur via several mechanisms such as flocculation, fusion, molecular diffusion, and coalescence. Over a relatively short period of time these processes can coarsen the formulation to the point where it is no longer usable. As such, while conventional systems comprising fluorochemical suspensions for MOls or liquid ventilation are certainly a substantial improvement over prior art non.

fluorochemical delivery vehicles, the drug suspensions may be improved upon to enable formulations with improved stability that also offer more efficient and accurate dosing at the desired site.

Similarly, conventional powdered preparations for use in DPIs often fail to provide accurate, reproducible dosing over extended periods, in this respect, those skilled in the art will appreciate that conventional powders li.e. micronized) tend to aggregate due to hydrophobic or electrostatic interactions between the fine particles. These changes in particle size and increases in cohesive forces over time tend to provide powders that give undesirable pulmonary distribution profiles upon activation of the device. More particularly, fine particle aggregation disrupts the aerodynamic properties of the powder, thereby preventing large amounts of the aerosolized medicament from reaching the deeper airways of the lung where it is most effective.

In order to overcome the unwanted increases in cohesive forces, prior art formulations have typically used large carrier particles comprising lactose to prevent the fine drug particles from aggregating.

Such carrier systems allow for at least some of the drug particles to loosely bind to the lactose surface and 26/03/2088 15:56 GRIFFITH HACK 4 00262937999 N0.671 0009 0 0 c disengage upon inhalation. However, substantial amounts of the drug fail to disengage from the large lactose particles and are deposited in the throat As such, these carrier systems are Srelatively inefficient with respect to the fine particle fraction provided per actuation of the DPI.

Another solution to particle aggregation Is proposed in WO 98/31346 wherein particles having relatively large geometric diameters preferably greater than 10 pm) are used to reduce the amount of particle interactions thereby preserving the flowability of the powder. As with the pdrior p.

I> art canier systems, the use of large particles apparently reduces the overall surface area of the O powder preparation reportedly resulting in improvements in flowability and fine particle fraction.

C Unfortunately, the use of relatively large particles may result in dosing limitations when used in stardard DPIs and provide for less than optimal dosing due to the potentially prolonged dissolution Stimes. As such, there still remains a need for standard sized particles that resist aggregation and preserve the flowability and dispersibility of the resulting powder.

Summary of the Invention In one aspect the present invention relates to an inhaleable powder composition comprising a plurality of particulates, the particulates comprising a structural matrix and a nonphospholipd active agent, the structural matr* comprising phosphoipid and calcium, and the particulates having a mean geometric diameter of 1-30 microns, a mean aerodynamic diameter of less than 5 microns, and a bulk density of less than about 0.5 glcm 3 In a further aspect the present invention relates to a pulmonary delivery medicament comprising; a plurality of particulates, the particulates having a perforated microstructure comprising a phospholipid structural matrix and active agent, the phospholipid structural matrix comprising a..\fzaK\W\BsciW~t.dec 26/03/C1 COMS ID No: ARCS-184305 Received by IP Australia: Time 16:58 Date 2008-03-26 26/03/2008 15:56 GRIFFITH HPCK 4 00262R37999 NO. 671 D010 -4greater than about 50%/ w/w phospholipid, and the particulates having a geometric diameter of from 0.5 to 50 pm.

In a further aspect the present invention relates to a method of delivering a therapeutic dose of a bioactive agent to the pulmonary air passages In a single breath, the method comprising: providing an inhaleable powder composition or pulmonary delivery medicament; and administering the powder composition to a subject's respiratory tract.

Brief Description of the Drawings S:\MarKR\AwQp\Bpecsi\PS9 SB.dvoc 26/3/a COMS ID No: ARCS-184305 Received by IP Australia: Time 16:58 Date 2008-03-26 26/03/2009 26/032009 15:56 GRIFFITH HPCK 4 002628378999N.7 01 NO. 67 1 P011 [This page has been eft deliberatel blank] R-.\~rR\X~pqpej\PSK4.doC 26/03/0R COMS ID No: ARCS-184305 Received by IP Australia: Time 16:58 Date 2008-03-26 26/03/2008 26/3/209 15:56 GRIFFITH HACK( 4 00262837999 NO. 671 U012 -6 This page has been left deliberatly blank] It; braf\Kt~\Bp~i\P~6~t~nc 6/03/08 COMS ID No: ARCS-1843o5 Received by IP Australia: Time 16:58 Date 2008-03-26 SBrief Description of the Drawings CFigs. 1A1 to 1F2 illustrate changes in partice morphology as a function of variation in the ratio of fluorocarbon blowing agent to phospholipid (PFCIPCI present in the spray dry feed. The micrographs, Sproduced using scanning electron microscopy and transmission electron microscopy techniques, show that in

CN

0

O

0 0 -7- H:\MhraR\Kee\Speci\PS964S.doc 23fO1/ue 0 the absence of FCs, or at low PFCIPC ratios, the resulting spray dried microstructures comprising gentamicin sulfate are neither particularly hollow nor porous. Conversely, at high PFC/PC ratios, the particles contain numerous pores and are substantially hollow with thin walls.

SFig. 2 depicts the suspension stability of gentamicin particles in Perflubron as a function of formulation PFCIPC ratio or particle porosity. The particle porosity increased with increasing PFCIPC ratio.

Maximum stability was observed with PFCIPC ratios between 3 to 15, illustrating a preferred morphology for the perftubron suspension media.

Fig. 3 is a scanning electron microscopy image of perforated microstructures comprising cromolyn O sodium illustrating a preferred hollowjporous morphology.

Figs. 4A to 4D are photographs illustrating the enhanced stability provided by the dispersions of the o present invention over time as compared to a commercial cromolyn sodium formulation (Intlr, Rhone-Poulenc- SRorer). In the photographs, the commercial formulation on the left rapidly separates while the dispersion on the right, formed in accordance with the teachings herein, remains stable over an extended period.

Fig. 5 presents results of in-vitro Andersen cascade impactor studies comparing the same hollow porous albuterol sulfate formulation delivered via a MDI in HFA-134a, or from an exemplary DPI. Efficient delivery of particles was observed from both devices. MDI delivery of the particles was maximized on plate 4 corresponding to upper airway delivery. DPI delivery of the particles results in substantial deposition on the later stages in the impactor corresponding to improved systemic delivery in-vivo.

Detailed Description Preferred Embodments While the present invention may be embodied in many different forms, disclosed herein are specific illustrative embodiments thereof that exemplify the principles of the invention. It should be emphasized that As discussed above, the present invention provides methods, systems and compositions that comprise perforated microstructures which, in preferred embodiments, may advantageously be used for the delivery of bioactive agents. More particularly, the present invention may provide Sfor the delivery of bioactive agents to selected physiological target sites using perforated microstructure powders. In preferred embodiments, the bioactive agents are in a form for administration to at least a portion of the pulmonary air passages of a patient in need thereof. In particularly preferred embodiments, the disclosed perforated microstructure powders may be used in a dry state as in a OPI) or in the form of a stabilized dispersion as in a MDI, LDI or nebulizer formulation) to deliver bioactive agents to the nasal or pulmonary air passages of a 8a

OD

O patient. It will be appreciated that the perforated microstructures disclosed herein comprise a Cstructural matrix that exhibits, defines or comprises voids, pores, defects, hollows, spaces, Sinterstitial spaces, apertures, perforations or holes. The absolute shape (as opposed to the morphology) of the perforated microstructure is generally not critical and any overall configuration that provides the desired characteristics is contemplated as being within the scope of the invention. Accordingly, preferred embodiments can comprise approximately microspherical l'shapes. However, collapsed, deformed or fractured particulates are also compatible. With this caveat, it will further be appreciated that, particularly preferred embodiments of the invention Scomprise spray dried hollow, porous microspheres. In any case the disclosed powders of perforated microstructures provide several advantages including, but not limited to, increases in Ssuspension stability, improved dispersibility, superior sampling characteristics, elimination of carrier particles and enhanced aerodynamics.

H:\oNirk\Keep\SpeCi\PS94 .doc 23/C1/06 ICN \O Those skilled in the art will appreciate that many of these aspects are of particular use for dry powder inhaler applications. Unlike prior art formulations, the present invention provides CKI unique methods and compositions to reduce cohesive forces between dry particles, thereby minimizing particulate aggregation which can result in an improved delivery efficiency. To that 1end, the present invention provides for the formation and use of perforated microstructures and delivery systems comprising such powders, as well as individual components thereof. The 10 disclosed powders may further be dispersed in selected suspension media to provide stabilized

IND

dispersions. Unlike prior art powders or dispersion for drug delivery, the present invention Cpreferably employs novel techniques to reduce attractive forces between the particles. As such, the disclosed powders exhibit improved flowability and dispersibility while the disclosed dispersions exhibit reduced degradation by flocculation, sedimentation or creaming. As such, the disclosed preparations provide a highly flowable, dry powders that can be efficiently aerosolized, uniformly delivered and penetrate deeply in the lung or nasal passages. Furthermore, the perforated microstructures of the present invention result in surprisingly low throat deposition upon administration.

The dispersions or powders may be used, for example, in conjunction with metered dose inhalers, dry powder inhalers, atomizers, nebulizers or liquid dose instillation (LDI) techniques to provide for effective drug delivery.

With regard to particularly preferred embodiments, the hollow and/or porous perforated microstructures substantially reduce attractive molecular forces, such as van de Waals forces, which dominate prior art powdered preparations and dispersions. In this respect, the powdered compositions typically have relatively low bulk densities which contribute to the flowability of the preparations while providing the desired characteristics for inhalation therapies. More particularly, the use of relatively low density perforated (or porous) microstructures or microparticulates significantly reduces attractive forces between the particles thereby lowering the shear forces and increasing the flowability of the resulting powders. The relatively low density of the perforated microstructures also provides for superior aerodynamic performance when used in inhalation therapy. When used in dispersions, the physical characteristics of the powders provide for the formation of stable preparations. Moreover, by selecting dispersion components in accordance -9- H:\araR\Xeep\pec1\$964; .doc 23/01/vC 9a

N

D with the teachings herein, interparticle attractive forces may further be reduced to provide Sformulations having enhanced stability.

F1 With respect to the disclosed powders, the selected agent or bioactive agent, or agents, c may be used as the sole structural component of the perforated microstructures. Conversely, the LC- 5 perforated microstructures may comprise one or more components structural materials, surfactants, excipients, etc.) in addition to the incorporated agent. In particularly preferred embodiments, the suspended perforated microstructures will comprise relatively high Sconcentrations of surfactant (greater than about 10% w/w) along with an incorporated bioactive agenl(s). Finally, it should be appreciated that the particulate or perforated microstructure may be

ID

coated, linked or otherwise associated with an agent or bioactive agent in a non-integral manner.

Lc- Whatever configuration is selected, it will be appreciated that any associated bioactive agent may be used in its natural form, or as one or more salts known in the art.

While the powders or stabilized dispersions of the present invention are particularly suitable for the pulmonary administration of bioactive agents, they may also be used for the localized or systemic administration of compounds to any location of the body. Accordingly, it should be emphasized that, in preferred embodiments, the formulations may be administered using a number of different routes including, but not limited to, the gastrointestinal tract, the respiratory tract, topically, intramuscularly, intraperiloneally, nasally, vaginally, rectally, aurally, orally or ocularly.

H:\MaraR\Keep\Spec\P59646.doc 23/01/06 -9b SIn preferred embodiments, the perforated microstructure powders have relatively low bulk density, O allowing the powders to provide superior sampling properties over compositions known in the art. Currently, N 10 as explained above, many commercial dry powder formulations comprise large lactose particles which have Smicronized drug aggregated on their surface. For these prior art formulations, the lactose particles serve as a O carrier for the active agents and as a bulking agent, thereby providing means to partially control the fine particle dose delivered from the device. In addition, the lactose particles provide the means for the commercial filling capability of dry particles into unit dose containers by adding mass and volume to the dosage form.

By way of contrast, the present invention uses methods and compositions that yield powder formulations having extraordinarily low bulk density, thereby reducing the minimal filling weight that is commercially feasible for use in dry powder inhalation devices. That is, most unit dose containers designed for DPIs are filled using fixed volume or gravimetric techniques. Contrary to prior art formulations, the p~ieni iiven nproviiispowiiers wherein the active or bioactive agent and the incipients or bulking agent -meke-up the entire inhaled particle. Compositions according to the present invention typically yield powders with bulk densities less than 0.5 glcm 3 or 0.3 gncm, preferably less 0.1 glcmn and most preferebly less than 0.05 glcm 3 By providing particles with very low bulk density, the minimum powder mass that can be filled into a unit dose container is reduced, which eliminates the need for carrier particles. That is, the relatively low density of the powders of the present invention provides for the reproducible administration of relatively low dose pharmaceutical compounds. Moreover, the elimination of carrier particles will potentially minimize throat deposition and any "gag" effect, since the large lactose particles will impact the throat and upper airways due to their size.

In accordance with the teachings herein the perforated microstructures will preferably be provided in a "dry" state. That is the microparticles will possess a moisture content that allows the powder to remain chemically end physically stable during storage at ambient temperature and easily dispersible. As such, the moisture content of the micropartides is typically less than 8% by weight, end preferably less 3% by weight.

H:\\araR\Keep\Spec1\PF964B.doc 23/01/,

VO

0 0 In some instances the moisture content will be as low as 1% by weight. Of course it will be appreciated that the moisture content is, at least in part, dictated by the formuletion and is controlled by the process C conditions employed, inlet temperature, feed concentration, pump rate, and blowing agent type, concentration and post drying.

C 5 With respect to the composition of the structural matrix defining the perforated microstructures, they may be formed of any material which possesses physical and chemical characteristics that are compatible with any incorporated active agents. While a wide variety of materials may be used to form the particles, in particularly Cpreferred pharmaceutical embodiments the structural matrix is associated with, or comprises, a surfactant such as Sphospholipid or fluorinated surfactant. Although not required, the incorporation of a compatible surfactant can improve powder flowabilty, increase aerosol efficiency, improve dispersion stability, and facilitate preparation of a suspension. It will be appreciated that, as used herein, the terms "structural matrix" or "microstructure matrix" are C equivalent and shal be held to mean any solid material forming the perforated microstructures which define a plurality of voids, apertures, hollows, defects, pores, holes, fissures, etc. that provide the desired characteristics. In preferred embodiments, the perforated microstructure defined by the structural matrix comprises a spray dried hollow porous microsphere incorporating at least one surfactant. It will further be appreciated that by altering the matrix components, the density of the structural matrix may be adjusted. Finally, as will be discussed in further detail below, the perforated microstructures preferably comprise at least one active or bioactive agent.

As indicated, the perforated microstructures of the present invention may optionally be associated with, or comprise, one or more surfactants. Moreover, miscible surfactants may optionally be combined in the case where the microprticles are formulated in a suspension medium liquid phase. It will be appreciated by those skilled in the art that the use of surfactants, while not necessary to practice the instant invention, may further increase dispersion stability, powder flowability, simplify formulation procedures or increase efficiency of delivery. Of course combinations of surfactants, including the use of one or more in the liquid phase and one or more associated with the perforated microstructures are contemplated as being within the scope of the invention. By "associated with or comprise" it is meant that the structural matrix or perforated microstructure may incorporate, adsorb, absorb, be coated with or be formed by the surfactent.

In a broad sense, surfactants suitable for use in the present invention include any compound or composition that aids in the formation of perforated microparticles or provides enhanced suspension stability, improved powder dispersibility or decreased particle aggregation. The surfactant may comprise a single compound or any combination of compounds, such as in the case of co-surfactants. Particularly preferred surfactants ere nonfluorinated and selected from the group consisting of saturated and unsaturated lipids, nonionic detergents, nonionic block copolymers, ionic surfactants and combinations thereof. In those embodiments comprising stabilized dispersions, such nonfluorinated surfactants will preferably be relatively insoluble in the suspension medium.

It should be emphasized that, in addition to the aforementioned surfactants, suitable fluorinated surfactants are compatible with the teachings herein and may be used to provide the desired preparations.

O

0 SLipids, including phospholipids, from both natural and synthetic sources are particularly compatible with the present invention and may be used in varying concentrations to form the structural matrix.

Generally compatible lipids comprise those that have a gel to liquid crystal phase transition greater than about Preferably the incorporated lipids are relatively long chain Cl 1 -Cn saturated lipids and more preferably comprise phospholipids. Exemplary phospholipids useful in the disclosed stabilized preparations comprise, dipelmitoylphosphatidylchaline, disteroylphosphatidylcholine, diarachidoylphosphatidylcholine dibehenoylphosphatidylcholine, short-chain phosphatidylcholines, long-chain saturated phosphatidylethanolamines. long-chain saturated phosphatidylserines, long-chain saturated Sphosphatidylglycerols, long-chain saturated phosphatidylinositols, glycolipids, ganglioside GM1, sphingomyelin, phosphatidic acid, cardiolipin; lipids bearing polymer chains such as polyethylene glycol, chitin, hyaluronic acid, Sor polyvinylpyrroiidone; lipids bearing sulfonated mono-, di-, and polysaccharides; fatty acids such as palmitic 0 acid, stearic acid, and oleic acid; cholesterol, cholesterof esters, and cholesterol hemisuccinate. Due to their excellent hiocompatibility characteristics, phospholipids and combinations of phospholipids and poloxamers are particularly suitable for use in the pharmaceutical embodiments disclosed herein.

Compatible nonionic detergents comprise: sorbitan esters including sorbitan trioleate (Spanr sorbitan sesquioleate, sorbitan monooleate, sorbitan monolaurate, pofyoxyethylene 120) sorbitan monolaurate, and polyoxyethylene (20) sorbitan monooleate, oleyl potyoxyethylene ether, stearyl polyoxyethylene 121 ether, lauryl polyoxyethylene 14) ether, glycerol esters, and sucrose esters. Other suitable nonionic detergents can be easily identified using McCutcheon's Emulsifiers and Detergents (McPublishing Co., Glen Rock, New Jersey) which is incorporated herein in its entirety. Preferred block copolymers include dibock and triblock copolymers of polyoxyethylene and polyoxypropylene, including poloxamer 188 (PluronicL F-68), poloxamer 407 (Pluronic' F-127), and poloxamer 338. Ionic surfactants such as sodium suftosuccinate, and fatty acid soaps may also be utilized. In preferred embodiments the microstructures may comprise oleic acid or its alkali salt.

In addition to the aforementioned surfactants, cationic surfactants or lipids are preferred especially in the case of delivery or RNA or DNA. Examples of suitable cationic lipids include: OTMA, N-1142,3dioleyloxylpropyll-NN,N-trimathylammonium chloride; DOTAP, 1,2-dioleyoxy-3-(trimethylammonio)propene; and DOTB, 1,2-didleyl-3(4'-trimethylammonio)butanoyl-sn.glycerol. Polycationic amino acids such as polylysine. and polyarginina ore also contemplated.

Besides those surfactants enumerated above, it will further be appreciated that a wide range of surfactants may optionally be used in conjunction with the present invention. Moreover, the optimum surfactant or combination thereof for a given application can readily be determined by empirical studies that do not require undue experimentation. Finally, as discussed in more detail below, surfactants comprising the structural matrix may also be useful in the formation of precursor oil-in-water emulsions spray drying feed stock) used during processing to form the perforated microstructures.

Y

VO

0 O Unlike prior art formulations, it has surprisingly been found that the incorporation of relatively high levels of surfactants phospholipids) may be used to improve powder dispersibility, increase suspension stability and t decrease powder aggregation of the disclosed applications. That is, on a weight to weight basis, the structural matrix of the perforated microstructures may comprise relatively high levels of surtactant In this regard, the C 5 perforated microstructures will preferably comprise greater than about 10%, 15%, 18%, or even 20% wlw surfactant. More preferably, the perforated microstructures will comprise greater than about 25%, 30%, 35%, 45%, or 50% wvw surfactant. Still other exemplary embodments will comprise perforated microstructures wherein Sthe surfactant or surfactants are present at greater than about 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or Seven 95% wlw. In selected embodiments the perforated microstructures will comprise essentially 100% wlw of a surfactant such as a phospholipid. Those skilled in the art will appreciate that, in such cases, the balance of the Sstructural matrix (where applicable) will likely comprise a bioactive agent or non surface active excipients or Sadditives.

While such surfactant levels are preferably employed in perforated microstructures, they may be used to provide stabilized systems comprising relatively nonporous, or substantially solid, particulates. That is, while preferred embodiments will comprise perforated microstructures associated with high levels of suriactant acceptable microspheres may be formed using relatively low porosity particulates of the same surfactant concentration li.e.

greater than about 20% wlw). In this respect such high surfactont embodiments are specifically contemplated as being within the scope of the present invention.

in other preferred embodiments, of the invention the structural matrix defining the perforated microstructure optionally comprises synthetic or natural polymers or combinations thereof. In this respect useful polymers comprise polylactides, polylactide-glycolides, cydodextrins, polyacrylates, methylcellulose, carboxymethytcellulose, polyvinyl alcohols, polyanhydrides, polylactams, polyvinyl pyrrolidones, pdysaccharides (dextrans, starches, chitin, chitosan, etc.), hyaluronic acid, proteins, (albumin, collagen, gelatin, etc.). Examples of polymeric resins that would be useful for the preparation of perforated ink microparticles include: styrenebutadiene, styrene-isoprene, styrene-acrylonitrile, ethylene-vinyl acetate, ethylene-acrylate, ethylene-acrylic acid, ethylene-methylacryletate, ethylene-ethyl acrylate, vinyl-methyl methacrylate, acrylic acid-methyl methacrylate, and vinyl chloride-vinyl acetate. Those skilled in the art will appreciate that by selecting the appropriate polymers, the delivery efficiency of the perforated microparticles andlor the stability of the dispersions may be tailored to optimize the effectiveness of the active or bioactive agent.

