van der Waals attraction between two particles at a distance S

(i) for two spheres of equal radius r is —Ar/12S, and

(ii) for two spheres of unequal radii ri and r2 is —Ar1r2/6S(r1+r2).

Source: Adapted from Refs. 20 and 21.

van der Waals attraction between two particles at a distance S

(i) for two spheres of equal radius r is —Ar/12S, and

(ii) for two spheres of unequal radii ri and r2 is —Ar1r2/6S(r1+r2).

Source: Adapted from Refs. 20 and 21.

5. Analysis of the colloidal behavior of nanoparticles and especially the influence of surface ligands on this behavior.

As suggested above, the addition of specific ligands to the surface of nanoparticles, whether by covalent attachment or by adsorption, does not always lead to improved targeting in animals. Thus, the manner in which the ligands affect the physical stability and interactions of nanosystems is a worthy goal to elucidate the optimal conformation and configuration of adsorbed ligands.

6. Nanoparticle navigation in complex biological networks.

A better understanding of the movement of nanoparticles in the complex environment in which they are deposited in tissues, in tumors, and in blood, lymph, and the extracellular matrix is essential for prediction of behavior. The influence of particle size, shape, and flexibility on such movement is key (22). Does shape matter? If flow matters, then asymmetric particle flow is clearly different from the flow of spherical particles. Hence, there is a need for better comprehension of such behavior, particularly with the advent of carbon nanotubes whose rheological and diffusional properties will differ from those of spherical systems.

7. Analysis of published data to move pharmaceutical nanotechnology toward greater predictability of nanoparticle behavior.

Targeting activity is essential in the design of many delivery systems, vaccines, and gene delivery vectors, hence collating the already voluminous material that has been published and finding common threads to improve predictive powers are important. One of the difficulties here is the variation in size measurement techniques and their interpretation, as has been emphasized in two recent publications (23,24), one going so far as to suggest that 90% of published measurements are faulty. Accurate size measurements are essential. If size is key to access to targets or interactions with receptors, then the width of the particle size distribution must be known. Figure 4 illustrates this in a general way. If the optimal size range is as shown, then particles in region A will no doubt have access but will have different flow characteristics, particles in B will be in the desired range, while those in C will not access the target. It may be that particles in category D will, in fact, exhibit toxicity. It is perhaps

Figure 4 A diagrammatic particle size distribution with a hypothetical optimum-size band for biological activity, extravasation, transport, and receptor interactions. Zones A to D are discussed in the text.

timely to explore a "gold standard" for particle sizing so that all laboratories routinely use and cite the values they obtain with their equipment using a standard material, for example, a gold sol. After all, this is a common practice in surface science, where the surface tension of water is routinely cited as a marker of accuracy and precision.

8. Pharmaceutical aspects of nanotoxicology or nanosafety.

The study of nanotoxicology has been referred to by the Oberdosters in a review (25), which will repay reading as a discipline emerging from studies of ultrafine particles. Nanoparticles, unlike the majority of microparticles, can penetrate the body in a variety of ways and can be absorbed and translocated to organs such as the liver and spleen. It is clear that we must have more specific information on the safety of nanosystems, the influence of the nature of their surfaces and the material of which they are composed, and the influence of porosity, size, and shape.

9. Pharmacokinetics of drugs and other agents encapsulated in nanosystems and more studies on the kinetics of distribution of carriers in vivo.

This is a fairly self-evident need. It is important that we distinguish between the pharmacokinetics of drug that is released from the carrier and the biokinetics of the carriers themselves (i.e., carrier kinetics). It is wrong etymologically to discuss the pharmacokinetics of vectors.

10. The physical chemistry of peptide, protein, or macromolecule—polymer miscibility in relation to the incorporation of these molecules in polymer nanoparticles, microparticles, and implants, their stability, and release.

Given sometimes overwhelming biological interests, the pharmaceutical and physicochemical issues in formulation must not be underestimated. One lack seems to be a systematic study of the interactions between peptides, proteins, and DNA and the variety of polymers used in the construction of nanosystems. The basic thermodynamics of mixing under the conditions of preparation will yield valuable data. Gander et al. (26) have approached this subject in relation to the microencapsulation of proteins by PLGA spheres by spray drying and sought correlations between Hildebrand constants, partial Hansen solubility parameters, and other thermodynamic measures. They were able to conclude that encapsulation efficiency is increased and burst release reduced if polymer-drug interactions are dominant and polymer-solvent and drug-solvent interactions are reduced. The same authors also studied the thermodynamics of interactions in the preparation of microcapsules (27). More studies of this kind are important especially when polymer mixtures are used and polymer-polymer interactions turn out to be complex. Figure 5 illustrates a study of protein-polysaccharide interactions (28), which points out regions of compatibility and incompatibility in the phase diagram.

The above subject areas are possibly an idiosyncratic and certainly an incomplete list of topics in nanotechnology. They arise from the need to counteract the exaggerated claims for nanosystems in drug delivery and targeting by addressing the core factors which prevent quantitative delivery of therapeutic agents to complex targets such as tumors and sites of inflammation.

