Iloprost reverses established fibrosis in experimental right ventricular failure.

Prostacyclin and its analogues improve cardiac output and functional capacity in patients with pulmonary arterial hypertension (PAH); however, the underlying mechanism is not fully understood. We hypothesised that prostanoids have load-independent beneficial effects on the right ventricle (RV). Angio-obliterative PAH and RV failure were induced in rats with a single injection of SU5416 followed by 4 weeks of exposure to hypoxia. Upon confirmation of RV dysfunction and PAH, rats were randomised to 0.1 µg·kg(-1) nebulised iloprost or drug-free vehicle, three times daily for 2 weeks. RV function and treadmill running time were evaluated pre- and post-iloprost/vehicle treatment. Pulmonary artery banded rats were treated 8 weeks after surgery to allow for significant RV hypertrophy. Inhaled iloprost significantly improved tricuspid annulus plane systolic excursion and increased exercise capacity, while mean pulmonary artery pressure and the percentage of occluded pulmonary vessels remained unchanged. Rats treated with iloprost had a striking reduction in RV collagen deposition, procollagen mRNA levels and connective tissue growth factor expression in both SU5416/hypoxia and pulmonary artery banded rats. In vitro, cardiac fibroblasts treated with iloprost showed a reduction in transforming growth factor (TGF)-ß1-induced connective tissue growth factor expression, in a protein kinase A-dependent manner. Iloprost decreased TGF-ß1-induced procollagen mRNA expression as well as cardiac fibroblast activation and migration. Iloprost significantly induced metalloproteinase-9 gene expression and activity and increased the expression of autophagy genes associated with collagen degradation. Inhaled iloprost improves RV function and reverses established RV fibrosis partially by preventing collagen synthesis and by increasing collagen turnover.

Tobramycin disposition in the rat lung following airway administration.

A realistic ex vivo model, the isolated perfused rat lung (IPRL), was used to investigate tobramycin's pulmonary disposition at typical therapeutic concentrations. Different nominal doses were administered in aqueous solution to the airways alongside nonbinding absorption markers, fluorescein and mannitol. The mean fraction of each administered dose reaching the perfusate (Fp) was determined as a function of time following administration. Dynamic dialysis was also used to quantify the kinetics of tobramycin binding and/or tissue retention in the IPRL immediately after drug administration. Whereas the absorption markers fluorescein and mannitol both showed monoexponential dose-independent increases in Fp with time, tobramycin's pulmonary absorption into the perfusate was biexponential and dose-dependent due to tissue binding or retention. Best estimates for the first-order rate constants of tobramycin absorption appeared dose-independent (0.065-0.070 min(-1)), with values close to the mean for fluorescein (0.076 min(-1)). The rate constant for dissociation from IPRL tissue was also relatively constant (0.018-0.022 min(-1)), whereas that for association decreased from 0.16 to 0.07 min(-1) with increasing airway dose from 0.002 to 2 mg. Dynamic dialysis data from sliced IPRL tissue following identical airway administration were consistent with those from the intact IPRL, confirming tobramycin's "slow on, slow off" binding and sequestration by the rat lung. Overall, tobramycin absorption was fast following airway administration. However, dose- and concentration-dependent slow-onset tissue binding extended the duration of tobramycin's presence in the rat lung. These findings may explain, in part, the apparent success of inhaled tobramycin therapy when treating pulmonary infections.

Inhaling medicines: delivering drugs to the body through the lungs.

Remarkably, with the exception of anaesthetic gases, the ancient human practice of inhaling substances into the lungs for systemic effect has only just begun to be adopted by modern medicine. Treatment of asthma by inhaled drugs began in earnest in the 1950s, and now such 'topical' or targeted treatment with inhaled drugs is considered for treating many other lung diseases. More recently, major advances have led to increasing interest in systemic delivery of drugs by inhalation. Small molecules can be delivered with very rapid action, low metabolism and high bioavailability; and macromolecules can be delivered without injections, as highlighted by the recent approval of the first inhaled insulin product. Here, we review these advances, and discuss aspects of lung physiology and formulation composition that influence the systemic delivery of inhaled therapeutics.

