AU2006297394B9

AU2006297394B9 - Receptacles and kits, such as for dry powder packaging

Info

Publication number: AU2006297394B9
Application number: AU2006297394A
Authority: AU
Inventors: Leo Chan; Scot Cheu
Original assignee: Novartis AG
Current assignee: Novartis AG
Priority date: 2005-09-29
Filing date: 2006-09-26
Publication date: 2013-09-19
Anticipated expiration: 2026-09-26
Also published as: AU2006297394A1; US20090032427A1; CA2623256A1; WO2007041090A2; WO2007041090A3; EP1928525A2; AU2006297394B2

Abstract

A receptacle (100) includes a holder (5) forming a cavity (25) that holds a pharmaceutical (110) , a lid (15) , and adhesive (17) that forms a bond (20) between the holder (5) and the lid (15) . As an example, the bond (20) has a shape that includes a protrusion (30) that facilitates removal of the lid (15) from the holder (5) . A kit (60) includes a plurality of containers containing powder including amphotericin B and pharmaceutically acceptable excipient. The kit (60) also includes an aerosolization apparatus (1100) and instructions. As an example, the pharmaceutical composition is made from particles including amphotericin B having a mass median diameter less than about 3 μm, such as from about 1.1 μm to about 1.9 μm.

Description

WO 2007/041090 PCT/US2006/037422 Receptacles and Kits, such as for Dry Powder Packaging BACKGROUND Related Applications [001] The present application claims priority under 35 U.S.C. §119 (e) of U.S. Application SN 60/722,303, filed 29 September 2005, which is incorporated herein by reference in its entirety. Field of the Invention [002] One or more embodiments of the present invention include receptacles and kits, such as for powder packaging, such as pharmaceutical powder packaging. One or more embodiments of the present invention include receptacles and kits for compositions and formulations comprising amphotericin B, to methods of using amphotericin B compositions and formulations, and systems for using amphotericin B compositions and formulations. Background [003] The need for effective therapeutic treatment of patients has resulted in the development of a variety of pharmaceutical composition delivery techniques. One traditional technique involves the oral delivery of a pharmaceutical composition in the form of a pill, capsule, elixir, or the like. However, oral delivery can in some cases be undesirable. For example, many pharmaceutical compositions may be degraded in the digestive tract before they can be effectively absorbed by the body. Inhaleable drug delivery, where an aerosolized pharmaceutical composition is orally or nasally inhaled by a patient to deliver the formulation to the patient's respiratory tract, has proven to be a particularly effective and/or desirable alternative. For example, in one inhalation technique, an aerosolized pharmaceutical composition provides local therapeutic relief to a portion of the respiratory tract, such as the lungs, to treat diseases such as asthma, emphysema, and cystic fibrosis. In another inhalation technique, a pharmaceutical composition is delivered deep within a patient's lungs where it may be absorbed into the blood stream. Many types of inhalation devices exist including devices that aerosolize a dry powder pharmaceutical composition. [004] In one powder aerosolization technique, a receptacle, such as a capsule or a blister pack, containing an inhaleable dry powder is loaded into a chamber in an WO 2007/041090 PCT/US2006/037422 aerosolization apparatus. Within the chamber, the dry powder is at least partially emptied and dispersed to aerosolize the dry powder so that it may be inhaled by a patient. However, in conventional devices, the separate packaging of the apparatus and the receptacle is inconvenient for the user and/or for a pharmacist. [005] In view of the above, an example of a lung condition is pulmonary fungal infection. Pulmonary fungal infections, such as invasive filamentous pulmonary fungal infection (IFPFI), are major causes of morbidity and mortality in immunocompromised patients. The immune system of an individual may be compromised by some diseases, such as acquired immunodeficiency syndrome (AIDS), and/or may be deliberately compromised by immunosuppressive therapy. Immunosuppressive therapy is often administered to patients undergoing cancer treatments and/or patients undergoing a transplant procedure. Immunocompromised patients have an increased susceptibility to pulmonary and/or nasal fungal infections. Severely immunocompromised patients, such as those with prolonged neutropenia or patients requiring 21 or more consecutive days of prednisone at doses of at least 1 mg/kg/day in addition to their other immunosuppressants, are particularly susceptible to pulmonary and/or nasal fungal infection. Among immunocompromised patients, overall fungal infection rates range from 0.5 to 28%. Of the autopsied bone marrow transplant patients with idiopathic pneumonia syndrome (IPS) at the Fred Hutchinson Cancer Center, 7.3% had IFPFI. In another study by Vogeser et al, a 4% rate of IFPFI was found in 1187 consecutive autopsies in European patients dying of any cause during the period from 1993 to 1996. An overwhelming majority of these European patients had received (1) high dose steroid doses; (2) treatment for a malignancy; (3) a solid organ transplant; or (4) some form of bone marrow transplant. [006] The most common pulmonary and/or nasal fungal infection in immunocompromised patients is pulmonary and/or nasal aspergillosis. Aspergillosis is a disease caused by Aspergillus fungal species (Aspergillus spp.), which invade the body primarily through the lungs. The incidence of aspergillosis depends on duration and depth of neutropenia, patient factors (e.g., age, corticosteroid use, and prior pulmonary and/or nasal disease), levels of environmental contamination, criteria for diagnosis, and persistence in determining the cause of the disease. [007] Other filamentous and dimorphic fungi can lead to pulmonary fungal infections as well. These additional fungi are usually endemic and regional and may include, for example, blastomycosis, disseminated candidiasis, coccidioidomycosis, cryptococcosis, 2 WO 2007/041090 PCT/US2006/037422 histoplasmosis, mucormycosis, and sporotrichosis. Though typically not affecting the pulmonary system, infections caused by Candida spp., which are usually systemic and most often result from infections via an indwelling device or IV catheter, wound, or a contaminated solid organ transplant, account for 50 to 67% of total fungal infections in immunocompromised patients. [008] Amphotericin B is the only approved fungicidal compound currently used to treat aspergillosis and is generally delivered intravenously. Amphotericin B is an amphoteric polyene macrolide obtained from a strain of Streptomyces nodosus. In its commercial form, amphotericin B is present in both amorphous and crystalline forms. Amphotericin B formulated with sodium desoxycholate was the first parenteral amphotericin B preparation to be marketed. Systemic intravenous therapies are constrained by dose-dependent toxicities, such as renal toxicity and hepatotoxicity, which hamper the effectiveness of the treatment and lessen the desirability of prophylactic use of amphotericin B. Even with the approved therapy, aspergillosis incidence is rising and estimated to cause mortality in more than 50% of those infected who receive treatment. [009] Other conditions and/or diseases may benefit from treatment according to one or more embodiments of the compositions and/or methods and/or systems of the present invention. In some embodiments, the conditions and/or diseases are those which primarily or initially affect the pulmonary system. For example patients with asthma, COPD and other sensitive lung conditions may be treated thereby. In other embodiments, the conditions and/or diseases are systemic, and pulmonary administration provides a safe and effective mode of administration. For example patients with AIDS (particularly late stage with neutropnia), genetic diseases and conditions, aplastic anemia, bone marrow transplants, organ transplants and leukemias, may be treated thereby. Thus the present invention provides for the prevention of fungal infections in patients at risk for aspergillosis due to immunosuppressive therapy including those receiving organ or stem cell transplants, or treated with chemotherapy or radiation for hematologic malignancies [010] There remains a need in the art for improved receptacles, such as receptacles that are easy to open. There also remains a need in the art for kits for powder packaging, such as kits comprising safe and effective amphotericin B powders. There further remains a need in the art for safe and effective amphotericin B compositions, methods of using such compositions, and systems for using such compositions. 3 WO 2007/041090 PCT/US2006/037422 SUMMARY OF THE INVENTION [011] Accordingly, one or more embodiments of the present invention satisfies one or more of these needs. One or more embodiments of the present invention include improved receptacles and kits, such as for powder packaging. Other features and advantages of embodiments of the present invention will be set forth in the description of invention that follows, and in part will be apparent from the description or may be learned by practice of the invention. Embodiments of the invention will be realized and attained by the compositions and methods particularly pointed out in the written description and claims hereof. [012] In one aspect, one or more embodiments are directed to a receptacle. The receptacle includes a holder forming a cavity that holds a pharmaceutical, a lid, and adhesive. The adhesive forms a bond between the holder and the lid. The bond has a shape that includes a protrusion that facilitates removal of the lid from the holder. [013] In another aspect, one or more embodiments are directed to a receptacle. The receptacle includes a holder forming a cavity, a lid, and adhesive. The forms a bond between the holder and the lid. The bond has a shape that includes a protrusion comprising an arc and substantially straight lines. [014] In still another aspect, one or more embodiments are directed to a kit. The kit includes a plurality of containers containing powder comprising amphotericin B and pharmaceutically acceptable excipient. The kit also includes an aerosolization apparatus and instructions. The pharmaceutical composition is made from particles comprising amphotericin B having a Mass Median Diameter (MMD) of less than about 3 pm. In some embodiments the MMD ranges from about 1.1 pm to about 1.9 gm. [015] In still another aspect, one or more embodiments are directed to a kit. The kit includes a plurality of containers containing powder comprising an antifungal and optionally, a pharmaceutically acceptable excipient. The kit also includes an aerosolization apparatus and instructions. [016] In yet another aspect, one or more embodiments are directed to a kit including a plurality of receptacles each containing at least one capsule containing powder comprising amphotericin B and pharmaceutically acceptable excipient. The kit also includes an aerosolization apparatus. The pharmaceutical composition is made from particles comprising amphotericin B having a mass median diameter of less than about 3 pm. In some embodiments the MMD is between about 1.1 gm and about 1.9 gm. 4 [017] In another aspect, one or more embodiments are directed to a kit including a plurality of containers containing powder comprising amphotericin B and pharmaceutically acceptable excipient. The kit also includes an aerosolization apparatus and instructions. The powder is made from particles comprising amphotericin B, wherein at least about 50 wt%, or 60 wt.%, or 70 wt.% or 80 wt.%, of the particles comprising amphotericin B have a geometric diameter, or a MAD, or both, of between about 1.1 pm and about 1.9 pm. [018] In yet another aspect, one or more embodiments are directed to a kit including a plurality of receptacles each containing a capsule containing powder comprising amphotericin B and pharmaceutically acceptable excipient The kit also includes an aerosolization apparatus. The powder is made from particles comprising amphotericin B, wherein at least about 50 wt%, or 60 wt.%, or 70 wt.% or 90 wt.%, of the particles comprising amphotericin B have a geometric diameter ranging from about 1.1 pm to about 1.9 p.Lm. [019] In still another aspect, one or more embodiments are directed to a kit including a plurality of containers containing powder comprising amphotericin B and pharmaceutically acceptable excipient. The kit also includes an aerosolization apparatus and instructions. The powder is made from particles comprising amphotericin B) wherein the amphotericin B has a crystallinity level of at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, such as at least about 80%, at least about 90%, at least about 95%, or at least about 99%. [020] In another aspect, any two or more of the foregoing aspects, features, versions or embodiments are combined. 5 [020a] Various aspects and embodiments are described herein. In particular aspects and embodiments, the present invention provides the following items (1) to (21): 1. A receptacle, comprising: a holder forming a cavity that holds an aerosolizable pharmaceutical; 5 a lid comprising a substantially flat surface, wherein the substantially flat surface includes a portion extending across the cavity; and an adhesive that forms a bond between the holder and the lid, wherein the adhesive does not extend to the end of the holder to form an unbonded portion, wherein the bond has a shape relative to the unbonded portion, and wherein the shape 10 comprises an arcuate protrusion extending away from the cavity, wherein the unbonded portion extends from the protrusion to an end of the holder and facilitates removal of the lid from the holder. 2. The receptacle of item 1, wherein the length of the unbonded portion from the protrusion to the end of the holder is at least about 5 mm. 15 3. The receptacle of item 1, wherein the unbonded portion extends from one side edge of the holder to the opposite side edge of the holder. 4. The receptacle of item 1, wherein the holder includes a substantially flat surface, and said adhesive forms a bond between said substantially flat surfaces of the holder and the lid, and wherein the substantially flat surface of the lid comprises the 20 unbonded portion that facilitates removal of the lid from the holder. 5. The receptacle of item 1, wherein the lid comprises a raised portion. 6. The receptacle of item 1, wherein the holder comprises a laminate comprising thermoplastic. 7. The receptacle of item 1, wherein the lid comprises one or more of the 25 group consisting of a metal foil, a paper, and a laminate comprising thermoplastic. 5a 461254_1 (GHMalter) P77206AIJ 8. The receptacle of item 1, wherein the receptacle contains a capsule containing the aerosolizable pharmaceutical. 9. The receptacle of item 8, wherein the aerosolizable pharmaceutical comprises amphotericin B. 5 10. The receptacle of item 8, wherein the aerosolizable pharmaceutical comprises a hormone. 11. The receptacle of item 10, wherein the hormone comprises one or more of the group consisting of a parathyroid hormone, a fragment of a parathyroid hormone, a derivative of a parathyroid hormone, and an analog of a parathyroid hormone. 10 12. The receptacle of item 8, wherein the acrosolizable pharmaceutical comprises an anti-infective. 13. The receptacle of item 12, wherein the anti-infective is an antibiotic. 14. The receptacle of item 13, wherein the antibiotic comprises one or more of the group consisting of amikacin, gentamicin, vancomycin, tobramycin, and 15 ciprofloxacin. 15. The receptacle of item 13, wherein the antibiotic is tobramycin. 16. An array, comprising a plurality of the receptacles of item 1, wherein the plurality of receptacles are attached to each other. 17. The array of item 16, wherein the array comprises a one-dimensional 20 array. 18. The array of item 16, wherein the array comprises a two-dimensional array. 19. The array of item 16, wherein adjacent receptacles are separated by perforations. 5b 461294_1 (GI9a3eM2) PT7205AU 20. The array of item 16, wherein adjacent receptacles are separated by at least one score cut. 21. The array of item 16, further comprising a backing on which the receptacles are mounted, wherein the backing is separable from the receptacles. 5 The invention as claimed herein is defined by items (1) to (21) above. DRAWINGS [021] Various embodiments of the present invention are further described in the description of invention that follows, in reference to the noted plurality of non-limiting 10 drawings, wherein: [022] Fig. 1 shows a cross-section of a receptacle containing a capsule in accordance with one or more embodiments of the present invention. [023] Fig. 2 shows a top view of the receptacle of Fig. 1 with the lid removed. [024] Fig. 3 shows a cross-section of one or more embodiments of a receptacle of 15 the present invention, with a lid having a raised portion. 5c 461294 1 (OHNIOeCI) PT720AU WO 2007/041090 PCT/US2006/037422 [025] Fig. 4 shows a cross-section of a receptacle of one or more embodiments of the present invention, with a lid having a portion overlapping a holder. [026] Fig. 5 shows a back view of a one-dimensional array of one or more embodiments of receptacles of the present invention. [027] Fig. 6 shows a back view of a two-dimensional array of receptacles of one or more embodiments of the present invention. [028] Fig. 7 is a schematic sectional side view of a version of a package comprising a multi-layered package. [029] Fig. 8 is a schematic sectional side view of another version of a package comprising a multi-layered package. [030] Figs. 9A through 9C illustrate a process of sealing the multi-layered package of Fig. 7 or 8. [031] Figs. 1 OA and 1 OB are schematic sectional side views of a sealing apparatus at different stages of a sealing process. [032] Figs. 11 A through 11 C are schematic sectional side views of versions of packages comprising a bottle. [033] Figs. 12A through 12C are schematic sectional side views of versions of packages comprising evacuatable bottles. [034] Figs. 13A and 13B are schematic sectional side views of versions of packages that eject one or more capsules. [035] Figs. 14A and 14B are schematic perspective views of versions of packages comprising a housing with compartments. [036] Figs. 15A through 15C are schematic perspective views of rotary versions of packages comprising a housing with compartments. [037] Fig. 16 is a schematic sectional side view of a capsule with a metal containing wall. [038] Figs. 17A through 17C are schematic sectional side views of capsules having metal containing layers. [039] Fig. 18 is a schematic sectional side view of a capsule having multiple layers. [040] Fig. 19 is a schematic sectional side view of a sealing apparatus for sealing the capsule of Fig. 18. [041] Fig. 20A is a schematic sectional side view of a version of an aerosolization apparatus in an initial position. 6 WO 2007/041090 PCT/US2006/037422 [042] Fig. 20B is a schematic sectional side view of the version of an aerosolization apparatus shown in Fig. 20A at the beginning of an aerosolization process. [043] Fig. 20C is a schematic sectional side view of the version of an aerosolization apparatus shown in Fig. 20A during an aerosolization process. [044] Fig. 21 A is a schematic sectional side view of a version of an aerosolization apparatus in a rest position. [045] Fig. 21B is a schematic sectional side view of the version of an aerosolization apparatus shown in Fig. 21 A just before capsule puncture. [046] Fig. 21 C is a schematic sectional side view of the version of an aerosolization apparatus shown in Fig. 21A as the capsule is being punctured. [047] Fig. 21 D is a schematic sectional side view of the version of an aerosolization apparatus shown in Fig. 21A just after capsule puncture. [048] Fig. 21 E is a schematic sectional side view of the version of an aerosolization apparatus shown in Fig. 21A in use. [049] Fig. 22 is a schematic top view of a version of a kit according to one or more embodiments of the invention. [050] Fig. 23 is a schematic perspective view of another version of a kit according to one or more embodiments of the invention. [051] Fig. 24 is a schematic perspective view of still another version of a kit according to one or more embodiments of the invention. [052] Fig 25 shows predicted amphotericin B concentration in the lungs after administering a pharmaceutical composition according to one or more embodiments of the present invention. [053] Fig. 26 shows predicted amphotericin B plasma concentration after administering a pharmaceutical composition according to one or more embodiments of the present invention. DESCRIPTION [054] It is to be understood that unless otherwise indicated the present invention is not limited to specific formulation components, drug delivery systems, manufacturing techniques, administration steps, or the like, as such may vary. In this regard, unless otherwise stated, a reference to a compound or component includes the compound or component by itself, as well 7 WO 2007/041090 PCT/US2006/037422 as the compound in combination with other compounds or components, such as mixtures of compounds. [055] Before further discussion, a definition of the following terms will aid in the understanding of embodiments of the present invention. [056] As used herein, the singular forms "a," "an," and "the" include the plural reference unless the context clearly dictates otherwise. Thus, for example, reference to "a phospholipid" includes a single phospholipid as well as two or more phospholipids in combination or admixture unless the context clearly dictates otherwise. Reference herein to "one embodiment", "one version" or "one aspect" shall include one or more such embodiments, versions or aspects, unless otherwise clear from the context. [057] As used herein, "particulates" refer to particles comprising amphotericin B and at least one pharmaceutically acceptable excipient. The particulates can assume various shapes and forms, such as hollow and/or porous microstructures. The hollow and/or porous microstructures may exhibit, define, or comprise voids, pores, defects, hollows, spaces, interstitial spaces, apertures, perforations, or holes, and may be spherical, collapsed, deformed, or fractured particles, [058] When referring to an active agent, the term encompasses not only the specified molecular entity, but also its pharmaceutically acceptable, pharmacologically active analogs, including, but not limited to, salts, esters, amides, hydrazides, N-alkyl derivatives, N-acyl derivatives, prodrugs, conjugates, active metabolites, and other such derivatives, analogs, and related compounds. Therefore, as used herein, the term "amphotericin B" refers to amphotericin B per se or derivatives, analogs, or related compounds noted above, as long as such amphotericin B derivatives, analogs, or related compounds exhibit antifungal activity. [059] Antifungal means any agent, compound, composition or formulation which has efficacy against infections comprising systemic or topical infections, caused or precipitated by a fungus, yeast, mold, spores or the like. [060] A pharmaceutical composition means any compound or composition which induces a desired pharmacologic and/or physiologic effect, when administered appropriately to the target organism (human or animal). [061] As used herein, the terms "treating" and "treatment" refer to