Development of Fully Redispersible Dried Nanocrystals by Using Sucrose Laurate as Stabilizer for Increasing Surface Area and Dissolution Rate of Poorly Water-Soluble Drugs

There is much interest in converting poorly water-soluble drugs into nanocrystals as they provide extremely high surface area that increases dissolution rate and oral bioavailability. However, nanocrystals are prepared as aqueous suspensions, and once the suspensions are dried for development of solid dosage forms, the nanocrystals agglomerate as large particles to reduce the excess surface energy. For successful development of drug products, it is essential that any agglomeration is reversible, and the dried nanocrystals regain original particle sizes after redispersion in aqueous media. We have established that sucrose laurate serves as a superb stabilizer to ensure complete redispersion of dried nanocrystals in aqueous media with mild agitation. Nanocrystals (150–300 nm) of three neutral drugs (fenofibrate, danazol and probucol) were produced with sucrose laurate by media milling, and suspensions were dried by tray drying under vacuum, spray drying, and lyophilization. Dried solids and their tablets redispersed into original particle sizes spontaneously. Preliminary studies showed that sucrose laurate can also redisperse acidic and basic drugs, indicating its versatile application. Fatty acid ester of another disaccharide, lactose laurate, also performed like sucrose laurate. Thus, we have developed a method of retaining high dissolution rate and, by implication, high bioavailability of nanocrystals from solid formulations.     

Conversion of Nanosuspensions into Dry Powders by Spray Drying: A Case Study

Purpose  Drying of nanosuspensions can cause destabilization of the particles, leading to irreversible aggregation. In order to prepare an effective solid dosage form for a nanosuspension, it is imperative that the spray-dried nanoparticles should go back to their original particle size when reconstituted in an aqueous system. This case study examines impact of various formulation and processing parameters on redispersibility of the spray dried nanoparticles. Methods  Nanosuspensions were prepared using the microprecipitation–homogenization process. Spray drying of nanosuspensions was achieved using a lab-scale Buchi spray dryer. Results  Formulation components appeared to have the most significant impact on redispersibility of spray dried particles. Absence of surface charge led to particles that could not be redispersed. On the other hand, charged particles stabilized with an appropriate sugar led to spray dried powders that were flowable and easily redispersible. Dissolution testing showed the presence of two phases—a lag phase that represented dispersion of the loose aggregates, and dissolution of the dispersed nanoparticles. Conclusions  Nanosuspensions of a poorly soluble drug could be spray dried to obtain flowable powders that could be easily redispersed. These optimized powders also showed significantly improved dissolution rates as compared to the micronized drug, or unoptimized nanosuspensions.     

Studies on the spray dried lactose as carrier for dry powder inhalation

The purpose of this study was to investigate the spray dried lactose as carrier for dry powder inhalation (DPI). The lactose particles were prepared by spray drying, then the particle size, shape and crystal form were characterized by laser diffraction, scanning electron microscopy (SEM), X-ray diffraction (XRD) and differential scanning calorimetry (DSC). The spray dried lactose particles were spherical and amorphous, but would transfer to crystal form when storage humidity was above 32%. Thus, the humidity of the storage environment should be controlled below 30% strictly in order to maintain the amorphous nature of spray dried lactose which is a great benefit to DPI development.     

Effect of Lipidic Excipients on the Particle Properties and Aerosol Performance of High Drug Load Spray Dried Particles for Inhalation

High drug load inhalable particles were prepared by co-spray drying a hydrophobic, crystalline, small molecule drug with various lipid or phospholipid excipients at a 9:1 molar ratio to understand the primary drivers of aerosol performance. The effect of excipient structure on solid-state, surface characteristics, and aerodynamic performance of the co-spray dried particles was studied while keeping the spray drying parameters constant. Spray drying of the drug with lipids produced crystalline drug particles, whereas phospholipids produced partially amorphous drug particles. All of the co-spray dried particles were nearly spherical with a smooth surface, except for the spray dried drug particles without excipients – which showed the presence of rough crystals on the surface. All co-spray dried particles showed surface enrichment of the excipient. The surface enrichment of the phospholipids was higher compared to the lipids. Co-spray dried particles that showed higher surface enrichment of excipients showed improved aerosol performance. In comparing all the excipients studied, distearyolphosphatidylcholine (DSPC) showed maximum enrichment on the particle surface and thereby significantly improved aerosol performance. This study demonstrated that the addition of small amounts of lipid excipients during spray drying can change surface morphology, composition, and cohesion, impacting aerosol performance of drugs.     

