Aerosol dosing reproducibility

Dose reproducibility Several human studies comparing aerosol insulin administration to subcutaneously administered insulin showed that the variability in glucose response from a liquid nebulizer that utilized the standing cloud concept was equivalent or better than that seen with insulin injection. Inhale Therapeutics Systems, Inc. has adopted this standing cloud concept for its dry powder inhaler to achieve reproducibility of delivery of macromolecules to the systemic circulation that is equivalent to subcutaneous injections. 

Another issue is reproducibility. The formulation may work perfectly in an in vitro test system, but the dosage form requires aerosolization, and lung deposition is a function of the characteristics of the aerosol (dose, mass concentration, droplet/particle size, etc.) and the nature of the inspiratory maneuver, a factor that the patient has control over. These factors can influence performance to a far greater extent than can be built into a particle, and thus the term controlled does not seem a defensible objective for pulmonary delivery. The vagaries of the deposition profile and of the amount that will deposit also imply that sustaining a certain drug concentration is a difficult proposition, but the loosest definition extended release, seems an acceptable goal within the boundaries set by the clearance mechanisms. 

Developments in the administration of insulin through the skin, the mouth, the nose, and the lung have been reviewed (183). Methods of absorption other than subcutaneous, such as nasal insulin, buccal insulin, rectal insulin, and insulin in enteric-coated capsules, are still experimental. A problem in nasal administration is still how to get a daily reproducible dose (184). The frequency of hypoglycemia is comparable to the frequency with subcutaneous insulin (185). Nasal irritation, sometimes with congestion, and dyspnea (186) can occur. Pulmonary insulin, delivered by aerosol inhalation, is another experimental method. No lung obstruction was reported, but the uptake varied considerably (187). 

Cutie, A., Burger, J., Clawans, C., Dolinsky, D., Feinstein, W., Gupta, B., Gruene-berg, A., Sciarra, J. Test for reproducibility of metered-dose aerosol valves for pharmaceutical solutions. J Pharm Sci 70 1085-1987 (1981). 

Spray pattern and container pressure for aerosol products for a metered dose product, reproducibility of actuated dose and defined limits for dose administered per actuation... 

Current challenges facing the development of these systems for macromolecules include moisture control, efficient powder manufacturing, reproducible powder filling, unit dose packaging and development of efficient reliable aerosol dispersion and delivery devices. 

Device characteristics play an important role in the delivery of pharmaceutical compounds to human lungs. The mechanism by which aerosols are created affect particle size distribution, kinetics of aerosol delivery, and the reproducibility of drug dosing from the delivery device. These factors are key to controlling the delivery of a constant amount of drug aerosol acrossa diverse patient population. 

Systems producing fine-particle insulin aerosols have been tested extensively in humans [156], A clear dose response of glucose reduction and reproducibilities comparable to subcutaneous injections were obtained with an inhaler that combines almost monodisperse insulin particles (MM AD 2-3 pm)... 

In addition, the cumulative size distribution obtained for pure micron-ized and supercritically produced powders, combined with computation of the aerodynamic diameter according to Eqs. (2) and (3), shows that FPF of supercritically produced particles is about 50%, twice as much as FPF for micronized powder and close to the dispersion efficiency found with lactose (76). The correct values for the total emitted dose of drug particles also were confirmed. In all cases, the state of dispersion for the different formulations was correctly predicted and the results obtained showed good agreement with the cascade impactor measurements made on the same samples. Therefore laser diffraction has distinct advantages over impactor techniques with respect to the speed and reproducibility of measurements and can be used as a complementary method for analysis of aerosol behaviour of different formulations. 

Aerobiologists at the U.S. Army Medical Research Institute of Infectious Diseases (Fort Detrick, MD) have developed a reproducible, head-only ricin aerosol exposure model for laboratory nonhuman primates (NHP) that yielded acute LCtso values for African green monkeys or rhesus monkeys corresponding to approximately 6-10 or 15 pg/kg, respectively (Wilhelmsen and Pitt, 1996). Exposure of NHP to aerosolized ricin (particle size 1-2 pm) caused a dose-dependent toxicity that is delayed from 8 to 24 h early anorexia and lethargy were frequently observed, followed by gastric distress, hypothermia, hypotension, acute respiratory distress, and death. Rhesus monkeys exposed to the equivalent of approximately 20-40 pg/kg ricin by aerosol died from acute respiratory distress about 36-48 h after exposure necropsy revealed fibrinopurulent pneumonia, acute inflammation of the trachea and airways, and massive pulmonary alveolar flooding (Wilhelmsen and Pitt, 1996). 

It is generally accepted that in vitro measurements are important in monitoring the production process of aerosolized drugs, as they allow an estimation of reproducibility of dose and particle size distribution of the aerosol delivered by a given formulation. The clinical relevance of specific in vitro measurements has to be evaluated for each parameter. For instance, recent data show that the variability in... 

Figure 14.3 Metered-dose inhaler. Copyright (1996) from Lung Biology in Health and Disease, Vol. 94, Dalby et ah. Inhalation Aerosols, p. 452. Reproduced by permission of Routledge/Taylor Francis Group, LLC...

Kohler (207) discusses problems with reproducibility of an inhaled dose with a Pari Provocation test Device 1 nebulizer as an example. The author eon-cludes that up to 50% of the volume loss in a nebulizer is due to vapor losses and, from this, it is clear that the intrabronchial dose cannot be caleulated aeeording to the weight loss of the nebulizer. It is also clear that evaporation of the nebulized solution leads to an increase in the eoncentration of the test substance, especially toward the end of the evaporation proeess. Kohler also concludes that, for the Pari inhalation device, a slower inhalation maneuver gives better reproducibihty, and that reservoirs that store the aerosol before inhalation increase reproducibility, for they stabilize the aerosol by vapor saturation. 

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