reduction in severity and/or frequency of symptoms, elimination of symptoms and/or underlying cause, reduction in likelihood of the occurrence of symptoms and/or underlying cause, and improvement or remediation of damage. Thus, "treating" a patient with an active agent as 8 WO 2007/041090 PCT/US2006/037422 ATOMey .Uocket No. U'/9TU provided herein includes prevention of a particular condition, disease or disorder in a susceptible individual as well as treatment of a clinically symptomatic individual. [062] As used herein, "effective amount" refers to an amount covering both therapeutically effective amounts and prophylactically effective amounts. [063] As used herein, "therapeutically effective amount" refers to an amount that is effective to achieve the desired therapeutic result. A therapeutically effective amount of a given active agent will typically vary with respect to factors such as the type and severity of the disorder or disease being treated and the age, gender, and weight of the patient. [064] As used herein, "prophylactically effective amount" refers to an amount that is effective to achieve the desired prophylactic result. Because a prophylactic dose is administered in patients prior to onset of disease, the prophylactically effective amount typically is less than the therapeutically effective amount. [065] As used herein, "mass median diameter" or "MMD" refers to the median diameter of a plurality of particles, typically in a polydisperse particle population, i.e., consisting of a range of particle sizes. MMD values as reported herein are determined by laser diffraction (Sympatec Helos, Clausthal-Zellerfeld, Germany), unless the context indicates otherwise. Typically, powder samples are added directly to the feeder funnel of the Sympatec RODOS dry powder dispersion unit. This can be achieved manually or by agitating mechanically from the end of a VIBRI vibratory feeder element. Samples are dispersed to primary particles via application of pressurized air (2 to 3 bar), with vacuum depression (suction) maximized for a given dispersion pressure. Dispersed particles are probed with a 632.8 nrm laser beam that intersects the dispersed particles' trajectory at right angles. Laser light scattered from the ensemble of particles is imaged onto a concentric array of photomultiplier detector elements using a reverse-Fourier lens assembly. Scattered light is acquired in time-slices of 5 ms. Particle size distributions are back-calculated from the scattered light spatial/intensity distribution. [066] As used herein, "geometric diameter" refers to the diameter of a single particle, as determined by microscopy, unless the context indicates otherwise. [067] As used herein, "mass median aerodynamic diameter" or "MMAD" refers to the median aerodynamic size of a plurality of particles or particulates, typically in a polydisperse population. The "aerodynamic diameter" is the diameter of a unit density sphere having the same settling velocity, generally in air, as a powder and is therefore a useful way to characterize an aerosolized powder or other dispersed particle or particulate 9 WO 2007/041090 PCT/US2006/037422 formulation in terms of its settling behavior. The aerodynamic diameter encompasses particle or particulate shape, density, and physical size of the particle or particulate. As used herein, MMAD refers to the median of the aerodynamic particle or particulate size distribution of an aerosolized powder determined by cascade impaction, unless the context indicates otherwise. [068] As used herein, "crystallinity level" refers to the percentage of amphotericin B in crystalline form relative to the total amount of amphotericin B. Unless the context indicates to the contrary, crystallinity levels in this document are measured by wide angle X ray powder diffraction. X-ray diffraction powder patterns were measured with a Shimadzu X-ray diffractometer model XRD-6000, with a dwell time of 2 seconds (fixed time scan), step size of 0.02'20, a scanning range of 3-42'20, 0.5' divergence slit, 10 scattering slit, and 0.3 mm receiving slit, as described in more detail in Example 1 of U.S. Application No. 11/158,332, which is incorporated herein by reference in its entirety. [069] As used herein, "amorphicity" refers to the percentage of amphotericin B in amorphous form relative to the total amount of amphotericin B. Unless the context indicates to the contrary, amorphicity levels in this document are measured by wide angle X-ray powder diffraction. [070] As used herein, the term "emitted dose" or "ED" refers to an indication of the delivery of dry powder from an inhaler device after an actuation or dispersion event from a powder unit or reservoir. ED is defined as the ratio of the dose delivered by an inhaler device to the nominal dose (i.e., the mass of powder per unit dose placed into a suitable inhaler device prior to firing). The ED is an experimentally determined amount and may be determined using an in vitro device set up which mimics patient dosing. To determine an ED value, as used herein, a nominal dose of dry powder (as defined above) is placed into a Dry Powder Inhaler (DPI), such as a Turbospin® DPI device (PH&T, Italy), described in U.S. Patent Nos. 4,069,819 and 4,995,385, which are incorporated herein by reference in their entireties. The DPI is actuated, dispersing the powder. The resulting aerosol cloud is then drawn from the device by vacuum (30 L/min) for 2.5 seconds after actuation, where it is captured on a tared glass fiber filter (Gelman, 47 mm diameter) attached to the device mouthpiece. The amount of powder that reaches the filter constitutes the delivered dose. For example, for a capsule containing 5 mg of dry powder that is placed into an inhalation device, if dispersion of the powder results in the recovery of 4 mg of powder on a tared filter 10 WO 2007/041090 PCT/US2006/037422 as described above, then the ED for the dry powder composition is 80% (= 4 mg (delivered dose)/5 mg (nominal dose)). [071] As used herein, "passive dry powder inhaler" refers to an inhalation device that relies upon a patient's inspiratory effort to disperse and aerosolize a pharmaceutical composition contained within the device in a reservoir or in a unit dose form and does not include inhaler devices which comprise a means for providing energy, such as pressurized gas and vibrating or rotating elements, to disperse and aerosolize the drug composition. [072] As used herein, "active dry powder inhaler" refers to an inhalation device that does not rely solely on a patient's inspiratory effort to disperse and aerosolize a pharmaceutical composition contained within the device in a reservoir or in a unit dose form and includes inhaler devices that comprise a means for providing energy to disperse and aerosolize the drug composition, such as pressurized gas and vibrating or rotating elements. [073] As an overview, one or more embodiments are directed to a receptacle. The receptacle includes a holder forming a cavity that holds a composition or material to be dispensed, such as a pharmaceutical or pharmaceutical composition. The receptacle further includes a lid, and adhesive or sealing means. The adhesive or sealing means forms a bond between the holder and the lid. The bond has a shape that includes a protrusion that facilitates removal of the lid from the holder. [074] In one or more embodiments, a receptacle includes a holder forming a cavity, a lid, and adhesive. The adhesive or sealing means forms a bond between the holder and the lid. The bond has a shape that includes a protrusion comprising an arc and substantially straight lines. [075] In one or more embodiments, a kit includes a plurality of containers containing powder comprising amphotericin B and pharmaceutically acceptable excipient. The kit also includes an aerosolization apparatus and instructions. The pharmaceutical composition is made from particles comprising amphotericin B having a mass median diameter less than about 3 pm. In one or more embodiments, pharmaceutical composition is made from particles comprising amphotericin B having a MMD ranging from about 1.1 gm to about 1.9 pim, and/or a geometric diameter of from about 1.2 Im to about 1.8 pLm. In one or more embodiments, the pharmaceutical composition is made from particles comprising amphotericin B having a mass median aerodynamic diameter of less than about 10 pim. [076] In one or more embodiments, a kit includes a plurality of receptacles each containing at least one capsule containing powder comprising amphotericin B and 11 WO 2007/041090 PCT/US2006/037422 pharmaceutically acceptable excipient. The kit also includes an aerosolization apparatus. The pharmaceutical composition is made from particles comprising amphotericin B having a mass median diameter ranging from about 1.1 tm to about 1.9 pm. [077] In one or more embodiments, a kit includes a plurality of containers containing powder comprising an antifungal, such as amphotericin B and optionally, a pharmaceutically acceptable excipient. The kit also includes an aerosolization apparatus and instructions. In one or more embodiments, the powder is made from particles comprising amphotericin B, wherein at least about 60 wt.% or 70 wt.% or 80 wt% of the particles comprising amphotericin B have a mass median diameter ranging from about 1.1 pm to about 1.9 pm, [078] In one or more embodiments, a kit includes a plurality of receptacles each containing a capsule containing powder comprising amphotericin B and pharmaceutically acceptable excipient. The kit also includes an aerosolization apparatus. The powder is made from particles comprising amphotericin B, wherein at least about 80 wt% of the particles comprising amphotericin B have a geometric diameter ranging from about 1.1 pm to about 1.9 pm. [079] In one or more embodiments, a kit includes a plurality of containers containing powder comprising amphotericin B and pharmaceutically acceptable excipient. The kit also includes an aerosolization apparatus and instructions. The powder is made from particles comprising amphotericin B, wherein the amphotericin B has a crystallinity level of at least about 20%. [080] In view of the above, pharmaceutical compositions may be contained in a container. Examples of containers include, but are not limited to, capsules, blisters, vials, ampoules, or container closure systems made of metal, polymer (e.g., plastic, elastomer), glass, or the like. [081] As shown in Fig. 1, a receptacle 100 includes a holder 5 forming a cavity 25 that holds a pharmaceutical composition 110, a lid 15, and adhesive or sealing means 17. The adhesive or sealing means 17 forms a releasable bond between the holder 5 and the lid 15. In one or more embodiments, the releasable bond is congruent with the shape or pattern of the adhesive or sealing means 17. [082] In this example, the receptacle 100 contains a first container, such as a capsule 105, that is capable of being at least partially filled with a composition 110. In one or more embodiments, the composition 110 is a a pharmaceutical composition. The capsule 105 12 WO 2007/041090 PCT/US2006/037422 contains the composition 110 and provides the composition 110 with at least some protection against environmental conditions, such as moisture. The receptacle 100 comprises a moisture barrier 115 that is adapted to provide further protection against undesirable amounts of moisture coming in contact with the composition 110. [083] Some compositions, especially some pharmaceutical compositions, are particularly sensitive to moisture. For example, some dry powder pharmaceutical compositions that are to be aerosolized and inhaled by a user may become agglomerated when in the presence of excessive moisture. The agglomerations may affect the aerosol characteristics of the pharmaceutical composition and reduce the therapeutic effects of the pharmaceutical composition delivery. Accordingly, the receptacle 100 may be adapted to provide sufficient moisture protection over a predetermined amount of time for a particular pharmaceutical composition. For example, the moisture barrier 115 or the combination of the moisture barrier 115 with the capsule 105 may provide moisture protection for at least about 2 days, such as at least about 1 week, at least about 3 weeks, at least 1 year. [084] The moisture barrier 115 may be sufficiently thick and impermeable to decrease the amount of moisture that is able to pass through the barrier 115. In one version, the moisture barrier 115 comprises a material that is resistant to moisture passage in order to reduce the thickness of the barrier 115. For example, the moisture barrier 115 may comprise one or more metals, such as aluminum or the like, and/or other moisture barrier materials, such as polyamides, polyvinyl chlorides and the like. [085] Additionally or alternatively, the receptacle 100 may be packaged with, or placed in close proximity to, a moisture scavenging agent or absorber (not shown) such as a dessicant. [086] Fig. 2, which is a top view of the holder 5 without the lid 15, shows that the bond 20 forms a shape that includes a protrusion 30 that facilitates removal of the lid 15 from the holder 5. The bond may form one or more protrusions 30, and the protrusion(s) 30 may be substantially any shape. For example, the protrusion may comprise an are 32, a substantially straight line 34, or both an arc 32 and a substantially straight line 34. Other examples of shapes for the protrusion include, but are not limited to, one or more triangle, rectangle, irregular, and combinations of the above. In one or more embodiments, the protrusion 30 is dimensioned and configured to permit manual removal of the lid 15, such as user removal. 13 WO 2007/041090 PCT/US2006/037422 [087] In view of the protrusion 30, an unbonded portion 36 facilitates removal of the lid 15 from the holder 5. For example, the adhesive may form a bond between a substantially flat surface of the holder and a substantially flat surface of the lid. The substantially flat surface of the lid comprises an unbonded portion that facilitates removal of the lid from the holder. The unbonded portion typically has a shortest length, L, of at least about 5 mm, such as at least about 10 mm, or at least about 15 mm. [088] In the example of Fig. 2, the adhesive 17 consists of a pattern corresponding to the shape of the bond. Alternatively, the adhesive covers an entire surface of the holder and/or lid, such that only a portion of the adhesive forms the bond. For example, the bond may be formed by heating, pressing, or applying wave energy to the adhesive in a pattern corresponding to the shape of the bond. [089] In view of the above, the receptacle 100 may be made by bonding a holder 5 comprising adhesive 17 to a lid 15. Alternatively, the receptacle 100 may be made by bonding a lid 15 comprising adhesive 17 to a holder 5. As another alternative, the holder 5 and the lid 15 both comprise adhesive 17. [090] The adhesive or sealing means 17 may be any which provide the desired sealing and release characteristics for the receptacle type and material, as well as considering the composition characteristics and release force. Examples of the adhesives include, chemical bonding compositions, such as but are not limited to, polymer and lacquer adhesives. Other sealing means, such as thermal bonding physical and mechanical bonding may be used. [091] As shown in Fig. 3, the lid 15 may include a raised portion 40 to facilitate removal of the lid 15. Conversely, the holder 5 may comprise a lowered portion (not shown). The length of the raised portion and/or lowered portion is typically at least about 2 mm, such as at least about 4 mm, at least about 6 mm, at least about 8 mm, or at least about 10 mm. In one or more embodiments, the raised portion 40 is dimensioned and configured to permit manual removal of the lid 15, such as user removal. [092] As shown in Fig. 4, the lid 15 overlaps the holder 5 to facilitate removal of the lid 15. Conversely, the holder 5 may overlap the lid 15 (not shown). An amount of the overlap may be sufficient to facilitate removal, such as at least about 2 mm, such as at least about 4 mm, at least about 6 mm, or at least about 8 mm. [093] The holder 5 may comprise a laminate comprising thermoplastic. The holder 5 may comprise metal foil. 14 WO 2007/041090 PCT/US2006/037422 [094] Materials for making lids 15 are known in the art. For example, the lid may comprise a laminate comprising thermoplastic, a metal foil, paper, and combinations thereof. [095] In one or more embodiments, the present invention comprises an array of a plurality of the receptacles that are attached to each other. The array may comprise a one dimensional array 50, as shown in Fig. 5, or a two-dimensional array 50, as shown in Fig. 6. In the array, the receptacles may be detachable, i.e. capable of being separated from each other. For instance, adjacent receptacles may be separated by perforations 52, and/or scoring and/or at least one kiss cut. [096] The array may comprise a backing 54 on which the receptacles are mounted. The mounting may be accomplished, e.g., by adhesive. The receptacles may be peeled from the backing. Examples of the backing materials include, but are not limited to, paperboards, thermoplastics, and laminates. [097] In one version, the receptacle 100 comprises a multi-layered package 400. In one particular version, the multi-layered package 400 surrounds a capsule 105 containing a pharmaceutical composition 110 that is susceptible to degradation and/or reduced aerosol performance when exposed to excessive amounts of moisture, such as a powder aerosolizable pharmaceutical composition. The multi-layered package 400 may comprise one or more materials that provide improved moisture barrier properties. For example, the multi-layered package 400 may comprise one or more metals, such as aluminum or the like, and/or other moisture barrier materials. The moisture barrier may be provided below and above the pharmaceutical composition to provide additional moisture protection. [098] For example, as shown in the version of Fig. 7, the multi-layered package 400 may comprise a holder or lower layer 405 comprising a metal containing layer 410 and a lid or an upper layer 415 comprising a metal containing layer 420. The metal containing layers 410, 420 may be sufficiently thick to substantially prevent a significant amount of moisture from passing therethrough. For example, the metal containing layers 410, 420 may be from about 10 pm to about 100 pm, such as about 20 pim to about 80 pm. The lower layer 405 and the upper layer 415 are sealed together by a layer of adhesive or sealing material 417, such as a layer of lacquer that may have a thickness ranging from about 1 jpm to about 20 im. Within a cavity 425 is a capsule 105 containing a pharmaceutical composition, such as a pharmaceutical composition in powder form that may be aerosolized. [099] The lower layer 405 and/or the upper layer 415 of the multi-layered package 400 may optionally include additional materials that serve to improve the sealing or 15 WO 2007/041090 PCT/US2006/037422 moldability of the layers. For example, Fig. 8 shows a particular version of a multi-layered package 400 useful in providing a moisture barrier package for a pharmaceutical composition. In this version, the lower layer 405 comprises a first layer 430 comprising polymeric material, such as polyvinyl chloride, and having a thickness of about 60 im, a second layer 435 comprising a polyamide, such as nylon, and having a thickness of about 25 jim, a third layer 440 comprising a metal, such as aluminum, and having a thickness of about 60 pm, and a fourth layer 445 comprising a polymeric material, such as polyvinyl chloride, and having a thickness of about 60 pm. The upper layer 415 comprises a first layer 450 comprising a metal, such as aluminum, and having a thickness of about 25 ptm, and a second layer 455 comprising a sealing material, such as lacquer, and having a thickness of about 6 ptm. The multi-layered package 400 comprising a lower layer 405 comprising a metal containing layer 410 and an upper layer 415 comprising a metal containing layer 420 also has the added benefit of protecting the mechanical integrity of the capsule 105. The metal containing layers provide sufficient rigidity to prevent damage from occurring to the capsule 105 during storage or transport of the capsule 105. As a result, when the capsule 105 is inserted into an aerosolization device, the chances of consistent aerosolization of the pharmaceutical composition are increased. [0100] Figs. 9A through 9C illustrate a method of sealing the capsule 105 within a multi-layered package 400. A sealing apparatus 460 comprises a first platform 465 which has a surface 470 which supports a multi-layered package that is to be sealed. The sealing apparatus 460 seals a plurality of layers to one another with the capsule 105 contained between the layers. As shown in Fig. 9B, the lower layer 405 of a multi-layered package is placed on the platform surface 470. The cavity 425 of in the lower layer 405 is positioned within a recess 475 in the surface 470 while a rim portion 480 rests on the surface 470. The cavity 425 may be formed on the platform 465 and/or the capsule 105 (not shown in Fig. 9B) may be inserted into the cavity 425 while the lower layer 405 is positioned on the surface 470. Alternatively, a lower layer 405 with a preformed cavity 425 prefilled with the capsule 105 may be positioned onto the surface 470. An upper layer 415 is then, or previously, positioned over the lower layer 405, as shown in Fig. 9C. When the layers are positioned on the first platform 465, a second platform 485 is lowered toward the first platform 465. The second platform may be heated so that it heats the upper layer 415. The heating and/or compression of the layers 405,415 seals the layers to one another and secures the capsule 105 containing the pharmaceutical composition within the sealed multi-layered package 400. 