Drug transformation: Advances in drug delivery systems

Orlando Hung (Pharmacy) FRCPC - Scompounds have been discovered, isolated UCCESS stories often have a painful past. For decades, many pharmacologically active and synthesized. Unfortunately, many of these promising compounds did not advance beyond the laboratory bench to the clinical setting because of difficulties in finding a suitable delivery system. This is particularly true with highly lipophilic compounds, such as 9- tetrahydrocannabinol (the active ingredient of cannabis), and other pharmacological agents with large molecular structures, such as peptides, proteins, genes, and nucleotides. In fact, propofol, probably the most commonly used iv anesthetic to date, had a somewhat tenuous introduction to clinical anesthesia. Propofol, a highly lipophilic anesthetic agent with a log octanol-water partition coefficient of 4.33,1 was developed and dissolved in Cremaphor EL for clinical trial in 1977.2 Unfortunately, Cremaphor EL had been shown to cause anaphylactic reactions,3,4 and propofol was subsequently withdrawn from development.2 Propofol was reformulated in a soybean macroemulsion in mid-1980 and was used clinically in the United Kingdom and New Zealand in 1986 and in the United States in 1989.5,6 The introduction of this new propofol formulation has transformed propofol into one of the most important iv anesthetics ever employed. The development of a suitable formulation for propofol exemplifies how drug delivery systems can play a significant role in modern therapeutics. Over the past several decades, significant advances in the development of delivery systems have taken place to meet the challenges associated with the unique physicochemical properties of various pharmacological agents. New drug carrier technologies, such as colloidal drug carriers (liposomes and nanoparticles), have been used to modify the delivery of large molecules or molecules with exceptional lipophilicity.7 Colloidal drug carriers are particularly useful in the delivery of peptides, genes, and oligonucleotides because they can provide pharmacologically-active agent protection from degradation in biological fluids and they can promote the penetration of active substances into cells. Liposomes are microscopic phospholipid-bilayered vesicles that are biocompatible, biodegradable and nonimmumnogenic. They can be used to entrap both hydrophilic and lipophilic drug molecules,8 making them highly versatile as drug delivery systems. In this context, the rate of drug release by the liposome into the local environment is primarily determined by the physicochemical properties of the liposome. Liposomes can be tailored by modification of their size, layers (unilamellar, or multilamellar), composition, and surface charge to provide a controlled and sustained drug release system. In this issue of the Journal, using a rat infraorbital nerve blockade technique to evaluate anesthetic effect, Cereda et al. report that liposomes can be used to provide effective drug-delivery systems for prilocaine, lidocaine and mepivacaine.9 Their findings suggest that encapsulated formulations can induce an increase in the intensity of anesthetic effect, and time to recovery when compared to plain local anesthetic solutions. They conclude that liposome encapsulation can be used to increase both the anesthetic duration and intensity. The use of liposomes to encapsulate drugs is not new. Liposomal lidocaine (ELA-Max Topical Anesthetic) has been commercially available for several years in the United States and offers a more rapid onset and less expensive alternative to the eutectic mixture of local anesthetic (EMLA) formulations.10 Many pharmaceutical companies conduct studies on encapsulation of macromolecules, such as peptides, proteins and nucleic acids. These macromolecules are protected from in vivo hydrolysis by encapsulation. In addition to sustained drug release, liposomes have also been shown to improve the therapeutic index of drugs by increasing their efficacy and reducing their toxicity. This has been notably the case for chemotherapeutic agents (Doxil and Caelyx - liposomal doxorubicin)11 and antimicrobials (AmbisomeTM - Amphotericin B).12,13 Although these liposomal preparations have been shown to be effective and safe, the bioavailability of iv liposomal chemotherapeutic agents is reduced by the rapid uptake of liposomes by the reticuloendothelial system. To minimize rapid uptake of liposomes by the reticuloendothelial system and to improve their bioavailability, a novel pegylated liposomal system coated with polyethylene glycol (stealth liposomes) have been developed,11,14,15 thus improving drug delivery to the tumour while decreasing toxicity to other cells. More recently, substantial interest has been shown in developing drug delivery systems utilizing nanoparticles, micro-particles composed of biodegradable polymers.16,17 Like liposomes, nanoparticles have been developed as an important strategy to deliver drugs, proteins, vaccines and nucleotides. However, they have some advantages over liposomes in terms of stability both during storage and in vivo.7 They may consist of either a polymeric matrix (nanospheres) or a reservoir system in which an oily or aqueous medium is surrounded by a polymeric wall (nanocapsules). Nanoparticles have been shown to modify release, pharmacokinetics, and body distribution of wellestablished drugs.18 So why should we, as anesthesiologists, care about these advances in drug delivery systems? Simply because these advances will likely change the future of drug development. Instead of searching only for newer drug molecules, it is possible to modify the pharmacokinetic and pharmacodynamic properties of existing drugs by manipulating different drug delivery systems. As Rosen and Abribat have suggested, it is now possible to make old drugs new by utilizing these advanced drug delivery technologies.19 Wellestablished drugs with proven efficacy and safety can be transformed into new entities with modified and enhanced clinical applications by manipulating the formulation of the drug delivery systems. We are beginning to see evidence of this transformation of old into new again in the practice of anesthesia. Recently, the Food and Drug Administration of the United States approved the use of epidural administration of liposomal morphine (DepoDur) for prolonged postoperative analgesia with up to 48 hr of relief after a single injection.20 Clinical trials of the pulmonary administration of liposomal fentanyl (AeroLEF) for rapid onset and long duration of analgesia are currently being conducted for patients suffering from postoperative and cancer pain.21 Recently, Morey and colleagues reported the successful preparation of propofol nanoparticles (microemulsion) which has the potential to reduce the risk of bacterial contamination associated with soybean oilbased macroemulsions of propofol.22 These are exciting developments for anesthesiologists and we should embrace this ne (...truncated)