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Background: The anti-interleukin 13 (IL-13) monoclonal antibody lebrikizumab improves lung function in patients with moderate-to-severe uncontrolled asthma, but its effects on airway inflammation and remodelling are unknown. CLAVIER was designed to assess lebrikizumab's effect on eosinophilic inflammation and remodelling., Objective: To report safety and efficacy results from enrolled participants with available data from CLAVIER., Methods: We performed bronchoscopy on patients with uncontrolled asthma before and after 12 weeks of randomized double-blinded treatment with lebrikizumab (n = 31) or placebo (n = 33). The pre-specified primary end-point was relative change in airway subepithelial eosinophils per mm 2 of basement membrane (cells/mm 2 ). Pre-specified secondary and exploratory outcomes included change in IL-13-associated biomarkers and measures of airway remodelling., Results: There was a baseline imbalance in tissue eosinophils and high variability between treatment groups. There was no discernible change in adjusted mean subepithelial eosinophils/mm 2 in response to lebrikizumab (95% CI, -82.5%, 97.5%). As previously observed, FEV 1 increased after lebrikizumab treatment. Moreover, subepithelial collagen thickness decreased 21.5% after lebrikizumab treatment (95% CI, -32.9%, -10.2%), and fractional exhaled nitric oxide, CCL26 and SERPINB2 mRNA expression in bronchial tissues also reduced. Lebrikizumab was well tolerated, with a safety profile consistent with other lebrikizumab asthma studies., Conclusions & Clinical Relevance: We did not observe reduced tissue eosinophil numbers in association with lebrikizumab treatment. However, in pre-specified exploratory analyses, lebrikizumab treatment was associated with reduced degree of subepithelial fibrosis, a feature of airway remodelling, as well as improved lung function and reduced key pharmacodynamic biomarkers in bronchial tissues. These results reinforce the importance of IL-13 in airway pathobiology and suggest that neutralization of IL-13 may reduce asthmatic airway remodelling., Clinical Trial Registration: NCT02099656., (© 2020 The Authors. Clinical & Experimental Allergy published by John Wiley & Sons Ltd.)

Current asthma treatments address symptoms rather than the underlying disease pathophysiology, a better understanding of which has led to the identification of the Th2 high endotype. The activation of Toll-like receptors to induce Type I interferons directly in the lungs represents a novel therapeutic approach to reset this underlying Th2 pathophysiology with the potential to provide long-term disease modification. We present the nonclinical data and phase I clinical profile of an inhaled TLR9 agonist, AZD1419, a C-type CpG designed to induce interferon in the lung. In healthy volunteers, AZD1419 was found to be safe and well-tolerated. Target engagement in the lung was demonstrated at all dose levels tested. No evidence of tolerization or amplification of responses was evident on repeated dosing and 15.4 mg was defined as the maximum tolerated dose. AZD1419 clinical data supports its continued development as a potentially disease-modifying therapeutic in asthma., (© 2017 American Society for Clinical Pharmacology and Therapeutics.)

Purpose: To characterise a biorelevant simulated lung fluid (SLF) based on the composition of human respiratory tract lining fluid. SLF was compared to other media which have been utilized as lung fluid simulants in terms of fluid structure, biocompatibility and performance in inhalation biopharmaceutical assays., Methods: The structure of SLF was investigated using cryo-transmission electron microscopy, photon correlation spectroscopy and Langmuir isotherms. Biocompatibility with A549 alveolar epithelial cells was determined by MTT assay, morphometric observations and transcriptomic analysis. Biopharmaceutical applicability was evaluated by measuring the solubility and dissolution of beclomethasone dipropionate (BDP) and fluticasone propionate (FP), in SLF., Results: SLF exhibited a colloidal structure, possessing vesicles similar in nature to those found in lung fluid extracts. No adverse effect on A549 cells was apparent after exposure to the SLF for 24 h, although some metabolic changes were identified consistent with the change of culture medium to a more lung-like composition. The solubility and dissolution of BDP and FP in SLF were enhanced compared to Gamble's solution., Conclusion: The SLF reported herein constitutes a biorelevant synthetic simulant which is suitable to study biopharmaceutical properties of inhalation medicines such as those being proposed for an inhaled biopharmaceutics classification system.

Background: Exposure following oral inhalation depends on the deposition pattern of the inhaled aerosol, the extent and rate of oral and pulmonary absorption, as well as systemic distribution and clearance. For lipophilic inhaled compounds with low water solubility and high permeability, the extent and rate of pulmonary absorption can be assumed dependent on deposition pattern as well as dissolution rate., Materials and Methods: A mechanistic model of airway deposition, mucociliary clearance, dissolution, absorption, and dissipation was applied to simulate systemic exposure of the novel selective glucocorticoid receptor modulator, AZD5423, when dosed to healthy volunteers using two different nebulizers and two different dry powder inhalers in combination with two different primary particle size distributions. Results from simulations were compared with observed pharmacokinetic data., Results: Variations in systemic exposure (plasma concentration profile, AUC, and C max ) resulting from variations in dose, deposition pattern, and dissolution rate could not be predicted solely from variations in delivered dose or predicted lung dose (as assessed using an anatomical mouth-throat model), suggesting incomplete pulmonary bioavailability. However, simulated systemic exposure well predicted observed systemic exposures for all tested formulations and devices. Furthermore, simulations of airway tissue exposure suggested that it was not directly linked to systemic exposure., Conclusions: Results support the initial hypothesis that systemic exposure of poorly soluble inhaled drugs is a complex but predictable function of dose, deposition pattern, and rate of dissolution. Furthermore, simulations indicate that local exposure for these types of drugs is not well correlated with systemic exposure. Hence, equivalence with respect to local exposure, and thus with respect to pharmacodynamic effect, cannot be fully inferred from systemic pharmacokinetic equivalence alone.