16 WO 2007/041090 PCT/US2006/037422 [0101] The sealing process is further illustrated in Figs. 1OA and 1OB, which show cross-sectional views before and after the lowering of the second platform 485, respectively. In Fig. 1 OA, the lower layer 405 is positioned on the platform surface 470 with the cavity 425, which is filled with a capsule 105 containing the pharmaceutical composition, positioned within the recess 475. Alternatively to the configuration shown, the recess 475 may be shaped to more closely resemble the contour of the cavity 425. The upper layer 415 is positioned over the lower layer 405. Between the upper layer 415 the lower layer 405 is a sealing material 417 that may cause a seal to be formed between the upper layer 415 and the lower layer 405 when heated and/or compressed. To seal the layers, the second platform 485 is heated and lowered onto the first platform 465 as discussed above and as shown in Fig. 1OB. [0102] The adhesive or sealing material 417 is positioned between the upper layer 415 and the lower layer 405 and comprises a material that can seal the upper layer 415 to the lower layer 405 when heat and/or compression is applied to the sandwiched layers. For example, in one version, the sealing material comprises a layer of heat activated sealer, such as lacquer, or polymethyl methacrylate (PMMA), or the like. The heat activated sealer may be provided on the lower surface of the upper layer 415. When heated to a sufficient temperature, such as at least about 160*C, and often at least about 180'C, the heat activated sealer changes state so that when cooled, the upper layer 415 is sealed to the lower layer 405. Alternatively, the heat activated sealer may be provided on an upper surface of the lower layer 405 or may be a separate sheet positioned between the upper layer 415 and the lower layer 405. In another version, the heat activated sealer may be the material of the upper layer 415 and/or the lower layer 405. In this version, sufficient heat may be applied to melt the material between the layers so that the layers may be fused to one another upon cooling. Alternatively, the sealing material may comprise a bonding material that does not require heat to activate. [0103] In one version, the moisture barrier 115 may comprise a bottle 125 that holds a single dose of an aerosolizable pharmaceutical composition. For example, in the version shown in Fig. 11 A, one or more capsules 105 containing an aerosolizable pharmaceutical composition are inserted into the body 130 of the bottle 125 and a cap 135 is inserted thereonto. In one version, the bottle 135 is at least partially evacuated or at least a portion of the moisture is otherwise removed as the one or more capsules 105 are inserted. The dose of single dose of the aerosolizable pharmaceutical composition may be made up of a particular number of capsules selected to deliver a predetermined amount of the pharmaceutical 17 WO 2007/041090 PCT/US2006/037422 composition in aerosolized form to a user. For example, as shown in Fig. 11 A, the single dose may consist of three capsules 105. Alternatively, the single dose may consist of one, two, or any number of capsules 105. The cap 135 may be secured to the body 130 by threads, snap fit, friction fit, or any suitable manner. Preferably, the manner of attachment provides sufficient protection against the passage of moisture. [0104] To provide even further moisture protection, the moisture barrier 115 may comprise the bottle 125 and an additional layer of protection. For example, in the version shown in Fig. 11 B, the moisture barrier 115 comprises a metal-containing layer 140 that surrounds the bottle 125. In one version, the metal containing layer 140 comprises a foil of aluminum that is heat shrunk around the bottle. The foil may be, for example, from about 10 pLm to about 100 gm, such as about 20 gm to about 80 pm. The foil may also be provided with a manner of allowing the foil to be removed, such as tabbing, scoring, or the like. [0105] In another version, as shown in Fig. 11 C, the cap 135 may be removed and the metal-containing layer 140 may serve as the covering to secure the one or more capsules 105 within the body 130 of the bottle 125. [0106] In still another version, the moisture barrier 115 may comprise a bottle 150 that contains multiple doses of an aerosolizable pharmaceutical composition. Unlike the versions of FIGS. 12A through 12C, a bottle 150 containing multiple doses of a pharmaceutical composition may be opened and closed one or more times, and with each opening the capsules 105 within the bottle 150 are subjected to environmental conditions, including potentially undesirable amounts of moisture. Accordingly, in one version, the moisture barrier comprises a bottle 150 that is capable of reducing the effects of the environmental exposure. [0107] For example, in the version of Fig. 12A, the bottle 150 comprises a body 155 capable of containing multiple doses of capsules containing an aerosolizable pharmaceutical composition and a cap 160 that is attachable to the body 155 in a suitable manner to secure the capsules 105 within the body 155. The bottle 150 also comprises an evacuation mechanism 165. In the version of Fig. 12A, the evacuation mechanism 165 comprises a one way valve 170 on the body 155 that allows passage of air from within the body 155 to pass out of the body 155 but prevents the passage of air into the body 155. The evacuation mechanism 165 also comprises a bellows member 175 that has a one-way valve 180 that allows air to pass out of the bellows 175 but not into the bellows 175. After withdrawing a dose of pharmaceutical composition, the user secures the cap 160 on the body and then 18 WO 2007/041090 PCT/US2006/037422 compresses the bellows 175. Air within the bellows 175 is forced out through the one-way valve 180 on the bellows 175. The user then expands the bellows 175 or the bellows 175 is designed to automatically expand by the nature of its configuration. As a result of the expansion, air from the body 155 is pulled through the one-way valve 170 thereby at least partially evacuating the body 155 and removing some potentially undesirable moisture. [0108] Fig. 12B illustrates another version of an evacuation mechanism 165. In this version, the evacuation mechanism 165 comprises a squeezable bladder 185 that is normally biased into an expanded condition. Squeezing the bladder 185 forces air out the one-way valve 180 and the recovery of the bladder pulls air from the body 155 through the one way valve 170 to at least partially evacuate the body 155. As shown in the version of Fig. 12B, the evacuation mechanism 165 may be provided on the cap 160 to allow for use of a conventional body 155. [0109] Another version of an evacuation mechanism 165 is shown in Fig. 12C. In this version, the evacuation mechanism 165 comprises a bi-stable dome 190. By pressing on the dome 190, the dome takes on the shape shown by the dotted lines and forces air though the one-way valve 170. Afterwards, the dome 190 is returned to the position shown by the solid lines by a bias thereby at least partially evacuating the body 155 and at least partially reducing the amount of moisture within the body 155. [0110] In the versions of Figs. 12A through 12C, the moisture protection may be further improved by providing a metal-containing layer around, within, or on the interior of the body 155 and/or the cap 160. [0111] In another version, the moisture barrier 115 may comprise a container 200 that stores capsules 105 containing an aerosolizable pharmaceutical composition in a reduced moisture environment and ejects a predetermined number of the capsules 105 while maintaining the reduced moisture environment. For example, as shown in Fig. 13A, a series of capsules 105 may be stored within an evacuated interior 205 of a cartridge 210. The cartridge 210 has an end that is covered by a flexible membrane 215 that has a slit 220 near its center. When the flexible membrane 215 is in the position shown in Fig. 13A, the slit 220 is closed and air is not allowed to pass through the slit 220. A capsule 105 is ejected from the cartridge 210 by an ejection mechanism 225. [0112] In the version of Fig. 13, the ejection mechanism 225 comprises a plate 230 that is forced into contact with the series of capsules 105 by a compressed spring 235. A series of notches 240 are provided within the cartridge 210 to prevent or inhibit movement of 19 WO 2007/041090 PCT/US2006/037422 the plate 230. When the plate 230 is disengaged from a notch 240 the spring 235 forces the plate 230 toward the flexible membrane 215. As a result, the plate 230 presses on the series of capsules 105 and the topmost capsule is pressed against the flexible membrane 215 and pressed through the slit 220. The slit 220 slides around the capsule 105 being ejected and maintains contact with the capsule 105. In this way, the air is prevented from entering the interior 205 and the interior 205 maintains its reduced moisture condition. After ejection, the plate 230 nestles within the next notch 240. In the version shown, the plate 230 includes an extension portion 245 that sealingly extends through a slot 250. The extension portion 245 allows the user to advance the plate 230 from one notch 240 to the next, for example by pulling on the extension. Though the notches 140 are shown as being spaced so as to allow a single capsule 105 to be ejected, they may alternatively be spaced so that multiple capsules 105 maybe ejected. [0113] Another version of an ejection mechanism 225 is shown in Fig. 13B. In this version, interior threads 255 are provided on the interior 205 of the cartridge 210. The interior threads 255 engage exterior threads 260 on a pushing member 265. Accordingly, as the pushing member 265 is rotated relative to the cartridge 210, the pushing member 265 advanced within the interior 205. Continued rotation will advance the pushing member 265 a sufficient amount to eject the topmost capsule 105 through the slit 215. [0114] In another version, the moisture barrier 115 comprises a housing 280 having a plurality of compartments 285 that each contains a single dose or a portion of a single dose of an aerosolizable pharmaceutical composition in a capsule 105, as shown in Figs. 14A and 14B. The compartments 285 may be at least partially evacuated or moisture may be otherwise removed prior to or during insertion of one or more capsules 105 thereinto. The compartments 285 have an opening for accessing the compartment 285, and a cover member 290 covers the openings. In the version of Figure of Fig. 14A, the cover member 290 comprises a slidable plate 295 that may be slid to provide access to a compartment 285. The slidable plate 295 may ride in grooves or the like (not shown) in the housing 280. Around each opening on the top of the housing 280 is a seal 299, such as an O-ring type seal that engages the slidable plate 295 when the slidable plate 295 is positioned over a compartment 285 to prevent excessive moisture from penetrating into the compartment 285. [0115] Another version of a cover member 290 is shown in Fig. 14B. In this version, the cover member 290 comprises metal containing layer 300, such as a foil comprising aluminum, that sealingly covers the compartments 285. 20 WO 2007/041090 PCT/US2006/037422 [0116] In one version, a spool 305 is provided so that the rotation of the spool 305 causes the metal-containing layer 300 to be removed from a compartment 285. Figs. 15A, 15B, and 15C show rotary versions of a moisture barrier 115 comprises a housing 280 having a plurality of compartments 285 that each contain a single dose or a portion of a single dose of an aerosolizable pharmaceutical composition in a capsule 105. In the version of Fig. 15A, the cover member 290 comprises a round or circular disc 310 having an opening 315. The disc 310 includes a bore 320 that may be received on a shaft 325 of the housing 280 so that the disc 310 may rotate relative to the housing 280 to align the opening 315 with a compartment 285. The seal 299 about the compartment 285 prevents moisture from reaching the compartments 285 before the opening 315 is in alignment. A ratchet or other locking mechanism may be provided to control the relative rotation between the disc 310 and the housing 280. [0117] In the version of Fig. 15B, the compartments 285 are provided on the edge of a circular housing 280, and the cover member 290 comprises a cylinder 330 having an opening 335 that may be aligned with the compartments 285. A post 340 receives a bore 345 in the housing 280 to provide the rotation between the housing 280 and the cover member 290, which may be controlled as discussed above. In the version of Fig. 15C, the compartments 285 are covered by the metal-containing layer 300, and a spool 305 is optionally provided to take up the metal-containing layer 300. The housing 280 and/or the spool 305 may be rotatable by having bores 355, 365 that may be received on respective posts 350, 360. In one version, a handle may be provided for rotating the spool 305 which in turn causes the body 280 to rotate. [0118] The capsules may be of a suitable shape, size, and material to contain the pharmaceutical composition and to provide the pharmaceutical composition in a usable condition. For example, the capsules may comprise a wall which comprises a material that does not adversely react with the pharmaceutical composition. In addition, the wall may comprise a material that allows the capsule to be opened to allow the pharmaceutical composition to be aerosolized. In one version, the wall comprises one or more of gelatin, cellulosic polymer such as hydroxypropyl methylcellulose (HPMC), hydroxyl methylcellulose (HMC) polyethyleneglycol-compounded HPMC, hydroxyproplycellulose, agar, aluminum foil, or the like. Alternatively or additionally, the capsule wall may comprise a polymeric material, such as polyvinyl chloride (PVC) or polyvinyl acetate (PVA). In one version, the capsule may comprise telescopically adjoining sections, as described for example 21 WO 2007/041090 PCT/US2006/037422 in U.S. Patent No. 4,247,066 which is incorporated herein by reference in its entirety. The size of the capsule may be selected to adequately contain the dose of the pharmaceutical composition. The sizes generally range from size 5 to size 000 with the outer diameters ranging from about 4.91 mm to 9.97 mm, the heights ranging from about 11.10 mm to about 26.14 mm, and the volumes ranging from about 0.13 mL to about 1.37 mL, respectively. Exemplary standard capsule sizes, and their corresponding volumes are shown in Table A below: Table A Capsule Size 00 0 0 1 2 3 4 5 Volume (ml) 1.37 0.95 0.68 0.50 0.37 0.30 0.21 0.13 [0119] Suitable capsules are available commercially from, for example, Shionogi Qualicaps Co. in Nara, Japan and Capsugel in Greenwood, South Carolina. After filling, a top portion may be placed over the bottom portion to form a capsule shape and to contain the powder within the capsule, as described in U.S. Patent Nos. 4,846,876 and 6,357,490, and in WO 00/07572, which are incorporated herein by reference in their entireties. After the top portion is placed over the bottom portion, the capsule can optionally be banded. [0120] In one version, as shown in Fig. 16, the capsule 105 may have a moisture barrier 115 comprising a wall 120 that comprises a metal, such as aluminum. In the version shown, an opening 500 is provided in the wall 120 to allow for the dispersion of the pharmaceutical composition 110 during use. A metal-containing layer 505, such as a foil comprising aluminum, covers the opening 500. The metal-containing layer 505 may be heat sealed to the wall 120 and may optionally be provided with a tab by which the cover may be removed by a user prior to use. Alternatively or additionally, moisture barrier 115 may be provided by a metal-containing layer 505 that is applied around, within, or on the interior of the wall 120 of a capsule 105. [0121] For example, Fig. 17A shows of a version where a metal-containing layer 510 is applied around a capsule that has been filled with a pharmaceutical composition 110. The metal-containing layer 510, such as a foil comprising aluminum, may be heat shrunk onto the capsule 105 or may be otherwise applied. Tabs may be included to allow the foil to be removed from the capsule 105. Alternatively, the capsule 105 with the foil overwrapping may be inserted into an aerosolization device and the pharmaceutical composition 110 may be accessed by the capsule opening mechanism utilized by the aerosolization device. In other 22 WO 2007/041090 PCT/US2006/037422 versions, a metal containing layer 510 may be provided on the interior of the capsule wall 120, as shown in Fig. 17B, or may be within the capsule wall 120, as shown in Fig. 17C. [0122] FIG. 18 shows a multi-layered capsule 105. In this version, the multi-layered capsule 105 may be filled with a pharmaceutical composition 110. For example, the multi layered capsule 105 may be placed in an aerosolization device and used by a user. The materials of the upper layer 415 and the lower layer 405 may be as discussed above. For example, the layers may comprise a metal or other moisture barrier material in order to provide sufficient moisture protection for the pharmaceutical composition within the multi layered capsule 105. [0123] Fig. 19 shows a sealing process for making the multi-layered capsule 105. In this version, the recess 475 in the first platform 465 is sized to accommodate the semi-capsule shaped cavity 555 formed in the lower layer 405. In addition, a recess 565 is provided in the second platform 485 to accommodate a semi-capsule shaped cavity 560 formed in the upper layer 415. The platforms 465, 485 compress to heat seal the upper layer 485 to the lower layer 465, as discussed above, along the rim portions 480. After sealing, the rim portion 480 may be trimmed to create a smoother profile. [0124] In one or more versions, the packaging is adapted to contain a powder pharmaceutical composition. The capsule 105 may contain the pharmaceutical composition in a form where it may be aerosolized for inhalation by the user. For example, when in a powdered form, the powder may be initially stored in the capsule 105, as described in U.S. Patent Nos. 4,995,385; 3,991,761; and 6,230,707, and WO 97/27892, which are all incorporated herein by reference in their entireties, the capsule being openable before, during, or after insertion of the capsule into an aerosolization device. [0125] Aerosolization apparatuses are known in the art. Powder may be aerosolized by an active element, such as compressed air, as described in U.S. Patent Nos. 5,458,135; 5,785,049; and 6,257,233, or propellant, as described in U.S. Application No. 09/556,262 and WO 00/72904. Alternatively the powder may be aerosolized in response to a user's inhalation, as described for example in U.S. Application No. 09/583,312 and U.S. Patent No. 4,995,385. All of the above references being incorporated herein by reference in their entireties. [0126] In one or more embodiments, the receptacle is effective when used to store a capsule that is to be used in an aerosolization device that includes a puncturing element, such as the device described in U.S. Patent No. 4,995,385, which is incorporated herein by 23 WO 2007/041090 PCT/US2006/037422 reference in its entirety, and similar devices. For example, the improved moisture protection provided by the receptacle may allow for better deagglomeration during the aerosolization process, which results in more finely divided particles for inhalation by the user. In addition, the improved moisture protection may prevent the capsule material from becoming brittle. This brittle prevention allows the puncturing element to more efficiently and consistently create one or more openings into the capsule during use. Without the moisture protection, the capsule may become brittle and may shatter, create capsule particles, and/or have less reproducible openings when punctured. Accordingly, the moisture barrier afforded by the receptacle typically provides numerous aerosolization benefits. [0127] The aerosolization apparatus may comprise a housing defining a chamber having one or more air inlets and one or more air outlets, the chamber being sized to contain at least one of the plurality of capsules. The aerosolization apparatus may further comprises a puncturing mechanism moveable within the housing to create one or more openings in at least one of the plurality of capsules when placed in the chamber. Still further, the aerosolization apparatus may further comprise a mouth or nose piece in communication with the one or more air outlets. [0128] In one or more embodiments, an aerosolization apparatus 1100 is capable of aerosolizing the pharmaceutical composition contained in the capsule 105. An example of an aerosolization apparatus 1100 is shown schematically in Fig. 20A. The aerosolization apparatus 1100 comprises a housing 1105 defining a chamber 1110 having one or more air inlets 1115 and one or more air outlets 1120. The chamber 1110 is sized to receive a capsule 105 which contains an aerosolizable pharmaceutical composition. A puncturing mechanism 1130 comprises a puncture member 1135 that is moveable within the chamber 1110. Near or adjacent the outlet 1120 is an end section 140 that may be sized and shaped to be received in a user's mouth or nose so that the user may inhale through an opening 1145 in the end section 1140 that is in communication with the outlet 1120. [0129] The aerosolization apparatus 1100 utilizes air flowing through the chamber 1110 to aerosolize the pharmaceutical composition in the capsule 105. For example, Figs. 20A through 20E illustrate the operation of a version of an aerosolization apparatus 1100 where air flowing through the inlet 1115 is used to aerosolize the pharmaceutical composition and the aerosolized pharmaceutical composition flows through the outlet 1120 so that it may be delivered to the user through the opening 1145 in the end section 1140. The aerosolization 24 WO 2007/041090 PCT/US2006/037422 apparatus 1100 is shown in its out-of-the-package or initial condition in Fig. 20A. A capsule 105 is removed from the receptacle 100 and is positioned within the chamber 1110. [0130] To use the aerosolization apparatus 1100, the pharmaceutical composition in the capsule 105 is exposed to allow it to be aerosolized. In the version of Figs. 20A though 20E, the puncture mechanism 1130 is advanced within the chamber 1110 by applying a force 1150 to the puncture mechanism 1130. For example, a user may press against a surface 1155 of the puncturing mechanism 1130 to cause the puncturing mechanism 1130 to slide within the housing 1105 so that the puncture member 1135 contacts the capsule 105 in the chamber 1110, as shown in Fig. 20B. By continuing to apply the force 1150, the puncture member 1135 is advanced into and through the wall of the capsule 105, as shown in Fig. 20C. The puncture member may comprise one or more sharpened tips 1152 to facilitate the advancement through the wall of the capsule 105. The puncturing mechanism 1130 is then retracted to the position shown in Fig. 20D, leaving an opening 1160 through the wall of the capsule 105 to expose the pharmaceutical composition in the capsule 105. [0131] Air or other gas then flows through an inlet 1115, as shown by arrows 1165 in Fig. 20E. The flow of air causes the pharmaceutical composition to be aerosolized. When the user inhales 1170 through the end section 1140 the aerosolized pharmaceutical composition is delivered to the user's respiratory tract. In one version, the air flow 1165 may be caused by the user's inhalation 1170. In another version, compressed air or other gas may be ejected into the inlet 1115 to cause the aerosolizing air flow 1165. [0132] Another version of an aerosolization apparatus 1100 is shown in Figs. 21A through 21 E. In this version, the housing 1105 of the aerosolization apparatus 1100 comprises a body 1205 and a removable endpiece 1210. The endpiece 1210 may be removed from the body 1205 to insert a capsule 105 in the chamber 1110, which is formed when the body 1205 and the endpiece 1210 are connected together. The endpiece 1210 comprises a partition 1215 that blocks the forward end of the chamber 1110, and the partition 1215 has the one or more outlets 1120 extending therethrough. An example of an aerosolization apparatus with a partition 1215 and chamber 1110 are described in U.S. Patent Nos. 4,069,819 and 4,995,385, both of which are incorporated herein by reference in their entireties. In such an arrangement, the chamber 1110 comprises a longitudinal axis that lies generally in the inhalation direction, and the capsule 105 is insertable lengthwise into the chamber 1110 so that the receptacle's longitudinal axis may be parallel to the longitudinal axis of the chamber 1110. In the version of Figs. 21A through 21E, the chamber 1110 is sized 25 WO 2007/041090 PCT/US2006/037422 to receive a capsule 105 containing a pharmaceutical composition in a manner which allows the receptacle to move within the chamber 1110. The inlets 1115 comprise a plurality of tangentially oriented slots 1220. When a user inhales 1170 through the endpiece 2110, outside air is caused to flow