Ciprofloxacin Dry Powder for Inhalation (ciprofloxacin DPI): Technical design and features of an efficient drug-device combination.

Bronchiectasis is a chronic respiratory disease with heterogeneous etiology, characterized by a cycle of bacterial infection and inflammation, resulting in increasing airway damage. Exacerbations are an important cause of morbidity and are strongly associated with disease progression. Many patients with bronchiectasis suffer from two or more exacerbations per year. However, there are no approved therapies to reduce or delay exacerbations in this patient population. Ciprofloxacin DPI is in development as a long-term, intermittent therapy to reduce exacerbations in patients with non-cystic fibrosis (CF) bronchiectasis and evidence of respiratory pathogens. Ciprofloxacin DPI combines drug substance, dry powder manufacturing technology, and an efficient, pocket-sized, dry powder inhaler to deliver an effective antibiotic directly to the site of infection, with minimal systemic exposure and treatment burden. Here we review the drug substance and particle engineering (PulmoSphere™) technology used, and key physical properties of Ciprofloxacin Inhalation Powder, including deposition, delivered dose uniformity, consistency, and stability. Design features of the T-326 Inhaler are described in relation to lung targeting, safety and tolerability of inhalation powders, as well as treatment burden and adherence. If approved, Ciprofloxacin DPI may provide a valuable treatment option for those with frequent exacerbations and respiratory pathogens.

Idealhalers Versus Realhalers: Is It Possible to Bypass Deposition in the Upper Respiratory Tract?

This review discusses how advances in formulation and device design can be utilized to dramatically improve lung targeting and dose consistency relative to current marketed dry powder inhalers (DPIs). Central to the review is the development of engineered particles that effectively bypass deposition in the upper respiratory tract (URT). This not only reduces the potential for off-target effects but it also reduces variability in dose delivery to the lungs resulting from anatomical differences in the soft tissue in the mouth and throat. Low-density porous particles are able to largely bypass URT deposition due to the fact that both the primary particles and their agglomerates are respirable. The low-density particles also exhibit dose delivery to the lungs that is largely independent of inspiratory flow rate across a range of flow rates that most subjects achieve with portable DPIs. Coupling this with delivery devices that are breath actuated, simple to operate (open-inhale-close), and have adherence-tracking capability enables drug delivery that is largely independent of how a subject inhales, with a user experience that is close to that of an "idealhaler."

Inhalation of tobramycin using simulated cystic fibrosis patient profiles.

INTRODUCTION: TOBI® Podhaler™ is a capsule-based drug-device combination (tobramycin inhalation powder [TIP] 28 mg capsules via unit-dose dry powder T-326 Inhaler [Podhaler™]) developed for treatment of Pseudomonas aeruginosa infection in cystic fibrosis (CF). We explored how inspiratory flow profiles and mouth-throat geometries affect drug delivery with the T-326 Inhaler. METHODS: Inspiratory flow profiles were recorded from 38 subjects aged 6-71 who had CF and varying degrees of lung function impairment. Ten of the inspiratory flow profiles were simulated in the laboratory using a custom breath simulator to determine delivered dose (DD) from the T-326 Inhaler. In vitro total lung dose (TLDin vitro ) was measured using four anatomical throat models, ranging from a child to a large adult. RESULTS: Aerosol performance was assessed across a range of inspiratory flow profiles. Mean DD ranged from 88.8% to 97.0% of declared capsule content. TLDin vitro ranged from 54.8% to 72.4% of capsule content between the flow profile/throat options tested, and the mean TLDin vitro across the range of flow profiles and anatomical throats tested was 63 ± 5%. CONCLUSIONS: Our findings indicate that the T-326 Inhaler provides reliable drug delivery at flow rates likely to be achieved by a broad spectrum of patients with CF. Importantly, forceful inhalation was not required to achieve a robust TLDin vitro . Pediatr Pulmonol. 2016;51:1159-1167. © 2016 Wiley Periodicals, Inc.

In Vitro-In Vivo Correlations Observed With Indacaterol-Based Formulations Delivered with the Breezhaler®.

BACKGROUND: Establishing robust in vitro-in vivo correlations (IVIVC) between aerosol performance, pharmacokinetics, and clinical efficacy is critical in developing bioequivalent drug-device combination products. Recent studies have demonstrated that realistic throat models tested under realistic test conditions may provide good IVIVC with respect to total lung deposition. METHODS: The Alberta idealized throat (AIT) model was utilized with mean peak inspiratory flow rates determined from patient breathing studies. Various formulations of indacaterol (e.g., lactose blends, fixed dose combinations, engineered PulmoSphere™ particles) were tested in the AIT model and in clinical pharmacokinetic studies. RESULTS: Good IVIVC were observed with respect to total lung deposition, systemic delivery, and the contribution of oral absorption to systemic delivery, with percentage differences from the mean in vivo measurements <15%, with most comparisons <5%. CONCLUSIONS: Anatomical throat models represent an exciting tool to aid in formulation development of pharmaceutical aerosols.