Montelukast, a cysteinyl leukotriene receptor antagonist available as oral tablets, is used as a second-line therapy in asthma. In this study, we sought to enhance the availability of montelukast in the lungs by encapsulating the drug in poly (lactide-co-glycolic acid)-based (PLGA) respirable large porous particles. We determined the oral and lung specific availability of montelukast by assessing metabolic stability of the drug in the lung and liver homogenates, respectively. We similarly measured the oral and inhalational bioavailability by monitoring the pharmacokinetics and disposition of the drug in live animals. After preparing montelukast-loaded particles with various polymers, in the absence or presence of polyethylenimine (PEI-1), we characterized the particles for physical-chemical properties, entrapment efficiency, in vitro release, uptake by alveolar macrophages, deposition in the lungs, and safety after pulmonary administration. When incubated in lung or liver homogenates, the amount of intact drug in the lung homogenates was greater than that in the liver homogenates. Likewise, the extent of montelukast absorption via the lungs was greater than that via the oral route. Compared with smaller non-porous particles, large porous particles (PEI-1) were taken up by the alveolar macrophages at a lesser extent but deposited in the lungs at a greater extent. The levels of injury markers in the bronchoalveolar lavage fluid (BALF), collected from rat lungs treated with PEI-1, were no different from that in BALF collected from saline treated rats. Overall, the retention time and concentration of montelukast in the lungs can be increased by formulating the drug in large porous particles of PLGA., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Pressurized metered-dose inhalers (pMDIs) are sometimes viewed as old-fashioned and as having been superseded by dry powder inhalers (DPIs). Here, we review the technological advances that characterize modern pMDIs, and consider how they can influence the effectiveness of drug delivery for patients with asthma and chronic obstructive pulmonary disease. Compared with old chlorofluorocarbon (CFC)-based inhalers, many hydrofluoroalkane (HFA)-driven pMDIs have more favorable plume characteristics such as a reduced velocity and a higher fine particle fraction; together, these advances have resulted in the development of pMDIs with reduced oropharyngeal deposition and increased lung deposition. In addition, the plume from many HFA-pMDIs is warmer, which may facilitate their use by patients; moreover, devices are equipped with dose counters, which improves their reliability. As well as reviewing the technological advances of pMDIs, we also discuss the importance of individualizing inhaler therapies to each patient by accounting for their personal preferences and natural breathing patterns. Because pMDIs and DPIs differ considerably in their handling characteristics, matching the right inhaler to the right patient is key to ensuring effective therapy and good compliance. Finally, the majority of patients can be trained successfully in the correct use of their pMDI; training and regular monitoring of inhalation technique are essential prerequisites for effective therapy. While the 'ideal inhaler' may not exist, pMDIs are an effective device option suitable for many patients. pMDIs, together with other types of devices, offer opportunities for the effective individualization of treatments.

Background: In allergen-induced asthma, activated mast cells start the lung inflammatory process with degranulation, cytokine synthesis, and mediator release. Bruton's tyrosine kinase (Btk) activity is required for the mast cell activation during IgE-mediated secretion., Methods: This study characterized a novel inhaled Btk inhibitor RN983 in vitro and in ovalbumin allergic mouse models of the early (EAR) and late (LAR) asthmatic response., Results: RN983 potently, selectively, and reversibly inhibited the Btk enzyme. RN983 displayed functional activities in human cell-based assays in multiple cell types, inhibiting IgG production in B-cells with an IC50 of 2.5 ± 0.7 nM and PGD2 production from mast cells with an IC50 of 8.3 ± 1.1 nM. RN983 displayed similar functional activities in the allergic mouse model of asthma when delivered as a dry powder aerosol by nose-only inhalation. RN983 was less potent at inhibiting bronchoconstriction (IC50(RN983) = 59 μg/kg) than the β-agonist salbutamol (IC50(salbutamol) = 15 μg/kg) in the mouse model of the EAR. RN983 was more potent at inhibiting the antigen induced increase in pulmonary inflammation (IC50(RN983) = <3 μg/kg) than the inhaled corticosteroid budesonide (IC50(budesonide) = 27 μg/kg) in the mouse model of the LAR., Conclusions: Inhalation of aerosolized RN983 may be effective as a stand-alone asthma therapy or used in combination with inhaled steroids and β-agonists in severe asthmatics due to its potent inhibition of mast cell activation., Competing Interests: Author Disclosure Statement All authors were employed by Hoffmann-La Roche Inc. when experiments were performed.

During recent years, extra-fine particle inhaled corticosteroids with a median aerodynamic diameter ≤2 μm have been introduced in the treatment of asthma. The aim of this paper was to review pharmacokinetics and systemic activity of extra-fine particle hydroalkane pressurized metered dose inhaled (pMDI) ciclesonide and beclomethasone dipropionate in children. A literature review was performed. Systemic bioavailability of oral and pulmonary deposition of extra-fine ciclesonide and beclomethasone dipropionate was 52% and 82%, the half-life in serum 3.2 and 1.5 h and first-pass hepatic metabolism >99% and 60%, respectively. Secondary analyses of urine cortisol/creatinine excretion found no effects of ciclesonide pMDI between 40 and 320 μg/day or of beclomethasone dipropionate pMDI between 80 and 400 μg/day. Ciclesonide pMDI 40, 80 and 160 μg/day caused no effects on short-term lower leg growth rate as assessed by knemometry. Ciclesonide 320 μg/day was associated with a numerically short-term growth suppression equivalent to 30% which was similar to 25% and 36% suppression caused by beclomethasone dipropionate HFA and CFC 200 μg/day, respectively. Consistent with the differences in key pharmacokinetic features, beclomethasone dipropionate is associated with a systemic activity detected by knemometry at a lower dose than ciclesonide. Whether that correlates with a clinically important difference remains to be explored. Assessments of systemic activity of beclomethasone dipropionate <200 μg/day and of ciclesonide >180 μg/day as well as head-to-head comparisons are warranted. Preferably, such studies should apply the sensitive method of knemometry., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Reslizumab, a neutralizing anti-IL-5 monoclonal antibody, is a promising adjunctive treatment for severe eosinophilic asthma. Monthly intravenous 3.0 mg/kg reslizumab had resulted in improvements in lung function and asthma control. It is well tolerated and common adverse events include headache, nasopharyngitis and upper respiratory tract infection. Rebound eosinophilia after cessation of reslizumab and attenuation of the treatment response with repeated dosing had been reported. Stringent selection of patients with a high eosinophil burden, who are poorly controlled despite moderate to high doses of inhaled corticosteroid, confers the most significant treatment response. Future trials should compare the dose, delivery platform, frequency of dosing and study combinations with other biologics, which will affect its maximal clinical efficacy.

The present paper reviews pharmacokinetics and systemic activity of a new patent of fluticasone fumarate/vilanterol trifenatate and summarises the efficacy data in children, adolescents and adults with asthma. Bioavailability of oral deposition of fluticasone furoate is approximately 1%, of oral and pulmonary deposition 15%. Fluticasone furoate 400, 600 and 800 µg have been associated with reductions in 24h urine cortisol excretion in adults, whereas several studies on fluticasone furoate/ vilanterol trifenatate 100/25 µg and 200/25 µg once daily found no suppressive effects. Bronchodilation was detected in adults with asthma from 5 minutes after vilanterol trifenatate was inhaled and up to 24 hours after. Five large clinical trials which were sponsored by the manufacturer GlaxoSmithKline provided evidence that dry powder fluticasone furoate/vilanterol trifenatate 100/25 µg and 200/25 µg once daily are efficacious in asthma in patients ≥ 12 years of age. It remains to be proven, however, that once daily dosing may improve asthma control as compared to twice daily dosing. Efficacy and the systemic activity potential for hypothalamic-pituitary-adrenal and growth suppression of fluticasone furoate have not been established in children. The potential for systemic activity of fluticasone furoate in children may be assessed by knemometry.

