Widespread airway distribution and short-term phenotypic correction of cystic fibrosis pigs following aerosol delivery of piggyBac/adenovirus.

Cystic fibrosis (CF) is a common genetic disease caused by mutations in the gene coding for cystic fibrosis transmembrane conductance regulator (CFTR). Although CF affects multiple organ systems, chronic bacterial infections and inflammation in the lung are the leading causes of morbidity and mortality in people with CF. Complementation with a functional CFTR gene repairs this defect, regardless of the disease-causing mutation. In this study, we used a gene delivery system termed piggyBac/adenovirus (Ad), which combines the delivery efficiency of an adenoviral-based vector with the persistent expression of a DNA transposon-based vector. We aerosolized piggyBac/Ad to the airways of pigs and observed widespread pulmonary distribution of vector. We quantified the regional distribution in the airways and observed transduction of large and small airway epithelial cells of non-CF pigs, with ∼30-50% of surface epithelial cells positive for GFP. We transduced multiple cell types including ciliated, non-ciliated, basal, and submucosal gland cells. In addition, we phenotypically corrected CF pigs following delivery of piggyBac/Ad expressing CFTR as measured by anion channel activity, airway surface liquid pH, and bacterial killing ability. Combining an integrating DNA transposon with adenoviral vector delivery is an efficient method for achieving functional CFTR correction from a single vector administration.

Comparison of Tissue and Blood Concentrations of Oxaliplatin Administrated by Different Modalities of Intraperitoneal Chemotherapy.

BACKGROUND: Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a new technology for delivering intraperitoneal chemotherapy. It is generally assumed that with PIPAC, the ratio of peritoneal to systemic drug concentration is superior to liquid hyperthermic intraperitoneal chemotherapy (HIPEC). To date, no direct comparative data are available supporting such an assumption. MATERIALS AND METHODS: Twelve 65-day-old pigs were randomly separated into three groups of four pigs each, all of which received intraperitoneal chemotherapy using the following administration methods: PIPAC with oxaliplatin 92 mg in 150 ml dextrose 5% (Group 1); PIPAC with electrostatic aerosol precipitation (ePIPAC; Group 2); or laparoscopic HIPEC (L-HIPEC) with oxaliplatin 400 mg in 4 L dextrose 5% at 42 °C (Group 3). Serial blood and peritoneal tissue concentrations of oxaliplatin were determined by spectrometry. RESULTS: In all three groups, the maximum concentration of oxaliplatin in blood was detected 50-60 min after onset of the chemotherapy experiments, with no significant differences among the three groups (p = 0.7994). Blood oxaliplatin concentrations (0-30 min) were significantly higher in the L-HIPEC group compared with the ePIPAC group (p < 0.05). No difference was found for the overall systemic oxaliplatin absorption (area under the curve). Overall concentrations in the peritoneum were not different among the three groups (p = 0.4725), but were significantly higher in the visceral peritoneum in the PIPAC group (p = 0.0242). CONCLUSIONS: Blood and tissue concentrations were comparable between all groups; however, depending on the intraperitoneal area examined and the time points of drug delivery, the concentrations differed significantly between the three groups.

Inhaled salbutamol from aerolizer and diskus at different inhalation flows, inhalation volume and number of inhalations in both healthy subjects and COPD patients.

