Farmacotecnia 11

In Vitro-ln Vivo Correlations
Correlalions were demonslraled belween dissolution properties and in vivo disposilion of a model compound, disodium fluorescein, delivered as a dry powder aerosol in dogs (168). The ralio of Ihe half-lime for dissolulion of coaled particles lo Ihal of uncoaled particles was shown lo be remarkably cióse lo similar ratios for the half-times for appearance in Iheplasma of dogs. On a more sublle level, il was predicled (169) Ihat manipulation of
the residence lime of sleroids in Ihe lungs would lead lo an improved larget-ing of lung receplors and Ihis subsequenlly proved to be the case for a coated parliculate formulalion (138). Good correlalion was reporled wilh large porous particles (159).
MAJOR OBSTACLES ENCOUNTERED DURING RESEARCH AND DEVELOPMENT AND HOWTHEY WERE OVERCOME
The variabilily in drug delivery as a function of inspiralory ñow rate for pas-sive inhalers has been seen as a potential obstacle to broad applicability of Ihese devices. Aclive dispersión systems to achieve flow rale independence have been one approach to resolving this issue. However, an inleresling solution has been proposed in which the formulation itself leads lodevice-and flow rale-independenl in vilro performance. While Ihis will inevilably vary from one drug lo Ihe nexl, some success has been achieved in this área by increasing the porosity of particles and thereby reducing the van der Waals fores of interaclion (8,170,140). Il musí be remembered, how-ever, Ihat the deposilion in Ihe respiratory tract itself depends on inspiratory flow rate, and Iherefore,merely keeping Ihe in vilro performance flow rate independen! does nol guaranlee consislency of lung deposilion, and clinical safely and efficacy. Device-independent formulations have been the subject of much research in receñí years (84,85). Additionally, characterizing Ihe aerodynamic properlies of DPI systems, independen! of a specific inhaler device, has been successfully atlained Ihroughslandardized entrainment lubes (171).
FABRICATION TECHNIQUES
II is oflen the case thal particles cannot be manufactured easily without aggregating for a number of reasons. Aggregalion may occur because of Ihe fundamenlal forces of association occurring al the surfaces of particles, such as van der Waals, capillary forces, electrostatic forces or mechanical interlocking (slruclural cohesión)(28,35,45,52,172-176). These surface forces and inleraclions are significanl in dry powder respiralory particles (i.e., microparticles and nanoparticles) which have large surface area-to-volume ratios. Gravitational forces become negligible in these size ranges and surface forces domínate, giving rise to strong inlerfacial inleraclions al Ihe solid-solid interface existing between respirable particles.Additionally, pharmaceutical processing resulling in these respirable particles very often affecls Iheir surfaces by introducing "surface defects" having a higher sur¬face free energy and oflen acl as "active siles" for enhanced inlerparliculale interaclions leading to aggregalion. In addilion, if particles have low melting points and high vapor pressures, Ihey may deform on impací and aggregale lo alarger extent on milling ralher Ihan being dispersed in small sizes.
Furthermore, partióles of this nature, even when prepared as small partióles, may cohere upon storage. In certain circumstances, these phenomena, as well as a tendency to be heat labile, may be overeóme by low temperature milling. Any tendency to degradation by oxidation can be avoided by using inert gases rather than air as themilling ñuid.
SCALE-UP PROBLEMS/MANUFACTURING ISSUES
The most serious problems in scale-up for conventional DPI are unit operations of milling, drying, blending, and filling (177,178). Pilot or large scale milling, spray drying, or blending require process optimization not unlike any other pharmaceutical unit operation being translated from the bench scale. It is important to recognize the...