Comparison of the aerosol velocity and spray duration of Respimat Soft Mist inhaler and pressurized metered dose inhalers.

Apart from particle size distribution, spray velocity is one of the most important aerosol characteristics that influence lung deposition of inhaled drugs. The time period over which the aerosol is released (spray duration) is also important for coordination of inhalation. Respimat Soft Mist Inhaler (SMI) is a new generation, propellant-free inhaler that delivers drug to the lung much more efficiently than pressurised metered dose inhalers (pMDIs). The objective of this study was to compare the velocity and spray duration of aerosol clouds produced by Respimat SMI with those from a variety of chlorofluorocarbon (CFC) and hydrofluoroalkane (HFA) pMDIs. All inhalers contained solutions or suspensions of bronchodilators. A videorecording method was used to determine the aerosol velocity. For spray duration, the time for generation of the Soft Mist by Respimat SMI was initially determined using three different methods (videorecording [techniques A and B], laser light diffraction and rotating disc). Videorecording was then used to compare the spray duration of Respimat SMI with those from the other inhalers. The Soft Mist produced by Respimat SMI moved much more slowly and had a more prolonged duration than aerosol clouds from pMDIs (mean velocity at a 10-cm distance from the nozzle: Respimat SMI, 0.8 m/sec; pMDIs, 2.0-8.4 m/sec; mean duration: Respimat SMI, 1.5 sec; pMDIs, 0.15-0.36 sec). These characteristics should result in improved lung and reduced oropharyngeal deposition, and are likely to simplify coordination of inhaler actuation and inhalation compared with pMDIs.     

An in vitro study to assess facial and ocular deposition from Respimat Soft Mist inhaler.

Respimat Soft Mist() inhaler (SMI) is a novel multidose propellant-free inhaler device for delivery of inhaled drugs to patients with asthma and chronic obstructive pulmonary disease. In vitro studies have been undertaken to assess facial and ocular deposition from Respimat SMI in several potential misuse situations. A placebo aqueous drug formulation in Respimat SMI was radiolabeled by addition of (99m)Tc. Deposition was quantified by gamma camera on a removable facemask that was fitted over the head of a resuscitation mannequin. The eyes were simulated by adhesive plaster patches. When Respimat SMI was fired in three preselected positions away from the head, total face deposition (% ex-valve dose) averaged 7.3%, 7.8%, and 9.1%, and eye deposition averaged 0.6%, 0.1%, and 0.3%. When the inhaler was fired into a simulated exhalation, upper face deposition (mean 3.8%) and eye deposition (mean 0.1%) were also small. It is concluded that low deposition on the face, and especially in the eyes, is to be expected when Respimat SMI is fired accidentally outside the body, or is fired at the same time as the patient exhales. When Respimat SMI is misused in the ways described in this study, there is likely to be little potential for unwanted side effects resulting from ocular deposition.     

Relative bioavailability of salbutamol to the lung following inhalation via a novel dry powder inhaler and a standard metered dose inhaler

Aims The number of dry powder inhaler (DPI) devices could increase because they are easier to use than a metered dose inhaler (MDI). Using urinary excretion, the relative bioavailability of salbutamol to the lungs and the body for a prototype DPI has been compared with an MDI.
Methods A randomized, double-blind, two way crossover study compared the amount of salbutamol in the urine 30  min following inhalation of 2×100  μg salbutamol from a prototype DPI (Innovata Biomed Ltd, UK) and a Ventolin^® (Allen and Hanburys Ltd, UK) MDI in 10 volunteers. The amount of salbutamol and its metabolite, the ester sulphate conjugate, renally excreted up to 24  h post inhalation was also determined to evaluate the relative bioavailability of salbutamol to the body.
Results The mean (s.d.) 30  min post-treatment urinary excretion for the prototype DPI and MDI was 8.4 (2.6) and 5.0 (1.9)  μg, respectively ( P <0.001). The total amount of salbutamol and its ester metabolite excreted in the urine over the 24  h period after inhalation was 187.9 (77.6) and 137.6 (40.0)  μg ( P <0.05).
Conclusions The prototype DPI delivered more salbutamol to the body and the lungs than a conventional MDI. This finding supports further development of the prototype DPI. The urinary salbutamol method is able to discriminate between two different inhalation systems.     