Characterisation of excipient-free nanoporous microparticles (NPMPs) of bendroflumethiazide.

The purpose of this study was to prepare excipient-free porous microparticles of bendroflumethiazide by spray drying and to characterise the physicochemical properties of the particles produced. Solutions of bendroflumethiazide in ethanol/water, ethanol/water/ammonium carbonate or methanol/water/ammonium carbonate were spray dried using a laboratory spray dryer. Spray dried products were characterised by scanning electron microscopy, X-ray powder diffraction, differential scanning calorimetry, FTIR, laser diffraction particle sizing and density measurement. Nanoporous microparticles (NPMPs) were prepared from the alcoholic solutions containing ammonium carbonate. NPMPs were amorphous in nature, had median particles sizes less than 3mum and densities that were significantly reduced compared to non-porous spray dried bendroflumethiazide powder. The novel process may be used to produce excipient-free amorphous microparticles with desirable physical properties such as amorphous solid state, porosity and low bulk density. This new engineering technology has applications in the design of other therapeutic agents such as those used in pulmonary delivery.     

Single step bottom-up process to generate solid phospholipid nano-particles

Abstract

Context: The particularity of the Nano Spray Dryer B-90 is the nozzle containing a mesh vibrating at ultrasonic frequency.

Objective: To study process parameters and processability of crude phospholipid dispersions, in particular the effect of concentration and mesh aperture on both particle size of the dry solid phospholipid nano-particles and on the re-dispersed powder.

Materials and methods: Phospholipid dispersions containing trehalose as a stabilizer were spray dried. Particle size distributions of dry powders were evaluated by SEM micrographs and by PCS and cryo-TEM for the re-dispersed particles.

Results: Spray drying of crude liposome dispersions revealed solid phospholipid nano-particles. Aperture of nozzle mesh and concentration of the dispersions, respectively, both increased the size of solid phospholipid nano-particles. For crude dispersions, an upper limit with respect to processability was found close to below 10% (m/m) even if the crude dispersion was passed along the mesh several times; however, more effective dispersing methods such as pre-sonication can push the limit of processability to higher values.

Discussion and conclusion: The nano spray dryer is capable of spray drying crude dispersions of phospholipids in concentrations below 10% (m/m) generating solid phospholipid nano-particles relevant for pulmonary delivery. Re-dispersion of spray dried powder reveals liposomes.     

喷雾干燥法固化黄豆苷元固体脂质纳米粒的研究

目的：建立一种干燥的固体脂质纳米粒的制备方法。方法：采用超声分散法制备黄豆苷元固体脂质纳米粒的混悬液,然后采用喷雾干燥法将其制成干燥的、可再分散的固体脂质纳米粒。结果：在混悬液中黄豆苷元固体脂质纳米粒为球形粒子,平均粒径约为280 nm,喷雾干燥后得到的纳米粒仍为球型,分散后的粒径与喷干前相比有所增大,平均粒径约为720 nm,稳定性较好。结论：喷雾干燥法制备黄豆苷元固体脂质纳米粒是可行的。     

Aerosol Delivery of Nanoparticles in Uniform Mannitol Carriers Formulated by Ultrasonic Spray Freeze Drying

Purpose

While most examples of nanoparticle therapeutics have involved parenteral or IV administration, pulmonary delivery is an attractive alternative, especially to target and treat local infections and diseases of the lungs. We describe a successful dry powder formulation which is capable of delivering nanoparticles to the lungs with good aerosolization properties, high loadings of nanoparticles, and limited irreversible aggregation.

Methods

Aerosolizable mannitol carrier particles that encapsulate nanoparticles with dense PEG coatings were prepared by a combination of ultrasonic atomization and spray freeze drying. This process was contrasted to particle formation by conventional spray drying.

Results

Spray freeze drying a solution of nanoparticles and mannitol (2 wt% solids) resulted in particles with an average diameter of 21?±?1.7 μm, regardless of the fraction of nanoparticles loaded (0–50% of total solids). Spray freeze dried (SFD) powders with a 50% nanoparticle loading had a fine particle fraction (FPF) of 60%. After formulation in a mannitol matrix, nanoparticles redispersed in water to < 1 μm with hand agitation and to < 250 nm with the aid of sonication. Powder production by spray drying was less successful, with low powder yields and extensive, irreversible aggregation of nanoparticles evident upon rehydration.

