Thomas E. Tarara

Hollow porous particles in metered dose inhalers

AbstractPurpose. To assess the physical stability and aerosol characteristicsof suspensions of hollow porous microspheres (PulmoSpheres™) inHFA-134a. Methods. Cromolyn sodium, albuterol sulfate, and formoterol fumaratemicrospheres were prepared by a spray-drying method. Particle sizeand morphology were determined via electron microscopy. Particleaggregation and suspension creaming times were assessed visually,and aerosol performance was determined via Andersen cascadeimpaction and dose uniformity studies. Results. The hollow porous particle morphology allows the propellantto permeate freely within the particles creating a novel form ofsuspension termed a homodispersion™, wherein the dispersed and continuousphases are identical, separated by an insoluble interfacial layer of drugand excipient. Homodispersion formation improves suspension stabilityby minimizing the difference in density between the particles andthe medium, and by reducing attractive forces between particles. Theimproved physical stability leads to excellent dose uniformity. Excellentaerosolization efficiencies are also observed with PulmoSpheresformulations, with fine particle fractions of about 70%. Conclusions. The formation of hollow porous particles provides anew formulation technology for stabilizing suspensions of drugs inhydrofluoroalkane propellants with improved physical stability, contentuniformity, and aerosolization efficiency.

Improved Lung Delivery from a Passive Dry Powder Inhaler Using an Engineered PulmoSphere® Powder

AbstractPurpose. To assess the pulmonary deposition and pharmacokinetics of an engineered PulmoSphere® powder relative to standard micronized drug when delivered from passive dry powder inhalers (DPIs). Methods. Budesonide PulmoSphere (PSbud) powder was manufactured using an emulsion-based spray-drying process. Eight healthy subjects completed 3 treatments in crossover fashion: 370 μg budesonide PulmoSphere inhaled from Eclipse® DPI at target PIF of 25 L·min-1 (PSbud25), and 50 L·min-1 (PSbud50), and 800 μg of pelletized budesonide from Pulmicort® Turbuhaler® at 60 L·min-1(THbud60). PSbud powder was radiolabeled with 99mTc and lung deposition determined scintigraphically. Plasma budesonide concentrations were measured for 12 h after inhalation. Results. Pulmonary deposition (mean ± sd) of PSbud was 57 ± 7% and 58 ± 8% of the nominal dose at 25 and 50 L·min-1, respectively. Mean peak plasma budesonide levels were 4.7 (PSbud25), 4.0 (PSbud50), and 2.2 ng·ml-1 (THbud60). Median tmax was 5 min after both PSbud inhalations compared to 20 min for Turbuhaler (P < 0.05). Mean AUCs were comparable after all inhalations, 5.1 (PSbud25), 5.9 (PSbud50), and 6.0 (THbud60) ng·h·ml-1. The engineered PSbud powder delivered at both flow rates from the Eclipse® DPI was twice as efficiently deposited as pelletized budesonide delivered at 60 L·min-1 from the Turbuhaler. Intersubject variability was also dramatically decreased for PSbud relative to THbud. Conclusion. Delivery of an engineered PulmoSphere formulation is more efficient and reproducible than delivery of micronized drug from passive DPIs.

Novel lipid-based hollow-porous microparticles as a platform for immunoglobulin delivery to the respiratory tract.

AbstractPurpose. Delivery of specific antibodies or immunoglobulin constructsto the respiratory tract may be useful for prophylaxis or active treatmentof local or systemic disorders. Therefore, we evaluated the utilityof lipid-based hollow-porous microparticles (PulmoSpheres™) as apotential delivery vehicle for immunoglobulins. Methods. Lipid-based microparticles loaded with humanimmunoglobulin (hIgG) or control peptide were synthesized by spray drying and testedfor: i) the kinetics of peptide/protein release, using ELISA and bioassays;ii) bioavailability subsequent to nonaqueous liquid instillation into therespiratory tract of BALB/c mice, using ELISA and Western blotting;iii) bioactivity in terms of murine immune response to xenotypic epitopeson human IgG, using ELISA and T cell assays; and iv) mechanismsresponsible for the observed enhancement of immune responses, usingmeasurement of antibodies as well as tagged probes. Results. Human IgG and the control peptide were both readily releasedfrom the hollow-porous microspheres once added to an aqueousenvironment, although the kinetics depended on the compound. Nonaqueousliquid instillation of hIgG formulated in PulmoSpheres into the upperand lower respiratory tract of BALB/c mice resulted in systemicbiodistribution. The formulated human IgG triggered enhanced local andsystemic immune responses against xenotypic epitopes and wasassociated with receptor-mediated loading of alveolar macrophages. Conclusions. Formulation of immunoglobulins in hollow-porousmicroparticles is compatible with local and systemic delivery via therespiratory mucosa and may be used as means to trigger or modulateimmune responses.