Comparison of the lung absorption of FK224 inhaled from a pressurized metered dose inhaler and a dry powder inhaler by healthy volunteers.

FK224 is a cyclopeptide drug with poor oral absorption due to proteolysis in the gastrointestinal tract. The objectives of this study were to investigate the absorption of FK224 from the lung in healthy volunteers, and compare the pharmacokinetic profiles of FK224 after inhalation from a pressurized metered dose inhaler (pMDI) and dry powder inhaler (DPI). The pMDI (Suspension type, 1 mg as FK224/puff) and DPI (4 mg and 10 mg as FK224/capsule, using Spinhaler as the device) were developed by formulating the same micronized particles of FK224 which were premixed with beta-cyclodextrin (beta-CyD) to improve the solubility of FK224. In the case of pMDI, 1, 4 or 8 mg was inhaled by the corresponding number of puffs with the pMDI. In addition, the in vitro drug delivery characteristics of the inhalers were evaluated using a multistage liquid impinger. In both inhalers, it was observed that FK224 could be absorbed into the systemic circulation from the lungs of the healthy volunteers, and the AUC and C(max) were proportionally increased depending on the emitted dose after inhalation. However, the pharmacokinetic (PK) parameters for DPI were significantly higher than that of pMDI, in spite of usage of the same fine particles for the formulations in both inhalers. Based on the distribution from the in vitro examination, the fine particle dose, which is defined as the dose region delivered as particles <3.8 microm, was calculated from the emitted dose inhaled by the healthy volunteers. It was found that the PK parameters for both inhalers were proportionally increased depending on the predicted fine particle dose regardless of the type of inhaler. This suggests that the absorption from the lung is influenced by the fine particle dose. We concluded that DPI is a suitable inhaler for FK224, and the alveolus, which is generally known as the site of action of the fine particles, is a possible absorptive site for FK224.     

Comparative lung delivery of salbutamol given via Turbuhaler and Diskus dry powder inhaler devices

Objective: The environmental concerns surrounding the use of chlorofluorocarbons (CFC) have led to a resurgence of interest in dry powder inhaler devices. The aim of our study was to compare two commonly used dry powder inhaler devices, namely the Turbuhaler and Diskus. Methods: Eight healthy volunteers with a mean (SEM) age of 21 years (0.8) were studied using a randomised single-investigator blind crossover design. Single doses of 1.2 mg salbutamol as Turbuhaler (12 × 100 μg) and Diskus (6 × 200 μg) were administered over 6 min. Mouth rinsing was performed after every inhalation. Lung delivery from each device was assessed by measuring the early plasma salbutamol profile at 5, 10, 15 and 20 min after inhalation. Results: Significant differences in lung delivery were found between the Diskus and the Turbuhaler for salbutamol C_max 3.21 vs 4.04 ng · ml⁻¹, respectively and C_av 2.65 vs 3.73 ng · ml⁻¹, respectively. This amounted to a 1.28-fold difference (95% CI 1.09 to 1.45) between these devices for C_max and a 1.42-fold difference (95% CI 1.57 to 1.66) for C_av. Conclusion: We have demonstrated that, in vivo, the Turbuhaler dry powder inhaler produces significantly greater lung delivery of salbutamol than the Diskus. This illustrates that dry powder inhaler devices may have different in vivo deposition characteristics. Received: 27 January 1997 / Accepted in revised form: 21 May 1997     

Assessment of adrenal suppression from two new dry powder inhaler formulations of budesonide delivered by Clickhaler compared with the Pulmicort Turbuhaler.