through the tangential slots 1220 as shown by arrows 1225 in Fig. 21 E. This airflow 1225 creates a swirling airflow within the chamber 1110. The swirling airflow causes the capsule 105 to contact the partition 1215 and then to move within the chamber 1110 in a manner that causes the pharmaceutical composition to exit the capsule 105 and become entrained within the swirling airflow. In one version, the capsule 105 may rotate within the chamber 1110 in a manner where the longitudinal axis of the receptacle is remains at an angle less than 80 degrees, such as less than 45 degrees from the longitudinal axis of the chamber. The movement of the capsule 105 in the chamber 1110 may be caused by the width of the chamber 1110 being less than the length of the capsule 105. In one specific version, the chamber 1110 comprises a tapered section 1230 that terminates at an edge 1235. During the flow of swirling air in the chamber 1110, the forward end of the capsule 105 contacts and rests on the partition 1215 and a sidewall of the capsule 105 contacts the edge 1235 and slides and/or rotates along the edge 1235. This motion of the receptacle is particularly effective in forcing a large amount of the pharmaceutical composition through one or more openings 1160 in the rear of the capsule 105. [0133] The one or more openings 1160 in the rear of the capsule 105 in the version of Figs. 21A through 21E are created by a puncturing mechanism 1130 that is slidable within the body 1205. The puncturing mechanism 1130, shown in its rest position in Figs. 21A, comprises a plunger 1240 attached at its forward end 1245 to the puncture member 1135, which in the version shown is a U-shaped staple 1250 having two sharpened tips 1152. The puncturing mechanism 1130 further comprises a seating member 1255 which contacts the plunger 1240 and/or the puncture member 1135 and is slidable relative to the plunger 1240 and the puncture member 1135. To create the openings 1160 in the capsule 105, the user applies a force 1150 to the plunger 1240, as shown in Fig. 21B, such as by pressing against the end surface 1155 of the plunger 1240 with the user's finger or thumb. The force 1150 causes the plunger to slide within the body 1205. A slight frictional contact between the plunger 1240 the a rear section 1260 of the seating member 1255 causes the seating member 1255 to also slide within the body 1205 until a forward seating surface 1265 of the seating member 1255 contacts the capsule 105, as shown in Fig. 21B. The forward seating surface 1265, which may be shaped to generally match the shape of the capsule 105, secures the 26 WO 2007/041090 PCT/US2006/037422 capsule 105 between the seating member 1255 and the partition 1215. The continued application of force 1150 causes the plunger 1240 and the puncture member 1135 to slide relative to the seating member 1255, as shown in Fig. 21C, to advance the puncture member 1135 through openings 1270 in the forward seating surface 1265 and into the capsule 105. Upon the removal of the force 1150, a spring 1275 or other biasing member urges the puncturing mechanism 1130 back to its rest position. For example, the spring 1275 may contact a shoulder 1280 in the body 1205 and press a flange 1285 on the plunger 1240 toward a rim 1290 in the body 1205. The frictional engagement between the plunger 1240 and the seating member 1255 also returns the seating member 1255 to its retracted position when the plunger is returned to its retracted position. [0134] In other versions the aerosolization apparatus 1100 may be configured differently than as shown in Figs. 20A through 20E and 21A through 21E. For example, the chamber 1100 may be sized and shaped to receive the capsule 105 so that the capsule 105 is orthogonal to the inhalation direction, as described in U.S. Patent No. 3,991,761. As also described in U.S. Patent No. 3,991,761, the puncturing mechanism 1130 may puncture both ends of the capsule 105. In another version, the chamber may receive the capsule 105 in a manner where air flows through the capsule 105 as described for example in U.S. Patent Nos. 4,338,931 and 5,619,985. In another version, the aerosolization of the pharmaceutical composition may be accomplished by pressurized gas flowing through the inlets, as described for example in U.S. Patent Nos. 5,458,135; 5,785,049; and 6,257,233, or propellant, as described in WO 00/72904 and U.S. Patent No. 4,114,615. All of the above references being incorporated herein by reference in their entireties. [0135] In one or more embodiments, a kit includes a plurality of containers, such as receptacles containing at least one capsule. The containers may contain powder comprising amphotericin B and pharmaceutically acceptable excipient. Powders comprising amphotericin B are discussed in more detail below. The kit may also include an aerosolization apparatus and instructions. [0136] In one or more versions, the kit contains sufficient supplies for a predetermined dosage regimen. For example, the kit may contain a single dose of pharmaceutical composition. For some medicaments, an aerosolization apparatus must be operated two or more times, each time with a new container, in order to administer a desired dose. Accordingly, in one version, the kit comprises an aerosolization apparatus 1100 and the number of containers necessary for administering the desired dose. The number of containers 27 WO 2007/041090 PCT/US2006/037422 depends on the size of the containers and the amount of pharmaceutical composition filled into the containers. A pharmacist may prepare the kit for or administer the kit to a user in accordance with a physician's prescription. When the user needs to intake the medicament, the user need only open the kit and operate the aerosolization apparatus for each of the containers in the kit. The empty kit, the aerosolization apparatus, and the used containers may then all be disposed of [0137] A kit 60 according to the present invention is shown schematically in Fig. 22. The kit 60 comprises a first compartment 65 and a second compartment 70. The first and second compartments are optionally separated by a wall or barrier 75. The first compartment is sized and shaped to securely receive and store an aerosolization apparatus 1100. The second compartment is sized and shaped to securely store one or more capsules 105, which contain a pharmaceutical composition. The capsules 105 may be contained in receptacles comprising a moisture barrier that is adapted to provide protection against undesirable amounts of moisture coming in contact with the pharmaceutical composition in the capsules 105. [0138] Thus, the kit 60 may contain an aerosolization apparatus 1100 and a plurality of capsules 105. For example, the aerosolization apparatus 1100 may have a certain usage life and the number of capsules 105 may be an amount equal to the amount that would be used during the usage life. A version of such a kit 60 is shown in Fig. 23. In this exemplary version, the aerosolization apparatus 1100 has a usage life of 30 days. The capsules 105 are provided so that two capsules 105 per day may be used for the 30 days. [0139] A moisture barrier 80 may be sufficiently thick to decrease the amount of moisture that is able to pass through the barrier 80. In one version, the moisture barrier 80 comprises a material that is resistant to moisture passage in order to reduce the thickness of the barrier 80. For example, the moisture barrier 80 may comprise one or more metals, such as aluminum or the like, and/or other moisture barrier materials, such as polyamides, polyvinyl chlorides and the like. [0140] In one or more versions, the packaging of the capsules may be in calendar format. As shown in FIG. 24, a plurality of the kits 60 may be packaged together to provide, for example, a 90 day supply of the medicament. In FIG 24, each colored block represents a periodic subset package, for example a 30 day dose. [0141] The kit 60 may be sufficient to cover an entire length of a therapy for a user. For example, the kit 60 may be designed to cover a 30 day, or other period, or a one-time 28 WO 2007/041090 PCT/US2006/037422 therapy. In one version, the kit 60 may be prescribed to a patient undergoing anti-fungal therapy, such as amphotericin B therapy. A typical dosing regimen for amphotericin B therapy involves an initial dosing period of 90-100 days. The treatment is intended during the patient's neutropenic stage first in the hospital and then as an outpatient. The therapy may further be extended in some patients for an additional dosing period of 90 days either in or out of the hospital. [0142] The kit 60 of the present invention is advantageous in that it provides convenience to both the pharmacist and the user. The user does not need to make separate visits to the pharmacist for an aerosolization apparatus and for the pharmaceutical composition. In addition, the user knows when to dispose of the device and is not tempted to over-use the aerosolization apparatus 1100. [0143] In one or more versions, the first compartment 65 may store a portion of an aerosolization apparatus, rather than the entire aerosolization apparatus. For example, the first compartment 65 may store a transjector, such as a transjector assembly described in U.S. Patent No. 5,740,794 which is incorporated herein by reference in its entirety. [0144] As noted above, the kit may include instructions. The instructions may include instructions for carrying out the methods of the invention, e.g., prophylactic treatment of aspergillosis. The methods of the invention are discussed in more detail below. [0145] The kit may further comprise a carrying case. For instance, the carrying case may contain the plurality of containers or receptacles containing capsules, the aerosolization apparatus, and the instructions. [0146] The active agent described herein includes an agent, drug, compound, composition of matter or mixture thereof which provides some pharmacologic, often beneficial, effect. This includes foods, food supplements, nutrients, drugs, vaccines, vitamins, and other beneficial agents. As used herein, the terms further include any physiologically or pharmacologically active substance that produces a localized or systemic effect in a patient. An active agent for incorporation in the pharmaceutical composition described herein may be an inorganic or an organic compound, including, without limitation, drugs which act on: the peripheral nerves, adrenergic receptors, cholinergic receptors, the skeletal muscles, the cardiovascular system, smooth muscles, the blood circulatory system, synoptic sites, neuroeffector junctional sites, endocrine and hormone systems, the immunological system, the reproductive system, the skeletal system, autacoid systems, the alimentary and excretory systems, the histamine system, and the central nervous system. Suitable active agents may be 29 WO 2007/041090 PCT/US2006/037422 selected from, for example, hypnotics and sedatives, psychic energizers, tranquilizers, respiratory drugs, anticonvulsants, muscle relaxants, antiparkinson agents (dopamine antagnonists), analgesics, anti-inflammatories, antianxiety drugs (anxiolytics), appetite suppressants, antimigraine agents, muscle contractants, anti-infectives (antibiotics, antivirals, antifungals, vaccines) antiarthritics, antimalarials, antiemetics, anepileptics, bronchodilators, cytokines, growth factors, anti-cancer agents, antithrombotic agents, antihypertensives, cardiovascular drugs, antiarrhythmics, antioxicants, anti-asthma agents, hormonal agents including contraceptives, sympathomimetics, diuretics, lipid regulating agents, antiandrogenic agents, antiparasitics, anticoagulants, neoplastics, antineoplastics, hypoglycemics, nutritional agents and supplements, growth supplements, antienteritis agents, vaccines, antibodies, diagnostic agents, and contrasting agents. The active agent, when administered by inhalation, may act locally or systemically. [0147] The active agent may fall into one of a number of structural classes, including but not limited to small molecules, peptides, polypeptides, proteins, polysaccharides, steroids, proteins capable of eliciting physiological effects, nucleotides, oligonucleotides, polynucleotides, fats, electrolytes, and the like. [0148] Examples of active agents suitable for use in this invention include but are not limited to one or more of calcitonin, erythropoietin (EPO), Factor VIII, Factor IX, ceredase, cerezyme, cyclosporin, granulocyte colony stimulating factor (GCSF), thrombopoietin (TPO), alpha-i proteinase inhibitor, elcatonin, granulocyte macrophage colony stimulating factor (GMCSF), growth hormone, human growth hormone (HGH), growth hormone releasing hormone (GHRH), heparin, low molecular weight heparin (LMWH), interferon alpha, interferon beta, interferon gamma, interleukin- 1 receptor, interleukin-2, interleukin- 1 receptor antagonist, interleukin-3, interleukin-4, interleukin-6, luteinizing hormone releasing hormone (LHRH), factor IX, insulin, pro-insulin, insulin analogues (e.g., mono-acylated insulin as described in U.S. Pat. No. 5,922,675, which is incorporated herein by reference in its entirety), amylin, C-peptide, somatostatin, somatostatin analogs including octreotide, vasopressin, follicle stimulating hormone (FSH), insulin-like growth factor (IGF), insulintropin, macrophage colony stimulating factor (M-CSF), nerve growth factor (NGF), tissue growth factors, keratinocyte growth factor (KGF), glial growth factor (GGF), tumor necrosis factor (TNF), endothelial growth factors, parathyroid hormone (PTH), glucagon-like peptide thymosin alpha 1, Ilb/Illa inhibitor, alpha-i antitrypsin, phosphodiesterase (PDE) compounds, VLA-4 inhibitors, bisphosponates, respiratory syncytial virus antibody, cystic 30 WO 2007/041090 PCT/US2006/037422 fibrosis transmembrane regulator (CFTR) gene, deoxyreibonuclease (Dnase), bactericidal/permeability increasing protein (BPI), anti-CMV antibody, 13-cis retinoic acid, macrolides such as erythromycin, oleandomycin, troleandomycin, roxithromycin, clarithromycin, davercin, azithromycin, flurithromycin, dirithromycin, josamycin, spiromycin, midecamycin, leucomycin, miocamycin, rokitamycin, andazithromycin, and swinolide A; fluoroquinolones such as ciprofloxacin, ofloxacin, levofloxacin, trovafloxacin, alatrofloxacin, moxifloxicin, norfloxacin, enoxacin, grepafloxacin, gatifloxacin, lomefloxacin, sparfloxacin, temafloxacin, pefloxacin, amifloxacin, fieroxacin, tosufloxacin, prulifloxacin, irloxacin, pazufloxacin, clinafloxacin, and sitafloxacin, aminoglycosides such as gentamicin, netilmicin, paramecin, tobramycin, amikacin, kanamycin, neomycin, and streptomycin, vancomycin, teicoplanin, rampolanin, mideplanin, colistin, daptomycin, gramicidin, colistimethate, polymixins such as polymixin B, capreomycin, bacitracin, penems; penicillins including peniclinase-sensitive agents like penicillin G, penicillin V, penicillinase-resistant agents like methicillin, oxacillin, cloxacillin, dicloxacillin, floxacillin, nafcillin; gram negative microorganism active agents like ampicillin, amoxicillin, and hetacillin, cillin, and galampicillin; antipseudomonal penicillins like carbenicillin, ticarcillin, azlocillin, mezlocillin, and piperacillin; cephalosporins like cefpodoxime, cefprozil, ceftbuten, ceftizoxime, ceftriaxone, cephalothin, cephapirin, cephalexin, cephradrine, cefoxitin, cefamandole, cefazolin, cephaloridine, cefaclor, cefadroxil, cephaloglycin, cefuroxime, ceforanide, cefotaxime, cefatrizine, cephacetrile, cefepime, cefixime, cefonicid, cefoperazone, cefotetan, cefinetazole, ceftazidime, loracarbef, and moxalactam, monobactams like aztreonam; and carbapenems such as imipenem, meropenem, pentamidine isethiouate, albuterol sulfate, lidocaine, metaproterenol sulfate, beclomethasone diprepionate, triamcinolone acetamide, budesonide acetonide, fluticasone, ipratropium bromide, flunisolide, cromolyn sodium, ergotamine tartrate and where applicable, analogues, agonists, antagonists, inhibitors, and pharmaceutically acceptable salt forms of the above. In reference to peptides and proteins, the invention is intended to encompass synthetic, native, glycosylated, unglycosylated, pegylated forms, and biologically active fragments and analogs thereof. [0149] Active agents for use in the invention further include nucleic acids, as bare nucleic acid molecules, vectors, associated viral particles, plasmid DNA or RNA or other nucleic acid constructions of a type suitable for transfection or transformation of cells, i.e., suitable for gene therapy including antisense. Further, an active agent may comprise live 31 WO 2007/041090 PCT/US2006/037422 attenuated or killed viruses suitable for use as vaccines. Other useful drugs include those listed within the Physician's Desk Reference (most recent edition). [0150] In one or more embodiments, an active agent comprises a methionine containing peptide or protein, such as a cyclized parathyroid hormone analog. In some embodiments, the cyclized parathyroid hormone analog comprises Ostabolin-CTM, which is a cyclized 31-amino acid analog of parathyroid hormone (PTH) and is expected to have chemical and physical properties similar to other PTH analogs, such as PTH 1-34. Compositions and formulations of cyclized parathyroid hormone analogs are more fully disclosed in US Patent Application SN 60/773,384, filed February 13, 2006. In one or more embodiments, an active agent comprises an aminoglycoside antibiotic, such as those disclosed in US Patent Application SN60/580,848, filed June 18, 2004, and in WO 2006/002178, filed June 20, 2005. A particular aminoglycoside comprises tobramycin. In one or more embodiments, an active agent comprises a fluoroquinolone antibiotic, such as ciprofloxacin. [0151] The amount of active agent in the pharmaceutical composition will be that amount necessary to deliver a therapeutically effective amount of the active agent per unit dose to achieve the desired result. In practice, this will vary widely depending upon the particular agent, its activity, the severity of the condition to be treated, the patient population, dosing requirements, and the desired therapeutic effect. The composition will generally contain anywhere from about 1 wt% to about 99 wt%, such as about 2 wt% to about 95 wt%, or about 5 wt% to about 85 wt%, of active agent, and will also depend upon the relative amounts of additives contained in the composition. The compositions of the invention are particularly useful for active agents that are delivered in doses of from 0.001 mg/day to 100 mg/day, such as in doses from 0.01 mg/day to 75 mg/day, or in doses from 0.10 mg/day to 50 mg/day. It is to be understood that more than one active agent may be incorporated into the formulations described herein and that the use of the term "agent" in no way excludes the use of two or more such agents. [0152] The pharmaceutical composition may comprise a pharmaceutically acceptable excipient or carrier which may be taken into the lungs with no significant adverse toxicological effects to the subject, and particularly to the lungs of the subject. In addition to the active agent, a phannaceutical composition may optionally include one or more pharmaceutical excipients which are suitable for pulmonary administration. These excipients, if present, are generally present in the composition in amounts ranging from about 0.01 wt% 32 WO 2007/041090 PCT/US2006/037422 to about 95 wt%, such as about 0.5 wt% to about 80 wt%, or about 1 wt% to about 60 wt%. Such excipients may, in part, serve to further improve the features of the active agent composition, for example by providing more efficient and reproducible delivery of the active agent, improving the handling characteristics of powders, such as flowability and consistency, and/or facilitating manufacturing and filling of unit dosage forms. In particular, excipient materials can often function to further improve the physical and chemical stability of the active agent, minimize the residual moisture content and hinder moisture uptake, and to enhance particle size, degree of aggregation, particle surface properties, such as rugosity, ease of inhalation, and the targeting of particles to the lung. One or more excipients may also be provided to serve as bulking agents when it is desired to reduce the concentration of active agent in the formulation. [0153] Pharmaceutical excipients and additives useful in the present pharmaceutical composition include but are not limited to amino acids, peptides, proteins, non-biological polymers, biological polymers, carbohydrates, such as sugars, derivatized sugars such as alditols, aldonic acids, esterified sugars, and sugar polymers, which may be present singly or in combination. Suitable excipients are those provided in WO 96/32096, which is incorporated herein by reference in its entirety. The excipient may have a glass transition temperature (Tg) above about 35'C, such as above about 40'C, above about 45'C, or above about 55 0 C. [0154] Exemplary protein excipients include albumins such as human serum albumin (HSA), recombinant human albumin (rHA), gelatin, casein, hemoglobin, and the like. Suitable amino acids (outside of the dileucyl-peptides of the invention), which may also function in a buffering capacity, include alanine, glycine, arginine, betaine, histidine, glutamic acid, aspartic acid, cysteine, lysine, leucine, isoleucine, valine, methionine, phenylalanine, aspartame, tyrosine, tryptophan, and the like. Preferred are amino acids and polypeptides that function as dispersing agents. Amino acids falling into this category include hydrophobic amino acids such as leucine, valine, isoleucine, tryptophan, alanine, methionine, phenylalanine, tyrosine, histidine, and proline. Dispersibility-enhancing peptide excipients include dimers, trimers, tetramers, and pentamers comprising one or more hydrophobic amino acid components such as those described above. [0155] Carbohydrate excipients suitable for use in the invention include, for example, monosaccharides such as fructose, maltose, galactose, glucose, D-mannose, sorbose, and the like; disaccharides, such as lactose, sucrose, trehalose, cellobiose, and the like; 33 WO 2007/041090 PCT/US2006/037422 polysaccharides, such as raffinose, melezitose, maltodextrins, dextrans, starches, and the like; and alditols, such as mannitol, xylitol, maltitol, lactitol, xylitol sorbitol (glucitol), pyranosyl sorbitol, myoinositol and the like. [0156] The pharmaceutical composition may also include a buffer or a pH adjusting agent, typically a salt prepared from an organic acid or base. Representative buffers include organic acid salts of citric acid, ascorbic acid, gluconic acid, carbonic acid, tartaric acid, succinic acid, acetic acid, or phthalic acid, Tris, tromethamine hydrochloride, or phosphate buffers. [0157] The pharmaceutical composition may also include polymeric excipients/additives, e.g., polyvinylpyrrolidones, derivatized celluloses such as hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylmethylcellulose, Ficolls (a polymeric sugar), hydroxyethylstarch, dextrates (e.g., cyclodextrins, such as 2 hydroxypropyl--cyclodextrin and sulfobutylether-p-cyclodextrin), polyethylene glycols, and pectin. [0158] The pharmaceutical composition may further include flavoring agents, taste masking agents, inorganic salts (for example sodium chloride), antimicrobial agents (for example benzalkonium chloride), sweeteners, antioxidants, antistatic agents, surfactants (for example polysorbates such as "TWEEN 20" and "TWEEN 80"), sorbitan esters, lipids (for example phospholipids such as lecithin and other