The response to drug treatment in asthma is a complex trait and is markedly variable even in patients with apparently similar clinical features. Pharmaco-genomics, which is the study of variations of human genome characteristics as related to drug response, can play a role in asthma therapy. Both a traditional candidate-gene approach to conducting genetic association studies and genome-wide association studies have provided an increasing list of genes and variants associated with the three major classes of asthma medications: β2-agonists, inhaled corticosteroids, and leukotriene modifiers. Moreover, a recent integrative, systems-level approach has offered a promising opportunity to identify important pharmacogenomics loci in asthma treatment. However, we are still a long way away from making this discipline directly relevant to patients. The combination of network modeling, functional validation, and integrative omics technologies will likely be needed to move asthma pharmacogenomics closer to clinical relevance.

Purpose: To evaluate whether PDSC, an L-carnitine ester derivative of prednisolone and OCTN2 substrate, could provide a targeted delivery of the corticosteroid into the lung tissues of an asthmatic guinea pig model., Methods: PRED (prednisolone) and PDC (an L-carnitine prodrug of prednisolone not recognized by OCTN2) served as controls. Water solubility and logP values were determined, and PDSC and PDC in vivo were quantified by LC-MS/MS., Results: Unlike PRED, the intra-tracheal instillation of PDSC resulted in effective and prolonged accumulation of prednisolone in the lung tissues, leading to 3.8-fold higher reduction in inflammatory cell count in the bronchoalveolar fluid, and less severe lung and bronchial lesions in the asthmatic guinea pig. PDC showed similar pharmacokinetic profile to PRED, but exhibited higher efficiency (1.7-fold higher) at reducing the inflammatory cell count and the severity of lung histopathology, possibly due to the release of L-carnitine in vivo., Conclusions: The collective data suggest that PDSC has the potential to be an effective prodrug for the treatment of asthma with concomitant reduction in systemic side effects, and that novel prodrugs produced by L-carnitine conjugation can have useful applications in the targeted accumulation of drugs in the lungs., (Copyright © 2014 Elsevier B.V. All rights reserved.)

In vitro measures of aerosol particles size, such as the fine particle mass, play a pivotal role for approval of inhaled anti-asthmatic drugs. However, the validity as a measure of dose to the lungs in children lacks evidence. In this study we investigated for the first time the association between an in vivo estimate of lung dose of inhaled drug in children and the corresponding particle size segments assessed ex vivo. Lung dose of fluticasone propionate after inhalation from a dry powder inhaler (Diskus®) was studied in 23 children aged 4-7 and 12-15 years with mild asthma. Six-hour pharmacokinetics was assessed after single inhalation. The corresponding emitted mass of drug in segments of aerosol particle size was assessed ex vivo by replicating the inhalation flows recorded by transducers built into the Diskus® inhaler and re-playing them in a breathing simulator. There was no correlation between any inhaled particle size segment and lung dose assessed by pharmacokinetics and adjusted for age and body size. Measures of particles size segments were not related to lung dose in children. Until further evidence is provided it may be warranted to emphasize pharmacokinetic or pharmacodynamic assessments of drug delivery to the lung., (© The Author(s) 2013.)

Background: Fixed combination fluticasone-salmeterol is the most used anti-inflammatory asthma treatment in North America, yet no studies report the actual respiratory tract dose or the distribution of drug within the lungs. Inflammation due to asthma affects all airways of the lungs, both large and small. Inhaled steroid delivery to airways results from a range of drug particle sizes, with emphasis on smaller drug particles capable of reaching the peripheral airways. Previous studies suggested that smaller drug particles increase pulmonary deposition and decrease oropharyngeal deposition., Objectives: To characterize the dose of fluticasone-salmeterol hydrofluoroalkane-134a (HFA) (particle size, 2.7 μm) delivered to asthmatic patients and examine the drug distribution within the lungs. The results were compared with the inhalation delivery of HFA beclomethasone (particle size, 0.7 μm)., Methods: A crossover study was conducted in asthmatic patients with commercial formulations of fluticasone-salmeterol and HFA beclomethasone radiolabeled with technetium Tc 99m. Deposition was measured using single-photon emission computed tomography/computed tomography gamma scintigraphy., Results: Two-dimensional planar image analysis indicated that 58% of the HFA beclomethasone and 16% of the fluticasone-salmeterol HFA were deposited in the patient's lungs. The oropharyngeal cavity and gut analyses indicated that 77% of the fluticasone-salmeterol HFA was deposited in the oropharynx compared with 35% of the HFA beclomethasone., Conclusions: The decreased peripheral airway deposition and increased oropharyngeal deposition of fluticasone-salmeterol HFA was a result of its larger particle size. The smaller particle size of HFA beclomethasone allowed a greater proportion of lung deposition with a concomitant decrease in oropharyngeal deposition., (Copyright © 2012 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

The novel technologies in pulmonary drug delivery propelled the development of new strategies for pharmacological intervention in human diseases. In particular, this review will focus on pulmonary parameters which influence the delivery of inhaled therapeutics and summarize novel applications and recent innovations. The central issues of pulmonary drug application are optimal effectiveness under conditions of greatest safety. They not only depend on the properties of the drug but also feature the application vehicle and drug formulation. The optimization of the whole system (drug, formulation and vehicle) is therefore a necessary prerequisite for reliable inhaling medicines. Depending on the desired locus of drug action, the inhaled medicine has to be adjusted to particle size, concentration and chemical composition to guarantee a local or systemic drug action. Local asthma therapy represents the established concept for inhalation therapy. Due to the disease status, deposition of drugs is therefore often seen in central rather than peripheral airways. Recent developments in ultrafine therapeutic particles should therefore provide enough drug deposition even in the deeper airways. Recent approvals and interesting new therapy concepts will be discussed. Beside a pulmonary drug action there is an accumulating number of applications also for systemic drug action after pulmonary drug delivery. These involve among others inhaled insulin, glucagon-like-peptide 1 or growth hormone. But also novel therapeutic systems for gene therapy and vaccination are currently under investigation. Successful feasibility of these novel concepts will be expected in the near future.