Assessment of adrenal suppression via systemic cortisol levels provides an indirect measure of the lung delivery of inhaled corticosteroids. This randomized, placebo-controlled, double-blind, double-dummy crossover study compared urinary and plasma cortisol levels in healthy adult volunteers following single 1,000-microg doses of budesonide from two multiple dose dry powder inhalers (DPIs). Two new formulations of budesonide (lactose and PassCal) delivered from the Clickhaler were compared with Pulmicort from the Turbuhaler. An open dose (2,000 microg) of Pulmicort Turbuhaler was included to validate the experimental model. Overnight (22:00-07:00 h) and early morning (07:00-08:00 h) urine and 08:00 h plasma samples were collected after each treatment and cortisol levels analyzed by radioimmunoassay. Combined overnight and early morning urinary cortisol values for PassCal Clickhaler and Pulmicort Turbuhaler (1,000 microg) were statistically significantly lower than placebo (p < 0.05). The lactose budesonide Clickhaler showed a non-significant urinary cortisol reduction compared with placebo. Differences between the three 1,000-microg budesonide treatments were not significant. The Pulmicort Turbuhaler 2,000 microg showed significant urinary cortisol suppression compared with placebo. Plasma cortisol showed similar effects, with significance between the two Pulmicort doses. These results suggest that adrenal suppression can be used to assess the pulmonary bioavailability of different formulation.     

Drug delivery from the Turbuhaler and Nebuhaler pressurized metered dose inhaler to various age groups of children with asthma.

A total of 198 children aged 3 to 15 years inhaled a single dose of 200 micrograms budesonide from a Nebuhaler pressurized metered dose inhaler (pMDI) and a Turbuhaler dry powder inhaler in a randomized crossover study. The budesonide dose delivered to a patient was assessed by measuring the amount of drug deposited on a filter inserted between the inhaler outlet and the patient's mouth. The dose of budesonide deposited on the filter and the estimated dose of particles with a mass median aerodynamic diameter (MMAD) of 5 microns or less after inhalation from the Turbuhaler were both approximately twice the values inhaled from the pMDI Nebuhaler in children less than 5 years of age (P < 0.01). The variation in the dose delivered to the patient was similar for the two inhalers in children over 5 years old. In 3- to 4-year-old children, dose delivery to the patient was higher and/or more consistent from the pMDI Nebuhaler than from the Turbuhaler. Filter dose after Turbuhaler treatment varied significantly from peak inspiratory flow rate through the Turbuhaler (PIFTbh) (P < 0.01). The percentage of children producing a PIFTbh greater than 50 L/min decreased with age (89%, 45%, and 14% in 5-, 4-, and 3-year-old children, respectively). It is concluded that drug delivery to a child with asthma varies with age and inhalation device. Further studies are needed to assess the clinical importance of this finding.     

A critical comparison of the dose delivery characteristics of four alternative inhalation devices delivering salbutamol: pressurized metered dose inhaler, Diskus inhaler, Diskhaler inhaler, and Turbuhaler inhaler.

Salbutamol is a short-acting beta 2 agonist which is effective as a rescue therapy in the treatment of asthma. This study uses in vitro test methods to compare the capability of four alternative devices to deliver an accurate and precise dose of salbutamol. It is demonstrated that the conventional metered dose inhaler (MDI) achieves excellent accuracy and precision in dose delivery. Additionally, it is the most efficient inhaler in terms of generating in-vitro a fine particle fraction from the dose. A spacer device has been shown to further enhance the dosing characteristics. When tested over a wide range of inspiratory air flow rates, the Diskus (GlaxoWellcome, Hertfordshire, UK) has comparable accuracy and precision to the MDI tested at 60 L/min, and it offers an advantage over two alternative dry powder inhalers (DPIs), delivering a more consistent dose across the range of flow rates tested and being more efficient at generating a fine particle fraction than either Turbuhaler (Astra, Lund, Sweden) or Diskhaler (GlaxoWellcome) at both 28 and 60 L/min inspiratory flow rates. Diskus, Diskhaler, Ventolin, Volumatic, and Rotadisk are trademarks of the GlaxoWellcome Group of companies. The Accuhaler is the alternative to the Diskus in those countries where the Diskus trademark is not available. Inspiryl and Turbuhaler are trademarks of the Astra Group of companies.     