The aim of the present study was to demonstrate the effect of inhalation-flow, inhalation-volume and number of inhalations on aerosol-delivery of inhaled-salbutamol from two different dry powder inhalers (DPIs) in both healthy-subjects and chronic obstructive pulmonary disease (COPD) patients. Relative pulmonary-bioavailability and systemic-bioavailability of inhaled-salbutamol, delivered by Diskus and Aerolizer, was determined in 24-COPD patients and 24-healthy subjects. The healthy-subjects and the COPD-patients participated in the study for 7 days in which they received 4 study doses of 200 µg salbutamol (one slow-inhalation, two slow-inhalations, one fast-inhalation, and two fast-inhalations) in four alternative days with 24 hr washout period after each dose. Two urine-samples were collected from each study subjects. The first was provided 30 min post inhalation (USAL0.5), as an index of relative pulmonary-bioavailability, and the second was pooled to 24 hr post inhalation (USAL24), as an index of systemic-bioavailability. Fast-inhalation resulted in significantly higher USAL0.5 and USAL24 than slow-inhalation (p˂0.05) after one-inhalation in both healthy-subjects and COPD-patients but there was no significant difference between slow and fast-inhalation after two-inhalations. One-inhalation resulted in significantly higher USAL0.5 and USAL24 in healthy-subjects compared to COPD-patient at both slow and fast-inhalation (p˂0.05) except USAL0.5 with Diskus at slow-inhalation there was no significant difference. Also, two-inhalations resulted in significantly higher USAL0.5 and USAL24 compared to one-inhalation at slow-inhalation only (p˂0.05). No significant difference was found between Aerolizer and Diskus except in USAL0.5 of one slow-inhalation in both health-subjects and COPD-patients (p = 0.048 and 0.047, respectively). Device-formula relation is present at low inhalation-flow since Diskus resulted in significantly higher USAL0.5 and USAL24 in healthy-subjects compared to COPD-patient at slow inhalation than Aerolizer. It is essential to inhale-twice and as hard and deep as possible from each dose when using DPI especially with COPD-patients having poor inspiratory efforts such as elderly patients and children.

A Novel Simulation-Based Approach for Comparing the Population Against Average Bioequivalence Statistical Test for the Evaluation of Nasal Spray Products on Spray Pattern and Droplet Size Distribution Parameters.

The aim of this work is to evaluate average bioequivalence (ABE) and population bioequivalence (PBE) statistical approaches so as to identify which approach is most suitable for in vitro bioequivalence (IVBE) testing of nasal spray products. For droplet size distribution (DSD) and spray pattern (SP), in vitro data were collected using a well-established nasal spray on the market (Nasonex®, manufactured by Merck Sharp & Dohme Limited). Simulations were performed using in vitro data to comparatively investigate ABE and PBE tests. For highly variable parameters such as SP area, this study clearly demonstrates that the level of agreement between ABE and PBE test conclusions is much smaller as compared with that of DSD Dv(50), which was found to have moderate variability. PBE approach dictates equivalence for both means and variances, and was found to handle both SP and DSD parameters with similar passing rates compared to the passing rates from the ABE approach. However, pronounced asymmetric behavior of PBE empirical power curves for highly variable SP area was observed. A modified PBE statistical approach is proposed for DSD span and Dv(50) in vitro parameters, where acceptance criteria would be based on comparison of reference/branded product to itself as part of "pre-IVBE study" via innovative statistical bootstrap simulations. Due to inherent high variability of the SP area parameter driving pronounced asymmetric behavior of PBE power curves, and due to unclear in vivo relevance for SP area and ovality, authors propose that SP parameters be used as development and quality control tools rather than for demonstration of IVBE.

Pulmonary and Regional Deposition of Nebulized and Dry Powder Aerosols in Ferrets.

The utilization of ferrets as a non-clinical model for disease is rapidly increasing within drug development. Many of these models include respiratory diseases that involve targeted drug delivery via nose-only inhalation. While the deposition patterns within other non-clinical models (mice, rats, canines, and non-human primates) have been well studied, the local and regional deposition of aerosols in ferrets has not been well characterized. Therefore, inhalation aerosols were developed, radiolabeled and the radiolabeling methods validated to support SPECT-CT imaging and quantification of regional deposition within ferrets. The studies were conducted with one liquid formulation and one dry powder formulation (two concentrations of dry powder). Additionally, both aerosols were polydisperse and therefore reflect the majority of pharmaceutical aerosols. Overall, the studies showed lung deposition fractions between 5 and 10% with median aerodynamic particle sizes of 2.5 and 2.8 µm. The lung deposition fraction of the liquid aerosol was ~ 9%, nearly double observed in rats with a similarly sized aerosol. Analysis of respiratory tract (oropharynx, laryngopharynx, trachea, bifurcation area, and lung) deposition indicates increased deposition of the liquid aerosol compared to the dry powder aerosol, however, when this analysis was refined to the pulmonary region (trachea, bifurcation, and lung) the deposition was similar between formulations. These data provide the first description of the regional deposition of inhalation aerosols in ferrets with standard nose-only inhalation procedures. These data can be used for calculations of both total and regional doses within ferret inhalation drug delivery.

