Stephen J. Farr

The Pharmacokinetics of Pulmonary-Delivered Insulin: A Comparison of Intratracheal and Aerosol Administration to the Rabbit

The pulmonary deposition and pharmacokinetics of insulin, administered via an endotracheal tube as an aerosol and instillate, in formulations containing either 113mIn-DTPA or 99mTc-DTPA (for gamma scintigraphic imaging) have been studied in four male New Zealand White rabbits. Using a randomized crossover design, the pharmacokinetics of intravenous insulin were also characterized. Recovery of immunoreactive insulin after nebulization was greater than 90%, indicating that the aerosolisation procedure did not cause appreciable insulin degradation. Gamma scintigraphy demonstrated that the penetration index (peripheral:central deposition) for the aerosolized formulation (1.52) was much greater than that for the instillate (0.32). Gamma scintigraphy also allowed exact quantification of the dose deposited after aerosol administration and thus permitted accurate determination of bioavailabilities. The bioavailable fraction for aerosolized insulin was 10-fold greater than for instilled insulin (57.2 vs 5.6%). Mucociliary clearance was likely to be greater for the instillate since it showed a preferential central deposition; this may account for the lower bioavailability. Insulin pharmacokinetics from both pulmonary formulations were absorption rate limited, resulting in postpeak half-lives which were approximately 20-fold greater than the intravenous elimination half-life (3 min). The apparent absorption rate constants resulting from instillation and aerosolisation were statistically equivalent (0.015 and 0.011 min−1, respectively). Mucociliary clearance of insulin would result in an overestimation of the true absorption rate constant; hence if mucociliary transport were greater for the instillate, then the true airways to blood transfer rate constant will be higher for the aerosolized formulation.

Aerosol deposition in the human lung following administration from a microprocessor controlled pressurised metered dose inhaler.

BACKGROUND--Gamma scintigraphy was employed to assess the deposition of aerosols emitted from a pressurised metered dose inhaler (MDI) contained in a microprocessor controlled device (SmartMist), a system which analyses an inspiratory flow profile and automatically actuates the MDI when predefined conditions of flow rate and cumulative inspired volume coincide. METHODS--Micronised salbutamol particles contained in a commercial MDI (Ventolin) were labelled with 99m-technetium using a method validated by the determination of (1) aerosol size characteristics of the drug and radiotracer following actuation into an eight stage cascade impactor and (2) shot potencies of these non-volatile components as a function of actuation number. Using nine healthy volunteers in a randomised factorial interaction design the effect of inspiratory flow rate (slow, 30 l/min; medium, 90 l/min; fast, 270 l/min) combined with cumulative inspired volume (early, 300 ml; late, 3000 ml) was determined on total and regional aerosol lung deposition using the technique of gamma scintigraphy. RESULTS--The SmartMist firing at the medium/early setting (medium flow and early in the cumulative inspired volume) resulted in the highest lung deposition at 18.6 (1.42)%. The slow/early setting gave the second highest deposition at 14.1 (2.06)% with the fast/late setting resulting in the lowest (7.6 (1.15)%). Peripheral lung deposition obtained for the medium/early (9.1 (0.9)%) and slow/early (7.5 (1.06)%) settings were equivalent but higher than those obtained with the other treatments. This reflected the lower total lung deposition at these other settings as no difference in regional deposition, expressed as a volume corrected central zone:peripheral zone ratio, was apparent for all modes of inhalation studied. CONCLUSIONS--The SmartMist device allowed reproducible actuation of an MDI at a preprogrammed point during inspiration. The extent of aerosol deposition in the lung is affected by a change in firing point and is promoted by an inhaled flow rate of up to 90 l/min-that is, the slow and medium setting used in these studies.

Comparison of in vitro and in vivo efficiencies of a novel unit-dose liquid aerosol generator and a pressurized metered dose inhaler

Gamma scintigraphic imaging was employed in 10 healthy volunteers to compare the total and regional lung deposition of aerosols generated by two delivery platforms that permitted microprocessor-controlled actuation at an optimal point during inhalation. An aqueous solution containing 99mTc-DTPA was used to assess the deposition of aerosols delivered by inhalation from two successive unit-dosage forms (44 microl volume) using a prototype of a novel liquid aerosol system (AERx Pulmonary Delivery System). This was compared with aerosol deposition after inhalation of two 50 microl puffs of a 99mTc-HMPAO-labeled solution formulation from a pressurized metered dose inhaler (MDI). The in vitro size characteristics of the radiolabeled aerosols were determined by cascade impaction. For the AERx system, the predicted lung delivery efficiency based on the product of emitted dose (60.8%, coefficient of variation (CV)=12%) and fine particle fraction (% by mass of aerosol particles <5.7 microm in diameter) was 53.3% (CV=13%). For the solution MDI, the emitted dose was 62.9% (CV=13%) and the predicted lung dose was 44. 9% (CV=15%). The AERx system demonstrated efficient and reproducible dosing characteristics in vivo. Of the dose loaded into the device, the mean percent reaching the lungs was 53.3% (CV=10%), with only 6. 9% located in the oropharynx/stomach. In contrast, the lung deposition from the solution MDI was significantly less (21.7%) and more variable (CV=31%), with 42.0% of the radiolabel detected in the oropharynx/stomach. Analysis of the regional deposition of the radioaerosol indicated a homogeneous pattern of deposition after delivery from the AERx system. A predominantly central pattern of distribution occurred after MDI delivery, where the pattern of deposition was biased towards a central zone depicting the conducting airways. The AERx system, in contrast to MDIs, seems highly suited to the delivery of systemically active agents via pulmonary administration.