Besides the aforementioned polymer materials and surfectants, it may be desirable to add other excipients to a microsphere formulation to improve particle rigidity, production yield, delivery efficiency and deposition, shelf-life and patient acceptance. Such optional excipients include, but are not limited to: coloring agents, taste masking agents, buffers, hygroscopic agents, antioxidants, and chemical stabilizers. Further, various excipients may be incorporated in, or added to, the particulate matrix to provide structure and form to the perforated microstructures microspheres such as latex particles). In this regard it will be appreciated 26/03/200e 29/3/206 15:59 GRIFFITH HPCK< 4 00292637999 NO. 6?1 9013 00 tha Jim riifvin Ms~as a be wing a pastrodttai wi~m M. a muloe she"l munsamcuiba, dIauzludka mnd palydwesidim Far mugis, ssfdhmoid. such as d~as Eadtydmus ad .utsylsi. idt. amnsuit, Aauuma amdn, madm and th k ~din-du vah 99 laena wit.-as as, iiivaam n the Ift t~ixcrdas such m ia d l. RX mnd o8r carbhydrtamasok a I Ids ll-yehyls*tsd qcabna dtdflaL Rnaidsd arm du mat~ ec~itsa 0nt glydmapmtarL Kbin., of aubdrgfss and min s am ft, 1mh te In uviiin thpulla. of the gra mingo. The lndan. of WOI hwic ftp Keiln aMidLt cdllii' 0 0 chlor,intl sipe si* Ots la. aial chutea, Uma ueattat% ma19 s musst gaau.

Ni thi hd yrkdd ot- Qas Luftu inMIo CDmuqdtl Tim kcins of suis and salieni sids o such a eMOa cuebuea. silwam sace, sancin. dkda or sshu we a@W caatmipltad.

witl dag* a*$nw tWa Pitan teaitim ff Ole ank d c i ai.. panslm daOnh uma, 13 Formmxnt satni uaw tanin to fear nahusam mAi comaic clawm euto md to emanate thet Int rriitapff*nds msb sgfludy impSed. nget m swim.a gunt mmlt. The dam may be hita m theh ii asodaras rg mupoarmmn at pulyanmick or pijdmic ais ach a piyumxt acids.

Pdii&M pclMcuicf maEnd chinse In addition to. or instead of, the components dismused above, the perforate-d microstructures will preferably comprise at least one active or bloactive ageint. As used herein, the term ~active agent" simply irefels to a substance that enables the perforaited mlcrostructuree to perform the desired function. Further, the term "active agent" shall be held inclusive of the term ticactive agenf unless etheiuse dictated by contextual restraints. As to the term ticactive agent" it shall be held to comprise any substance that Is used ia connection with an application that is therapeutic or diagnostic in nalture, such as methods for diagnosing the presence or absence of a disease in a patient, the diagnosis or tretm of a disease, and a condition or physiological abnormality in patient- Particularly profanred bioecthse agents for use in accordance with the invention Include ant-llerglcs. paptides, andl proteins, bronchoddlatora and mntl-iflanmmtory steroids for use in the treatlment of respir"tr disorders such as asthma by inhalation therapy. Preferred active agents for use i ardance with the present invention include pigments, dyes inks, paints, detergents, food sweeteners, spices, adsorbants, stintlaismatorles, anlireoplastics anesthetics, antuberculars, imaging agents, cardivascular agents, enzymes steroids, genetic material. vial vectors, antiswe agents, proteins, peplicle. and combinations thereof. I prefered embocirnents the bioactw agents comprise conapotmds which are to be alkuninistered systemnically to the systemic circulatlon of' a patint such as peptides, protens or polynuceotidee. abwbetfl, catalysts.

nucleating agenila, thicening agents, polymers, resins, Insulators, fllers, fertilizers.

phytohormones. insect phecaitones Insect repelletis. pet repellent.s antlouling agents, pesticides, fungicides, dlsindfett, pertams, deodorants, mnd combinations of thet. As will be disclosed in more detilt below, the bioaive agent may be incorporated, blended In, coated on or othiwvise associated with the perforated microstructure.

-13- COMS ID No: ARCS-184305 Received by IP Australia: Time 16:58 Date 2008-03-26 14 IN With regard to the formation of the perforated microstructures it will be appreciated that, 0 Sin preferred embodiments, the particles will be spray dried using commercially available Sequipment. In this regard the feed stock will preferably comprise a blowing agent that may be c- selected from fluorinated compounds and nonfluorinated oils. Preferably, the fluorinated compounds will have a boiling point of greater than about 60° C. Within the context of the instant invention the fluorinated blowing agent may be retained in the perforated microstructures to further increase the dispersibility of the resulting powder or improve the stability of dispersions incorporating the same. Further, nonfluorinated oils may be used to increase the solubility of Sselected bioactive agents steroids) in the feed stock, resulting in increased concentrations of Io 10 bioactive agents in the perforated microstructures.

SThe blowing agent may be dispersed in the carrier using techniques known in the art for the production of homogenous dispersions such a sonication, mechanical mixing or high pressure homogenization. Other methods contemplated for the dispersion of blowing agents in the feed solution include co-mixing of two fluids prior to atomization as described for double nebulization techniques. Of course, it will be appreciated that the atomizer can be customized to optimize the desired particle characteristics such as particle size. In special cases a double liquid nozzle may be employed. In another embodiment, the blowing agent may be dispersed by introducing the agent into the solution under elevated pressures such as in the case of nitrogen or carbon dioxide gas.

It will be appreciated that the perforated microstructures of the present invention may exclusively comprise one or more active or bioactive agents 100% However, in selected embodiments the perforated microstructures may incorporate much less bioactive agent depending on the activity thereof. Accordingly, for highly active materials the perforated microstructures may incorporated as little as 0.001% by weight although a Hi: \Mr4ar\Kep\Specl\L.5,B.4.doc 23/,II/06 26/03/2008 26/3/208 15:56 GRIFFITH HACK 4 00262037999 [O.671 P014 00 ct VNW~~ 6m su 10% 15. Mas o e e rn 4(kW e r Wm d t LEL -9we psfufly t. pefrmeS. wkr s my cpius gituw WW 6Wm M~i 7M. 0 75%, Wt -rV IM. urn edy fur hupomt Theii M u hr snu qq'watud shuc-hiu~~ my ha ~~7j With rqwrd to plarnmutIcd prpwdua4 any hiuuctivu api that nay be Imsnaed in Oin o AdideSPf[O putwtlicrouuclwuu is unpacl hed to be udt. the scopa of the fles WbeSSELn In rmfli mirfend ambadhmnz, the slaecil Mhe qwenly he $uoitm d in thme termn of .nahza mu8LIdlcuuaatz Acctudiql, pwicuddy mpsuhlu tacci,.Wi gun. m my ebq Otint y o~b h o W tw som a fluuhh dry pm&r orrich ist seMiey insuflls in *ctud iapS. meiai. In CA uddlie it is prulrra that the Iundatle r inm S st~ct to pulmonay or maui wuk. in $1!id*dIY ofsi 1fli m CunpalfM. Mici alot- upiw, hy'qddt and fgiy*a m~harq upafl "lawt or rntp$Se "atknw mgisa, Uimw uts timn winz eauiumaw* api:. SUnCf mai~d indudi DNA nd RA. iii wut iuumusiu opnt; hroqng qasi F0 lC' timuiNqmumu iM M 1116 PMWU' Nsf wuiflu tinse Particularly peferred Mouectiva agen for infiolatin therpy 010030 mal cd iudhtogw Ieu~dbic kowfadud W and dbfamu y suiu ob auch fo Ift Upe.aMYOcte (ePg the sm atan anmd Salbmm l*e fg fut i Marm apudltut, nag eianzme or Nwneamam may he Sselce from, lot awrqig -11is eLg. ndu11iuu Ejhydraopnr .pwaa il ttmrt or nofplil wV'd puoporadmo. &g.

iliaunm mE heel luba elandyn spann; .rwfiez e.g. eephiuamidns tarS.,t lilinE puuina flhauydn, amphiniidun, telracydills .5 ptewidina: 8SMUsuiUU; 64. tepiitilew anlifiv~iudea a-9. flaticaw preOnuhIs. hedomnhue iphimt.. fiWsolido htdiidi tIOPed.1, crtrNw, preiuomu, podnalm, ekxumeia...e hsouismeiao orundtiin am emude: OeIpamup, atrui f at uitptim w ung eaal eg. Stelmin, lintL &nmww zmauffiw. &f.

uwiibptmk tohhim, eufft* 1'wrquudui pru ped pep6T dmi @4 t2IAn hw ghkga L11IBE Ofsutgsa hwih. iSofsan, thdu rile1-1 uuputs. mucopg aethatimn fttu stuck w Ihi uldacV IU011 adm dipptqA idid po aptnd' meupids such a Udrepbaluws andqlft meob mR~ts, GmWygehinjM M3Jk grwN horleak~ Iua'iiew ittic uS tin fit. In eddtia.

Mutwfie, mgas tisg M NUA ofrO N gs patliciudy shoame ufofr gum *ump. SSIN ewdi0ri muSOc Sukasu~ Or afti1.uuu euiicalium may IW *axpwd in tho iambuse depemions a -14a COMS ID No: ARCS-184305 Received by IP Australia: Time 16:58 Date 2008-03-26

O

0 0 described herein. Representative DNA plasmids include, but are not limited to pCMVP (available from Genzyme Corp, Framington, MA) and pCMV-0-gal (a CMV promotor linked to the E. coli Lac-Z gene, which Ccodes for the enzyme p-galactosidasel.

SIn any event, the selected active or bioactive agent(s) may be associated with, or incorporated in, C 5 the perforated microstructures in any form that provides the desired efficacy end is compatible with the chosen production techniques. As used herein, the terms "associate" or "associating" mean that the structural matrix or perforated microstructure may comprise, incorporate, adsorb, absorb, be coated with or be formed by the C active or bioective agent. Where appropriate, the actives may be used in the form of salts alkali metal or Oamine salts or as acid addition salts) or as esters or as solvates (hydrates). In this regard the form of the active or bioactive agents may be selected to optimize the activity andlor stability of the actives andlor to Sminimize the solubility of the agent in the suspension medium andfor to minimize particle aggregation.

C It will further be appreciated that the perforated microstructures according to the invention may, if desired, contain a combination of two or more active ingredients. The agents may be provided in combination in a single species of perforated microstructure or individually in separate species of perforated microstructures. For example, two or more active or bioactive agents may be incorporated in a single feed stock preparation and spray dried to provide a single microstructure species comprising a plurality of active agents. Conversely, the individual actives could be added to separate stocks and spray dried separately to provide a plurality of microstructure species with different compositions. These individual species could be added to the suspension medium or dry powder dispensing compartment in any desired proportion and placed in the aerosol delivery system as described below. Further, as alluded to above, the perforated microstructures (with or without an associated agent) may be combined with one or more conventional a micronized drug) active or bioactive agents to provide the desired dispersion stability or powder dispersibility.

Based on the foregoing, it will be appreciated by those skilled in the art that a wide variety of active or bioactive agents may be incorporated in the disclosed perforated microstructures. Accordingly, the list of preferred active agents above is exemplary only and not intended to be limiting. It will also be appreciated by those skilled in the art that the proper amount of bioactive agent and the timing of the dosages may be determined for the formulations in accordance with already existing information and without undue experimentation.

As seen from the passages above, various components may be associated with, or incorporated in the perforated microstructures of the present invention. Similarly, several techniques may be used to provide particulates having the desired morphology a perforated or hollow/porous configuration), dispersibility and density. Among other methods, perforated microstructures compatible with the instant invention may be formed by techniques including spray drying, vacuum drying, solvent extraction, emulsification or tyophilization, and combinations thereof. It will further be appreciated that the basic concepts of many of these techniques are well known in the prior art and would not, in view of the teachings herein, require undue experimentation to adapt them so as to provide the desired perforated microstructures.

I

0 0 While several procedures are generally compatible with the present invention, particularly preferred embodments typically comprise perforated microstructures formed by spray drying. As is well known, spray drying Cis a one-step process that converts a liquid feed to a dried particulate form. With respect to pharmaceutical applications, it wilt be appreciated that spray drying has been used to provide powdered material for various administrative routes including inhalation. See, for example, M. Sacchatti and M.M. Van Oort in: Inhalation Aerosols: Physical and Biological Basis for Therapy, A.J. Hickey, ed. Marcel Dekkar, New York, 1996, which is incorporated herein by reference.

SIn general, spray drying consists of bringing together a highly dispersed liquid, and a sufficient Svolume of hot air to produce evaporation and drying of the liquid droplets. The preparation to be spray dried or feed (or feed stock) can be any solution, course suspension, slurry, colloidal dispersion, or paste that may Sbe atomized using the selected spray drying apparatus. In preferred embodiments the feed stock will comprise a colloidal system such as an emulsion, reverse emulsion, microemulsion, multiple emulsion, particulate dispersion, or slurry. Typically the feed is sprayed into a current of warm filtered air that evaporates the solvent and conveys the dried product to a collector. The spent air is then exhausted with the solvent. Those skilled in the art will appreciate that several different types of apparatus may be used to provide the desired product. For example, commercial spray dryers manufactured by Buchi Ltd. or Niro Corp.

will effectively produce particles of desired size.

It will further be appreciated that these spray dryers, and specifically their atomizers, may be modified or customized for specialized applications, i.e. the simultaneous spraying of two solutions using a double nozzle technique. More specifically, a water-in-oil emulsion can be atomized from one nozzle and a solution containing an anti-adherent such as mannitol can be co-atomized from a second nozzle. In other cases it may be desirable to push the feed solution though a custom designed nozzle using a high pressure liquid chromatography (HPLC) pump. Provided that mricmstructures comprising the correct morphology and/or composition are produced the choice of apparatus is not critical and would be apparent to the skilled artisan in view of the teachings herein.

While the resulting spray-dried powdered particles typically are approximately spherical in shape, nearly uniform in size and frequently are hollow, there may be some degree ol irregularity in shape depending upon the incorporated medicament and the spray drying conditions. In many instances dispersion stability and dispersibility of the perforated microsiructures appears to be improved if an inflating agent for blowing agentl is used in their production. Particularly preferred embodiments may comprise an emulsion with the inflating agent as the disperse or continuous phase. The inflating agent is preferably dispersed with a surfactant solution, using, for instance, a commercially available microfluidizer at a pressure of about 5000 to 15,000 psi. This process forms an emulsion, preferably stabilized by an incorporated surfactant, typically comprising submicron draplets of water immiscible blowing agent dispersed in an aqueous continuous phase. The formation of such emulsions using this and other techniques are common and well known to those in the art. The blowing agent is

VO

0 O preferably a fluorinated compound perfluorahexane, perfluorooctyl bromide, perfluorodecalin, perfluorobutyl ethane) which vaporizes during the spray-drying process, leaving behind generally hollow, cporous aerodynamically light microspheres. As will be discussed in more detail below, other suitable liquid blowing agents include nonfluorinated oils, chloroform, Freons, ethyl acetate, alcohols and hydrocarbons.

Nitrogen and carbon dioxide gases are also contemplated as a suitable blowing agent.

Besides the aforementioned compounds, inorganic and organic substances which can be removed under reduced pressure by sublimation in a post-production step are also compatible with the instant C invention. These sublimating compounds can he dissolved or dispersed as micronized crystals in the spray Sdrying feed solution and include ammonium carbonate and camphor. Other compounds compatible with the present invention comprise rigidifying solid structures which can be dispersed in the feed solution or prepared Sin-situ. These structures are then extracted after the initial particle generation using a post-production Ssolvent extraction step. For example, latex particles can be dispersed and subsequently dried with other wall forming compounds, followed by extraction with a suitable solvent.

Although the perforated microstructures are preferably formed using a blowing agent as described above, it will be appreciated that, in some instances, no additional blowing agent is required and an aqueous dispersion of the medicament and/or excipients and surfactant(s) are spray dried directly, in such cases, the formulation may be amenable to process conditions le.g., elevated temperatures) that may lead to the formation of hollow, relatively porous microparticles. Moreover, the medicament may possess special physicochemical properties high crystallinity, elevated melting temperature, surface activity, etc.) that makes it particularly suitable for use in such techniques.

When a blowing agent is employed, the degree of porosity and dispersibility of the perforated microstructure appears to depend, at least in part, on the nature of the blowing agent, its concentration in the feed stock as an emulsion), and the spray drying conditions. With respect to controlling porosity and, in suspensions, dispersibility it has surprisingly been found that the use of compounds, heretofore unappreciated as blowing agents, may provide perforated microstructures having particularly desirable characteristics. More particularly, in this novel and unexpected aspect of the present invention it has been found that the use of fluorinated compounds having relatively high boiling points greater than about may be used to produce particulates that are particularly porous. Such perforated microstructures are especially suitable for inhalation therapies. In this regard it is possible to use fluorinated or partially fluorinated blowing agents having boiling points of greater than about 40C, 5000C, 60"C, 700C, 80°C, 900C or even 950C. Particularly preferred blowing agents have boiling points greater than the boiling point of water, i.e. greater than 100°C le.g. perflubron, perfluorodecalinl. in addition blowing agents with relatively low water solubility 10"' M) are preferred since they enable the production of stable emulsion dispersions with mean weighted particle diameters less than 0.3 umn.

0 O As previously described, these blowing agents will preferably be incorporated in an emulsified feed stock prior to spray drying. For the purposes of the present invention this feed stock will also preferably C comprise one or more active or bioactive agents, one or more surfactants or one or more excipienls. 01 course, combinations of the aforementioned components are also within the scope of the invention. While C 5 high boiling 100°C) fluorinated blowing agents comprise one preferred aspect of the present invention, it will be appreciated that nonfluorinated blowing agents with similar boiling points 1000°C may be used to provide perforated microstructures. Exemplary nonfluorinated blowing agents suitable for use in the present Sinvention comprise the formula:

SR'-X.R

2 or R'-X wherein: R' or R'is hydrogen, alkyl, alkenyl, alkynl, aromatic, cyclic or combinations thereof, X is any group containing carbon, sulfur, nitrogen, halogens, phosphorus, oxygen and combinations thereof.

SWhile not limiting the invention in any way it is hypothesized that, as the aqueous feed component evaporates during spray drying it leaves a thin crust at the surface of the particle. The resulting particle wall or crust formed during the initial moments of spray drying appears to trap any high boiling blowing agents as hundreds of emulsion droplets (ca. 200-300 nml. As the drying process continues, the pressure inside the particulate increases thereby vaporizing at least part of the incorporated blowing agent and forcing it through the relatively thin crust. This venting or outgassing apparently leads to the formation of pores or other defects in the microstructure. At the same time remaining particulate components Ipossibly including some blowing agentl migrate from the interior to the surface as the particle solidifies. This migration apparently slows during the drying process as a result of increased resistance to mass transfer caused by an increased internal viscosity. Once the migration ceases the particle solidifies, leaving voids, pores, defects, hollows, spaces, interstitidal spaces, apertures, perforations or holes. The number of pores or defects, their size, and the resulting wail thickness is largely dependent on the formulation and/or the nature of the selected blowing agent boiling point), its concentration in the emulsion, total solids concentration, and the spray-drying conditions. It can be greatly appreciated that this type of particle morphology in part contributes to the improved powder dispersibility, suspension stability and aerodynamics.

It has been surprisingly found that substantial amounts of these relatively high boiling blowing agents may be retained in the resulting spray dried product. That is, spray dried perforated microstructures as described herein may comprise as much as 10%, 20%, 30% or even 40% wfw of the blowing agent. In such cases, higher production yields were obtained as a result an increased particle density caused by residual blowing agent. It will be appreciated by those skilled in the art that retained fluorinated blowing agent may alter the surface characteristics of the perforated microstructures, thereby minimizing particle aggregation during processing and further increasing dispersion stability. Residual fluorinated blowing agent in the particle may also reduce the cohesive forces between particles by providing a barrier or by attenuating the attractive forces produced during manufacturing le.g., electrostatics). This reduction in cohesive forces o may be particularly advantageous when using the disclosed microstructures in conjunction with dry powder inhalers.

cFurthermore, the amount of residual blowing agent can be attenuated through the process conditions (such as outlet temperaturel, blowing agent concentration, or boiling point. If the outlet temperature is at or above the boiling point, the blowing agent escapes the particle and the production yield decreases. Preferred outlet temperature will generally he operated at 20, 30, 40, 50, 60, 70, 80, 90 or even 100 0 C less than the blowing agent boiling point. More preferably the temperature differential between the Soutlet temperature and the boiling point will range from 50 to 150°C. It will be appreciated by those skilled in Sthe art that particle porosity, production yield, electrostatics and dispersibility can be optimized by first identifying the range of process conditions le.g., outlet temperature) that are suitable for the selected active O agents and/or excipients. The preferred blowing agent can be then chosen using the maximum outlet C-i temperature such that the temperature differential with be at least 20 and up to 150°C. In some cases, the temperature differential can be outside this range such as, for example, when producing the particulates under supercritical conditions or using lyophilization techniques. Those skilled in the art will further appreciate that the preferred concentration of blowing agent can be determined experimentally without undue experimentation using techniques similar to those described in the Examples herein.