Effect of Roughness on the Dispersion of Dry Powders for Inhalation: a Dynamic Visualization Perspective.

Dry powder inhalers have attracted more interest over the years in every aspect related to them. Interestingly, when focusing on the effects of particle morphology of the active or carrier (excipient), it is generally regarded particle size and shape to influence drug availability of aerosolized particles. However, to date, few studies have examined the effect of texture, i.e., roughness, on this relationship. The main objective of the present work is to gain a closer understanding of the influence of carrier morphology on the aerosolization performance of dry powder inhaler formulations. Image analysis and microscopy were used to visualize the aerosolization process. It is considered that the scale of morphological features on the surface of the carrier particles is responsible for the dispersion of the powder formulation, separation of the drug/carrier, and entrainment from a dry powder inhaler. Thus, for this study, the carrier particles of different surface roughness were mixed with micronized salbutamol sulphate. Aerosolization in vitro testing was used to evaluate the performance. The results indicate a connection between the qualitative surface roughness of coarse carriers and aerosolization performance during powder dispersibility. This investigation demonstrated that indeed, powder dispersion, a dynamic process, is influenced by the scale of the carrier morphology.

Spray-Dried PulmoSphere™ Formulations for Inhalation Comprising Crystalline Drug Particles.

Over the past 20 years, solution-based spray dried powders have transformed inhaled product development, enabling aerosol delivery of a wider variety of molecules as dry powders. These include inhaled proteins for systemic action (e.g., Exubera®) and high-dose inhaled antibiotics (e.g., TOBI® Podhaler™). Although engineered particles provide several key advantages over traditional powder processing technologies (e.g., spheronized particles and lactose blends), the physicochemical stability of the amorphous drug present in these formulations brings along its own unique set of constraints. To this end, a number of approaches have been developed to maintain the crystallinity of drugs throughout the spray drying process. One approach is to spray dry suspensions of micronized drug(s) from a liquid feed. In this method, minimization of drug particle dissolution in the liquid feed is critical, as dissolved drug is converted into amorphous domains in the spray-dried drug product. The review explores multiple formulation and engineering strategies for decreasing drug dissolution independent of the physicochemical properties of the drug(s). Strategies to minimize particle dissolution include spray blending of particles of different compositions, formation of respirable agglomerates of micronized drug with small porous carrier particles, and use of common ions. The formulations extend the range of doses that can be delivered with a portable inhaler from about 100 ng to 100 mg. The spray-dried particles exhibit significant advantages in terms of lung targeting and dose consistency relative to conventional lactose blends, while still maintaining the crystallinity of drug(s) in the formulated drug product.

Scintigraphic peritoneography reveals a non-uniform 99mTc-Pertechnetat aerosol distribution pattern for Pressurized Intra-Peritoneal Aerosol Chemotherapy (PIPAC) in a swine model.

BACKGROUND: Although recent data are contradictory, it is still claimed that Pressurized Intra-Peritoneal Aerosol Chemotherapy (PIPAC) would deliver an aerosol which distributes homogeneously throughout the entire abdominal cavity. METHODS: 99mTc-Pertechnetat was administered in four postmortem swine using either PIPAC or liquid intra-peritoneal chemotherapy (IPC). The animals were examined by planar scintigraphy and SPECT/CT. Planar distribution images were divided into four regions of interest (ROIs: right/left upper and lower abdominal quadrant). SPECT/CT slices were scanned for areas of intense nuclide accumulation ("hot spots"). The percentage of relative distribution for planar scintigraphy was calculated by dividing the summed individual counts of each ROI by total counts measured in the entire abdominal cavity. The relative distribution of the "hot spots" was analyzed by dividing the counts of the local volume of interest (VOI) by the summed volume counts measured in the entire abdominal cavity. RESULTS: In all four animals, planar scintigraphy showed inhomogeneous nuclide distribution. After PIPAC only 8-10% of the delivered nuclide was detected in one ROI with a mean deviation of 40% and 74% from a uniform nuclide distribution pattern. In all animals, SPECT/CT revealed "hot spots" beneath the PIPAC Micropump, catheter tip, and in the cul-de-sac region which comprise about 25% of the total amount of delivered nuclide in 2.5% of the volume of the entire abdominal cavity. CONCLUSIONS: Our present data indicate that the intra-abdominal aerosol distribution pattern of PIPAC therapy is non-homogeneous and that the currently applied technology has still not overcome the problem of inhomogeneous drug distribution of IPC.