Pulmonary Insulin Administration Using the AERx® Insulin Diabetes System

THE UNITED KINGDOM PROSPECTIVE DIABETES TRIAL (UKPDS) in type 2 diabetics1 and the Diabetes Control and Complications Trial Research Group study (DCCT) in type 1 diabetics2 demonstrated that early intervention with intensive blood glucose monitoring and therapy to achieve careful glycemic control resulted in a significant reduction in microvascular complications of diabetes such as diabetic neuropathy, nephropathy, and retinopathy, as well as impacting on myocardial infarction.1 Intensive therapy with insulin is achieved with a multiple daily injection schedule consisting of a short-acting insulin prior to each meal. A longor intermediate-acting insulin is also administered once or twice daily to cover the basal insulin needs. This combination is the best mimetic of the normal physiological release of insulin in response to appropriate stimuli. In addition to the blood glucose monitoring, the required dose adjustments, and the frequent injections, intensive therapy places enormous burdens on a diabetic’s life-style and quality of life. Minor factors that may seem trivial to nondiabetics may profoundly affect a diabetic patient’s willingness to comply with a treatment regimen. Advances such as easy-touse home glucose monitors, pen injectors, and premixtures of intermediateand short-acting insulins may make intensive therapy more acceptable to patients. Recently, rapid-acting insulin analogs allow diabetics to inject their insulin close to a meal. This is a significant advantage compared with regular (short-acting) insulin, which requires an injection around 30 min prior to a meal. One potential disadvantage of rapid-acting analogs is the short duration of action. One of the earliest studies of pulmonary insulin was conducted in 1925.3 A few sporadic studies since then continued to show the potential of delivering insulin via the lung. Pulmonary insulin is now under intensive development by a number of companies,4 as it offers the advantage of a noninvasive method to administer insulin. In addition, the pharmacokinetic profile of pulmonary insulin may afford certain benefits5 over subcutaneous (SC) injec-

Formulation of solution metered dose inhalers and comparison with aerosols emitted from conventional suspension systems

Abstract Micellar solubilisation was used to enhance the solubility of salbutamol (SB) and triamcinolone acetonide (TAA) in chlorofluorocarbon solvents with the aim of formulating solution metered dose inhaler (MDI) products of these drugs. Stable, isotropic solutions of soya phosphatidylcholine (SPC) were obtained in trichlorotrifluoroethane (P113) and a 30:70 mixture of trichlorofluoromethane (P11) and dichlorodifluoromethane (P12) containing water at a maximum level of R (mol water/mol SPC) = 4. The solubility of SB and TAA in both the non-pressurised solvent (P113) and the pressurised mixture (Pll/P12) increased proportionately with SPC concentration but was reduced on increasing values of R . The incorporation of a charged lipid, dicetyl phosphate, into the micellar structure promoted the solubilisation of SB in both solvent systems. In SPC solutions, the optimal solubility of either drug was achieved at R value of 0.9. Solution MDI formulations of SB and TAA gave reproducible shot potency throughout the pack-life, comparable to the performance of commercially available suspension products (SB, Ventolin; TAA, Azmacort). In contrast to suspension systems, however, there was no loss of potency in the first spray actuated after storage with SB solution MDIs. The respirable fraction (RF) of drug emitted from solution MDIs was significantly increased by altering the orifice diameter of the actuator. These studies confirmed that the highest RF values (in excess of those achieved with suspension products) were achieved when the MDIs were fired through an actuator with the smallest (0.25 mm) orifice.

Surfactant mediated effects in pressurized metered dose inhalers formulated as suspensions. I. Drug/surfactant interactions in a model propellant system

Abstract The surface interaction of surfactants (sorbitan trioleate and oleic acid) with various microparticulate systems dispersed in a model chlorofluorocarbon, trichlorotrifluoroethane (P113), has been examined. Oleic acid showed Langmuirian adsorption onto α-alumina, the extent of adsorption inversely proportional to the equilibrium moisture content of the adsorbent. ATR spectroscopy coupled to FTIR was employed to demonstrate that oleic acid adsorbed onto salbutamol via an acid-base reaction resulting in a breakdown of crystal structure at surfactant/drug weight ratios > 0.6. The same surfactant demonstrated relatively poor adsorption onto micronized particulate dispersions of the sulphate and bitartrate salts of isoprenaline. Sorbitan trioleate showed physisorption onto all drug particles; adsorption and multilayer formation were favoured at higher surfactant concentrations and with more hydrophilic surfaces (isoprenaline sulphate > isoprenaline bitartrate > salbutamol). The electrophoretic mobility of salbutamol in P113, determined by laser Doppler velocimetry, became more negative on increasing oleic acid concentration but remained largely unchanged in the presence of sorbitan trioleate. However, in all cases, calculated values for surface zeta potential were very low. The collective data are discussed in relation to the likely mechanism of stabilization of drug dispersions within metered dose inhalers formulated as suspensions.