Conclusions

This study reveals the unique advantages of processing by ultrasonic spray freeze drying to produce aerosol dry powders with controlled properties for the delivery of therapeutic nanoparticles to the lungs.     

Combination Chemotherapeutic Dry Powder Aerosols via Controlled Nanoparticle Agglomeration

Purpose  To develop an aerosol system for efficient local lung delivery of chemotherapeutics where nanotechnology holds tremendous potential for developing more valuable cancer therapies. Concurrently, aerosolized chemotherapy is generating interest as a means to treat certain types of lung cancer more effectively with less systemic exposure to the compound. Methods  Nanoparticles of the potent anticancer drug, paclitaxel, were controllably assembled to form low density microparticles directly after preparation of the nanoparticle suspension. The amino acid, l-leucine, was used as a colloid destabilizer to drive the assembly of paclitaxel nanoparticles. A combination chemotherapy aerosol was formed by assembling the paclitaxel nanoparticles in the presence of cisplatin in solution. Results  Freeze-dried powders of the combination chemotherapy possessed desirable aerodynamic properties for inhalation. In addition, the dissolution rates of dried nanoparticle agglomerate formulations (∼60% to 66% after 8 h) were significantly faster than that of micronized paclitaxel powder as received (∼18% after 8 h). Interestingly, the presence of the water soluble cisplatin accelerated the dissolution of paclitaxel. Conclusions  Nanoparticle agglomerates of paclitaxel alone or in combination with cisplatin may serve as effective chemotherapeutic dry powder aerosols to enable regional treatment of certain lung cancers. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Drying-Induced Variations in Physico-Chemical Properties of Amorphous Pharmaceuticals and Their Impact on Stability II: Stability of a Vaccine

Objectives To investigate the impact of drying method on the storage stability of dried vaccine formulations. Materials and Methods A sucrose-based formulation of a live attenuated virus vaccine of a parainfluenza strain, with and without surfactant, was dried from by different methods; freeze drying, spray drying and foam drying. Dried powders were characterized by differential scanning calorimetry, specific surface area (SSA) analysis and by electron spectroscopy for chemical analysis (ESCA) to evaluate vaccine surface coverage in the dried formulations. Dried formulations were subjected to storage stability studies at 4, 25 and 37°C. The vaccine was assayed initially and at different time points to measure virus-cell infectivity, and the degradation rate constant of the vaccine in different dried preparations was determined. Results SSA was highest with the spray dried preparation without surfactant (∼ 2.8 m²/g) and lowest in the foam dried preparations (with or without surfactant) (∼ 0.1 m²/g). Vaccine surface coverage was estimated based on ESCA measurements of nitrogen content. It was predicted to be highest in the spray dried preparation without surfactant and lowest in the foam with surfactant. Stability studies conducted at 25°C and 37°C showed that the vaccine was most stable in the foam dried preparation with surfactant and least stable in spray dried preparations without surfactant and in all freeze dried preparations regardless of the presence of surfactant. Addition of surfactant did lower the SSA and vaccine surface coverage in freeze dried preparations but still did not improve storage stability. Conclusions In drying methods that did not involve a freezing step, good storage stability of Medi 534 vaccine in the dried form was found with low SSA and low vaccine surface accumulation, both of which integrate into low fraction of vaccine at the surface. Ice appears to be a major destabilizing influence.     

Excipient-free nanoporous microparticles of budesonide for pulmonary delivery

The aim of this study was to investigate the application of a spray-drying process for the production of nanoporous microparticles (NPMPs) to budesonide, and to characterise the particles produced in terms of their suitability for pulmonary delivery.Budesonide was spray dried with and without ammonium carbonate from ethanol/water or methanol/water solutions. The solid-state characteristics and micromeritic (particle size, density, surface area) properties of spray dried powders were assessed. In vitro deposition studies were performed to assess aerosol performance.The densities of the NPMPs were significantly lower and the surface areas significantly higher than for non-porous spray dried or micronised material. NPMPs of budesonide demonstrated improved aerosolisation properties compared to spray dried non-porous, micronised material and two budesonide commercial products. All spray dried materials were amorphous in nature. The glass transition temperature (90 °C) was sufficiently high to suggest good physical stability at room temperature. When stored at 25 °C/60% RH NPMPs showed a reduced tendency to recrystallise compared to the equivalent non-porous spray dried powder. The physical stability and amorphous nature of NPMPs was retained, under these storage conditions for at least one year and the in vitro aerosolisation properties were not affected by the storage conditions.Excipient-free porous microparticles, prepared by the novel process described, show good potential for drug delivery by oral inhalation with improved in vitro deposition properties compared to non-porous particles.     