While residual blowing agent may be advantageous in selected embodiments it may be desirable to substantially remove any blowing agent from the spray dried product. In this respect, the residual blowing agent can easily be removed with a post-production evaporation step in a vacuum oven. Moreover, such post production techniques may be used to provide perforations in the particulates. For example, pores may be formed by spray drying a bioactive agent and an excipient that can be removed from the formed particulates under a vacuum.

In any event, typical concentrations of blowing agent in the feed stock are between 2% and vlv, and more preferably between about 10% to 45% v/v. In other embodiments blowing agent concentrations will preferably be greater than about 10%. 15%, 20%, 25% or even 30% v/v. Yet other feed stock emulsions may comprise 35%, 40%, 45% or even 50% viv of the selected high boiling point compound.

In preferred embodiments, another method of identifying the concentration of blowing agent used in the feed is to provide it as a ratio of the concentration ol the blowing agent to that of the stabilizing surfactant le.g. phosphatidylcholine or PC) in the precursor or feed emulsion. For fluorocarbon blowing agents perfluorooctyl bromide), end for the purposes of explanation, this ratio has been termed the PFCIPC ratio. More generally, it will be appreciated that compatible blowing agents and/or surfactants may be substituted for the exemplary compounds without falling outside of the scope of the present invention. In any event, the typical PFCPC ratio will range from about 1 to about 0BO and more preferably from about 10 to about 50. For preferred embodiments the ratio will generally be greater than about 5, 10, 20, 25, 30, 40 or

O

0 o even 50. In this respect Fig. 1 shows a series of pictures taken of perforated microstructures formed of phosphatidylcholine (PC) using various amounts of perfluorooctyl bromide (PFCI, a relatively high boiling point cfluorocarbon as the blowing agent. The PFC/PC ratios are provided under each subset of pictures, i.e. from 1A to 1F. Formation and imaging conditions are discussed in greater detail in Examples I and II below. With regard to the micrographs, the column on the left shows the intact microstructures while the column on the right illustrates cross-sections of fractured microstructures from the same preparations.

SAs may easily be seen in the Fig. 1, the use of higher PFCIPC ratios provides structures of a more Shollow and porous nature. More particularly, those methods employing a PFCIPC ratio of greater than about S4.8 tended to provide structures that are particularly compatible with the dry power formulations and dispersions disclosed herein. Similarly, Fig. 3, a micrograph which will be discussed in more detail in Example SXII below, illustrates a preferably porous morphology obtained by using higher boiling point blowing agents (in C this case perfluorodecafin).

While relatively high boiling point blowing agents comprise one preferred aspect of the instant invention, it will be appreciated that more conventional and unconventional blowing or inflating agents may also he used to provide compatible perforated microstructures. The blowing agent comprises any volatile substance, which can be incorporated into the feed solution for the purpose of producing a perforated foam-like structure in the resulting dry microspheres. The blowing agent may be removed during the initial drying process or during a post-production step such as vacuum drying or solvent extraction. Suitable agents include: 1. Dissolved low-boiling (below 100 C) agents miscible with aqueous solutions, such as methytene chloride, acetone, ethyl acetate, and alcohols used to saturate the solution.

2. A gas, such as CO, or N 2 ,or liquid such as Freons, CFCs, HFAs, PFCs, HFCs, HFBs, fluoroalkanes, and hydrocarbons used at elevated pressure.

3. Emulsions of immiscible low-boiling (below 100 C) liquids suitable for use with the present invention are generally of the formula:

R'.X.R

2 or R'-X wherein: 8' or R 2 is hydrogen, alkyl, alkenyl, alkynl, aromatic, cyclic or combinations thereof, X is any groups containing carbon, sulfur, nitrogen, halogens, phosphorus, oxygen and combinations thereof.. Such liquids include: Freons, CFCs, HFAs, PFCs, HFCs, HFBs, fluoroalkanes, and hydrocarbons.

4. Dissolved or dispersed salts or organic substances which can be removed under reduced pressure by sublimation in a post-production step, such as ammonium salts, camphor, etc.

Dispersed solids which can be extracted after the initial particle generation using a post-production solvent extraction step, such particles include latex, etc.

O

o With respect to these lower boiling point inflating agents, they are typically added to the feed stock in Squantities of about 1% to 40% viv of the surfactant solution. Approximately 15% v/v inflating agent has been found to produce a spray dried powder that may be used to form the stabilized dispersions of the present invention.

Regardless of which blowing agent is ultimately selected, it has been found that compatible perforated microstructures may be produced particularly efficiently using a Biichi mini spray drier Imodel B- 191, Switzerlandl. As will be appreciated by those skilled in the art, the inlet temperature and the outlet temperature ol the spray drier are not critical but will be of such a level to provide the desired particle size cand to result in a product that has the desired activity of the medicament. In this regard, the inlet end outlet Stemperatures are adjusted depending on the melting characteristics of the formulation components and the composition of the feed stock. The inlet temperature may thus be between 60C and 1700C, with the outlet temperatures of about 40 0 C to 1200C depending on the composition of the feed and the desired particulate Scharacteristics. Preferably these temperatures will be from 9000C to 120C for the inlet and from 6000 to 900C for the outlet. The flow rate which is used in the spray drying equipment will generally be about 3 ml per minute to about 15 ml per minute. The atomizer air flow rate will vary between values of 25 liters per minute to about 50 liters per minute. Commercially available spray dryers are well known to those in the art, and suitable settings for any particular dispersion can be readily determined through standard empirical testing, with due reference to the examples that follow. Of course, the conditions may be adjusted so as to preserve biological activity in larger molecules such as proteins or peptides.

Though the perforated microstructures are preferably formed using fluorinated blowing agents in the form of an emulsion, it will be appreciated that nonfluorinated oils may be used to increase the loading capacity of active or bioective agents without compromising the microstructure. In this case, selection of the nonfluorinated oil is based upon the solubility of the active or bioactive agent, water solubility, boiling point, and flash point. The active or bioactive agent will be dissolved in the oil and subsequently emulsified in the feed solution. Preferably the oil will have substantial solubilization capacity with respect to the selected agent, low water solubility 10'M), boiling point greater than water and a flash point greeter than the drying outlet temperature. The addition of surfactants, and co-solvents to the nonfluorinated oil to increase the solubilization capacity is also within the scope of the present invention.

In particularly preferred embodiments nonfluorinated oils may be used to solubilize agents or bioactive agents that have limited solubility in aqueous compositions. The use of nonfluorinated oils is of particular use for increasing the loading capacity of steroids such as beclomethasone dipropionate and triamcinolone acetonide. Preferably the oil or oil mixture for solubilizing these caethrate forming steroids will have a refractive index between 1.36 and 1.41 ethyl butyrate, butyl carbonate, dibutyl ether). In addition, process conditions, such as temperature and pressure, may be adjusted in order to boost solubility of the selected agent. It will be appreciated that selection of an appropriate oil or oil mixtures and processing

I

VO

0 0 conditions to maximize the loading capacity of an agent are well within the purview of a skilled artisan in view of the teachings herein and may be accomplished without undue experimentation.

Particularly preferred embodiments of the present invention comprise spray drying preparations comprising Sa surfactani such as a phospholipid and at least one active or bioactive agent. In other embodiments the spray drying preparation may further comprise an excipient comprising a hydrophilic moiety such as, for example, a carbohydrate glucose, lactose, or starch) in eddition to any selected surfactant. In this regard various starches and derivatized starches suitable lor use in the present invention. Other optional components may include Sconventional viscosity modifiers, buffers such as phosphate buffers or other conventional hiocompatible buffers or SpH adjusting agents such as acids or bases, and osmotic agents (to provide isotonicity, hyperosmolarity, or hyposmolarity). Examples of suitable salts include sodium phosphate (both monobasic and dibasic), sodium chloride, Scalcium phosphate, calcium chloride and other physiologically acceptable salts.

K Whatever components are selected, the first step in particulate production typically comprises feed stock preparation. Preferably the selected drug is dissolved in water to produce a concentrated solution. The drug may also be dispersed directly in the emulsion, particularly in the case of water insoluble agents.

Alternatively, the drug may be incorporated in the form of a solid particulate dispersion. The concentration of the active or bioactive agent used is dependent on the amount of agent required in the final powder and the performance of the delivery device employed the fine particle dose for a MDI or OPI). As needed, cosurfactants such as potoxamer 188 or span 80 may be dispersed into this annex solution. Additionally, excipients such as sugars and starches can also be added.

In selected embodiments an oil-in-water emulsion is then formed in a separate vessel. The oil employed is preferably a fluorocarbon le.g., perfluorooctyl bromide, perfluorodecafin) which is emulsified using a surfactant such as a long chain saturated phospholipid. For example, one gram of phospholipid may be homogenized in 150 g hot distilled water 60 0 C) using a suitable high shear mechanical mixer Ultra.

Turrax model T-25 mixerd at 8000 rpm for 2 to 5 minutes. Typically 5 to 25 g of fluorocarbon is added dropwise to the dispersed surfactant solution while mixing. The resulting perfluorocarbon in water emulsion is then processed using a high pressure homogenizer to reduce the particle size. Typically the emulsion is processed at 12,000 to 18,000 psi, 5 discrete passes and kept at 50 to The active or bioactive agent solution and perfluorocarbon emulsion are then combined and fed into the spray dryer. Typically the two preparations will be miscible as the emulsion will preferably comprise an aqueous continuous phase. While the bioactive agent is solubilized separately for the purposes of the instant discussion it will be appreciated that, in other embodiments, the active or bioactive agent may be solubiized (or dispersed) directly in the emulsion. In such cases, the active or bioactive emulsion is simply spray dried without combining a separate drug preparation.

In any event, operating conditions such as inlet and outlet temperature, feed rate, atomization pressure, flow rate of the drying air, and nozzle configuration can be adjusted in accordance with the 0 O manufacturer's guidelines in order to produce the required particle size, and production yield of the resulting dry microstructures. Exemplary settings are as follows: an air inlet temperature between 60 0 C and 170 0

C;

c an air outlet between 40 0 C to 120°C; a feed rate between 3 mi to about 15 ml per minute; and an aspiration air flow of 300 L/min. and an atomization air flow rate between 25 to 50 L/min. The selection of appropriate apparatus and processing conditions are well within the purview of a skilled artisan in view of the teachings herein and may be accomplished without undue experimentation. In any event, the use of these and substantially equivalent methods provide for the formation of hollow porous aerodynamically light microspheres with particle diameters appropriate for aerosol deposition into the lung. microstructures that are Sboth hollow and porous, almost honeycombed or foam-like in appearance. In especially preferred iO 10 embodiments the perforated microstructures comprise hollow, porous spray dried microspheres.

SAlong with spray drying, perforated microstructuras useful in the present invention may be formed C(K by lyophilization. Those skilled in the art will appreciate that lyophilization is a freeze-drying process in which water is sublimed from the composition after it is frozen. The particular advantage associated with the lyophilization process is that biologicals and pharmaceuticals that are relatively unstable in an aqueous solution can be dried without elevated temperatures (thereby eliminating the adverse thermal effects), and then stored in a dry state where there are few stability problems. With respect to the instant invention such techniques are particularly compatible with the incorporation of peptides, proteins, genetic material and other natural end synthetic macromolecules in particulates or perforated microstructures without compromising physiological activity. Methods for providing lyophilized particulates ere known to those of skill in the art and it would dearly not require undue experimentation to provide dispersion compatible microstructures in accordance with the teachings herein. The lyophilized cake containing a fine foam-like structure can be micronized using techniques known in the art to provide 3 to 1Oum sized particles. Accordingly, to the extent that lyophilization processes may be used to provide microstructures having the desired porosity and size they are conformance with the teachings herein and are expressly contemplated as being within the scope of the instant invention.

Besides the aforementioned techniques, the perforated microstructures or particles of the present invention may also be formed using a method where a feed solution (either emulsion or equeousl containing wall forming agents is rapidly added to a reservoir of heated oil perflubron or other high boiling FCs) under reduced pressure. The water and volatile solvents of the feed solution rapidly boils and are evaporated.

This process provides a perforated structure from the wall forming agents similar to puffed rice or popcorn.

Preferably the wall forming agents are insoluble in the heated oil. The resulting particles can then separated from the heated oil using a filtering technique and subsequently dried under vacuum.

Additionally, the perforated microstructures of the present invention may also be formed using a double emulsion method. In the double emulsion method the medicament is first dispersed in a polymer dissolved in an organic solvent mathylene chloride by sonication or homogenization. This primary

VO

0 0 emulsion is then stabilized by forming a multiple emulsion in a continuous aqueous phase containing an emulsifier such as polyvinylalcohol. Evaporation or extraction using conventional techniques and apparatus C then removes the organic solvent. The resulting microspheres are washed, filtered and dried prior to Scombining them with an appropriate suspension medium in accordance with the present invention Whatever production method is ultimately selected for production of the perforated microstructures, the resulting powders have a number of advantageous properties that make them particularly compatible for use in devices for inhalation therapies. in particular, the physical characteristics of the perforated microstructures make them extremely effective for use in dry powder inhalers and in the formation of Sstabilized dispersions that may be used in conjunction with metered dose inhalers, nebulizers and liquid dose instillation. As such, the perforated microstructures provide for the effective pulmonary administration of Sbioactive agents.

SIn order to maximize dispersibility, dispersion stability and optimize distribution upon administration, the mean geometric particle size of the perforated microstructures is preferably about 0.5-50 m, more preferably 1.30 m. It will be appreciated that large particles greater than 50 mj may not be preferred in applications where a valve or small orifice is employed, since large particles tend to aggregate or separate from a suspension which could potentially clog the device. In especially preferred embodiments the mean geometric particle size (or diameter) of the perforated microstructures is less than 20 m or less than 10m. More preferably the mean geometric diameter is less than about 7 m or 5 m, and even more preferably less than about 2.5 m. Other preferred embodiments will comprise preparations wherein the mean geometric diameter of the perforated microstructures is between about 1 m and 5 m. In especially preferred embodiments the perforated microstructures will comprise a powder of dry, hollow, porous microspherical shells of approximately 1 to 10 m or 1 to 5 m in diameter, with shell thicknesses of approximately 0.1 m to approximately 0.5 m. it is a particular advantage of the present invention that the particulate concentration of the dispersions and structural matrix components can be adjusted to optimize the delivery characteristics of the selected particle size.

As alluded to throughout the instant specification the porosity of the microstructures may play a significant part is establishing dispersibility in DPIs) or dispersion stability le.g. for MOls or nebulizers). in this respect, the mean porosity of the perforated microstructures may be determined through electron microscopy coupled with modern imaging techniques. More specifically, electron micrographs of representative samples of the perforated microstructures may be obtained and digitally analyzed to quantify the porosity of the preparation. Such methodology is well known in the art and may be undertaken without undue experimentation.

For the purposes of the present invention, the mean porosity the percentage of the particle surface area that is open to the interior andlor a central void) of the perforated microstructures may range from approximately 0.5% to approximately 80%. in more preferred embodiments, the mean porosity will range from approximately 2% to approximately 40%. Based on selected production parameters, the mean porosity may be greater than approximately, 10%, 15%, 20%, 25% or 30% of the microstructure surface area. In other

I

O

0 Sembodiments, the mean porosity of the microstructures may be greater than about 40%, 50%, 60%, 70% or even As to the pores themselves, they typically range in size from about 5 nm to about 400 nm with mean pore csizes preferably in the range of from about 20 nm to about 200 nm. In particulady preferred embodiments the mean pore size will be in the range of from about 50 nm to about 100 nm. As may be seen in Figs. 1A1 to 1F2 end discussed in more detail below, it is a significant advantage of the present invention that the pore size and porosity may be closely controlled by caref u selection of the incorporated components and production parameters.

In this regard, the particle morphology andlor hollow design of the perforated microstructures also plays an Simportant role on the dispersibility or cohesiveness of the dry powder formulations disclosed herein. That is, it has Sbeen surprisingly discovered that the inherent cohesive character of fine powders can be overcome by lowering the van der Weals, electrostatic attractive and liquid bridging forces that typically exist between dry particles. More specifically, in concordance with the teachings herein, improved powder dispersibility may be provided by engineering the particle morphology and density, as well as control of humidity and charge. To that end, the perforated microstructures of the present invention comprise pores, voids, hollows, defects or other interstitial spaces which reduce the surface contact area between particles thereby minimizing interparticle forces. In addition, the use of surfactants such as phospholipids and fluorinated blowing agents in accordance with the teachings herein may contribute to improvements in the flow properties of the powders by tempering the charge and strength of the electrostatic forces as well as moisture content.

Most fine powders le.g. 5 uml exhibit poor dispersibility which can be problematic when attempting to deliver, aerosolize and/or package the powders. In this respect the major forces which control particle interactions can typically be divided into long and short range forces. Long range forces include gravitational attractive forces and electrostatics, where the interaction varies as a square of the separation distance or particle diameter.

Important short range forces for dry powders include van der Weals interactions, hydrogen bonding and liquid bridges. The latter two short range forces differ from the others in that they occur where there is already contact between particles. It is a major advantage of the present invention that these attractive forces may he substantially attenuated or reduced through the use of perforated microstructures as described herein.

In an effort to overcome these attractive forces, typical prior art dry powder formulations for DPIs comprise micronized drug particles that are deposited on large carrier particles 30 to 90 pm such as lactose or agglomerated units of pure drug particles or agglomeration of fine lactose particles with pure drug, since they are more readily fluidized than neat drug particles. In addition, the mass of drug required per actuation is typically less than 100 pg and is thus prohibitively too small to meter. Hence, the larger lactose partides in prior art formulations function as both a carrier particle for aerosolization and a bulking agent for metering. The use of large particles in these formulations are employed since powder dispersibility and aerosolization efficiency improves with increasing increasing particle size as a result of diminished interparticle forces (French, Edwards, sand Niven, J.

Aerosol Sci. 27, 769-783, 1996 which is incorporated herein by referencel. That is, prior art formulations often use

VO

0 0 large particles or carriers to overcome the principle fotres controlling dispersibility such as van der Waals forces, liquld bridging, and electrostatic attractive forces that exists between particles.

c3 Those skilled in the art will appreciate that the van der Weals (VDW) attractive force occurs at short range and depends, at least in part, on the surface contact between the interacting particles. When two dry particles approach each other the VDW forces increase with an increase in contact area. For two dry particles, the magnitude of the VDW interaction force, can be calculated using the following equation: 0O ato r r,

O

0 where h is Planck's constant, w is the angular frequency, d, is the distance at which the adhesional force is at a maximum, and r, and r, are the radii of the two interacting particles. Accordingly, it will be appreciated that one way to minimize the magnitude and strength of the VDW force for dry powders is to decrease the interparticle area of contact. It is important to note that the magnitude dois a reflection of this area of contact. The minimal area of contact between two opposing bodies will occur if the particles are perfect spheres. In addition, the area of contact will be further minimized if the particles are highly porous. Accordingly, the perforated microstructures of the present invention act to reduce interparticle contact and corresponding VDW attractive forces. It is important to note that this reduction in VDW forces is largely a result of the unique particle morphology of the powders of the present invention rather than an increase in geometric particle diameter. In this regard, it will be appreciated that particulady preferred embodiments of the present invention provide powders having average or small particulates le.g. mean geometric diameter 10 pm) exhibiting relatively low VDW attractive forces. Conversely, solid, non-spherical particles such as conventional micronized drugs of the same size will exert greater interparticle forces between them and, hence, will exhibit poor powder dispersibility.

Further, as indicated above, the electrostatic force affecting powders occurs when either or both of the particles are electrically charged. This phenomenon will result with either an attraction or repulsion between particles dependng on the similarity or dissimilarity of charge. In the simplest case, the electric charges can be described using Coulomb's Law. One way to modulate or decrease the electrostatic forces between particles is if either or both particles have non-conducting surfaces. Thus, if the perforated microstructure powders comprise excpients, surfactants or active agents that are relatively non-conducting, then any charge generated in the particle will be unevenly distributed over the surface. As a result, the charge half-life of powders comprising non-conducting components will be relatively short since the retention of elevated charges is dictated by the resistivity of the material. Resistive or non-conducting components are materials which will neither function as an efficient electron donor or acceptor.

VO

0 0 Derjaguin et el. Muller, Yushchenko, V.S, and Derjaguin, B.V, J. Colloid Interface Sci. 1980, 77, 115- 119), which is incorporated herein by reference, provide a list ranking moleculr groups for their ability to accept or Cdonate an electron, In this regard exemplary groups may be ranked as follows: Donor-NH, -OH -OR -COOR -CH, -CH -halogen -COOH -CO CN Acceptor CThe present invention provides for the reduction of electrostatic effects in the disclosed powders though Sthe use of relatively non-conductive materials. Using the above rankings, preferred non-conductive materials would include halogenated and/or hydrogenated components. Materials such as phospholipids and fluorinated blowing agents (which may be retained to some extent in the spray dried powders) are preferred since they can provide Sresistance to particle charging. it will be appreciated that the retention of residual blowing agent (e.g.

fluorochemicals) in the particles, even at relatively low levels, may help minimize charging of the perforated microstructures as is typically imparted during spray drying and cyclone separation. Based on general electrostatic principles and the teachings herein, one skilled in the art would be able to identify additional materials that serve to reduce the electrostatic forces of the disclosed powders withoul undue experimentation. Further, if needed, the electrostatic forces can also be manipulated and minimized using electrification and charging techniques.