phosphatidylcholines, phosphatidylethanolamines), fatty acids and fatty esters, steroids (for example cholesterol), and chelating agents (for example EDTA, zinc and other such suitable cations). Other pharmaceutical excipients and/or additives suitable for use in the compositions according to the invention are listed in "Remington: The Science & Practice of Pharmacy", 19th ed., Williams & Williams, (1995), and in the "Physician's Desk Reference", 52nd ed., Medical Economics, Montvale, N.J. (1998), both of which are incorporated herein by reference in their entireties. [0159] In one or more versions, the powdered formulation for use in the present invention includes a powder having a particle size selected to permit penetration into the alveoli of the lungs, that is less than 10 pm mass median diameter (MMD), less than 7.5 pLm, or less than 5 tm, and usually being in the range of 0.1 ptm to 5 ptm in diameter. The delivered dose efficiency (DDE) of these powders may be greater than 30%, such as greater than 40%, greater than 50%, or greater than 60%, and the aerosol particle size distribution is less than about 10 jim MMAD, such as about 1.0-5.0 pim MMAD, 1.5-4.5 pim MMAD, or 34 WO 2007/041090 PCT/US2006/037422 1.5-4.0 pm MMAD. Dry powders have a moisture content below about 10 wt%, usually below about 5 wt%, such as below about 3% by weight. Such powders are described in WO 95/24183, WO 96/32149, WO 99/16419, and WO 99/16422, all of which are all incorporated herein by reference in their entireties. [0160] One or more embodiments relate to amphotericin B compositions that have reduced toxicity, and/or relatively high crystallinity, such as those disclosed in U.S. Application No. 11/158,332, filed June 21, 2005, which is incorporated herein by reference in its entirety. One or more embodiments relate to amphotericin B compositions that have reduced levels of degradants, such as those disclosed in U.S. Application No. 60/745,515, filed December 28, 2005, which is incorporated herein by reference in its entirety. While not bound to theory, a crystallinity level of the amphotericin B appears to affect amphotericin B toxicity. One or more embodiments relate to amphotericin B compositions that have a reduced level of degradants, such as those disclosed in US SN 60/754,515, filed December 28, 2005, which is incorporated herein by reference in its entirety. [0161] In one or more embodiments of the invention, a composition comprises amphotericin B. Amphotericin B is a heptaene macrolide containing seven conjugated double bonds in the trans position and a 3-amino-3,6-dideoxymannose (mycosamine) moiety connected to the main ring by a glycosidic bond. Amphotericin B bulk drug substance may be obtained from Alpharma in Copenhagen, Denmark or Chemwerth, Woodbridge, Connecticut. [0162] In one or more embodiments of the invention, a composition comprises an amphotericin B derivative having antifungal activity. The amphotericin B derivative can be an ester, amide, hydrazide, N-alkyl, and/or N-amino acyl. Examples of ester derivatives of amphotericin B include, but are not limited to, methyl esters, choline esters, and dimethylaminopropyl esters. Examples of amide derivatives of amphotericin B include, but are not limited to, primary, secondary and tertiary amides of amphotericin B. Examples of hydrazide derivatives of amphotericin B include, but are not limited to, N-methylpiperazine hydrazides. Examples of N-alkyl derivatives of amphotericin B include, but are not limited to, N',N',N'-trimethyl and N',N'-dimethylaminopropyl succininimidyl derivatives of amphotericin B methyl ester. Examples of N-aminoacyl derivatives of amphotericin B include, but are not limited to, N-ornithyl-, N-diaminopropionyl-, N-lysil-, N hexamethyllysil-, and N-piperdine-propionyl- or N',N'-methyl- 1 -piperazine-propionyl amphotericin B methyl ester. 35 WO 2007/041090 PCT/US2006/037422 [0163] Compositions including amphotericin B may include various amounts of amphotericin B. For example, the amount of amphotericin B may range from at least about 0.01 wt%, such as at least about 1 wt%, at least about 10 wt%, at least about 50 wt%, at least about 90 wt%, at least about 95 wt%, or at least about 98 wt%. [0164] As noted above, the crystallinity level of amphotericin B appears to be a factor in reducing toxicity. For instance, when administered to the lungs, more crystalline forms of amphotericin B appear to dissolve slower and have a longer half-life than more amorphous forms of amphotericin B. While not bound by theory, the slow dissolution and longer half life appear to reduce toxicity. In contrast, while bound by theory, the amorphous form appears to develop soluble aggregates which might be toxic to the lung tissue. While not bound by theory, it is believed that these principals are not limited to the lungs. [0165] The desired crystallinity level of the amphotericin B will depend on factors such as dosage and treatment regimen. The crystallinity level of the amphotericin B may be at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, such as at least about 80%, at least about 90%, at least about 95%, or at least about 99%. Accordingly, the crystallinity level may range from about 10% to 100%, such as about 20% to about 99%, about 50% to about 99%, about 70% to about 99%, about 70% to about 98%, about 80% to about 98%, or about 90% to about 97%, as well as combinations of the foregoing ranges. [0166] The crystallinity level may be determined by any of several known techniques. For instance, the crystallinity level may be determined by X-ray diffraction, Raman and/or infrared spectroscopy, dynamic vapor sorption, heat of solution calorimetry, or isothermal microcalorimetry. As noted above, unless the context indicates to the contrary, crystallinity levels in this document are measured by X-ray diffraction using the method set forth in Example 1 of U.S. Application No. 11/158,332, which is incorporated herein by reference in its entirety. [0167] In some cases, small diameter amphotericin B particles are used. In one version, the particles of amphotericin B have a mass median diameter less than about 3 pm, such as less than about 2.5 pm, less than about 2 pm, less than about 1.9 pm, or less than about 1.5 pm. For example, the particles of amphotericin B may have a mass median diameter ranging from about 0.5 pm to about 3 pm, such as about 0.5 pm to about 1.8 pim, about 0.8 pm to about 2.5 pm, about 1.1 jim to about 1.9 jm, about 1.2 jim to about 1.8 jim, or about 1 pim to about 2 pim. In some versions, at least about 20% of the amphotericin B 36 WO 2007/041090 PCT/US2006/037422 particles have a size less than about 3 pm, such as at least about 50% are less than about 3 Rm, at least about 90% are less than about 3 pm, or at least about 95% are less than about 3 pm, in diameter. For example, 60 wt%, 70 wt%, 80 wt%, or 90 wt% of the particles may have a mass median diameter of about 1.1 pm to 1.9 pm. [0168] In some versions, the amphotericin B has a high crystallinity level, and the amphotericin B particle size is small. The crystallinity level may be any of those discussed above, and the particle size may be any of those discussed above. For instance, in one version, the crystallinity level is at least about 50%, and the mass median diameter is less than about 3 pim. In another version, the crystallinity level is at least about 70%, and the mass median diameter is less than about 2.8 ptm. In still another version, the crystallinity level is at least about 80%, and the mass median diameter is less than about 2.6 pm. In yet another version, the crystallinity level is at least about 90%, and the mass median diameter is less than about 2.4 pm. [0169] The crystallinity level may be at the levels discussed above, and the amphotericin B particle size may be larger than the sizes discussed above. For instance, the crystallinity level may be at least about 50%, and the mass median diameter may be greater than about 3 pm. Conversely, the amphotericin B particle size may be within the sizes discussed above, and the crystallinity level may be outside the levels discussed above. For instance, the mass median diameter may be less than about 3 ptm, and the crystallinity level may be less than about 50%. [0170] The pharmaceutical composition according to one or more embodiments of the invention may comprise amphotericin B and, optionally, one or more other active ingredients and/or pharmaceutically acceptable excipients. For example, the pharmaceutical composition may comprise neat particles of amphotericin B, may comprise neat particles of amphotericin B together with other particles, and/or may comprise particulates comprising amphotericin B and one or more active ingredients and/or one or more pharmaceutically acceptable excipients. [0171] Thus, the pharmaceutical composition according to one or more embodiments of the invention may, if desired, contain a combination of amphotericin B and one or more other active ingredients. Examples of other active agents include, but are not limited to, agents that may be delivered through the lungs or nasal passages. For example, the other active agent(s) may be long-acting agents and/or active agents that are active against pulmonary and/or nasal infections such as antivirals, antifungals, and/or antibiotics. 37 WO 2007/041090 PCT/US2006/037422 [0172] Examples of antivirals include, but are not limited to, acyclovir, gangcyclovir, azidothymidine, cytidine arabinoside, ribavirin, rifampacin, amantadine, iododeoxyuridine, poscarnet, and trifluridine. [0173] Examples of antifungals include, but are not limited to, azoles (e.g., imidazoles, itraconazole, pozaconazole), micafungin, caspafungin, salicylic acid, oxiconazole nitrate, ciclopirox olamine, ketoconazole, miconazole nitrate, and butoconazole nitrate. [0174] Examples of antibiotics include, but are not limited to, penicillin and drugs of the penicillin family of antimicrobial drugs, including but not limited to penicillin-G, penicillin-V, phenethicillin, ampicillin, amoxacillin, cyclacillin, bacampicillin, hetacillin, cloxacillin, dicloxacillin, methicillin, nafcillin, oxacillin, azlocillin, carbenicillin, mezlocillin, piperacillin, ticaricillin, and imipenim; cephalosporin and drugs of the cephalosporin family, including but not limited to cefadroxil, cefazolin, caphalexn, cephalothin, cephapirin, cephradine, cefaclor, cefamandole, cefonicid, cefoxin, cefuroxime, ceforanide, cefotetan, cefinetazole, cefoperazone, cefotaxime, ceftizoxime, ceftizone, moxalactam, ceftazidime, and cefixime; aminoglycoside drugs and drugs of the aminoglycoside family, including but not limited to streptomycin, neomycin, kanamycin, gentamycin, tobramycin, amikacin, and netilmicin; macrolide and drugs of the macrolide family, exemplified by azithromycin, clarithromycin, roxithromycin, erythromycin, lincomycin, and clindamycin; tetracyclin and drugs of the tetracyclin family, for example, tetracyclin, oxytetracyclin, democlocyclin, methacyclin, doxycyclin, and minocyclin; quinoline and quinoline-like drugs, such as, for example, naladixic acid, cinoxacin, norfloxacin, ciprofloxacin, ofloxicin, enoxacin, and pefloxacin; antimicrobial peptides, including but not limited to polymixin B, colistin, and bacatracin, as well as other antimicrobial peptides such as defensins, magainins, cecropins, and others, provided as naturally-occurring or as the result of engineering to make such peptides resistant to the action of pathogen-specific proteases and other deactivating enzymes; other antimicrobial drugs, including chloramphenicol, vancomycin, rifampicin, metronidazole, voriconazole, fluconazole, ethambutol, pyrazinamide, sulfonamides, isoniazid, and erythromycin. [0175] When a combination of active agents is used, the agents may be provided in combination in a single species of pharmaceutical composition or individually in separate species of pharmaceutical compositions. Further, the pharmaceutical composition may be combined with one or more other active or bioactive agents that provide the desired dispersion stability or powder dispersibility. 38 WO 2007/041090 PCT/US2006/037422 [0176] The amount of active agent(s), e.g., amphotericin B, in the pharmaceutical composition may vary. The amount of active agent(s) is typically at least about 5 wt%, such as at least about 10 wt%, at least about 20 wt%, at least about 30 wt%, at least about 40 wt%, at least about 50 wt%, at least about 60 wt%, at least about 70 wt%, or at least about 80 wt%, of the total amount of the pharmaceutical composition. The amount of active agent(s) generally varies between about 0.1 wt% to 100 wt%, such as about 5 wt% to about 95 wt%, about 10 wt% to about 90 wt%, about 30 wt% to about 80 wt%, about 40 wt% to about 70 wt%, or about 50 wt% to about 60 wt%. [0177] As noted above, the pharmaceutical composition may include one or more pharmaceutically acceptable excipient. Examples of pharmaceutically acceptable excipients include, but are not limited to, lipids, metal ions, surfactants, amino acids, carbohydrates, buffers, salts, polymers, and the like, and combinations thereof. [0178] Examples of lipids include, but are not limited to, phospholipids, glycolipids, ganglioside GM1, sphingomyelin, phosphatidic acid, cardiolipin; lipids bearing polymer chains such as polyethylene glycol, chitin, hyaluronic acid, or polyvinylpyrrolidone; lipids bearing sulfonated mono-, di-, and polysaccharides; fatty acids such as palmitic acid, stearic acid, and oleic acid; cholesterol, cholesterol esters, and cholesterol hemisuccinate. [0179] In one or more embodiments, the phospholipid comprises a saturated phospholipid, such as one or more phosphatidylcholines. Exemplary acyl chain lengths are 16:0 and 18:0 (i.e., palmitoyl and stearoyl). The phospholipid content may be determined by the active agent activity, the mode of delivery, and other factors. [0180] Phospholipids from both natural and synthetic sources may be used in varying amounts. When phospholipids are present, the amount is typically sufficient to coat the active agent(s) with at least a single molecular layer of phospholipid. In general, the phospholipid content ranges from about 5 wt% to about 99.9 wt%, such as about 20 wt% to about 80 wt%. [0181] Generally, compatible phospholipids comprise those that have a gel to liquid crystal phase transition greater than about 40 'C, such as greater than about 60 'C, or greater than about 80 *C. The incorporated phospholipids may be relatively long chain (e.g., C 16 C 22 ) saturated lipids. Exemplary phospholipids useful in the disclosed stabilized preparations include, but are not limited to, phosphoglycerides such as dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, diarachidoylphosphatidylcholine, dibehenoylphosphatidylcholine, diphosphatidyl glycerols, short-chain phosphatidylcholines, 39 WO 2007/041090 PCT/US2006/037422 hydrogenated phosphatidylcholine, E-100-3 (available from Lipoid KG, Ludwigshafen, Germany), long-chain saturated phosphatidylethanolamines, long-chain saturated phosphatidylserines, long-chain saturated phosphatidylglycerols, long-chain saturated phosphatidylinositols, phosphatidic acid, phosphatidylinositol, and sphingomyelin. [0182] Examples of metal ions include, but are not limited to, divalent cations, including calcium, magnesium, zinc, iron, and the like. For instance, when phospholipids are used, the pharmaceutical composition may also comprise a polyvalent cation, as disclosed in WO 01/85136 and WO 01/85137, which are incorporated herein by reference in their entireties. The polyvalent cation may be present in an amount effective to increase the melting temperature (Tm) of the phospholipid such that the pharmaceutical composition exhibits a Tm which is greater than its storage temperature (T,) by at least about 20 'C, such as at least about 40 *C. The molar ratio of polyvalent cation to phospholipid may be at least about 0.05:1, such as about 0.05:1 to about 2.0:1 or about 0.25:1 to about 1.0:1. An example of the molar ratio of polyvalent cation:phospholipid is about 0.50:1. When the polyvalent cation is calcium, it may be in the form of calcium chloride. Although metal ion, such as calcium, is often included with phospholipid, none is required. [0183] As noted above, the pharmaceutical composition may include one or more surfactants. For instance, one or more surfactants may be in the liquid phase with one or more being associated with solid particles or particulates of the composition. By "associated with" it is meant that the pharmaceutical compositions may incorporate, adsorb, absorb, sorb, be coated with, or be formed by the surfactant. Surfactants include, but are not limited to, fluorinated and nonfluorinated compounds, such as saturated and unsaturated lipids, nonionic detergents, nonionic block copolymers, ionic surfactants, and combinations thereof. 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. [0184] Examples of nonionic detergents include, but are not limited to, sorbitan esters including sorbitan trioleate (SpanTM 85), sorbitan sesquioleate, sorbitan monooleate, sorbitan monolaurate, polyoxyethylene (20) sorbitan monolaurate, and polyoxyethylene (20) sorbitan monooleate, oleyl polyoxyethylene (2) ether, stearyl polyoxyethylene (2) ether, lauryl polyoxyethylene (4) ether, glycerol esters, and sucrose esters. Other suitable nonionic detergents can be easily identified using McCutcheon's Emulsifiers and Detergents 40 WO 2007/041090 PCT/US2006/037422 (McPublishing Co., Glen Rock, New Jersey), which is incorporated by reference herein in its entirety. [0185] Examples of block copolymers include, but are not limited to, diblock and triblock copolymers of polyoxyethylene and polyoxypropylene, including poloxamer 188 (Pluronic T M F-68), poloxamer 407 (Pluronic T M F-127), and poloxamer 338. [0186] Examples of ionic surfactants include, but are not limited to, sodium sulfosuccinate, and fatty acid soaps. [0187] Examples of amino acids include, but are not limited to, hydrophobic amino acids. Use of amino acids as pharmaceutically acceptable excipients is known in the art as disclosed in WO 95/31479, WO 96/32096, and WO 96/32149, which are incorporated herein by reference. [0188] Examples of carbohydrates include, but are not limited to, monosaccharides, disaccharides, and polysaccharides. For example, monosaccharides such as dextrose (anhydrous and monohydrate), galactose, mannitol, D-mannose, sorbitol, sorbose and the like; disaccharides such as lactose, maltose, sucrose, trehalose, and the like; trisaccharides such as raffinose and the like; and other carbohydrates such as starches (hydroxyethylstarch), cyclodextrins and maltodextrins. [0189] Examples of buffers include, but are not limited to, tris or citrate. [0190] Examples of acids include, but are not limited to, carboxylic acids. [0191] Examples of salts include, but are not limited to, sodium chloride, salts of carboxylic acids, (e.g., sodium citrate, sodium ascorbate, magnesium gluconate, sodium gluconate, tromethamine hydrochloride, etc.), ammonium carbonate, ammonium acetate, ammonium chloride, and the like. [0192] Examples of organic solids include, but are not limited to, camphor, and the like. [0193] The pharmaceutical composition of one or more embodiments of the present invention may also include a biocompatible, such as biodegradable polymer, copolymer, or blend or other combination thereof. In this respect useful polymers comprise polylactides, polylactide-glycolides, cyclodextrins, polyacrylates, methylcellulose, carboxymethylcellulose, polyvinyl alcohols, polyanhydrides, polylactams, polyvinyl pyrrolidones, polysaccharides (dextrans, starches, chitin, chitosan, etc.), hyaluronic acid, proteins, (albumin, collagen, gelatin, etc.). Those skilled in the art will appreciate that, by selecting the appropriate polymers, the delivery efficiency of the composition and/or the 41 WO 2007/041090 PCT/US2006/037422 stability of the dispersions may be tailored to optimize the effectiveness of the active agent(s). [0194] Besides the above mentioned pharmaceutically acceptable excipients, it may be desirable to add other pharmaceutically acceptable excipients to the pharmaceutical composition to improve particulate rigidity, production yield, emitted dose and deposition, shelf-life, and patient acceptance. Such optional pharmaceutically acceptable excipients include, but are not limited to: coloring agents, taste masking agents, buffers, hygroscopic agents, antioxidants, and chemical stabilizers. Further, various pharmaceutically acceptable excipients may be used to provide structure and form to the particulate compositions (e.g., latex particles). In this regard, it will be appreciated that the rigidifying components can be removed using a post-production technique such as selective solvent extraction. [0195] The pharmaceutical compositions may also include mixtures of pharmaceutically acceptable excipients. For instance, mixtures of carbohydrates and amino acids are within the scope of the present invention. [0196] The compositions of one or more embodiments of the present invention may take various forms, such as dry powders, capsules, tablets, reconstituted powders, suspensions, or dispersions comprising a non-aqueous phase, such as propellants (e.g., chlorofluorocarbon, hydrofluoroalkane). The moisture content of dry powder may be less than about 15 wt%, such as less than about 10 wt%, less than about 5 wt%, less than about 2 wt%, less than about 1 wt%, or less than about 0.5 wt%. Such powders are described in WO 95/24183, WO 96/32149, WO 99/16419, WO 99/16420, and WO 99/16422, which are incorporated herein by reference in their entireties. [0197] One or more embodiments of the invention involve homogeneous compositions of amphotericin B incorporated in a matrix material with little, if any, unincorporated amphotericin B particles. For instance, at least about 40 wt%, at least about 50 wt%, at least about 60 wt%, at least about 70%, at least about 80%, at least about 90 wt%, at least about 95 wt%, or at least about 99 wt%, of the composition may comprise particulates including both amphotericin B and matrix material. [0198] In some cases, however, a heterogeneous composition may be desirable in order to provide a desired pharmacokinetic profile of the amphotericin B to be administered, and in these cases, a large amphotericin B particle (e.g., mass median diameter of about 3 pim to about 10 Rm, or larger) may be used. 42 WO 2007/041090 PCT/US2006/037422 [0199] Homogeneous compositions may comprise small amphotericin B particles. Amphotericin B particles having a mass median diameter less than about 3 pJm, as discussed above, can be dispersible and can facilitate production of homogenous compositions of amphotericin B incorporated into matrix material. It should be noted, however, that a heterogeneous distribution of particles may be ameliorated via appropriate processing, such as by an atomization processes, which can result in a homogeneous distribution even for larger amphotericin B particles. [0200] In view of the above, in some versions, the pharmaceutical composition has high homogeneity, the amphotericin B has a high crystallinity level, and the size of amphotericin B particles forming the composition is small. The degree of homogeneity, the crystallinity level, and the particle size may be any of those discussed above. For instance, in one version, the crystallinity level is at least about 50%, and the mass median diameter is less than about 3 tm. In another version, the crystallinity level is at least about 70%, and the mass median diameter is less than about 2.8 pm. In still another version, the crystallinity level is at least about 80%, and the mass median diameter is less than about 2.6 pm. In yet another version, the crystallinity level is at least about 90%, and the mass median diameter is less than about 2.4 tm. [0201] In some cases, however, the degree of homogeneity is high, and one or more of the crystallinity level and amphotericin B are outside the ranges discussed above. Alternatively, in some cases, the degree of homogeneity is low, and one or more of the crystallinity level and amphotericin B are within the ranges discussed above. [0202] In one version, the pharmaceutical composition comprises amphotericin B incorporated into a phospholipid matrix. The pharmaceutical composition may comprise phospholipid matrices that incorporate the active agent and that are in the form of particulates that are hollow and/or porous microstructures, as described in the aforementioned WO 99/16419, WO 99/16420, WO 99/16422, WO 01/85136, and WO 01/85137, which are incorporated herein by reference in their entireties. The hollow and/or porous microstructures are useful in delivering the amphotericin B to the lungs because the density, size, and aerodynamic qualities of the hollow and/or porous microstructures facilitate transport into the deep lungs during a user's inhalation. In addition, the phospholipid-based hollow and/or porous microstructures reduce the attraction forces between particulates, making the pharmaceutical composition easier to deagglomerate during aerosolization and improving the flow properties of the pharmaceutical composition making it easier to process. 