In Vitro Tests for Aerosol Deposition. VI: Realistic Testing with Different Mouth-Throat Models and In Vitro-In Vivo Correlations for a Dry Powder Inhaler, Metered Dose Inhaler, and Soft Mist Inhaler.

Background:In vitro-in vivo correlations (IVIVC) for lung deposition may be established by testing inhalers in vitro with realistic mouth-throat (MT) models and inhalation profiles (IP). This study was designed to compare the currently available MT models and their ability to predict in vivo lung deposition. Methods: Budelin® Novolizer®, Ventolin® Evohaler®, and Respimat® fenoterol were chosen to represent a dry powder inhaler (DPI), metered dose inhaler (MDI), and soft mist inhaler (SMI) in tests using eight MT models: small, medium, and large Virginia Commonwealth University (VCU) models; small, medium, and large oropharyngeal consortium (OPC) models, the medium adult Alberta Idealized Throat (AIT), and the United States Pharmacopeia (USP) Induction Port, with IPs that simulated those used by volunteers in lung scintigraphy studies. Drug deposition in MT was compared across the models, and IVIVCs evaluated by comparing values for total lung dose in vitro (TLDin vitro) to those reported in the clinic. Results: MT deposition was dependent on both the flow condition and MT geometry for all the inhalers, while the deposition rank order was independent of both factors. The overall ranking was USP

Product Quality Research Institute evaluation of cascade impactor profiles of pharmaceutical aerosols. Part 3. Final report on a statistical procedure for determining equivalence.

The purpose of this article is to report final results of the evaluation of a chi-square ratio test proposed by the US Food and Drug Administration (FDA) for demonstrating equivalence of aerodynamic particle size distribution (APSD) profiles of nasal and orally inhaled drug products. A working group of the Product Quality Research Institute previously published results demonstrating some limitations of the proposed test. In an effort to overcome the test's limited discrimination, the group proposed a supplemental test, a population bioequivalence (PBE) test for impactor-sized mass (ISM). In this final report the group compares the chi-square ratio test to the ISM-PBE test and to the combination of both tests. The basis for comparison is a set of 55 realistic scenarios of cascade impactor data, which were evaluated for equivalence by the statistical tests and independently by the group members. In many instances, the combined application of these 2 tests appeared to increase the discriminating ability of the statistical procedure compared with the chi-square ratio test alone. In certain situations the chi-square ratio test alone was sufficient to determine equivalence of APSD profiles, while in other situations neither of the tests alone nor their combination was adequate. This report describes all of these scenarios and results. In the end, the group did not recommend a statistical test for APSD profile equivalence. The group did not investigate other in vitro tests, in vivo issues, or other statistical tests for APSD profile comparisons. The studied tests are not intended for routine quality control of APSD.

In Vitro Tests for Aerosol Deposition. V: Using Realistic Testing to Estimate Variations in Aerosol Properties at the Trachea.

BACKGROUND: The dose and aerodynamic particle size distribution (APSD) of drug aerosols' exiting models of the mouth and throat (MT) during a realistic inhalation profile (IP) may be estimated in vitro and designated Total Lung Dose, TLDin vitro, and APSDTLDin vitro, respectively. These aerosol characteristics likely define the drug's regional distribution in the lung. METHODS: A general method was evaluated to enable the simultaneous determination of TLDin vitro and APSDTLDin vitro for budesonide aerosols' exiting small, medium and large VCU-MT models. Following calibration of the modified next generation pharmaceutical impactor (NGI) at 140 L/min, variations in aerosol dose and size exiting MT were determined from Budelin® Novolizer® across the IPs reported by Newman et al., who assessed drug deposition from this inhaler by scintigraphy. RESULTS: Values for TLDin vitro from the test inhaler determined by the general method were found to be statistically comparable to those using a filter capture method. Using new stage cutoffs determined by calibration of the modified NGI at 140 L/min, APSDTLDin vitro profiles and mass median aerodynamic diameters at the MT exit (MMADTLDin vitro) were determined as functions of MT geometric size across Newman's IPs. The range of mean values (n ≥ 5) for TLDin vitro and MMADTLDin vitro for this inhaler extended from 6.2 to 103.0 µg (3.1%-51.5% of label claim) and from 1.7 to 3.6 µm, respectively. CONCLUSIONS: The method enables reliable determination of TLDin vitro and APSDTLDin vitro for aerosols likely to enter the trachea of test subjects in the clinic. By simulating realistic IPs and testing in different MT models, the effects of major variables on TLDin vitro and APSDTLDin vitro may be studied using the general method described in this study.