In addition to the surprising advantages described above, the present invention further provides for the attenuation or reduction of hydrogen and liquid bonding. As known to those skilled in the art both hydrogen bonding and liquid bridging can result from moisture that is absorbed by the powder. In general, higher humidities produce higher interparticle forces for hydrophilic surfaces. This is a substantial problem in prior art pharmaceutical formulations for inhalation therapies which tend to employ relatively hydrophilic compounds such as lactose.

However, in accordance with the teachings herein, adhesion forces due to adsorbed water can be modulated or reduced by increasing the hydrophobicity of the contacting surfaces. One skilled in the art can appreciate that an increase in particle hydrophobicity can be achieved through excipient selection andlor use a post-production spray drying coating technique such as employed using a fuidized bed. Thus, preferred excipients include hydrophobic surfactants such as phospholipids, fatty acid soaps and cholesterol. In view of the teachings herein, it is submitted that a skilled artisan would be able to identify materials exhibiting similar desirable properties without undue experimentation.

In accordance with the present invention, methods such as angle of repose or shear index can be used to assess the flow properties of dry powders. The angle of repose is defined as the angle formed when a cone of powder is poured onto a flat surface. Powders having en angle of repose ranging from 45° to 200 are preferred and indicate suitable powder flow. More particularly, powders which possess an angle of repose between 330 and exhibit relatively low shear forces and are especially useful in pharmaceutical preparations for use in inhalation therapies OP[s). The shear index, though more time consuming to measure than angle of repose, is considered

O

O more reliable and easy to detennine. Those skilled in the art will apprecate that the experimental procedure outlined by Amidon end Houghton Amidon, and M.E. Houghton, Pharm. Manuf, 2, 20, 185, incorporated herein by reference) can be used estimate the shear index for the purposes of the present invention. As described in S. Kocova and N. Pilpel, J. Pharm. Phamnacol. 8, 33-55, 1973, also incorporated herein by reference, the shear index is I 5 estimated from powder parameters such as, yield stress, effective angle of internal friction, tensile strength, and specific cohesion. In the present invention powders having a shear index less than about 0.98 are desirable. More preferably, powders used in the disclosed compositions, methods and systems will have shear indices less than about C1.1. In particularly preferred embodiments the shear index will be less than about 1.3 or even less than about 0 Of course powders having different shear indices may be used provided the result in the effective deposition of the O 10 active or bioactive agent at the site of interest.

SIt will also be appreciated that the flow properties of powders have heen shnwn ronrelate well with bulk l density measurements. In this regard, conventional prior art thinking Harwood, J. Pharm. Sci., 60, 161-163, 19711 held that an increase in bulk density correlates with improved flow properties as predicted by the shear index of the material. Conversely, it has surprisingly been found that, for the perforated microstructures of the present invention, superior flow properties were exhibited by powders having relatively low bulk densities. That is, the hollow porous powders of the present invention exhibited superior flow properties over powders substantially devoid of pores. To that end, it has been found that it is possible to provide powders having bulk densities of less than glcm 3 that exhibit particularly favorable flow properties. More surprisingly, it has been found that it is possible to provide perforated microstructure powders having bulk densities of less than 0.3 g/cml or even less than about 0.1 glcmr that exhibit excellent flow properties. The ability to produce low bulk density powders having superior flowabilty further accentuates the novel and unexpected nature of the present invention.

In addition, it will be appreciated that the reduced attractive forces van der Weals, electrostatic, hydrogen and liquid bonding, etc.) and excellent flowability provided by the perforated microstructure powders make them particularly useful in preparations for inhalation therapies in inhalation devices such as OPIs, MOls, nebuizers). Along with the superior flowebility, the perforated or porous andlor hollow design of the microstructures also plays an important role in the resulting aerosol properties of the powder when discharged. This phenomenon holds true for perforated microstructures eerosolized as a suspension, as in the case of an MDI or a nebulizer, or delivery of perforated microstructures in dry form as in the case of a DPI. In this respect the perforated structure and relatively high surface area of the dispersed microparticles enables them to be carried along in the flow of gases during inhalation with greater ease for longer distances than non-perforated particles of comparable size.

More particularly, because of their high porosity, the density of the perticles is significantly less then gfcm', typically less than 0.5 glcm 3 more often on the order of 0.1 glcm 3 and as low as 0.01 gfcm'.

Unlike the geometric particle size, the aerodynamic particle size, of the perforated microstructures depends substantially on the particle density, p: dp, where is the geometric diameter.

0 0 For a particle density of 0.1 gncm d.r will be roughly three times smaller than leading to increased particle deposition into the peripheral regions of the lung and correspondingly less deposition in the throat. In Sthis regard, the mean aerodynamic diameter of the perforated microstructures is preferably less than about Cc pm, more preferably less than about 3 and, in particularly preferred embodiments, less than about 2 pm.

Such particle distributions will act to increase the deep lung deposition of the bioactive agent whether administered using a DPI, MDI or nebulizer. Further, having a larger geometric diameter than aerodynamic diameter brings the particles closer to the wall of the alveolus thus increasing the deposition of smeall Saerodynamic diameter particles.

O As will be shown subsequently in the Examples, the particle size distribution of the aerosol \D 10 formulations of the present invention are measurable by conventional techniques such as, for example, Scascade impaction or by time of flight analytical methods. In addition, determination of the emitted dose from 1 inhalation devices were done according to the proposed U.S. Pharmacopeia method lPharmacopeial/Previews, 22(1996) 3065) which is incorporated herein by reference. These and related techniques enable the "fine particle fraction" of the aerosol, which corresponds to those particulates that are likely to effectively deposited in the lung, to be calculated. As used herein the phrase "fine particle fraction" refers to the percentage of the total amount of active medicament delivered per actuation from the mouthpiece of a DPI, MDI or nebulizer onto plates 2-7 of an 8 stage Andersen cascade impactor. Based on such measurements the formulations of the present invention will preferably have a fine particle fraction of approximately 20% or more by weight of the perforated microstructures more preferably they will exhibit a fine particle fraction of from about 25% to 80% w/w, and even more preferably from about 30 to 70% wlw. In selected embodiments the present invention will preferably comprise a fine particle fraction of greeter than about 40%, 50%, 60%, 70% or 80% by weight.

Further, it has also been found that the formulations of the present invention exhibit relatively low deposition rates, when compared with prior art preparations, on the induction port and onto plates 0 and 1 of the impactor. Deposition on these components is linked with deposition in the throat in humans. More specifically, most commercially available MOIs and DPs have simulated throat depositions of approximately 40-70% of the total dose, while the formulations of the present invention typically deposit less than about 20% w/w. Accordingly, preferred embodiments of the present invention have simulated threat depositions of less than about 40%, 35%, 30%, 25%, 20%, 15% or even 10% wiw. Those skilled in the art will appreciate that significant decrease in throat deposition provided by the present invention will result in a corresponding decrease in associated local side-effects such as throat irritation and cendidiesis.

With respect to the advantageous deposition profile provided by the instant invention it is well known that MDI propellants typically force suspended particles out of the device at a high velocity towards the back of the throat. Since prior art formulations typically contain a significant percentage of large particles andfor aggregates, as much as two-thirds or more of the emitted dose may impact the throat.

VO

0 0 Moreover, the undesirable delivery profile of conventional powder preparations is also exhibited under conditions of low particle velocity, as occurs with DPI devices. In general, this problem is inherent when aerosolizing solid, dense, particulates which are subject to aggregation. Yet, as discussed above, the novel and unexpected properties of the stabilized dispersions of the present invention result in surprisingly low throat deposition upon administration from inhalation device such as a DPI, MDi atomizer or nebulizer.

While not wishing to be bound by any particular theory, it appears that the reduced throat deposition provided by the instant invention results from decreases in particle aggregation and from the Shollow andlor porous morphology of the incorporated microstructures. That is, the hollow and porous nature Sof the dispersed microstructures slows the velocity of particles in the propellant stream (or gas stream in the case of OPls), just as a hollowiporous whiffle ball decelerates faster than a baseball. Thus, rather than Simpacting and sticking to the back of the throat, the relatively slow traveling particles are subject to CI inhalation by the patient. Moreover, the highly porous nature of the particles allows th propellant within the perforated microstructure to rapidly leave and the particle density to drop before impacting the throat.

Accordingly, a substantially higher percentage of the administered bioactive agent is deposited in the pulmonary air passages where it may be efficiently absorbed.

With respect to inhalation therapies, those skilled in the art will appreciate that the perforated microstructure powders of the present invention are particularly useful in DPIs. Conventional DPis, or dry powder inhalers, comprise powdered formulations end devices where a predetermined dose of medicament, either alone or in a blend with lactose carder particles, is delivered as a fine mist or aerosol of dry powder for inhalation. The medicament is formulated in a way such that it readily disperses into discrete particles with a size rage between to 20 pm. The powder is actuated either by inspiration or by some external delivery force, such as pressurized air.

DPI formulations are typically packaged in single dose units or they employ reservoir systems capable of metering multiple doses with manual transfer of the dose to the device.

DPs are generally classified based on the dose delivery system employed. In this respect, the two major types of DPIs comprise unit dose delivery devices and bulk reservoir delivery systems. As used herein, the term "reservoir" shall be used in a general sense and held to encompass both configurations unless otherwise dictated by contextual restraints. In any event, unit dose delivery systems require the dose of powder formulation presented to the device as a single unit With this system, the formulation is prefilled into dosing wells which may be foil-packaged or presented in blister strips to prevent moisture ingress. Other unit dose packages include hard gelatin capsules.

Most unit dose containers designed for DPIs are filled using a fixed volume technique. As a result, there are physical limitations (here density) to the minimal dose that can be metered into a unit package, which is dictated by the powder flowability and bulk density. Currently, the range of dry powder that can be filled into a unit dose container is in the range of 5 to 15 mg which corresponds to drug loading in the range of to 500g per dose. Conversely, bulk reservoir delivery systems provide a precise quantity of powder to be metered upon individual delivery for up to approximately 200 doses. Again like the unit dose systems, the 0 0 powder is metered using a fixed volume cell or chamber that the powder is filled into. Thus, the density of the powder is a major factor limiting the minimal dose that can be delivered with this device. Currently bulk c3 reservoir type OPIs can meter between 200/,g to 20 mg powder per actuation.

DPIs are designed to be manipulated such that they break open the capsule/blister or to load bulk Ci 5 powder during actuation, followed by dispersion from a mouthpiece or actuator due to the patient's inspiration. When the prior art formulations are actuated from a DPI device the lactoseidrug aggregates are aerosolized and the patient inhales the mist of dry powder. During the inhalation process, the carrier particles C' encounter shear forces whereby some of the micronized drug particles are separated from the lactose Sparticulate surface. It will be appreciated that the drug particles are subsequently carried into the lung. The large lactose particles impact the throat and upper airways due to size and inertial force constraints. The Sefficiency of delivery of the drug particles is dictated by their degree of adhesion with the carrier particles and their aerodynamic property.

Deaggregation can be increased through formulation, process and device design improvements. For example fine particle lactose (FPLI is often mixed with coarse lactose carriers, wherein the FPL will occupy high-energy binding sites on the carrier particles. This process provides more passive sites for adhesion of the micronized drug particles. This tertiary blend with the drug has been shown to provide statistically significant increases in fine particle fraction. Other strategies include specialized process conditions where drug particles are mixed with FPL to produce agglomerated units. In order to further increase particulate deposition, many OPIs era designed to provide deaggregation by passing the dosage form over baffles, or through tortuous channels that disrupts the flow properties.

The addition of FPL, agglomeration with FPL and specialized device design provides an improvement in the deaggregetion of formulations, however, the clinically important parameter is the fine particle dose received by the patient. Though improvements in deaggregation can be provided, a major problem still exists with current DPI devices in that there is an increase in respirable dose with an increased inspiratory effort.

This is a result of an increased fine particle fraction corresponding to the increased disaggregation of particle agglomerates as the airflow increases through the inhaler with increasing inspiratory effort. Consequently dosing accuracy is compromised, leading to complications when the devices are used to administer highly efficacious drugs to sensitive populations such as children, adolescents end the elderly. Moreover, the dosing inaccuracy associated with conventional preparations could complicate regulatory approval.

30 In stark contrast the perforated midrostructure powders of the present invention obviate many of the difficulties associated with prior art carrier preparations. That is, an improvement in DPI performance may be provided by engineering the particle, size, aerodynamics, morphology and density, as well as control of humidity and charge. In this respect the present invention provides formulations wherein the medicament and the incipients S- or bulking agentsare preferably associated with or comprise the perforated microstructures. As set forth above, preferred compositions according to the present invention typically yield powders with bulk densities

VO

o less than 0.1 glcm' and often less than 0.05 glcm 3 It will be appreciated that providing powders having bulk C] densities an order of a magnitude less than conventional DPI formulations allows for much lower doses of the selected bioactive agent to be filled into a unit dose container or metered via reservoir-based OPIs. The ability to effectively mater small quantities is of particular importance for low dose steroid, long acting bronchodilators and new protein or peptide medicaments proposed for DPI delivery. Moreover, the ability to effectively deliver particulates without associated carrier particles simplifies product formulation, filling end Sreduces undesirable side effects.

As discussed above, the hollow porous powders of the present invention exhibit superior flow properties, as measured by the angle of repose or shear index methods described herein, with respect to equivalent powders C 10 substantially devoid of pores. That is, superior powder flow, which appears to be a function of bulk density and O particle morphology, is observed where the powders have a bulk density less than 0.5 glcm'. Preferably the 0 powders have bulk densities of less than about 0.3 glcm 3 0.1 glcm' or even less than about 0.05 glcm 3 In this regard, it is theorized that the perforated microstructures comprising pores, voids, hollows, defects or other interstitial spaces contribute to powder flow properties by reducing the surface contact area between particles and minimizing interparticle forces. In addition, the use of phospholipids in preferred embodiments and retention of fluorinated blowing agents may also contribute to improvements in the flow properties of the powders by tempering the charge and strength of the electrostatic forces as well as moisture content.

In addition to the aforementioned advantages, the disclosed powders exhibit favorable aerodynamic properties that make them particularly effective for use in DPls. More specifically, the perforated structure and relatively high surface area of the micropartides enables them to be carried along in the flow of gases during inhalation with greater ease and for longer distances than relatively non-perforated particles of comparable size.

Because of their high porosity and low density, administration of the perforated microstructures with a DPI provides for increased particle deposition into the peripheral regions of the lung and correspondingly less deposition in the throat. Such particle distribution acts to increase the deep lung deposition of the administered agent which is preferable for systemic administration. Moreover, in a substantial improvement over prior art DPI preparations the low-density, highly porous powders of the present invention preferably eliminate the need for carrier particles. Since the large lactose carrier particles will impact the throat and upper airways due to their size, the elimination of such particles minimizes throat deposition and any associated "gag" effect associated with conventional DPIs.

Along with their use in a dry powder configuration, it will be appreciated that the perforated microstructures of the present invention may be incorporated in a suspension medium to provide stabilized dispersions. Among other uses, the stabilized dispersions provide for the effective delivery of bioactive agents to the pulmonary air passages of a patient using MOls, nebulizers or liquid dose instillation (LDI techniques).

O

0 CO As with the DPI embodiments, Administration of a bioactive agent using an MDI, nebuizer or LDI technique may be indicated for the treatment of mild, moderate or severe, acute or chronic symptoms or for prophylactic treatment. Moreover, the bioactive agent may be administered to treat local or systemic conditions or dsorders. It will be appreciated that, the precise dose edministered will depend on the age and condtion of the patient, the C 5 particular medicament used and the frequency of administration, and wil ultimately be at the discretion of the attendant physician. When combinations of bioactive agents are employed, the dose of each component of the combination will generally be that employed for each component when used alone.

t'- SThose skilled in the art will appreciate the enhanced stability of the disclosed dispersions or Ssuspensions is largely achieved by lowering the van der Weals attractive forces between the suspended particles, and by reducing the differences in density between the suspension medium and the particles. In Saccordance with the teachings herein, the increases in suspension stability may be imparted by engineering Sperforated microstructures which are then dispersed in a compatible suspension medium. As discussed above, the perforated microstructures comprise pores, voids, hollows, defects or other interstitial spaces that allow the fluid suspension medium to freely permeate or perfuse the particulate boundary. Particularly preferred embodiments comprise perforated microstructures that are both hollow and porous, almost honeycombed or foam-like in appearance. In especially preferred embodiments the perforated microstructures comprise hollow, porous spray dried microspheres.

When the perforated microstructures are placed in the suspension medium propellent), the suspension medium is able to permeate the particles, thereby creating a "homodispersion", wherein both the continuous and dispersed phases are indistinguishable. Since the defined or "virtual" particles comprising the volume circumscribed by the microparticulate matrix) are made up almost entirely of the medium in which they are suspended, the forces driving particle aggregation (flocculation) are minimized. Additionally, the differences in density between the defined particles and the continuous phase are minimized by having the microstructures filled with the medium, thereby effectively slowing particle creaming or sedimentation. As such, the perforated microspheres and stabilized suspensions of the present invention are particularly compatible with many aerosolization techniques, such as MDI and nebulizetion. Moreover, the stabilized dispersions may be used in liquid dose instillation applications.

Typical prior art suspensions for MOls) comprise mostly solid particles and small amounts 1% wlwl of surfactant lecithin, Span-85, oleic acid) to increase electrostatic repulsion between particles or polymers to sterically decrease particle interaction. In sharp contrast, the suspensions of the present invention are designed not to increase repulsion between particles, but rather to decrease the attractive forces between particles. The principal forces driving flocculation in nonaqueous media are van der Weals attractive forces. As discussed above, VDW forces are quantum mechanical in origin, and can be visualized as attractions between fluctuating dipoles induced dipole-induced dipole interactions).

Dispersion forces are extremely short-range and scale as the sixth power of the distance between atoms.

0 0 When two macroscopic bodies approach one another the dispersion attractions between the atoms sums up.

The resulting force is of considerably longer range, and depends on the geometry of the interacting bodies.

More specifically, for two spherical particles, the magnitude of the VDW potential, can be en approximated by: YA -AO R,R where is the effective Hamaker constant which N 6H. R,) accounts for the nature of the particles and the medium, H o is the distance between particles, and R, and R, are the radii of spherical particles 1 and 2. The effective Hemaker constant is proportional to the Cdifference in the polarizabilities of the dispersed particles and the suspension medium: O A, 3 where and A,RT are the Hamaker constants for the suspension IN medium and the particles, respectively. As the suspended particles and the dispersion medium become similar O 10 in nature, and ApAT become closer in magnitude, and and V, become smaller. That is, by reducing the differences between the Hamaker constant associated with suspension medium and the Hamaker constant associated with the dispersed particles, the effective Hamaker constant (and corresponding van der Waals attractive forces) may be reduced.

One way to minimize the differences in the Hamaker constants is to create a "homodispersion", that is make both the continuous and dispersed phases essentially indistinguishable as discussed above. Besides exploiting the morphology of the particles to reduce the effective Hamaker constant, the components of the structural matrix (defining the perforated microstructures) will preferably be chosen so as to exhibit a Hamaker constant relatively close to that of the selected suspension medium. In this respect, one may use the actual values of the Hamaker constants of the suspension medium and the particulate components to determine the compatibility of the dispersion ingredients and provide a good indication as to the stability of the preparation. Alternatively, one could select relatively compatible perforated microstructure components and suspension mediums using characteristic physical values that coincide with measurable Hamaker constants but are more readily discernible.

In this respect, it has been found that the refractive index values of many compounds tend to scale with the corresponding Hamaker constant. Accordingly, easily measurable refractive index values may be used to provide a fairly good indication as to which combination of suspension medium end particle excipients will provide a dispersion having a relatively low effective Hamaker constant and associated stability. It will be appreciated that, since refractive indices of compounds are widely available or easily derived, the use of such values allows for the formation of stabilized dispersions in accordance with the present invention without undue experimentation. For the purpose of illustration only, the refractive indices of several compounds compatible with the disclosed dispersions are provided in Table I immediately below: Table I

VO

0 o Compound Refractive index FH FA-134a 1.172 C HFA-227 1.223 CFC-12 1.287 SCFC-114 1.288 SPFOB 1.305 Mannitol 1.333 Ethanol 1.361 n-octana 1.397 SDMPC 1.43 SPluronic F-68 1.43 SSucrose 1.538 SHydroxyethylstarch 1.54 Sodium chloride 1.544 0 l Consistent with the compatible dispersion components set forth above, those skilled in the art will appreciate that, the formation of dispersions wherein the components have a refractive index differential of less than about 0.5 is preferred. That is, the refractive index of the suspension medium will preferably be within about 0.5 of the refractive index associated with the perforated particles or microstructures. It will further be appreciated that, the refractive index of the suspension medium and the particles may be measured directly or approximated using the refractive indices of the major component in each respective phase. For the perforated microstructures, the major component may be determined on a weight percent basis. For the suspension medium, the major component will typically be derived on a volume percentage basis. In selected embodiments of the present invention the refractive index differential value will preferably be less than about 0.45, about 0.4, about 0.35 or even less than about 0.3. Given that lower refractive index differentials imply greater dispersion stability, particularly preferred embodiments comprise index differentials of less than about 0.28, about 0.25, about 0.2, about 0.15 or even less than about 0.1. It is submitted that a skilled artisan will be able to determine which excipients are particularly compatible without undue experimentation given the instant disclosure. The ultimate choice of preferred excipients will also be influenced by other factors, including biocompatibility, regulatory status, ease of manufacture, cost.