43 WO 2007/041090 PCT/US2006/037422 [0203] A variety of amphotericin B particle and composition particle sizes, distributions and/or physical characteristics are suitable for one or more embodiments of the present invention. Exemplary sizes and/or characteristics are disclosed in US Patent Application Nos. SN1 1/156,791, filed 20 June 2005, SNI 1/158,332, filed 21 June 2005, SN11/1 87,757, filed 22 July 2005, and SN 60/754,515, filed 28 December 2005, each of which is incorporated by reference herein in its entirety, and with particular reference to amphotericin B particle and/or composition particles sizes, distributions and/or characteristics. [0204] In one or more versions, the pharmaceutical composition is composed of hollow and/or porous microstructures having a bulk density less than about 1.0 g/cm 3 , less than about 0.5 g/cm 3 , less than about 0.3 g/cm 3 , less than about 0.2 g/cm 3 , or less than about 0.1 g/cm 3 . By providing low bulk density particles or particulates, 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 one or more embodiments of the present invention provides for the reproducible administration of relatively low dose pharmaceutical compounds. Moreover, the elimination of carrier particles will potentially reduce throat deposition and any "gag" effect or coughing, since large carrier particles, e.g., lactose particles, will impact the throat and upper airways due to their size. [0205] In one version, the pharmaceutical composition is in powder form and is contained within a unit dose receptacle which may be inserted into or near the aerosolization apparatus to aerosolize the unit dose of the pharmaceutical composition. This version is useful in that the powder form may be stably stored in its unit dose receptacle for a long period of time. In some examples, pharmaceutical compositions of one or more embodiments of the present invention have been stable for at least about 2 years. In some versions, no refrigeration is required to obtain stability. In other versions, reduced temperatures, e.g., at 2-8 *C, may be used to prolong stable storage. In many versions, the storage stability allows aerosolization with an external power source. [0206] It will be appreciated that the pharmaceutical compositions disclosed herein may comprise a structural matrix that exhibits, defines or comprises voids, pores, defects, hollows, spaces, interstitial 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, some embodiments comprise approximately 44 WO 2007/041090 PCT/US2006/037422 spherical shapes. However, collapsed, deformed or fractured particulates are also compatible. [0207] In one or more versions, the amphotericin B is incorporated in a matrix that forms a discrete particulate, and the pharmaceutical composition comprises a plurality of the discrete particulates. The discrete particulates may be sized so that they are effectively administered and/or so that they are available where needed. For example, for an aerosolizable pharmaceutical composition, the particulates are of a size that allows the particulates to be aerosolized and delivered to a user's respiratory tract during the user's inhalation. In practice, in one or more embodiments, there may be a distribution of particles comprising matrix with amphotericin B, matrix alone and amphotericin B alone. [0208] In some versions, the pharmaceutical composition comprises particulates having a mass median diameter less than about 20 pm, such as less than about 10 pm, less than about 7 pm, or less than about 5 pm. The particulates may have a mass median aerodynamic diameter ranging from about 1 pm to about 6 pm, such as about 1.5 gm to about 5 pm, or about 2 pm to about 4 pm. If the particulates are too large, toxicity in rats has been observed. If the particulates are too small, a larger percentage of the particulates may be exhaled. [0209] In view of the above, in some versions, the pharmaceutical composition comprises particulates having a small mass median aerodynamic diameter, the pharmaceutical composition has high homogeneity, the amphotericin B has a high crystallinity level, and the size of amphotericin B particles forming the pharmaceutical composition is small. The mass median aerodynamic diameter, degree of homogeneity, crystallinity level, and amphotericin B particle size may be any of those discussed above. For instance, in one version, the mass median aerodynamic diameter is less than about 20 pm, at least about 60 wt% of the pharmaceutical composition comprise both amphotericin B and matrix material, the crystallinity level is at least about 50%, and the mass median diameter is less than about 3 pm. In another version, the mass median aerodynamic diameter is less than about 10 pm, at least about 70 wt% of the pharmaceutical composition comprise both amphotericin B and matrix material, the crystallinity level is at least about 70%, and the mass median diameter is less than about 2.8 pm. In still another version, the mass median aerodynamic diameter is less than about 7 pm, at least about 80 wt% of the pharmaceutical composition comprise both amphotericin B and matrix material, the crystallinity level is at least about 80%, and the mass median diameter is less than about 2.6 pm. In yet another 45 WO 2007/041090 PCT/US2006/037422 version, the mass median aerodynamic diameter is less than about 7 pm, at least about 90 wt% of the pharmaceutical composition comprise both amphotericin B and matrix material, the crystallinity level is at least about 90%, and the mass median diameter is less than about 2.4 pm. [0210] In some cases, however, the mass median aerodynamic diameter is small and one or more of the homogeneity, crystallinity level, and amphotericin B particle size are outside the ranges discussed above. Similarly, in other cases, the mass median aerodynamic diameter is large and one or more of the homogeneity, crystallinity level, and amphotericin B particle size are within the ranges discussed above. [0211] The matrix material may comprise a hydrophobic or a partially hydrophobic material. For example, the matrix material may comprise a lipid, such as a phospholipid, and/or a hydrophobic amino acid, such as leucine or tri-leucine. Examples of phospholipid matrices are described in WO 99/16419, WO 99/16420, WO 99/16422, WO 01/85136, and WO 01/85137 and in U.S. Patent Nos. 5,874,064; 5,855,913; 5,985,309; and 6,503,480, and in copending and co-owned U.S. Application No. 10/750,934, filed on December 31, 2003, each of which are incorporated herein by reference in their entireties. Examples of hydrophobic amino acid matrices are described in U.S. Patent Nos. 6,372,258 and 6,358,530, and in U.S. Application No. 10/032,239, filed on December 21, 2001, each of which are incorporated herein by reference in their entireties. [0212] When phospholipids are utilized as the matrix material, the pharmaceutical composition may also comprise a polyvalent cation, as disclosed in WO 01/85136 and WO 01/85137, which are incorporated herein by reference in their entireties. [0213] According to another embodiment, release kinetics of the active agent(s) containing composition is controlled. According to one or more embodiments, the compositions of the present invention provide immediate release of the active agent(s). Alternatively, the compositions of other embodiments of the present invention may be provided as non-homogeneous mixtures of active agent incorporated into a matrix material and unincorporated active agent in order to provide desirable release rates of antifungal agent. According to this embodiment, antifungal agents formulated using the emulsion-based manufacturing process of one or more embodiments of the present invention have utility in immediate release applications when administered to the respiratory tract. Rapid release is facilitated by: (a) the high specific surface area of the low density porous powders; (b) the 46 WO 2007/041090 PCT/US2006/037422 small size of the drug crystals that are incorporated therein, and; (c) the low surface energy of the particulates. [0214] Additionally, or alternatively, it may be desirable to engineer the particulate matrix so that extended release of the active agent(s) is effected. This may be particularly desirable when the active agent(s) is rapidly cleared from the lungs or when sustained release is desired. For example, the nature of the phase behavior of phospholipid molecules is influenced by the nature of their chemical structure and/or preparation methods in spray drying feedstock and drying conditions and other composition components utilized. In the case of spray-drying of active agent(s) solubilized within a small unilamellar vesicle (SUV) or multilamellar vesicle (MLV), the active agent(s) are encapsulated within multiple bilayers and are released over an extended time. [0215] In contrast, spray-drying of a feedstock comprised of emulsion droplets and dispersed or dissolved active agent(s) in accordance with the teachings herein leads to a phospholipid matrix with less long-range order, thereby facilitating rapid release. While not being bound to any particular theory, it is believed that this is due in part to the fact that the active agent(s) are never formally encapsulated in the phospholipid, and the fact that the phospholipid is initially present on the surface of the emulsion droplets as a monolayer (not a bilayer as in the case of liposomes). The spray-dried particulates prepared by the emulsion based manufacturing process of one or more embodiments of the present invention often have a high degree of disorder. Also, the spray-dried particulates typically have low surface energies, where values as low as 20 mN/m have been observed for spray-dried DSPC particulates (determined by inverse gas chromatography). Small angle X-ray scattering (SAXS) studies conducted with spray-dried phospholipid particulates have also shown a high degree of disorder for the lipid, with scattering peaks smeared out, and length scales extending in some instances only beyond a few nearest neighbors. [0216] It should be noted that a matrix having a high gel to liquid crystal phase transition temperature is not sufficient in itself to achieve sustained release of the active agent(s). Having sufficient order for the bilayer structures is also important for achieving sustained release. To facilitate rapid release, an emulsion-system of high porosity (high surface area), and minimal interaction between the drug substance and phospholipid may be used. The pharmaceutical composition formation process may also include the additions of other composition components (e.g., small polymers such as Pluronic F-68; carbohydrates, salts, hydrotropes) to break the bilayer structure are also contemplated. 47 WO 2007/041090 PCT/US2006/037422 [0217] To achieve a sustained release, in one or more embodiments incorporation of the phospholipid in bilayer form may be used, especially if the active agent is encapsulated therein. In this case increasing the Tm of the phospholipid may provide benefit via incorporation of divalent counterions or cholesterol. As well, increasing the interaction between the phospholipid and drug substance via the formation of ion-pairs (negatively charged active + steaylamine, positively charged active + phosphatidylglycerol) would tend to decrease the dissolution rate. If the active is amphiphilic, surfactant/surfactant interactions may also slow active dissolution. [0218] The addition of divalent counterions (e.g., calcium or magnesium ions) to long-chain saturated phosphatidylcholines results in an interaction between the negatively charged phosphate portion of the zwitterionic headgroup and the positively charged metal ion. This results in a displacement of water of hydration and a condensation of the packing of the phospholipid lipid headgroup and acyl chains. Further, this results in an increase in the Tm of the phospholipid. The decrease in headgroup hydration can have profound effects on the spreading properties of spray-dried phospholipid particulates on contact with water. A fully hydrated phosphatidyicholine molecule will diffuse very slowly to a dispersed crystal via molecular diffusion through the water phase. The process is exceedingly slow because the solubility of the phospholipid in water is very low (about 10-0 mol/L for DPPC). Prior art attempts to overcome this phenomenon include homogenizing the crystals in the presence of the phospholipid. In this case, the high degree of shear and radius of curvature of the homogenized crystals facilitates coating of the phospholipid on the crystals. In contrast, "dry" phospholipid powders according to one or more embodiments of this invention can spread rapidly when contacted with an aqueous phase, thereby coating dispersed crystals without the need to apply high energies. [0219] For example, upon reconstitution, the surface tension of spray-dried DSPC/Ca mixtures at the air/water interface decreases to equilibrium values (about 20 mN/m) as fast as a measurement can be taken. In contrast, liposomes of DSPC decrease the surface tension (about 50 mN/m) very little over a period of hours, and it is likely that this reduction is due to the presence of hydrolysis degradation products such as free fatty acids in the phospholipid. Single-tailed fatty acids can diffuse much more rapidly to the air/water interface than can the hydrophobic parent compound. Hence the addition of calcium ions to phosphatidylcholines can facilitate the rapid encapsulation of crystalline drugs more rapidly and with lower applied energy. 48 WO 2007/041090 PCT/US2006/037422 [0220] In another version, the pharmaceutical composition comprises low density particulates achieved by co-spray-drying nanocrystals with a perfluorocarbon-in-water emulsion. The nanocrystals may be formed by precipitation and may, e.g., range in size from about 45 tm to about 80 pLm. Examples of perfluorocarbons include, but are not limited to, perfluorohexane, perfluorooctyl bromide, perfluorooctyl ethane, perfluorodecalin, perfluorobutyl ethane. [0221] In accordance with the teachings herein the particulate compositions will preferably be provided in a "dry" state. That is, in one or more embodiments, the particulates will possess a moisture content that allows the powder to remain chemically and physically stable during storage at ambient or reduced temperature and/or remain dispersible, and/or flowable. In this regard, there is little or no change in primary particulate size, content, purity, and aerodynamic particulate size distribution. [0222] As such, the moisture content of the particulates is typically less than about 20 wt%, such as less than about lOwt%, less than about 6 wt%, or less than about 3 wt%. The moisture content is, at least in part, dictated by the composition and is controlled by the process conditions employed, e.g., inlet temperature, feed concentration, pump rate, and blowing agent type, concentration and post drying. Reduction in bound water leads to significant improvements in the dispersibility and flowability of phospholipid based powders, leading to the potential for highly efficient delivery of powdered lung surfactants or particulate composition comprising active agent dispersed in the phospholipid. The improved dispersibility allows simple passive DPI devices to be used to effectively deliver these powders. [0223] Yet another version of the pharmaceutical composition includes particulate compositions that may comprise, or may be partially or completely coated with, charged species that prolong residence time at the point of contact or enhance penetration through mucosae. For example, anionic charges are known to favor mucoadhesion while cationic charges may be used to associate the formed particulate with negatively charged bioactive agents such as genetic material. The charges may be imparted through the association or incorporation of polyanionic or polycationic materials such as polyacrylic acids, polylysine, polylactic acid, and chitosan. [0224] In one version, the pharmaceutical composition comprising crystalline amphotericin B is aerosolizable so that it may be delivered to the lungs of a patient during the patient's inhalation. In this way the amphotericin B in the pharmaceutical composition is 49 WO 2007/041090 PCT/US2006/037422 delivered directly to the site of infection. This is advantageous over systemic administration. Because the active agent(s) often have renal or other toxicity, minimizing systemic exposure is typically preferred. Therefore, the amount of active agent(s) that may be delivered to the lungs is preferably limited to the minimum pharmacologically effective dose. By administering the active agent(s) directly to the lungs, a greater amount may be delivered to the site in need of the therapy while significantly reducing systemic exposure. Furthermore, by predominantly delivering amphotericin B in its crystalline form, the desired concentration of amphotericin B can be maintained at the site of infection over a period of time with a reduced likelihood of the generation of a toxic effect within the lungs. [0225] The pharmaceutical compositions of one or more embodiments of the present invention lack taste. In this regard, although taste masking agents are optionally included within the composition, the compositions often lack taste even without a taste masking agent. [0226] The compositions of one or more embodiments of the present invention may be administered by known techniques, such as inhalation, oral, intramuscular, intravenous, intratracheal, intraperitoneal, subcutaneous, and transdermal. [0227] In one or more embodiments, the invention provides a system and method for aerosolizing a pharmaceutical composition and delivering the pharmaceutical composition to the respiratory tract of the user, and in particular to the lungs of the user. The pharmaceutical composition may comprise powdered medicaments, liquid solutions or suspensions, and the like, and may include an active agent. [0228] For example, the pharmaceutical compositions of one or more embodiments of the invention are effective in the treatment, including adjunctive treatment, of pulmonary and/or nasal fungal infections. Amphotericin B acts as an antifungal agent to treat a pulmonary and/or nasal fungal infection and/or to prevent the onset of a pulmonary and/or nasal fungal infection. It is believed that amphotericin B acts to slow down the growth and multiplication of susceptible fungi. If the concentrations of amphotericin B are sufficiently high, they can also destroy the fungi. Amphotericin B appears to act on the cell membrane of the fungi, altering the integrity of the cell membrane. [0229] In one or more versions, the compositions, when inhaled, penetrate into the nasal cavities and/or airways of the lungs to achieve effective amphotericin B concentrations, such as in the infected secretions and lung tissue, including the epithelial lining fluid, alveolar macrophages, and neutrophils. Moreover, the doses of composition that are inhaled are typically much less than those administered by other routes and required to obtain similar 50 WO 2007/041090 PCT/US2006/037422 antifungal effects, due to the efficient targeting of the inhaled composition directly to the site of fungal infection. [0230] In one or more embodiments of the invention, a pharmaceutical composition comprising amphotericin B, wherein a predominant amount of the amphotericin B is in crystalline form (such as 50% or more), is administered to the lungs of a patient in need thereof. For example, the patient may have been diagnosed with a pulmonary and/or nasal fungal infection or the patient may be determined to be susceptible to a pulmonary and/or nasal fungal infection. Examples of pulmonary and/or nasal fungal infections include aspergillosis, blastomycosis, disseminated candidiasis, coccidioidomycosis, cryptococcosis, histoplasmosis, mucormycosis, sporotrichosis, some infections caused by Candida spp, and others as known in the art. [0231] Thus, the pharmaceutical compositions of one or more embodiments of the present invention can be used to treat and/or provide prophylaxis for a broad range of patients. A suitable patient for receiving treatment and/or prophylaxis as described herein is any mammalian patient in need thereof, preferably such mammal is a human. Examples of patients include, but are not limited to, pediatric patients, adult patients, and geriatric patients. The patients are typically at risk for obtaining a fungal infection. [0232] In one version, the pharmaceutical compositions of one or more embodiments of the present invention are useful in the prophylaxis of pulmonary and/or nasal fungal infections, such as for immunocompromised patients, e.g., individuals undergoing chemotherapy or radiation therapy for cancer, organ transplant recipients, patients suffering from conditions that adversely affect the immune system, such as HIV, or any other condition which predisposes a patient to pulmonary and/or nasal fungal infections. The pharmaceutical compositions may also be used in the treatment of active pulmonary and/or nasal fungal infections, such as aspergillosis (most commonly due to Aspergillusfumigatus, Aspergillus flavus, Aspergillus niger, Aspergillus nidulans, and Aspergillus terreus), coccidioidomycosis, histoplasmosis, blastomycosis, and other fungal pathogens. [0233] In one version, an aerosolizeable pharmaceutical composition comprising amphotericin B is administered to the lungs and/or nasal cavity of a patient in a manner that results in an amphotericin B concentration greater than a minimum inhibitory concentration (MIC) of the fungus. The MIC is defined as the lowest concentration of amphotericin B that inhibits fungal growth. The MIC may be expressed as a particular concentration value or as a range of concentrations. A method according to one or more embodiments of the present 51 WO 2007/041090 PCT/US2006/037422 invention administers a sufficient amount of the pharmaceutical composition to achieve a target lung concentration of amphotericin B that falls within the range of MIC values or is above a particular MIC value. In another version, the target lung concentration of amphotericin B exceeds the MIC range. In another version, the target lung concentration of amphotericin B exceeds the lowest value in an MIC range. In another version, the target amphotericin B concentration is a concentration that exceeds the MIC range and is at least about 2 times, such as at least about 3 times, at least about 4 times, or at least about 5 times, the maximum of the MIC range. The target amphotericin B concentration may be a target lung concentration range. In one version, the target lung amphotericin B concentration range fluctuates above and below a value that is from about 2 to about 20 times the midrange value of the MIC range, such as about 3 to about 10 times the midrange value, or about 5 times the midrange value. In one version, the amphotericin B concentrations and the MIC determinations are based on the concentrations in the epithelial lining fluid. In another version, the amphotericin B concentrations and the MIC determinations are based on the concentrations in the solid lung tissue. As used herein, unless otherwise specified, the MIC value shall be taken to be the particular value when a particular MIC value is determined and shall be taken to be a midrange value when a range of MIC values is determined. MIC determinations may be made according to processes known in the art. [0234] In one version, the pharmaceutical composition comprising amphotericin B is administered so that a target concentration is maintained over a desired period of time. For example, it has been determined that an administration routine that maintains a target concentration of amphotericin B that is at least about 2 times, such as at least about 3 times, the detennined MIC value is effective in treating and/or providing prophylaxis against a pulmonary and/or nasal fungal infection. It has been further determined that by maintaining the amphotericin B concentration at the target lung concentration for a period of at least about 1 week, such as at least about 2 weeks, or at least about 3 weeks, a pulmonary and/or nasal fungal infection can be effectively treated in some patients. Additionally or alternatively, by maintaining the amphotericin B lung concentration at the target concentration for the above periods in an immunocompromised patient, the likelihood of the patient developing a pulmonary and/or nasal fungal infection can be reduced. In many cases, the period of treatment and/or the period of prophylaxis may be extended to be more than about 1 month, more than about 2 months, more than about 3 months (e.g., 17 weeks), more than about 4 months, or longer. 