In Vitro Tests for Aerosol Deposition. IV: Simulating Variations in Human Breath Profiles for Realistic DPI Testing.

BACKGROUND: The amount of drug aerosol from an inhaler that can pass through an in vitro model of the mouth and throat (MT) during a realistic breath or inhalation flow rate vs. time profile (IP) is designated the total lung dose in vitro, or TLDin vitro. This article describes a clinical study that enabled us to recommend a general method of selecting IPs for use with powder inhalers of known airflow resistance (R) provided subjects followed written instructions either alone or in combination with formal training. METHODS: In a drug-free clinical trial, inhaler-naïve, nonsmoking healthy adult human volunteers were screened for normal pulmonary function. IPs were collected from each volunteer inhaling through different air flow resistances after different levels of training. IPs were analyzed to determine the distribution of inhalation variables across the population and their dependence on training and airflow resistance. RESULTS: Equations for IP simulation are presented that describe the data including confidence limits at each resistance and training condition. Realistic IPs at upper (90%), median (50%), and lower (10%) confidence limits were functions of R and training. Peak inspiratory flow rates (PIFR) were inversely proportional to R so that if R was assigned, values for PIFR could be calculated. The time of PIFR, TPIFR, and the total inhaled volume (V) were unrelated to R, but dependent on training. Once R was assigned for a powder inhaler to be tested, a range of simulated IPs could be generated for the different training scenarios. Values for flow rate acceleration and depth of inspiration could also be varied within the population limits of TPIFR and V. CONCLUSIONS: The use of simulated IPs, in concert with realistic in vitro testing, should improve the DPI design process and the confidence with which clinical testing may be initiated for a chosen device.

Respirable microspheres for inhalation: the potential of manipulating pulmonary disposition for improved therapeutic efficacy.

Several particle engineering technologies have recently emerged, which have enabled inhaled microspheres to seek to manipulate pulmonary biopharmaceuticals, and to improve therapeutic efficacy for both local and systemic treatments. These microspheres may be designed to sustain drug release, to prolong lung retention, to achieve drug targeting and/or to enhance drug absorption and thereby, to seek the potentials of reducing dosing frequency and/or drug dose, while maintaining therapeutic efficacy and/or reducing adverse effects. While product development is still in process, in many cases, considerable therapeutic benefits and/or new therapeutic opportunities can be envisaged. 'Proof-of-concept' results are now available for various drug classes including beta(2)-adrenoceptor agonists, corticosteroids, antimycobacterial antibacterials, estradiol and therapeutic macromolecules such as insulin. Nevertheless, their development success must overcome several critical and unique challenges including toxicological evaluations of microsphere materials, and, clearly, successful products should meet the needs of the patient and the market place. Unfortunately, such issues have not always been addressed or examined adequately in the current studies, and thus we may anticipate paradigm shifts in the research of several groups seeking to develop products with improved therapeutic profiles. Nevertheless, it seems likely that improved inhalation products, with greater therapeutic efficacy and reduced adverse effects, will result from next-generation respirable microspheres. These may be expected to contain drugs intended for both local and systemic activity.

The pharmacokinetics of pulmonary insulin in the in vitro isolated perfused rat lung: implications of metabolism and regional deposition.