Spray-drying preparation of microparticles containing cationic PLGA nanospheres as gene carriers for avoiding aggregation of nanospheres

Preparation of nano-sized particles using lyophilization, which is a standard drying technique for high-molecular-weight compounds such as bioactive peptides, proteins, plasmid DNA and siRNA, often results in particle aggregation. In this study, spray-drying was applied for preparation of cationic PLGA nanospheres as gene delivery vectors in order to minimize aggregation and loss of gene transfection efficiency. PLGA nanoparticle emulsions were prepared by dropping an acetone/methanol mixture (2/1) containing PLGA and a cationic material, such as PEI, DOTMA, DC-Chol or CTAB, into distilled water with constant stirring. The PLGA nanosphere emulsion was dried with mannitol by spray-drying, and mannitol microparticles containing PLGA nanospheres were obtained. Mean particle diameter of spray dried PLGA particles was 100-250 nm, which was similar to that of the nano-emulsion before drying, whereas the lyophilized PLGA particles showed increased particle diameter due to particle aggregation. PEI, DOTMA and DC-Chol were useful for maintaining nanoparticle size and conferring positive charge to nanospheres. Transfection of pDNA (pCMV-Luc) using these spray-dried cationic PLGA nanospheres yielded high luciferase activity in COS-7 cells, particularly with PLGA/PEI nanospheres. The present spray-drying technique is able to provide cationic PLGA nanospheres, and may improve redispersal and handling properties.     

Rapid,Room Temperature Nanoparticle Drying and Low-Energy Reconstitution via Electrospinning

Nanoparticle formulations offer advantages over free drugs; however, stability of the nanoparticle dispersions is a significant obstacle, and drying is often required for long-term size stability. The main limitation of current drying methods is particle aggregation upon reconstitution which can be overcome with sonication (impractical in a clinical setting) or large amounts of cryoprotectants (result in hypertonic dispersions). Therefore, new approaches to nanoparticle drying are necessary. We demonstrate conversion of nanoparticle dispersions to a dry, thermostable form via electrospinning. As a proof-of-concept, polyethylene glycol stabilized nanoparticles and polyvinyl alcohol were blended and electrospun into ～300 nm fibers. Following electrospinning, nanoparticles were stored for at least 7 months and redispersed with low osmolarity to their original size without sonication. The nanoparticles redisperse to their original size when the fiber diameter and nanoparticle diameter are comparable (nanoparticle:nanofiber ratio ～1). Nanoparticles with liquid cores and larger particles better maintained their size when compared to nanoparticles with solid cores and smaller particles, respectively. Storing the nanoparticles within nanofibers appears to prevent Ostwald ripening improving thermostability. Overall, this novel approach enables rapid, continuous drying of nanoparticles at room temperature to facilitate long-term nanoparticle storage. Improved nanoparticle drying techniques will enhance clinical translation of nanomedicines.     

The effect of vehicle on physical properties and aerosolisation behaviour of disodium cromoglycate microparticles spray dried alone or with L-leucine

The aim of this study was to improve the aerosolisation behaviour of disodium cromogycate (DSCG), using spray drying technique. The effect of vehicle on the drug particle properties was investigated. L-leucine was selected as a natural antiadherent amino acid to improve the deagglomeration of DSCG particles. Spray dried samples of DSCG alone or with L-leucine were prepared from water and ethanol under the same conditions. The powder properties of the samples were examined by laser diffraction, helium densitometer, X-ray diffraction, differential scanning calorimetry and thermogravimetric analysis. The in vitro deposition was determined, using an Andersen cascade impactor with a Spinhaler at a flow rate of 60 l/min. An amorphous form of the drug was obtained when water was used. However, crystal transformation of original DSCG in the presence of ethanol during spray drying resulted in production of elongated particles. These particles exhibited improved aerodynamic properties, compared to the amorphous and commercial materials. Significant differences in fine particle fraction were observed using the two vehicles. Co-spray drying of DSCG and L-leucine improved the deposition profiles of the drug. These results indicated that the change in crystal structure of DSCG during spray drying process was susceptible to the nature of the vehicle. A crystalline form of DSCG with good aerodynamic properties was achieved during spray drying process. In addition, the processing of DSCG with L-leucine in a single step using ethanol resulted in an improvement in dispersion properties of the drug particles.     

