New Paradigms

According to one dictionary, a paradigm is "a philosophical and theoretical framework of a scientific school of discipline within which theories, laws and generalizations and the experiments performed in support of them are formulated," but a simpler definition of "a generally accepted perspective of a particular discipline at a given time" is apposite too. Pharmaceutics is espousing new paradigms. The concept of the carrier system, traditionally tablets, capsules, suppositories, or the like with the drug internalized, has changed as the actives such as DNA and other macromolecules may not be internalized but may be intertwined with the complexing molecules, as hinted above, to form the delivery vector, usually leading to condensation. Active molecules may be adsorbed to the surface of nanoparticles. Products such as drug-releasing coated stents present new challenges, not least in quality control.

A More Predictive Science?

Reflecting on past decades of research in pharmaceutics, drug delivery, and drug targeting, one can detect a certain lack of an overall ability to predict the ultimate behavior of systems, not only but especially at the early formulation stage, and with behavior in vivo. Is pharmaceutics still too empirical, a shadow that has held the subject back for many years? There has been success in drug solubility prediction, as the work of Peterson (8) and others (9) has demonstrated, but in a related field, that of the micellar solubilization of drugs by surfactants, in spite of decades of research, it is not an easy task to predict the solubilization potential of a given surfactant system for a given drug molecule. In the same way, more recent research in gene delivery employing cationic complexing polymers, lipids or dendrimers to condense the DNA, has led to transfection of cells in culture with varying degrees of success, but there is no consensus yet as to the optimum size, shape, charge, or other characteristics of the gene construct to achieve maximal cell penetration, nor has it been possible to predict a priori the effectiveness of a given construct on a particular cell line.

Pharmaceutics has come a long way since its focus mainly on physical systems, but there must be a fresh look at the type of research problems that are tackled if we are to achieve a more predictive science. Not only this, but it seems a long time since new equations entered pharmaceutics' basic pantheon. It is several decades since Takeru Higuchi developed the equations for the diffusion of drugs in, and release from, complex systems (10). There is a need to explore new areas of pharmaceutics, to explain phenomena that otherwise will not be treated theoretically. Issues of adhesion, including mucoadhesion, film coating, tack, and cracking in films, are but some of the areas that require a greater theoretical approach after considerable amounts of phenomenological research has been published.

The study of the behavior of dosage forms in vivo, not least of nanosystems, is desperately short of a comprehensive theoretical base, which will relate properties, both physical and biological, not only to the size of particulate systems but also to their surface characteristics. On the other hand, while pharmaceutics must continue to reinvent itself, all those involved in medicines development and drug delivery and targeting must be acquainted and absorb the canon of pharmaceutics that already exists. This centers around the quality, pharmacy, and standards of products, modes of production and sterilization and characterization, their reproducibility, their quality (both intrinsic and quality related to activity), as well as studies of the potential of products themselves to cause harm. All this is a unified holistic approach. It is little use concentrating on the fabrication of physical devices if these are not able to be manufactured, or are not stable and not safe. This must be balanced by the imperative to carry out research that explores new materials and ideas whether or not we have all the requisite information that might be required ultimately for their conversion to dosage forms.

In drug targeting, much effort goes into the design of nanoparticles (although here again the approach is often necessarily empirical when there should be a more comprehensive understanding of, say, drug- or protein-polymer interactions), but little attention is paid, other than in a descriptive sense, to the issues surrounding the flow and movement of nanoparticles toward their distant targets and destinations. The nature of the flow of nanoparticles in vivo has been largely neglected, yet it is a branch of pharmaceutical engineering science. Flow, interactions between particles, and interactions of particles with blood components, erythrocytes, and proteins must be addressed in a unified manner before there can be any major advance in the predictability or, indeed, the reality of targeting, especially with nanoparticles decorated with ligands intended to interact with epithelial receptors. The flow of asymmetric carbon nanotubes in blood can be predicted to an extent by extant equations linking viscosity to axial ratio, but experimental proof is required.

This introductory chapter explores some areas of pharmaceutics and also the academic and educational aspects of the discipline. If we are to attract the best scientists into the field, the subject must be presented at undergraduate levels in an exciting and relevant manner. It must show the promise of controlling drug and therapeutic agents and the fact that that there is still much to do. Above all, it must demonstrate connections to avoid insularity and isolation as a discipline while remembering its heartland.

