Peter R. Byron

Aerosol Electrostatics I: Properties of Fine Powders Before and After Aerosolization by Dry Powder Inhalers

AbstractPurpose. To evaluate the dependence of fine particle dose charge (FPD charge) generated from powder inhalers on physico-chemical properties of the inhalation powder, inhaler type, deaggregation mechanism, dose number and/or retained powder. Methods. Electrostatic charges were determined on micronized powders and aerosolized fine particle doses withdrawn from two, high efficiency, multidose powder inhalers, Turbohaler™and prototype Dryhaler™. The behavior of terbutaline sulfate, budesonide, albuterol (sulfate and base), beclomethasone dipropionate and lactose was assessed before and after aerosolization. Results. Both inhalers conferred triboelectric FPD charges during aerosolization in the range −400 pC through +200 pC. Specific charges (charge/unit mass) on the fine particle doses of budesonide from Dryhaler were significantly less than those from Turbohaler (p < 0.01). Electrostatic charges on the potentially respirable cloud of terbutaline sulfate generated by Bricanyl Turbohaler were positive and/or negative and unpredictable. With Pulmicort Turbohaler, FPD charges on budesonide were always positive. Dryhaler was used to determine the chemical dependence of fine particle triboelectrification during the aerosolization of pure materials. A triboelectric series was constructed from the Dryhaler results ranking the powders from positive to negative as budesonide > lactose > albuterol sulfate > terbutaline sulfate ≥ albuterol ≥ beclomethasone dipropionate. Conclusions. While there was no evidence of FPD charge dependence upon dose number with either inhaler, FPD charges were dependent upon the powder under investigation, as well as the construction and deaggregation mechanism of the inhaler. The specific charge on the fine particle dose of budesonide from Turbohaler corresponded to approximately 200 electronic charges per particle, a value which is known to affect both total and regional aerosol deposition in the human lung. Electrostatic charge effects may be important determinants of aerosol behavior and should not be neglected.

Determinants of drug and polypeptide bioavailability from aerosols delivered to the lung

Abstract Inhalation offers some exciting possibilities for the delivery of new generation products of biotechnology like polypeptides and proteins. Although the lungs and respiratory tract can metabolize some fraction of a delivered dose, the route offers an enormous absorptive surface area capable of delivering even large compounds to the circulation at acceptable rates. Dosimetry problems which are commonly associated with the administration of inhalation aerosols are inapplicable when lung-normal patients are considered. However, the dependence of lung metabolism and absorption upon molecular structure is poorly understood and requires further research. In the near future, it is likely that optimal formulations will be combined with modified aerosol delivery devices to maximize and achieve reproducible values for dose to lung. These will be used as alternatives to parenteral delivery for small through intermediate dose drugs which are not absorbed via the gastro-intestinal tract. Aerosol formulation, dosing and stability issues are discussed for proteins and other macromolecules, alongside the factors which are known to control and enhance pulmonary absorption. Issues concerning local immune responses are discussed especially as they may limit macromolecule delivery via inhalation.

Testing of dry powder aerosol formulations in different environmental conditions

Dry powder aerosol performance of albuterol and albuterol sulfate from a model dry powder inhaler (DPI) was studied under varying environmental conditions using a twin stage impinger (TSI). Pure micronized drug was metered into the DPI and the loaded inhaler inserted into the inlet of the TSI housed in a pre-equilibrated environmental chamber. After 3 min, the drug was aerosolized at 60 1/min for 20 s. Washings from the DPI and TSI were analyzed by UV spectroscopy. Temperature and relative humidity (RH) were varied (20, 30 and 45°C; 30–95% RH). Drug collected in stage 2 of the TSI was expressed as fine particle dose or fine particle percent of either the loaded dose or the amount emitted from the mouthpiece of the DPI. These values decreased with increasing relative humidity for both albuterol and albuterol sulfate at any given temperature with differences being more marked at higher temperatures. For example, at 30°C, the mean(experimental range) fine particle percent of the emitted dose of albuterol sulfate was 59.4(3.1) and 35.8(5.7)% at 43 and 85% RH, respectively, n = 3 (p < 0.05). Increasing temperature also resulted in diminished aerosol performance. These differences were more marked for albuterol sulfate. The fine particle percent of the emitted dose of albuterol base was always greater than that of albuterol sulfate under similar environmental conditions. The reverse was true when fine particle percents of the loaded dose were considered because only 32 +- 6.6% of the loaded albuterol was emitted from the inhaler as compared to 58.5 +- 6.3% of albuterol sulfate mean +- SD, n = 27). There is a need, in some circumstances, to define specific ranges of temperature and humidity for the testing of dry powder aerosols.

Dry powder aerosol generation in different environments : performance comparisons of albuterol, albuterol sulfate, albuterol adipate and albuterol stearate

Abstract Aerosols formed by three salts and the free base of albuterol were compared following their formation from similarly micronized crystalline powders held in a model dry powder inhaler (DPI) under varying environmental conditions. Aqueous solubility at 22°C was the greatest for albuterol adipate diethanolate (353 mg/ml), followed by albuterol sulfate (250 mg/ml), albuterol free base (15.7 mg/ml) and albuterol stearate (0.6 mg/ml). Temperature and relative humidity (RH) of the air drawn through the inhaler was systematically varied in the range 20–45°C and 30–95% RH. Several inhaler performance outcomes were compared statistically between physical forms and across the applied environmental conditions. Significant differences (P 0.05) although only albuterol adipate diethanolate and albuterol sulfate were insensitive at 94% RH and 45°C. At 20°C and 50% RH, the fine particle percent of the emitted doses [mean (experimental range)] were 77.7 (7.3)%, 63.6 (4.2)%, 9.0 (1.8)% and 55.7 (3.4)% for the free base, sulfate, adipate diethanolate and stearate salts of albuterol, respectively. Fine particle doses and percents of albuterol and albuterol sulfate decreased progressively with increasing relative humidity and temperature while albuterol adipate diethanolate and albuterol stearate aerosol performance remained largely unaffected; these latter salts showed changes in fine particle percents only at 45°C and 95% RH although the adipate diethanolate deaggregated very poorly under all conditions. Overall, albuterol stearate, the most hydrophobic salt, emptied and aerosolized best from the inhaler and showed least sensitivity to temperature and humidity. Neither solubility nor moisture sorption correlated directly with inhaler performance in high humidity environments, showing that the multiplicity of factors controlling the quality of the emitted aerosol from DPIs prevents straightforward prediction of optimal physical forms and mandates their experimental review. Nevertheless, salt selection is an important area to screen as new compounds are developed for inhalation and DPI device performance continues to improve.