Background: Spacer devices facilitate respirable drug delivery. A novel breath-actuated antistatic spacer with integrated vortex chamber (Synchro-Breathe) device has been developed, which is compact,portable and user friendly as compared to conventional spacers which are bulky and cumbersome. The relative bioavailability to the lung of inhaled fluticasone and salmeterol combination is primarily dependent on respirable dose delivery and can be reliably quantified using adrenal suppression and early fall in serum potassium (marker of systemic beta-2 adrenoreceptor response) as surrogate markers for delivered lung dose., Aims and Objectives: To compare the in vivo relative bioavailability to the lung of Hydrofluoroalkane(HFA) Seretide delivered via Synchro-Breathe (SB); an optimally prepared 750 ml large volume plastic spacer, Volumatic (VM); and conventional Evohaler pMDI (EH)., Methods: Nineteen healthy volunteers completed the study using a randomised double blind, double dummy crossover design. Single doses of placebo or Seretide HFA 250 (total dose ex-valve: fluticasone 2000 mcg/salmeterol 200 mcg) were administered via SB, VM and EH. Overnight urinary cortisol creatinine (OUCC) and serum potassium (K) were measured at baseline and after each dose as systemic surrogates of relative respirable dose delivery for the fluticasone and salmeterol moieties, respectively., Results: Significant suppression of OUCC and K occurred from baseline with SB and VM but not EH devices(geometric mean fold suppression, 95% CI, p and arithmetic mean fall mmol/L, 95% CI, respectively); EH:1.51(0.43-1.01), p 1/4 0.06; VM: 2.52(1.57-4.04), p < 0.001; SB: 2.66(1.57-4.49), p < 0.001(equating to 33.8%,60.2% and 62.3% falls, respectively). For K, the falls for EH were 0.09(0.25 to 0.07), p 1/4 0.69; VM: 0.27(0.46 to 0.08), p 1/4 0.003; SB: 0.32(0.53 to 0.11), p 1/4 0.002 (equating to 2.2%, 6.8%, and 8.06% fall,respectively). There were no significant differences between SB and VM., Conclusion: The breath-actuated Synchro-Breathe device was comparable to an optimally prepared Volumatic spacer, and resulted in commensurate improvement in relative lung bioavailability for both fluticasone and salmeterol moieties compared to pMDI.

Aim: To compare pulmonary deposition after inhalation with three different nebulisers in preterm infants under conditions relevant to practice., Methods: The relative lung deposition (bioavailability) was estimated by inhalation of the marker substance, sodium cromoglycate (SCG), and measurement of urinary excretion of SCG. Seventeen spontaneously breathing preterm infants received 20 mg of SCG as nebuliser solution by means of (a) an LC Star jet nebuliser; (b) an LS 290 ultrasonic nebuliser; and (c) a Projet ultrasonic nebuliser in a randomised three-period, crossover design. Serial urine samples were collected until about 12 hours after inhalations, and the excreted SCG was determined by high-performance liquid chromatography., Results: The mean (SD) total amounts of SCG excreted in urine measured after inhalation with the LC Star nebuliser (0.089 (0.036) mg) were significantly higher than those obtained with the LS 290 (0.055 (0.019) mg) or the Projet nebuliser (0.046 (0.025) mg). The average pulmonary deposition after inhalation using the LC Star, LS 290 and Projet devices was estimated as 0.89%, 0.55% and 0.46% of the nominal dose, respectively., Conclusion: Inhalation with the LC Star jet nebuliser producing the greatest proportion of droplets <2 mum yielded a higher lung deposition in preterm infants than the LS 290 and Projet ultrasonic nebulisers.

Purpose: To compare the pulmonary pharmacokinetics and relative bioavailability of salmon calcitonin delivered as aqueous droplets, pH 6.6 and pH 4.8 with that of a spray dried powder in healthy volunteers., Methods: Spray dried powders (1.6 microm [GSD 2.1]) containing 5% by wt. sCal, 6.25% human serum albumin, 73.55% mannitol and 15% citric acid/sodium citrate were prepared using a Buchi model 190 spray drier. Aqueous solutions were prepared by dissolving the spray dried powder at a sCal concentration of 1.25 mg/ml, pH was adjusted using 21 mM sodium hydroxide. Aerosols were delivered as part of a 4 way cross-over study to 16 healthy volunteers. The Nektar pulmonary delivery device was used to deliver the dry powder aerosol. A Salter nebulizer controlled by a Rosenthal dosimeter was used to deliver the aqueous aerosols. Miacalcin injection was used as the subcutaneous control. Dose delivered to the lung was estimated by gamma scintigraphy. Plasma concentrations of sCal were measured using a radioimmunoassay., Results: Aerosol size distributions were matched, 3.3 microm MMAD and approximately 2.2 GSD. Inhaled flow rates were similar, although not equal, 5.8 and approximately 9.8 l/min respectively for dry powder and liquid inhalations. Lung doses of sCal ranged from 53 to 88 microgm, peripheral lung doses from 25 to 51 microgm. Pharmacokinetic profiles and lung bioavailability relative to subcutaneous injection for all formulations were similar (not statistically significantly different p > 0.05), relative lung bioavailability ranged from 11% to 18%, estimates of relative bioavailability based on peripheral lung dose ranged from 20% to 33%., Conclusion: The study showed no difference in pharmacokinetic profiles between the various aerosol dosage forms. pH of the aqueous solutions did not affect kinetics or relative bioavailability.

In general, drugs are well absorbed from the lung, and the pulmonary absorption of therapeutic protein and peptide drugs, which are poorly absorbed from the gastrointestinal tract, was observed. However, locally acting drugs including antiasthmatic agents, bronchodilators, and expectorants should be localized for a long period in the lung tissues. In this study, the effects of various viscous vehicles on the absorption of theophylline and fluticasone propionate after intrapulmonary administration were examined in rats. Carrageenans were effective in regulating the absorption rate of these drugs. On the other hand, the bioavailability of therapeutic protein and peptide drugs with relatively high molecular weights from the pulmonary route is still poor when compared with the parenteral route. Therefore we examined the effects of chitosan and chitosan oligomers on the pulmonary absorption of interferon-alpha and salmon calcitonin in rats. Chitosan oligomers were effective in improving the pulmonary absorption of these drugs, and chitosan hexamer appeared to be markedly more effective than other oligomers. Furthermore, the present study indicated that chitosan oligomers did not cause any membrane damage to rat pulmonary tissues. In conclusion, it is suggested that various pharmaceutical excipients achieved the sustained pulmonary absorption of locally acting drugs and the improved pulmonary bioavailability for therapeutic protein and peptide drugs.

The aim of the present study was to measure airway, oropharyngeal and gastrointestinal deposition of (99m)Tc-labelled hydrofluoroalkane-beclomethasone dipropionate after inhalation via a pressurised metered-dose inhaler and spacer (Aerochamber Plus) in asthmatic children. A group of 24 children (aged 5-17 yrs) with mild asthma inhaled the labelled drug. A total of 12 children took five tidal breaths after each actuation (tidal group). The other 12 children used a slow maximal inhalation followed by a 5 - 10-s breath-hold (breath-hold group). Simultaneous anterior and posterior planar gamma-scintigraphic scans (120-s acquisition) were recorded. For the tidal group, mean+/-sd lung deposition (% ex-actuator, attenuation corrected) was 35.4+/-18.3, 47.5+/-13.0 and 54.9+/-11.2 in patients aged 5-7 (n = 4), 8-10 (n = 4) and 11-17 yrs (n = 4), respectively. Oropharyngeal and gastrointestinal deposition was 24.0+/-10.5, 10.3+/-4.4 and 10.1+/-6.2. With the breath-hold technique, lung deposition was 58.1+/-6.7, 56.6+/-5.2 and 58.4+/-9.2. Oropharyngeal and gastrointestinal deposition was 12.9+/-3.2, 20.1+/-9.5 and 20.8+/-8.8. Inhalation of the extrafine formulation with the breath-hold technique showed significantly improved lung deposition compared with tidal breathing across all ages. Oropharyngeal and gastrointestinal deposition was markedly decreased, regardless of which inhalation technique was applied, compared with a previous paediatric study using the same formulation delivered via a breath-actuated metered-dose inhaler.