Some phenomena are extremely difficult, if not impossible, at present to investigate in vivo; hence, there needs to be a theoretical approach to many of the phenomena we invoke to explain delivery and targeting with nanoparticles. The stochastic nature of many interactions must be incorporated into predictions. While we are studying the biological barriers to delivery and targeting, we should devise new systems, which are better able to

I one-phase region % Biopolymer I

II two-phases separated region

I one-phase region % Biopolymer I

II two-phases separated region

Associative phase separation Segregative phase separation

Figure 5 Phase diagrams for biopolymer 1-biopolymer 2 solvent systems from Doublier et al. (28). Not shown is the Flory-Huggins lattice model for predicting experimental tie lines, whose equations exhibit enthalpic and entropic terms. The diagram on the right illustrates the most common form of thermodynamic incompatibility or "segregative phase separation" where solventbiopolymer 1 interactions are favored over biopolymer 1-biopolymer 2 interactions and solventsolvent interactions, hence demixing. In the associative phases separation, interactions between the two biopolymers are favored (e.g., because of interactions between a positively and a negatively charged molecule).

take their load quantitatively to their targets yet release them in a predictable manner when and only when they reach their site of action. A tall order.

Nanotechnology offers the opportunity not only to enhance delivery and targeting but also to produce new material and devices: in the formation of fine membranes, meshes, lubricant material for fine valves, and so on. There is also the recognition of the potential of the toxicity of materials such as titanium dioxide, used not as a carrier but as an excipient in tablets. Titanium dioxide is absorbed from the GI tract in the form of rutile, some 50 nm in diameter (29), and particles of 2 to 5 nm after inhalation (30). The ever present possibility of aggregation and its influence on interpretation of nanoparticle toxicity has been discussed (31).

Fundamental Topics

The late Nobel laureate in physics Pierre-Gilles de Gennes, for much of his research career, worked in the field of soft matter, which has so much significance in pharmaceutical systems. In his 1994 Dirac Memorial Lecture (32) given in Cambridge, he ranged widely over topics such as the dynamics of partial and complete wetting, principles of adhesion and tack, and polymer/polymer welding. "Compared to the giants of quantum physics," de Gennes wrote modestly, "we soft-matter theorists look like the dwarfs of German folk tales. These dwarfs were often miners or craft-workers: we, also, are strongly motivated by industrial purposes. We see fundamental problems emerging from practical questions." It is this last sentence that is especially relevant to pharmaceutics, where the issues of compaction, flow, film formation, wetting, and adhesion and tack can be of industrial relevance but are incompletely understood. Yet there are pressing issues raised by the necessity to formulate and deliver drugs that are macromolecules or labile and which possess the "wrong" physical and chemical characteristics as drug molecules. The objective de Gennes proposes is that we need to obtain "simple impressionistic visions of complex phenomena, ignoring many details, actually in many cases operating only at the level of scaling laws."

Pharmaceutical formulations and systems are frequently, and possibly usually, extremely complex. We use multicomponent systems, polymers of varied molecular weight, surfactants, products of polymerization processes, which are impure, particles of a wide distribution of sizes and shapes, and processes that are themselves often complex and ill defined at a molecular level. Then we administer these systems to a complex biological environment. We are a long way from a pharmaceutical theory of everything. To return to an earlier theme, we need the theoretical bases on which to become less empirical. This present book contains a chapter by Frenning and Alderborn (chap. 11, vol. 2) on aspects of pharmaceutical physics, written to illustrate the approaches that can be made to complex fields in pharmacy. Some of the topics once of great interest in pharmaceutics laboratories, say in the domain of powder technology, are still pursued elsewhere, for example, in physics. As an example, a paper on the wet granular pile stability recently tackled problems of spherical and nonspherical particle mixing and agglomeration (33).

Other Topics

Aqueous Interaction with Solids: Wetting and Dewetting

Water repellency (34) is relevant to pharmaceutical systems. With porous dosage forms, there is generally a desire to avoid water repellency to allow ingress of water. A

A Breakup of tear film

Figure 6 Analogies II. (Left) A film of sodium dodecyl sulfate in air a few microseconds after a spark bursts the film and causes rapid contraction of the surfactant layers with thickening in the so-called aureole region around the hole. (Right) An image of tear film rupture on a solid surface. Source: Left figure from A. T. Florence and K. J. Mysels, 1967 (unpublished photograph); right figure from the laboratory of A. Dubra (38), Imperial College London.