Physiochemical and pharmacological characterization of a Δ9-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.

Solute Absorption from the Airways of the Isolated Rat Lung. IV. Mechanisms of Absorption of Fluorophore-Labeled Poly-α,β-[N(2-Hydroxyethyl)-DL-Aspartamide]

The pulmonary absorption kinetics of a single molecular weight distribution (MWD) of fluorophore-labeled poly-α,β-[N(2-hydroxyethyl)-DL-aspartamide] (F-PHEA), a hydrophilic and biocompatible synthetic polypeptide, were studied in the isolated, perfused rat lung (iprl) as functions of administered polymer concentration, dose, vehicle, and presence and absence of fluorophore. The MWD was characterized before and after absorption by measurement of weight- and number-averaged molecular weights (Mwand Mn, respectively) using high-performance gel-permeation chromatography. Values for Mw and Mn were 8.6 and 5.3 kD before, and 6.7 and 4.7 kD after, absorption into the perfusate; there was no significant metabolism and the MWD of the absorbed polymer was independent of both dose and sampling time over a 3-hr period. F-PHEA failed to show any evidence of aggregation in solution or changes in dose distribution within the airways as functions of increasing polymer concentration and dose. A concentration ranging study indicated the presence of a saturable, carrier-mediated transport process for F-PHEA with a maximum absorption rate, Vmax, of approximately 180 µg or 0.027 µmol/hr. Coadministration of fluorophore-free PHEA was capable of depressing the absorption of F-PHEA. The transport process for F-PHEA appeared to have a molecular weight limit of about 7 kD for this hydrophilic polymer.

The quantitative determination of aspirin and its degradation products in a model solution aerosol

Formulation of pressurized aerosol solutions in propellants for inhalation requires the use of high quantities of surfactants to solubilize the drug. Due to the lipophilic nature of these surfactants, analytical difficulties are created for those wishing to quantify the drug and its degradation products. In order to quantify drug and degradation products by LC it is necessary to separate surfactant and analytes prior to chromatography. To illustrate a typical situation, a method was developed for the analysis of acetylsalicyclic acid (approximately 2.5 x 10(-3) M) and its major degradation products (salicylic acid, acetylsalicylsalicylic acid and salicylsalicylic acid) solubilized in trichloromonofluoromethane (CFC-11) containing 10(-2) M sorbitan trioleate (Span 85). Surfactant extraction problems were reviewed experimentally. The presentation of all analytes and the surfactant, dissolved in hexane, to silica solid phase extraction columns, followed by elution in a polar solvent, was found to be an efficient way of separating this lipophilic surfactant from the analytes. The final assay employed propellant evaporation, reconstitution of the non-volatiles in hexane, normal phase solid phase extraction (recoveries of 100 +/- 10% were observed for all analytes), elution and dilution with mobile phase, and reversed-phase liquid chromatography (Econosphere C8 5 microns, 4.6 x 250 mm). The assay utilized a mobile phase of water, methanol, tetrahydrofuran and 1 M phosphoric acid with ultraviolet detection at 275 nm. Using external standards, linear calibration curves of peak height versus concentration were obtained for all analytes in the expected concentration ranges (r > 0.991). As it is described, the assay had a relative standard deviation of < or = 3.7% for all analytes.

Control of Particle Size by Coagulation of Novel Condensation Aerosols in Reservoir Chambers

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

Cascade impaction methods for dry powder inhalers using the high flowrate Marple-Miller Impactor

Abstract The magnitude and effects of stage overload and particle re-entrainment in the new, Marple-Miller cascade impactor (MMI) were evaluated at 60 liter/min by sampling and determining the aerodynamic size distributions from two, excipient-free, powder inhalers (Turbohaler TM and Spinhaler TM ) according to a variety of experimental protocols. Drug distributions were compared statistically, for both inhalers, following single dose experiments in the presence and absence of silicone oil impactor stage coating and between single dose and multiple dose experiments in its presence. Stage coating was found to be essential to prevent re-entrainment of drug from both inhalers. One or ≤ 25 dose sampling was shown to produce valid results provided impaction stages were coated for the 0.5 mg Bricanyl Turbohaler (44.7 ± 9.6% of emitted dose

Physicochemical effects on lung disposition of pharmaceutical aerosols

The physical control of drug release in the airways (formulation control) and the chemical manipulation of lung disposition and longevity (by prodrug and analogue design) are both discussed as means of providing improved therapeutics for aerosol delivery. Control of drug release by physical entrapment suffers from two major disadvantages: dilution of the active with inert ingredients requires larger total doses to be delivered; and adverse immunologic reactions due to particulate insolubility may be increased by some formulation approaches. Molecular modification, to form prodrugs, analogues, or macromolecular drugs with altered airway affinities and bioavailabilities seems to offer greater promise for future therapeutic aerosols. We should be able to target inhaled drugs, temporally and spatially, by careful control of molecular characteristics.