Relative lung and total systemic bioavailability following inhalation from a metered dose inhaler compared with a metered dose inhaler attached to a large volume plastic spacer and a jet nebuliser

OBJECTIVE: To compare the lung and systemic delivery of salbutamol following inhalation from a metered dose inhaler (MDI), a MDI attached to a spacer (MDI+SP) and a nebuliser (NEB) using a urinary pharmacokinetic method. METHOD: Twelve healthy subjects each provided urine samples at 0, 30 min and pooled up to 24 h after the start of 5 x 100 microg salbutamol inhaled from MDI and MDI + SP and after 2.5 mg was delivered by NEB. Following nebulisation, the amount of salbutamol trapped on an exhalation filter together with that remaining in the apparatus was determined. The amount left in the spacer and that leaving the MDI mouthpiece was also determined. Thus, for all the methods, the amount available for inhalation from each study dose was determined. RESULTS: The mean (+/- SD) 30-min urinary excretion amounts of salbutamol for MDI, MDI+SP and NEB were 12.6+/-3.5, 27.1+/-6.0 and 16.1+/-4.6 microg, respectively. The mean ratios (90% confidence intervals) for MDI+SP compared with MDI and NEB were 230.2 (186.7, 273.8) and 183.0 (146.4, 219.7) (both P values<0.001), respectively, while that between MDI and NEB was 134 (110.4, 159.1) (P < 0.05). The mean (+/-SD) 24-h urinary excretion values for salbutamol and its metabolite were 287.0+/-46.5, 198.1+/-34.7 and 253.4+/-138.3 microg, respectively. Following inhalation a mean of 202.9+/-51.5 microg was left in the spacer. Similarly, after nebulisation 1387.7+/-88.9 microg was left in the nebuliser chamber, 26.3+/-8.0 microg in the mouthpiece and 553.8+/-68.5 microg exhaled. The mean emitted dose from the MDI was 88.4+/-6.1 microg per actuation. When normalised for the amounts available for inhalation, the mean amounts of salbutamol excreted in the urine during the first 30 min were 2.86+/-0.78, 9.15+/-1.69 and 3.06+/-0.70% following MDI, MDI + SP and NEB, respectively. CONCLUSION: Five 100-microg doses inhaled from a metered dose inhaler attached to a spacer delivered more to the lungs and less to the systemic circulation than either the same doses from a metered dose inhaler used alone or five times the dose given via a jet nebuliser. Spacers should be routinely used instead of nebulisers to manage patients unless they are short of breath.     

Effect of inhalation flow rate on the dosing characteristics of dry powder inhaler (DPI) and metered dose inhaler (MDI) products.

Both the dose delivered from the device and the particle size of the medication are important parameters for inhalation products because they influence the amount of drug that is delivered to the patient's lung. The inspiratory flow rate may vary from dose to dose in a given patient and between patients. The Marple-Miller Cascade Impactor, a new multistage inertial impactor that operates at two flow rates (30 and 60 liters/min) with comparable particle size cut-offs, provides a means to study the effect of inhalation flow rate on the particle size distributions of inhalation products. The medication delivery, mass median aerodynamic diameter (MMAD), and fine particle mass were determined, in a randomized fashion, for albuterol, beclomethasone, budesonide, and terbutaline in both metered dose inhaler (MDI) and dry powder inhaler (DPI) products as a function of flow rate. In all cases, independent of drug or device used, the MDI products had a more reproducible respirable dose than the breath-actuated DPI products tested as a function of inhalation flow rate.     

Variability in lung deposition of inhaled drug, within and between asthmatic patients, with a pMDI and a dry powder inhaler, Turbuhaler

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.     

Deposition and pharmacokinetics of an HFA formulation of triamcinolone acetonide delivered by pressurized metered dose inhaler.

