Micro- and Nanoparticles for Drug Delivery

Daniel S. Kohane

Laboratory for Biomaterials and drug Delivery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA

E-mail: daniel.kohane@childrens.harvard.edu

ABSTRACT

Biomedical drug delivery systems are frequently micro- or nanoparticle based. The difference in size between those two types of particles has important implications for formulation and performance. My presentation discusses that difference, reviews the scope of applications, and addresses some of the challenges that face the field today.

Particulate drug delivery systems have become widely employed in experimental therapeutics and as well as in clinical to address a range of applications and disease states. Their popularity can be attributed in part to the ease with which they can be applied as a suspension or a dry powder, and to a less degree and depending on the type of particle, by their ease of manufacture. The size of the particles plays a substantial role in determining the properties of the final product, and its potential applications. Here we shall use the terms “micro-” and “nano-” to refer to particles whose principal dimensions are usefully described in micrometers and nanometers respectively. We will also focus on polymeric particles produced by emulsion methods (Watts et al. 1990), as these are in relatively widespread use. It is important to bear in mind that conclusions derived from these particles may not apply to others (e.g. liposomes), but they do provide a useful illustration of certain principles.

It is important to be mindful of a number of important differences between the biomedical application that I will discuss and the professional interests of many of the attendees of this forum. Formulations developed for medicine and experimental pharmaceutics are intended for a relatively low-volume, high margin market. In contrast, the food industry is high volume, low margin. While pharmaceutical companies will not be overly concerned by the use of complex processes and expensive ingredients (e.g. polymers) – as these costs can be recouped – these would be impossible for the business plan of most food products. It is also worth noting that the fact that a given regulatory agency has approved a material for use in a drug delivery system does not mean that that material is also approved for use in a food. In part, the rationale for the distinction between these two cases has to do with the potential mass of material that would be consumed. While drug-related formulations may have to release their payloads over days to weeks, food-related products generally (though not necessarily) release theirs in the course of a single transit through the gastrointestinal tract. The barriers and conditions encountered by systemic drug delivery systems are also different from those to which foods are exposed.

Perhaps the most obvious difference between micro- and nanoparticles is the difference in the surface area to volume ratio. Many of the other differences result from that. For example, larger particles are more likely to lose payload during formulation than are smaller ones. Similarly, drug efflux will be proportionally more rapid from smaller than larger particles, and polymer degradation more rapid – especially if it is dependent on water penetration into the matrix. Smaller particles are more likely to aggregate than larger ones.

Size has a marked effect on particle distribution throughout the body. When injected into tissues, large particles will tend to stay where placed (Kohane et al. 2002), while smaller ones may be taken away by white blood cells or –this is particularly true of nanoparticles – may travel away by themselves (Kohane et al. 2006). Large particles injected into the bloodstream are likely to lodge in small vessels, while nanoparticles will circulate for a period of time determined by size, surface chemistry, and other factors. Microparticles will not cross most biological barriers unless they are injected across them or a particular cell type carries them across. Nanoparticles have considerably less difficulty in doing so. While microparticles can only be taken up by phagocytic cells, nanoparticles may enter through pinocytosis.

Particle size also dictates the types of applications for which particles can be used. In general – and this is only a slight oversimplification – applications can be described by the intended site of drug action or distribution (local or systemic) and the method of particle delivery (local or systemic). In general, microparticles will be useful if the particles are delivered locally, whether for local or systemic drug effect. Examples include local anesthetic microspheres and microspheres containing growth hormone. Nanoparticles can be used for all of these applications, but may or not be the best candidates. They are generally preferable if systemic delivery of the particles themselves is desired, especially through the bloodstream. Examples of uses include liposomes containing the anti-fungal agent amphotericin B (systemic delivery for systemic use) and ligand-targeted chemotherapeutics (systemic delivery for local or systemic targets).

There are many challenges remaining today, not the least of which is creating particles that can enhance gastrointestinal uptake. Other challenges include delivery of macromolecules, crossing of specific biological barriers, environmentally-sensitive triggers, patient-triggered drug release, active targeting, convergence (mixing of previously disparate technologies to enhance drug delivery), and the usual panoply of formulational woes. It bears noting that the food and beverage industries have now take note of the opportunities presented by drug delivery technology, and are hastening to implement the lessons that can be learned from it.

References

Kohane DS, Lipp M, Kinney RC, Anthony DC, Louis DN, Lotan N, Langer R. 2002. Biocompatibility of lipid-protein-sugar particles containing bupivacaine in the epineurium. J. Biomed. Mater. Res. 59: 450-9

Kohane DS, Tse JY, Yeo Y, Padera R, Shubina M, Langer R. 2006 Biodegradable polymeric microspheres and nanospheres for drug delivery in the peritoneum. J. Biomed. Mat. Res. ; 77

Watts PJ, Davies MC, Melia CD. 1990. Microencapsulation using emulsification/solvent evaporation: an overview of techniques and applications. Crit. Rev. Ther. Drug Carr. Sys. 7: 235-259