The pharmacokinetics of several lung disposition pathways for pulmonary insulin were studied and modeled in the isolated perfused rat lung (IPRL). Insulin solution was administered by forced instillation into the airways of the IPRL as 0.1 or 0.02 ml doses of coarse spray, with or without bacitracin (BAC), N-ethylmaleimide (NEM) and atrial natriuretic peptide (ANP). Each insulin absorption profile was fitted to a kinetic model that incorporated the distribution fraction of the dose reaching the lobar region (DF) and the rate constants for absorption into perfusate (k(a)) and non-absorptive loss (k(nal)); k(nal) was shown to be due to the sum of mucociliary clearance and metabolism. Insulin absorption occurred largely by passive diffusion with values for k(a) = 0.39-0.50 h(-1). With DF = 0.91 following 0.1 ml doses, 11.9 +/- 3.4% of bioavailabilities were observed in 1h. In contrast, derived values for k(nal) = 2.34-3.45 h(-1) were significantly larger than the rate constant for mucociliary clearance determined previously in this IPRL (0.96-1.74 h(-1)) due to lung metabolism. Indeed, BAC, but neither NEM nor ANP, was found to decrease the value of k(nal), which suggested that BAC-inhibitable lung ectopeptidases, and not insulin degrading enzyme (IDE), were responsible for this pulmonary metabolism. Shallower lung distribution with DF = 0.73 following 0.02 ml doses resulted in reduced values for k(a) = 0.27 h(-1) and k(nal) = 2.79 h(-1), indicating that these kinetic processes may be lung-region dependent, even within this model and emphasizing the likely importance of reliable lung deposition in vivo.

Stability and characterization of perphenazine aerosols generated using the capillary aerosol generator.

Perphenazine (a potent antiemetic) was aerosolized using capillary aerosol generator to generate respirable condensation aerosols from drug in propylene glycol (PG) solutions, by pumping the liquids through a heated capillary tube. The study characterized the stability of perphenazine during and following aerosol generation. The stability-indicating HPLC method (C-8 column with a mobile phase of 52% 0.01 M pH 3.0 acetate buffer+48% acetonitrile) also enabled the study of perphenazine stability in solution under acidic, basic, oxidizing and photolysing conditions. An LC-MS (ESI+) method was used to characterize the degradation products. Perphenazine was found to be stable in acidic and basic conditions, while perphenazine sulfoxide was the major product formed in dilute peroxide solutions. Two photo-degradation products were formed in PG that were tentatively identified by LC-MS; one of these was synthesized and confirmed to be 2-[4-(3-phenothiazin-10-yl-propyl)-piperazino]-ethanol. Both photolysis products showed that aromatic dechlorination had occurred and one appeared to also result from interaction with the solvent. Within an aerosolization energy window of 84-95 J, fine particle aerosols were generated from perphenazine PG formulations with no significant degradation. Small amounts of degradation products were produced in all samples during aerosolization at elevated (non-optimal) energies. These were largely consistent with those seen to result from oxidation and photolysis in solution, showing that oxidation and dehalogenation appeared to be the main degradation pathways followed when the CAG system was overheated.

Chromatographic and mass spectral characterization of budesonide and a series of structurally related corticosteroids using LC-MS.

The LC-MS characteristics of budesonide and a series of structurally related corticosteroids were reviewed to commence the construction of a library of chromatographic and mass spectral information to aid identification of budesonide degradation products during formulation stabilization investigations. The LC-ESI(+)-MS technique employing a Hypersil C18 column with a mobile phase of ethanol-acetonitrile-formic acid (pH 3.8; 0.14 mM) (2:30:68, v/v/v) was then used to characterize 23 corticosteroids. Based on their structures, the corticosteroids were classified into three groups: (I) 4-pregnene-3-one steroids; (II) 1,4-pregnadien-3-one steroids with no fluorine substituents; and (III) 1,4-pregnadiene-3-one steroids with fluorine substituents. Chromatographic (retention time and UV absorbance) and mass spectral properties were correlated with the known chemical structures of these corticosteroids. Base peak and mass spectral fragmentation patterns were related to steroid structural characteristics.