Effects of various viscous vehicles on pulmonary absorption of antiasthmatic drugs were examined by an in situ pulmonary absorption experiment. Theophylline and fluticasone propionate were used as antiasthmatic drugs. The serum concentration-time profile of theophylline without viscous vehicles was similar to that following the intravenous injection, indicating that pulmonary absorption of theophylline was rapid and absolute. The serum concentration of theophylline was not controlled in the presence of 5% gelatin or 2% sodium alginate. However, 1% iota-carrageenan could control and regulate the serum concentration of theophylline. In the pharmacokinetic analysis, the C(max) values of theophylline significantly decreased, and its T(max) values increased in the presence of 1% and 2% iota-carrageenan, 1% kappa-carrageenan, and 2% sodium alginate compared with the control. The MRT and MAT values of theophylline with 1% iota-carrageenan were significantly higher than those without viscous vehicles. The local concentration of theophylline in the lung at 1h after intratracheal administration increased five-fold with 1% iota-carrageenan compared with the control. On the other hand, the pulmonary absorption of fluticasone propionate was controlled and regulated in the presence of 0.5% kappa-carrageenan. Additionally, the pulmonary inflammation after the exposure of carrageenans administered to the lung was evaluated in rats. Iota- and kappa-carrageenans did not cause local serious damage and inflammation to the pulmonary tissue. Therefore, these findings indicated that the carrageenans were effective to regulate the absorption rate of antiasthmatic drugs including theophylline and fluticasone propionate.

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.

Inhaled corticosteroids have become indispensable for the treatment of asthma and chronic obstructive pulmonary disease. Significant progress has been made toward minimizing side effects through the use of increasingly selective molecules, and through a variety of lung targeting strategies. Many of these developments have occurred in advance of a greatly improved understanding of corticosteroid biology at the molecular and pharmacologic level, and it has become clear that additional opportunities exist for the further enhancement of therapeutic index. This article discusses significant recent developments in the chemistry, biology, and pharmacology of corticosteroids, and considers the implications for the future use of inhaled corticosteroids.

Inhaled corticosteroids are now recommended as maintenance therapy for all but the mildest cases of asthma, and may be delivered by a variety of devices and formulations. Drug delivery may be assessed by both in vitro and in vivo methods. Although drug deposition in the lungs is expected to predict clinical response, this relationship is often masked by the flat nature of corticosteroid dose-response curves. The effects of inhaled corticosteroids depend not only upon the pharmacology of the drug being administered, but also upon its delivery system, with more efficient devices not only improving therapeutic effect but also potentially increasing systemic adverse effects. Modern delivery systems that enhance drug targeting to the lungs make it possible to use lower dosages of inhaled corticosteroid, such that the clinical response is maintained but systemic exposure reduced.

The relative lung and systemic bioavailability of sodium cromoglycate following inhalation by different methods have been determined using a urinary excretion pharmacokinetic method. On three separate randomised study days, 7 days apart, subjects inhaled (i) 4x5 mg from an Intal metered dose inhaler (MDI), (ii) 4x5 mg from an MDI attached to a large volume spacer (MDI+SP) and (iii) 20 mg from an Intal Spinhaler (DPI). Urine samples were provided at 0, 0.5, 1, 2, 5 and 24 h post dose. The mean (S.D.) amount of sodium cromoglycate excreted in the urine during the first 30 min post inhalation was 38.1 (27.5), 222.3 (120.3) and 133.1 (92.2) microg following MDI, MDI+SP and DPI, respectively. The mean ratio (90% confidence interval) of these amounts excreted in the urine over the first 30 min for MDI+SP vs. MDI, DPI vs. MDI and MDI+SP vs. DPI was 801.0 (358.0, 1244; p<0.002)%, 457.0 (244.0, 670.0; p<0.02)% and 262.4 (110.2, 414.5)%, respectively. Similarly for the 24 h cumulative amount of sodium cromoglycate excreted over the 24 h post inhalation the ratios were 375.4 (232.9, 517.9; p<0.005)%, 287.5 (183.4, 391.6; p<0.02)% and 211.4 (88.3, 334.5)%, respectively. The results highlight better lung deposition of sodium cromoglycate from a metered dose inhaler attached to a large volume spacer., (Copyright 2002 John Wiley & Sons, Ltd.)

Objectives: High-dose nebulised fluticasone propionate (FP) has been advocated for use in patients with severe persistent asthma. As there is complete first-pass inactivation of FP for the swallowed fraction, systemic absorption is due solely to its lung bioavailability. We wished to compare the relative lung delivery of FP, using adrenal suppression as a surrogate for the respirable dose, when administered via large volume spacer (FP-spacer) or nebuliser (FP-neb) in healthy adults., Methods: Fourteen healthy subjects, mean (SEM) age 29.4 +/- 2.6 years, were studied in a placebo-controlled, randomised study with three-way crossover design. Single nominal 2-mg doses of the following were given at 1700 hours in randomised sequence: a. FP-spacer: fluticasone pressurised metered dose inhaler (as Flixotide 250 microg ex-valve per actuation), eight puffs via a primed Volumatic 750-ml spacer. b. FP-neb: (as Flixotide Nebule 2 mg/2 ml) via Pari LC Plus nebuliser. c. Placebo nebuliser. Following each dose, measurements were made of corrected 0800-hours urinary cortisol/creatinine ratio (the primary outcome variable) and 0800-hours plasma cortisol., Results: Significant (P<0.05) suppression of both endpoints occurred only with FP-spacer, FP-neb being statistically no different from placebo. Geometric mean fold differences between FP-spacer and placebo were 9.8-fold [95% confidence interval (CI) 3.4, 28.8] for urinary cortisol/creatinine and 4.1-fold (95% CI 2.2, 7.5) for plasma cortisol. Comparing FP-spacer with FP-neb, these differences were 6.8-fold (95% CI 2.3, 20.0) for urinary cortisol/creatinine and 3.3-fold (95% CI 1.8, 6.0) for plasma cortisol., Conclusion: For a 2-mg labelled nominal dose of fluticasone, the spacer produced about a sevenfold higher relative lung dose than the nebuliser. This suggests that a very little of the labelled nebulised dose is respirable. Other factors such as patient preference, cost and compliance will determine the inhaler device that is chosen.