52 WO 2007/041090 PCT/US2006/037422 [0235] In one version, the method of administering the crystalline amphotericin B takes advantage of the lung retention properties of the pharmaceutical composition comprising amphotericin B. In this regard, one or more embodiments of the present invention involves the discovery that amphotericin B of the pharmaceutical compositions has an amphotericin B lung-residence half-life of (1) at least about 10 hours, such as at least about 15 hours or at least about 20 hours in lung epithelial fluid, as measured by bronchoalveolar lavage, and/or (2) at least about 1 week, such as at least about 2 weeks, in lung tissue, as measured by lung tissue homogenization. [0236] Since the amphotericin B has a long lung-residence half-life and since low doses may be used in one or more embodiments, systemic exposure (blood/plasma amphotericin B concentrations) remains low enough to avoid renal and/or hepatic toxicity. For instance, after a 5 mg dose of inhaled amphotericin B, the blood level of the amphotericin B can remain less than about 1000 ng/mL, such as less than about 750 ng/mL, less than about 500 ng/mL, less than about 250 ng/mL, less than about 100 ng/mL, less than about 80 ng/mL, less than about 60 ng/mL, or less than about 40 ng/mL. [0237] In view of the long residence half-life, once the target lung tissue amphotericin B concentration is reached, limited dosing is required to maintain the lung tissue amphotericin B concentration. For example, the pharmaceutical composition may be administered once per week in order to maintain the lung amphotericin B concentration within the target. [0238] The dosage necessary and the frequency of dosing for maintaining the amphotericin B concentration within the target concentration depends on the composition and concentration of the amphotericin B within the composition. In each of the administration regimens, the dosages and frequencies are determined to give a lung amphotericin B concentration that is maintained within a certain target range. In one version, the amphotericin B may be administered weekly. In this version, the weekly dosage of amphotericin B ranges from about 2 mg to about 75 mg, such as about 2 mg to about 50 mg, about 4 mg to about 25 mg, about 5 mg to about 20 mg, and about 7 mg to about 10 mg. [0239] The dose may be administered during a single inhalation or may be administered during several inhalations. The fluctuations of lung amphotericin B concentration can be reduced by administering the pharmaceutical composition more often or may be increased by administering the pharmaceutical composition less often. Therefore, the pharmaceutical composition of one or more embodiments of the present invention may be 53 WO 2007/041090 PCT/US2006/037422 administered from about three times daily to about once a month, such as about once daily to about once every two weeks, about once every two days to about once a week, and about once per week. [0240] In one version, the pharmaceutical composition is administered prophylactically to a patient who is likely to become immunocompromised. For example, a patient who will undergo drug immunosuppressive therapy, such as a patient expecting a bone marrow transplant, can be prophylactically treated with a pharmaceutical composition comprising crystalline amphotericin B to reduce the likelihood of developing a fungal infection during an immunocompromised risk period. In this version, the amphotericin B administration is initiated a sufficient amount of time before the patient is immunocompromised to allow the lung amphotericin B concentration to reach the target concentration on or before the time of immunocompromise. When a dose is administered once weekly, the prophylactic period may vary from about 1 week to about 20 weeks, depending on the composition and dosage. However, in one or more embodiments of the invention, the time to effective prophylactic amphotericin B concentrations is shortened by either providing high doses of amphotericin B during the initial prophylactic period and/or by more frequently administering the dosages during the initial prophylactic period (e.g., loading dose). In this version, additional doses are administered during the first week of therapy. For example, doses may be administered on Days 1, 2, 3, and 4 (or 4 doses on Day 1) and then on every seventh day thereafter. This early loading allows the target lung amphotericin B concentrations to be achieved much sooner. Accordingly, the time for attaining effective prophylaxis is reduced and a patient may begin his or her immunocompromised period sooner. In the some examples, a patient may become immunocompromised after 1-4 days, with a significantly reduced likelihood of developing a pulmonary and/or nasal fungal infection. Additionally or alternatively, the dosage administered during the pre immunosuppression period may be higher than the dosage administered to maintain the target lung amphotericin B concentration (e.g., loading dose). For example, in one version, the first dose may be at least about two times the steady-state dosage given once the target lung amphotericin B concentration has been achieved. [0241] Thus, in one version, the amphotericin B is administered as a loading dose followed by maintenance doses. The loading dose of amphotericin may range, e.g., from about 5 mg to about 75 mg, such as from about 10 mg to about 50 mg, from about 15 mg to about 40 mg, or from about 20 mg to about 30 mg, such as about 25 mg. The maintenance 54 WO 2007/041090 PCT/US2006/037422 doses may be administered on a regular basis, e.g., weekly, after the loading dose. The maintenance dose typically ranges from about 2 mg to about 20 mg, such as from about 3 mg to about 15 mg or from about 4 mg to about 10 mg, such as about 5 mg. [0242] The early loading may also be desirable when treating a patient who has been diagnosed with a pulmonary and/or nasal fungal infection. By early loading, the target lung amphotericin B concentration is achieved sooner than when no early loading is administered. Therefore, the treatment of the pulmonary and/or nasal fungal infection may be more rapidly initiated or provided. [0243] In one specific therapeutic method, prophylaxis of pulmonary and/or nasal fungal infections is provided for a patient undergoing immunosuppressive therapy. According to this version, the patient is administered at least about 5 mg, such as from about 5 mg to about 10 mg, of aerosolized amphotericin B during the patient's inhalation at least about two times per week during an initial period. The aerosolized amphotericin B can be administered at least about three times per week during the initial period. In one version, the initial period may last from about one week to about three weeks. Following the initial period, the patient is administered the same dosage less frequently. For example, the aerosolized amphotericin B may be administered once every two weeks or once per week. Following the initial period or near the end of the initial period, the immunosuppressive therapy can be initiated. The second period of administration is continued so that the target lung amphotericin B concentration is maintained at least through the immunocompromised risk period and longer if needed or if a pulmonary and/or nasal fungal infection develops. Additionally or alternatively, the dosage administered during the first period may be larger than the dosage administered during the second period. For example, during the first period, from about 10 mg to about 20 mg of amphotericin B may be administered and a lesser amount, such as from about 5 mg to about 10 mg, is administered during the second period. Optionally, a third dosing period may be provided where the dosage is administered less frequently and/or in a lesser amount than in the second period. The third dosing period may be initiated near the end of an immunocompromised period, such as by being initiated when the immunosuppressive therapy is terminated or reduced in severity. [0244] In one version, the amphotericin B concentration is maintained for a period of time at a concentration above a determined minimum inhibitory concentration, such as described in U.S. Application No. 10/751,342, filed on December 31, 2003, which is incorporated herein by reference in its entirety. The lung amphotericin B concentration may 55 WO 2007/041090 PCT/US2006/037422 either be the amphotericin B concentration in the epithelial lining or the amphotericin B concentration in solid lung tissue, and is preferably the latter. In some versions, the lung amphotericin B concentration is at least about 4 ptg/g, such as at least about 9 pg/g, and may range from about 4.5 pg/g to about 20 gg/g, such as about 9 pg/g to about 15 pg/g. [0245] For prophylaxis, the amount per dose of amphotericin B may be an amount that is effective to prevent pulmonary and/or nasal infection by a fungus and generally ranges from about 0.01 mg/kg to about 5.0 mg/kg, such as about 0.4 mg/kg to about 4.0 mg/kg, or about 0.7 mg/kg to about 3.0 mg/kg. [0246] The pharmaceutical composition may be administered to a patient in any regimen which is effective to prevent pulmonary infection by a fungus. Illustrative prophylactic regimes include administering an antifungal dry powder as described herein 1 to 21 times per week over a time course from 1 to 6 weeks, followed, if needed, thereafter by administration once or twice weekly. [0247] An example of an embodiment of the present invention for administration of aerosolized predominantly crystalline amphotericin B is shown in Fig. 25, which shows prophylactic loading. The MIC value for amphotericin B in this version has been determined to range from about 0.5 pg/g to about 4 pg/g, as shown by block 300. The midrange MIC value 300' is about 2.25 pg/g. The curve 301 shows a predicted lung amphotericin B concentration according to a particular administration regimen. As can be seen, the amphotericin B concentration reaches a target lung amphotericin B concentration range 302 that is above the MIC range 300 and is at least two times greater than the midrange MIC value 300'. The target lung amphotericin B concentration range 302 may in this version range from 4 pg/g to 50 pg/g, such as from 4.5 pg/g to 20 pg/g. In the specific version shown, the target lung amphotericin B concentration range 302 is a range from 9 pg/g tol5 pg/g, and fluctuates about a concentration value that is about five times the midpoint value 300' of the MIC range 300. [0248] The maintenance of the lung amphotericin B concentration within a target lung amphotericin B concentration range according to one or more embodiments of the present invention is advantageous in its effectiveness in treating and/or providing prophylaxis against fungal infections and is also safer than conventional treatment. Fig. 26 shows the resulting predicted plasma amphotericin B concentration 400 during administration of amphotericin B according to one or more embodiments of the invention. As can be seen, the amphotericin B concentrations are significantly less than the plasma amphotericin B 56 WO 2007/041090 PCT/US2006/037422 concentration minimum toxicity concentrations 401, thereby increasing the safety of the administration. [0249] For treating a patient suffering from a pulmonary and/or nasal fungal infection, the amount per dose of amphotericin B administered may be an amount that is effective to treat the infection. The amount of amphotericin B for the treatment of infection will generally be higher than that used for prevention, and will typically range from about 0.01 mg/kg to 7.0 mg/kg, such as from about 0.2 mg/kg to about 6.0 mg/kg, or from about 0.8 mg/kg to about 5.0 mg/kg. In one exemplary treatment regimen, an antifungal powder in accordance with one or more embodiments of the invention may be administered about 1 to about 8 times daily, such as about 2 to about 6 times daily, over a course of from about 7 to about 28 days. [0250] In treating these respiratory fungal conditions, the pharmaceutical compositions are typically administered in doses that are about 3 to about 10 or more times the MIC of the causative fungal pathogens. Generally, the dose of amphotericin B delivered to a patient will range from about 2 mg to about 400 mg daily, such as from about 10 mg to 200 mg daily, depending on the condition being treated, the age and weight of the patient, and the like. [0251] While not bound by theory, by providing the amphotericin B in accordance with one or more embodiments of the invention, the local toxicity of the amphotericin B can be reduced by decreasing the rate of dissolution of the amphotericin B and/or by increasing deposition throughout the lung and avoiding local toxicity in the upper lung. Thus, the administration of crystalline amphotericin B is believed to be safer than the administration of a predominantly amorphous form of amphotericin B. Furthermore, the administration of smaller inhaled particulates formed from smaller amphotericin B particles tends to improve safety and/or may improve efficacy. [0252] When larger doses are administered, safety becomes a more important issue. Thus, higher crystallinity amphotericin B is indicated for higher doses. For instance, for a dose of greater than 50 mg, a skilled artisan may want to use a composition in which the amphotericin B crystallinity level is at least about 90%, the amphotericin B mass median diameter is less than about 2.8 gm, and the inhaled particle or particulate has an MMAD of less than about 2.8 im. [0253] When solid particles or particulates comprising amphotericin B are administered to the lungs, it has been determined that it is desirable to control the rate of 57 WO 2007/041090 PCT/US2006/037422 dissolution of the solid particles or particulates within the lungs. When the rate of dissolution is undesirably high, soluble, supermolecular aggregates may form at local sites within the lungs. These soluble aggregates may in some instances be toxic to the lung tissue. However, when the rate of dissolution is sufficiently low, there is a lower likelihood that soluble toxic aggregates will develop. While not bound by theory, it is believed that providing the solid particles or particulates comprising crystalline amphotericin B lowers the rate of dissolution when compared to amphotericin B in its amorphous form. Furthermore, it has been discovered that the lung amphotericin B concentrations in its crystalline form may be maintained at concentrations that are sufficiently high to provide a therapeutic effect against pulmonary and/or nasal fungal infections while significantly decreasing or preventing the development of toxic soluble aggregates. [0254] Thus, in one or more versions, the pharmaceutical composition may be delivered to the lungs of a patient in the form of a powder, especially a dry powder. Accordingly, the pharmaceutical composition comprises a powder that may be effectively delivered to the deep lungs or to another target site. This pharmaceutical composition is in the form of a powder comprising particles or particulates having a size selected to permit penetration into the alveoli of the lungs. [0255] In some instances, it is desirable to deliver a unit dose, such as doses of 5 mg or 10 mg or greater of amphotericin B to the lung in a single inhalation. The above described phospholipid hollow and/or porous powder particulates allow for doses of about 5 mg or greater, often greater than about 10 mg, and sometimes greater than about 25 mg, to be delivered in a single inhalation and in an advantageous manner. Alternatively, a dosage may be delivered over two or more inhalations. For example, a 10 mg dosage may be delivered by providing two unit doses of 5 mg each, and the two unit doses may be separately inhaled. [0256] The dispersions or powder pharmaceutical compositions may be administered using an aerosolization device. The aerosolization device may be a nebulizer, a metered dose inhaler (MDI), a liquid dose instillation device, or a dry powder inhaler. The powder pharmaceutical composition may be delivered by a nebulizer as described in WO 99/16420, by a metered dose inhaler as described in WO 99/16422, by a liquid dose instillation apparatus as described in WO 99/16421, and by a dry powder inhaler as described in U.S. Patent Application No. 09/888,311 filed on June 22, 2001, in WO 99/16419, in WO 02/83220, in U.S. Patent No. 6,546,929, and in U.S. Patent Application No. 10/616,448, filed on July 8, 2003, which are incorporated herein by reference in their entireties. As such, an 58 WO 2007/041090 PCT/US2006/037422 inhaler may comprise a canister containing the particles or particulates and propellant, and wherein the inhaler comprises a metering valve in communication with an interior of the canister. The propellant may be a hydrofluoroalkane. [0257] A particularly useful class of MDIs are those which use hydrofluoroalkane (HFA) propellants. The HFA propellants are further particularly well suited to be used with stabilized dispersions of an active agent such as formulations and composition of amphotericin B. Suitable propellants, formulations, dispersions, methods, devices and systems comprise those disclosed in US 6,309,623, the disclosure of which is incorporated by reference in its entirety. The various embodiments of the compositions, formulations, systems and methods of the present invention are suited to, and often optimal for, combination with such HFA-propellant based MDIs. In part, this is due to physical properties of the various embodiments of the amphotericin B particles and/or composition, such as the density, specific surface area, MMD and/or MMAD, as well as due in part to the methods of administration and methods of treatment herein. [0258] The pharmaceutical composition of one or more embodiments of the present invention typically has improved emitted dose efficiency. Accordingly, high doses of the pharmaceutical composition may be delivered using a variety of aerosolization devices and techniques. [0259] The emitted dose (ED) of these powders may be greater than about 30%, such as greater than about 40%, greater than about 50%, greater than about 60%, or greater than about 70%. [0260] The time for dosing is typically short. For a single capsule (e.g., 5 mg dose), the total dosing time is normally less than about 1 minute. A 2 capsule dose (e.g., 10 mg) usually takes about 1 min. A 5 capsule dose (e.g., 25 mg) may take about 3.5 min to administer. Thus, the time for dosing may be less than about 5 min, such as less than about 4 min, less than about 3 min, less than about 2 min, or less than about 1 min. [0261] In view of the above, one or more embodiments, relate to storing a pharmaceutical composition. Although the process is illustrated in the context of packaging a dry powder pharmaceutical composition receptacle and aerosolization apparatus, the present invention can be used in other processes and should not be limited to the examples provided herein. [0262] Although several embodiments of the present invention has been described in considerable detail with regard to certain preferred versions thereof, other versions are 59 possible, and alterations, permutations and equivalents of the version shown will become apparent to those skilled in the art upon a reading of the specification and study of the drawings. For example, the relative positions of the elements in the aerosolization device may be changed, and flexible parts may be replaced by more rigid parts that are hinged, or otherwise movable, to mimic the action of the flexible part. In addition, the passageways need not necessarily be substantially linear, as shown in the drawings, but may be curved or angled, for example. Also, the various features of the versions herein can be combined in various ways to provide additional embodiments of the present invention. Furthermore, certain terminology has been used for the purposes of descriptive clarity, and not to limit the present invention. Therefore, any appended claims submitted in relation to this disclosure should not be limited to the description of the preferred versions contained herein and should include all such alterations, permutations, and equivalents as fall within the true spirit and scope of the present invention. [0263] It is to be understood that, if any prior art publication is referred to herein, such reference does not constitute an admission that the publication forms a part of the common general knowledge in the art, in Australia or any other country. [0264] In the claims which follow and in the preceding description of the invention, except where the context requires otherwise due to express language or 0 necessary implication, the word "comprise" or variations such as "comprises" or "comprising" is used in an inclusive sense, i.e. 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. 60 4A0126 (GHMfne-s P7720B.AU