Physiochemical and pharmacological characterization of a Delta(9)-THC aerosol generated by a metered dose inhaler.

The goal of the present study was to formulate a Delta(9)-tetrahydrocannabinol (Delta(9)-THC) metered-dose inhaler (MDI) that can be used to provide a systemic dose of Delta(9)-THC via inhalation. Following physiochemical characterization and accelerated stability testing of the aerosol, mice were exposed to the aerosol and evaluated for pharmacological effects indicative of cannabinoid activity, including hypomotilìty, antinociception, catalepsy, and hypothermia. The fine particle dose of Delta(9)-THC was 0.22 +/- 0.03 mg (mean +/- S.D.) or 25% of the emitted dose and was not affected by accelerated stability testing. A 10-min exposure to aerosolized Delta(9)-THC elicited hypomotility, antinociception, catalepsy, and hypothermia. Additionally, Delta(9)-THC concentrations in blood and brain at the antinociceptive ED(50) dose were similar for both inhalation and intravenous routes of administration. Finally, pretreatment with the CB(1) receptor antagonist SR 141716A (10 mg/kg, i.p.) significantly antagonized all of the Delta(9)-THC-induced effects. These results indicate that an MDI is a viable method to deliver a systemic dose of Delta(9)-THC that elicits a full spectrum of cannabinoid pharmacological effects in mice that is mediated via a CB(1) receptor mechanism of action. Further development of a Delta(9)-THC MDI could provide an appropriate delivery device for the therapeutic use of cannabinoids, thereby reducing the need for medicinal marijuana.

Randomized controlled trial of three different doses of aerosol beclomethasone versus systemic dexamethasone to promote extubation in ventilated premature infants.

Our objective was to determine the safety and efficacy of aerosol beclomethasone vs. systemic dexamethasone for extubation in premature infants at high risk for chronic lung disease (CLD). Intubated preterm infants who were identified as being at high risk for moderate-severe CLD on day 14 of life were randomized to one of four groups. The control group received systemic dexamethasone and aerosol placebo, while the other three groups received either high (2.40-3.69 microg/kg/day delivered to lungs), medium (1.0-1.85 microg/kg/day), or low (0.48-0.74 microg/kg/day) dose aerosol beclomethasone and systemic placebo. Those receiving aerosol steroids who remained ventilator-dependent after 7 days were switched to standard 42-day tapering doses of systemic dexamethasone. The primary outcome was extubation within 1 week of starting steroids, using predefined criteria. Secondary variables included changes in lung function, rates of side effects, and tracheal aspirate white blood cell counts. Sixty-one infants with birth weights of 761 +/- 18 g (mean +/- SEM) and gestational ages of 25.7 +/- 0.2 weeks were randomized to one of the four groups. Seven of 15 infants in the control systemic dexamethasone group were successfully extubated compared with 3/16 in the high-dose beclomethasone group, 1/15 in the medium-dose group, and 2/15 in the low-dose group (P < 0.01). Only dexamethasone subjects demonstrated improvements in lung function over the study period. These infants also had significant increases in blood pressure and blood glucose levels, as well as a decline in their tracheal aspirate white blood cell count. In conclusion, aerosol beclomethasone at the very low doses used in this study did not facilitate extubation in intubated premature infants at high risk for moderate-severe CLD.

Biochemical evidence for transcytotic absorption of polyaspartamide from the rat lung: effects of temperature and metabolic inhibitors.

