Inhalation micronization

Rave, K. Nosek, L. Heinemann, L. Gonzales, C Ernest, C.S. Chien, J. Muchmore, D. Inhaled micronized crystalline human insulin using a dry powder inhaler dose-response and time-action profiles. Diabet. Med. 2001, 21 (7), 763-768. 

Fig. 75. A ciliated and a serous cell from the bronchiolar epithelium of a female white rat (breeder Winkelmann, Borchen-Kirchborchen) which inhaled micronized deptro-pine citrate and isoprenaline hydrochloride aa from a suspension type self-propelled aerosol (Medihaler). 12 Puffs/min were dispersed into a 164.5 1 box where the animals stayed for 15 min. 1 h later under methitural anaesthesia, the lung was fixed by intratracheal instillation of 2.5 % glutaraldehyde in phosphate buffer (pH 7.4) before opening the thorax. Postfix-ation with 1 % osmium tetroxide in phosphate buffer (pH 7.4). Contrasted en bloc for 12 h with 0.5 % uranyl acetate in 70% ethanol. Embedded in a 2 8 mixture of methyl and butyl methacrylate. Sectioned at 50 nm. Lead citrate after Reynolds (1963). Plate 52/03...

Fig. no. Peroxisomes in an alveolar macrophage adjacent to a type I pneumocyte of a female rat (breeder Winkelmann, Borchen-Kirchborchen) which inhaled micronized deptro-pine citrate and isoprenaline hydrochloride Sa from a suspen-... 

MT Vidgren, PA Vidgren, TP Paronen. Comparison of physical and inhalation properties of spray-dried and mechanically micronized disodium cromoglycate. Int J Pharm 35 139-144, 1987. 

The available data on retention in the respiratory tract, as summarized by Mitchell (M6) indicate that upwards of 20% of inhaled aerosols are retained in the respiratory tract, approaching 100% for particles over 5 microns in diameter. The order of retention follows reasonably well what would be expected from the physics of the various deposition mechanisms assuming that once deposited a particle is retained by the surface. This would,... 

The pulmonary lymphatic system contributes to the clearance of fluid and protein from the lung tissue interstitium and helps to prevent fluid accumulation in the lungs [108], The lymphatic endothelium allows micron-sized particles (e.g. lipoproteins, plasma proteins, bacteria and immune cells) to pass freely into the lymph fluid [103], After administration of aerosolised ultrafine particles into rats, particles were found in the alveolar walls and in pulmonary lymph nodes [135], which suggests that drainage into the lymph may contribute to the air-to-blood transport of the inhaled particles. 

Exubera is an inhaled insulin. It represents a major step forward since the first insulin injection was approved in the 1920s. The insulin particles are formulated to a certain micron size for deep lung delivery. An inhaler is used to achieve the delivery. The large surface area of the thin alveolar walls in the lungs allows for fast absorption of the insulin into the bloodstream. 

Takahashi, H., Yoshida, M., Murao, N., and Maita, K. Different inhalation lethality between micron-sized and submicron-sized aerosols of organophosphorus insecticide, chlorfenvinphos, in rats, Toxicol Lett., 73(2) 103-111, 1994. 

Health hazards associated with exposure to fibrous materials have been studied since the turn of the century. Fibers less than 5 microns in diameter are likely to become airborne and, as part of the enviromnent, may be inhaled or ingested. The relationship of fiber size to cell size and function, especially clearance once the fiber is inside the human body, sets off a cascade of events that can, and often does, lead to disease. The dimensions, dose, and durability of inorganic fibers are the salient determinants of disease (Lei-neweber, 1981). 

Inhalation in the form of an aerosol (p. 12), a gas, or a mist permits drugs to be applied to the bronchial mucosa and, to a lesser extent, to the alveolar membranes. This route is chosen for drugs intended to affect bronchial smooth muscle or the consistency of bronchial mucus. Furthermore, gaseous or volatile agents can be administered by inhalation with the goal of alveolar absorption and systemic effects (e.g inhalational anesthetics, p. 218). Aerosols are formed when a drug solution or micron-ized powder is converted into a mist or dust, respectively. 

Respirable (dust) Tenn used to indicate particulate matter which an be inhaled. Generally considered to be 5 microns or less in aerodynamic diameter. 

Williams RO III, Brown J, Liu J. Influence of micronization method on the performance of a suspension triamcinolone acetonide pressurized metered-dose inhaler formulation. Pharm Dev Technol 1999 4(2) 167-179. 

The coarse carrier particles blended with micronized drug form an ordered or interactive mixture (Fig. 8.11) (Hersey 1975) stabilized by adhesive Lifshitz—van der Waals and electrostatic forces (Podczeck 1998 Hickey et al. 1994). The shear forces exerted in the airflow of a DPI device must be greater than the adhesive forces in order to provide sufficient deaggregation and dispersion of the drug particles. Unfortunately, however, this process is more or less incomplete and disperses only a proportion of the agglomerated drug particles depending on the inhalation airflow (Zanen et al. 1992). 

Inhalation toxicity studies are conducted in inhalation chambers. The complete system contains an apparatus for the generation of aerosol particles, dusts, or gas mixtures of defined composition and particle size, a chamber for the exposure of experimental animals, and a sampling apparatus for the determination of the actual concentration within the chamber. All these devices present technical problems that are difficult to resolve. For rat studies, a particle size of 4 microns is usually targeted. 

If the test material is particulate, consideration must be given to the particle size and its inhalation potential. Particles of 4 microns in size are considered to be inhal-able larger particles will be cleared from the respiratory tract by ciliary action and subsequently swallowed (oral exposure) or expelled by sneezing or expectoration. 

Scientific debate continues as to whether dogs detect odorants as vapors or whether they may be trapped and carried on particles inhaled. It has been shown with the aid of micron-sized graphite dust that inhaled particles are trapped by the hairs and mucus at the front of the nasal cavity, although a small fraction may pass through to the olfactory epithelium [12]. Accordingly, this would suggest that olfaction is primarily a vapor process, although particles may still play a role. 

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