Novel formulations of asthma drugs contained in pressurized metered dose inhalers (pMDIs) are being developed containing hydrofluoroalkane (HFA) propellants. The objectives of this study were to assess the deposition in the lungs and oropharynx of triamcinolone acetonide (TAA; Azmacort, Aventis Pharma, Collegeville, PA) delivered by pMDI formulated with HFA-134a, together with the pharmacokinetic profile of TAA, and to determine the extent to which the Azmacort spacer improves targeting of TAA to the lungs. The deposition of TAA, labelled with 99mTc, was assessed by gamma scintigraphy in 10 patients with mild to moderate asthma (mean forced expiratory volume in one second [FEV1] 76% predicted), who received in randomized order three delivered (ex-device) doses of 75 microg TAA via pMDI coupled to an Azmacort spacer (TAA-spacer), and three delivered doses of 230 microg TAA via the same device, but with the spacer removed (TAA-no spacer). Mean lung deposition expressed as mass of drug was similar for each regimen (TAA-no spacer 175 microg; TAA-spacer 188 microg), but when expressed as percentage delivered dose, lung deposition was higher for TAA-spacer (53.8%) versus TAA-no spacer (26.0%), indicating superior drug targeting for TAA-spacer. The spacer reduced oropharyngeal deposition. The pharmacokinetic data showed higher plasma levels of drug for TAA-no spacer, resulting from higher oropharyngeal deposition. "Pharmacoscintigraphic" data showed proof of concept for a novel HFA delivery system for an inhaled corticosteroid based on pulmonary targeting of drug.     

Influence of particle size and patient dosing technique on lung deposition of HFA-beclomethasone from a metered dose inhaler.

The objective of this study was to determine the lung delivery of HFA-134a-beclomethasone dipropionate (HFA-BDP) from a breath-activated inhaler (QVAR Autohaler) compared with proper and improper press and breathe (QVAR P&B) metered dose inhaler (MDI) technique. The hypothesis was that that the smaller particles of BDP from HFA-BDP would stay suspended longer in the inspiratory air of patients and thus reduce the deleterious effects of inhaler discoordination. The study was an open label, four period, cross-over design. Asthmatic patients (n = 7) with a history of asthma symptoms, an FEV-1 of >70% of predicted normal, and a history of reversibility to a beta-agonist of >or=12% were utilized. BDP was radiolabeled with technetium-99m and delivered from the QVAR Autohaler or QVAR P&B device in patients trained to reproducibly utilize coordinated and discoordinated P&B MDI technique. Patients using Autohaler MDI exhibited 60% lung deposition of BDP. Patients using coordinated technique with the P&B MDI exhibited 59% lung deposition. Patients trained to consistently actuate the P&B MDI before inhaling exhibited 37% lung deposition. Patients trained to consistently actuate the P&B MDI late in the inspiration (i.e., 1.5 sec into a 3-sec inspiration) exhibited 50% lung deposition. In conclusion, the breath-activated Autohaler automatically provided optimal BDP lung deposition of 60%. Patients with good P&B MDI technique also received optimal lung deposition of 59%. The degree of lung deposition was decreased as patients demonstrated poor inhaler technique. However patients with poor technique still received a large lung dose of BDP (i.e., >or=37%) compared with lung deposition values of 4-7% for CFC-BDP MDIs previously published and confirmed in this study.     

Characterization of a microprocessor-controlled tubular multiple metered dose inhaler aerosol generator for inhalation exposures of pharmaceuticals.

A microprocessor-controlled tubular multiple metered dose inhaler (MDI) aerosol generator was constructed for the delivery of pharmaceutical aerosols to inhalation chambers. The MDIs were mounted in four cassettes containing one to four MDIs on a stepped end plate. The MDIs in each cassette were pneumatically activated at intervals that were controlled by the microprocessor. The cassettes permitted easy replacement of each set of MDIs with a fresh set of MDIs whenever necessary. Aerosol concentration was controlled by varying the number of active MDIs in each cassette and the frequency of activations per minute of each row. Aerosol from the MDIs flowed along the long axis of the tube, which provided a path length sufficient to diminish impaction losses. Using a light-scattering device to monitor the aerosol concentration, the pulsatile output from the MDIs in the cassettes was demonstrated to be adequately damped out provided that the dilution/mixing/aging chamber exceeded 3 ft in length. The tube diameter selected was the minimum compatible with mounting the required number of MDIs so that the linear velocity of the aerosol was adequate to efficiently transport the aerosol out of the dilution chamber. Aerosol concentration and particle size data were recorded for a nose-only rodent exposure chamber. Reproducible aerosol concentrations ranging from 0.03 to 0.6 mg/L were generated. Particle sizes ranged from 2- to 3-microm mass median aerodynamic diameter. Thus, the aerosol generated was within the size range suitable for inhalation exposures.     