Evaluation of the Malvern Spraytec with inhalation cell for the measurement of particle size distribution from metered dose inhalers.

The purpose of this study was to evaluate the Malvern Spraytec with inhalation cell attachment as a means of analyzing the particle size distribution of aerosols from pressurized metered dose inhalers (pMDIs). The aerosol particle size distribution of various commercially available, placebo, and experimental pMDI formulations was determined using Spraytec under various experimental conditions and the relevant data were compared with the Andersen cascade impactor data. The Spraytec volume median diameter (Dv 50) values for commercial chlorofluorocarbon- and hydrofluoroalkane (HFA)-based pMDIs were respectively smaller and higher compared with their reported mass median aerodynamic diameter values. It was possible to obtain a close agreement between Spraytec Dv 50 and the reported mass median aerodynamic diameter values for a solution-type pMDI formulation, Qvar 50, by equilibrating the pMDI to 55 degrees C before the measurement and using a 20-cm throat extension. Incorporation of a nonvolatile solvent propylene glycol (PG) in placebo pMDIs (15% w/w ethanol, 0.5-20.0% w/w PG in HFA 134a) showed an increase in Dv 50 with increasing concentration of PG. Furthermore, it was possible to obtain a correlation (R(2) = 0.8037) between Spraytec and Andersen cascade impactor data for the experimental nimesulide-pMDI formulations containing 0.1% w/w drug, 0.25-10% w/w PG, and 15% ethanol in HFA 134a.

Optimized dose delivery of the peptide cyclosporine using hydrofluoroalkane-based metered dose inhalers.

The goal of this study was to illustrate the potential to deliver relatively high doses of a therapeutic peptide using hydrofluoroalkane (HFA) metered dose inhaler (MDI) drug delivery systems. For the purposes of this study, cyclosporine was used as the model compound. Cyclosporine formulations, varying in peptide concentration, ethanol cosolvent concentration, and propellant type, were evaluated and optimized for product performance. As ethanol concentration was decreased from 10 to 3% by weight, fine particle fraction (the mass of cyclosporine which passes through a 4.7-micron cut point divided by the total mass of cyclosporine delivered ex-valve) increased from 34 to 68% for 227 and 33 to 52% for 134a formulations. Because of the excellent solubility properties of cyclosporine in HFA-based systems, minimal or no ethanol was needed as a cosolvent to achieve cyclosporine concentrations of 1.5% w/w. With these formulations, it was possible to obtain a fine particle mass (mass of particles <4.7 microns) greater than 500 microg per actuation. In addition, one formulation was chosen for stability analysis: 0.09% w/w cyclosporine, 10% w/w ethanol, 134a. Three different types of container closure systems (stainless steel, aluminum, and epoxy-coated canisters) and two storage configurations (upright and inverted) were evaluated. Cyclosporine was determined to be stable in HFA 134a-based MDI systems, regardless of container closure system and configuration, over a 2-year period. Cyclosporine represents a compelling example of how significant peptide doses are attainable through the use of solution-based MDIs. It has been shown that through formulation optimization, 2-3 mg of the peptide, cyclosporine, may be delivered in five actuations to the lung for local or systemic therapy.

Inhalation delivery of anticancer agents via HFA-based metered dose inhaler using methotrexate as a model drug.

In the present study, the feasibility of delivering anticancer drugs via metered dose inhaler (MDI) was demonstrated using methotrexate (MTX) as a model anticancer drug. MDI formulations of MTX were prepared using hydrofluoroalkane-134a containing 0.67% MTX and 10% ethyl alcohol. The particle size of MTX was reduced by cryo milling with or without a surfactant (Pluronic F77) and the milled drug was employed for MDI formulations, which were subsequently evaluated for their medication delivery, mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD). Further, the efficacy of aerosolized MTX was evaluated by determining the in-vitro cytotoxicity of MTX against HL-60 cells using a six-stage viable impactor and the induction of apoptosis in HL-60 cells by acridine orange staining. Our results indicate that MTX aerosols having an MMAD varying between 2.2 and 3.2 microm (GSD 2.6-3.7) with a respirable fraction varying between 14.2 and 17.1% could be obtained by using MTX, which was cryo milled either alone or in combination with Pluronic F77. Exposure of HL-60 cells plated in third, fourth, fifth, and sixth stages of viable impactor to two actuations of MDI showed a cell kill of greater than 50%. Further, aerosolized MTX was found to induce apoptosis in HL-60 cells, as assessed by the morphological examination of the cells with fluorescent and confocal microscopy. Our results demonstrate that it is possible to deliver cytotoxic concentrations of MTX in an in vitro system simulating the lower respiratory tract (by using a six-stage viable impactor) via MDI and the cytotoxicity of the aerosolized MTX could be further improved by the optimization of the aerodynamic size.

