In order to alter the pharmacokinetic and biodistribution properties of drugs, a variety of lipid- and polymer-based particles have been developed and characterized that include liposomes, i.e. small lipid bilayer particles with a diameter in the nanometer to micrometer size range, wherein the lipid bilayer surrounds an aqueous environment on the inside. Liposomes are presently used in medicine for drug delivery and in research for drug detoxification.
Drugs can be encapsulated in liposomes by a number of techniques, e.g. by passive methods and pH-gradient techniques. For a review see Fenske and Cullis, Encapsulation of Drugs within Liposomes by pH-Gradient Techniques, Liposome Technology, Volume II, Edited by Gregory Gregoriadis, Informa Healthcare September 2006, 27-50. The advantage of a pH gradient across the lipid bilayer is that once the drug is inside, it can be charged by protonation or deprotonation depending on the drug and the pH, so that its back transfer through the lipophilic membrane to the outside is hindered. See for example Mayer et al., Biochimica et Biophysica Acta, 857:123-126, 1986 and Madden et al., Chemistry and Physics of Lipids, 53:37-46, 1990. Therefore, liposomal carrier systems can significantly buffer the toxicity of drugs by entrapping them in their lumen. Liposomal drugs are regularly administered intravenously or at the site of intended drug action, e.g. intraperitoneally. For intraperitoneal liposome drug delivery, reference is made, for example, to Verschraegen et al., J. Cancer Res. Clin. Oncol., 129:549-555, 2003 and Parker et al., Cancer Res. 41: 1311-1317, 1981. Peritoneal retention of intraperitoneally administered liposomally entrapped drugs depends on the composition of the formulation, for example, the lipid composition of the lipid bilayer, the amount of cholesterol included, the size of the liposome, the charge of the liposome, and/or the coating of the liposome, e.g. with PEG (polyethylene glycol). Intraperitoneally administered liposomal drugs are subject to blood and lymphatic transport and can be detected in blood, lymph nodes as well as in a number of organs. In particular the size of liposomes has an influence on peritoneal retention. For intravenously injected liposomes, a diameter of about 100 nm is often considered as optimal for prolonged blood circulation, whereas increasing liposome size produces higher peritoneal retention when injected intraperitoneally. Liposomes having a size of about 1000 nm or greater have the highest peritoneal cavity retention. For further information on factors influencing the peritoneal retention of intraperitoneally administered liposomes, reference is made to, for example, Sadzuka et al., Toxicology Letters 116:51-59, 2000; Dadashzadeh et al., Journal of Controlled Release, 148:177-186, 2010; Mirahmadhi et al., International Journal of Pharmaceutics, 383:7-13, 2010; Hirano and Hunt, Journal of Pharmaceutical Sciences, 74 (9), 915-921, 1985.
Moreover, liposomes as well as lipids in emulsion have utility in drug detoxification.
Jamaty et al., Clinical Toxicology 48:1-27, 2010 review the literature on the use of intravenous fat emulsions (IFE), i.e. lipid emulsions in the treatment of acute drug poisoning. Intralipid® is a brand name for a clinically relevant commercial fat emulsion comprising 10, 20 or 30% by weight of purified soy bean oil as well as purified egg phospholipids, glycerin and water for intravenously or parenterally administered nutrition in case of malnourishment. Moreover, it has utility as vehicle for the anesthetic drugs propofol and etomidate as well as for treating severe cardiotoxicity caused by overdose of local anaesthetic drugs such as bupivacaine to save patients otherwise unresponsive to common resuscitation methods. For nutritional and antidote therapy, Intralipid® is administered intravenously. Cave and Harvey (Academic Emergency Medicine, 16:151-156, 2009) reviewed the literature on the use of IFE in antidote therapy. And in an animal model of clomipramine infusion-treated rabbits, Intralipid® administered intravenously and concomitantly by peritoneal administration showed an enhanced clomipramine extraction over intravenous administration of Intralipid® alone (see Harvey et al., Academic Emergency Medicine, 16:815-824, 2009). The antidote mechanism underlying IFE is that the lipid formulation scavenges and thereby masks the toxic drug by lipid extraction. Of course, this mechanism is only available for drugs with sufficient lipophilicity and depends on the extraction coefficient of the drug in the lipid composition.
Like IFE, intravenously administered liposomes are investigated to treat cardiovascular drug intoxication. J.-C. Leroux, Nature Biotechnology, 2:679-864, 2007, reviews the use of injectable nanocarriers, in particular of liposomes for drug detoxification. Bertrand et al., ACS Nano, 4 (12), 7552-7558, 2010 demonstrated a detoxification with intravenously administered, transmembrane, pH-gradient liposomes in rats receiving intravenous bolus of or perfusion with diltiazem, a cardiovascular drug. Unlike the lipid extraction with IFE the liposomal mechanism of action is the liposomal uptake and charging of the drug by the pH gradient to make the uptake irreversible. Compared to IFE, drug scavenging liposomes are much more efficient in capturing drugs, in particular calcium channel blockers, see for example, Forster et al., Biomaterials 33, 3578-3585, 2012.
Hyperammonemia refers to a clinical condition associated with elevated ammonia levels manifested by a variety of symptoms including central nervous system (CNS) abnormalities. When present in high concentration ammonia is toxic. Endogenous ammonia intoxication can occur when there is an impaired capacity of the body to excrete nitrogenous waste, as seen with congenital enzymatic deficiencies. A variety of environmental causes and medications may also lead to ammonia toxicity. For a review of ammonemia reference is made to Auron and Brophy, Pediatr. Nephrol., 27:207-222, 2012; and Clay and Hainline, CHEST, Official journal of the American College of Chest Physicians, (132), 1368-1378, 2007. Usually, hyperammonemia is associated with cerebral edema, decreased cerebral metabolism and increased cerebral blood flow. Next to therapies that treat intracranial hypertension, nutritional support to prevent protein catabolism and stopping nutritional intake of protein, it may be necessary to reduce ammonia levels by actively removing ammonia. Besides nitrogen elimination through pharmacological manipulation, e.g. administration of sodium phenylacetate and sodium benzoate, to promote the clearance of ammonia through “alternative” metabolic pathways, peritoneal dialysis, hemodialysis, continuous venovenous hemofiltration, continuous venovenous hemodiafiltration and continuous arteriovenous hemodiafiltration are effective ways of removing ammonia and have been helpful in treating hyperammonemia associated with urea cycle disorders in children and adults. In particular for children with inborn metabolism errors venovenous haemodialysis and continuous peritoneal dialysis are a treatment of choice for the acute management of hyperammonemia, e.g. see Arbeiter et al., Nephrol. Dial. Transplant., 25:1257-1265, 2010 and Pela et al.; Pediatr. Nephrol., 23:163-168, 2008.