Peak inspiratory flow rates generated through the Novolizer and the Turbuhaler dry powder inhaler devices by children with stable asthma.

We compared the peak inspiratory flows (PIF) generated through a novel dry powder inhaler device, the Novolizer (PIF-N), and the Turbuhaler (PIF-T). Forty-six pediatric patients with stable bronchial asthma were randomized in an open-label, multicenter, crossover trial. No drug was administered during the inhalation maneuvers that were spaced by 10 min. There was neither a carryover nor a sequence effect. The patients were characterized by mean age of 8.5 years, mean FEV(1) of 1.79 L, and mean PIF without any device (baseline, PIF-B) of 185 L/min. Through the devices mean PIF-N of 94 L/min and mean PIF-T of 69 L/min were achieved, calculated from the maxima of three inhalations. This resulted in p < 0.0001 for the difference. The median PIFN/PIF-T ratio was estimated as 1.39. Each child achieved a higher PIF-N than PIF-T and was able to release the feedback mechanisms of the Novolizer indicating sufficient inhalation performance. We conclude that the PIF through the Novolizer is higher than the PIF through the Turbuhaler in stable asthmatic children. The flow rates achieved through the Novolizer allow for sufficient lung deposition even in children as young as 6 years.     

Effect of the new spacer-device on the deposition of the inhaled metered dose aerosol

The effect of the new spacer-device on the in vitro and in vivo deposition of inhaled drug particles was studied. The in vitro deposition of beclomethasone dipropionate 250 micrograms/dose aerosol administered either through the conventional aerosol actuator with the short plastic mouthpiece or through the new pear-shaped spacer-device was evaluated with the modified cascade impactor method. For the in vivo study the disodium cromoglycate particles were labelled with a pure gamma-radiator 99mTc using a coprecipitation technique based on spray drying. The deposition of the inhaled disodium cromoglycate particles in the human respiratory tract after administration of the drug doses from the devices tested was determined by means of a gamma camera. The new spacer-device increased both in the in vitro and in vivo tests the fraction of the drug dose deposited into the therapeutically significant regions of the respiratory tract. In addition, the therapeutically insignificant fraction deposited in the upper airways and mouth clearly decreased. Thus using the new spacer-device evaluated in this study the local side effects would be decreased.     

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.     

驱动器的规格与吸入辅助装置对气雾剂体外沉积性质的影响

目的 考察驱动器的规格——孔径、孔长以及吸入辅助装置的使用对气雾剂体外沉积性质的影响.方法 以自制丙酸氟替卡松混悬型气雾剂为模型药物,装配不同规格的驱动器,使用Andersen多级撞击器(Andersen cascade impactor,ACI)测定体外沉积率;将丙酸氟替卡松气雾剂装配筛选好的特定规格的驱动器,分别在不使用吸入辅助装置与使用吸入辅助装置的情况下,对体外沉积性质进行对比研究.结果 在孔径固定的情况下,随着孔长的延长,驱动器的残留量降低,Andersen多级撞击器装置的L型连接管沉积量增加,微细粒子剂量降低.在孔长固定的情况下,随着孔径的增加,驱动器的残留量降低,Andersen多级撞击器装置的L型连接管沉积量增加,微细粒子剂量降低.根据试验结果、混悬型气雾剂本身的剂型特点以及驱动器的实际使用情况,最终,将0.42 mm孔径、0.70 mm孔长的驱动器作为优选驱动器;在使用吸入辅助装置的情况下,Andersen多级撞击器装置L型连接管的沉积量极大地降低,微细粒子剂量增加,原来沉积在L型连接管的大粒子很大一部分被截留在吸入辅助装置当中.结论 驱动器的规格会对吸入气雾剂的体外沉积产生一定的影响,在药品研发的过程中,可根据气雾剂产品的具体特点(溶液型或混悬型,原料药的粒径大小等)进行驱动器的筛选;吸入辅助装置的使用可以提高气雾剂的药物利用率,推荐患者用药时使用.     