Formulation and evaluation of aerosolized celecoxib for the treatment of lung cancer.

PURPOSE: We examined the effect of aerosolized celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, on the in vitro cytotoxicity and apoptotic response of docetaxel against the human lung carcinoma cell lines A549 and H460. METHODS: A metered dose inhaler (MDI) formulation of celecoxib was prepared and evaluated for its medication delivery and aerodynamic properties. The in vitro cytotoxicity of the aerosolized celecoxib-MDI alone or in combination with docetaxel was assessed using a six-stage viable impactor by a previously established method. The induction of apoptosis was evaluated by morphologic examination (acridine orange and Hoechst staining) and DNA fragmentation. Furthermore, in an attempt to identify molecular targets involved in the anticancer mechanisms of celecoxib and docetaxel, we examined their effect on the expression of an array of markers involved in the COX-2 dependent and independent pathways. RESULTS: The celecoxib-MDI had a medication delivery of 231.3 microg/shot, mass median aerodynamic diameter (MMAD) of 1.4 microm (GSD = 1.9), and respirable fraction of 50.7%. The celecoxib-MDI (2 shots) in combination with docetaxel had cell kills as high as 81.3% and 67.7% in A549 and H460 cells, respectively. Hoechst and acridine orange staining showed an enhanced induction of apoptosis in A549 and H460 cells exposed to aerosolized celecoxib with docetaxel, which was further confirmed by DNA fragmentation. Western blot analysis showed a significant reduction in cPLA2 expression in both A549 and H460 cells treated with the combination of celecoxib with docetaxel. In the COX-2 independent pathway, there was a significant increase in the expression of PPAR-gamma and p53, whereas pro-caspase-3 expression was significantly decreased, which may contribute to the enhanced apoptotic response observed with the combination treatment. CONCLUSIONS: Our results suggest that aerosolized celecoxib significantly enhances the in vitro cytotoxicity and apoptotic response of docetaxel against A549 and H460 cells, and this enhanced activity is mediated via alterations in expression of various molecular targets involved in apoptosis.

Evaluation of an aerosolized selective COX-2 inhibitor as a potentiator of doxorubicin in a non-small-cell lung cancer cell line.

PURPOSE: To evaluate the in vitro effects of an aerosolized cyclooxygenase-2 (COX-2) inhibitor, nimesulide, on the cytotoxicity and apoptotic response of doxorubicin against the human lung adenocarcinoma cell line A549. METHODS: Nimesulide was formulated into a metered dose inhaler (MDI) formulation and characterized for aerodynamic particle size and medication delivery. The in vitro cytotoxicity of nimesulide-MDI in the presence or absence of doxorubicin was assessed by using the six-stage viable impactor by an already standardized method. Induction of apoptosis in A549 cells by nimesulide (nonaerosolized or aerosolized) in combination with doxorubicin was evaluated by established techniques such as caspase-3 estimation and terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) staining. Finally, to understand the mechanism of action, the influence of different treatments on the expression of COX-2 and peroxisome proliferator-activated receptor-gamma (PPAR-gamma) in A549 cells was studied by immunoblotting. RESULTS: The nimesulide-MDI formulation had a mass median aerodynamic diameter (MMAD) of 1.1 microm, (GSD = 2.8) and a medication delivery of 51 microg/shot. Nimesulide-MDI (40 shots) in combination with doxorubicin (0.01 microg/ml) had a cell kill of more than 60% as determined by in vitro cytotoxicity assay. The specific caspase-3 activity in A549 cells treated with nimesulide (40 microg/ml) and doxorubicin (0.25 microg/ml) in combination was 3 and 5 times higher than doxorubicin and nimesulide, respectively. Further, TUNEL staining showed apoptosis in over 30% of A549 cells treated with aerosolized nimesulide and doxorubicin combination vs. negligible as seen in cells treated individually. The expression of COX-2 was not altered in control or treatments, whereas PPAR-gamma was expressed only in the combination treatment. CONCLUSION: Our results indicate that aerosolized nimesulide significantly enhances doxorubicin activity against A549 cells, and the enhanced cytotoxicity was probably mediated via a COX-2-independent mechanism.