As discussed above, the minimization of density differences between the particles and the continuous phase is largely dependent on the perforated endlor hollow nature of the microstructures, such that the suspension medium constitutes most of the particle volume. As used herein, the term "particle volume" corresponds to the volume of suspension medium that would be displaced by the incorporated hollowlporous particles if they were solid, i.e. the volume defined by the particle boundary. For the purposes of explanation, and as discussed above, these fluid filled particulate volumes may be referred to as "virtual particles." Preferably, the average volume of the bioactive agentlexcipient shell or matrix the volume of medium actually displaced by the perforated microstructure) comprises less then 70% of the average particle volume (or less than 70% of the virtual particle). More preferably, the volume of the microperticulate matrix

I

0 o comprises less than about 50%, 40%, 30% or even 20% of the average particle volume. Even more preferably, the average volume of the shelljmatrix comprises less than about 10%, 3% or 1% of the average particle volume. Those skilled in the art will appreciate that, such a matrix or shell volumes typically contributes little to the virtual particle density which is overwhelmingly dictated by the suspension medium Cl 5 found therein. Of course, in selected embodiments the excipients used to form the perforated microstructure may be chosen so the density of the resulting matrix or shell approximates the density of the surrounding Ssuspension medium.

C- It will further be appreciated that, the use of such microstructures will allow the apparent density o of the virtual particles to approach that of the suspension medium substantially eliminating the attractive van der Weals forces. Moreover, as previously discussed, the components of the microparticulate matrix are Spreferably selected, as much as possible given other considerations, to approximate the density of suspension medium. Accordingly, in preferred embodiments of the present invention, the virtual particles and the suspension medium will have a density differential of less than about 0.6 glcm 3 That is, the mean density of the virtual particles (as defined by the matrix boundary) will be within approximately 0.6 g/cm 3 of the suspension medium. More preferably, the mean density of the virtual particles will be within 0.5, 0.4, 0.3 or 0.2 gfcm' of the selected suspension medium. In even more preferable embodiments the density differential will be less than about 0.1, 0.05, 0.01, or even less than 0.005 gfcm 3 In addition to the aforementioned advantages, the use of hollow, porous particles allows for the formation of free-flowing dispersions comprising much higher volume fractions of particles in suspension. It should be appreciated that, the formulation of prior art dispersions at volume fractions approaching close.

packing generally results in dramatic increases in dispersion viscoelastic behavior. Rheological behavior of this type is not appropriate for MDI applications. Those skilled in the art will appreciate that, the volume fraction of the particles may be defined as the ratio of the apparent volume of the particles the particle volume) to the total volume of the system. Each system has a maximum volume fraction or packing fraction.

For example, particles in a simple cubic arrangement reach a maximum packing fraction of 0.52 while those in a face centered cubic/hexagonal close packed configuration reach a maximum packing fraction of approximately 0.74. For non-spherical particles or polydisperse systems, the derived values are different.

Accordingly, the maximum packing fraction is often considered to be an empirical parameter for a. given system.

Here, it was surprisingly found that the porous structures of the present invention do not exhibit undesirable viscoelastic behavior even at high volume fractions, approaching dose packing. To the contrary, they remain as free flowing, low viscosity suspensions having little or no yield stress when compared with analogous suspensions comprising solid particulates. The low viscosity of the disclosed suspensions is thought to be due, at least in large part, to the relatively low van der Weals attraction between the fluid-filled hollow, porous particles. As such, in selected embodiments the volume fraction of the disclosed dispersions is

I

0 0 greater than approximately 0.3. Other embodiments may have packing values on the order of 0.3 to about or on the order of 0.5 to about 0.8, with the higher values approaching a dose packing condition.

C3 Moreover, as particle sedimentation tends to naturally decrease when the volume fraction approaches dose C) packing, the formation of relativeliy concentrated dispersions may further increase formulation stability. C1 5 Although the methods and compositions of the present invention may be used to form relatively concentrated suspensions, the stabilizing factors work equally well at much lower packing volumes and such dispersions are contemplated as being within the scope of the instant disclosure. In this regard, it wilt be appreciated that, dispersions comprising low volume fractions are extremely difficult to stabilize using prior o art techniques. Conversely, dispersions incorporating perforated microstructures comprising a bioactive agent as described herein are particularly stable even at low volume fractions. Accordingly, the present O invention allows for stabilized dispersions, and particularly respiratory dispersions, to be formed and used at Svolume fractions less than 0.3. In some preferred embodiments, the volume fraction is approximately 0.0001 0.3, more preferably 0.001 0.01. Yet other preferred embodiments comprise stabilized suspensions having volume fractions from approximately 0.01 to approximately 0.1.

The perforated microstructures of the present invention may also he used to stabilize dilute suspensions of micronized bioactive agents. In such embodiments the perforated microstructures may be added to increase the volume fraction of particles in the suspension, thereby increasing suspension stability to creaming or sedimentation. Further, in these embodiments the incorporated microstructures may also act in preventing close approach (aggregation) of the micronized drug particles. It should be appreciated that, the perforated microstructures incorporated in such embodiments do not necessarily comprise a bioactive agent.

Rather, they may be formed exclusively of various excipients, including surfactants.

Those skilled in the art wil further appreciate that the stabilized suspensions or dispersions of the present invention may be prepared by dispersal of the microstructures in the selected suspension medium which may then be placed in a container or reservoir. In this regard, the stabilized preparations of the present invention can be made by simply combining the components in sufficient quantity to produce the final desired dispersion concentration. Although the microstructures readily disperse without mechanical energy, the application of mechanical energy to aid in dispersion with the aid of sonication) is contemplated, particularly for the formation of stable emulsions or reverse emulsions. Altematively, the components may be mixed by simple shaking or other type of agitation. The process is preferably carried out under anhydrous conditions to obviate any adverse effects of moisture on suspension stability. Once formed, the dispersion has a reduced susceptibility to flocculation and sedimentation.

As indicated throughout the instant specification, the dispersions of the present invention are preferably stabilized. In a broad sense, the term "stabiized dispersion" will be held to mean any dispersion that resists aggregation, flocculation or creaming to the extent required to provide for the effective delivery of a bioactive agent.

While those sldled in the art will appreciate that there are several methods that may be used to assess the stability 1

VO

0 0 of a given dispersion, a preferred method for the purposes of the present invention comprises determination of creaming or sedimentation time using a dynamic photosedimentation method. As seen in Example IX end Figure 2, a 0 preferred method comprises subjecting suspended particles to a centrifugal force and measuring absorbance of the suspension as a function of time. A rapid decrease in the absorbance identifies a suspension with poor stability. It is submitted that those skilled in the art will be able to adapt the procedure to specific suspensions without undue experimentation.

For the purposes of the present invention the creaming time shall be defined as the time for the suspended C drug particulates to cream to 112 the volume of the suspension medium. Similary, the sedimentation time may be Sdefined as the time it takes for the particulates to sediment in 112 the volume of the liquid medium. Besides the photosedimentation technique described above, a relatively simple way to determine the creaming time of a Spreparation is to provide the particulate suspension in a sealed glass vial. The vials are agitated or shaken to provide N relatively homogeneous dispersions which are then set aside and observed using appropriate instrumentation or by visual inspection. The time necessary for the suspended particulates to cream to 1/2 the volume of the suspension medium to rise to the top half of the suspension mediuml, or to sediment within 112 the volume to settle in the bottom 112 of the medium), is then noted. Suspension fonnmations having a creaming time greater than 1 minute are preferred and indcate suitable stability. More preferably, the stabilized dispersions comprise creaming times of greater than 1, 2, 5, 10, 15, 20 or 30 minutes. In particularly preferred embodiments, the stabilized dispersions exhibit creaming times of greater than about 1, 1.5, 2, 2.5, or 3 hours. Substantially equivalent periods for sedmentation times are indicative of compatible dispersions.

As discussed herein, the stabilized dispersions disclosed herein may preferably be administered to the nasal or pulmonary air passages of a patient via aerosolizetion, such as with a metered dose inhaler. The use of such stabilized preparations provides for superior dose reproducibility and improved lung deposition as described above.

MODs are well known in the art and could easily be employed for administration of the claimed dispersions without undue experimentation. Breath activated MDIs, as well as those comprising other types of improvements which have been, or will be, developed are also compatible with the stabilized dispersions and present invention and, as such, are contemplated as being with in the scope thereof. However, it should be emphasized that in preferred embodiments, the stabilized dispersions may be administered with an MDI using a number of different routes including, hut not limited to, topical, nasal, pulmonary or oral. Those skilled in the art will appreciate that, such routes are well known and that the dosing and administration procedures may be easily derived for the stabilized dispersions of the present invention.

MDI canisters generally comprise a container or reservoir capable of withstanding the vapor pressure of the propellent used such as, a plastic or plastic-coated glass bottle, or preferably, a metal can or, for example, an aluminum can which may optionally be anodzed, lacquer-coated and/or plastic-coated, wherein the container is closed with a metering valve. The metering valves are designed to deliver a metered amount of the formulation per actuation. The valves incorporate a gasket to prevent leakage of propellant through the valve. The gasket may

VO

0 Scomprise any suitable elastomeric material such as, for example, low density polyethylene, chlorobutyl, black and white butadene-acrylonitrile rubbers, butyl rubber and neoprene. Suitable valves are commercially available from manufacturers wel known in the aerosol industry, for example, from Valois, France OFiO, DF30, OF 31150 ACT, Bespak pic, LTK BK300, BK3561 and 3M-Neotechric Ltd., LIK Spraymiser).

C 5 Each filed canister is conveniently fitted into a suiteble channeling device or actuator prior to use to form a metered dose inhaler for administration of the medicament into the lungs or nasal cavity of a patient. Suitable channeling devices comprise for example a valve actuator and a cylindrical or cone-like passage through which Cmedicament may be delivered from the filled canister via the metering valve, to the nose or mouth of a patient a o mouthpiece actuator. Metered dose inhalers are designed to deliver a fixed unit dosage of medicament per actuation such as, for example, in the range of 10 to 5000 micrograms of bioactive agent per actuation. Typically, a single Scharged canister will provide for tens or even hundreds of shots or doses.

SWith respect to MDIs, it is an advantage of the present invention that any biocompatible suspension medium having adequate vapor pressure to act as a propellant may be used. Particularly preferred suspension made are compatible with use in a metered dose inhaler. That is, they will be able to form aerosols upon the activation of the metering valve and associated release of pressure. In general, the selected suspension medium should be biocompatible i.e. relatively non-toxic) and non-reactive with respect to the suspended perforated microstructures comprising the bioactive agent. Preferably, the suspension medium will not act as a substantial solvent for any components incorporated in the perforated microspheres. Selected embodiments of the invention comprise suspension media selected from the group consisting of fluorocarbons (including those substituted with other halogens), hydrofluoroalkanes, perfluorocarbons, hydrocarbons, alcohols, ethers or combinations thereof. It will be appreciated that, the suspension medium may comprise a mixture of various compounds selected to impart specific characteristics.

Particularly suitable propellants for use in the MDI suspension mediums of the present invention are those propellant gases that can be liquefied under pressure at room temperature and, upon inhalation or topical use, are safe, toxicologically innocuous and free of side effects. In this regard, compatible propellants may comprise any hydrocarbon, fluorocarbon, hydrogen-containing fluorocarbon or mixtures thereof having a sufficient vapor pressure to efficiently form aerosols upon activation of a metered dose inhaler. Those propellants typically termed hydrofluoroalkanes or HFAs are especially compatible. Suitable propellants include, for example, short chain hydrocarbons, hydrogen-containing chlorofluorocarbons such as CH 2 CIF, CCIF 2 CHCIF, CF 3

CHCIF.

CHFCCIF

2

CHCIFCHF

2

CF,CH

2 CI, and CCIF2CH 3 CG1 hydrogen-containing fluorocarbons HFAs) such as CHFzCHF 2 CFzCHF, CHF 2

CH

3 and CF,CHFCF 3 and perfluorocarhons such as CFiCF 3 and CFCF,CF,.

Preferably, a single perfluorocarbon or hydrogen-containing fluorocarbon is employed as the propellant.

Particularly preferred as propellants are 1,1,1,2.tetrafluoroethane (CFCH2F) IHFA-134a) end 1,1,1,2,3,3,3 heptefluoro-n-propane (CFCHFCFa) (HFA-227), perffuoroethane, monochlorodifluoromethane, 1,1-difluoroethane, and combinations thereof. It is desirable that the formulations contain no components that deplete

\O

0 0 stratospheric ozone. In particular it is desirable that the formulations are substantially free of chlorofluorocarbons such as CCIF, CCI 2 and CFCCI 3 SSpecific fluorocarbons, or dasses of fluorinated compounds, that are useful in the suspension media incude, but are not limited to, fluoroheptane, fluorocydoheptane, fluoromethylcydoheptane, fluorohexane, l 5 fluorocyclohexane, fluoropentane, fluorocyclopentene, fluaromethylcydopentane, fluorodimethylcydopentanes, fluoromethylcycdbutane, fluorodimethycyclobutna, fluorotrimethylcyclobutane, fluorobutane, fluorocydobutane, fluoropropane, fluoroethers, fluoropolyethers and fluorotriethylamines. It will be appreciated that these compounds t'- C may be used alone or in combination with more volatile propellants. It is a distinct advantage that such compounds Sare generally environmentally sound and biologicelly non-reactive.

In addition to the aforementioned fluorocarbons and hydrofluoroalkanes, various Schlorofluorocarbons and substituted fluorinated compounds may also be used as suspension mediums in Cl accordance with the teachings herein. In this respect, FC-11 (CCL3F), FC-11B1 (CBrC12FI, FC-11B2 (CBr2CIFI, FC12B2 (CF2Br2), FC21 (CHCI2F), FC21B1 (CHBrCIFI, FC-21B2 (CHBr2FI, FC-3181 ICH2BrF), FC113A (CCI3CF3), FC-122 ICCIF2CHC21, FC-123 (CF3CHC12), FC-132 (CHCIFCHCIFl, FC-133 (CHCIFCHF2I, FC-141 ICH2CICKCIF), FC-141B (CC12FCH3), FC-142 ICHF2CH2C1), FC.151 ICH2FCH2CI), FC-152 ICH2FCH2F), FC-1112 (CCIF-CCIF), FC-1121 (CHCI-CFCI) and FC-1131 (CHCI-CHF) are all compatible with the teachings herein despite possible attendant environmental concerns. As such, each of these compounds may be used, alone or in combination with other compounds less volatile fluorocarbons) to form the stabilized respiratory dispersions of the present invention.

Along with the aforementioned embodiments, the stabilized dispersions of the present invention may also be used in conjunction with nebulizers to provide an aerosolized medicament that may be administered to the pulmonary air passages of a patient in need thereof. Nebulizers are well known in the art and could easily be employed for administration of the claimed dispersions without undue experimentation. Breath activated nebulizers, as well as those comprising other types of improvements which have been, or will be, developed are also compatible with the stabilized dispersions and present invention end amr contemplated as being with in the scope thereof.

Nebulizers work by forming aerosols, that is converting a bulk iquid into small droplets suspended in a breathable gas. Here, the aerosolized medicament to be administered (preferably to the pulmonary air passages) will comprise small droplets of suspension medium associated with perforated microstructures comprising a bioactive agent. In such embodiments, the stabilized dispersions of the present invention will typically be placed in a fluid reservoir operably associated with a nebulizer. The specific volumes of preparation provided, means of filling the reservoir, etc., will largely be dependent on the selection of the individual nebulizer and is wel within the purview of the skilled artisan. Of course, the present invention is entirely compatible with single-dose nebulizers and mldtiple dose nebulizers.

Traditional prior art nebulizer preparations typically comprise aqueous solutions of the selected pharmaceutical compound. With such prior art nebulizer preparations, it has long been established that corruption of 0 0 the incorporated therapeutic compound can severely reduce efficacy. For example, with conventional aqueous multidose nebutizer preparations, bacterial contamination is a constant problem. In addition, the solubilized medicament Smay precipitate out, or degrade over time, adversely affecting the delivery profile. This is particulady true of larger, Smore labile biopdymers such as enzymes or other types of proteins. Precipitation of the incorporated bioactive agent may lead to particle growth that results in a substantial reduction in lung penetration and a corresponding decrease in bioavailability. Such dosing incongruities markedly decrease the effectiveness of any treatment.

The present invention overcomes these and other difficulties by providing stabilized dispersions with a suspension medium that preferably comprises a fluorinated compound a fluorochemical, fluorocarbon or Sperfluorocarbonl. Particulady preferred embodiments of the present invention comprise fluorochemicals that are Q 10 liquid at room temperature. As indicated above, the use of such compounds, whether as a continuous phase or, as Sa suspension medium, provides several advantages over prior art liquid inhalation preparations. in this regard, it is well established that many fluorochemicals have a proven history of safety and biocompatibility in the lung. Further, in contrast to aqueous solutions, fluorochemicals do not negatively impact gas exchange following pulmonary administration. To the contrary, they may actually be able to improve gas exchange and, due to their unique wettability characteristics, are able to carry an aerosolized stream of particles deeper into the lung, thereby improving systemic delivery of the desired pharmaceutical compound. In addition, the relatively non-reactive nature of fluorochemicals acts to retard any degradation of an incorporated bioactive agent. Finally, many fluorochemicals are also bacteriostatic thereby decreasing the potential for microbial growth in compatible nebulizer devices.

In any event, nebulizer mediated aerosolization typically requires an input of energy in order to produce the increased surface area of the droplets and, in some cases, to provide transportation of the atomized or aerosolized medcament. One common mode of aerosolization is forcing a stream of fluid to be ejected from a nozzle, whereby droplets are formed. With respect to nebulized administration, additional energy is usually imparted to provide droplets that will be sufficiently small to be transported deep into the lungs. Thus, additional energy is needed, such as that provided by a high velocity gas stream or a piezoelectric crystal. Two popular types of nebulizers, jet nebulizers and ultrasonic nebulizers, rely on the aforementioned methods of applying additional energy to the fluid during atomization.

In terms of pulmonary delivery of bioactive agents to the systemic circulation via nebulization, recent research has focused on the use of portable hand-held ultrasonic nebulizers, also referred to as metered solutions.

These devices, generally known as single-bolus nebulizers, aerosolize a single bolus of medication in an aqueous solution with a particle size efficient for deep lung delivery in one or two breaths. These devices fall into three broad categories. The first category comprises pure piezoelectric single-bolus nebutizers such as those described by Miitterfein, t. at, Aerosol Med. 1988; 1:231). In another category, the desired aerosol cloud may be generated by microchannel extrusion single-bolus nebulizers such as those described in U.S. Pat. No. 3,812,854. Finally, a third category comprises devices exemplified by Robertson, et. al., (WO 92111050) which describes cyclic pressurization single-bolus nebulizers. Each of the aforementioned references is incorporated herein in their entirety. Most devices

VO

0 0 are manually actuated hut some devices exist which are breath actuated. Breath actuated devices work by releasing aerosol when the device senses the patient inhaling through a circuit. Breath actuated nebulizers may also Sbe pieced in-line on a ventilator circuit to release aerosol into the air flow which comprises the inspiration gases for a n patient.

C 5 Regardless of which type of nebulizer is employed, it is an advantage of the present invention that biocompatible nonaqueous compounds may be used as suspension mediums. Preferably, they will be able to form aerosols upon the application of energy thereto. In general, the selected suspension mediun should be biocompatible C(i.e. relatively non-toxic) and non-reactive with respect to the suspended perforated micrslructures comprising the Obioactive agent. Preferred embodiments comprise suspension media selected from the group consisting of fluorochemicals, fluorocarbons (including those substituted with other halogens), perfluorocerbons, Sftuorocarbonlhydrocarbon diblocks, hydrocarbons, alcohois, ethers, or combinations thereof. It will be appreciated Cthat, the suspension medium may comprise a mixture of various compounds selected to impart specific characteristics. It will also be appreciated that the perforated micrstructures are preferably insoluble in the suspension medium, thereby providing for stabilized medicement particles, and effectively protecting a selected bioactive agent from degradation, as might occur during prolonged storage in an aqueous solution. In preferred embodiments, the selected suspension medium is bacteriostatic. The suspension formdation also protects the hioactive agent from degradation during the nebulization process.

As indicated above, the suspension media may comprise any one of a number of different compounds including hydrocarbons, fluorocarbons or hydrocarbonifluorocarbon diblocks. In general, the contemplated hydrocarbons or highly fluorinated or perfluorinated compounds may be linear, branched or cyclic, saturated or unsaturated compounds. Conventional structural derivatives of these fluorochemicals and hydrocarbons are also contemplated as being within the scope of the present invention as well. Selected embodiments comprising these totally or partially fluorinated compounds may contain one or more hetero-atoms and/or atoms of bromine or chlorine.

