Richard N. Dalby

Predicting the Quality of Powders for Inhalation from Surface Energy and Area

AbstractPurpose. To correlate the surface energy of active and carrier components in an aerosol powder to in vitro performance of a passive dry powder inhaler. Methods. Inverse gas chromatography (IGC) was used to assess the surface energy of active (albuterol and ipratropium bromide) and carrier (lactose monohydrate, trehalose dihydrate and mannitol) components of a dry powder inhaler formulation. Blends (1%w/w) of drug and carrier were prepared and evaluated for dry powder inhaler performance by cascade impaction. The formulations were tested with either of two passive dry powder inhalers, Rotahaler® (GlaxoSmithKline) or Handihaler® (Boehringer Ingelheim). Results. In vitro performance of the powder blends was strongly correlated to surface energy interaction between active and carrier components. Plotting fine particle fraction vs. surface energy interaction yielded an R2 value of 0.9283. Increasing surface energy interaction between drug and carrier resulted in greater fine particle fraction of drug. Conclusions. A convincing relationship, potentially useful for rapid formulation design and screening, was found between the surface energy and area parameters derived from IGC and dry powder inhaler performance.

Inhalation therapy: technological milestones in asthma treatment.

The humble origins of the propellant driven metered dose inhaler, as a response to a childs enquiry, initiated an industry which supplies approximately a half billion inhalers globally for the treatment of asthma. These inhalers fall into three major groups: nebulizers; propellant driven metered dose inhalers and dry powder inhalers. Each requires drug formulation, metering and device technology to be successful. In recent years there have been several new developments in the field including auxiliary systems to improve drug delivery from the device to the patient and new categories of device, notably single breath aqueous systems. As device technology improves and our understanding of the disease leads to new drugs the only barrier to therapy is the patient. Patient training and compliance will continue to be important factors in the success, or failure, of inhaled therapy and the role of health care professionals will depend on who sponsors their intervention.

The efficacy of slow versus faster inhalation of cromolyn sodium in protecting against allergen challenge in patients with asthma

BACKGROUND Approximately one third of patients with allergy-induced asthma who are treated with aerosolized cromolyn sodium (CS) fail to achieve a full therapeutic effect. This lack of effectiveness could involve nonhomogeneous distribution of drug in the lung as a result of high inspiratory flow rates. OBJECTIVE We sought to determine the efficacy of slow versus faster inhalation of CS in protecting against allergen challenge in patients with asthma. METHODS Eight patients with asthma underwent two allergen challenges 30 minutes after pretreatment with CS that was inhaled from a large holding chamber at approximately 30 L/min or approximately 70 L/min. Percent decreases in FEV1 at a common dose of allergen on the two challenge days were compared. Values of skew (an indicator of aerosol distribution homogeneity) obtained from gamma camera lung images after slow and faster inhalation of radiolabeled CS were also compared. RESULTS Mean (+/- SD) allergen-induced decrease in FEV1 was 5.4% +/- 4.2% after slow inspiration of CS, which was significantly less than the allergen-induced decrease in FEV1 after faster inhalation of CS with 12.6% +/- 11% (p < 0.05). Mean skew values were also significantly decreased after slow inspiration of CS, and differences in decreases in allergen FEV1 and skew values for the two breathing maneuvers were significantly correlated. CONCLUSION These data indicate that protection against allergen-induced asthma can be optimized by slowly inspiring CS from a large holding chamber compared with faster inhalation of the drug. These results appear to be related to enhanced distribution homogeneity of CS within the lungs.Abstract Background: Approximately one third of patients with allergy-induced asthma who are treated with aerosolized cromolyn sodium (CS) fail to achieve a full therapeutic effect. This lack of effectiveness could involve nonhomogeneous distribution of drug in the lung as a result of high inspiratory flow rates. Objective: We sought to determine the efficacy of slow versus faster inhalation of CS in protecting against allergen challenge in patients with asthma. Methods: Eight patients with asthma underwent two allergen challenges 30 minutes after pretreatment with CS that was inhaled from a large holding chamber at ~30 L/min or ~70 L/min. Percent decreases in FEV 1 at a common dose of allergen on the two challenge days were compared. Values of skew (an indicator of aerosol distribution homogeneity) obtained from gamma camera lung images after slow and faster inhalation of radiolabeled CS were also compared. Results: Mean (± SD) allergen-induced decrease in FEV 1 was 5.4% ± 4.2% after slow inspiration of CS, which was significantly less than the allergen-induced decrease in FEV 1 after faster inhalation of CS with 12.6% ± 11% ( p 1 and skew values for the two breathing maneuvers were significantly correlated. Conclusion: These data indicate that protection against allergen-induced asthma can be optimized by slowly inspiring CS from a large holding chamber compared with faster inhalation of the drug. These results appear to be related to enhanced distribution homogeneity of CS within the lungs.