Physicochemical properties of tadalafil solid dispersions – Impact of polymer on the apparent solubility and dissolution rate of tadalafil

To improve solubility of tadalafil (Td), a poorly soluble drug substance (3 μg/ml) belonging to the II class of the Biopharmaceutical Classification System, its six different solid dispersions (1:1, w/w) in the following polymers: HPMC, MC, PVP, PVP-VA, Kollicoat IR and Soluplus were successfully produced by freeze-drying. Scanning electron microscopy showed a morphological structure of solid dispersions typical of lyophilisates. Apparent solubility and intrinsic dissolution rate studies revealed the greatest, a 16-fold, increase in drug solubility (50 μg/ml) and a significant, 20-fold, dissolution rate enhancement for the Td/PVP-VA solid dispersion in comparison with crystalline Td. However, the longest duration of the supersaturation state in water (27 μg/ml) over 24 h was observed for the Td solid dispersion in HPMC. The improved dissolution of Td from Td/PVP-VA was confirmed in the standard dissolution test of capsules filled with solid dispersions. Powder X-ray diffraction and thermal analysis showed the amorphous nature of these binary systems and indicated the existence of dispersion at the molecular level and its supersaturated character, respectively. Nevertheless, as evidenced by film casting, the greatest ability to dissolve Td in polymer was determined for PVP-VA. The crystallization tendency of Td dispersed in Kollicoat IR could be explained by the low T_g (113 °C) of the solid dispersion and the highest difference in Hansen solubility parameters (6.8 MPa^0.5) between Td and the polymer, although this relationship was not satisfied for the partially crystalline dispersion in PVP. Similarly, no correlation was found between the strength of hydrogen bonds investigated using infrared spectroscopy and the physical stability of solid dispersions or the level of supersaturation in aqueous solution.     

Preparation of Polymeric Submicron Particle-Containing Microparticles Using a 4-Fluid Nozzle Spray Drier

Purpose We studied a novel method for preparing polymeric submicron particle-containing microparticles using a 4-fluid nozzle spray drier. Method Ethylcellulose (EC) and poly(lactic-co-glycolic acid) (PLGA), either alone or in combination with polyethylenimine (PEI), were used as polymers to produce submicron particles, and mannitol (MAN) was used as a water-soluble carrier for the microparticles. The polymer and MAN solutions were supplied through different liquid passages of a 4-fluid nozzle and then dried to obtain MAN microparticles containing EC or PLGA submicron particles. The polymer/MAN ratio was controlled by changing the concentration of the polymer and MAN solutions. EC or PLGA microparticles were observed via scanning electron microscopy, and the size of microparticles was determined by image analysis. The particle size distribution of EC or PLGA submicron particles was measured with a super dynamic light scattering spectrophotometer. Results The method generated submicron-sized (<1 μm) particles of EC and PLGA. The mean diameters of EC and PLGA particles at a polymer/MAN ratio of 1:10 were 631 and 490 nm, respectively. The mean diameter of PLGA particles decreased as the PLGA/MAN ratio was reduced, reaching ∼200 nm at a PLGA/MAN ratio of 1:100. The mean diameter of PLGA/PEI particles at PLGA/PEI/MAN ratios of 1:0.5:10 and 1:0.5:100 were 525 and 223 nm, respectively, and their zeta potentials were +50.8 and +58.2 mV, respectively. The size of EC submicron particles could be controlled by varying the spray conditions. Conclusions This study demonstrated that it is possible to prepare polymeric submicron particles dispersed in MAN microparticles in a single process using the 4-fluid nozzle spray drying method. Cationic PLGA particles with a diameter of ∼200 nm could be prepared by adding PEI, suggesting the possibility of its use as a carrier for delivering DNA into cells. The precipitation of EC may occur by the mutual dispersion and mixing of solvents after collision of EC and MAN mists by antisolvent effect, thereby producing MAN microparticles containing EC submicron particles.     

An atomic force microscopy approach for assessment of particle density applied to single spray-dried carbohydrate particles

To evaluate an atomic force microscopy (AFM) approach for effective density analysis of single spray dried carbohydrate particles in order to investigate the internal structure of the particles. In addition, the AFM method was compared to an established technique, that is gas pycnometry. Resonant frequency AFM analysis was employed for determination of the mass of individual particles of spray-dried lactose, mannitol, and a mixture of sucrose/dextran (4:1). The effective particle density was calculated using the diameter of the spherical particles obtained from light microscopy. The apparent particle density was further analyzed with gas pycnometry. It was observed by microscopy that particles appeared either "solid" or "hollow." A solid appearance applied to an effective particle density close to the true density of the material, whereas a density around 1 g/cm(3) corresponded to a hollow appearance. However, carbohydrates, which crystallized during spray drying, for example, mannitol appeared solid but the average effective particle density was 0.95 g/cm(3), indicating a continuous but porous structure. AFM measurements of effective particle density corroborate the suggestion of differences in particle structure caused by the varying propensity of carbohydrates to crystallize during spray drying, resulting in mainly either amorphous hollow or crystalline porous particles.     