Airway-to-perfusate polyhydroxyethylaspartamide (PHEA) absorption was studied in the isolated perfused rat lung at a reduced temperature and by the use of metabolic inhibitors, to kinetically clarify the mechanisms and cellular pathways of its active absorption. Fluorophore-labeled PHEA (F-PHEA; 7.4 kDa) was administered into the airways, and its absorption followed with time at 25 degrees C and in the presence of 2,4-dinitrophenol (DNP), ouabain (OUA), monensin (MON), and nocodazole (NOC). Across-dose absorption profiles were analyzed using a kinetic model incorporating active (V(max,P) and K(m,P)) and passive (k(a,P)) absorption from the pulmonary lung region alongside the competing, pulmonary-to-bronchial mucociliary escalator (k(E)). The model was validated at 25 degrees C and a lack of perturbation on the k(a,P) and k(E) values for passively absorbed solutes confirmed by studying the disposition of sodium fluorescein and 4.4 kDa fluorescein isothiocyanate-labeled dextran. F-PHEA absorption was significantly suppressed at 25 degrees C, compared with 37 degrees C, because of a significant decrease in the value of the maximum rate of active absorption, V(max,P) (4.37 --> 0.67 microg/min; p < 0.05), whereas the carrier-affinity term, K(m,P), was statistically unchanged. F-PHEA's active absorption was also significantly inhibited by DNP (> or =0.5 mM), OUA (> or =50 microM), MON (> or =10 microM), and NOC (> or =1 microM), whereas these inhibitors had no significant effect on the values for k(a,P) and k(E). Thus, F-PHEA's pulmonary active absorption in the rat lung was temperature- and adenosine 5'-triphosphate-derived intracellular energy-dependent (DNP and OUA inhibition) and apparently mediated via transcytosis through cytoplasmic endosomes and microtubules (MON and NOC inhibition).

Aerodynamic sizing of metered dose inhalers: an evaluation of the Andersen and Next Generation pharmaceutical impactors and their USP methods.

The particle sizing performance of a Next Generation Pharmaceutical Impactor (NGI) was compared to that of an Andersen cascade impactor (ACI). A single lot of Vanceril MDIs containing beclomethasone dipropionate (BDP) was used throughout. MDIs were sampled into NGI and ACI in accordance with USP recommendations, at 30.0 and 28.3 L/min, respectively, following 1, 2, 6, and 30 actuations with or without a silicone cup or stage coating, to determine the apparent particle size distributions (PSD) of BDP. The mass balance and the statistical comparability of drug deposits were assured on a "per actuation basis" across all experiments, demonstrating "good cascade impactor practices." Interstage deposition or "wall losses" in NGI were found to be lower than those in ACI, although their determination was laborious in NGI. The PSD profiles for Vanceril from a single actuation were distinguishable between NGI and ACI, when uncoated collection surfaces were used, most specifically for drug mass <4-microm aerodynamic diameter (p < 0.05). Silicone coating of collection surfaces and an increased number of actuations were shown to result in PSD profile shifts for both NGI and ACI. Such effects were most pronounced for NGI, although coating the collection surfaces and/or increasing the number of actuations improved drug retention significantly on the upper stages of NGI, and thereby, minimized the effects of particle bounce of BDP from Vanceril MDIs. PSD profiles from a single actuation could be determined reliably in either of these impactors, provided that coated collection surfaces were employed; also, cumulative % mass undersize profiles were similar between instruments. However, small differences in PSD profiles still existed to support NGI's design claims for reduced "overlap" in its stage collection efficiency curves.

Solute disposition in the rat lung in vivo and in vitro: determining regional absorption kinetics in the presence of mucociliary escalator.

Solute absorption from the airways was compared and modeled in vivo and in vitro isolated perfused rat lung (IPRL), and its regional kinetic descriptors in the presence of competing mucociliary escalator were estimated. 7.4 kDa fluorophore-labeled polyhydroxyethylaspartamide (F-PHEA), FITC-labeled dextran 40 (FD-4) and sodium fluorescein (F-Na) were used as model solutes. They were reproducibly administered into the airways in a range of doses in vivo and in vitro IPRL, and their initial deposition and subsequent absorption profiles compared. Each of the absorption data was fitted across doses to a kinetic model in which rate constants for Michaelis-Menten-type active (V(max,P) and K(m,P)) and/or first-order passive (k(a,P)) absorption and mucociliary escalator (k(E)) were estimated simultaneously. Statistically indistinguishable initial solute distribution was ensured in vivo and in vitro. The absorption profiles for F-PHEA were kinetically identical in vivo and in vitro, and their modeling analysis revealed the presence of competing, solute-independent pulmonary-to-bronchial mucociliary escalator with a half-life of 28.9 min. F-PHEA's active absorption was found to be 77 times faster than its passive absorption, yet this was present only in the pulmonary region. Passive solute absorption was inversely related to solute molecular weight [F-PHEA < FD-4 < F-Na]. Bronchial absorption was shown for F-Na in vivo and its rate indistinguishable from that from the pulmonary region. Thus, a single kinetic model was developed, enabling regional absorption kinetic analysis both in vivo and in vitro, in the presence of competing, solute-independent mucociliary escalator.