Formulation and in Vitro Evaluation of Pressurized Inhalation Aerosols Containing Isotropic Systems of Lecithin and Water

Reverse micellization of nonionic surfactants in apolar media was applied to the formulation of solution phase, pressurized inhalation aerosols, employing soya lecithin (SPC) and water in chlorofluorocarbon (CFC) blends. The use of a 30/70 mixture of trichlorofluoromethane (Pll) and dichlorodifluoromethane (P12) resulted in the formation of stable, isotropic systems containing 0.5–2.0% (w/v) SPC and solubilized water; R (moles water/moles SPC), 0.9 to 4.28. In systems containing <30% Pll, phase separation became apparent, particularly at higher water and surfactant concentrations. Dramatic changes in solution viscosity were noted on increasing R values and were attributed to an increase in asymmetry of SPC micelles. Dynamic fractionation of the output from pressurized aerosols using a four-stage liquid impinger showed that the respira-ble fraction (as measured by the percentage of emitted droplets with aerodynamic diameters <5.5 µm) was highly dependent on SPC concentration and R. A significant correlation between RF and actuator score, based on orifice diameter and length, was also found and confirmed that the highest RF values were achieved with the systems of lowest SPC and water concentrations sprayed through an actuator with the smallest and shortest orifice dimensions. This novel mechanism for the formulation of hydrophilic drugs as solutions within CFC-based pressurized aerosols may offer advantages over the traditional suspension approach to pulmonary drug delivery

Comparison of solute partitioning and efflux in liposomes formed by a conventional and an aerosolised method

Abstract The liposomal partitioning and efflux of two solutes, salbutamol and hydrocortisone 21-octanoate, were studied in multilamellar vesicles (MLVs) produced either in a conventional manner or following actuation of a chlorofluorocarbon based pressure pack formulation in a multistage liquid impinger (MLI). Partitioning of salbutamol in MLVs following hydration of egg phosphatidylcholine ER) films was independent of the addition of cholesterol but proportionately increased when dicetylphosphate (DCP) was included up to a maximum value when the salbutamol: DCP molar ratio was equal to 1. Increased entrapment was not accompanied by any electrostatically induced increase in vesicle size suggesting that the improved entrapment was a function of the formation of a lipophilic, membrane associated complex between salbutamol and DCP. Salbutamol partitioning in liposomes derived from aerosols emitted from drug/lipid pressure pack formulations in the MLI was comparable to conventional systems and was independent of the stage of the MLI on which the liposomes were generated (i.e. originating from different size aerosol fractions). Similar conclusions were drawn from studies using hydrocortisone 21-octanoate as a model hydrophobic compound. In addition, equivalent release kinetics of the steroid ester from conventional and aerosolised liposome preparations was observed which suggests MLVs produced from phospholipid aerosols in the MLI possess similar structural characteristics to conventionally prepared liposomes.

Technetium-99m labelling of suspension type pressurised metered dose inhalers comprising various drug/surfactant combinations

Abstract The aerosol distribution, as assessed by cascade impaction, of 99m Tc relative to drug and surfactant has been determined for various commercial formulations of pressurized metered dose inhalers (MDIs), labelled by two surfactant has been determined for of the radiolabel (i.e. drug or surfactant-associated) was independent of the labelling method but highly dependent on the surfactant/drug combination within the MDI.

The accumulation of pentamidine into rat lung slices and its interaction with putrescine

The aromatic diamidine, pentamidine, accumulated into rat lung slices by an uptake system that obeyed saturation kinetics, with an average Km value of 554 microM and a Vmax value of 4077 nmol/g lung wet wt/30 min, respectively. This system was not inhibited by metabolic inhibitors but was greatly diminished by lowering the temperature from 37 degrees to 4 degrees. Both compounds, pentamidine and putrescine, inhibited the uptake of the other and the inhibition of pentamidine accumulation by putrescine was demonstrated to be non-competitive. Uptake of putrescine was inhibited by increasing concentrations of pentamidine. As putrescine accumulates in epithelial type 1 and type 2 cells and in Clara cells, it is likely that pentamidine is also accumulated in these cell types but does not utilize the pulmonary uptake system for polyamine transport. Within the time period studied, toxic effects of the drug were not observed.