Connections

Connections between research in pharmaceutics and education in pharmacy are vital, but so too are the connections not only between the different types of research but also between different disciplines that can underpin pharmaceutics. Perhaps pharmaceutics could benefit from more research for its own sake, with less directed research aimed at the production of marketable dosage forms. Research on phenomena that are interesting in themselves, research into potential situations (what if?), and research into real systems and situations to answer the question "How does this work?" or "What causes this system to behave as it does?" are all legitimate. Some of these connections are illustrated in Figure 1, some being vital in the educational process.

Pharmaceutics as such is a distinct subject professed within schools of pharmacy worldwide. With the increasing trend toward a more clinical orientation of pharmacy graduates, as already has been achieved in the United States, there may be diminished attention paid to the teaching of pharmaceutics. As in research, there must be a greater effort to present the subject not only in its physicochemical envelope but to demonstrate the importance of the subject matter ultimately in the clinic. As examples, consider the

Figure 1 The connections between research of all types in pharmaceutics from the real to the imagined and the link to education. Education must inspire a questioning attitude in students and stimulate them about a subject, pharmaceutics, that continues to adapt and to evolve.
Figure 2 Examples of the connections between phenomena known in physical pharmacy and biological events using the examples of rheology, diffusion, aggregation, surface tension, adhesion, and percolation, and their biological importance in particulate systems as an example.

connections in Figure 2 between the physical phenomena of rheology, diffusion, aggregation, surface tension, adhesion, and percolation, some of the staples of physical pharmacy, to the behavior of systems in vivo.

These topics might be thought of as biopharmaceutics, but they are more than this. They are about the relevance of physicochemical phenomena in all aspects of therapy: rheology relating to blood flow and joint lubrication, crystallization as relevant to crystalluria and drug precipitation from formulations, surface tension and lung surfactant expansion and solubilization of drugs, colloidal interactions and interactions between nanoparticles and surfaces in vivo, and so on. This is what we might call clinical pharmaceutics. Clinical pharmaceutics also deals with the adverse effects of dose forms, induced by their excipients and by colors, flavors, tonicifiers, or impurities (11). It also concerns the beneficial influence of dose forms and modes of delivery on clinical outcomes.

Pharmaceutics faces two challenges in schools of pharmacy, one from the clinical impetus that exists and one from the need to maintain the basic and fundamental science in the subject, one which is distinctively pharmaceutics. The latter is not for its own sake, but because the combination of physical, chemical, and biological knowledge that the subject encompasses is vital for improved therapy and the development of safe and novel systems. It could be argued that while there has been progress in the subject in controlled-release technologies with direct patient benefit, pharmaceutical nanotechnology, and aspects of drug targeting, the study of basic phenomena perhaps deserves reinforcement. In particular, we require the application of physical pharmacy concepts to delivery and targeting issues. One example would be the interaction between a nanoparticle and a cell surface as characterized by Sun and Wirtz (12) in Figure 3A. This has clear analogies to, say, indentation testing of pharmaceutical materials shown in Figure 3B, two widely separated topics. Such connections or analogies are intriguing as well as useful.

Figure 3 Analogies I. (A) Comparison between a diagram from Sun and Wirtz (12) on the interaction of a viral particle with a plasma membrane and (B) an illustration demonstrating an indentation measurement on a solid. (A) R = radius of the particle and h = the depth of "indentation" of the viral particle. Various receptor and ligand molecules are denoted in addition to ligand-receptor complexes. Sun and Wirtz invoke Young's modulus and other physical terms to describe the interaction. Hiestand and Smith (13) cite Tabor's (14, 15) equation for indentation hardness P, obtained using a pendulum indenter (which actually might be a relevant model for particle-receptor interactions during flow):

Figure 3 Analogies I. (A) Comparison between a diagram from Sun and Wirtz (12) on the interaction of a viral particle with a plasma membrane and (B) an illustration demonstrating an indentation measurement on a solid. (A) R = radius of the particle and h = the depth of "indentation" of the viral particle. Various receptor and ligand molecules are denoted in addition to ligand-receptor complexes. Sun and Wirtz invoke Young's modulus and other physical terms to describe the interaction. Hiestand and Smith (13) cite Tabor's (14, 15) equation for indentation hardness P, obtained using a pendulum indenter (which actually might be a relevant model for particle-receptor interactions during flow):

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