Respiratory pathophysiologic responses: The efficacy of slow versus faster inhalation of cromolyn sodium in protecting against allergen challenge in patients with asthma

BACKGROUND Approximately one third of patients with allergy-induced asthma who are treated with aerosolized cromolyn sodium (CS) fail to achieve a full therapeutic effect. This lack of effectiveness could involve nonhomogeneous distribution of drug in the lung as a result of high inspiratory flow rates. OBJECTIVE We sought to determine the efficacy of slow versus faster inhalation of CS in protecting against allergen challenge in patients with asthma. METHODS Eight patients with asthma underwent two allergen challenges 30 minutes after pretreatment with CS that was inhaled from a large holding chamber at approximately 30 L/min or approximately 70 L/min. Percent decreases in FEV1 at a common dose of allergen on the two challenge days were compared. Values of skew (an indicator of aerosol distribution homogeneity) obtained from gamma camera lung images after slow and faster inhalation of radiolabeled CS were also compared. RESULTS Mean (+/- SD) allergen-induced decrease in FEV1 was 5.4% +/- 4.2% after slow inspiration of CS, which was significantly less than the allergen-induced decrease in FEV1 after faster inhalation of CS with 12.6% +/- 11% (p < 0.05). Mean skew values were also significantly decreased after slow inspiration of CS, and differences in decreases in allergen FEV1 and skew values for the two breathing maneuvers were significantly correlated. CONCLUSION These data indicate that protection against allergen-induced asthma can be optimized by slowly inspiring CS from a large holding chamber compared with faster inhalation of the drug. These results appear to be related to enhanced distribution homogeneity of CS within the lungs.Abstract Background: Approximately one third of patients with allergy-induced asthma who are treated with aerosolized cromolyn sodium (CS) fail to achieve a full therapeutic effect. This lack of effectiveness could involve nonhomogeneous distribution of drug in the lung as a result of high inspiratory flow rates. Objective: We sought to determine the efficacy of slow versus faster inhalation of CS in protecting against allergen challenge in patients with asthma. Methods: Eight patients with asthma underwent two allergen challenges 30 minutes after pretreatment with CS that was inhaled from a large holding chamber at ~30 L/min or ~70 L/min. Percent decreases in FEV 1 at a common dose of allergen on the two challenge days were compared. Values of skew (an indicator of aerosol distribution homogeneity) obtained from gamma camera lung images after slow and faster inhalation of radiolabeled CS were also compared. Results: Mean (± SD) allergen-induced decrease in FEV 1 was 5.4% ± 4.2% after slow inspiration of CS, which was significantly less than the allergen-induced decrease in FEV 1 after faster inhalation of CS with 12.6% ± 11% ( p 1 and skew values for the two breathing maneuvers were significantly correlated. Conclusion: These data indicate that protection against allergen-induced asthma can be optimized by slowly inspiring CS from a large holding chamber compared with faster inhalation of the drug. These results appear to be related to enhanced distribution homogeneity of CS within the lungs.

Effect of Formulation- and Administration-Related Variables on Deposition Pattern of Nasal Spray Pumps Evaluated Using a Nasal Cast

ABSTRACTPurposeTo systematically evaluate the effect of formulation- and administration-related variables on nasal spray deposition using a nasal cast.MethodsDeposition pattern was assessed by uniformly coating a transparent nose model with Sar-Gel®, which changes from white to purple on contact with water. Sprays were subsequently discharged into the cast, which was then digitally photographed. Images were quantified using Adobe® Photoshop. The effects of formulation viscosity (which influences droplet size), simulated administration techniques (head orientation, spray administration angle, spray nozzle insertion depth), spray pump design and metering volume on nasal deposition pattern were investigated.ResultsThere was a significant decrease in the deposition area associated with sprays of increasing viscosity. This appeared to be mediated by an increase in droplet size and a narrowing of the spray plume. Administration techniques and nasal spray pump design also had a significant effect on the deposition pattern.ConclusionsThis simple color-based method provides quantitative estimates of the effects that different formulation and administration variables may have on the nasal deposition area, and provides a rational basis on which manufacturers of nasal sprays can base their patient instructions or post approval changes when it is impractical to optimize these using a clinical study.

Evaluation of Aerosol Drug Output from the OptiChamberTM and AeroChamberTM Spacers in a Model System

Metered-dose inhalers (MDIs) are an effective means of generating drug-containing aerosols targeted for delivery to intrapulmonary airways. Many problems associated with incorrect patient use of MDIs are mitigated by adding a valved spacer device to the inhaler mouthpiece. This in vitro study compared the efficiency of drug output through a new spacer device, OptiChamber (HealthScan Products Inc., Cedar Grove, NJ), to that of a device commercially available since the 1980s, AeroChamber (Monaghan Medical, Plattsburgh, NY). Testing utilized MDI formulations of albuterol, beclomethasone dipropionate, and cromolyn sodium. OptiChamber equaled or, in the majority of cases, exceeded AeroChamber in output of the three drugs at two simulated inspiratory flow rates. Drug output from OptiChamber was found to be less sensitive to changes in flow rate than that from AeroChamber. OptiChamber also showed less decrease in drug output than AeroChamber when time delays were introduced between MDI actuation and the start of a simulated inhalation. Mass median aerodynamic diameters of drugs exiting the two spacers were generally similar to those of drugs exiting the MDI alone. However, spacers were shown to nearly eliminate the output of large-size drug particles (>5.8 microm), which can result in oropharyngeal drug deposition. Emitted fine-particle drug (<5.8 microm) doses from OptiChamber were greater than those from AeroChamber with or without a delay between canister actuation and the start of a simulated inhalation. The results suggest that OptiChamber may provide more efficacious aerosol drug delivery than AeroChamber under both ideal and suboptimal conditions.

