Dendrimers have come a long way in the last 25 years since their inception. Originally created as a wonder molecule of chemistry, dendrimer is now in the fourth class of polymers. Dr. Donald Tomalia first published his seminal work on Poly(amidoamine) (PAMAM) dendrimers in 1985. Application of dendrimers as a drug delivery system started in late 1990s. Dendrimers for drug delivery are employed using two approaches: (i) formulation and (ii) nanoconstruct. In the formulation approach, drugs are physically entrapped in a dendrimer using non-covalent interactions, whereas drugs are covalently coupled on dendrimers in the nanoconstruct approach. We have demonstrated the utility of PAMAM dendrimers for enhancing solubility, stability and oral bioavailability of various drugs. Drug entrapment and drug release from dendrimers can be controlled by modifying dendrimer surfaces and generations. PAMAM dendrimers are also shown to increase transdermal permeation and specific drug targeting. Dendrimer platforms can be engineered to attach targeting ligands and imaging molecules to create a nanodevice. Dendrimer nanotechnology, due to its multifunctional ability, has the potential to create next generation nanodevices.

Approximately 40% of newly developed drugs are rejected by the pharmaceutical industry and will never benefit a patient because of low water solubility. Another 17% of launched drugs exhibit suboptimal performance for the same reason. Given the growing impact and need for drug delivery, a thorough understanding of delivery technologies that enhance the bioavailability of drugs is important. The high level of control over the dendritic architecture (size, branching density, surface functionality) makes dendrimers ideal excipients for enhanced solubility of poorly water-soluble drugs. Many commercial small-molecule drugs with anticancer, anti-inflammatory and antimicrobial activity have been formulated successfully with dendrimers, such as poly(amidoamine) (PAMAM), poly(propylene imine) (PPI or DAB) and poly(etherhydroxylamine) (PEHAM). Some dendrimers themselves show pharmaceutical activity in these three areas, providing the opportunity for combination therapy in which the dendrimers serve as the drug carrier and simultaneously as an active part of the therapy.

This work includes investigation on solubility enhancement of indomethacin (IND) in the presence of poly(amidoamine) (PAMAM) dendrimers and passive targeting of the PAMAM/IND complex so formed to the inflamed regions in an animal model. The complex formation was confirmed by infrared and ¹H nuclear magnetic resonance spectroscopy methods. Solubility of IND in aqueous G4-PAMAM followed Higuchi's A_N curve depending on pH of the solubilizing medium. The solubility was decreased upon addition of dendrimer to the IND saturated solution at various pH, indicating aggregation behavior of the PAMAM/IND complex and conforming to the Higuchi's A_N solubility profile. The in vitro release of IND from the PAMAM/IND complex through a cellophane membrane, from a Franz diffusion cell, showed 79±3.2% drug release in 24 h. The drug release was further retarded in the presence of human serum albumin (HSA) suggesting the significance of complex HSA binding in altering in vivo behavior of the complex. Intravenous administration of the PAMAM/IND complex formulation in rats showed a two-compartment pharmacokinetic profile. Enhanced effective IND concentrations in the inflamed regions were obtained for the prolonged time period with the PAMAM/IND complex compared to the free drug in arthritic rats indicating preferred accumulation of IND to the inflamed region. The targeting efficiency of PAMAM/IND complex was 2.29 times higher compared to free drug. In contrast to the previous investigations, two interesting findings reported here are: (a) solubility behavior of IND in G4-PAMAM dendrimer deviates from linearity with increasing concentrations of dendrimer at acidic to neutral pH values and (b) inspite of lymphatic drainage, retention of PAMAM/IND complexes occurs at the inflammatory site.