Metoclopramide nasal spray in vitro evaluation and in vivo pharmacokinetic studies in dogs.

Metoclopramide (MCP) can effectively alleviate motion sickness-caused nausea and vomiting. Nasal administration offers the greatest patient compliance. It is suitable for self-administration and offers rapid and complete absorption, no first-pass effects and high bioavailability. In the present study, a MCP nasal spray was prepared and evaluated in vitro and in vivo. Nasal cilia toxicity of Bufo toads was used to screen the preservative types and concentrations. Rabbit nasal mucosa was used to evaluate the mucosa permeability of different MCP nasal sprays with different penetration enhancers and preservative. A three-period crossover trial was then carried out in beagle dogs with three different MCP dosage forms: nasal sprays, oral tablets and intramuscular (IM) solution. Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) was performed to measure dog plasma MCP, and pharmacokinetic parameters were calculated. The results of ciliatoxicity and permeation study showed that 0.03% methyl paraben lacking penetration enhancers was optimal. Compared to control IM, the bioavailability of oral tablets of MCP was 24.9%, while that of nasal spray was 62.3%. Meanwhile time-to-maximal plasma concentration (Tmax) of nasal spray was significantly shorter than that of oral tablets. In conclusion, MCP nasal spray prepared here is safe with minimal ciliatoxicity, rapid onset and high relative bioavailability.

Drug Delivery from an Innovative LAMA/LABA Co-suspension Delivery Technology Fixed-Dose Combination MDI: Evidence of Consistency, Robustness, and Reliability.

To ensure consistency of clinical outcomes, orally inhaled therapies must exhibit consistent delivered dose and aerosol properties at the time of manufacturing, throughout storage, and during various patient-use conditions. Achieving consistency across these scenarios has presented a significant challenge, especially for combination products that contain more than one drug. This study characterized the delivered dose and aerosol properties of glycopyrrolate/formoterol fumarate metered dose inhaler (GFF MDI; Bevespi Aerosphere™). GFF MDI, a fixed-dose combination (FDC) of a long-acting muscarinic antagonist, glycopyrrolate (18 µg, equivalent to glycopyrronium 14.4 µg), and a long-acting ß2-agonist, formoterol fumarate (9.6 µg; equivalent to formoterol fumarate dihydrate 10 µg), is formulated using innovative co-suspension delivery technology, which suspends micronized drug crystals with spray-dried phospholipid porous particles in hydrofluoroalkane propellant. In this study, delivered dose uniformity was assessed through the labeled number of doses, and aerosol properties, such as percent fine particle fraction (FPF) and mass median aerodynamic diameter, were determined by cascade impaction. GFF MDI achieved reproducible dose delivery and an FPF greater than 55%, whether formulated and delivered as a monocomponent or dual FDC. The performance of GFF MDI was maintained across various manufacturing batches, under extended storage, and with variations in flow rate. Furthermore, unlike a GFF drug crystal-only suspension, drug delivery remained consistent for GFF MDI when simulated patient-handling errors were applied, such as reduced shake energy and delays between shaking and actuation. These results demonstrate that co-suspension delivery technology overcomes well-known sources of variability in MDI drug delivery.

A Simple and Rapid Method for Deposition and Measurement of Drug Transport Across Air Interface Respiratory Epithelia.

The purpose of this study was to present a novel and simple drug deposition method to evaluate drug transport of aerosol microparticles across airway epithelial cells. Microparticles containing ciprofloxacin HCl (Cip) and doxycycline (Dox), alone or in a 50:50% w/w ratio, were spray dried and suspended using 2H, 3H-perfluoropentane, model propellant. The suspension was then used to assess deposition, and transport of these drug microparticles across sub-bronchial epithelial Calu-3 cells was also studied. In comparison with other methods of depositing microparticles, this proposed method, using drug suspended in HPFP, provides control over the amount of drugs applied on the surface of the cells. Therefore, cell permeability studies could be conducted with considerably smaller and more reproducible doses, without the physicochemical characteristics of the drugs being compromised or the use of modified pharmacopeia impactors. The suspension of microparticles in HPFP as presented in this study has provided a non-toxic, simple, and reproducible novel method to deliver and study the permeability of specific quantity of drugs across respiratory epithelial cells in vitro.