Templated Open Flocs of Nanorods for Enhanced Pulmonary Delivery with Pressurized Metered Dose Inhalers

Purpose  A novel concept is presented for the formation of stable suspensions composed of low density flocs of high aspect ratio drug particles in hydrofluoroalkane (HFA) propellants, and for subdividing (templating) the flocs with aerosolized HFA droplets to achieve high fine particle fractions with a pressurized metered dose inhaler. Methods  Bovine serum albumin (BSA) nanorods, produced by thin film freezing (TFF), were added to HFA to form a suspension. Particle properties were analyzed with an Anderson cascade impactor (ACI), static and dynamic light scattering and optical microscopy. Results  The space filling flocs in HFA were stable against settling for one year. The pMDI produced high fine particle fractions (38–47%) with an emitted dose of 0.7 mg/actuation. The atomized HFA droplets break apart, that is template, the highly open flocs. Upon evaporation of HFA, capillary forces shrink the templated flocs to produce porous particles with optimal aerodynamic diameters for deep lung delivery. Conclusions  Open flocs composed of nanorods, stable against settling, may be templated during actuation with a pMDI to produce optimal aerodynamic diameters and high fine particle fractions. This concept is applicable to a wide variety of drugs without the need for surfactants or cosolvents to stabilize the primary particles.     

Preparation of amorphous cefuroxime axetil nanoparticles by sonoprecipitation for enhancement of bioavailability.

The aim of the present work was to prepare amorphous discreet nanoparticles by sonoprecipitation method for enhancing oral bioavailability of cefuroxime axetil (CA), a poorly water-soluble drug. CA nanoparticles (SONO-CA) were prepared by sonoprecipitation and compared with particles obtained by precipitation without sonication (PPT-CA) and amorphous CA obtained by spray drying. Spray drying present broad particle size distribution (PSD) with mean particle size of 10mum and low percent yield, whereas, precipitation without sonication resulted in large amorphous aggregates with broad PSD. During sonoprecipitation, particle size and yield improve with an increase in the amplitude of sonication and lowering the operation temperature due to instantaneous supersaturation and nucleation. The overall symmetry and purity of CA molecule was maintained as confirmed by FTIR and HPLC, respectively. All the three methods resulted in the formation of amorphous CA with only sonoprecipitation resulting in uniform sized nanoparticles. Sonoprecipitated CA nanoparticles showed enhanced dissolution rate and oral bioavailability in Wistar rat due to an increased solubility attributed to combination of effects like amorphization and nanonization with increased surface area and reduced diffusion pathway.     

Amorphous cyclosporin nanodispersions for enhanced pulmonary deposition and dissolution

Aqueous colloidal dispersions of amorphous cyclosporin A (CsA) nanoparticles, intended for pulmonary delivery, were formed by antisolvent precipitation and stabilized with 10% polysorbate 80. Dissolution of the dispersion of CsA nanoparticles produced supersaturation values 18 times the aqueous equilibrium solubility. Nebulization of the dispersion to mice produced therapeutic lung levels and systemic concentrations below toxic limits. The sizes of the aerosolized aqueous droplets are optimal for deep lung deposition, whereas the amorphous drug nanoparticles facilitate rapid dissolution. A dissolution/permeation model was developed to characterize the effects of particle size, solubility, and drug dose on the absorption half-lives of poorly water soluble drugs in the alveolar epithelium. For crystalline 3 microm particles with a solubility of 1 microg/mL, the half-life for absorption was estimated to be 500 min. The half-life may be reduced to less than 1 min by increasing the solubility by a factor of 100 with an amorphous form as well as by decreasing the particle size 10-fold. The in vitro and in vivo data, as well as the dissolution/permeation model, indicate that nebulization of amorphous nanoparticle suspensions has the potential to enhance lung epithelial absorption markedly for poorly water soluble drugs, relative to respiratory delivery of crystalline, micron-sized particles.