Dry powder inhalers (DPIs) provide a means of delivering inhaled asthma drugs without the use of propellants. Easyhaler is a multidose DPI, delivering 200 doses of beclomethasone dipropionate (BDP), 200 microg/dose. A gamma scintigraphic study has been carried out in 10 healthy volunteers to compare the deposition of BDP from Easyhaler with that from a pressurized metered dose inhaler (pMDI) coupled to a Volumatic spacer device delivering 250 microg BDP per dose. The spacer was used without any pretreatment to reduce static charge on the spacer walls. The study was conducted according to an open, randomized, crossover design. The volunteers inhaled the study drug using optimal inhalation technique for both devices. Lung deposition of 99mTc-labeled BDP averaged 18.9% (SD 9.5%) of the metered dose for Easyhaler, and 11.2% (SD 5.3%) for pMDI plus spacer (p < 0.05); when the data were expressed as mass of BDP deposited in the lungs, the difference in lung deposition just failed to reach statistical significance (Easyhaler 37.8 microg; pMDI plus spacer 28.0 microg). Oropharyngeal deposition was significantly reduced by use of the spacer. The results of this study show that Easyhaler delivers drug more efficiently to the lungs than pMDI plus Volumatic spacer when no measures are taken to eliminate static charge on the spacer walls.

Delivery of more drug to the lung may appear to be a desirable goal in the treatment of asthma and chronic obstructive pulmonary disease, since only 10 to 15% of a drug dose administered via a metered dose inhaler (MDI) reaches the lung. However, increasing the dose of most inhaled drugs may only lead to an increase in side effects, since maximal clinical benefit is usually obtained with the currently recommended dosages. Improving the regional deposition of inhaled drugs may be a more effective way of modifying clinical response. Particle size is the most significant determinant of the deposition pattern of inhaled drugs. Optimum drug delivery to the conducting airways occurs with particles ranging from 2.5 to 6 microm; particles <2.5 microm are deposited mainly in the alveoli where they may exert no pharmacodynamic effect and are rapidly absorbed, increasing the risk of systemic adverse events. Delivery devices can be compared by estimating the lung and systemic exposures, taking into account the efficacy and safety dose-response relationships for the drug-device combination. Current devices have profoundly different lung deposition profiles that could affect clinical efficacy when switching devices. Devices that achieve a high lung to systemic ratio for the inhaled drug are preferable.

The delivery of an inhaled drug to the lungs can be measured by adding a gamma-emitting radiotracer to the formulation and using two-dimensional planar imaging or three-dimensional single photon emission computerized tomography (SPECT) to provide detailed information on lung deposition. The isotope most commonly used is the low energy (140 KeV) isotope, 99m technetium. Radiolabeling techniques have been successfully developed for use with nebulizers, pressurized metered dose inhalers (pMDIs), and dry powder inhaler formulations (DPI), and to investigate drug delivery to the respiratory tract for a variety of drug formulations and patient populations. However, for pMDIs and DPIs, the radiotracer is usually only physically associated with, rather than chemically bound, to the drug. Therefore, once deposited, the radiotracer may disassociate from the drug and cannot be used to track its subsequent fate; however, incorporation of a radiotracer directly into the drug molecule can overcome this. By using positron emitters such as 11carbon or 18fluorine it is possible to generate three-dimensional images of the drug in the lung using positron emission tomography (PET) scanning, which has a higher resolution and is more accurate than SPECT. Labeling drugs with PET emitters is more complex as the drug molecule must first be synthesized to contain the radioactive isotope before the drug is formulated for the inhaler. As with gamma-scintigraphy, PET scanning can be used to investigate physiological changes in the lung following therapeutic intervention, but as biological radiotracers are used, functional images (i.e., of the drug's uptake and metabolism) can also be obtained.

When assessing inhaled drug absorption, standard pharmacokinetic analyses cannot differentiate drug that reaches the systemic circulation from the lungs from that of the gut. Pulmonary absorption kinetics can be assessed for drugs with negligible gastrointestinal absorption or for drugs that are eliminated via first-pass metabolism. For other drugs, pulmonary absorption kinetics can be studied by blocking gastrointestinal absorption with charcoal, or by studying absorption during the first 30 minutes post inhalation before appreciable oral absorption has occurred. Pharmacokinetic data generally agree well with pulmonary deposition data derived by measuring inhaled radiotracer-labelled drug using gamma-scintigraphy. Monitoring pulmonary and oral absorption also provides information on total systemic exposure and therefore safety. Furthermore, the duration of action of different inhaled drugs and the degree of pulmonary targeting can be obtained by determining the corticosteroid occupancy of lung and systemic glucocorticoid receptors. Pharmacokinetic data from healthy volunteers cannot be extrapolated to patients with asthma, as systemic exposure to inhaled drugs can be markedly less in patients than in healthy volunteers. This correlates with the observed differences in side effects in these two groups. Although pharmacokinetic methods do not provide information on regional deposition, they do generate data on systemic and pulmonary exposure, and so play a role in the development of delivery systems.

Regulatory dossiers for new inhaled drug products generally contain in vitro data, which assess delivered dose and particle size distribution, together with clinical efficacy and safety data. Human lung deposition data may be generated using radionuclide imaging techniques or appropriate pharmacokinetic methods, and can act as a 'bridge' via which a seamless transition can be made between in vitro testing in the laboratory and efficacy/safety testing in the clinic. By enabling informed decisions to be made about the evaluation of new devices or formulations in man, lung deposition data permit a long and expensive clinical trials programme to be commenced with much greater certainty of a successful outcome. Human lung deposition data should be considered for supplementing the information required for regulatory dossiers.

The systemic availability of inhaled beclomethasone dipropionate (BDP) is the net result of the absorption of the glucocorticoid from the lower respiratory and gastrointestinal tracts, and metabolism in the lung, plasma, and other sites. The metabolism kinetics of BDP and its active metabolite, beclomethasone 17-monopropionate (17-BMP), in human lung 1000 x g supernatant (HLu) and human plasma (HP) at 37 degrees C were compared. The effect of MgCl(2) and/or an NADPH-generating system on the decomposition of BDP and 17-BMP in HLu was also investigated. The concentrations of BDP and its metabolites were determined by HPLC with UV detection at 242 nm. Kinetics of decomposition of BDP and 17-BMP in HLu and HP were qualitatively and quantitatively different. The decomposition of BDP in HLu involved only hydrolysis. In comparison, three reactions are involved following incubation of BDP in HP; namely, hydrolysis, transesterification, and loss of hydrogen chloride. The hydrolysis of BDP and 17-BMP in HLu seem to be inhibited appreciably by MgCl(2) with the NADPH-generating system. Effective activation of BDP in HLu, in combination with transesterification of 17-BMP in HP, might favor a high ratio of local antiinflammatory activity to systemic side effects following inhalation of BDP.