Phase I Clinical Trial of Repeat Dose Terameprocol Vaginal Ointment in Healthy Female Volunteers

Objectives: This safety study of terameprocol (also called M4N, EM-1421) daily vaginal application in healthy women explores its potential application as a microbicide in interrupting human immunodeficiency virus sexual transmission and additional interruption of human papillomavirus and herpes simplex virus transmission. Methods: A double-blind placebo controlled phase I repeat dose tolerability and pharmacokinetic, crossover study of 90 mg terameprocol (2% w/w ointment) administered intravaginally for 7 consecutive days in healthy female subjects. The pharmacokinetics after administration was examined on days 1 and 7 of dosing. Subjects underwent vaginal examination following the 6-hour pharmacokinetic sample on day 7 of each study period. Results: Recruitment started January 2006 and ended May 2006, and 14 subjects completed the study. Median age was 24 years. No treatment-related serious adverse events were reported, and there were a total of 17 treatment-emergent adverse events (AE) reported by 11 participants. The most common AE was headache. Terameprocol was not detectable in serum in pharmacokinetic samples. Conclusions: Terameprocol was well tolerated at a 90 mg dose (2% wt/wt) administered vaginally daily for 7 days. No serious adverse events occurred and any AEs were mild. The excellent safety profile supports future clinical trial to evaluate the application of intravaginal terameprocol in women.

INHALED ATP CAUSES MUCIN RELEASE FROM GOBLET CELLS OF INTACT RATS

Secretion of mucins from airway epithelial cells has been studied almost exclusively using in vitro cell culture systems. Our understanding of in vivo secretion is greatly limited due to the unavailability of both suitable model systems and adequate assays. It has been reported that ATP induces mucin release from the cultured primary tracheal surface epithelial cell, but there is no clear demonstration of the effect of ATP on mucin release in vivo, which is important to understand the mechanism of mucin release in vivo and also to devise means for regulation of mucin release. The objective of this experiment was to see if inhaled ATP could stimulate airway mucin release in intact rats using both enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry. The results were: (1) a new monoclonal antibody (mAbRT03) developed against purified rat mucins specifically recognized high-molecular-mass mucins; (2) ELISA results with conventional gel-filtration assay results are virtually superimposable; (3) inhalation of ATP in intact rats resulted in a dose-independent increase in the amount of mucins in the tracheal lavage fluid with a concomitant decrease in the number of mucin-positive cells in the trachea. We conclude that extracellular ATP can stimulate mucin release from the airway in vivo, and the present rat inhalation system combined with ELISA of the airway secretions should serve a useful model for studying the pharmacology of airway mucin secretion in vivo.

Automated actuation of nasal spray products: determination and comparison of adult and pediatric settings

Objective: To determine and compare patient-relevant settings for automated nasal spray actuation stations from adult and pediatric hand data. Methods: Twenty adults and 20 pediatric participants were asked to spray Flonase® Nasal Spray six times in a Hand Actuation Monitor, which records force and displacement data in 5-ms increments. Settings for force- and velocity-controlled actuation stations were determined from the data using a predefined set of calculations. Results: For force-controlled settings, hand spraying by children resulted in lower actuation forces, and longer force rise, hold and fall times. Pediatric velocity-controlled actuator settings were lower for travel, compression velocity, and release velocity compared with adults. The pediatric spray weight recorded during hand spraying was significantly lower than the spray weight generated by adult participants. Adult participants were able to generate full sprays with each attempt, whereas 11 out of 120 actuations performed by pediatric participants resulted in partial and ‘no spray’ events. No differences in spray weight were detected in participants who chose to actuate the nasal spray using both hands. Conclusions: A predefined set of calculations was used to determine patient-relevant settings from force and displacement hand data for force- and velocity-controlled automated actuation stations. This study determined and quantified, for the first time, the differences in hand spraying between adults and children.

Use of inverse gas chromatography (IGC) to determine the surface energy and surface area of powdered materials.

Dear Editor: The paper published by Cline and Dalby (1) claims to have established a “convincing relationship between the surface energy and area parameters derived from IGC and dry powder inhaler performance.” As experienced users of IGC for material characterization, we deem it appropriate to highlight several inaccuracies (both technical and fundamental) in this paper, which appear serious enough to require reassessment of the published work. The errors are discussed below.