Mometasone furoate dry powder inhaler: a once-daily inhaled corticosteroid for the treatment of persistent asthma

ABSTRACT

Background: Mometasone furoate (MF), a potent synthetic inhaled corticosteroid (ICS) with a high affinity for the glucocorticoid receptor, is approved for use in the treatment of asthma.

Scope: Publications reviewed in this article were identified via searches of MEDLINE and EMBASE databases using the terms ‘mometasone furoate AND pharmacology’ and ‘mometasone furoate AND asthma AND clinical trial’. Data from abstracts presented at respiratory society meetings, and relevant background information, are also reviewed.

Findings: In clinical studies, MF, administered by dry powder inhaler (MF-DPI), was effective in treating all severities of persistent asthma, improving pulmonary function, reducing asthma symptoms, and reducing or eliminating the need for oral corticosteroids. Once-daily dosing of MF-DPI was effective in patients with mild or moderate persistent asthma previously taking twice-daily regimens of inhaled corticosteroids (ICSs), and in patients taking only inhaled β₂?agonists for symptom relief. Once-daily dosing in the evening with MF-DPI 200?µg conferred a greater benefit than morning dosing with MF-DPI 200?µg. Patients with severe asthma who were dependent on oral corticosteroids (OCSs) and high doses of ICSs were able to achieve greater asthma control and reduce or even eliminate OCSs when switched to MF-DPI. In trials of up to 1 year in duration, MF-DPI was well tolerated, with the majority of adverse events considered mild or moderate in intensity. MF had low systemic bioavailability and no clinically significant hypothalamic–pituitary–adrenal-axis suppression at therapeutic doses. The DPI device is a multiple-dose inhaler with a counter containing agglomerates of MF and lactose. Patients of all severities of persistent asthma were able to generate and maintain airflow profiles necessary to provide a uniform and accurate dose.

Limitations: Only one study evaluated both morning and evening administration of once-daily doses, and one of the comparative clinical trials was an open-label study.

Conclusion: Once-daily administration of MF-DPI 200–400?µg in patients with mild to moderate persistent asthma effectively improved lung function and asthma control. In patients with severe persistent asthma dependent on oral corticosteroids, treatment with MF-DPI 400?µg BID permitted substantial reduction of oral corticosteroid use. All MF-DPI treatments were well tolerated and had minimal systemic effects.     

A new Pharmaceutical Aerosol Deposition Device on Cell Cultures (PADDOCC) to evaluate pulmonary drug absorption for metered dose dry powder formulations

Absorption studies with aerosol formulation delivered by metered dose inhalers across cell- and tissue-based in vitro models of the pulmonary epithelia are not trivial due to the complexity of the processes involved: (i) aerosol generation and deposition, (ii) drug release from the carrier, and (iii) absorption across the epithelial air-blood barrier. In contrast to the intestinal mucosa, pulmonary epithelia are only covered by a thin film of lining fluid. Submersed cell culture systems would not allow to studying the deposition of aerosol particles and their effects on this delicate epithelial tissue.We developed a new Pharmaceutical Aerosol Deposition Device on Cell Cultures (PADDOCC) to mimic the inhalation of a single metered aerosol dose and its subsequent deposition on filter-grown pulmonary epithelial cell monolayers exposed to an air-liquid interface. The reproducibility of deposition of these dry powder aerosols and subsequent drug transport across Calu-3 monolayers with commercially available dry powder inhalers containing salbutamol sulphate or budesonide could be demonstrated.In the context of developing new dry powder aerosol formulations, PADDOCC appears as a useful tool, allowing reducing animal testing and faster translation into clinical trials.