Studies involving the direct measurement of clinical response to inhaled asthma drugs, especially inhaled corticosteroids, may be very difficult to conduct. However, the deposition of drug in the lungs may be considered as a measure of local bioavailability, and may be quantified by radionuclide imaging techniques, or for some drugs by pharmacokinetic methods. This paper reviews evidence for considering lung deposition data as a surrogate for the clinical response to inhaled asthma drugs, based mainly upon a series of case histories. The appropriate use of lung deposition data in regulatory packages, especially to document the equivalence or comparability of two products, offers the possibility of significant time saving in the drug development process, and hence a faster drug development programme for inhaled asthma products.

In vitro analysis of inhaled formulations measures, among other parameters, the variability in delivered dose, while a corresponding in vivo analysis also includes the variability caused by patient performance and distribution of drug between the oropharynx and the lungs. In vitro, the dose variability is higher for Turbuhaler(R) than for the corresponding pMDI, whereas in vivo, the converse is true: the variability in lung deposition is significantly higher, both between and within subjects, for pMDI than for Turbuhaler. The observation can be due to several factors such as the non-continuous working principle of inhalation via pMDI as opposed to the continuous working principle of inhalation via Turbuhaler.

The present study was designed to evaluate the bronchodilating role of zafirlukast, a CysLT(1)receptor antagonist, at the standard dosage currently recommended in the marketing of this agent in smokers with COPD. The study was performed using a double-blind, cross-over, randomized design and was conducted on 2 non-consecutive days. Sixteen outpatients suffering from stable COPD received 40 mg oral zafirlukast, or placebo. Lung function was controlled before drug administration and 30, 60, 120, 180, 240 min thereafter. At the end of the 4-h period, each patient received 400 microg inhaled salbutamol and spirometric testing was performed 30 min later. Zafirlukast, but not placebo, produced a significant (P<0.05) bronchodilation between 30 min and 4 h following administration, with a maximum mean increase in FEV(1)of 0.134 l (11.2%) above baseline after 2 h. Nine of 16 patients showed an increase in FEV(1)of at least 15% above baseline after zafirlukast. The maximum mean increase in FEV(1)after zafirlukast in these subjects, who were considered responders, observed after 2 h, was 0.221 (19.4%). The mean difference of post-salbutamol FEV(1)values after zafirlukast and placebo (-0.036 l) was not significant (P<0.05). In responders, the mean of differences in pre- and post-salbutamol FEV(1)values after zafirlukast was 0.077 l, whereas the mean of differences between post-salbutamol values after zafirlukast and those after placebo was -0.064 l. The mean AUC(0-4 h)for all patients was 0.121 l for placebo and 0.385 l for zafirlukast. The difference between the placebo and zafirlukast AUC(0-4 h)was significant (P<0.05). The individual FEV(1)AUC(0-4 h)after zafirlukast were higher than those after placebo in 12 out of 16 patients. These findings suggest that cysteinyl leukotrienes might be one of the causes of persistent bronchoconstriction in COPD, at least in several smokers, but do not confirm the hypothesis that the effects of zafirlukast and salbutamol are independent and additive., (Copyright 2000 Academic Press.)

Aims: To determine if a urinary excretion method, previously described for salbutamol, could also indicate the relative bioavailability of sodium cromoglycate to the lung following inhalation from a metered dose inhaler. Method Inhaled (INH), inhaled+oral charcoal (INHC), oral (ORAL) and oral+oral charcoal (ORALC) 20 mg doses of sodium cromoglycate were given via a randomised cross-over design to 11 healthy volunteers trained on how to use a metered dose inhaler. Urine samples were collected at 0.0, 0.5, 1.0 and up to 24 h post dosing and the sodium cromoglycate urinary concentration was measured using a high performance liquid chromatographic method., Results: No sodium cromoglycate was detected in the urine up to 24 h following ORALC dosing. A mean (s.d.) of 3.6 (4.3) microg, 10.4 (10.9) microg and 83.7 (71.1) microg of the ORAL dose was excreted, in the urine, during the 0.5, 1.0 and 24 h post dose collection periods, respectively. Following INH dosing, the renal excretion was significantly higher (P<0.01) with 32.9 (14.5) microg, 61.2 (28.3) microg and 305.6 (82.3) microg excreted, respectively. The SCG excreted at 0.5, 1.0 and 24 h collection periods following INHC dosing were 26.3 (8.4) microg, 49.3 (18.1) microg and 184.9 (98.4) microg, respectively. There was no significant difference between the excretion rate of sodium cromoglycate following INHC when compared with INH dosing in the first 0.5 and 1.0 h., Conclusions: The urinary excretion of sodium cromoglycate in the first 0.5 h post inhalation can be used to compare the relative lung deposition of two inhaled products or of the same product using different inhalation techniques. This represents the relative bioavailability of sodium cromoglycate to the lung following inhalation. Similar 24 h urinary excretion of sodium cromoglycate can be use to compare the total dose delivered to the body from two different inhalation products/inhalation methods. This represents the relative bioavailability of sodium cromoglycate to the body following inhalation. Because of the lack of difference between the INH and INHC in the first 0.5 h, the use of activated charcoal is not necessary when this method is used to compare the relative lung bioavailability of different products or techniques.

The pulmonary distribution and clearance of 99mTc-labelled beclomethasone dipropionate (Bec) dilauroylphosphatidylcholine (DLPC) and dipalmitoylphosphatidylcholine (DPPC) liposomes were compared in 11 healthy volunteers using gamma scintigraphy. As delivered by using the Aerotech jet nebulizer both liposome aerosols had a suitable droplet size (mass median aerodynamic diameter 1.3 microm) allowing deep pulmonary deposition. However, in the total drug output during the inhalation there was a relatively large difference between DLPC and DPPC of 11.4 and 3.1 microg, respectively. In a gamma camera study no significant differences existed in the central/peripheral lung deposition between the DLPC and DPPC formulations. Progressive clearance of both Tc-labelled Bec liposomes was seen: 24 h after inhalation, 79% of the originally deposited radioactivity of DLPC liposomes and 83% of that of DPPC liposomes remained in the lungs. Thus there was slightly slower clearance of inhaled liposomes using DPPC instead of DLPC. We conclude that both liposome formulations are suitable for nebulization, although aerosol clouds were more efficiently made from the DLPC liposome suspension. Our results support the view that liposome encapsulation of a drug can offer sustained release and drug action in the lower airways., (Copyright.)