Control of particle size by coagulation of novel condensation aerosols in reservoir chambers.

The coagulation growth behavior of capillary aerosol generator (CAG) condensation aerosols was investigated in a series of reservoir chambers. Aerosols consisted of a condensed system of 0.7% w/w benzil (model drug) in propylene glycol (vehicle). These were generated into 250-, 500-, 1,000-, and 2,000-mL reservoirs in both flowing air-stream and static air experiments. Changes in drug and total aerosol particle size were measured by a MOUDI cascade impactor. In both series of experiments the CAG aerosols grew in size. Growth in flowing air-stream experiments was attributed to the amount of accumulation aerosols experienced in reservoirs during sampling and increased with increasing reservoir volume. Mean (SD) MMAD's for the total mass distribution measured for the 250- and 2,000-mL reservoirs were 0.70 (0.02) and 0.87 (0.03) microm, respectively. For the benzil mass distribution, they were 0.64 (0.02) and 0.87 (0.06) microm, respectively. Growth in static air experiments was dependent on the volume aerosol boluses were restricted to and increased with decreasing reservoir volume. Mean (SD) initial MMAD's for the benzil mass distribution for the 250- and 2,000-mL reservoirs were 1.44 (0.03) and 1.24 (0.08) microm, respectively. Holding aerosols for up to 60 sec further increased their size. Mean (SD) MMAD's for benzil after holding for 60 sec in these reservoirs were 2.28 (0.04) and 1.67 (0.09) microm, respectively. The coagulation behavior and therefore particle size of CAG aerosols may be modified and controlled by reservoir chambers for drug targeting within the respiratory tract.

In vitro tests for aerosol deposition II: IVIVCs for different dry powder inhalers in normal adults.

BACKGROUND: A new in vitro test method for dry powder inhalers (DPIs) was recently found to be predictive of the published in vivo results for Budelin Novolizer. The present study was intended to assess the method's robustness by evaluating correlations between average drug deposition in vitro and in vivo from five different DPIs. METHODS: In vitro drug deposition from five marketed DPIs was assessed in a realistic physical airway model of a "medium" sized adult in an experimental setup that allowed deposition to be characterized regionally for carefully selected simulated air flow rate versus time profiles. The DPIs studied were Spiriva(®) HandiHaler(®), Relenza(®) Diskhaler(®), Salbutamol Easyhaler(®), Pulmicort(®) Turbuhaler(®), and Foradil(®) Aerolizer(®). In vitro regional deposition results were compared with those reported in the literature in order to create in vitro-in vivo correlations (IVIVCs) for each inhaler. RESULTS: Mean percent total lung deposition (TLD ± SD) in vitro for Spiriva HandiHaler, Relenza Diskhaler, Salbutamol Easyhaler, Pulmicort Turbuhaler, and Foradil Aerolizer were 17.3 ± 1.2, 22.6 ± 1.1, 29.0 ± 1.1, 28.0 ± 3.0, and 21.7 ± 1.2, respectively. These results showed excellent agreement with reported in vivo values, with absolute prediction errors in TLD of ≤ 2% for all DPIs except Relenza Diskhaler. Similarly, in vitro mouth-throat and device deposition results were stoichiometrically comparable to those reported in vivo for all DPIs except Relenza Diskhaler and Turbuhaler. Inspection of the scintigraphy studies for Relenza Diskhaler and Turbohaler revealed possible problems with powder labeling and result interpretation in their in vivo clinical assessments. CONCLUSIONS: A characteristic physical airway model representing a medium-sized adult, when coupled to carefully chosen characteristic inhalation maneuvers used in the clinic, produced results that correlated with regional drug deposition estimates from scintigraphy across a group of different DPIs.