Pulmonary Pharmacokinetics of Colistin following Administration of Dry Powder Aerosols in Rats.

Colistin has been administered via nebulization for the treatment of respiratory tract infections. Recently, dry powder inhalation (DPI) has attracted increasing attention. The current study aimed to investigate the pharmacokinetics (PK) of colistin in epithelial lining fluid (ELF) and plasma following DPI and intravenous (i.v.) administration in healthy Sprague-Dawley rats. Rats were given colistin as DPI intratracheally (0.66 and 1.32 mg base/kg of body weight) or i.v. injection (0.66 mg base/kg). Histopathological examination of lung tissue was performed at 24 h. Colistin concentrations in both ELF and plasma were quantified, and a population PK model was developed and compared to a previously published PK model of nebulized colistin in rats. A two-compartment structural model was developed to describe the PK of colistin in both ELF and plasma following pulmonary or i.v. administration. The model-estimated clearance from the central plasma compartment was 0.271 liter/h/kg (standard error [SE] = 2.51%). The transfer of colistin from the ELF compartment to the plasma compartment was best described by a first-order rate constant (clearance of colistin from the ELF compartment to the plasma compartment = 4.03 × 10-4 liter/h/kg, SE = 15%). DPI appeared to have a higher rate of absorption (time to the maximum concentration in plasma after administration of colistin by DPI, ≤10 min) than nebulization (time to the maximum concentration in plasma after administration of colistin by nebulization, 20 to 30 min), but the systemic bioavailabilities by the two routes of administration were similar (∼46.5%, SE = 8.43%). Histopathological examination revealed no significant differences in inflammation in lung tissues between the two treatments. Our findings suggest that colistin DPI is a promising alternative to nebulization considering the similar PK and safety profiles of the two forms of administration. The PK and histopathological information obtained is critical for the development of optimal aerosolized colistin regimens with activity against lung infections caused by Gram-negative bacteria.

Curcumin Nanotechnologies and Its Anticancer Activity.

Cancer is one of the leading causes of death worldwide. Curcumin is a well-established anticancer agent in vitro but its efficacy is yet to be proven in clinical trials. Poor bioavailability of curcumin is the principal reason behind the lack of efficiency of curcumin in clinical trials. Many studies prove that the bioavailability of curcumin can be improved by administering it through nanoparticle drug carriers. This review focuses on the efforts made in the field of nanotechnology to improve the bioavailability of curcumin. Nanotechnologies of curcumin come in various shapes and sizes. The simplest curcumin nanoparticle that increased the bioavailability of curcumin is the curcumin-metal complex. On the other hand, we have intricate thermoresponsive nanoparticles that can release curcumin upon stimulation (analogous to a remote control). Future research required for developing potent curcumin nanoparticles is also discussed.

Good Things in Small Packages: an Innovative Delivery Approach for Inhaled Insulin.

PURPOSE: The design development of a small, hand held, battery operated, breath actuated inhaler as a drug/device platform for inhaled insulin posed a number of technical challenges. Our goal was to optimize lung deposition and distribution with aerosol generators producing 3-6 µm particle size distribution. METHODS: In silico modeling with computational fluid dynamics (CFD) and in vitro testing of device components were assessed using an Alberta idealized adult airway (Copley, UK) to optimize mouthpiece and aerosol path design for dose delivered distal to the trachea. Human factors use testing was designed to determine the ability to perform inspiratory manuevers with LED guidance within target flow limits. In vivo testing with healthy normal subjects of radiolabeled aerosol compared 2 breathing patterns for lung deposition efficiency, distribution, and subject preference. RESULTS: CFD demonstrated that flows ≤5 L/min and ≥15 L/min reduced the delivery efficiencg. Prototypes tested with inspiratory flow of 10 L/min provided up to 70% of dose delivered distal to the model throat with aerosols of 3 to 6 µm. Users guided by LED were able to inhale for 8-24 s with 5 s breath hold. Lung dose >70% with peripheral to central ratios >2.0 were achieved, with subject preference for the longer inspiratory time with breath hold. CONCLUSION: The device design phase integration led to a novel design and inspiratory pattern with greater levels of peripheral deposition than previously reported with commercial inhalers. The rationale and process of the application of these methods are described with implications for use in future device development.