Objective: To determine the relative lung deposition of nedocromil sodium following inhalation by comparing the amounts of nedocromil sodium excreted in the urine after oral and inhaled dosing., Methods: Ten healthy volunteers swallowed 8 mg of nedocromil and inhaled 4 x 2-mg doses on separate days. Urine was collected at 0.0, 0.5. 1.0, 2.0, 5.0, 24 h and 36 h after dosing. Urinary excretion of nedocromil was determined by high-performance liquid chromatography., Results: A significantly greater amount of nedocromil was excreted following inhalation than after oral dosing. The mean with (SD) amount excreted at 0.5, 1.0 h and 24 h following inhalation of 4 x 2-mg doses was 41.0 (19.5), 93.0 (39.1) and 319.9 (138.1) microg. Corresponding values after oral administration of 8 mg of nedocromil were 2.1 (2.2), 6.3 (4.7) microg and 74.4 (58.8) microg, respectively., Conclusion: Nedocromil excreted in the urine at 0.5 h and 1.0 h after dosing is representative of the amount of drug delivered to the lungs. This method could be used to compare the relative bioavailability to the lungs following inhalation, and hence the performance of different inhaled products and inhalation techniques. The amount of nedocromil excreted in 24 h post-dose is representative of the emitted dose which was delivered to the body.

Microsomes from human lung and liver catalyze the formation of fatty acid esters of budesonide, a glucocorticoid used for inhalation treatment of asthma. The conjugation was dependent on coenzyme A and ATP. Addition of free fatty acids to the incubations affected the pattern of metabolites, but ester formation was observed also without such addition. Budesonide oleate, palmitate, linoleate, palmitoleate, and arachidonate were identified as metabolites. The fatty acid conjugates of budesonide were shown to be substrates for lipase in vitro, thus budesonide is regainable from the conjugates. The data suggest that an equilibrium between budesonide and these pharmacologically inactive lipoidal conjugates will be established in tissues at repeated exposure to budesonide. Since the fatty acid conjugates most likely will be retained intracellularly for a longer time than unchanged budesonide, the duration of tissue exposure to budesonide will depend partly on the rate of lipase-catalyzed hydrolysis of the conjugates. The findings in this study provide a possible explanation for the efficacy of budesonide in mild asthmatics also when inhaled once daily.

We espouse the application of a novel chemical delivery system (CDS) approach to a delivery mechanism for drug targeting to lung tissue using the 1,2-dithiolane-3-pentyl moiety of lipoic acid as the "targetor moiety". The synthesis and the physicochemical and pharmacokinetic evaluation of a CDS modeling the lipoyl and other ester derivatives of chlorambucil (an antineoplastic agent) and cromolyn (a bischromone used in antiasthma prophylaxis) as compared with their respective parent drugs are described. The chlorambucil CDS was synthesized by esterifying the alcohol derivative of lipoic acid with chlorambucil using dicyclohexylcarbodiimide as the coupling agent. The cromolyn CDS was prepared by a multistep synthetic procedure culminating in the reaction of the alkyl bromide derivative of lipoic acid with the disodium salt of the bischromone compound. All the esters were highly lipophilic unlike the parent compounds. The in-vitro kinetic and in-vivo pharmacokinetic studies showed that the respective CDSs were sufficiently stable in buffer and biological media, hydrolyzed rapidly into the respective active parent drugs, and significantly enhanced delivery and retention of the active compound to lung tissue in comparison with the underivatized parent compounds used in conventional therapy.

The development of new inhalation devices for asthma drugs raises the issue of the relationship between pulmonary deposition and therapeutic effect of inhaled drugs in patients with obstructive lung diseases. We thus conducted a randomized, double-blind and double-dummy, four-period crossover study in 13 patients with moderate asthma (mean age 36 yr; FEV1 59% of predicted), who inhaled 0.25 and 0.5 mg terbutaline sulphate on separate occasions either via a pressurized metered dose inhaler (pMDI) or Turbuhaler (TBH). Pulmonary deposition was 8.1 +/- 2.7% and 8.3 +/- 2.3%, respectively, of the nominal dose for pMDI and 19.0 +/- 7.3%, and 22.0 +/- 8.1% for TBH. The FEV1 increase after 0.25 mg terbutaline sulphate via TBH was significantly greater than after 0.25 mg via pMDI. No significant differences in FEV1 increase were observed between 0.25 mg via TBH, 0.5 mg via pMDI, or 0.5 mg via TBH. Other lung function variables showed similar dose- and device-related changes. We concluded that: (1) the dose of terbutaline sulphate deposited in the lungs is dependent on which inhalation system is used; (2) TBH delivers about twice the amount of drug to the lungs as the pMDI; and (3) the observed difference in deposition is reflected in the bronchodilating effect.

The pulmonary deposition and pharmacokinetics of fine and coarse radioactive aerosols of nedocromil sodium, of mass median aerodynamic diameters 16 microns and 24 microns respectively, delivered by metered dose inhaler (MDI) have been investigated. The corresponding geometric standard deviations of the particle size distributions were 5.32 and 3.93. Pulmonary deposition was assessed by both planar radionuclide scintigraphy and multi-modality three dimensional imaging using single photon emission computed tomography (SPECT) and x-ray computed tomography (CT). The three dimensional data were analysed by transformation to a hemispherical shape based on the fractional radial distance of each point in the lung from the centre to the corresponding extrapolated point on the periphery. This enabled parameters on the variation of both concentration of deposition and total amount deposited with penetration distance to be calculated. For both planar and SPECT data the central to peripheral concentration ratio (C/P ratio) was calculated. The three dimensional C/P ratio showed a median value (3.21) which was significantly higher than for the planar imaging (2.03) (p < 0.001). The parameter used to express the variation of total amount deposited was the median dose position. This showed that for both aerosols 50% of the dose was deposited at sites with a percentage central to peripheral distance of greater than 68%. There was a trend for total percentage of the fine aerosol in the lungs to be higher than for the coarse and for its deposition to be more peripheral. In addition the mean concentrations in blood were measured to be greater for the fine aerosol. However these differences were relatively small and none were individually statistically significant. The technique of combined SPECT and CT imaging was shown to be valuable in obtaining more accurate information on pulmonary distribution of inhaled aerosol deposition. The merits, limitations and potential applications of the technique are discussed.

Drugs for the treatment and prophylaxis of asthma are delivered to the lungs by inhalation and this is facilitated by the use of pressurized metered dose inhalers (pMDIs), pMDIs with spacer devices and dry powder inhalers (DPIs). Lung deposition of drugs from pMDIs depends upon both the physicochemical nature of the aerosol formulation and the patient's inhalation technique, however, the majority of the dose from a pMDI is deposited in the oropharynx. Large volume spacer devices can reduce oropharyngeal deposition; however, lung deposition may be increased or decreased with a spacer in comparison with a pMDI, according to the design of the spacer, the aerosol formulation, the patient's inhalation technique and the extent to which the electrostatic charge on the spacer is controlled. Lung deposition of drug from DPIs also varies according to the design of the device. One DPI, Turbuhaler, deposits twice as much drug in the lungs as a pMDI, has a lower intersubject variability of lung deposition and results in lower oropharyngeal deposition.