In vitro tests for aerosol deposition. III: effect of inhaler insertion angle on aerosol deposition.

BACKGROUND: Inhaler orientation with respect to a patient's mouth may be an important variable determining the efficiency of aerosol lung delivery. The effect of insertion angle on regional deposition was evaluated for a series of inhalers using concurrent in vitro and computational fluid dynamics (CFD) analysis. METHODS: Geometrically realistic physical mouth-throat (MT) and upper tracheobronchial (TB) models were constructed to connect different inhalers at a series of insertion angles relative to the horizontal plane of the model. These models were used to assess albuterol sulfate deposition from the Novolizer(®) dry powder inhaler (DPI), Proventil(®) HFA pressurized metered dose inhaler (MDI), and Respimat(®) Soft Mist™ Inhaler (SMI) following the actuation of a single dose. Drug deposition from Novolizer DPI was studied for Salbulin(®) and an experimental "drug only" formulation. Albuterol sulfate was recovered and quantified from the device and the MT and TB regions. RESULTS: Significant differences in MT and total lung dose (TLD) of albuterol sulfate deposition were not observed for Salbulin Novolizer DPI and Respimat SMI inserted at different angles. In contrast, drug-only Novolizer DPI and Proventil HFA MDI showed a significant difference in MT and TLD deposition using different insertion angles. For drug-only Novolizer DPI and Proventil HFA MDI, the lowest and the highest MT depositions were observed at +10° and -20°, respectively; for Respimat SMI and Salbulin Novolizer DPI, these angles were -10° and +10°, and +20° and -20°, respectively. CFD simulations were in agreement with the experimental results and illustrated shifts in local particle deposition associated with changes in insertion angle. CONCLUSION: The effect of inhaler orientation at the inhaler-mouth interface on MT aerosol deposition appeared to be dependent on velocity, aerosol size, and formulation. These findings not only demonstrate the need for patient education on correct inhaler orientation, but provide important new methods for those designing new inhalers.

In vitro tests for aerosol deposition. I: Scaling a physical model of the upper airways to predict drug deposition variation in normal humans.

BACKGROUND: In vitro-in vivo correlations (IVIVCs) are needed to relate in vitro test results for deposition to mean data from clinical trials, as well as the extremes in a population. Because drug deposition variations are related to differences in airway dimensions and inhalation profiles, this article describes the development and validation of models and methods to predict in vivo results. METHODS: Three physical models of the upper airways were designed as small, medium, and large versions to represent 95% of the normal adult human population. The physical dimensions were validated by reference to anatomy literature. The models were constructed by rapid prototyping, housed in an artificial thorax, and used for in vitro testing of drug deposition from 200 µg Budelin Novolizers using a breath simulator to mimic the inhalation profiles used in the clinic. In vitro results were compared to those reported in vivo. RESULTS: The "average" model was scaled to produce "small" and "large" versions by multiplying linear dimensions by 0.748 or 1.165, respectively, based on reports of the mean and standard deviation of airway volume across a normal adult population. In vitro deposition variation under fixed test conditions was small. Testing in the model triplet however, using air flow rate versus time profiles based on the mean and the extremes reported in the clinic, produced results for total lung deposition (TLD) in vitro consistent with the complete range of drug deposition results reported in vivo. The effects of variables such as flow rate in vitro were also predictive of in vivo deposition. CONCLUSIONS: A new in vitro test method is described to predict the median and range of aerosol drug deposition seen in vivo. The method produced an IVIVC that was consistent with 1:1 predictions of total lung deposition from a marketed powder inhaler in trained normal adults.