Design of fine particles for pulmonary drug delivery

Particle design for inhalation is characterized by advances in particle processing methods and the utilization of new excipients. Processing methods such as spray drying allow control over critical particle design features, such as particle size and distribution, surface energy, surface rugosity, particle density, surface area, porosity and microviscosity. Control of these features has enabled new classes of therapeutics to be delivered by inhalation. These include therapeutics that have a narrow therapeutic index, require a high delivered dose, and/or elicit their action systemically. Engineered particles are also being utilized for immune modulation, with exciting advances being made in the delivery of antibodies and inhaled vaccines. Continued advances are expected to result in ‘smart’ therapeutics capable of active targeting and intracellular trafficking.

In Vivo Lung Deposition of Hollow Porous Particles from a Pressurized Metered Dose Inhaler

AbstractPurpose: PulmoSphere™ particles are specifically engineered for delivery by the pulmonary route with a hollow and porous morphology, physical diameters < 5 μm, and low tap densities (circa 0.1 g.cm-3). Deposition of PulmoSphere particles in the human respiratory tract delivered by pressurized metered dose inhaler (pMDI) was compared with deposition of a conventional micronized drug pMDI formulation. Methods: Nine healthy nonsmoking subjects (5 male, 4 female) completed a two-way crossover gamma scintigraphic study, assessing the lung and oropharyngeal depositions of albuterol sulfate, formulated as 99mTc-radiolabeled PulmoSphere particles or micronized particles (Ventolin EvohalerTM, GlaxoSmithKline, Ltd.) suspended in HFA-134a propellant. Results: Mean (standard deviation) lung deposition, (% ex-valve dose) was doubled for the PulmoSphere formulation compared with Evohaler pMDI (28.5 (11.3) % vs. 14.5 (8.1) %, P < 0.01), whereas oropharyngeal deposition was reduced (42.6 (9.0) % vs. 72.0 (8.0) %, P < 0.01). Both PulmoSphere and Evohaler pMDIs gave uniform deposition patterns within the lungs. Conclusions: These data provided “proof of concept” in vivo for the PulmoSphere technology as a method of improving targeting of drugs to the lower respiratory tract from pMDIs, and suggested that the PulmoSphere technology may also be suitable for the delivery of systemically acting molecules absorbed via the lung.

Characterization of Suspension-Based Metered Dose Inhaler Formulations Composed of Spray-Dried Budesonide Microcrystals Dispersed in HFA-134a

AbstractPurpose. To assess the physicochemical characteristics and aerosol properties of suspensions of lipid-coated budesonide microcrystals dispersed in HFA-134a. Methods. Lipid-coated budesonide microcrystals were prepared by spray-drying an emulsion-based feedstock. Physicochemical characteristics of spray-dried particles were assessed by electron microscopy, laser diffraction, and differential scanning calorimetry. Purity and content were determined by reverse-phase HPLC. Particle aggregation and suspension stability were assessed visually, and aerosol performance was assessed by Andersen cascade impaction and dose content uniformity. Results. Spray-drying of micronized budesonide microcrystals in the presence of phospholipid-coated emulsion droplets results in the production of low-density lipid-coated microcrystals with low surface energy. These spray-dried particles form stable suspensions in HFA-134a. This translates into good uniformity in the metered dose across the contents of the inhaler and acceptable aerodynamic particle size distributions (MMAD = 3.2 to 3.4 μm). The formulation was observed to maintain its performance over 6 months at 40°C/75% RH and 16 months at 25°C/60% RH. No effect of storage orientation was observed on the content of first sprays following storage (i.e., no Cyr effect). The fine particle dose was found to be linear out to suspension concentrations of about 2% wt/vol, and FPD4.7μm values approaching 400 μg can be delivered in a single inhalation. Conclusions. Engineered particles comprised of lipid-coated microcrystals may provide an acceptable alternative formulation technology for metered dose inhalers in the new hydrofluoroalkane propellants.

The PulmoSphere™ platform for pulmonary drug delivery

Spray-dried PulmoSphere™ formulations comprise phospholipid-based small, porous particles. Drug(s) may be incorporated in or with PulmoSphere formulations in three formats: solution-, suspension-, and carrier-based systems. The multiple formats may be administered to the respiratory tract with multiple delivery systems, including portable inhalers (pressurized, metered-dose inhaler and dry-powder inhaler), nebulizers, and via liquid dose instillation in conjunction with partial liquid ventilation. The PulmoSphere platform (particles, formats, delivery systems) enables pulmonary delivery of a broad range of drugs independent of their physicochemical properties and lung dose. The engineered particles provide significant improvements in lung targeting and dose consistency, relative to current marketed inhalers.