Preferably, these fluorochemicals comprise from 2 to 1B carbon atoms and include, but are not imited to, linear, cyclic or polycyclic perfluoroalkanes, bistperfluoroalkyl)alkenes, perfluoroethers, perfluoroaminas, perfluoroalkyl bromides and perfluoroalkyl chlorides such as dichlornoctane. Particularly preferred fluorinated compounds for use in the suspension medium may comprise perfluorooctyl bromide CeF,Br (PFOB or perflubron), dchlorofluorooctane

C

e FAC1 and the hydrfluoroalkane perfluorooctyl ethane CF7,C 2 H (PFOE. With respect to other embodments, the use of perfluorohexane or perftuoropentene as the suspension medium is especially preferred.

More generally, exemplary fluorochemicals which are contemplated for use in the present invention generally include halogenated fluorochemicals C,F2,X, XC,F,X, where n 2-10, X Br, Cl or 1) and, in particular, 1-bromo-F-butane n-C 4 F,Br, 1-bromo-F-hexane (n-CF, 3 Br), 1-bromo-F-heptane (n-CF,Br, 1,4-dibromo-Fbutane end 1,6-dibromo-F-hexane. Other useful brominated fluorochemicals are dsclosed in US Patent No.

3,975,512 to Long and are incorporated herein by reference. Specific fluorochemicals having chloride substituents,

VO

O such as perfluorooctyl chioride (n-CF,CI), 1,8-dichloro-F-octane (n-CICF,.C), 1,6-dichloro-Fhexane (nCICsFC1, and 1, 4-dchloro-F-butana f(-CIC 4 FOCI) are also preferred.

Fluorocarbons, fluorocarbon-hydrocarbon compounds and halogenated fluorochemrnicals containing other linkage groups, such as esters, thioethers and emines are also suitable for use as suspension media in the present invention. For instance, compounds having the general formuda, C,F,.iFOCF 2 or C,F.,ICH-CHCmFa,,.,, las for example C 4

FCH-CHC

4 F F-44E), i-C 3

FCH-CHC

6

F

3 (F-i36E), and CEF,,CH-CHCF,, (F-66E)) where n and m are the same or different end n and m are integers from about 2 to about 12 are compatible with teachings herein. Useful fluorochemical-hydrocarbon diblock and tIibDlock compounds include those with the general formulas CF2.

1 -CH2.

1 and CF,, wherem n 2-12; m 2-16 or CpH 2 ,.-C,F,CmH 2 where p 1-12, m 1-12 and n 2-12.

Preferred compounds of this type include C,F,,C 2 H, CF 3

CH,,,H

2

CF

7

CH,

7

CF,CH-CHCH,

3 and

\O

CF

1 7

CH-CHC

10

H

2 Substituted ethers or polyathars XChF,,OC,F,,,X XCFOC,FOCF 2 X, where n and m 1-4, X C Br, CI or 1) and fluorochermical-hydrocarbon ether diblocks or tiblocks i.e. C,F,,-O-CH 2 where n 2-10; m 2-16 or where p 2-12, m 1-12 and n 2-12) may also used as well as wherein n, m and p are from 1-12. Furthermore, depending on the application, perfluoroalkylated ethers or polyethers may be compatible with the claimed dispersions.

Polycyclic and cyclic fluorochemicals, such as C, 0 F IF-decalin or perfluorodecalin, perfluorperhydrophenanthrne, perfluoraotetrmethycyclohexane lAP-144) and perfluoro n-butyldecalin are also within the scope of the invention. Additional useful fluorochemicals include perfluorinated amines, such as Ftripropylainne ("FTPA"1 and F-tributylamine F-4-methyloctahydrquinolizine F-N-methyldecahydroisoquintcline F-N-methyldecahydroquindine F-N-cyclohexylpyrrolidine ("FCHP" and F2butyltetrahydroturan ("FC-75"or Still other useful fluorinated compounds include perfluorophenanthrene, perfluoromethyldecalin, perfluorodimethyethylcyclohexane, perfluorodimethyldecalin, perfluorodiethyldecalin, perfluoramethyladamentane, perfluorodimethyladamantane. Other contemplated fluerochemicals having nonfluorine substituents, such as, perfluorooctyl hydride, and similar compounds having different numbers of carbon atoms are also useful. Those skilled in the art will further appredciate that other variously modified fluorochemicals are encompassed within the broad definition of fluorochemical as used in the instant application and suitable for use in the present invention. As such each of the foregoing compounds may be used, alone or in combination with other compounds to form the stabilized dispersions of the present inventon.

Specific fluorocarbons, or classes of fluorinated compounds, that may be useful as suspension media include, but are not limited to, fluoroheptane, fluorcycloheptane fluoromethylcycloheptane, fluorohexane, fluorocyclohexane, fluoropentane, fluorocyclopentane, fluoromethycyclopentane. fluorodimethylcyclopentanes, fluoromethylcydcobutane, fluorodimethylcydclobutane, fluorotrimethylcyclobutane, fluorobutane, fluorocyclobutane, fluoropropane, fluorcethers, fluoropolyethers and fluorotriethylamines. Such compounds are generally environmentally sound and are biologically non-reactive.

VO

0 SWhile any fluid compound capable of producing an aerosol upon the application of energy may be used in conjunction with the present invention, the selected suspension medium will preferably have a vapor pressure less C than about 5 atmospheres and more preferably less than about 2 atmospheres. Unless otherwise specified, a vapor pressures recited herein are measured at 25*C. In other embodiments, preferred suspension media compounds will have vapor pressures on the order of about 5 tor to about 760 tort, with more preferable compounds having vapor pressures on the order of from about 8 torr to about 600 torn, while still more preferable compounds will have vapor pressures on the order of from about 10 torr to about 350 torr. Such suspension media may be used in conjunction C with compressed air nebulizers, ultrasonic nebuizers or with mechanical atomizers to provide effective ventilation Stherapy. Moreover, more volatile compounds may be mixed with lower vapor pressure components to provide suspension media having specified physical characteristics selected to further improve stability or enhance the Sbioavailability of the dispersed bioactive agent.

SOther embodiments of the present invention directed to nebulizers will comprise suspension media that boil at selected temperatures under ambient conditions li.e. 1 atml. For example, preferred embodiments will comprise suspension media compounds that boil above O0C, above 5CC, above 10CC, above 15", or above 20°C. In other embodiments, the suspension media compound may boil at or above 25°C or at or above 300C. In yet other embodiments, the selected suspension media compound may boil at or above human body temperature 37°Cl, above 45°C, 55°C, 650C, 75°C, 85*C or above 100°C.

Along with MOls and nebulizers, it will be appreciated that the stabilized dispersions of the present invention may be used in conjunction with liquid dose instillation or LDI techniques. Liquid dose instillation involves the direct administration of a stabilized dispersion to the lung. In this regard, direct pulmonary administration of bioactive compounds is particduarty effective in the treatment of dsorders especially where poor vascular circulation of diseased portions of a lung reduces the effectiveness of intravenous drug delivery. With respect to LDI the stabilized dispersions are preferably used in conjunction with partial liquid ventilation or total liquid ventilation.

Moreover, the present invention may further comprise introducing a therapeutically beneficial amount of a physiologicaly acceptable gas (such as nitric oxide or oxygen) into the pharmaceutical microdispersion prior to, during or following administration.

For LI1, the dispersions of the present invention may be administered to the lung using a pulmonary delivery conduit. Those skilled in the art will appreciate the term "pulmonary delivery conduit", as used herein, shall be construed in a broad sense to comprise any device or apparatus, or component thereof, that provides for the instillation or administration of a liquid in the lungs. In this respect a pulmonary delivery conduit or delivery conduit shall be held to mean any bore, lumen, catheter, tube, conduit, syringe, actuator, mouthpiece, endotracheal tube or bronchoscope that provides for the administration or instillation of the disclosed dispersions to at least a portion of the pulmonary air passages of a patient in need thereof. It will be appreciated that the delivery conduit may or may not be associated with a liquid ventilator or gas ventilator.

0 0 In particularly preferred embodiments the delivery conduit shall comprise an endotrecheal tube or bronchoscope.

CHere it must be emphasized that the dispersions of the present invention may be administered to Sventilated those connected to a mechanical ventilator) or nonventilated, patients those undergoing spontaneous respiration). Accordingly, in preferred embodiments the methods and systems of the present invention may comprise the use or inclusion of a mechanical ventilator. Further, the stabilized dispersions of the present invention may also be used as a lavage agent to remove debris in the lung, or for diagnostic lavage C procedures. In any case the introduction of liquids, particularly fluarochemicals, into the lungs of a patient is Swell known and could be accomplished by a skilled artisan in possession of the instant specification without undue experimentation.

SThose skilled in the art will appreciate that suspension media compatible with LOI techniques are Csimilar to those set forth above for use in conjunction with nebulizers. Accordingly, for the purposes of the present application suspension media for dispersions compatible with LDI shall be equivalent to those enumerated above in conjunction with use in nebulizers. In any event, it will be appreciated that in particularly preferred LDI embodiments the selected suspension medium shall comprise a fluorochemical that is liquid under ambient conditions.

It will be understood that, in connection with the present invention, the disclosed dispersions are preferably administered directly to at least a portion of the pulmonary air passages of a mammal. As used herein, the terms "direct instillation" or "direct administration" shall be held to mean the introduction of a stabilized dispersion into the lung cavity of a mammal. That is, the dispersion will preferably be administered through the trachea of a patient and into the lungs as a relatively free flowing liquid passing through a delivery conduit and into the pulmonary air passages. In this regard, the flow of the dispersion may be gravity assisted or may be afforded by induced pressure such as through a pump or the compression of a syringe plunger. In any case, the amount of dispersion administered may be monitored by mechanical devices such as flow meters or by visual inspection.

While the stabilized dispersions may be administered up to the functional residual capacity of the lungs of a patient, it will be appreciated that selected embodiments will comprise the pulmonary administration of much smaller volumes on the order of a milliliter or less). For example, depending on the disorder to be treated, the volume administered may be on the order of 1. 3, 5, 10, 20, 50, 100, 200 or 500 militers. In preferred embodiments the liquid volume is less than 0.25 or 0.5 percent FRC. For particularly preferred embodiments, the liquid volume is 0.1 percent FRC or less. With respect to the administration of relatively low volumes of stabilized dispersions it will be appreciated that the wettahbility and spreading characteristics of the suspension media (particularly fluorochemicals) will facilitate the even distribution of the bioactive agent in the lung. However, in other embodiments it may be preferable to administer the suspensions a volumes of greater than 0.5, 0.75 or 0.9 percent FRC. In any event, LDI treatment as disclosed herein represents a new alternative for critically

VO

0 0 ill patients on mechanical ventilators, and opens the door for treatment of less ill patients with bronchoscopic administration.

SIt will also be understood that other components can be included in the stabilized dispersions of the present invention. For example, osmotic agents, stabilizers, chelators, buffers, viscosity modulators, salts, and sugars can be C 5 added to fine tune the stabdized dispersions for maximum life and ease of administration. Such components may be added directly to the suspension medium or associated with, or incorporated in, the perforated microstructures.

SConsiderations such as sterility, isotonicity, and biocompatibility may govern the use of conventional additives to the C disclosed compositions. The use of such agents will be understood to those of ordnary skil in the art and, the Sspecific quantities, ratios, and types of agents can be determined empirically without undue experimentation.

Moreover, while the stabilized dispersions of the present invention are particularly suitable for the pulmonary administration of bi active agents, they may also be used for the localized or systemic administration of C compounds to any location of the body. Accordingly, it should be emphasized that, in preferred embodiments, the formulations may be administered using a number of different routes including, but not limited to, the gastrointestinal tract, the respiratory tract, topically, intramuscularly, intraperitoneally, nasally, vaginally, rectally, aurally, orally or ocular. More generally, the stabilized dispersions of the present invention may be used to deliver agents topically or by administration to a nonpulmonary body cavity. In preferred embodiments the body cavity is selected from the group consisting of the peritoneum, sinus cavity, rectum, urethra, gastrointestinal tract, nasal cavity, vagina.

auditory meatus, oral cavity, buccal pouch and pleura. Among other indications, stabilized dispersions comprising the appropriate bioactive agent, an antibiotic or an anti-inflammatory), may be used to treat infections of the eye, sinusitis, infections of the auditory tract and even infections or disorders of the gastrointestinal tract. With respect to the latter, the dispersions of the present invention may be used to selectively deliver pharmaceutical compounds to the liing of the stomach for the treatment of H. pyiioinfections or other ulcer related disorders.

With regard to the perforated microstructure powders and stabilized dispersions disclosed herein those skilled in the art will appreciate that they may be advantageously supplied to the physician or other health care professional, in a sterile, prepackaged or kit form. More particularly, the formulations may be supplied as stable powders or preformed dispersions ready for administration to the patient. Conversely, they may be provided as separate, ready to mix components. When provided in a ready to use form, the powders or dispersions may be packaged in single use containers or reservoirs, as well as in multi-use containers or reservoirs. In either case, the container or reservoir may be associated with the selected inhalation or administration device and used as described herein. When provided as individual components le.g., as powdered microspheres and as neat suspension medium) the stabilized preparations may then be formed at any time prior to use by simply combining the contents of the containers as directed. Additionally, such kits may contain a number of ready to mix, or prepackaged dosing units so that the user can then administer them as needed.

VO

0 SAlthough preferred embodiments of the present invention comprise powders and stabilized dispersions for use in pharmaceutical applications, it will be appreciated that the perforated microstructures and disclosed C dispersions may be used for a number of non pharmaceutical applications. That is, the present invention provides Sperforated microstructures which have a broad range of appfications where a powder is suspended andlor aerosoiized. In particular, the present invention is especially effective where an active or bioactive ingredient must be dissolved, suspended or solubilized as fast as possible. By increasing the surface area of the porous micropartices or by incorporation with suitable excipients as described herein, will result in en improvement in t'- Cdispersibility, and/or suspension stability. In this regard, rapid dispersement applications include, but are not Slimited to: detergents, dishwasher detergents, food sweeteners, condiments, spices, mineral flotation detergents, thickening agents, foliar fertilizers, phylohormones, insect pheromones, insect repellents, pet repellents, pesticides, fungicides, disinfectants, perfumes, deodorants, etc.

SApplications that require finely divided particles in a non-aqueous suspension media solid, liquid or gaseous) are also contemplated as being within the scope of the present invention. As explained herein, the use of perforated microstructures to provide a "homodispersion" minimizes particle-particle interactions.

As such, the perforated microspheres and stabilized suspensions of the present invention are particularly compatible with applications that require: inorganic pigments, dyes, inks, paints, explosives, pyrotechnic, adsorbents, absorbents, catalyst, nucleating agents, polymers, resins, insulators, fillers, etc. The present invention offers benefits over prior art preparations for use in applications which require eerosolization or atomization. In such non pharmaceutical uses the preparations can be in the form of a liquid suspension (such as with a propellant) or as a dry powder. Preferred embodiments comprising perforated microstructures as described herein include, but are not limited to, ink jet printing formulations, powder coating, spray paint, spray pesticides etc.

The foregoing description will be more fully understood with reference to the following Examples. Such Examples, are, however, merely representative of preferred methods of practicing the present invention and should not be read as limiting the scope of the invention.

Preparation of Hollow Porous Particles of Gentamicin Sufeate by Snrav-Drving to 60ml of the following solutions were prepared for spray drying: 50% wlw hydrogenated phosphetidylcholine, E-100-3 Ilipoid KG, Ludwigshafen, Germany) wlw gentamicin sulfate (Amresco, Solon, OHI Perfluorooctylbromide, Perflubron (NMK, Japan) Deionized water Perforated microstructures comprising gentamicin sulfate were prepared by a spray drying technique using a B-191 Mini Spray-Drier (Bichi, Flawil, Switzerland) under the following conditions:

VO

0 0 aspiration: 100%, inlet temperature: 85°C; outlet temperature: 61°C; feed pump: 10%; N 2 flow: 2,800 LUhr.

Variations in powder porosity were examined as a function of the blowing agent concentration.

Fl uorocerbon-in-water emulsions of perfluorooctyl bromide containing a 1:1 wiw ratio of phosphatidylcholine and gentamicin sulfate were prepared varying only the PFCIPC ratio. 1.3 grams of C 5 hydrogenated egg phosphatidylcholine was dispersed in 25 mL deionized water using an Ultra-Turrax mixer (model T-25) at 8000 rpm for 2 to 5 minutes (T 60-700C). A range from 0 to 40 grams of perflubron was added dropwise during mixing IT 60-700 After addition was complete, the fluorocarbon-in-water emulsion was Smixed for an additional period of not less than 4 minutes. The resulting coarse emulsions were then homogenized o under high pressure with an Avestin (Ottawa, Canada) homogenizer at 15,000 psi for 5 passes. Gentamicin sulfate was dissolved in approximately 4 to 5 mL deionized water and subsequently mixed with the perflubron emulsion immediately prior to the spray dry process. The gentamicin powders were then obtained by spray drying using C] the conditions described above. A free flowing pale yellow powder was obtained for all perflubron containing formulations. The yield for each of the various formulations ranged from 35% to

II

Morphology of Gentamicin Sulfate Spray-Dried Powders A strong dependence of the powder morphology, degree of porosity, and production yield was observed as a function of the PFCIPC ratio by scanning electron microscopy ISEM). A series of six SEM micrographs illustrating these observations, labeled 1A1 to 1F1, are shown in the left hand column of Fig. 1. As seen in these micrographs, the porosity and surface roughness was found to be highly dependent on the concentration of the blowing agent, where the surface roughness, number and size of the pores increased with increasing PFCIPC ratios. For example, the formulation devoid of perfluorooctyl bromide produced microstructures that appeared to be highly agglomerated and readily adhered to the surface of the glass vial.

Similarly, smooth, spherically shaped microparticles were obtained when relatively little (PFCIPC ratio 1.1 or 2.2) blowing agent was used. As the PFCIPC ratio was increased the porosity and surface roughness increased dramatically.

As shown in the right hand column of Fig. 1, the hollow nature of the microstructures was also enhanced by the incorporation of additional blowing agent. More particularly, the series of six micrographs labeled 1A2 to 1F2 show cross sections of fractured microstructures as revealed by transmission electron microscopy (TEM). Each of these images was produced using the same microstructure preparation as was used to produce the corresponding SEM micrograph in the left hand column. Both the hollow nature and wall thickness of the resulting perforated microstructures appeared to be largely dependent on the concentration of the selected blowing agent. That is, the hollow nature of the preparation appeared to increase and the thickness of the particle walls appeared to decrease as the PFCIPC ratio increased. As may be seen in Figs. 1A2 to 102 substantially solid structures were obtained from formulations containing little or no fluorocarbon blowing

O

0 0 agent. Conversely, the perforated microstructures produced using a relatively high PFC IPC ratio of approximately 45 (shown in Fig. 1F2 proved to be extremely hollow with a relatively thin wall ranging from Sabout 43.5 to 2B1nm. Both types of particles are compatible for use in the present invention.

III

Preparation of Spray Dried Gentamicin Sulfate Particles using Various Blowing Agents 40 milliliters of the following solutions were prepared for spray drying: o 50% wfw Hydrogenated Phosphatidylcholine. E100-3 1 0 (Lipoid KG, Ludwigshafen, Germany) wlw Gentamicin Sulfate IAmresco, Solon Ohio) SDeionized water.

0 Ci Blowing Agents: Perfluorodecalin, FOC (Air products, Allenton PA) Perfluorooctylbromide, Perflubron (Atochem, Paris, France) Perfluorhexane, PFH (3M, St. Paul, MN) 1,1,2-trichlorotrifluoroethane, Freon 113 IBaxter, McGew Park, IL) Hollow porous microspheres with a model hydrophilic drug, genlamicin sulfate, were prepared by spray drying. The blowing agent in these formulations consisted of an emulsified fluorochemical (FC) oil.

Emulsions were prepared with the following FCs: PFH, Freon 113, Perflubron and FDC. 1.3 grams of hydrogenated egg phosphatidylcholine was dispersed in 25 mL deionized water using a Ultra-Turrax mixer (model T-25) at 8000 rpm for 2 to 5 minutes IT 60-70). 25 grams of FC was added dropwise during mixing (T 60-70°CI. After the addtion was complete, the FC-i n water emulsion was mixed for a total of not less than 4 minutes. The resulting emulsions were then further processed using an Avestin (Ottawa, Canada) high pressure homogenizer at 15,000 psi and 5 passes. Gentamicin sulfate was dissolved in approximately 4 to 5 mL deionized water and subsequently mixed with the FC emulsion. The gentamicin powders were obtained by spray drying (Bichi, 191 Mini Spray Dryer). Each emulsion was fed at a rate of 2.5 mLimin. The inlet and outlet temperatures of the spray dryer were 85°C and 55°C respectively. The nehulization air and aspiration flows were 2800 Llhr and 100% respectively.

A free flowing pale yellow dry powder was obtained for all formulations. The yield for the various formulations ranged from 35 to 80%. The various gentamicin sulfate powders had a mean volume weighted particle diameters that ranged from 1.52 to 4.91 /Jm.