Multicomponent aerosol particle deposition in a realistic cast of the human upper respiratory tract.

Inhalation of aerosols generated by electronic cigarettes leads to deposition of multiple chemical compounds in the human airways. In this work, an experimental method to determine regional deposition of multicomponent aerosols in an in vitro segmented, realistic human lung geometry was developed and applied to two aerosols, i.e. a monodisperse glycerol aerosol and a multicomponent aerosol. The method comprised the following steps: (1) lung cast model preparation, (2) aerosol generation and exposure, (3) extraction of deposited mass, (4) chemical quantification and (5) data processing. The method showed good agreement with literature data for the deposition efficiency when using a monodisperse glycerol aerosol, with a mass median aerodynamic diameter (MMAD) of 2.3 µm and a constant flow rate of 15 L/min. The highest deposition surface density rate was observed in the bifurcation segments, indicating inertial impaction deposition. The experimental method was also applied to the deposition of a nebulized multicomponent aerosol with a MMAD of 0.50 µm and a constant flow rate of 15 L/min. The deposited amounts of glycerol, propylene glycol and nicotine were quantified. The three analyzed compounds showed similar deposition patterns and fractions as for the monodisperse glycerol aerosol, indicating that the compounds most likely deposited as parts of the same droplets. The developed method can be used to determine regional deposition for multicomponent aerosols, provided that the compounds are of low volatility. The generated data can be used to validate aerosol deposition simulations and to gain insight in deposition of electronic cigarette aerosols in human airways.

Absorption and Clearance of Pharmaceutical Aerosols in the Human Nose: Effects of Nasal Spray Suspension Particle Size and Properties.

PURPOSE: The objective of this study was to use a recently developed nasal dissolution, absorption, and clearance (DAC) model to evaluate the extent to which suspended drug particle size influences nasal epithelial drug absorption for a spray product. METHODS: Computational fluid dynamics (CFD) simulations of mucociliary clearance and drug dissolution were used to calculate total and microscale epithelial absorption of drug delivered with a nasal spray pump. Ranges of suspended particle sizes, drug solubilities, and partition coefficients were evaluated. RESULTS: Considering mometasone furoate as an example, suspended drug particle sizes in the range of 1-5 µm did not affect the total nasal epithelial uptake. However, the microscale absorption of suspended drug particles with low solubilities was affected by particle size and this controlled the extent to which the drug penetrated into the distal nasal regions. CONCLUSIONS: The nasal-DAC model was demonstrated to be a useful tool in determining the nasal exposure of spray formulations with different drug particle sizes and solubilities. Furthermore, the model illustrated a new strategy for topical nasal drug delivery in which drug particle size is selected to increase the region of epithelial surface exposure using mucociliary clearance while minimizing the drug dose exiting the nasopharynx.

A Comparison of the Pharmacokinetics and Pulmonary Lymphatic Exposure of a Generation 4 PEGylated Dendrimer Following Intravenous and Aerosol Administration to Rats and Sheep.

PURPOSE: Cancer metastasis to pulmonary lymph nodes dictates the need to deliver chemotherapeutic and diagnostic agents to the lung and associated lymph nodes. Drug conjugation to dendrimer-based delivery systems has the potential to reduce toxicity, enhance lung retention and promote lymphatic distribution in rats. The current study therefore evaluated the pharmacokinetics and lung lymphatic exposure of a PEGylated dendrimer following inhaled administration. METHODS: Plasma pharmacokinetics and disposition of a 22 kDa PEGylated dendrimer were compared after aerosol administration to rats and sheep. Lung-derived lymph could not be sampled in rats and so lymphatic transport of the dendrimer from the lung was assessed in sheep. RESULTS: Higher plasma concentrations were achieved when dendrimer was administered to the lungs of rats as a liquid instillation when compared to an aerosol. Plasma pharmacokinetics were similar between sheep and rats, although some differences in disposition patterns were evident. Unexpectedly, less than 0.5% of the aerosol dose was recovered in pulmonary lymph. CONCLUSIONS: The data suggest that rats provide a relevant model for assessing the pharmacokinetics of inhaled macromolecules prior to evaluation in larger animals, but that the pulmonary lymphatics are unlikely to play a major role in the absorption of nanocarriers from the lungs.