Receptor-mediated targeting of spray-dried lipid particles coformulated with immunoglobulin and loaded with a prototype vaccine.

AbstractPurpose. Spray-dried lipid-based microparticles (SDLM) serve as a platform for delivery of a wide variety of compounds including peptides, proteins, and vaccines to the respiratory mucosa. In the present study, we assessed the impact of IgG-mediated targeting to phagocytic cells of inactivated influenza virus formulated in SDLM, on subsequent immune responses. Methods. SDLM were produced containing inactivated influenza virus strain A/WSN/32/H1N1 (WSN), with or without IgG. Using phagocytic antigen presenting cells (APC) and a T cell hybridoma (TcH) line specific for a dominant influenza virus epitope, we compared the in vitro responses elicited by ligand-formulated (SDLM-IgG-WSN) and non-ligand particles (SDLM-WSN). The effect of including the IgG ligand in the formulation was further characterized by measuring the immune responses of rodents vaccinated with SDLM. Results. SDLM-IgG-WSN were internalized in an Fc receptor (FcR)-dependent manner by phagocytic APC that were then able to effectively present a dominant, class II-restricted epitope to specific T cells. While SDLM-WSN elicited a lower response than administration of plain inactivated virus in saline, the level of the T cell response was restored both in vitro and in vivo by incorporating the APC FcR ligand, IgG, in the SDLM. Conclusions. Incorporation of FcR ligand (IgG) in SDLM restored the limited ability of formulated virus to elicit T-cell immunity, by receptor-mediated targeting to phagocytes.

Liquid ventilation with perflubron in the treatment of rats with pneumococcal pneumonia.

Objective To determine the efficacy of liquid ventilation using a medical-grade perfluorocarbon (perflubron) combined with parenteral or intratracheal antibiotics in a rat model of pneumonia. Design Prospective, laboratory investigation. Setting Experimental laboratory in a university medical center. Subjects Wistar rats (n = 112). Interventions One day after intratracheal inoculation with Streptococcus pneumoniae, rats received one of five experimental treatments or no treatment (control): modified liquid ventilation (MLV), intramuscular ampicillin, MLV plus intramuscular ampicillin, MLV with intratracheal ampicillin, or MLV plus ampicillin PulmoSpheres. Measurements and Main Results Animals receiving MLV plus intramuscular ampicillin, MLV with intratracheal ampicillin, or MLV plus ampicillin PulmoSpheres had significantly improved 10-day survival rates (85%, 72%, and 72%, respectively) compared with all other groups (0% to 25%). Conclusions MLV in combination with either intramuscular, intratracheal, or PulmoSpheres ampicillin improved survival as compared with MLV alone or the same dose of antibiotics delivered intramuscularly.

Liquid dose pulmonary instillation of gentamicin PulmoSpheres® formulations : Tissue distribution and pharmacokinetics in rabbits

AbstractPurpose. To assess the pharmacokinetics and biodistribution of gentamicin, delivered as PulmoSpheres® formulations in rabbit serum and lung tissue following intratracheal instillation in a perflubron vehicle. Methods. Rabbits were anesthetized, intubated, and mechanically ventilated with O2(FiO2 = 0.50). Animals were then given 5 mg/kg gentamicin either intravenously, intramuscularly (IM), or intratracheally (IT) gentamicin PulmoSpheres® formulation, instilled in 1.8 ml/kg of liquid perflubron vehicle. Serum and lung lobe sections were collected at multiple time points and assayed for gentamicin content. Results. Serum gentamicin levels peaked at 64.7 μg/ml, 11.2 μg/ml, and 5.0 μg/ml following intravenous, IM, and IT administration, respectively. Absolute bioavailability at 8 h for IM administration was 76.8% and 57.0% when delivered IT. Although peak lung levels of drug were reached within 1 h, total lung gentamicin concentration after IT administration was more than two orders of magnitude greater than that achieved following IM administration (680,540 vs. 4,985 μg min, respectively) with significant levels of the antibiotic remaining in the lung even after 1 week. Conclusions. High levels of gentamicin in lung tissue can be achieved by instillation of a gentamicin PulmoSpheres® formulation in a perflubron vehicle, termed liquid dose installation, without reaching toxic systemic levels allowing for increased local delivery of agents such as gentamicin at the site of the infection.