IV

Effect of Blowing Agent on the Morphology of Gentamicin Sulfate Sprey-Dried Powders

O

0 O A strong dependence of the powder morphology, porosity, and production yield (amount of powder captured in the cyclone) was observed as a function of the blowing agent boiing point. In this respect the powders Sproduced in Example III were observed using scanning electron microscopy. Spray drying a fluorochemical (FC) Semulsion with a boiing point below the 55°C outlet temperature perfluorahexane IPFH] or Freon 113), c 5 yielded amorphously shaped (shriveled or deflated) powders that contained little or no pores. Whereas, emulsions formulated with higher boiling FCs perflubron, perfluorodecalin, FOCI produced spherical porous particles. Powders produced with higher boiling blowing agents also had production yields approximately two times greater than powders produced using relatively low boiling point blowing agents.

SThe selected blowing agents and their boiling points are shown in Table II directly below.

STable II ci Blowing Agent (bp 6C) Freon 113 47.6 PFH 56 FDC 141 Perflubron 141 Example IV illustrates that the physical characteristics of the blowing agent boiling point) greatly influences the ability to provide perforated microparticles. A particular advantage of the present invention is the ability to alter the microstructure morphology and porosity by modifying the conditions and nature of the blowing agent.

V

Preparation of Spray Dried Albuterol Sulfate Particles using Various Blowing Agents Approximately 185 ml of the following solutions were prepared for spray drying: 49% whw Hydrogenated Phosphatidylcholine, £100-3 (Lipoid KG, Ludwigshafen, Germany) 50% wlw Albuterol Sulfate (Accurate Chemical, Westbury, NY) 1% wlw Poloxamer 188, NF grade (Mount Olive, NJ) Deionized water.

Blowing Agents: Perfluorodecalin, FDC (Air products, Allenton PA) Perfluorooctylbromide, Perflubron (Atochem, Paris) Perfluorobutylethane F4H2 (F-Tech, Japan) Perfluorotributylamine FTBA (3M, St. Paul, MN) Albuterol sulfate powder was prepared by spray-drying technique by using a B-191 Mini Spray-Drier (Bichi, Flawil, Switzerland) under the following conditions: Aspiration: 100%

\O

0 0 Inlet temperature: 85 C ClOutlet temperature: 61 C F Feed pump: 2.5 mUmin.

C N 2 flow: 47 Llmin.

The feed solution was prepared by mixing solutions A and B prior to spray drying.

Solution A: Twenty grams of water was used to dissolve 1.0 grams of Albuterol sulfate and 0.021 grams of poloxamer 188.

Solution B represented an emulsion of a fluorocarbon in water, stabilized by a phospholipid, which was prepared in the following way. Hydrogenated phosphatidylcholine (1.0 grams) was homogenized in 150 0 Ci grams of hot deionized water (T 50 to 60 0 C) using an Ultra-Turrax mixer tmodel T-25) at 8000 rpm, for 2 I to 5 minutes IT 60-70°C). Twenty-five grams of Perflubron (Atochem, Paris, France) was added dropwise 0 during mixing. After the addition was complete, the Ruorochemical-in-water emulsion was mixed for at least 4 minutes. The resulting emulsion was then processed using an Avestin (Ottawa, Canada) high-pressure homogenizer at 18,000 psi and 5 passes. Solutions A and B were combined and fed into the spray dryer under the conditions described above. A free flowing, white powder was collected at the cyclone separator as is standard for this spray dryer. The albuterol sulfate powders had mean volume weighted particle diameters ranging from 1.28 to 2.77 pm, as determined by an Aerosizer (Amherst Process Instruments, Amherst, MA.

By SEM, the albuterol sulfatelphosphofipid spray dried powders were spherical and highly porous.

Example V further demonstrates the wide variety of blowing agents that may be used to provide perforated microparticles. A particular advantage of the present invention is the ability to alter the microstructure morphology and porosity by manipulating the formulation and spray drying conditions.

Furthermore, Example V demonstrates the particle diversity achieved by the present invention and the ability to effectively incorporate a wide variety of pharmaceutical agents therein.

VI

Preparation of Hollow Porous PVA Particles by Spray Drving a Water-in-oil Emulsion 100 ml of the following solutions were prepared for spray drying: 80% wfw Bis-12-ethylhexyll Suffosuccinic Sodium Salt, (Aerosol OT, Kodak, Rochester, NY| wlw Polyvinyl Alcohol, average molecular weight -30,000-70,000 (Sigma Chemicals, St. Louis, MD) Carbon Tetrachloride (Aldrich Chemicals, Milwaukee, WIl Deionized water.

Aerosol OTIpolyvinyl alcohol particles were prepared by spray-drying technique using a B-181 Mini Spray-Drier (BOchi, Rawil, Switzerland) under the following conditions: Aspiration:

VO

0 SInlet temperature: 60 0

C

COutlet temperature: 430C SFeed pump: 7.5 minmin.

c N 2 flow: 38 Lmin.

C Solution A: Twenty grams of water was used to dissolve 500 milligrams of polyvinyl alcohol (PVAI.

Solution B represented an emulsion of carbon tetrechloride in water, stabilized by aerosol OT, which was prepared in the following way. Two grams of aerosol OT, was dispersed in 80 grams of carbon Stetrachloride using a Ultra-Turrax mixer (model T-251 at 8000 rpm for 2 to 5 minutes IT 15* to 20 0

C).

o 10 Twenty grams of 2.5% w/v PVA was added dropwise during mixing. After the addition was complete, the water- O inoil emulsion was mixed for a total of not less than 4 minutes (T 150 to 20°C). The resulting emulsion was then DO processed using an Avestin 10ttawa, Canada) high-pressure homogenizer at 12,000 psi and 2 passes. The emulsion Swas then fed into the spray dryer under the conditions described above. A free flowing, white powder was collected at the cyclone separator as is standard for this spray dryer. The Aerosol OTIPVA powder had a mean volume weighted particle diameter of 5.28 3.27 pm as determined by an Aerosizer (Amherst Process Instruments. Amherst, MAI.

Example VI further demonstrates the variety of emulsion systems (here, reverse water-in-oil), formulations and conditions that may be used to provide perforated microparticles. A particular advantage of the present invention is the ability to alter formulations and/or conditions to produce compositions having a microstructure with selected porosity. This principle is further illustrated in the following example.

VII

Preparation of Hollow Porous Povycaprolactone Particles by Spray Dryino a Water-in-Oil Emulsion 100 mis of the following solutions were prepared for spray drying: wiw Sorbitan Monostearate, Span 60 IAldrich Chemicals, Milwaukee, WI) wiw Polycaprolactone, average molecular weight 65,000 (Aldrich Chemicals, Milwaukee, WI) Carbon Tetrachloride (Aldrich Chemicals, Milwaukee, Wi) Deionized water.

Span 601polycaprolactone particles were prepared by spray-drying technique by using a B-191 Mini Spray-Drier (Biichi, Rawil, Switzerland) under the following conditions: Aspiration: 85% Inlet temperature: 50 0

C

Outlet temperature: 38°C Feed pump: 7.5 mUmin.

N

2 flow: 36 LUmin.

-52- VO 0 0 A water-in-carbon tetrachloride emulsion was prepared in the following manner. Two grams of SSpan 60, was dispersed in 80 grams of carbon tetrachloride using an Ultra-Turrax mixer (model T-25) at 8000 rpm for 2 to 5 minutes IT 15 to 20"C). Twenty grams of deionized water was added dropwise during Smixing. After the addition was complete, the water-in-oil emulsion was mixed for a total of not less than 4 minutes (T 15 to 20"C). The resulting emulsion was then further processed using an Avestin (Ottawa, Canada) highpressure homogenizer at 12,000 psi and 2 passes. Five hundred milligrams of polycaprolactone was added directly to the emulsion and, mixed until thoroughly dissolved. The emulsion was then fed into the spray dryer Cunder the conditions described above. A free flowing, white powder was collected at the cyclone separator Sas is standard for this dryer. The resulting Span 60/polycaprolactone powder had a mean volume weighted particle diameter of 3.15 2.17 pm. Again, the present Example demonstrates the versatility the instant Sinvention with regard to the feed stock used to provide the desired perforated microstructure.

VtII Preparation of hollow porous powder by spray drying a gasin-water emulsion The following solutions were prepared with water for injection: Solution 1: 3.9% wlv m.HES hydroxyethyist rch (Ajinomoto, Tokyo, Japan) 3.25% wlv Sodium chloride (Mallinckrodt, St. Louis, MO) 2.83% wlv Sodium phosphate, dibasic (Mallinckrodt, St. Louis, MOI 0.42% wlv Sodium phosphate, monobasic (Mallinckrodt, St. Louis, MO) Solution 2: 0.45% wlv Poloxamer 188 (BASF, Mount Olive, NJ) 1.35% w/v Hydrogenated egg phosphatidylcholine, EPC-3 (Lipoid KG, Ludwigshafen, Germany) The ingredients of solution 1 were dissolved in warm water using a stir plate. The surfactants in solution 2 were dispersed in water using a high shear mixer. The solutions were combined following emulsification and saturated with nitrogen prior to spray drying.

The resulting dry, free flowing, hollow spherical product had a mean particle diameter of 2.6 /pm. The particles were spherical and porous as determined by SEM.

This example illustrates the point that a wide of blowing agents (here nitrogen) may be used to provide microstructures exhibiting the desired morphology. Indeed, one of the primary advantages of the present invention is the ability to alter formation conditions so as to preserve biological activity with proteins), or to produce microstructures having selected porosity.

IX

Suspension Stability of Gentamicin Sulfate Spray-Dried Powders

O

0 0 The suspension stability was defined as, the resistance of powders to cream in a nonaqueous medium using a dynamic photosedimentation method. Each sample was suspended in Perflubron at a Sconcentration of 0.8 mg/mL. The creaming rates were measured using a Horiba CAPA-700 Sphotosedimentation particle size analyzer (Irvine, CA) under the following conditions: 0 (max): 3.00 pm D 0.30 pm D (Div): 0.10 pm Rotor Speed: 3000 rpm X: SThe suspended particles were subjected to a centrifugal force and the absorbance of the suspension Swas measured as a function of time. A rapid decrease in the absorbance identifies a suspension with poor Sstability. Absorbance data was plotted versus time and the area under the curve was integrated between 0.1 Ci and 1 min., which was taken as a relative measurement of stability. Figure 2 graphically depicts suspension stability as a function of PFCIPC ratio or porosity. In this case, the powder porosity was found to increase with increasing PFCIPC. Maximum suspension stability was observed with formulations having PFCIPC ratios between 3 to 15. For the most part, these formulations appeared stable for periods greater than 30 minutes using visual inspection techniques. At points beyond this ratio, the suspensions flocculated rapidly indicating decreased stability. Similar results were observed using the cream layer ratio method, where it was observed that suspensions with PFCIPC ratios between 3 to 15 had a reduced cream layer thickness, indicating favorable suspension stability.

X

Preparation of Hollow Porous Particles of Albuterol Sulfate by Spray-Drying Hollow porous albuterol sulfate particles were prepared by a spray-drying technique with a B-191 Mini Spray-Drier (Bachi, Flawil, Switzerland) under the following spray conditions: aspiration: 100%, inlet temperature: 85"C; outlet temperature: 61 0 C; feed pump: 10%; N 2 flow: 2,800 L/hr. The feed solution was prepared by mixing two solutions A and B immediately prior to spray drying.

Solution A: 20g of water was used to dissolve lg of albuterol sulfate (Accurate Chemical, Westbury, NY) and 0.021 g of poloxamer 188 NF grade (BASF, Mount Olive, NJ).

Solution 8: A fluorocarbon-in-water emulsion stabilized by phospholipid was prepared in the following manner. The phospholipid, Ig EPC-100-3 (Lipoid KG, Ludwigshafen, Germany), was homogenized in 150g of hot deionized water (T 50 to 500C using an Ultra-Turrax mixer (model T-251 at 8000 rpm for 2 to minutes (T 60-70"C). 25g of perfluorooctyJ bromide (Atochem, Paris, France) was added dropwise during mixing. After the fluorocarbon was added, the emulsion was mixed for a period of not less than 4 minutes. The resulting coarse emulsion was then passed through a high pressure homogenizer (Avestin, Ottawa, Canada) at 18,000 psi for 5 passes.

O

0 0 Solutions A and B were combined and fed into the spray-dryer under the conditions described above.

A free flowing, white powder was collected at the cyclone separator. The hollow porous albuterol sulfate particles had a volume-weighted mean aerodynamic diameter of 1.18 1.42 pm as determined by a time-of- Sflight analytical method (Aerosizer, Amherst Process Instruments, Amherst, MA). Scanning electron microscopy C 5 (SEM) analysis showed the powders to be spherical end highly porous. The tap density of the powder was determined to be less than 0.1 gcm 3 This foregoing example serves to ilustrate the inherent diversity of the present invention as a drug devery cplatform capable of effectively incorporating any one of a number of pharmaceutical agents. The principle is further Sillustrated in the next example.

O

o xl ClPreparation of Hollow Porous Particles of BDP by Spray-Drying Perforated microstructures comprising bedomethasone dipropionate (BDP) particles were prepared by a spray-drying technique with a B-191 Mini Spray-Drier (Bichi, Flewil, Switzerland) under the following spray conditions: aspiration: 100%, inlet temperature: 85"C; outlet temperature: 61 C; feed pump: 10%; N 2 flow. 2,800 L/hr. The feed stock was prepared by mixing 0.11g of tactose with a fluorocarbon-in-water emulsion immediately prior to spray drying. The emulsion was prepared by the technique described below.

74 mg of BDP (Sigma, Chemical Co., St. Louis, MO), 0.59 of EPC-100-3 ILipoid KG, Ludwigshafen, Germany), 15mg sodium oleate (Sigmea), and 7mg of poloxamer 188 (BASF, Mount Olive, NJ) were dissolved in 2 ml of hot methanol. The methanol was then evaporated to obtain a thin film of the phospholipidisteroid mixture. The phospholipidlsteroid mixture was then dispersed in 64g of hot deionized water IT 50 to using an Ultre-Turrax mixer Imodel T-25) at 8000 rpm for 2 to 5 minutes (T 60-701C). 8 g of perflubron (Atochem, Paris, France) was added dropwise during mixing. After the addition was complete, the emulsion was mixed for an additional period of not less than 4 minutes. The resulting coarse emulsion was then passed through a high pressure homogenizer (Avestin, Ottawa, Canada) at 18,000 psi for 5 passes. This emulsion was then used to form the feed stock which was spray dried as described above. A free flowing, white powder was collected at the cyclone separator. The hollow porous BOP particles had a tap density of less than 0.1 glcm'.

XII

Preparation of Hollow Porous Particles of Cromolyn Sodium by Sprev-Drying Perforated microstructures comprising cromolyn sodium were prepared by a spray-drying technique with a B-191 Mini Spray-Drier (Biichi, Flawil, Switzerland) under the following spray conditions: aspiration: 100%, inlet temperature: 850C; outlet temperature: 61"C; feed pump: 10%; Nz flow: 2,800 LUhr. The feed solution was prepared by mixing two solutions A and B immediately prior to spray drying.

O

0 0 Solution A: 20g of water was used to dissolve Ig of cromolyn sodium (Sigma Chemical Co, St. Louis, MO) and 0.021 g of poloxamer 188 NF grade (BASF, Mount Olive, NJ).

SSolution B: A fluorocarbon-inwater emulsion stabilized by phospholipid was prepared in the following manner. The phospholipid, 1g EPC-100-3 (Lipoid KG, Ludwigshafen, Germany), was homogenized in C] 5 15Dg of hot deionized water (T 50 to 600C) using an Ultra-Turrax mixer (model T-25) at 8000 rpm for 2 to minutes (T 60-70*C). 27g of perfluorodecelin (Air Products, Allentown, PA) was added dropwise during mixing. After the fluorocarbon was added, the emulsion was mixed for at least 4 minutes. The resulting coarse C- emulsion was then passed through a high pressure homogenizer (Avestin, Ottawa, Canada) at 18,000 psi for passes.

Solutions A and B were combined and fed into the spray dryer under the conditions described above.

SA free flowing, pale yellow powder was collected at the cyclone separator. The hollow porous cromolyn sodium particles had a volume-weighted mean aerodynamic diameter of 1.23 1.31 pm as determined by a time-of-flight analytical method (Aerosizer, Amherst Process Instruments, Amherst MA). As shown in Fig. 3, scanning electron microscopy (SEM) analysis showed the powders to be both hollow and porous. The tap density of the powder was determined to be less than 0.1 g/cm 3

XIII

Preparation of Hollow Porous Particles of DNase I by Spray-Drying Hollow porous ONase I particles were prepared by a spray drying technique with a 8-191 Mini Spray-Drier (BUchi, Rawil, Switzerland) under the following conditions: aspiration: 100%, inlet temperature: outlet temperature: 61'C; feed pump: 10%; N 2 flow: 2,800 Lhr. The feed was prepared by mixing two solutions A end B immediately prior to spray drying.

Solution A: 20g of water was used to dissolve 0.5gr of human pancreas ONase I (Calbiochem, San Diego CA) and 0.012g of poloxamer 188 NF grade (BASF, Mount Olive, NJI.

Solution B: A fluorocarbon-in.water emulsion stabilized by phospholipid was prepared in the following way. The phospholipid, D.52g EPC-100-3 (Lipoid KG, Ludwigshafen, Germany), was homogenized in 87g of hot deionized water IT 50 to 600C) using an Ultre-Turrax mixer (model T-25) at 8000 rpm for 2 to minutes (T 60-700CL. 13g of perflubron (Atochem, Paris, France) was added dropwise during mixing. After the fluorocarbon was added, the emulsion was mixed for at least 4 minutes. The resulting coarse emulsion was then passed through a high pressure homogenizer (Avestin, Ottawa, Canada) at 18,000 psi for 5 passes.

A free flowing, pale yellow powder was collected at the cyclone separator. The hollow porous ONase I particles had a volume-weighted mean aerodynamic diameter of 1.29 1.40 prn as determined by a time-offlight analytical method (Aerosizer, Amherst Process Instruments, Amherst, MA). Scanning electron

O

0 0 microscopy (SEM) analysis showed the powders to be both hollow and porous. The tap density of the powder was determined to be less than 0.1 gcm'.

SThe foregoing example further illustrates the extraordnary compatibility of the present invention with a Svariety of bioactive agents. That is, in addition to relatively small hardy compounds such as steroids, the I 5 preparations of the present invention may be formulated to effectively incorporate larger, fragile molecules such as proteins and genetic material.

SPreparation of Perforated Ink Polymeric Particles by Spray Orying, 10 in the following hypothetical example, finely-divided porous spherical resin particles which may contain coloring material such as a pigment, a dye, etc. are formed using the following formulation in Caccordance with the teachings herein: Formulation: Butadiene 7.5 g co-monomer Styrene 2.5 g co-monomer Water 18.0 g carrier Fatty Acid Soap 0.5 g emulsifier n-Dodecyl Mercaptan 0.050 g modifier potassium persulfate 0.030 g initiator carbon Black 0.50 g pigment The reaction is allowed to proceed at 50 0 C for 8 hours. The reaction is then terminated by spray drying the emulsion using a high pressure liquid chromatography (HPLCI pump. The emulsion is pumped through a 200 x 0.030 inch i.d. stainless steel tubing into a Niro atomizer portable spray dryer INiro Atomize, Copenhagen, Denmark) equipped with a two fluid nozzle (0.01" employing the following settings: Hot air flow rate: 39.5 CFM Inlet air temp.: 180 0

C

Outlet air temperature: 800C Atomizer nitrogen flow: 45 LUmin, 1,800 psi Liquid feed rate: 33 mLlmin It will be appreciated that unreacted monomers serve as blowing agents, creating the perforated microstructura. The described formulation and conditions yield free flowing porous polymeric particles ranging from 0.1-100pm that may be used in ink formulations. In accordance with the teachings herein the microparticfes have the advantage of incorporating the pigment directly into the polymeric matrix. The process allows for the production of different particle sizes by modifying the components and the spray drying conditions with the pigment particle diameter largely dictated by the diameter of the copolymer resin particles.

-57-

O

o xv Andersen Impactor Test for Assessing MDI and DPI Performance SThe MDls and DPts were tested using commonly accepted pharmaceutical procedures. The method Sutilized was compliant with the United State Pharmacopeia (USPI procedure (Pharmacopeial Previews (1996) I 5 22:3065-3098) incorporated herein by reference. After 5 shots to waste, 20 shots from the test MDI were made into an Andersen Impactor. The number of shots employed for assessing the DPI formulations was dictated by the drug concentration and ranged from 10 to 20 actuations.

l Extraction procedure. The extraction from all the plates, induction port, and actuator were 0 Sperformed in closed vials with 10 mL of a suitable solvent. The filter was installed but not assayed, because the polyacrylic binder interfered with the analysis. The mass balance and particle size distribution trends Sindicated that the deposition on the filter was negligibly small. Methanol was used for extraction of Sbeclomethasone dipropionate. Deionized water was used for albuterol sulfate, and cromolyn sodium. For albuterol MDIs. 0.5 ml of 1 N sodium hydroxide was added to the plate extract, which was used to convert the albuterol into the phenolate form.

Quantitation procedure. All drugs were quantitated by absorption spectroscopy (Beckman DU640 spectrophotometer) relative to an external standard curve with the extraction solvent as the blank.

