The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.
Identification of new compounds for use in pharmaceutical preparations is an important part of the search for more reliable and effective therapies. However just as important is the development and modification of known compounds, reducing the risks associated with a new drug candidate and significantly reducing the development and cost to bring the drug to clinical development.
Many drugs fail in clinical trials either because their physical properties (particularly solubility) make them difficult to formulate, or because of a poor therapeutic index that leads to toxic effects during the high drug concentrations that occur just after dosing. Other short comings include poor absorption, poor bioavailability, instability, systemic side effects due to an inability to target the drugs, and the inability to control their biodistribution, metabolism and renal or hepatic clearance once administered. Similarly some current products on the market can be improved with regard to such issues.
A number of approaches have been tried to improve a pharmaceutical compound's profile including the formulation of the pharmaceutical agent in a liposome, micellar or polymeric micelle formulation, as well as covalent attachment of the pharmaceutical agent to a hydrophilic polymer backbone.
The characteristics of an ideal profile modifying agent include being a well defined structure, allowing precise control of the absorption, distribution, metabolism and excretion (ADME) characteristics (also referred to as pharmacokinetics) of the compound in question and advantageously being able to carry multiple compounds per agent or construct. The toxicity of a compound in question can be ameliorated through its controlled release from the said agent or construct, the body only being exposed to therapeutic plasma concentrations of the compound.
In recent years, dendritic macromolecules, or dendrimers, have been found to have increasing applications in biotechnology and pharmaceutical applications. Dendritic macromolecules are a special class of polymers with densely branched structures that are characterized by higher concentrations of functional moieties per unit of molecular volume than ordinary polymers. There are three subclasses of dendritic macromolecules: random hyperbranched polymers; dendrigraft polymers and dendrimers (which includes dendrons), classified on the basis of the relative degree of structural control present in each of the dendritic architectures (Fréchet and Tomalia “Dendrimers and other Dendritic Polymers”, Wiley and Sons, New York, 2002). The unique properties of dendrimers in particular, such as their high degree of branching, multivalency, globular architecture and well-defined molecular weight, make them promising new scaffolds for pharmaceutical applications. In the past decade, research has increased on the design and synthesis of biocompatible dendrimers and their application to many areas of bioscience including macromolecular drugs, drug delivery, biomedical imaging and medical devices.
The potential utility of dendritic polymers both as drug delivery vectors and pharmaceutical actives has received increasing interest in recent years. However, whilst the literature is replete with reports of, for example, synthetic schemes for dendrimer assembly, descriptions of dendrimer-drug interactions and drug loading efficiencies and increasingly, in vitro evaluations of dendrimer interactions with cell lines, there is very little information describing the fundamental pharmacokinetic and metabolic fate of dendrimers.
Further, it is still a challenge to prepare dendrimers that circulate in the blood long enough to accumulate at target sites, but that can also be eliminated from the body at a reasonable rate to avoid long-term build up. In addition, the tissue localisation of dendrimers is still difficult to predict in advance and more studies are required to determine the effect of peripheral dendritic groups on these properties. An additional area that needs to be investigated is the release of drugs from dendrimers. Steric hindrance associated with the dense globular dendritic architecture makes the engineering of the enzymatically cleavable linkages difficult.
It has surprisingly been found that, by introducing one or more functional moieties, as described herein, the efficacy of the macromolecule may be significantly improved, but without significant adverse impact on, or interference with, other functional moieties which may be present.