A soap film bursting

A Breakup of tear film

Figure 6 Analogies II. (Left) A film of sodium dodecyl sulfate in air a few microseconds after a spark bursts the film and causes rapid contraction of the surfactant layers with thickening in the so-called aureole region around the hole. (Right) An image of tear film rupture on a solid surface. Source: Left figure from A. T. Florence and K. J. Mysels, 1967 (unpublished photograph); right figure from the laboratory of A. Dubra (38), Imperial College London.

possibility of reversible repellency might be of advantage in controlling release of drugs by first inhibiting uptake of water and then allowing it. Indeed, the wettability of textured materials can be tuned rapidly with an electric field, for example (35), leading to the possibility of pulsed release from dose forms as the systems are tuned and detuned. Dewetting is also related to issues of water repellency and is important in some biological situations. In xerophthalmia (dry eye), the dewetting of the cornea through the breakup of the tear film leads to dry spots. Studies on dewetting of polymer films on mica or viscous fluids or surfactant films or solutions can lead to understanding of many physical and biological processes. Photographs of thin surfactant film breakup obtained many years ago (36,37) in the late Karol Mysels' laboratory (Fig. 6) bear a remarkable similarity to recent work by Dubra et al. (38) on tear film breakup.

Flow of Complex Liquids

In Balaz's paper on the flow of complex liquids (such as binary fluids) through heterogeneous channels (39), it is argued that the dynamic behavior of complex fluids in confined geometries is vital if we are to understand a range of topics from the processing of polymeric materials to the flow of blood in confined spaces. Not least, the work has provided basic information and the optimal configurations for the production of emulsions having well-controlled structures. The molecular dynamics of sorbed fluids in mesoporous materials (40) are relevant to the understanding of hysteresis in porous systems, important in some pulsatile hydrogel delivery systems, which display considerable hysteresis, which may only be in part due to the mechanics of the polymer chains.

The chapter by Anthony Hickey (chap. 5, vol. 2) on inhalational delivery of drugs exemplifies the theory that has been derived to understand the processes of lung deposition so far. Nanoparticulate interaction with the lung surfactant layer has been discussed and a three-dimensional cellular model devised to study these processes (41).

Boundary Lubrication, Splashes, and Turbulence

Boundary lubrication under water discussed by Briscoe et al. (42) is relevant to particles with surfactant layers. They state,

Boundary lubrication, in which the rubbing surfaces are coated with molecular monolayers, has been studied extensively for over half a century. Such monolayers generally consist of amphiphilic surfactants anchored by their polar headgroups; sliding occurs at the interface between the layers, greatly reducing friction and especially wear of the underlying substrates. This process, widespread in engineering applications, is also predicted to occur in biological lubrication via phospholipid films, though few systematic studies on friction between surfactant layers in aqueous environments have been carried out. Here we show that the frictional stress between two sliding surfaces bearing surfactant monolayers may decrease, when immersed in water, to as little as one per cent or less of its value in air (or oil). We attribute this to the shift of the slip plane from between the surfactant layers, to the surfactant/substrate interface. The low friction would then be due to the fluid hydration layers surrounding the polar head groups attached to the substrate. These results may have implications for future technological and biomedical applications.

Investigation of splashes (43,44) might seem abstruse pharmaceutically, but such work would be of relevance to the nature of micro- and nanoparticle interaction with alveolar fluids from the airways: hydrophilic spheres have been shown to enter liquid surfaces without commotion, while hydrophobic particles cause a splash. Problems of turbulence (45), aspects of mixing (46), and the nature of complex liquids, inter alia, are studies on apparently nonpharmaceutical systems which nevertheless have or may have relevance to a theoretically based approach to pharmaceutical design and manufacture and thus a deeper understanding of product performance.

The Pharmaceutics of Cell Therapy

Pharmaceutics has progressed as drugs have developed first from natural product extracts, through synthetic and generally small molecules to peptides, proteins, and oligonucleo-tides and DNA itself, into the beginning era of cell-based therapies. Cell therapy, whether with stem cells, dendritic cells, or pancreatic cells, involves a host of pharmaceutical issues: of dose, of quality, of consistency, and of accurate delivery to specific sites. Several means of delivery cells have been explored, including direct intramuscular injection (e.g., into cardiac muscle) (47) and intravenous administration. It has been reported that stem cells when injected directly into the blood are able to locate myocardial infarctions by the process of cell homing (48). Cell-collagen composites have been employed (by implantation) for the repair of tendon injuries (49), biodegradable alginate beads for delivery of bone cells and antibiotics (50), and PEGylated fibrin patches for mesenchymal stem cell delivery (51). Clearly, the route of administration is key to determining the distribution of injected dendritic cells (52): intravenously administered cells accumulate in the spleen, whereas intramuscularly injected cells accumulate in the T-cell regions of lymph nodes, results confirmed by Morse et al. (53), who found intravenously administered dendritic cells localized first in the lungs and then distributed to liver, spleen, and bone marrow. Data on the biodistribution of nanoparticles are relevant to an understanding of some of the issues in cell-based therapeutics, while efficient delivery matrices are also key.

Guidelines of human somatic cell therapy developed by the FDA in the United States and by the EU's Committee for Medicinal Products for Human Use (CHMP) both address the triad of safety, quality, and efficacy that have been applied routinely to conventional therapeutic agents (54).

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