Beclomethasone dipropionate was quantitated by measuring the absorption of the plate extracts at 238 nm Albuterol MDIs were quantified by measuring the absorption of the extracts at 243 nm, while cromolyn sodium was quantitated using the absorption peak at 326 nm.

Calculation procedure. For each MDI, the mass of the drug in the stem (component actuator I.

induction port and plates (0-71 were quantified as described above. Stages -3 and -2 were not quantified for the DPI since this device was only a prototype. The main interest was to assess the aerodynamic properties of the powder which leaves this device. The Fine Particle Dose and Fine Particle Fraction was calculated according to the USP method referenced above. Throat deposition was defined as the mass of drug found in the induction port and on plates 0 and 1. The mean mass aerodynamic diameters (MMAD) and geometric standard diameters (GSD) were evaluated by fitting the experimental cumulative function with log-normal distribution by using two-parameter fitting routine. The results of these experiments are presented in subsequent examples.

XVI

Preparation of Metered Dose Inhalers Containing Hollow Porous Particles A pre-weighed amount of the hollow porous particles prepared in Examples I, X, XI, and XII were placed into 10 ml aluminum cans, and dried in a vacuum oven under the flow of nitrogen for 3 4 hours at C. The amount of powder filled into the can was determined by the amount of drug required for therapeutic effect. After this, the can was crimp sealed using a OF31150act 50 1 valve (Valois of America,

O

0 0 Greenwich, CT) and filled with HFA-134a (DuPont, Wilmington, DE) propellant by overpressure through the stem. The amount of the propellant in the can was determined by weighing the can before and after the fill.

CXVII

5 Effect of Powder Porosity on MDI Performance In order to examine the effect powder porosity has upon the suspension stability and aerodynamic diameter, MDIs were prepared as in Example XVI with various preparations of perforated microstructures Ccomprising gentamicin formulations as described in Example I. MDis containing 0.48 wt spray dried Spowders in HFA 134a were studied. As set forth in Example I, the spray dried powders exhibit varying 0 10 porosity. The formulations were filled in dear glass vials to allow for visual examination.

A strong dependence of the suspension stability and mean volume weighted aerodynamic diameter was observed as a function of PFCIPC ratio andlor porosity. The volume weighted mean aerodynamic diameter VMAD) decreased and suspension stability increased with increasing porosity. The powders that appeared solid and smooth by SEM and TEM techniques had the worst suspension stability and largest mean aerodynamic diameter. MOls which were formulated with highly porous and hollow perforated microstructures had the greatest resistance to creaming and the smallest aerodynamic diameters. The measured VMAD values for the dry powders produced in Example I are shown in Table Ill immediately below.

Table iII PFCIPC Powder VMAD, jm 0 6.1 1.1 5.9 2.2 8.4 4.8 3.9 18.8 2.6 44.7 1.8

XVIII

Comparison of Creaminq Rates in Cromolyn Sodium Formulations A comparison of the creaming rates of the commercial Intal formulation (Rhone-Poulenc lorerl and spray-dried hollow porous particles formulated in HFA-134a according to Example XII see Fig. 3) is shown in Figures. 4A to 40. In each of the pictures, taken at 0 seconds, 30 seconds, 6D seconds and two hours after shaking, the commercial formulation is on the left and the perforated microstructure dispersion formed accordance with the present invention is on the right. Whereas the commercial Intal formulation shows creaming within 30 seconds of mixing, almost no creaming is noted in the spray-dried particles after 2 hours.

Moreover, there was little creaming in perforated microstructure formulation after 4 hours (not shown). This

O

0 Sexample clearly illustrates the balance in density which can be achieved when the hollow porous particles are filled with the suspension medium in the formation of a homodispersion).

XIX

Andersen Cascade Imoactor Results for Cromolyn Sodium MDI Formulations The results of cascade impactor tests for a commercially available product lntae, Rhone-Poulenc Rorer) and an analogous spray-dried hollow porous powder in HFA-134a prepared according to Examples XII and XVI are shown below in Table IV. The tests were performed using the protocol set forth in Example XV.

0 Table IV 1 Cromolvn Sodium MDIs 6 ci MMAD Throat Fine particle fraction, Fine Particle Dose, (GSD) Deposition, g Intal',CFC in 4) 4.7 0.5 629 24.3 2.1 202 27 (Rhone Poulenc) 11.9 0.06) 800 pg dose Spray dried hollow porous 3.4 0.2 97 67.3 5.5 200 11 powder, HFA (2.0 0.3) (Alliance) (n-3) 300 pg dose The MDI formulated with perforated microstructures was found to have superior aerosol performance compared with Intel. At a comparable fine particle dose, the spray dried cromofyn formulations possessed a substantially higher fine panicle fraction and significantly decreased throat deposition (6-fold), along with a smaller MMAD value. It is important to note that the effective delivery provided for by the present invention allowed for a fine particle dose that was approximately the same as the prior art commercial formulation even though the amount of perforated microstructures administered 1300 pg) was roughly a third of the Intal' dose administered (800

XX

Comparison of Andersen Cascade Impactor Results for Albuterol Sulfate Microspheres Delivered From DPIs and MDls The in vitro aerodynamic properties of hollow porous albuteral sulfate microspheres as prepared in Example X was characterized using an Andersen Mark II Cascade impactor (Andersen Sampler, Atlanta, GA) and an Amherst Aerosizer (Amherst Instruments, Amherst, MA).

DPI testin. Approximately, 300mcg of spray-dried microspheres was loaded into a proprietary inhalation device. Activation and subsequent plume generation of the dry powder was achieved by the actuation of 50 p/ of pressurized HFA 134a through a long induction tube. The pressurized HFA 134a forced air through the induction tube toward the sample chamber, and subsequently aerosolized a plume of dry 0 powder into the air. The dry powder plume was then taken in the cascade impactor by means of the air flow through drawn through the testing device. A single actuation was discharged into the eerosizer sample C chamber for particle size analysis. Ten actuations were discharged from the device into the impactor. A second interval was used between each actuation. The results were quantitated as described in Example XV.

MDI testing. A MDI preparation of albuterol sulfate microspheres was prepared as in Example XVt.

1' A single actuation was discharged into the aerosizer sample chamber for particle size analysis. Twenty Cactuations were discharged from the device into the impactor. A 30 second interval was used between each Sactuation. Again, the results were quantitated as described in Example XV.

The results comparing the particle size analysis of the neat albuterol sulfate powder and the Salbuterol sulfate powder discharged from either a DPI or MDI are shown in Table V below. The albuterol Ssulfate powder delivered from the DPI was indistinguishable from the neat powder which indicates that little or no aggregation had occurred during actuation. On the other hand, some aggregation was observed using an MDI as evidenced by the larger aerodynamic diameter of particles delivered from the device.

Table V Sample Mean Size (um) under 5.4 pm 95% under (Wm) Neat powder 1.2 100 MDI 2.4 96.0 5.1 DPI 1.1 100 1.8 Similar results were observed when comparing the two dosage forms using an Andersen Cascade Impactor (Figure 51. The spray-dried albuterol sulfate powder delivered from the DPI had enhanced deep lung deposition and minimized throat deposition when compared with the MDI. The MDI formulation had a fine particle fraction IFPF) of 79% and a fine particle dose (FPD) of 77 pglactuation, while the DPI had a FPF of 87% and a FPD of 100,pg actuation.

Figure 5 and the Example above exemplifies the excellent flow and aerodynamic properties of the herein described spray-dried powders delivered from a DPI. Indeed, one of the primary advantages of the present invention is the ability to produce small aerodynamically light particles which aerosolize with ease and which have excellent inhalation properties. These powders have the unique properties which enable them to be effectively and efficiently delivered from either a MDI or DPI. This principle is further illustrated in the next Example.

XXI

Comparson of Andersen Cascade Impactor Results for Beclomethesone Dipropionate Microspheres Delivered From OPIs and MDIs -61-

VO

0 0 The in vitro aerodynamic properties of hollow porous beclomethasone dipropionate (BOP) microspheres as prepared in Example XI was characterized using an Andersen Mark 11 Cascade Impactor S(Andersen Sampler, Atlanta, GA) and an Amherst Aerosizer (Amherst Instruments, Amherst, MA).

CDPI testino. Approximately, 300pg of spray-dried microspheres was loaded into a proprietary inhalation device. Activation and subsequent plume generation of the dry powder was achieved by the actuation of 50 0p of pressurized HFA 134a through a long induction tube. The pressurized HFA 134a forced air through the induction tube toward the sample chamber, and subsequently aerosolized a plume of dry C- powder into the air. The dry powder plume was then taken in the cascade impactor by means of the air flow Sthrough drawn through the testing device. A single actuation was discharged into the aerosizer sample chamber for particle size analysis. Twenty actuations were discharged from the device into the impactor. A second interval was used between each actuation.

SMDI testing. A MDI preparation of beclomethasone dipropionate (BDP) microspheres was prepared as in Example XVI. A single actuation was discharged into the aerosizer sample chamber for particle size analysis. Twenty actuations were discharged from the device into the impactor. A 30 second interval was used between each actuation.

The results comparing the particle size analysis of the neat BDP powder and the 8DP powder discharged from either a DPI or MDI are shown in Table VI immediately below.

Table VI Sample Mean Size (pm) under 5.4 pm 95% under (pm) Neat powder 1.3 100 2.1 MOI 2.2 98.1 4.6 DPI 1.2 99.8 2.2 As with Example XX, the BDP powder delivered from the DPI was indistinguishable from the neat powder which indicates that little or no aggregation had occurred during actuation. On the other hand, some aggregation was observed using an MDI as evidenced by the larger aerodynamic diameter of particles delivered from the device.

The spray-dried BOP powder delivered from the DPI had enhanced deep lung deposition and minimized throat deposition when compared with the MOI. The MDI formulation had a fine particle fraction (FPF) of 79% and a fine particle dose (FPD) of 77 pgJactuation, while the DPI had a FPF of 87% and a FPD of l00ugJ actuation.

This foregoing example serves to illustrate the inherent diversity of the present invention as a drug delivery platform capable of effectively incorporating any one of a number of pharmaceutical agents and effectively delivered from various types of delivery devices (here MDI and DPI) currently used in the

O

0 0 pharmaceutical arena. The excellent flow and aerodynamic properties of the dry powders shown in the proceeding examples is further exemplified in the next example.

XXII

Comparison of Andersen Cascade Impactor Results for Albutarol Sulfate Microspheres and Ventotin Rotecaps' from a Rotahater Device The following procedure was followed to compare the inhalation properties of Ventolin Rotocaps' (a Ccommercially available formulation) vs. albuterol sulfate hollow porous microspheres formed in accordance with the present invention. Both prepartions were discharged from a Rotohaler' device into an B stage Andersen Mark II cascade impactor operated at a flow of 6OULmin. Preparation of the albuterol sulfate microspheres is described in Example X with elbuterol sulfate deposition in the cascade impactor analyzed as Sdescribed in Example XV. Approximately 300 pg of albuterol sulfate microspheres were manually loaded into empty Ventofin Rotocap gelatin capsules. The procedure described in the package insert for loading and actuating drug capsules with a Rolohaler" device was followed. Ten actuations were discharged from the device into the impactor. A 30 second interval was used between each actuation.

The results comparing the cascade impactor analysis of Ventolin Rotocaps' and hollow porous albuterol sulfate microspheres discharged from a Rotoheler' device are shown in Table VI immediately below.

Table VII Sample MMAD Fine Particle Fraction Fine Particle Dose (GSO) (mcgldose) Ventolin Rotacaps'ln-2) 7.869 20 (1.6064) Albuterol Sulfate 4.822 63 Microspheres (n 31 1.9082) The hollow porous albuterol sulfate powder delivered from the Rotohaler" device had a significantly higher fine particle fraction (3-fold) and a smaller MMAD value as compared with Ventolin Rotoceps'. In this regard, the commercially available Ventolin Rotocap' formulation had a fine particle fraction (FPF) of 20% and a fine particle dose (FPD) of 15 pglactuation, whereas the hollow porous albuterel sulfate microspheres had a FPF of 63% and a FPD of 60pgl actuation.

The example above exemplifies the excellent flow and aerodynamic properties of the spray-dried powders delivered from a Rotahaler" device. Moreover, this example demonstrates that fine powders can be effectively delivered without carrier particles.

XXIll Nebulization of Porous Particulate Structures Comprising Phosphaliids and Cromolvn sodium in Perfluoroctvlethane -63-

O

0 0 usino a MicroMist Nebulizer Forty milligrams of the lipid based microspheres containing 50% cromolyn sodium by weight (as from C Example XIII were dispersed in 10 ml perfluorooctylethene (PFOE) by shaking, forming a suspension. The suspension Swas nebulized until the fluorocarbon liquid was delivered or had evaporated using a MicroMist DeVilbiss) disposable nebulizer using a PulmoAide* air compressor (DeVilbiss). As described above in Example XV, an Andersen Cascade Impactor was used to measure the resulting particle size distribution. More specifically, cromolyn sodium content was measured by UV adsorption at 326nm. The fine particle fraction is the ratio of particles deposited in stages 2 Cthrough 7 to those deposited in all stages of the impactor. The fine particle mass is the weight of material deposited Sin stages 2 through 7. The deep lung fraction is the ratio of particles deposited in stages 5 through 7 of the impactor (which correlate to the alveoli) to those deposited in all stages. The deep lung mass is the weight of material Sdeposited in stages 5 through 7. Table VIII immediately below provides a summary of the results.

Table VIII Fine particle fraction fine particle mass deep lung fraction deep lung mass mg 75% 5 mg

XXIV

Nebulization of Porous Particulate Structures Comprisino Phospholipids and Cromolvn Sodium in Perfluorooctvlethane using a Raindropo Nebulizer A quantity of lipid based microspheres containing 50% cromotyn sodium, as from Example XII, weighing mg was dispersed in 10 ml perfluorooctylethane (PFOE) by shaking, thereby forming a suspension. The suspension was nebulized until the fluorocarbon liquid was delivered or had evaporated using a Raindrop" disposable nebulizer (Nellcor Puritan Bennet) connected to a PulmoAide air compressor (DeVilbiss). An Andersen Cascade Impactor was used to measure the resulting particle size distribution in the manner described in Examples XV and XXII1. Table IX immediately below provides a summary of the results.

Table IX Fine particle fraction fine particle mass Deep lung fraction deep lung mass 4 mg 80% 3 m

XXV

Nebulization of Aqueous Cromolvn Sodium Solution The contents of plastic vil containing a unit dose inhalation solution of 20 mg of crmolyn sodium in 2 ml N purified water (Day Laboratories) was nebulized using a MicroMist disposable nebulizer (DeViibissl using a PulmoAide' r air compressor (lVilbissl. The commlyn sodium solution was nebulized for 30 minutes. An Andersen Cascade s impactor was used to measure the resuting size distribution of the nebulized particles, by the method described

CC)

5 above in Example XV. Table X immdiately below provides a summnary of the results.

Table X fine particle fraction fine partidemass Deep lung fraction Deep lung mass 7 mg 60% 5 mg 0 0 With regard to the instant results, it will be appreciated that, the formulations nebuiized from fluorocerbon \suspension mediums in Examples XXIII and XXIV provided a greater percentage of deep lung deposition than the aqueous solution. Such high depositin rates deep in the tung is particularly desirable when delivering agents to the systemic circulation of a patient.

Those skiled in the art will further appreciate that the present invention may be embodied in other specific forms without departing from the spirit or central attributes thereof. In that the foregoing description of the present invention discloses only exemplary embodiments thereof, it is to be understood that other variations are contemplated as being within the scope of the present invention. Accordingly, the present invention is not limited to the particular embodiments which have been described in detail herein. Rather, reference should be made to the appended claims as indicative of the scope and content of the invention.

In the claims which follow and in the preceding description of the invention, except where the context requires otherwise due to express language or necessary implication, the word "comprise" or variations such as "comprises" or "comprising" is used in an inclusive sense, ie. to specify the presence of the stated features but not to preclude the presence or addition of further features in various embodiments of the invention.

Claims

1. An inhaleable powder composition comprising a plurality of particulates, the particulates comprising a structural matrix and a non-phospholipid active agent, the structural matrix comprising phosphoipid and calcium, and the particulates having a mean geometric diameter of 1-30 microns, a mean aerodynamic diameter of less than 5 microns, and a bulk density of less than about 0.5 g/cm 3

2. least one of; A composition according to claim 1 wherein the particulates are porous and have at a mean porosity of 0.5 a porosity of 2 40%; or a mean pore size of 20 200nm.

3. A composition according to claim 1 wherein the powder composition has a fine particle fraction of greater than 20% w/w.

4. A composition according to claim 1 wherein the particulates have a bulk density of less than 0.1 gWcm 1 A composition according to claim 4 wherein the bulk density is less than 0.05 g/cm 3

6. microspheres. A composition according to claim 1 wherein said particulates comprises hollow porous

7. A composition according to claim 8 wherein the microspheres have a shell thickness between 0.1 0.5 pm.

8. A composition according to claim I wherein particulates comprise at least one of: a mean aerodynamic diameter of between 0.5 pm and a mean geometric diameter of less than about 5 pm; or a mass median diameter of less than 10 pm.

9. A composition according to claim 1 wherein the phospholipid comprises selected from the group consisting of dlauroylphosphalidylcholine, dioleoylphosphatidylcholne, dipalmitoylphosphatidylcholine, disteroylphosphatidycholine, dibehenoylphosphatidylcholine, diarachidoylphosphattdytcholine and combinations thereof. A composition according to claim I wherein said phospholipid has a gel to liquid crystal transition temperature of greater than 40° C.

11. phospholipid. A composition according to claim 1 wherein the phospholpld comprises a zwitterionei si\Mranr e\epsplec\Psses-clew.doc 26ze/o/e COMS ID No: ARCS-184305 Received by IP Australia: Time 16:58 Date

2008-03-26 26/03/2008 15:56 GRIFFITH HACK 4 00262837999 NO.671 P016 0 67 0 12. A composition according to claim 1 wherein said active agent is a bioactlve agent. 13. A composition acording to claim 12 wherein the bioactive agent comprises one or \O 5 more of antiallergics, bronchodilators, analgesics, antibiotics, antiinfectives. leukotriene inhibitors or c antagonists, antihistamines, antinflammatorles, antineoplastics, anticholinergics, anesthetics, anti- tuberculars, antivirals, fungicides, immunoactive agents, vaccines, immunosuppressive agents, imaging agents, cardiovascular agents, enzymes, steroids, DNA, RNA, viral vectors, antisense agents, proteins, Speptides and combinations thereof. c O o 10 S14. A composition according to claim 12 wherein the bioactive agent comprises at least one of fentanyl, morphine, leuprolide, interferon, insulin, budesonide, fornrioterol, goserelin, and growth Shormones. 15. A composition according to claim 12 wherein the bioactive agent is an antibiotic. 16. A composition according to claim 12 wherein the bioactive agent is an aminoglycoside antibiotic. 17. A composition according to claim 12 wherein the bioactive agent Is a fungicide. 18. A pulmonary delivery medicament comprising: a plurality of particulates, the particulates having a perforated microstructure comprising a phospholipid structural matrix and a non-phosphollpld active agent, the phospholipid structural matrix comprising greater than about 50% w/w phospholipid. and the particulates having a geometric diameter of from 0.5 to 50 um. 19. A medicament according to claim 18 wherein the phospholipid structural matrix comprises greater than about 70% w/w phospholipid. A medicament according to claim 18 wherein the phospholipid comprises one or more of dipalmitoylphosphatidylcholine, disteroylphosphatidylcholine, diarachidoylphosphatidylcholine dibehenoylphoephatidylcholine, diphosphatidylglycerol. short-chain phosphatidylcholines, long-chain saturated phosphatidylethanolamines, long-chain saturated phosphatidylserines, long-chain saturated phosphaidylglycerols, and long-chain saturated phosphatidylinositols. 21. A medicament according to claim 18 wherein the active agent is water insoluble. 22. A medicament according to claim 21 wherein the water Insoluble active agent comprises a fungicide. 23. A medicament according to claim 18 wherein the active agent is crystalline. H. \flktTP\E spei'fls\P56 48 1 -do- 2/o/03/08 COMS ID No: ARCS-184305 Received by IP Australia: Time 16:58 Date 2008-03-26 26/03/2008 15:56 GRIFFITH HACK 4 00262837999 N0.671 D017 68 24. A pulmonary delivery medicament comprising: a plurality of particulates, the particulates having a perforated microstructure comprising a structural matrix and a water insoluble non-phospholipid active agent, and the particulates having a geometric diameter of 0.5 to 50 pm. A medicament according to claim 24 wherein the water insoluble active agent particle is crystalline. 26. inorganic salt. A medicament according to claim 24 wherein the particulates further comprise an 27. A medicament according to claim 24 wherein the particulates further comprise calcium. 28. A method of delivering a therapeutic dose of an active agent to the pulmonary air passages in a single breath, the method comprising: providing an inhaleable powder composition as claimed in any one of claims 1 to 17; and administering the powder composition to a subjects respiratory tract. 29. A method of delivering a therapeutic dose of a water Insoluble active agent to the pulmonary air passages, the method comprising: providing a pulmonary delivery medicament as claimed in any one of claims 24 to 27; and administering the medicament to a subjects respiratory tract in a single breath. 26/03O08 COMS ID No: ARCS-184305 Received by IP Australia: Time 16:58 Date 2008-03-26