Claims

1. A receptacle, comprising: a holder forming a cavity that holds an aerosolizable pharmaceutical; 5 a lid comprising a substantially flat surface, wherein the substantially flat surface includes a portion extending across the cavity; and an adhesive that forms a bond between the holder and the lid, wherein the adhesive does not extend to the end of the holder to form an unbonded portion, wherein the bond has a shape relative to the unbonded portion, and wherein the shape 10 comprises an arcuate protrusion extending away from the cavity, wherein the unbonded portion extends from the protrusion to an end of the holder and facilitates removal of the lid from the holder.

2. The receptacle of claim 1, wherein the length of the unbonded portion 15 from the protrusion to the end of the holder is at least about 5 mm.

3. The receptacle of claim 1, wherein the unbonded portion extends from one side edge of the holder to the opposite side edge of the holder. 20

4. The receptacle of claim 1, wherein the holder includes a substantially flat surface, and said adhesive forms a bond between said substantially flat surfaces of the holder and the lid, and wherein the substantially flat surface of the lid comprises the unbonded portion that facilitates removal of the lid from the holder. 25

5. The receptacle of claim 1, wherein the lid comprises a raised portion.

6. The receptacle of claim 1, wherein the holder comprises a laminate comprising thermoplastic. 61 4E12692.1 (GHMatl) P77206.AU

7. The receptacle of claim 1, wherein the lid comprises one or more of the group consisting of a metal foil, a paper, and a laminate comprising thermoplastic. 5

8. The receptacle of claim 1, wherein the receptacle contains a capsule containing the aerosolizable pharmaceutical.

9. The receptacle of claim 8, wherein the aerosolizable pharmaceutical comprises amphotericin B. 10

10. The receptacle of claim 8, wherein the aerosolizable pharmaceutical comprises a hormone.

11. The receptacle of claim 10, wherein the hormone comprises one or more 15 of the group consisting of a parathyroid hormone, a fragment of a parathyroid hormone, a derivative of a parathyroid hormone, and an analog of a parathyroid hormone.

12. The receptacle of claim 8, wherein the aerosolizable pharmaceutical comprises an anti-infective. 20

13. The receptacle of claim 12, wherein the anti-infective is an antibiotic,

14. The receptacle of claim 13, wherein the antibiotic comprises one or more of the group consisting of amikacin, gentamicin, vancomycin, tobramycin, and 25 ciprofloxacin.

15. The receptacle of claim 13, wherein the antibiotic is tobramycin. 62 48128021 (OHMa-te) P77206.AIJ

16. An array, comprising a plurality of the receptacles of claim 1, wherein the plurality of receptacles are attached to each other.

17. The array of claim 16, wherein the array comprises a one-dimensional 5 array.

18. The array of claim 16, wherein the array comprises a two-dimensional array. 10

19. The array of claim 16, wherein adjacent receptacles are separated by perforations.

20. The array of claim 16, wherein adjacent receptacles are separated by at least one score cut. 15

21. The array of claim 16, further comprising a backing on which the receptacles are mounted, wherein the backing is separable from the receptacles.

22. The receptacle of claim I or the array of claim 16 substantially as herein 20 described with reference to any one of the Examples or the accompanying figures. 63 40l2692_I (GHWWbvm) P7T2UGAA