Pharmacokinetics of Colistin Methansulphonate (CMS) and Colistin after CMS Nebulisation in Baboon Monkeys.

PURPOSE: The objective of this study was to compare two different nebulizers: Eflow rapid® and Pari LC star® by scintigraphy and PK modeling to simulate epithelial lining fluid concentrations from measured plasma concentrations, after nebulization of CMS in baboons. METHODS: Three baboons received CMS by IV infusion and by 2 types of aerosols generators and colistin by subcutaneous infusion. Gamma imaging was performed after nebulisation to determine colistin distribution in lungs. Blood samples were collected during 9 h and colistin and CMS plasma concentrations were measured by LC-MS/MS. A population pharmacokinetic analysis was conducted and simulations were performed to predict lung concentrations after nebulization. RESULTS: Higher aerosol distribution into lungs was observed by scintigraphy, when CMS was nebulized with Pari LC® star than with Eflow Rapid® nebulizer. This observation was confirmed by the fraction of CMS deposited into the lung (respectively 3.5% versus 1.3%).CMS and colistin simulated concentrations in epithelial lining fluid were higher after using the Pari LC star® than the Eflow rapid® system. CONCLUSIONS: A limited fraction of CMS reaches lungs after nebulization, but higher colistin plasma concentrations were measured and higher intrapulmonary colistin concentrations were simulated with the Pari LC Star® than with the Eflow Rapid® system.

Development of a new technique for the efficient delivery of aerosolized medications to infants on mechanical ventilation.

PURPOSE: To evaluate the efficiency of a new technique for delivering aerosols to intubated infants that employs a new Y-connector, access port administration of a dry powder, and excipient enhanced growth (EEG) formulation particles that change size in the airways. METHODS: A previously developed CFD model combined with algebraic correlations were used to predict delivery system and lung deposition of typical nebulized droplets (MMAD = 4.9 µm) and EEG dry powder aerosols. The delivery system consisted of a Y-connector [commercial (CM); streamlined (SL); or streamlined with access port (SL-port)] attached to a 4-mm diameter endotracheal tube leading to the airways of a 6-month-old infant. RESULTS: Compared to the CM device and nebulized aerosol, the EEG approach with an initial 0.9 µm aerosol combined with the SL and SL-port geometries reduced device depositional losses by factors of 3-fold and >10-fold, respectively. With EEG powder aerosols, the SL geometry provided the maximum tracheobronchial deposition fraction (55.7%), whereas the SL-port geometry provided the maximum alveolar (67.6%) and total lung (95.7%) deposition fractions, respectively. CONCLUSIONS: Provided the aerosol can be administered in the first portion of the inspiration cycle, the proposed new method can significantly improve the deposition of pharmaceutical aerosols in the lungs of intubated infants.

Dry Lung as a Physical Model in Studies of Aerosol Deposition.

A new physical model was developed to evaluate the deposition of micro- and nanoaerosol particles (NAPs) into the lungs as a function of size and charges. The model was manufactured of a dry, inflated swine lung produced by Nasco company (Fort Atkinson, WI). The dry lung was cut into two lobes and a conductive tube was glued into the bronchial tube. The upper 1-2-mm-thick layer of the lung lobe was removed with a razor blade to expose the alveoli. The lobe was further enclosed into a plastic bag and placed within a metalized plastic box. The probability of aerosol deposition was calculated by comparing the size distribution of NAPs passed through the lung with that of control, where aerosol passed through a box bypassing the lung. Using this new lung model, it was demonstrated that charged NAPs are deposited inside the lung substantially more efficiently than neutral ones. It was also demonstrated that deposition of neutral NAPs well fits prediction of the Multiple-Path Particle Dosimetry (MPPD) model developed by the Applied Research Associates, Inc. (ARA).